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The architectural properties of product-line architecture (PLA) design have been successfully optimised by multi-objective genetic algorithms (GAs). Memetic algorithms (MAs) extend GA by adding a local search after the global search process. MA outperformed GA in the context of class modelling, software testing and the next release problem. However, no studies on the application of MAs for PLA design optimisation were found in the literature. In light of this, the authors performed an exploratory study, where MA was used to apply design patterns for a search-based PLA design (SBPD) and achieved promising results. From the obtained results, they adjusted the MA-based implementation. This study aims at investigating if the MA is more profitable to SBPD than GAs. Two empirical studies that involve four PLA designs were carried out for this task by varying the pair of objective functions. Empirical results show that MA achieved satisfactory solutions, despite being influenced by the original PLA design.

Worked examples are instructional devices composed of the description of a problem, steps to solve the problem, and the final result. There is evidence that the use of the worked examples improves the learning process by reducing the learning time, reducing the cognitive load, and facilitating the construction of cognitive schemes. In addition, students who learn from worked examples tend to solve similar problems more quickly and easily. Worked examples are adopted in several areas of knowledge but are not well-explored in Software Engineering (SE) teaching. Thus, the goal of this work was to explore the use of worked examples in SE courses. To do so, we conducted an exploratory study split into two stages. In the first stage, we administered a survey with SE instructors to investigate the use of common examples, worked examples, and the difficulties find this type of material. In the second stage, we applied worked examples in the classroom and collected feedback from students. The second stage was carried out remotely due to the conditions imposed by COVID-19. The results showed that instructors are employing examples in their courses; some of them use worked examples, even when they do not know the definition. In addition, the feedback from the students was positive, which may encourage the use of worked examples in SE teaching.

Cancer is an urgent public health issue with a very huge number of cases all over the world expected to increase by 2040. Despite improved diagnosis and therapeutic protocols, it remains the main leading cause of death in the world. Cancer stem cells (CSCs) constitute a tumor subpopulation defined by ability to self-renewal and to generate the heterogeneous and differentiated cell lineages that form the tumor bulk. These cells represent a major concern in cancer treatment due to resistance to conventional protocols of radiotherapy, chemotherapy and molecular targeted therapy. In fact, although partial or complete tumor regression can be achieved in patients, these responses are often followed by cancer relapse due to the expansion of CSCs population. The aberrant activation of developmental and oncogenic signaling pathways plays a relevant role in promoting CSCs therapy resistance. Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy. Therefore, an urgent need to design alternative combinatorial strategies to replace conventional regimens exists. This review summarizes the preclinical studies which provide a proof of concept of therapeutic efficacy of combinatorial approaches targeting the CSCs.

Finding real examples that follow the evolution of Software Engineering is not an easy task for instructors in the field. Open Source Software (OSS) projects have been an alternative to support education in Software Engineering, as they allow contact with real development projects and environments. However, the adoption of these projects in the classroom presents some obstacles, such as choosing the appropriate project, and the time and effort needed to prepare the classes and get used to the open source environment. In order to reduce the difficulties faced by instructors, we are working on developing a portal to catalog worked examples extracted from OSS projects to assist instructors. In this paper, we present the first steps towards creating this catalog, which is creating a pattern for guiding the structuring the worked examples. We are applying the Design Science Research paradigm. The activities reported in this paper regards the first Design Cycle, and were divided into three stages related to the elaboration and evaluation of the pattern for cataloging the worked examples. In these stages, we carried out focus groups and interviews with Software Engineering instructors, including the instantiation of the pattern to catalog actual worked examples. After each stage, we had a new and improved version of the pattern for cataloging the worked examples. Such pattern served as a basis to create the first version of the worked examples portal, which will be evaluated in the next stages of the research.

The Multi-objective Optimization Approach for Product Line Architecture Design (MOA4PLA) is the seminal approach that successfully optimizes Product Line Architecture (PLA) design using search algorithms. The tool named OPLA-Tool was developed in order to automate the use of MOA4PLA. Over time, the customization of the tool to suit the needs of new research and application scenarios led to several problems. The main problems identified in the original version of OPLA-Tool are environment configuration, maintainability and usability problems, and PLA design modeling and visualization. Such problems motivated the development of a new version of this tool: OPLA-Tool v2.0, presented in this work. In this version, those problems were solved by the source code refactoring, migration to a web-based graphical user interface (GUI) and inclusion of a new support tool for PLA modeling and visualization. Furthermore, OPLA-Tool v2.0 has new functionalities, such as new objective functions, new search operators, intelligent interaction with users during the optimization process, multi-user authentication and simultaneous execution of several experiments to PLA optimization. Such a new version of OPLA-Tool is an important achievement to PLA design optimization as it provides an easier and more complete way to automate this task.

The Product Line Architecture (PLA) is one of the most important artifacts of a Software Product Line. PLA design requires intensive human effort as it involves several conflicting factors. In order to support this task, an interactive search-based approach, automated by a tool named OPLA-Tool, was proposed in a previous work. Through this tool the software architect evaluates the generated solutions during the optimization process. Considering that evaluating PLA is a complex task and search-based algorithms demand a high number of generations, the evaluation of all solutions in all generations cause human fatigue. In this work, we incorporated in OPLA-Tool a Machine Learning (ML) model to represent the architect in some moments during the optimization process aiming to decrease the architect's effort. Through the execution of a quantiqualitative exploratory study it was possible to demonstrate the reduction of the fatigue problem and that the solutions produced at the end of the process, in most cases, met the architect's needs.

Extensive maintenance leads to the Software Product Line Architecture (PLA) degradation over time. When there is the need of evolving the Software Product Line (SPL) to include new features, or move to a new platform, a degraded PLA requires considerable effort to understand and modify, demanding expensive refactoring activity. In the state of the art, search-based algorithms are used to improve PLA at package level. However, recent studies have shown that the most variability and implementation details of an SPL are described in the level of classes. There is a gap between existing approaches and existing practical needs. In this work, we extend the current state of the art to deal with feature modularization in the level of classes by introducing a new search operator and a set of objective functions to deal with feature modularization in a finer granularity of the architectural elements, namely at class level. We evaluated the proposal in an exploratory study with a PLA widely investigated and a real-world PLA. The results of quantitative and qualitative analysis point out that our proposal provides solutions to properly re-modularize features in a PLA, being preferred by practitioners, in order to support the evolution of SPLs.

Capacity building in public health is an urgent global priority. Recently, there has been an increasing emphasis on South–South and triangular cooperation. We describe our experience with a public health training collaboration between Peru and Bolivia, with Peru providing capacity building and expertise to Bolivia, while receiving supportive funding and training from the United States. This collaboration has led to a groundswell of research on clinically significant diseases, outreach to more than 800 scientists, several dozen publications, and the start of four institutional review boards. South–South and South–South–North collaborations should publish their experiences, and Northern funding organizations should consider funding such collaborations.

The software development process comprises a set of activities with the goal of developing high quality software. The software architecture design is a key activity of the software development processs as it allows the specification and visualization of products from different and structured point of views. One of the most used architectural views is the logical one, which represents the classes and their relationships. For this reason, the UML class diagram is one of the most used UML diagrams by software engineers [1]. Many companies use CASE (Computer-Aided Software Engineering) tools to carry out several software engineering activities, including modeling class diagrams. They are looking for independence and flexibility to adapt and integrate tools through the adoption of open-source tools, but this is not an easy task as there are a lot of CASE tools and most of them are incompatible. This problem arises when it is necessary to integrate tools to perform software engineering activity that needs to receive a UML class diagram as input. In this sense, the objective of this work is to assist software engineers in the selection of the tools by presenting results of a systematic review, whose goal was identifying existing free and open-source tools for UML class diagram modeling and analyzing their support to adaptation and integration with other tools. Twelve tools for UML class diagrams modeling were found and an analysis of their support to adaptation and integration with other tools was carried out. This analysis is useful in the choice and use of such kind of tool, either in industry or academic research.

Root canal refactoring is a software development activity that is intended to improve dependability-related attributes such as modifiability and reusability. Despite being an activity that contributes to these attributes, deciding when applying root canal refactoring is far from trivial. In fact, finding which elements should be refactored is not a cut-and-dried task. One of the main reasons is the lack of consensus on which characteristics indicate the presence of structural degradation. Thus, we evaluated whether the density and diversity of multiple automatically detected symptoms can be used as consistent indicators of the need for root canal refactoring. To achieve our goal, we conducted a multi-case exploratory study involving 6 open source systems and 2 systems from our industry partners. For each system, we identified the classes that were changed through one or more root canal refactorings. After that, we compared refactored and non-refactored classes with respect to the density and diversity of degradation symptoms. We also investigated if the most recurrent combinations of symptoms in refactored classes can be used as strong indicators of structural degradation. Our results show that refactored classes usually present higher density and diversity of symptoms than non-refactored classes. However, root canal refactorings that are performed by developers in practice may not be enough for reducing degradation, since the vast majority had little to no impact on the density and diversity of symptoms. Finally, we observed that symptom combinations in refactored classes are similar to the combinations in non-refactored classes. Based on our findings, we elicited an initial set of requirements for automatically recommending root canal refactorings.

INTRODUCTION: Trypanosoma cruzi (Tc) infection is usually acquired in childhood in endemic areas, leading to Chagas disease, which progresses to Chagas cardiomyopathy in 20-30% of infected individuals over decades. The pathogenesis of Chagas cardiomyopathy involves the host inflammatory response to T. cruzi, in which upstream caspase-1 activation prompts the cascade of inflammatory chemokines/cytokines, cardiac remodeling, and myocardial dysfunction. The aim of the present study was to examine the association of two caspase-1 single nucleotide polymorphisms (SNPs) with cardiomyopathy. METHODS: We recruited infected (Tc+, n = 149) and uninfected (Tc−, n = 87) participants in a hospital in Santa Cruz, Bolivia. Cardiac status was classified (I, II, III, IV) based on Chagas cardiomyopathy-associated electrocardiogram findings and ejection fractions on echocardiogram. Genotypes were determined using Taqman probes via reverse transcription-polymerase chain reaction of peripheral blood DNA. Genotype frequencies were analyzed according to three inheritance patterns (dominant, recessive, additive) using logistic regression adjusted for age and sex. RESULTS: The AA allele for the caspase-1 SNP rs501192 was more frequent in Tc+ cardiomyopathy (classes II, III, IV) patients compared to those with a normal cardiac status (class I) [odds ratio (OR) = −2.18, p = 0.117]. This trend approached statistical significant considering only Tc+ patients in class I and II (OR = −2.64, p = 0.064). CONCLUSIONS: Caspase-1 polymorphisms may play a role in Chagas cardiomyopathy development and could serve as markers to identify individuals at higher risk for priority treatment.

We propose feature-driven crossover to improve feature modularization in PLA design.We compare the performance of a search algorithm with and without that crossover.Empirical results show the feature-driven crossover provides benefits to PLA design.Such crossover allows achieving better solutions and greater diversity of solutions.Such crossover operator also contributes to improve basic design principles. The optimization of a Product Line Architecture (PLA) design can be modeled as a multi-objective problem, influenced by many factors, such as feature modularization, extensibility and other design principles. Due to this it has been properly solved in the Search Based Software Engineering (SBSE) field. However, previous empirical studies optimized PLA design using the multi-objective and evolutionary algorithm NSGA-II, without applying one of the most important genetic operators: the crossover. To overcome this limitation, this paper presents a feature-driven crossover operator that aims at improving feature modularization in PLA design. The proposed operator was applied in two empirical studies using NSGA-II in comparison with another version of NSGA-II that uses only mutation operators. The results show the usefulness and applicability of the proposed operator. The NSGA-II version that applies the feature-driven crossover found a greater diversity of solutions (potential PLA designs), with higher feature-based cohesion, and less feature scattering and tangling.

Software Product Lines (SPLs) is a reuse approach in which a family of products is generalized in a common architecture that can be adapted to different clients. The Product Line Architecture (PLA) is one of the most important artifacts of a SPL. PLA design requires great human effort as it involves several factors that are usually in conflict. To ease this task, PLA design can be formulated as an optimization problem with many factors, i.e, as a multi-objective optimization problem. In this context, the MOA4PLA approach was proposed to optimize PLA design using search algorithms and metrics specific to the context. This approach supported by OPLA-Tool has already been used in several works demonstrating its applicability. However, MOA4PLA does not take into account aspects that are subjective, such as the preferences of a particular Decision Maker (DM). To do so, this paper presents a proposal to incorporate the user preferences in the optimization process performed by MOA4PLA, through an interactive process in which the DM subjectively evaluates the solutions in processing time. Thus, the solutions generated can be better suited to the DM's needs or preferences. In order to allow the user interaction, modifications were made in MOA4PLA and implemented in the OPLA-Tool. Aiming at an initial validation of the proposal, an exploratory study was carried out, composed of two experiments: a qualitative and a quantitative. These experiments were realized with the participation of a software architect. Empirical results pointed out that the proposed interactive process enables the generation of PLAs that are in accordance with the architect's preferences. Another significant contribution are the lessons learned on how to improve the interactive process.

Microservice has been successfully employed in software industry [1, 11], as they provide modularization and easy management of small and autonomous services, high availability, scalability and short time-to-market. A recent study on microservices shows that most studies generate specific solutions, which emphasize the need for fundamental research, proposals of reusable practices and works that focus on providing information to ease communication between architects and stakeholders [11] -- software architecture can be a powerful tool for this regard. The definition and documentation of the software product line architecture (PLA) is an important activity, especially for inception and extraction of microservice-oriented PLA, because they involve decisions about how to design customizable microservices, how to arrange the communication between microsservices and APIs, etc. In this work, it is proposed a metamodel for the specification of microsserve-oriented PLA design in order to assist the developer in carrying out such an activity. The proposed metamodel was validated in an exploratory study, in which a new PLA was designed through the instantiation of the proposed metamodel and a product was configured from the designed PLA. Both the metamodel and its instantiation were evaluated in a survey involving software developers. The results indicate that the metamodel addresses the structural needs of microservice-oriented architectures. The main contributions of this work are (i) to assist the software product line developers in the specification and documentation of microservice-oriented PLA design and (ii) the lessons about the industrial practice learned from the surveys that are useful to enhance the proposed metamodel.

Microservices is an emerging industrial technique to promote better modularization and management of small and autonomous services. Microservice architecture is widely used to overcome the limitations of monolithic legacy systems, such as limited maintainability and reusability. Migration to a microservice architecture is increasingly becoming the focus of academic research. However, there is little knowledge on how microservices are extracted from legacy systems in practice. Among these limitations, there is a lack of understanding if variability is considered useful along the microservice extraction from a configurable system. In order to address this gap, we performed an exploratory study composed of two phases. Firstly, we conducted an online survey with 26 specialists that contributed to the migration of existing systems to a microservice architecture. Secondly, we performed individual interviews with seven survey participants. A subset of the participants (13 out of 26) dealt with systems with variability during the extraction, which stated that variability is a key criterion for structuring the microservices. Moreover, variability in the legacy system is usually implemented with simple mechanisms. Finally, initial evidence points out that microservices extraction can increase software customization.

The Product Line Architecture (PLA) is one of the most important artifacts of a Software Product Line (SPL). PLA design can be formulated as an optimization problem with many factors. In this context, the MOA4PLA approach was proposed to optimize PLA design using search algorithms and metrics specific to the context. MOA4PLA treats the PLA design as a multi-objective optimization problem. At the end of the search process several PLA design alternatives are presented to the decision maker, difficulting the decision about which PLA alternative best fits with his/her needs. In this sense, this work proposes the usage of clustering algorithms to group PLAs design alternatives, according to their characteristics and assist the decision maker in the choice of one PLA design for the SPL. For this purpose, an empirical study was carried out, involving quantitative and qualitative experiments. Such an study integrated the K-Means++ and DBSCAN clustering algorithms in the MOA4PLA approach. The results of the experiments were promising, since an appropriate grouping of the solutions can be quantitatively observed, and also, qualitatively, the suitability of the solutions to the decision makers needs was verified.

Concurrent software includes a number of key features such as communication, concurrency, and non-determinism, which increase the complexity of software testing. One of the main challenges is the test data generation. Techniques of search-based software can also benefit concurrent software testing. To do so, this paper adopts a bio-inspired approach, called BioConcST, to support the automatic test data generation for concurrent programs. BioConcST uses a Genetic Algorithm (GA) and an evolutionary strategy adapted to accept genetic information from some bad individuals (test data) in order to generate better individuals. Structural testing criteria for concurrent programs are used to guide the evolution of test data generation. An experimental study was carried out to compare BioConcST with an elitist GA strategy (EGA) in terms of adequacy of testing criteria for message-passing and shared-memory programs. Twelve concurrent Java programs were included and the results suggest BioConcST is a promising approach, since in all the testing criteria evaluated, it achieved a better coverage and the effect-size measure was large in most cases.

Background The detection of Trypanosoma cruzi genetic material in clinical samples is considered an important diagnostic tool for Chagas disease. We have previously demonstrated that PCR using clot samples yields greater sensitivity than either buffy coat or whole blood samples. However, phenol-chloroform DNA extraction from clot samples is difficult and toxic. The objective of the present study was to improve and develop a more sensitive method to recover parasite DNA from clot samples for the diagnosis of Chagas disease. Methodology/Principal findings A total of 265 match pair samples of whole blood–guanidine (GEB) and clot samples were analyzed; 150 were from Chagas seropositive subjects. DNA was extracted from both whole blood-guanidine samples, using a previously standardized methodology, and from clot samples, using a newly developed methodology based on a combination of the FastPrep technique and the standard method for GEB extraction. A qPCR targeting the nuclear satellite sequences was used to compare the sample source and the extraction method. Of the 150 samples from Chagas positive individuals by serology, 47 samples tested positive by qPCR with DNA extracted by both GEB and clot, but an additional 13 samples tested positive only in DNA extracted from clot. No serology-negative samples resulted positive when tested by qPCR. Conclusions The new methodology for DNA extraction from clot samples improves the molecular diagnosis of Chagas disease., Author summary Detection of nucleic acid has become an important tool for the diagnosis of Chagas disease. Whole blood samples are usually the source of DNA and qPCR the preferred technique to demonstrate the presence of T. cruzi DNA. Although DNA extracted from clot samples has shown higher sensitivity than from whole blood, DNA extraction is performed using phenol-chloroform, which has biohazard issues. We theorize that a clot traps parasites, making it a better source of DNA for Chagas diagnosis using PCR. The present study describes a new DNA extraction methodology from clot samples which avoids the use of phenol-chloroform. The new methodology was compared to the internationally standardized diagnostic method, which is based on extraction of DNA from whole blood preserved with guanidine EDTA and a commercial kit.

The year 2018 marked the tenth anniversary of the Symposium on Search Based Software Engineering (SSBSE). In order to better understand the characteristics and evolution of papers published in SSBSE, this work reports results from a mapping study targeting the ten proceedings of SSBSE. Our goal is to identify and to analyze authorship collaborations, the impact and relevance of SSBSE in terms of citations, the software engineering areas commonly studied as well as the new problems recently solved, the computational intelligence techniques preferred by authors and the rigour of experiments conducted in the papers. Besides this analysis, we list some recommendations to new authors who envisage to publish their work in SSBSE. Despite of existing mapping studies on SBSE, our contribution in this work is to provide information to researchers and practitioners willing to enter the SBSE field, being a source of information to strengthen the symposium, guide new studies, and motivate new collaboration among research groups.

Quantitative polymerase chain reaction (qPCR) for Toxoplasma gondii multicopy genes has emerged as a promising strategy for sensitive detection of parasite DNA. qPCR can be performed from blood samples, which are minimally invasive to collect. However, there is no consensus about what type of blood specimen yields the best sensitivity. The development of a novel protocol for qPCR detection of T. gondii using blood clot, involving an appropriate DNA extraction method and the use of an internal amplification control to monitor the reaction is presented in the current study. Assays directed to the B1 and REP529 genes were performed in spiked specimens of whole blood, guanidine–ethylenediaminetetraacetic acid blood, and clot. The clot-based qPCR was shown to be more sensitive when compared with other types of specimens, detecting five and 0.05 T. gondii genomes, using B1 and REP529 targets, respectively. Finally, a comparative analysis with samples from HIV patients with clinical suspicion of toxoplasmosis was performed, demonstrating the detection of four positive suspected cases with clots compared with only one using guanidine–ethylenediaminetetraacetic acid blood. The high analytical sensitivity and the cost-effective advantages offered by clot supports this methodology as a good laboratory tool to monitor parasite burden.

Autonomic dysfunction is common in Chagas disease and diabetes. Patients with either condition complicated by cardiac autonomic dysfunction face increased mortality, but no clinical predictors of autonomic dysfunction exist. Pupillary light reflexes (PLRs) may identify such patients early, allowing for intensified treatment. To evaluate the significance of PLRs, adults were recruited from the outpatient endocrine, cardiology, and surgical clinics at a Bolivian teaching hospital. After testing for Chagas disease and diabetes, participants completed conventional autonomic testing (CAT) evaluating their cardiovascular responses to Valsalva, deep breathing, and orthostatic changes. PLRs were measured using specially designed goggles, then CAT and PLRs were compared as measures of autonomic dysfunction. This study analyzed 163 adults, including 96 with Chagas disease, 35 patients with diabetes, and 32 controls. PLRs were not significantly different between Chagas disease patients and controls. Patients with diabetes had longer latency to onset of pupil constriction, slower maximum constriction velocities, and smaller orthostatic ratios than nonpatients with diabetes. PLRs correlated poorly with CAT results. A PLR-based clinical risk score demonstrated a 2.27-fold increased likelihood of diabetes complicated by autonomic dysfunction compared with the combination of blood tests, CAT, and PLRs (sensitivity 87.9%, specificity 61.3%). PLRs represent a promising tool for evaluating subclinical neuropathy in patients with diabetes without symptomatic autonomic dysfunction. Pupillometry does not have a role in the evaluation of Chagas disease patients.

The Product Line Architecture (PLA) defines a common design for all products derived from the software product line. PLA design is a high-effort task since it is influenced by several factors, such as feature modularity, PLA variability and extensibility. Given the complexity and variety of such influential factors, the use of search-based algorithms have recently been explored to derive PLA designs in the seminal approach named Multi-Objective Approach for Product-Line Architecture Design (MOA4PLA). MOA4PLA produces a set of alternative PLA designs that improve the different optimized factors. Besides the optimization of these factors, the obtained PLA designs should ideally have no architectural smell. An architectural smell may harm not only the PLA variability and extensibility, but also other non-functional attributes. However, no previous study was performed to investigate if and to what extent state-of-the-art search-based approaches, such as MOA4PLA, adversely introduce architectural smells in resulting designs. Thus, we performed an exploratory investigation about the presence of architectural smells in a set of PLA designs obtained from MOA4PLA. Such an investigation was also useful to derive guidelines for: (i) improving the resulting search-based PLA designs, or (ii) preventing upfront the emergence of architectural smells in PLA designs automatically obtained with search-based approaches.

The Product Line Architecture (PLA) is one of the most important artifacts of a Software Product Line (SPL). The Multi-Objective Approach for PLA Design (MOA4PLA) aims at optimizing the PLA design by using search algorithms easing the design activity. From an original PLA, MOA4PLA automatically obtains alternative designs to improve the original one in terms of the objectives selected for optimization. The use of search algorithms is an incipient research topic, which includes several open research questions. The evaluation model of MOA4PLA is composed of various objective functions, which use software metrics to evaluate different factors that influence on the PLA design. However, the simultaneous optimization of all objective functions is a computationally complex task. In this sense, it is worthwhile to investigate the possible correlation between objective functions because the discovery of correlated functions allows to reduce the number of objectives to be optimized by the search algorithm. Hence, in this paper we perform a preliminary study to investigate the correlation among five objective functions related to metrics that provide indicators on conventional architectural properties, such as coupling, cohesion and size. To accomplish the objective of this paper, four controlled experiments were carried out with four different PLA designs. Empirical results provide preliminary evidence that two pairs of functions are positively correlated and two other pairs of functions are negatively correlated. From such findings, several guidelines were derived to help architects to both reduce and select the objectives related to conventional architectural properties to be tackled during the PLA design optimization.

Background: Congenital Trypanosoma cruzi transmission is now estimated to account for 22% of new infections, representing a significant public health problem across Latin America and internationally. Treatment during infancy is highly efficacious and well tolerated, but current assays for early detection fail to detect >50% of infected neonates, and 9-month follow-up is low. Methods: Women who presented for delivery at 2 urban hospitals in Santa Cruz Department, Bolivia, were screened by rapid test. Specimens from infants of infected women were tested by microscopy (micromethod), quantitative PCR (qPCR), and immunoglobulin (Ig)M trypomastigote excreted-secreted antigen (TESA)-blots at birth and 1 month and by IgG serology at 6 and 9 months. Results: Among 487 infants of 476 seropositive women, congenital T. cruzi infection was detected in 38 infants of 35 mothers (7.8%). In cord blood, qPCR, TESA-blot, and micromethod sensitivities/specificities were 68.6%/99.1%, 58.3%/99.1%, and 16.7%/100%, respectively. When birth and 1-month results were combined, cumulative sensitivities reached 84.2%, 73.7%, and 34.2%, respectively. Low birthweight and/or respiratory distress were reported in 11 (29%) infected infants. Infants with clinical signs had higher parasite loads and were significantly more likely to be detected by micromethod. Conclusions: The proportion of T. cruzi-infected infants with clinical signs has fallen since the 1990s, but symptomatic congenital Chagas disease still represents a significant, albeit challenging to detect, public health problem. Molecular methods could facilitate earlier diagnosis and circumvent loss to follow-up but remain logistically and economically prohibitive for routine screening in resource-limited settings.

A common problem found during the integration testing is to determine an order to integrate and test the units. Important factors related to stubbing costs and constraints regarding to the software development context must be considered. To solve this problem, the most promising results were obtained with multi-objective algorithms, however few algorithms and contexts have been addressed by existing works. Considering such fact, this paper aims at introducing a generic approach based on multi-objective optimization to be applied in different development contexts and with distinct multi-objective algorithms. The approach is instantiated in the object and aspect-oriented contexts, and evaluated with real systems and three algorithms: NSGA-II, SPEA2 and PAES. The algorithms are compared by using different number of objectives and four quality indicators. Results point out that the characteristics of the systems, the instantiation context and the number of objectives influence on the behavior of the algorithms. Although for more complex systems, PAES reaches better results, NSGA-II is more suitable to solve the referred problem in general cases, considering all systems and indicators.

Search Based Software Engineering (SBSE) is the field of software engineering research and practice that applies search based techniques to solve different optimization problems from diverse software engineering areas. SBSE approaches allow software engineers to automatically obtain solutions for complex and labor-intensive tasks, contributing to reduce efforts and costs associated to the software development. The SBSE field is growing rapidly in Brazil. The number of published works and research groups has significantly increased in the last three years and a Brazilian SBSE community is emerging. This is mainly due to the Brazilian Workshop on Search Based Software Engineering (WOES), co-located with the Brazilian Symposium on Software Engineering (SBES). Considering these facts, this paper presents results of a mapping we have performed in order to provide an overview of the SBSE field in Brazil. The main goal is to map the Brazilian SBSE community on SBES by identifying the main researchers, focus of the published works, fora and frequency of publications. The paper also introduces SBSE concerns and discusses trends, challenges, and open research problems to this emergent area. We hope the work serves as a reference to this novel field, contributing to disseminate SBSE and to its consolidation in Brazil.

The Software Product Line (SPL) approach is associated with many benefits, and with some challenges too. In the SPL testing, a great challenge is the integration of test methods and techniques with the SPL engineering. To do this, some strategies have been proposed, however, they have not been properly evaluated and compared. In this paper a case study is described comparing three different test strategies: the product by product strategy that tests each product individually; an incremental strategy that tests the products reusing test cases from products previously tested; and a strategy that instantiates test data derived in the domain engineering, considering SPL commonalities and variabilities. In the study an SPL from the games domain was used, and the test data were generated from use cases. The results show that SPL oriented strategies are associated to greater percentages of reuse, and consequently, with lower effort to write test cases.

This paper focuses on the dynamic behaviour of the Fossanova cathedral (Latina, ITALY), which represents a magnificent example of pre-Gothic style church, whose structural typology is largely present in the Mediterranean area, especially in many Countries characterised by a High-Medium seismic hazard. In particular, within the European research project PROHITECH, aiming at investigating the seismic vulnerability of such a structural typology, experimental and numerical analyses have been carried out. Firstly, detailed investigations have been devoted to the identification of the geometry of the main constructional parts as well as of the mechanical features of the constituting materials of the cathedral. Then, both Ambient Vibration Tests (AVT) and Numerical Modal Identification analyses by Finite Element Method (FEM) have been applied, allowing the detection of the main dynamic features. Finally, a refined FEM model reproducing the dynamic behaviour of the cathedral by using scaled physical quantities according to the Buckingham theorem has been developed. In fact, the present study has to be intended as a preliminary activity devoted to se up a shaking table test on a reduced scale physical model of Fossanova cathedral, which will be shortly carried out at the IZIIS laboratory (Skopje, Macedonia).

Background: Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival.Objectives: This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital.Methods: The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal proeB-type natriuretic peptide [NT-pro—BNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality.Results: The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality.Conclusions: Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure.HighlightsOur study followed patients with severe Chagas cardiomyopathy who had a 40% mortality at 1- to 2-years follow-up.For those with severe Chagas cardiomyopathy, the characteristics between those who died and those who survived to follow-up were similar, except body mass index, which was significantly higher among the survivors.BNP, NT-proBNP, CK-MB, and MMP-2 were significantly higher among those that died than in those who survived.

The Product Line Architecture (PLA) design is a complex task, influenced by many factors such as feature modularization and PLA extensibility, which are usually evaluated according to different metrics. Hence, the PLA design is an optimization problem and problems like that have been successfully solved in the Search-Based Software Engineering (SBSE) area, by using metaheuristics such as Genetic Algorithm. Considering this fact, this paper introduces a tool named OPLA-Tool, conceived to provide computer support to a search-based approach for PLA design. OPLA-Tool implements all the steps necessary to use multi-objective optimization algorithms, including PLA transformations and visualization through a graphical interface. OPLA-Tool receives as input a PLA at the class diagram level, and produces a set of good alternative diagrams in terms of cohesion, feature modularization and reduction of crosscutting concerns.

Several projects have been discontinued in the history of the software industry due to the presence of software architecture problems. The identification of such problems in source code is often required in real project settings, but it is a time-consuming and challenging task. Some authors assume that architectural problems are reflected in source code through individual code anomalies. However, each architectural problem may be realized by multiple code anomalies, which are intertwined in several program elements. The relationships of these various code anomalies and their architecture problems’ counterparts are hard to reveal and characterize. To overcome this limitation, we are studying the architecture impact of a wide range of code-anomaly agglomerations. An agglomeration is a group of code anomalies that are explicitly related to each other in the implementation – e.g. two or more anomalies affecting the same class or method in the program. In our empirical study, we analyzed a total of 5418 code anomalies and 2229 agglomerations within 7 systems. In particular, our analysis focused in understanding (i) how agglomerations and architectural problems relate to each other, and (ii) how agglomerations can support the diagnosis of well-known architectural problems. We observed that most of the anomalous code elements related to architectural problems are members of one or more agglomerations. In addition, this study revealed that, for each agglomeration related to an architectural problem, an average of 2 to 4 anomalous code elements contribute to the architectural problem. Finally, the result of our study suggests that certain types of agglomerations are better indicators of architectural problems than others.

The adoption of the layered architectural style can improve the Product Line Architecture (PLA) design by providing a better organization of the elements, flexibility and maintainability. Search based optimization approaches can also benefit the PLA design, by generating PLA alternatives associated with the best trade-offs between different measures (fitness) related to cohesion, coupling and feature modularization. However, the usage of existing search operators changes the PLA organization, and consequently may violate layered rules, impacting negatively in the architecture understanding. In order to solve this problem, this work introduces search operators that consider the layered architectural style rules. Results show that the proposed operators contribute to obtain better solutions, maintaining the adopted style, with better or equivalent fitness values.

Background. We studied women and their infants to evaluate risk factors for congenital transmission and cardiomyopathy in Trypanosoma cruzi–infected women. Methods. Women provided data and blood for serology and quantitative polymerase chain reaction (PCR). Infants of infected women had blood tested at 0 and 1 month by microscopy, PCR and immunoblot, and serology at 6 and 9 months. Women underwent electrocardiography (ECG). Results. Of 1696 women, 456 (26.9%) were infected; 31 (6.8%) transmitted T. cruzi to their infants. Women who transmitted had higher parasite loads than those who did not (median, 62.0 [interquartile range {IQR}, 25.8–204.8] vs 0.05 [IQR, 0–29.6]; P < .0001). Transmission was higher in twin than in singleton births (27.3% vs 6.4%; P = .04). Women who had not lived in infested houses transmitted more frequently (9.7% vs 4.6%; P = .04), were more likely to have positive results by PCR (65.5% vs 33.9%; P < .001), and had higher parasite loads than those who had lived in infested houses (median, 25.8 [IQR, 0–64.1] vs 0 [IQR, 0–12.3]; P < .001). Of 302 infected women, 28 (9.3%) had ECG abnormalities consistent with Chagas cardiomyopathy; risk was higher for older women (odds ratio [OR], 1.06 [95% confidence interval {CI}, 1.01–1.12] per year) and those with vector exposure (OR, 3.7 [95% CI, 1.4–10.2]). We observed a strong dose-response relationship between ECG abnormalities and reported years of living in an infested house. Conclusions. We hypothesize that repeated vector-borne infection sustains antigen exposure and the consequent inflammatory response at a higher chronic level, increasing cardiac morbidity, but possibly enabling exposed women to control parasitemia in the face of pregnancy-induced Th2 polarization.

MOA4PLA is an approach proposed for Product Line Architecture (PLA) design optimization, based on multi-objective algorithms and different metrics that consider specific PLA characteristics. To allow the practical use of MOA4PLA, this paper describes OPLA-Tool, a supporting tool that implements the complete MOA4PLA process. OPLA-Tool has a graphical interface used to choose algorithms, parameters, search operators used in the optimization, and to visualize the alternative PLAs (solutions), with their fitness values associated and corresponding class diagrams. The paper also describes an experiment conducted to evaluate the usefulness of OPLA-Tool. Results show that OPLA-Tool achieves its purpose and that improved solutions are obtained.

Trypanosoma cruzicauses Chagas disease, which affects an estimated 7 million to 8 million people. Chagas disease is endemic throughout Latin America, with the highest prevalence in Bolivia. Conventional diagnosis requires a well-equipped laboratory with experienced personnel. We evaluated the Chagas Detect Plus (CDP) (InBios, Seattle, WA), a rapid immunochromatographic assay for IgG antibodies toT. cruzi. CDP performance was compared to infection status based on results obtained by indirect hemagglutination assay, immunofluorescent-antibody test, and enzyme-linked immunosorbent assay. Confirmed infection required positive results by at least 2 conventional assays. We used specimens from adults of both sexes in a general hospital in the city of Santa Cruz and from pregnant women in a hospital and children in villages in the Bolivian Chaco, an area of hyperendemicity. CDP was performed in paired whole-blood and serum specimens from 385 individuals in the two hospital studies and in 200 serum specimens from the community study. CDP showed sensitivities/specificities of 96.2% (95% confidence interval, 92.7 to 98.4)/98.8% (95.9 to 99.9) in whole blood and 99.3% (97.5 to 99.9)/96.9% (94.2 to 98.6) in serum, with no differences by sex, age group, or study site. CDP showed excellent sensitivity and specificity in our study population, comparable to those of conventional serology. The test is reliable for field surveys, requires no laboratory equipment, and performed well in serum and whole blood. The CDP could also be used for accurate maternal screening to identify neonates at risk of congenital transmission. CDP performance data in diverse geographic areas are needed to strengthen the evidence base for its use.

Background Twenty to thirty percent of persons with Trypanosoma cruzi infection eventually develop cardiomyopathy. If an early indicator were to be identified and validated in longitudinal studies, this could enable treatment to be prioritized for those at highest risk. We evaluated cardiac and extracellular matrix remodeling markers across cardiac stages in T. cruzi infected (Tc+) and uninfected (Tc−) individuals. Methods Participants were recruited in a public hospital in Santa Cruz, Bolivia and assigned cardiac severity stages by electrocardiogram and echocardiogram. BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP-9, TIMP-1, TIMP-2, TGFb1, and TGFb2 were measured in specimens from 265 individuals using multiplex bead systems. Biomarker levels were compared between Tc+ and Tc− groups, and across cardiac stages. Receivers operating characteristic (ROC) curves were created; for markers with area under curve>0.60, logistic regression was performed. Results Analyses stratified by cardiac stage showed no significant differences in biomarker levels by Tc infection status. Among Tc+ individuals, those with cardiac insufficiency had higher levels of BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 than those with normal ejection fraction and left ventricular diameter. No individual marker distinguished between the two earliest Tc+ stages, but in ROC-based analyses, MMP-2/MMP-9 ratio was significantly higher in those with than those without ECG abnormalities. Conclusions BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 levels rose with increasing severity stage but did not distinguish between Chagas cardiomyopathy and other cardiomyopathies. Among Tc+ individuals without cardiac insufficiency, only the MMP-2/MMP-9 ratio differed between those with and without ECG changes., Author Summary In Chagas disease, a parasitic disease found primarily in Central and South America, individuals are chronically infected with the parasite Trypanosoma cruzi. A few decades after initial infection, 20–30% of infected individuals will develop cardiac disease. If we were able to predict which individuals would progress to cardiac disease, treatment in these low resource areas could be targeted to those at highest risk. The ideal transition point to identify those at risk would be as individuals progress from a normal electrocardiogram to an abnormal electrocardiogram, the first step in the progression of cardiac disease. Previous studies have suggested a group of serum biomarkers able to differentiate between these stages of disease. However, our larger and more comprehensive study finds that none of the ten cardiac and remodeling biomarkers we tested are able to distinguish between healthy individuals and those with the earliest evidence of cardiac disease. We did find cardiac biomarkers to be elevated in those with severe cardiac disease as expected in both T. cruzi infected and uninfected individuals.

The Product Line Architecture (PLA) can be improved by taking into account key factors such as feature modularization, and by continuously evaluating its design according to metrics. Search-Based Software Engineering (SBSE) principles can be used to support an informed-design of PLAs. However, existing search-based design works address only traditional software design not considering intrinsic Software Product Line aspects. This paper presents MOA4PLA, a search-based approach to support the PLA design. It gives a multi-objective treatment to the design problem based on specific PLA metrics. A metamodel to represent the PLA and a novel search operator to improve feature modularization are proposed. Results point out that the application of MOA4PLA leads to PLA designs with well modularized features, contributing to improve features reusability and extensibility. It raises a set of solutions with different design trade-offs that can be used to improve the PLA design.

Several projects have been discontinued in the history of the software industry due to the presence of software architecture problems. The identification of such problems in source code is often required in real project settings, but it is a time-consuming and challenging task. Some authors assume that architectural problems are reflected in source code through individual code anomalies. However, each architectural problem may be realized by multiple code anomalies, which are intertwined in several program elements. The relationships of these various code anomalies and their architecture problems' counterparts are hard to reveal and characterize. In fact, there is little knowledge about the manifestation of code-anomaly agglomerations in software projects and when they adversely impact (or not) the software architecture. To overcome this limitation, we propose studying the architecture impact of a wide range of code-anomaly agglomerations. An agglomeration is a group of code anomalies that are related to each other for some reason -- e.g. all of them affect syntactically-related code elements in the program. In our study, we analyzed a total of 5418 code anomalies and 2229 agglomerations within 7 systems. We observed that architectural problems are much more often reflected as anomaly agglomerations rather than individual anomalies in the source code. More importantly, we also revealed when code-anomaly agglomerations were (or not) good indicators of architectural problems. For instance, the result of our study suggests that certain topologies of code-anomaly agglomerations are better indicators than others.

The Product Line Architecture (PLA) design is a multi-objective optimization problem that can be properly solved in the Search Based Software Engineering (SBSE) field. However, the PLA design has specific characteristics. For example, the PLA is designed in terms of features and a highly modular PLA is necessary to enable the growth of a software product line. However, existing search based design approaches do not consider such needs. To overcome this limitation, this paper introduces a feature-driven crossover operator that aims at improving feature modularization. The proposed operator was applied in an empirical study using the multi-objective evolutionary algorithm named NSGAII. In comparison with another version of NSGAII that uses only mutation operators, the feature-driven crossover version found a greater diversity of solutions (potential PLA designs), with higher feature-based cohesion, and less feature scattering and tangling.

Research communities evolve over time, changing their interests for specific problems or research areas. Mapping the evolution of a research community, including the most frequently addressed problems, the strategies selected to propose solution for them, the venues on which results observed from applying these strategies are published, and the collaboration among distinct groups may provide lessons on actions that can positively influence the growth of research in a given field. To this end, this paper presents an analysis of the Brazilian SBSE research community. We present our major research groups focusing on the field, the software engineering problems most addressed by them, the search techniques most frequently used to solve these problems, and an analysis of our publications and collaboration. We could conclude that the Brazilian community is still expanding, both geographically and in terms of publications, and that the creation of a national workshop focusing on the research field was a keystone to allow this growth.

The determination of an order for integration and testing of aspects and classes is a difficult optimization problem. This order should be associated to a minimal possible stubbing cost. To determine such order, different approaches exist. For example, traditional approaches are based on Tarjan’s algorithm; search-based approaches are based on metaheuristics, usually genetic algorithms (GA). In addition to such approaches, in the literature, there are different strategies to integrate aspect-oriented software. Some works suggest the integration of aspects and classes in a combined way. Other ones adopt an incremental strategy. Studies evaluating the approaches show that the multi-objective one presents better solutions. However, these studies were conducted applying only the combined strategy. In this paper, we present experimental results comparing both strategies with three different approaches: the traditional one, a simple GA-based, and a multi-objective one. The results show better performance of the multi-objective approach independently of the strategy adopted. A comparison of both strategies points out that the incremental strategy reaches a lower cost in most cases, considering a number of attributes and operations to be emulated in the stub. It seems that with Incremental+, the best choice is the multi-objective approach. If the system is very complex, PAES seems to be the best MOEA.

The application of design patterns through mutation operators in search-based design may improve the quality of the architectures produced in the evolution process. However, we did not find, in the literature, works applying such patterns in the optimization of Product Line Architecture (PLA). Existing works offer manual approaches, which are not search-based, and only apply specific patterns in particular domains. Considering this fact, this paper introduces a meta-model and a mutation operator to allow the design patterns application in the search-based PLA design. The model represents suitable scopes, that is, set of architectural elements that are suitable to receive a pattern. The mutation operator is used with a multi-objective and evolutionary approach to obtain PLA alternatives. Quantitative and qualitative analysis of empirical results show an improvement in the quality of the obtained solutions.

Design patterns have been successfully applied in the Search Based Software Engineering (SBSE) field to improve software architectures regarding some design principles, such as cohesion, coupling and reusability. However, we did not find, in the SBSE literature, approaches exploring the application of design patterns in software Product Line Architectures (PLAs). In this sense, this paper presents results from a feasibility analysis, conducted with GoF (Gang of Four) patterns, to verify their applicability in the context of a search-based approach for PLA design. The analysis considered the pattern structure, consequences of use according to some architectural metrics, flexibility and automation aspects. As a result, this paper also introduces a metamodel representation for scopes that are suitable to receive the design patterns application.

Subtle morphological changes and molecular alterations have been reported in normal-appearing tissue in prostates with high-grade prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa). The severity and the distribution of these changes and alterations within the prostate gland have not been addressed in previous publications. The aim of this study was to investigate morphometrically the nuclear changes of the normal-looking columnar epithelium adjacent to and distant from high-grade PIN and PCa. Karyometry was performed on the whole-mount histological sections of three radical prostatectomy (RP) specimens. Two concentrical lines, one corresponding to the outer surface (or capsule) of the prostate and the other corresponding to one centimeter towards the center, were drawn with a black pen on each whole-mount section. The part of the prostate tissue between these two boundaries was then divided into twelve equal sectors or regions. The part within the inner line was divided into two regions. The analysis was also performed on the slides of the apex and base of the prostate. One prostate contained normal-looking epithelium only (case no. 1). Another contained both high-grade PIN and PCa, the former occupying larger areas than the latter (case no. 2). Both high-grade PIN and PCa were present in the third sample, in which PCa was more widely distributed than PIN (case no. 3). The lesion measured in each region was always the most severe, e.g., either high-grade PIN or PCa. When neither were identifiable, then the normal-looking columnar epithelium was analyzed. For each sector, the mean and standard deviation of the nuclear area, maximum nuclear diameter, nuclear roundness factor, and nucleolar area were calculated. In normal-looking columnar epithelium, the mean of the mean nuclear area of the sectors of case no. 1 was 35.19 µm2 (SD 4.14). The mean nuclear areas in cases no. 2 and no. 3 were 37.94 µm2 (SD 4.65) and 37.31 µm2 (SD 4.36), respectively. The mean of the mean nuclear area of the sectors with high-grade PIN of case no. 2 was 49.85 µm2 (SD 8.44), whereas it was 54.26 µm2 (SD 2.91) in case no. 3. The mean of the nuclear area values obtained in the sectors of cases no. 2 and no. 3 with PCa was 56.74 µm2 (SD 6.56) and 61.17 µm2 (SD 8.13), respectively. When considering the normal-looking tissue of the second and third case, 79% and 90%, respectively, of the regions showed nuclear area values greater than 34.94 µm2 (e.g., the 50th percentile of the mean nuclear area values of the regions of the first case). Sectors with normal-looking epithelium, whose nuclear area was above this threshold, were both adjacent to and at a distance of more than 1 cm from those with PIN or PCa. The other nuclear features showed a similar trend of value changes. This study demonstrates that the normal-looking ducts and acini from prostate harboring preneoplastic and neoplastic lesions show morphological nuclear abnormalities that are not seen by the human eyes but that can be detected with image analysis. Such changes may be of diagnostic importance, especially in cases where clinical suspicion for cancer prevails after a negative biopsy.

Various grading systems have been proposed for renal cell carcinoma (RCC), using nuclear, cytoplasmic, and architectural features. The available evidence suggests that nuclear grading is a better prognostic indicator than other types of grading schemes. Nuclear morphometry may still improve the correlation of the nuclear grading with survival, however, because observer consistency is lacking in the subjective grading of RCC. The aim of this study was to investigate morphometrically whether RCC cases show a continuous spectrum of nuclear changes or whether there are discrete groups of cancer that correspond to the four Fuhrman grades. Karyometry was performed on 5- µm-thick, haematoxylin- and eosin-stained sections from 60 cases of conventional (clear cell) RCC. The analysis also included the evaluation of normal renal tissue (proximal tubules) adjacent to cancer. In each case the difference between the value of the cancer and the corresponding normal epithelium was calculated to represent, quantitatively, the degree of similarity between the tumour tissue and the internal normal control. When the differences were sorted into ascending order, a steady increase in values was observed for both the nuclear and the nucleolar features. A monotonic trend was evident for the differences in the mean maximum nuclear diameter and mean nucleolar area. When the differences between the values in the cancer and in the corresponding normal epithelium of these two features were summed up, the method resulted in a continuous variable, or nuclear morphometric index, related to the degree of deviation of each individual RCC from its internal normal control. The lowest index values were observed in of Fuhrman grade I cases, whereas values ranging from 2.679 to 5.422 were associated with cases graded II. Values equal to or higher than 5.951 were seen in the cases assigned to either grade III or grade IV. Partial overlap was present between the index values in grades III and IV. The RCC cases can be represented by a continuous index that corresponds to the morphological grading based on the Fuhrman scheme. This study shows that the index may be useful in supplementing the pathologist’s grading. This issue can be further addressed with follow-up studies.

OBJECTIVE: To develop a distance measure based methodology to support the morphological evaluation of high grade prostatic intraepithelial neoplasia (PIN), a direct precursor of prostate cancer. METHODS: Eight morphological and cellular features were analysed in 20 cases of high grade PIN found in radical prostatectomy specimens from patients with adenocarcinoma. The diagnostic distance was evaluated to measure the extent to which the feature outcomes of the individual high grade PIN cases differed from the expected outcome profile of normal prostate, low and high grade PIN, and cribriform and large acinar adenocarcinoma. The belief value for high grade PIN was evaluated with a Bayesian belief network (BBN). RESULTS: Complete separation existed between the cumulative absolute diagnostic distances of these 20 cases from the prototype feature outcomes of high grade PIN and normal prostate the values for which were < or = 3 (range 0 to 3) and > or = 9 (range 9 to 15), respectively. The distances from low grade PIN (range 3 to 9), cribriform adenocarcinoma (range 2 to 8), and large acinar adenocarcinoma (range 5 to 10) were intermediate and showed overlap in their distribution. When taking into consideration whether the severity of feature changes was increasing or decreasing in comparison with the category prototype outcomes, the cumulative directional diagnostic distances from high grade PIN ranged from -3 to +3. Positive distance values were seen relative to low grade PIN (range +3 to +9) and relative to normal prostate (range +9 to +15). Negative values were found relative to cribriform adenocarcinoma (range -8 to +2). The distance values from large acinar adenocarcinoma ranged from -2 to +4 and partly overlapped with those from the high grade PIN category. A bivariate scattergram derived from both diagnostic distance measures showed excellent separation between the groups' distances. BBN analysis confirmed the morphology based diagnosis. The distance evaluation resulted in 18 cases whose belief value for high grade PIN ranged from 0.60 to 0.87. In the remaining two cases the results of the BBN analysis showed a belief value of 0.50 and 0.57 for low grade PIN and of 0.49 and 0.38 for high grade PIN, respectively. CONCLUSIONS: Distance measure based methodology represents a useful diagnostic decision support tool for the accurate evaluation of high grade PIN.

During the integration test of aspect-oriented software, it is necessary to determine an aspect-class integration and test order, associated to a minimal possible stubbing cost. To determine such optimal orders an approach based on multi-objective evolutionary algorithms was proposed. It generates a set of good orders with a balanced compromise among different measures and factors that may influence the stubbing process. However, in the literature there are different strategies proposed to aspect-class integration. For instance, the classes and aspects can be integrated in a combined strategy, or in an incremental way. The few works evaluating such strategies do not consider the multi-objective and coupling based approach. Given the importance of such approach to reduce testing efforts, in this work, we conduct an empirical study and present results from the application of the multi-objective approach with both mentioned strategies. The approach is implemented with four coupling measures and three evolutionary algorithms that are also evaluated: NSGA-II, SPEA2 and PAES. We observe that different strategies imply in different ways to explore the search space. Moreover, other results related to the practical use of both strategies are presented.

A product-line architecture (PLA) entails a design reused by a family of products sharing several features. The long-term stability of a PLA largely depends on the modularization of each feature from the design outset. As many features of a product-line crosscut the PLA decomposition, their modularity and stability are often improved with aspect-orientation according to recent studies. However, the use of this technique in proactive design of PLAs is challenging and has rarely been investigated. The problem is that information about the crosscutting nature of features is limited in this case. This paper presents a first study aimed at analyzing the feasibility of deriving stable aspect-oriented PLAs through a proactive design method. Our study relies on a product line and presents an in-depth exploratory analyse. We compare the stability of aspect-oriented and alternative candidates for proactively-designed PLAs. The results indicate that it is possible to derive aspect-oriented PLAs with superior stability based on a proactive design method. In addition, it is possible to anticipate pros and cons of PLAs with aspects when the latter are incorporated at an early design stage.