Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.

Meta, tracer - MOF with traceability

The following document proposes a traceability solution for model-driven development. There as been already previous work done in this area, but so far there has not been yet any standardized way for exchanging traceability information, thus the goal of this project developed and documented here is not to automatize the traceability process but to provide an approach to achieve traceability that follows OMG standards, making traceability information exchangeable between tools that follow the same standards. As such, we propose a traceability meta-model as an extension of MetaObject Facility (MOF)1. Using MetaSketch2 modeling language workbench, we present a modeling language for traceability information. This traceability information then can be used for tool cooperation. Using Meta.Tracer (our tool developed for this thesis), we enable the users to establish traceability relationships between different traceability elements and offer a visualization for the traceability information. We then demonstrate the benefits of using a traceability tool on a software development life cycle using a case study. We finalize by commenting on the work developed.

MetaSketch OCL Interpreter

No contexto das tecnologias propostas pela OMG, o MOF é utilizado para definir a sintaxe de linguagens de modelação, contudo, os aspectos semânticos não podem ser capturados usando esta linguagem. A descrição dos aspectos não sintácticos é realizada com recurso à linguagem OCL. Consequentemente, para uma completa definição de uma linguagem de modelação é necessário incorporar o OCL no MOF, criando uma infra-estrutura que possui a expressividade necessária para realizar esta função. Este projecto visa complementar a ferramenta de metamodelação MetaSketch Editor, introduzindo a capacidade de executar expressões em OCL e permitindo, desta forma, a verificação semântica dos modelos construídos usando o MetaSketch Editor. A gramática da linguagem OCL adoptada está de acordo com a especificação elaborada pela OMG (2006-05-01), juntando-se algumas contribuições de trabalhos existentes sobre esta linguagem. O projecto envolveu a implementação de um parser com recurso ao sistema GOLD Parser, a implementação da standard library do OCL em C# e, por último, a implementação de uma estratégia de execução das expressões em OCL.

Uma estratégia dirigida a modelos e baseada em linguagem de descrição arquitetural para linhas de produtos de software

Model-oriented strategies have been used to facilitate products customization in the software products lines (SPL) context and to generate the source code of these derived products through variability management. Most of these strategies use an UML (Unified Modeling Language)-based model specification. Despite its wide application, the UML-based model specification has some limitations such as the fact that it is essentially graphic, presents deficiencies regarding the precise description of the system architecture semantic representation, and generates a large model, thus hampering the visualization and comprehension of the system elements. In contrast, architecture description languages (ADLs) provide graphic and textual support for the structural representation of architectural elements, their constraints and interactions. This thesis introduces ArchSPL-MDD, a model-driven strategy in which models are specified and configured by using the LightPL-ACME ADL. Such strategy is associated to a generic process with systematic activities that enable to automatically generate customized source code from the product model. ArchSPLMDD strategy integrates aspect-oriented software development (AOSD), modeldriven development (MDD) and SPL, thus enabling the explicit modeling as well as the modularization of variabilities and crosscutting concerns. The process is instantiated by the ArchSPL-MDD tool, which supports the specification of domain models (the focus of the development) in LightPL-ACME. The ArchSPL-MDD uses the Ginga Digital TV middleware as case study. In order to evaluate the efficiency, applicability, expressiveness, and complexity of the ArchSPL-MDD strategy, a controlled experiment was carried out in order to evaluate and compare the ArchSPL-MDD tool with the GingaForAll tool, which instantiates the process that is part of the GingaForAll UML-based strategy. Both tools were used for configuring the products of Ginga SPL and generating the product source code

CrossMDA-SPL: uma abordagem para gerência de variabilidades dirigida por modelos e aspectos

This paper proposes a systematic approach to management of variability modelsdriven and aspects using the mechanisms of approaches Aspect-Oriented Software Development (AOSD) and Model-Driven Development (MDD). The main goal of the approach, named CrossMDA-SPL, is to improve the management(gerência), modularization and isolation ou separation of the variability of the LPSs of architecture in a high level of abstraction (model) at the design and implementing phases of development Software Product Lines (SPLs), exploiting the synergy between AOSD and MDD. The CrossMDA-SPL approach defines some artifacts basis for advance the separation clear in between the mandatory (bounden) and optional features in the architecture of SPL. The artifacts are represented by two models named: (i) core model (base domain) - responsible for specify the common features the all members of the SPL, and (ii) variability model - responsible for represent the variables features of SPL. In addition, the CrossMDA-SPL approach is composed of: (i) guidelines for modeling and representation of variability, (ii) CrossMDA-SPL services and process, and (iii) models of the architecture of SPL or product instance of SPL. The guidelines use the advantages of AOSD and MDD to promote a better modularization of the variable features of the architecture of SPL during the creation of core and variability models of the approach. The services and sub-processes are responsible for combination automatically, through of process of transformation between the core and variability models, and the generation of new models that represent the implementation of the architecture of SPL or a instance model of SPL. Mechanisms for effective modularization of variability for architectures of SPL at model level. The concepts are described and measured with the execution of a case study of an SPL for management systems of transport electronic tickets

MaRISA-AOCode: uma abordagem genérica para geração de código orientado a aspectos

Currently there are several aspect-oriented approaches that are related to different stages of software development process. These approaches often lack integration with each other and their models and artifacts are not aligned in a coherent process. The integration of Aspect-Oriented Software development (AOSD) and Model-Driven Development (MDD) enables automatic propagation of models from one phase to another, avoiding loss of important information and decisions established in each. This paper presents a model driven approach, called Marisa-AOCode, which supports the processing of detailed design artifacts to code in different Aspect-Oriented Programming languages. The approach proposed by Maris- AOCode defines transformation rules between aSideML, a modeling language for aspectoriented detailed design, and Metaspin, a generic metamodel for aspect-oriented programming languages. The instantiation of the generic metamodel (Metaspin) provided by the approach of Maris-AOCode is illustrated by the transformation of Metaspin for two languages: AspectLua and CaesarJ. We illustrate the approach with a case study based on the Health Watcher System

Uma abordagem dirigida por modelos para desenvolvimento de middlewares auto-adaptativos para transmissão de fluxo de dados baseado em restrições de QoS

The use of middleware technology in various types of systems, in order to abstract low-level details related to the distribution of application logic, is increasingly common. Among several systems that can be benefited from using these components, we highlight the distributed systems, where it is necessary to allow communications between software components located on different physical machines. An important issue related to the communication between distributed components is the provision of mechanisms for managing the quality of service. This work presents a metamodel for modeling middlewares based on components in order to provide to an application the abstraction of a communication between components involved in a data stream, regardless their location. Another feature of the metamodel is the possibility of self-adaptation related to the communication mechanism, either by updating the values of its configuration parameters, or by its replacement by another mechanism, in case of the restrictions of quality of service specified are not being guaranteed. In this respect, it is planned the monitoring of the communication state (application of techniques like feedback control loop), analyzing performance metrics related. The paradigm of Model Driven Development was used to generate the implementation of a middleware that will serve as proof of concept of the metamodel, and the configuration and reconfiguration policies related to the dynamic adaptation processes. In this sense was defined the metamodel associated to the process of a communication configuration. The MDD application also corresponds to the definition of the following transformations: the architectural model of the middleware in Java code, and the configuration model to XML

Dos requisitos à arquitetura em linhas de produtos de software: uma estratégia de transformações entre modelos

The tracking between models of the requirements and architecture activities is a strategy that aims to prevent loss of information, reducing the gap between these two initial activities of the software life cycle. In the context of Software Product Lines (SPL), it is important to have this support, which allows the correspondence between this two activities, with management of variability. In order to address this issue, this paper presents a process of bidirectional mapping, defining transformation rules between elements of a goaloriented requirements model (described in PL-AOVgraph) and elements of an architectural description (defined in PL-AspectualACME). These mapping rules are evaluated using a case study: the GingaForAll LPS. To automate this transformation, we developed the MaRiPLA tool (Mapping Requirements to Product Line Architecture), through MDD techniques (Modeldriven Development), including Atlas Transformation Language (ATL) with specification of Ecore metamodels jointly with Xtext , a DSL definition framework, and Acceleo, a code generation tool, in Eclipse environment. Finally, the generated models are evaluated based on quality attributes such as variability, derivability, reusability, correctness, traceability, completeness, evolvability and maintainability, extracted from the CAFÉ Quality Model

AutoWebS: um Ambiente para Modelagem e Geração Automática de ServiçosWeb Semânticos

Typically Web services contain only syntactic information that describes their interfaces. Due to the lack of semantic descriptions of the Web services, service composition becomes a difficult task. To solve this problem, Web services can exploit the use of ontologies for the semantic definition of service s interface, thus facilitating the automation of discovering, publication, mediation, invocation, and composition of services. However, ontology languages, such as OWL-S, have constructs that are not easy to understand, even for Web developers, and the existing tools that support their use contains many details that make them difficult to manipulate. This paper presents a MDD tool called AutoWebS (Automatic Generation of Semantic Web Services) to develop OWL-S semantic Web services. AutoWebS uses an approach based on UML profiles and model transformations for automatic generation of Web services and their semantic description. AutoWebS offers an environment that provides many features required to model, implement, compile, and deploy semantic Web services

CALV3 - Uma linguagem específica de domínio para segurança em sistemas corporativos: um estudo de caso sistemático na indústria

The academic community and software industry have shown, in recent years, substantial interest in approaches and technologies related to the area of model-driven development (MDD). At the same time, continues the relentless pursuit of industry for technologies to raise productivity and quality in the development of software products. This work aims to explore those two statements, through an experiment carried by using MDD technology and evaluation of its use on solving an actual problem under the security context of enterprise systems. By building and using a tool, a visual DSL denominated CALV3, inspired by the software factory approach: a synergy between software product line, domainspecific languages and MDD, we evaluate the gains in abstraction and productivity through a systematic case study conducted in a development team. The results and lessons learned from the evaluation of this tool within industry are the main contributions of this work

Identificando interesses transversais em modelos de requisitos PL-AOVgraph

The occurrence of problems related to the scattering and tangling phenomenon, such as the difficulty to do system maintenance, increasingly frequent. One way to solve this problem is related to the crosscutting concerns identification. To maximize its benefits, the identification must be performed from early stages of development process, but some works have reported that this has not been done in most of cases, making the system development susceptible to the errors incidence and prone to the refactoring later. This situation affects directly to the quality and cost of the system. PL-AOVgraph is a goal-oriented requirements modeling language which offers support to the relationships representation among requirements and provides separation of crosscutting concerns by crosscutting relationships representation. Therefore, this work presents a semi-automatic method to crosscutting concern identification in requirements specifications written in PL-AOVgraph. An adjacency matrix is used to identify the contributions relationships among the elements. The crosscutting concern identification is based in fan-out analysis of contribution relationships from the informations of adjacency matrix. When identified, the crosscutting relationships are created. And also, this method is implemented as a new module of ReqSys-MDD tool

Fluvoxamina no transtorno depressivo maior: um estudo multicêntrico aberto

OBJETIVO: Este trabalho estudou a eficácia e a tolerabilidade da fluvoxamina no tratamento, de forma aberta, sem comparação com placebo ou outros agentes, por 6 semanas, de pacientes com o diagnóstico de transtorno depressivo maior (TDM). Constitui-se em objetivo secundário do estudo avaliar os efeitos da fluvoxamina sobre o sono dos pacientes. MÉTODOS: Foram incluídos 104 pacientes, maiores de 18 anos, com o diagnóstico de TDM, de acordo com os critérios do Manual Diagnóstico e Estatístico de Transtornos Mentais, 4ª edição (DSM-IV), e com escores, na Escala de Hamilton para Depressão, versão de 17 itens (HAM-D 17), de 17 pontos ou mais. Avaliou-se a eficácia da fluvoxamina por meio das Escalas HAM-D 17 e da CGI (Impressão Clínica Global). A análise dos itens 4, 5 e 6 da HAM-D 17 foi utilizada para a avaliação do sono dos pacientes. Avaliaram-se a segurança e a tolerabilidade da fluvoxamina ao longo das 6 semanas, registrando-se quaisquer eventos adversos. A fluvoxamina foi inicialmente ministrada em doses de 50 ou 100 mg/dia, podendo haver aumentos progressivos até 300 mg/dia. RESULTADOS: Dos 104 pacientes incluídos, 81 (78%) concluíram o estudo. Obtiveram resposta favorável (diminuição de 50% ou mais na HAM-D 17) 69% dos pacientes, e a taxa de remissão (HAM-D 17 < 7) foi de 52%. A análise da CGI indicou ter havido melhora significante (p < 0,001) em relação aos escores de base. A análise específica dos itens relativos ao sono, na HAM-D 17, revelou melhora significativa já na segunda visita, mantendo-se ao longo das 6 semanas. Os eventos adversos foram os esperados para inibidores seletivos de recaptação da serotonina, predominando as queixas gastrointestinais, em sua maioria transitórias e de pequena intensidade. CONCLUSÃO: O estudo vem confirmar a eficácia e a tolerabilidade da fluvoxamina no tratamento do transtorno depressivo maior, assim como sua eficácia no tratamento das alterações do sono encontradas nos pacientes deprimidos. O perfil de eventos adversos foi o esperado para os ISRS, ressaltando-se o fato de que poucos pacientes relataram disfunção sexual (2,5% dos pacientes).

A eficácia do milnaciprano em pacientes ambulatoriais com transtorno depressivo maior não respondedores ao tratamento com ISRSs: um estudo aberto de 12 semanas

CONTEXTO: O objetivo deste estudo é avaliar a eficácia do milnaciprano em pacientes ambulatoriais com depressão maior grave que não respondem em tempo e em dosagem adequados à terapia com ISRSs. MÉTODOS: Um estudo aberto multicêntrico com a duração de 12 semanas foi elaborado para avaliar a eficácia do milnaciprano após falha em um experimento com ISRS. Remissão completa (HAMD-17 < 8) foi o desfecho principal. Os desfechos secundários foram resposta (HAM > 50%), CGI e avaliação da qualidade de vida (WHOQOL-Bref). RESULTADOS: O escore HAMD-17 médio da amostra foi de 27 (7,2). As taxas de remissão com o milnaciprano foram de 17,5%, e as de resposta, 61,3%. Na linha de base, 70,9% dos pacientes foram classificados como gravemente sintomáticos. Ao final do tratamento, 48,1% dos pacientes foram classificados como normais assintomáticos ou sintomáticos limítrofes e 20,2% eram moderadamente sintomáticos. Além disso, os quatro domínios do WHOQOL-Bref, um instrumento genérico de mensuração de qualidade de vida, apresentou diferenças clínicas e estatísticas: CONCLUSÃO: Nossos resultados sugerem que o milnaciprano é uma possível opção para pacientes que não respondem a ISRSs. Uma vez que não há evidências na literatura de um antidepressivo que seja a melhor opção quando um ISRS falha, o uso do milnaciprano deveria ser considerado em casos de pacientes com depressão severa.

Treatment of pediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia: the Brazilian experience in the past decade

Background: Therapy strategies for myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) vary considerably. Objective: To review the treatment of Brazilian children who were diagnosed with MDS or JMML in the past decade and reported to the Brazilian Cooperative Group on Pediatric Myelodysplastic syndromes (BCG-MDS-PED). Results: of 173 children reported to the BCG-MDS-PED from January 1997 to January 2003 with a suspected diagnosis of MDS or JMML, 91 had the diagnosis confirmed after central review of the bone marrow aspirate and biopsy. Information on previous treatments was available for 78 MDS/JMML patients. Treatment varied from different schedules of low-dose (14%) and standard-dose chemotherapy (50%), granulocyte-colony-stimulating factor (G-CSF 7%), interferon (5%), steroids (2%) and erythropoietin (2%) to allogeneic stem-cell transplantation (SCT) (14%). No survival advantage could be demonstrated based on Hasle's classification or based on treatment. Conclusion: This report reflects the current practice in treating Brazilian children with MDS/JMML without specific Cooperative Group guidelines. Treatment modalities were very heterogeneous. The strategies for implementing a national protocol should consider international guidelines and focus on local experience and available resources. (C) 2004 Elsevier Ltd. All rights reserved.

Comorbid major depression in obsessive-compulsive disorder patients

Although major depressive disorder (MDD) has been consistently considered the most frequent complication of obsessive-compulsive disorder (OCD), little is known about the clinical characteristics of patients with both disorders. This study assessed 815 Brazilian OCD patients using a comprehensive psychiatric evaluation. Clinical and demographic variables, including OCD symptom dimensions, were compared among OCD patients with and without MDD. Our findings showed that prevalence rates of current MDD (32%) and lifetime MDD (67.5%) were similar for both sexes in this study. In addition, patients with comorbid MDD had higher severity scores of OCD symptoms. There was no preferential association of MDD with any particular OCD symptom dimension. This study supports the notion that depressed OCD patients present more severe general psychopathology. © 2011 Elsevier Inc. All rights reserved.