Combining unit and specification-based testing for meta-model validation and verification

This is the author’s version of a work that was accepted for publication in Information Systems. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Information Systems, VOL 62, (2016)] DOI 10.1016/j.is.2016.06.008Meta-models play a cornerstone role in Model-Driven Engineering as they are used to define the abstract syntax of modelling languages, and so models and all sorts of model transformations depend on them. However, there are scarce tools and methods supporting their Validation and Verification (V&V), which are essential activities for the proper engineering of meta-models. In order to fill this gap, we propose two complementary meta-model V&V languages. The first one has similar philosophy to the xUnit framework, as it enables the definition of meta-model unit test suites comprising model fragments and assertions on their (in-)correctness. The second one is directed to express and verify expected properties of a meta-model, including domain and design properties, quality criteria and platform-specific requirements. As a proof of concept, we have developed tooling for both languages in the Eclipse platform, and illustrate its use within an example-driven approach for meta-model construction. The expressiveness of our languages is demonstrated by their application to build a library of meta-model quality issues, which has been evaluated over the ATL zoo of meta-models and some OMG specifications. The results show that integrated support for meta-model V&V (as the one we propose here) is urgently needed in meta-modelling environments.This work has been funded by the Spanish Ministry of Economy and Competitivity with project “Flexor” (TIN2014-52129-R), the region of Madrid with project “SICOMORO-CM” (S2013/ICE-3006), and the EU commission with project “MONDO” (FP7- ICT-2013-10, #611125)

Example-driven meta-model development

The final publication is available at Springer via http://dx.doi.org/10.1007/s10270-013-0392-yThe intensive use of models in model-driven engineering (MDE) raises the need to develop meta-models with different aims, such as the construction of textual and visual modelling languages and the specification of source and target ends of model-to-model transformations. While domain experts have the knowledge about the concepts of the domain, they usually lack the skills to build meta-models. Moreover, meta-models typically need to be tailored according to their future usage and specific implementation platform, which demands knowledge available only to engineers with great expertise in specific MDE platforms. These issues hinder a wider adoption of MDE both by domain experts and software engineers. In order to alleviate this situation, we propose an interactive, iterative approach to meta-model construction, enabling the specification of example model fragments by domain experts, with the possibility of using informal drawing tools like Dia or yED. These fragments can be annotated with hints about the intention or needs for certain elements. A meta-model is then automatically induced, which can be refactored in an interactive way, and then compiled into an implementation meta-model using profiles and patterns for different platforms and purposes. Our approach includes the use of a virtual assistant, which provides suggestions for improving the meta-model based on well-known refactorings, and a validation mode, enabling the validation of the meta-model by means of examples.This work has been funded by the Spanish Ministry of Economy and Competitivity with project “Go Lite” (TIN2011-24139), and by the R&D programme of Madrid Region with project “eMadrid” (S2009/TIC-1650)

Engaging end-users in the collaborative development of domain-specific modelling languages

The final publication is available at Springer via http://dx.doi.org/10.1007/978-3-642-40840-3_16Proceedings of 10th International Conference, CDVE 2013, Alcudia, Mallorca, Spain, September 22-25, 2013Domain-Specific Modelling Languages (DSMLs) are high-level languages specially designed to perform tasks in a particular domain. When developing DSMLs, the participation of end-users is normally limited to providing domain knowledge and testing the resulting language prototypes. Language developers, which are perhaps not domain experts, are therefore in control of the language development and evolution. This may cause misinterpretations which hamper the development process and the quality of the DSML. Thus, it would be beneficial to promote a more active participation of end-users in the development process of DSMLs. While current DSML workbenches are mono-user and designed for technical experts, we present a process and tool support for the example-driven, collaborative construction of DSMLs in order to engage end-users in the creation of their own languages.This work was funded by the Spanish Ministry of Economy and Competitivity (project “Go Lite” TIN2011-24139), the R&D programme of the Madrid Region (project “e-Madrid” S2009/TIC-1650) and the European Commission under the ICT Policy Support Programme, grant no. 317859

Vulvar High-Grade Squamous Intraepithelial Lesions Treated with Imiquimod: Can Persistence of Human Papillomavirus Predict Recurrence?

Simple Summary Vulvar high-grade intraepithelial lesion (vulvar HSIL) is a premalignant vulvar condition that requires intervention, usually surgery. It recurs frequently, and its treatment involves repeated disfiguring surgeries. Vulvar HSIL is associated with human papillomavirus. Imiquimod is a medical treatment option currently attracting attention because vulvar high-grade intraepithelial neoplasia is frequent in young women with multiple vulvar lesions. Few studies have evaluated the long-term effects of the response to imiquimod and the association of human papillomavirus with response and recurrence. We describe a retrospective (with cases already treated) study designed to determine the long-term response to imiquimod in patients with vulvar HSIL, and also to analyze the role of human papillomavirus (HPV), and different HPV types, in the persistence or recurrence of vulvar HSIL after imiquimod treatment. Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod in a cohort of patients with vulvar HSIL and (2) and to analyze the role of HPV determined in pre- and post-imiquimod treatment biopsies in the persistence or recurrence of vulvar HSIL. Design: Retrospective study between 2011 and 2022. Setting: Referrals from the primary care area of Baix Llobregat treated in the gynecology department of a university hospital in Barcelona, Spain. Population: 20 women with vulvar HSIL treated with imiquimod. Methods: The inclusion criteria were vulvar HSIL, vulvar HPV determination by pre- and post-treatment biopsy, acceptance of medical treatment, at least one follow-up and 4 weeks of treatment. Main outcome measures: Histological diagnosis of vulvar HSIL with pre- and post-imiquimod HPV determination. Response to treatment (complete, partial, no response, recurrence). Results: After imiquimod, 10 (50%) and 6 (30%) cases had complete and partial responses, respectively. Another 4 cases (20%) did not respond. Before treatment, 19 (95%) cases were positive for vulvar HPV (16 cases had HPV type 16). After treatment, 10 cases (50%) were positive for HPV (8 cases with HPV type 16): 2 cases (20%) with a complete response, 5 cases (83.3%) with a partial response and 3 cases (75%) with no response. Eight of the 10 HPV-negative cases (80%) post-treatment showed a complete response. HPV type 16 was present in 16 cases (84.2%) pre-treatment and in 8 cases (80%) post-treatment. Ten patients underwent additional treatments following a partial response, no response or recurrence. The 2 HIV and 3 immunosuppressed patients treated with imiquimod showed a partial response and required additional treatment. All these patients were HPV-positive pre- and post-treatment (100%). Response to imiquimod was associated with post-treatment vulvar HPV positivity (p = 0.03). The median time to a complete response in HPV-negative cases was 4.7 months versus 11.5 months in HPV-positive cases post-imiquimod treatment. Recurrence of vulvar HSIL was observed in 7 patients (35%), with a median time to recurrence of 19.7 months (range 3.2-32.7). Recurrence was experienced in 10% of cases with a complete response, in 4/6 (66.6%) cases with a partial response, and in 2/4 (50%) women with no response. Four of the 7 recurrent cases (57%) were infected with HIV or immunosuppressed. Six (85%) of the recurrent cases were HPV-positive post-treatment (all were HPV type 16). Four (30.7%) of the non-recurrent cases were HPV-positive post-treatment with imiquimod (p = 0.05), two of which were HPV type 16 (50%). Conclusions: Imiquimod effectively treats vulvar HSIL. Cases with a complete response showed less HPV positivity post-treatment than partial or non-response cases. Recurrences were more frequent in those with a partial or no response to imiquimod, and in immunosuppressed patients. In recurrent cases, 85% were HPV-positive post-treatment, while 30.7% of non-recurrent cases were HPV-positive. HPV positivity in the post-treatment biopsy suggests the need for stricter follow-up of patients

DIGITALIZACIÓN DE LA CADENA DE SUMINISTRO Y LA COMPETITIVIDAD DE LAS EMPRESAS PERUANAS DEL SECTOR MINORISTA.

Las empresas están adoptando un paradigma de comercialización contemporáneo conocido como desarrollo ágil en respuesta a los cambios en el sector minorista. Se considera un enfoque sólido en un mercado tremendamente competitivo, con necesidades cambiantes de los clientes y mejoras sustanciales en la competitividad. Retail 4.0, se define como un meta concepto para mejorar aún más el desarrollo y construir estructuras de valor conectando el mundo físico con el entorno digital y juega una función vital en la simplificación de las redes de Internet. El presente estudio se centra en la tecnología moderna y el vínculo entre las máquinas y el contacto entre todos los elementos de la cadena de suministro, también conocido como producción digital. La cuarta revolución tecnológica es esta tecnología moderna, considerada como Internet de las cosas. Además, después de una muestra de más de 800 encuestados, se obtienen 579 respuestas, la consulta incorporaría un enfoque cuantitativo. La prueba se evaluó mediante el software estadístico SPSS y se utilizó el análisis de regresión para verificar las hipótesis. Los hallazgos indican que la digitalización y la cadena de distribución en la industria minorista tienen una conexión directa con la competitividad en el sector retail peruano

Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer

Background: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. Methods: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. Results: We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1- and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1- or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. Conclusions: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity

EducaFarma 4.0

Memoria ID-0264. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2015-2016

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Purpose: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. Methods: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. Results: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. Conclusion: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]