Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

INTRODUCTION Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. METHODS AND ANALYSIS A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. ETHICS AND DISSEMINATION The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study. TRIAL REGISTRATION NUMBER NCT01898338.

El proyecto EMECAM: Estudio Multicéntrico Español sobre la Relación entre la Contaminación Atmosférica y la Mortalidad. Antecedentes, participantes, objetivos y métodología.

In recent years, a growing number of studies suggests that increases in air pollution levels may have short-term impact on human health, even at pollution levels similar to or lower than those which have been considered to be safe to date. The different methodological approaches and the varying analysis techniques employed have made it difficult to make a direct comparison among all of the findings, preventing any clear conclusions from being drawn. This has led to multicenter projects such as the APHEA (Short-Term Impact of Air Pollution on Health. A European Approach) within a European Scope. The EMECAM Project falls within the context of the aforesaid multicenter studies and has a wide-ranging projection nationwide within Spain. Fourteen (14) cities throughout Spain were included in this Project (Barcelona, Metropolitan Area of Bilbao, Cartagena, Castellón, Gijón, Huelva, Madrid, Pamplona, Seville, Oviedo, Valencia, Vigo, Vitoria and Saragossa) representing different sociodemographic, climate and environmental situations, adding up to a total of nearly nine million inhabitants. The objective of the EMECAM project is that to asses the short-term impact of air pollution throughout all of the participating cities on the mortality for all causes, on the population and on individuals over age 70, for respiratory and cardiovascular design causes. For this purpose, with an ecological, the time series data analyzed taking the daily deaths, pollutants, temperature data and other factors taken from records kept by public institutions. The period of time throughout which this study was conducted, although not exactly the same for all of the cities involved, runs in all cases from 1990 to 1996. The degree of relationship measured by means of an autoregressive Poisson regression. In the future, the results of each city will be combined by means of a meta-analysis.

Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial.

INTRODUCTION Finding therapeutic alternatives to carbapenems in infections caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is imperative. Although fosfomycin was discovered more than 40 years ago, it was not investigated in accordance with current standards and so is not used in clinical practice except in desperate situations. It is one of the so-called neglected antibiotics of high potential interest for the future. METHODS AND ANALYSIS The main objective of this project is to demonstrate the clinical non-inferiority of intravenous fosfomycin with regard to meropenem for treating bacteraemic urinary tract infections (UTI) caused by ESBL-EC. This is a 'real practice' multicentre, open-label, phase III randomised controlled trial, designed to compare the clinical and microbiological efficacy, and safety of intravenous fosfomycin (4 g/6 h) and meropenem (1 g/8 h) as targeted therapy for this infection; a change to oral therapy is permitted after 5 days in both arms, in accordance with predetermined options. The study design follows the latest recommendations for designing trials investigating new options for multidrug-resistant bacteria. Secondary objectives include the study of fosfomycin concentrations in plasma and the impact of both drugs on intestinal colonisation by multidrug-resistant Gram-negative bacilli. ETHICS AND DISSEMINATION Ethical approval was obtained from the Andalusian Coordinating Institutional Review Board (IRB) for Biomedical Research (Referral Ethics Committee), which obtained approval from the local ethics committees at all participating sites in Spain (22 sites). Data will be presented at international conferences and published in peer-reviewed journals. DISCUSSION This project is proposed as an initial step in the investigation of an orphan antimicrobial of low cost with high potential as a therapeutic alternative in common infections such as UTI in selected patients. These results may have a major impact on the use of antibiotics and the development of new projects with this drug, whether as monotherapy or combination therapy. TRIAL REGISTRATION NUMBER NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.

Amazon Fund: financing deforestation avoidance

The Amazon Fund, created in 2008 by the Brazilian Federal Government, is managed by Banco Nacional de Desenvolvimento Econômico e Social (BNDES). It is a pioneering initiative to fundraise and manage financial resources to cut back deforestation and support sustainable development for 30 million inhabitants in the Amazon Biome. The Amazon Fund has already received more than R$ 1.7 billion in grants (about USD 787 million). This essay analyzes the Amazon Fund's governance and management with focus on its operation and from its stakeholders' perspectives. A combination of research methods includes: documental research, in-depth interviews, and speech analysis. The study offers a comparative analysis of strengths and weaknesses related to its governance. Furthermore, it proposes ways to improve its management towards greater effectiveness. The essay also includes an assessment of the government of Norway, a major donor to the fund. The governments of Norway and Germany, in partnership with Brazil, reveal how important it is to experiment with new means of international cooperation to successfully reduce greenhouse gas emissions through rainforest preservation.

Pooling of dentin microtensile bond strength data improves clinical correlation.

Purpose: To evaluate whether the correlation between in vitro bond strength data and estimated clinical retention rates of cervical restorations after two years depends on pooled data obtained from multicenter studies or single-test data. Materials and Methods: Pooled mean data for six dentin adhesive systems (Adper Prompt L-Pop, Clearfil SE, OptiBond FL, Prime & Bond NT, Single Bond, and Scotchbond Multipurpose) and four laboratory methods (macroshear, microshear, macrotensile and microtensile bond strength test) (Scherrer et al, 2010) were correlated to estimated pooled two-year retention rates of Class V restorations using the same adhesive systems. For bond strength data from a single test institute, the literature search in SCOPUS revealed one study that tested all six adhesive systems (microtensile) and two that tested five of the six systems (microtensile, macroshear). The correlation was determined with a database designed to perform a meta-analysis on the clinical performance of cervical restorations (Heintze et al, 2010). The clinical data were pooled and adjusted in a linear mixed model, taking the study effect, dentin preparation, type of isolation and bevelling of enamel into account. A regression analysis was carried out to evaluate the correlation between clinical and laboratory findings. Results: The results of the regression analysis for the pooled data revealed that only the macrotensile (adjusted R2 = 0.86) and microtensile tests (adjusted R2 = 0.64), but not the shear and the microshear tests, correlated well with the clinical findings. As regards the data from a single-test institute, the correlation was not statistically significant. Conclusion: Macrotensile and microtensile bond strength tests showed an adequate correlation with the retention rate of cervical restorations after two years. Bond strength tests should be carried out by different operators and/or research institutes to determine the reliability and technique sensitivity of the material under investigation.

Excessive alcohol consumption in young men: is there an association with their earlier family situation? A baseline-analysis of the C-SURF-study (Cohort Study on Substance Use Risk Factors).

AIMS: To determine whether parental factors earlier in life (parenting, single parent family, parental substance use problem) are associated with patterns of alcohol consumption among young men in Switzerland. METHODS: This analysis of a population based sample from the Cohort Study on Substance Use Risk Factors (C-SURF) included 5,990 young men (mean age 19.51 years), all attending a mandatory recruitment process for the army. These conscripts reported on parental monitoring and rule-setting, parental behaviour and family structure. The alcohol use pattern was assessed through abstention, risky single occasion drinking (RSOD), volume drinking and dependence. Furthermore, the impact of age, family socio-economic status, educational level of the parents, language region and civil status was analysed. RESULTS: A parental substance use problem was positively associated with volume drinking and alcohol dependence in young Swiss men. Active parenting corresponded negatively with RSOD, volume drinking and alcohol dependence. Single parent family was not associated with a different alcohol consumption pattern compared to standard family. CONCLUSION: Parental influences earlier in life such as active parenting (monitoring, rule-setting and knowing the whereabouts) and perceived parental substance use problem are associated with alcohol drinking behaviour in young male adults. Therefore, health professionals should stress the importance of active parenting and parental substance use prevention in alcohol prevention strategies.

A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial.

BACKGROUND: The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). METHODS: Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. RESULTS: Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. CONCLUSIONS: The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

Symbolic meaning of local identity – A case study on Barcelona place brand representation

The core objective of this research process was to design an operational tool for place brand analysis. By modelling the emotional significance and the deeper-lying symbols associated to a specific place identity I expected to create a semiotic tool that could be applied, mutatis mutandis, on other similar place brands. As a field case study to develop the instrument, my choice of the research arena was Barcelona city, the capital of Catalonia Autonomous Community, Spain. Barcelona brand identity was approached in the line of the Chicago Urban Anthropology School. The research methods were designed according to the prescriptions of the urban anthropology, namely qualitative methods: in-depth interviews and discourse analysis. The final research outcome was a model summarizing a range of specific emotional values that support a place brand to position in the collective mindset and to assume a positively valued status and identity in the world order.

Visual functions in the healthy and schizophrenic brain : from stimulus control to illusory perceptions using electrical neuroimaging

ABSTRACT (FRENCH)Ce travail de thèse basé sur le système visuel chez les sujets sains et chez les patients schizophrènes, s'articule autour de trois articles scientifiques publiés ou en cours de publication. Ces articles traitent des sujets suivants : le premier article présente une nouvelle méthode de traitement des composantes physiques des stimuli (luminance et fréquence spatiale). Le second article montre, à l'aide d'analyses de données EEG, un déficit de la voie magnocellulaire dans le traitement visuel des illusions chez les patients schizophrènes. Ceci est démontré par l'absence de modulation de la composante PI chez les patients schizophrènes contrairement aux sujets sains. Cette absence est induite par des stimuli de type illusion Kanizsa de différentes excentricités. Finalement, le troisième article, également à l'aide de méthodes de neuroimagerie électrique (EEG), montre que le traitement des contours illusoires se trouve dans le complexe latéro-occipital (LOC), à l'aide d'illusion « misaligned gratings ». De plus il révèle que les activités démontrées précédemment dans les aires visuelles primaires sont dues à des inférences « top- down ».Afin de permettre la compréhension de ces trois articles, l'introduction de ce manuscrit présente les concepts essentiels. De plus des méthodes d'analyses de temps-fréquence sont présentées. L'introduction est divisée en quatre parties : la première présente le système visuel depuis les cellules retino-corticales aux deux voix du traitement de l'information en passant par les régions composant le système visuel. La deuxième partie présente la schizophrénie par son diagnostic, ces déficits de bas niveau de traitement des stimuli visuel et ces déficits cognitifs. La troisième partie présente le traitement des contours illusoires et les trois modèles utilisés dans le dernier article. Finalement, les méthodes de traitement des données EEG seront explicitées, y compris les méthodes de temps-fréquences.Les résultats des trois articles sont présentés dans le chapitre éponyme (du même nom). De plus ce chapitre comprendra les résultats obtenus à l'aide des méthodes de temps-fréquenceFinalement, la discussion sera orientée selon trois axes : les méthodes de temps-fréquence ainsi qu'une proposition de traitement de ces données par une méthode statistique indépendante de la référence. La discussion du premier article en montrera la qualité du traitement de ces stimuli. La discussion des deux articles neurophysiologiques, proposera de nouvelles d'expériences afin d'affiner les résultats actuels sur les déficits des schizophrènes. Ceci pourrait permettre d'établir un marqueur biologique fiable de la schizophrénie.ABSTRACT (ENGLISH)This thesis focuses on the visual system in healthy subjects and schizophrenic patients. To address this research, advanced methods of analysis of electroencephalographic (EEG) data were used and developed. This manuscript is comprised of three scientific articles. The first article showed a novel method to control the physical features of visual stimuli (luminance and spatial frequencies). The second article showed, using electrical neuroimaging of EEG, a deficit in spatial processing associated with the dorsal pathway in chronic schizophrenic patients. This deficit was elicited by an absent modulation of the PI component in terms of response strength and topography as well as source estimations. This deficit was orthogonal to the preserved ability to process Kanizsa-type illusory contours. Finally, the third article resolved ongoing debates concerning the neural mechanism mediating illusory contour sensitivity by using electrical neuroimaging to show that the first differentiation of illusory contour presence vs. absence is localized within the lateral occipital complex. This effect was subsequent to modulations due to the orientation of misaligned grating stimuli. Collectively, these results support a model where effects in V1/V2 are mediated by "top-down" modulation from the LOC.To understand these three articles, the Introduction of this thesis presents the major concepts used in these articles. Additionally, a section is devoted to time-frequency analysis methods not presented in the articles themselves. The introduction is divided in four parts. The first part presents three aspects of the visual system: cellular, regional, and its functional interactions. The second part presents an overview of schizophrenia and its sensoiy-cognitive deficits. The third part presents an overview of illusory contour processing and the three models examined in the third article. Finally, advanced analysis methods for EEG are presented, including time- frequency methodology.The Introduction is followed by a synopsis of the main results in the articles as well as those obtained from the time-frequency analyses.Finally, the Discussion chapter is divided along three axes. The first axis discusses the time frequency analysis and proposes a novel statistical approach that is independent of the reference. The second axis contextualizes the first article and discusses the quality of the stimulus control and direction for further improvements. Finally, both neurophysiologic articles are contextualized by proposing future experiments and hypotheses that may serve to improve our understanding of schizophrenia on the one hand and visual functions more generally.

Designing phase III or IV trials for vaccines: choosing between individual or cluster randomised trial designs.

The choice of design between individual randomisation, cluster or pseudo-cluster randomisation is often made difficult. Clear methodological guidelines have been given for trials in general practice, but not for vaccine trials. This article proposes a decisional flow-chart to choose the most adapted design for evaluating the effectiveness of a vaccine in large-scale studies. Six criteria have been identified: importance of herd immunity or herd protection, ability to delimit epidemiological units, homogeneity of transmission probability across sub-populations, population's acceptability of randomisation, availability of logistical resources, and estimated sample size. This easy to use decisional method could help sponsors, trial steering committees and ethical committees adopt the most suitable design.

Narrative interviews: an important resource in qualitative research

Objetives This methodological study explain and emphasize the extent and fertility of the narrative interview in qualitative research. Methods To describe the narrative method within the qualitative research. Results The qualitative research method is characterized by addressing issues related to the singularities of the field and individuals investigated, being the narrative interviews a powerful method for use by researchers who aggregate it. They allow the deepening of research, the combination of life stories with socio-historical contexts, making the understanding of the senses that produce changes in the beliefs and values that motivate and justify the actions of possible informants. Conclusion The use of narrative is an advantageous investigative resource in qualitative research, in which the narrative is a traditional form of communication whose purpose is to serve content from which the subjective experiences can be transmitted.

Utilização do target costing na determinação do preço de venda: O caso da Alvo, s.a.

Com a crescente competitividade no mundo empresarial, os preços dos produtos passaram a exercer um papel fundamental na expansão e sobrevivência das empresas. Consequentemente, hoje em dia é o mercado que determina o preço de venda de um produto, devendo a empresa produzir ao menor custo possível para garantir o retorno financeiro desejado. O objectivo do trabalho é verificar se os procedimentos de Target Costing podem ser aplicados nas Pequenas e Médias Empresas industriais, em São Vicente, cuja actividade também se destina à produção de produtos alimentícios. Como produto teste foi selecionado o produto A, confecçionado pela empresa Alvo, SA. Para atingirmos os objectivos foram utilizadas várias técnicas e métodos de pesquisa, tais como: levantamento bibliográfico, entrevista, conversas informais, questionário, levantamento de dados nos documentos financeiros da empresa ALVO, SA. Para entendermos e aplicarmos o processo de Target Costing recorreu-se à literatura do mesmo. Foi aplicado um questionário para ver a percepção dos clientes da empresa objecto de estudo, quanto ao preço que considerariam ideal pagar por cada quilograma do produto A adquirida. A entrevista realizada com o director geral da ALVO, SA acompanhada com os dados obtidos do departamento de contabilidade serviram como um meio de conhecer a empresa e o seu funcionamento, realçando informações sobre a fixação do preço venda dos seus produtos, a gestão de custos, entre outros. Antes de testar, através de um caso prático, a aplicação do Target Costing, verificou-se, primeiramente, sua aplicação em termos teóricos, testando os seus princípios e premissas para o produto A, na Empresa ALVO, SA. Como resultado constactou-se que os procedimentos de Target Costing podem ser aplicados, tanto na teoria como na prática, nas Pequenas e Médias Empresas industriais, em São Vicente, cuja actividade se destina a produção do produto A. With the increasing competition in the business world, the prices of products have come to play a key role in the expansion and survival of businesses. Consequently, today the selling price of a product is determined by the market so companies should produce at the lowest possible cost to ensure the desired financial return. The purpose of this paper work is to verify if the Target Costing’s procedure can be applied in small and medium business enterprises in São Vicente, whose activity is production of food. For that, product A was selected for tests. In order to achieve these objectives, some techniques and research methods like bibliographic analysis, interviews, informal conversations, questionnaires and analysis of the financial documents of ALVO, SA that is the subject of this case study, were utilized. With the intention of understanding and applying the Target Costing process we also resorted to a detailed reading of related bibliography. A questionnaire was applied in order to know the customers’ opinions about the ideal price for each kilogram of product A. The interview with the managing director of ALVO, SA, combined with the data obtained in the accounting department, was also used as a way to know the company, and it ’s functioning, highlight ing items such as: selling price format ion, cost management, among other aspects. Before testing, through a practical case study, the use of the Target Costing, the theoretical application was firstly verified by testing its principles and assumptions. Secondly, the application of the Target Costing’s process was shown step by step concerning product A at ALVO SA company. As a result we came to the conclusion that procedures used with Target Costing can be applied, in theory and in practice, in small or medium-sized industrial enterprises, in São Vicente, where product A is being manufactured.

An adaptation of correspondence analysis for square tables

The application of correspondence analysis to square asymmetrictables is often unsuccessful because of the strong role played by thediagonal entries of the matrix, obscuring the data off the diagonal. A simplemodification of the centering of the matrix, coupled with the correspondingchange in row and column masses and row and column metrics, allows the tableto be decomposed into symmetric and skew--symmetric components, which canthen be analyzed separately. The symmetric and skew--symmetric analyses canbe performed using a simple correspondence analysis program if the data areset up in a special block format.

Analysis of matched matrices

We consider the joint visualization of two matrices which have common rowsand columns, for example multivariate data observed at two time pointsor split accord-ing to a dichotomous variable. Methods of interest includeprincipal components analysis for interval-scaled data, or correspondenceanalysis for frequency data or ratio-scaled variables on commensuratescales. A simple result in matrix algebra shows that by setting up thematrices in a particular block format, matrix sum and difference componentscan be visualized. The case when we have more than two matrices is alsodiscussed and the methodology is applied to data from the InternationalSocial Survey Program.

From correspondence analysis to multiple and joint correspondence analysis

The generalization of simple (two-variable) correspondence analysis to more than two categorical variables, commonly referred to as multiple correspondence analysis, is neither obvious nor well-defined. We present two alternative ways of generalizing correspondence analysis, one based on the quantification of the variables and intercorrelation relationships, and the other based on the geometric ideas of simple correspondence analysis. We propose a version of multiple correspondence analysis, with adjusted principal inertias, as the method of choice for the geometric definition, since it contains simple correspondence analysis as an exact special case, which is not the situation of the standard generalizations. We also clarify the issue of supplementary point representation and the properties of joint correspondence analysis, a method that visualizes all two-way relationships between the variables. The methodology is illustrated using data on attitudes to science from the International Social Survey Program on Environment in 1993.