Patterns of brain atrophy in dysexecutive amnestic mild cognitive impairment raise confidence about prodromal AD dementia

Background: Prediction models aimed at detecting risk of progression from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) dementia increase their accuracy when impaired executive functions enter the analysis. This suggests that impaired executive functions in MCI are likely linked to the prodromal stages of AD dementia. Neuroimaging assessment of such patients would allow exploring if they show AD related patterns of brain atrophy. We hypothesized that AD sensitive brain regions would show discrimination between dysexecutive amnestic MCI (maMIC) and healthy controls. Method: We analysed 32 healthy controls and 23 MCI patients. Patients were divided in single domain amnestic MCI, multidomain amnestic MCI (i.e., with the dysexecutive component), and non-amnestic MCI. Brain volume data entered regression models to analyse which brain regions predict group membership (control vs maMCI). Stepwise lineal regression model was then conducted to identify the brain regions with better prediction power. Results: Four variables were able to predict group membership in simple lineal regression models: entorhinal cortex, lingual gyrus and parahippocampal gyrus in the left hemisphere and fusiform gyrus in the right hemisphere. The entorhinal cortex provided the most accurate model (F(1, 42) = 14.19, p=0.001, R2=0.24). Linear regression models were run with performance on executive function tasks including tests of switching, planning, verbal fluency and working memory. The most accurate model returned Letters and Numbers and categories fluency (F(2, 44) = 21.35, p=0.000, R2=0.48) suggesting that working memory and category generation are the functions contributing to the dysexecutive profiles observed in maMCI patients. Conclusion: Dysexecutive profiles in multidomain amnestic MCI together with neuroimaging volumetric analysis increase the probability of identifying the prodromal stages of AD dementia

Role of executive functions in the conversion from mild cognitive impairment to dementia

BACKGROUND: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI) to dementia in Alzheimer's clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). OBJECTIVE: The present study analyzes the contributions of executive functions to predict MCI-dementia progression in ACS. METHODS: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. RESULTS: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI-dementia conversion, even after controlling for the severity of MCI at baseline (F(1, 68) = 116.25, p = 0.000, R2 = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F(1, 68) = 5.09, p = 0.955, R2 = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. CONCLUSION: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia

Minimizing the Impact of Large Freight Vehicles in the City: A Multicriteria Vision for Route Planning and Type of Vehicles

The impact of freight transport in cities is significant, and as such correct planning and management thereof help reduce their enormous negative impact. Above all, the special large vehicles have a greater impact than the remainder of freight vehicles, so a special attention should be paid to them.The vehicles which supply or pick up large amounts of goods at specific points throughout the city are an example of this type of vehicles.Theaimof this paper is to minimize the cost of this freight transport type froma social, economic, and environmental viewpoint. To this effect, an optimization model has been proposed based on bilevel mathematical programming which minimizes the total system costs. City networkmodel data are obtained on the lower level such as vehicle flow and travelling times, which are then used on the upper level to calculate total system costs.The model has been applied to a real case in Santander (Spain), whose final result shows the size and typology of the fleet of vehicles necessary to have the least impact on the city.The greater the vehicles size is (i.e., using fewer trucks), the less the cost of the freight transport is

Impact of CD68/(CD3+CD20) Ratio at the Invasive Front of Primary Tumors on Distant Metastasis Development in Breast Cancer

Tumors are infiltrated by macrophages, T and B-lymphocytes, which may favor tumor development by promoting angiogenesis, growth and invasion. The aim of this study was to investigate the clinical relevance of the relative amount of macrophages (CD68⁺), T-cells (CD3⁺ and B-cells (CD20⁺) at the invasive front of breast carcinomas, and the expression of matrix metalloproteases (MMPs) and their inhibitors (TIMPs) either at the invasive front or at the tumor center. We performed an immunohistochemical study counting CD3, CD20 and CD68 positive cells at the invasive front, in 102 breast carcinomas. Also, tissue sections were stained with MMP-2, -9, -11, -14 and TIMP-2 antibodies, and immunoreactivity location, percentage of reactive area and intensity were determined at the invasive front and at the tumor center. The results showed that an increased CD68 count and CD68/(CD3+CD20) ratio were directly associated with both MMP-11 and TIMP-2 expression by mononuclear inflammatory cells at the tumor center (p = 0.041 and p = 0.025 for CD68 count and p = 0.001 and p = 0.045 for ratio, respectively for MMP-11 and TIMP-2). In addition, a high CD68/(CD3+CD20) ratio (>0.05) was directly associated with a higher probability of shortened relapse-free survival. Multivariate analysis revealed that CD68/(CD3+CD20) ratio was an independent factor associated with distant relapse-free survival (RR: 2.54, CI: (1.23-5.24), p<0.01). Therefore, CD68/(CD3+CD20) ratio at the invasive front could be used as an important prognostic marker

fiabilidad intraexaminador y criterio de validez de una aplicación de smartphone para medir el test de flexión rotación en la columna cervical en sujetos asintomáticos

Introducción: actualmente los Smartphones contienen aplicaciones que pueden realizar la función de diversos instrumentos de medición. El objetivo fue estudiar la validez y fiabilidad intraexaminador de la aplicación Compass, en la medición del test de flexión-rotación en la columna cervical en sujetos asintomáticos. Material y método: la muestra estuvo formada por 42 sujetos asintomáticos. Se valoró el rango de movimiento del test de flexión-rotación cervical en dos ocasiones mediante la aplicación Compass y con el instrumento Cervical Range of Motion. Se calculó el coeficiente de correlación intraclase para obtener la fiabilidad y validez. Resultados: se observó una fiabilidad intra-examinador excelente en la medición del test de flexión-rotación mediante la aplicación Compass con un valor del coeficiente de correlación intraclase de 0,94. El valor para la validez de la aplicación Compass, en la medición del test de flexión-rotación en personas asintomáticas fue de 0,87 con un índice de kappa de 0,533. Discusión: además de la validez y fiabilidad demostrada, se trata de una herramienta muy económica y accesible para la valoración de la movilidad en el test de flexión-rotación. No obstante, para usar Compass como instrumento de medición en la práctica clínica, se debería realizar el estudio sobre pacientes con problemas en la columna cervical. Conclusiones: se encontró una fiabilidad intra-examinador excelente para la aplicación Compass en la medición del test de flexión-rotación en pacientes asintomáticos. Cuando se comparó con el Cervical Range Of Motion, esta aplicación mostró buena validez. Introduction: Nowadays we have Smartphones, applications that can carry out the functions of other measuring instruments. The purpose of this study was to analyze the intra-rater reliability as well as the criterion validity of the Compass app in measuring cervical flexion-rotation test in cervical spine in asymptomatic subjects. Material and method: The sample was 42 asymptomatic subjects. One examiner measured the range of motion in the cervical flexion-rotation test of each patient twice using Compass app and afterwards twice using the Cervical Range of Motion device. In order to calculate the intra-rater reliability and the criterion validity we used the intraclass correlation coefficient. Results: Excellent intra-rater reliability was observed for the cervical flexion-rotation test using Compass app and the value of intraclass correlation coefficient was 0.94. For the criterion validity of Compass app, the value of the intraclass correlation coefficient was 0.87 and the value of the kappa index was 0.533. Discussion: Apart from the shown reliability and validity, Compass is an economical and available tool to measure the range of movement of the flexion rotation test. However, for using Compass as a measurement instrument in the clinic, we should carry out the study in patients who have cervical dysfunctions. Conclusions: We found excellent intra-rater reliability for Compass to measure the flexion rotation test in healthy patients. When we compared Compass to Cervical Range of Motion, this app showed good validit

Siesta: Recent developments and applications

A review of the present status, recent enhancements, and applicability of the SIESTA program is presented. Since its debut in the mid-1990s, SIESTA’s flexibility, efficiency, and free distribution have given advanced materials simulation capabilities to many groups worldwide. The core methodological scheme of SIESTA combines finite-support pseudo-atomic orbitals as basis sets, norm-conserving pseudopotentials, and a realspace grid for the representation of charge density and potentials and the computation of their associated matrix elements. Here, we describe the more recent implementations on top of that core scheme, which include full spin–orbit interaction, non-repeated and multiple-contact ballistic electron transport, density functional theory (DFT)+U and hybrid functionals, time-dependent DFT, novel reduced-scaling solvers, density-functional perturbation theory, efficient van der Waals non-local density functionals, and enhanced molecular-dynamics options. In addition, a substantial effort has been made in enhancing interoperability and interfacing with other codes and utilities, such as WANNIER90 and the second-principles modeling it can be used for, an AiiDA plugin for workflow automatization, interface to Lua for steering SIESTA runs, and various post-processing utilities. SIESTA has also been engaged in the Electronic Structure Library effort from its inception, which has allowed the sharing of various low-level libraries, as well as data standards and support for them, particularly the PSeudopotential Markup Language definition and library for transferable pseudopotentials, and the interface to the ELectronic Structure Infrastructure library of solvers. Code sharing is made easier by the new open-source licensing model of the program. This review also presents examples of application of the capabilities of the code, as well as a view of on-going and future developments. Published under license by AIP Publishing.Siesta development was historically supported by different Spanish National Plan projects (Project Nos. MEC-DGES-PB95-0202, MCyT-BFM2000-1312, MEC-BFM2003-03372, FIS2006-12117, FIS2009-12721, FIS2012-37549, FIS2015-64886-P, and RTC-2016-5681-7), the latter one together with Simune Atomistics Ltd. We are thankful for financial support from the Spanish Ministry of Science, Innovation and Universities through Grant No. PGC2018-096955-B. We acknowledge the Severo Ochoa Center of Excellence Program [Grant Nos. SEV-2015-0496 (ICMAB) and SEV-2017-0706 (ICN2)], the GenCat (Grant No. 2017SGR1506), and the European Union MaX Center of Excellence (EU-H2020 Grant No. 824143). P.G.-F. acknowledges support from Ramón y Cajal (Grant No. RyC-2013-12515). J.I.C. acknowledges Grant No. RTI2018-097895-B-C41. R.C. acknowledges the European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodoswka-Curie Grant Agreement No. 665919. D.S.P, P.K., and P.B. acknowledge Grant No. MAT2016-78293-C6, FET-Open No. 863098, and UPV-EHU Grant No. IT1246-19. V. W. Yu was supported by a MolSSI Fellowship (U.S. NSF Award No. 1547580), and V.B. and V.W.Y. were supported by the ELSI Development by the NSF (Award No. 1450280). We also acknowledge Honghui Shang and Xinming Qin for giving us access to the honpas code, where a preliminary version of the hybrid functional support described here was implemented. We are indebted to other contributors to the Siesta project whose names can be seen in the Docs/Contributors.txt file of the Siesta distribution, and we thank those, too many to list, contributing fixes, comments, clarifications, and documentation for the code.Peer reviewe

Siesta: Recent developments and applications

A review of the present status, recent enhancements, and applicability of the Siesta program is presented. Since its debut in the mid-1990s, Siesta?s flexibility, efficiency, and free distribution have given advanced materials simulation capabilities to many groups worldwide. The core methodological scheme of Siesta combines finite-support pseudo-atomic orbitals as basis sets, norm-conserving pseudopotentials, and a real-space grid for the representation of charge density and potentials and the computation of their associated matrix elements. Here, we describe the more recent implementations on top of that core scheme, which include full spin?orbit interaction, non-repeated and multiple-contact ballistic electron transport, density functional theory (DFT)+U and hybrid functionals, time-dependent DFT, novel reduced-scaling solvers, density-functional perturbation theory, efficient van der Waals non-local density functionals, and enhanced molecular-dynamics options. In addition, a substantial effort has been made in enhancing interoperability and interfacing with other codes and utilities, such as wannier90 and the second-principles modeling it can be used for, an AiiDA plugin for workflow automatization, interface to Lua for steering Siesta runs, and various post-processing utilities. Siesta has also been engaged in the Electronic Structure Library effort from its inception, which has allowed the sharing of various low-level libraries, as well as data standards and support for them, particularly the PSeudopotential Markup Language definition and library for transferable pseudopotentials, and the interface to the ELectronic Structure Infrastructure library of solvers. Code sharing is made easier by the new open-source licensing model of the program. This review also presents examples of application of the capabilities of the code, as well as a view of on-going and future developments.SIESTA development was historically supported by different Spanish National Plan projects (Project Nos. MEC-DGES-PB95-0202, MCyT-BFM2000-1312, MEC-BFM2003-03372, FIS2006-12117, FIS2009-12721, FIS2012-37549, FIS2015-64886-P, and RTC-2016-5681-7), the latter one together with Simune Atomistics Ltd. We are thankful for financial support from the Spanish Ministry of Science, Innovation and Universities through Grant No. PGC2018-096955-

EoE CONNECT, the European Registry of Clinical, Environmental, and Genetic Determinants in Eosinophilic Esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe

Background: The growing prevalence of eosinophilic esophagitis (EoE) represents a considerable burden to patients and health care systems. Optimizing cost-effective management and identifying mechanisms for disease onset and progression are required. However, the paucity of large patient cohorts and heterogeneity of practice hinder the defining of optimal management of EoE. Methods: EoE CONNECT is an ongoing, prospective registry study initiated in 2016 and currently managed by EUREOS, the European Consortium for Eosinophilic Diseases of the Gastrointestinal Tract. Patients are managed and treated by their responsible specialists independently. Data recorded using a web-based system include demographic and clinical variables; patient allergies; environmental, intrapartum, and early life exposures; and family background. Symptoms are structurally assessed at every visit; endoscopic features and histological findings are recorded for each examination. Prospective treatment data are registered sequentially, with new sequences created each time a different treatment (active principle, formulation, or dose) is administered to a patient. EoE CONNECT database is actively monitored to ensure the highest data accuracy and the highest scientific and ethical standards. Results: EoE CONNECT is currently being conducted at 39 centers in Europe and enrolls patients of all ages with EoE. In its aim to increase knowledge, to date EoE CONNECT has provided evidence on the effectiveness of first- and second-line therapies for EoE in clinical practice, the ability of proton pump inhibitors to induce disease remission, and factors associated with improved response. Drug effects to reverse fibrous remodeling and endoscopic features of fibrosis in EoE have also been assessed. Conclusion: This prospective registry study will provide important information on the epidemiological and clinical aspects of EoE and evidence as to the real-world and long-term effectiveness and safety of therapy. These data will potentially be a vital benchmark for planning future EoE health care services in Europe

Accurate and timely diagnosis of Eosinophilic Esophagitis improves over time in Europe. An analysis of the EoE CONNECT Registry

BACKGROUND: Poor adherence to clinical practice guidelines for eosinophilic esophagitis (EoE) has been described and the diagnostic delay of the disease continues to be unacceptable in many settings. OBJECTIVE: To analyze the impact of improved knowledge provided by the successive international clinical practice guidelines on reducing diagnostic delay and improving the diagnostic process for European patients with EoE. METHODS: Cross‐sectional analysis of the EoE CONNECT registry based on clinical practice. Time periods defined by the publication dates of four major sets of guidelines over 10 years were considered. Patients were grouped per time period according to date of symptom onset. RESULTS: Data from 1,132 patients was analyzed and median (IQR) diagnostic delay in the whole series was 2.1 (0.7‐6.2) years. This gradually decreased over time with subsequent release of new guidelines (p < 0.001), from 12.7 years up to 2007 to 0.7 years after 2017. The proportion of patients with stricturing of mixed phenotypes at the point of EoE diagnosis also decreased over time (41.3% vs. 16%; p < 0.001), as did EREFS scores. The fibrotic sub‐score decreased from a median (IQR) of 2 (1‐2) to 0 (0‐1) when patients whose symptoms started up to 2007 and after 2017 were compared (p < 0.001). In parallel, symptoms measured with the Dysphagia Symptoms Score reduced significantly when patients with symptoms starting before 2007 and after 2012 were compared. A reduction in the number of endoscopies patients underwent before the one that achieved an EoE diagnosis, and the use of allergy testing as part of the diagnostic workout of EoE, also reduced significantly over time (p = 0.010 and p < 0.001, respectively). CONCLUSION: The diagnostic work‐up of EoE patients improved substantially over time at the European sites contributing to EoE CONNECT, with a dramatic reduction in diagnostic delay