GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus

Background: The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.<p></p> Methods: Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).<p></p> Results: Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.<p></p> Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients

El wushu como herramienta para el desarrollo motor, cognitivo y socio afectivo en la escuela: un estudio exploratorio

[ES] El presente estudio investigó la utilización del wushu en la escuela por profesores de Educación Física (FEP) como herramienta para el desarrollo motor, cognitivo y socio‐afectivo del alumnado, y comparó a profesores practicantes y no practicantes en concepto, comprensión y aplicación de prácticas resignificadas de wushu en los grados I y II Enseñanza Primaria en São Paulo, Brasil. Para este fin, 40 PEF fueron asignados a un grupo de dos, practicantes wushu (PW, n=27) o no practicantes de wushu (NPW, n=13). Todos los participantes respondieron a un cuestionario compuesto por 11 preguntas objetivas sobre la práctica de wushu por parte de los escolares, con respuestas divididas en cuatro niveles ("no asiste", "parcialmente", "completamente" y "excede"). Se utilizó la prueba de Mann Whitney para comparar las respuestas, p≤0,05. Los resultados mostraron diferencias entre los grupos, considerando los PW que el wushu es un contenido válido para enseñar a los escolares aspectos relacionados con las artes marciales, mientras que los NPW lo consideraron poco eficiente. Ambos grupos identificaron al wushu como una actividad que satisface y supera las necesidades de desarrollo motor, cognitivo y socioafectivo de los escolares. Por otro lado, alrededor del 30% de los NPW indicaron que el wushu es difícil de utilizaren el contexto escolar, y el 40% de los NPW consideraron que las prácticas de wushu recibidas durante su formación inicial fueron escasas o inexistentes. Estos resultados sugieren la posibilidad de que exista una relación entre la experiencia de los profesores y la promoción de ciertas prácticas, y que la enseñanza de las artes marciales puede depender de la propia condición de practicantes de los profesores de Educación Física.[EN] The present work investigated the use of wushu at school by Physical Education teachers (PEF) as a tool for the motor, cognitive and socioaffective development, and compared practitioners and non‐practitioners in concept, understanding and application of wushu resignified practices in Elementary School grades I and II in São Paulo, Brazil. For this purpose, 40 PEFs were assigned to one of two groups, wushu Practitioners (PW, n=27) or Non wushu Practitioners (NPW, n=13). All participants answered a questionnaire composed of 11 objective questions about the wushu practice by schoolchildren, with answers ranging on four levels ("does not attend", "partially", "fully" and "exceeds"). The Mann Whitney test was used to compare the responses, p≤0.05. Results showed differences between groups, in which PW considered wushu a valid content to teach aspects related to martial arts for schoolchildren, while NPW believed to be inefficient. Both groups identified wushu as an activity that meets and exceeds the needs of motor, cognitive and socioaffective development in schoolchildren. On the other hand, about 30% of NPWs indicated that wushu is difficult to use in schoolchildren, and 40% of NPWs reported that wushu practices during initial teacher training were only partially or not sufficiently taught. These results suggest the possibility of a relationship between the teachers' experience and the promotion of certain practices, depending the teaching of martial arts on the teachers’ practical experience.[PT] O presente trabalho investigou a utilização do wushu como ferramenta para o desenvolvimento motor, cognitivo e socioafetivo na escola entre professores de Educação Física (PEF) e comparou praticantes e não praticantes em conceito, compreensão e na aplicação de práticas ressignificadas no Ensino Fundamental I e II em São Paulo, no Brasil. Para isso, participaram 40 PEF, separados em dois grupos Praticantes de wushu (PW, n=27) e Não Praticantes de wushu (NPW, n=13).Todos responderam um questionário com 11 perguntas objetivas sobre a prática de wushu por escolares, com respostas em quatro escalas (“não atende”, “parcialmente”, “plenamente” e “supera”). Para comparar as respostas utilizou‐se o teste de Mann Whitney, p≤0,05. O resultado mostrou diferença entre os grupos, na qual PW consideram a modalidade um sistema válido para ensinar aspectos relacionados com as artes marciais para escolares, enquanto NPW acredita ser pouco eficiente. Ambos os grupos indicaram o wushu, como uma atividade que atende e supera as necessidades de desenvolvimento motor, cognitivo e socioafetivo em escolares. Em contrapartida, cerca de 30% dos NPW indicou que o wushu é difícil para ser utilizado em escolares e 40% desse grupo informou que as práticas de wushu durante a formação na graduação foram apenas parcialmente ou não foram realizadas de maneira clara. Esses resultados sugerem a possibilidade de haver relação entre a experiência dos professores na promoção de determinadas modalidades, podendo estar o ensino das artes marciais dependente do fato dos professores serem ou não praticantes

O wushu como uma ferramenta para o desenvolvimento motor, cognitivo e socioafetivo na escola: um estudo exploratório

The present work investigated the use of wushu at school by Physical Education teachers (PEF) as a tool for the motor, cognitive and socioaffective development, and compared practitioners and non-practitioners in concept, understanding and application of wushu resignified practices in Elementary School grades I and II in São Paulo, Brazil. For this purpose, 40 PEFs were assigned to one of two groups, wushu Practitioners (PW, n=27) or Non wushu Practitioners (NPW, n=13). All participants answered a questionnaire composed of 11 objective questions about the wushu practice by schoolchildren, with answers ranging on four levels ("does not attend", "partially", "fully" and "exceeds"). The Mann Whitney test was used to compare the responses, p<0.05. Results showed differences between groups, in which PW considered wushu a valid content to teach aspects related to martial arts for schoolchildren, while NPW believed to be inefficient. Both groups identified wushu as an activity that meets and exceeds the needs of motor, cognitive and socioaffective development in schoolchildren. On the other hand, about 30% of NPWs indicated that wushu is difficult to use in schoolchildren, and 40% of NPWs reported that wushu practices during initial teacher training were only partially or not sufficiently taught. These results suggest the possibility of a relationship between the teachers' experience and the promotion of certain practices, depending the teaching of martial arts on the teachers’ practical experience.El presente estudio investigó la utilización del wushu en la escuela por profesores de Educación Física (FEP) como herramienta para el desarrollo motor, cognitivo y socio-afectivo del alumnado, y comparó a profesores practicantes y no practicantes en concepto, comprensión y aplicación de prácticas resignificadas de wushu en los grados I y II Enseñanza Primaria en São Paulo, Brasil. Para este fin, 40 PEF fueron asignados a un grupo de dos, practicantes wushu (PW, n=27) o no practicantes de wushu (NPW, n=13). Todos los participantes respondieron a un cuestionario compuesto por 11 preguntas objetivas sobre la práctica de wushu por parte de los escolares, con respuestas divididas en cuatro niveles ("no asiste", "parcialmente", "completamente" y "excede"). Se utilizó la prueba de Mann Whitney para comparar las respuestas, p≤0,05. Los resultados mostraron diferencias entre los grupos, considerando los PW que el wushu es un contenido válido para enseñar a los escolares aspectos relacionados con las artes marciales, mientras que los NPW lo consideraron poco eficiente. Ambos grupos identificaron al wushu como una actividad que satisface y supera las necesidades de desarrollo motor, cognitivo y socioafectivo de los escolares. Por otro lado, alrededor del 30% de los NPW indicaron que el wushu es difícil de utilizar en el contexto escolar, y el 40% de los NPW consideraron que las prácticas de wushu recibidas durante su formación inicial fueron escasas o inexistentes. Estos resultados sugieren la posibilidad de que exista una relación entre la experiencia de los profesores y la promoción de ciertas prácticas, y que la enseñanza de las artes marciales puede depender de la propia condición de practicantes de los profesores de Educación Física.O presente trabalho investigou a utilização do wushu como ferramenta para o desenvolvimento motor, cognitivo e socioafetivo na escola entre professores de Educação Física (PEF) e comparou praticantes e não praticantes em conceito, compreensão e na aplicação de práticas ressignificadas no Ensino Fundamental I e II em São Paulo, no Brasil. Para isso, participaram 40 PEF, separados em dois grupos Praticantes de wushu (PW, n=27) e Não Praticantes de wushu (NPW, n=13). Todos responderam um questionário com 11 perguntas objetivas sobre a prática de wushu por escolares, com respostas em quatro escalas (“não atende”, “parcialmente”, “plenamente” e “supera”). Para comparar as respostas utilizou-se o teste de Mann Whitney, p<0,05. O resultado mostrou diferença entre os grupos, na qual PW consideram a modalidade um sistema válido para ensinar aspectos relacionados com as artes marciais para escolares, enquanto NPW acredita ser pouco eficiente. Ambos os grupos indicaram o wushu, como uma atividade que atende e supera as necessidades de desenvolvimento motor, cognitivo e socioafetivo em escolares. Em contrapartida, cerca de 30% dos NPW indicou que o wushu é difícil para ser utilizado em escolares e 40% desse grupo informou que as práticas de wushu durante a formação na graduação foram apenas parcialmente ou não foram realizadas de maneira clara. Esses resultados sugerem a possibilidade de haver relação entre a experiência dos professores na promoção de determinadas modalidades, podendo estar o ensino das artes marciais dependente do fato dos professores serem ou não praticantes

Relational Concurrent Refinement II: Internal Operations and Outputs

Two styles of description arise naturally in formal specification: state-based and behavioural. In state-based notations, a system is characterised by a collection of variables, and their values determine which actions may occur throughout a system history. Behavioural specifications describe the chronologies of actions -- interactions between a system and its environment. The exact nature of such interactions is captured in a variety of semantic models with corresponding notions of refinement; refinement in state based systems is based on the semantics of sequential programs and is modelled relationally. Acknowledging that these viewpoints are complementary, substantial research has gone into combining the paradigms. The purpose of this paper is to do three things. First, we survey recent results linking the relational model of refinement to the process algebraic models. Specifically, we detail how variations in the relational framework lead to relational data refinement being in correspondence with traces-divergences, singleton failures and failures-divergences refinement in a process semantics. Second, we generalise these results by providing a general flexible scheme for incorporating the two main ''erroneous'' concurrent behaviours: deadlock and divergence, into relational refinement. This is shown to subsume previous characterisations. In doing this we derive relational refinement rules for specifications containing both internal operations and outputs that corresponds to failures-divergences refinement. Third, the theory has been formally specified and verified using the interactive theorem prover KIV

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.We thank all members of the Brain Metastasis Group and A. Chalmers, E. Wagner, O. Fernández-Capetillo, R. Ciérvide and A. Hidalgo for critical discussion of the manuscript; the CNIO Core Facilities for their excellent assistance; and Fox Chase Cancer Center Transgenic Facility for generation of S100A9 mice. We thank EuCOMM repository for providing S100A9 targeted embryonic stem cells. We also thank J. Massagué (MSKCC) for some of the BrM cell lines and M. Bosenberg (Yale) for the YUMM1.1 cell line. Samples from patients included in this study that provided by the Girona Biomedical Research Institute (IDIBGI) (Biobanc IDIBGI, B.0000872) are integrated into the Spanish National Biobanks Network and in the Xarxa de Bancs de Tumors de Catalunya (XBTC) financed by the Pla Director d’Oncologia de Catalunya. All patients consented to the storage of these samples in the biobank and for their use in research projects. This study was funded by MINECO (SAF2017-89643-R) (M.V.), Fundació La Marató de TV3 (201906-30-31-32) (J.B.-B., M.V. and A.C.), Fundación Ramón Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V. and E.C.-J.M.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Portuguese Foundation for Science and Technology (SFRH/bd/100089/2014) (C.M.), Boehringer-Ingelheim Fonds MD Fellowship (L.M.), La Caixa International PhD Program Fellowship-Marie Skłodowska-Curie (LCF/BQ/DI17/11620028) (P.G.-G.), La Caixa INPhINIT Fellowship (LCF/BQ/DI19/11730044) (A.P.-A.), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A.-E.) and an AECC postdoctoral fellowship (POSTD19016PRIE) (N.P.). M.V. is an EMBO YIP member (4053). Additional support was provided by Gertrud and Erich Roggenbuck Stiftung (M.M.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award with the generous support of Walk the Walk (2019AugSF1310) (D.V.), Science Foundation Ireland (20/FFP-P/8597) (D.V.), Paradifference Foundation (C.F.-T.), “la Caixa” Foundation (ID 100010434) (A.I.), European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 847648 (CF/BQ/PI20/11760029) (A.I.), Champalimaud Centre for the Unknown (N.S.), Lisboa Regional Operational Programme (Lisboa 2020) (LISBOA01-0145-FEDER-022170) (N.S.), NCI (R01 CA227629; R01 CA218133) (S.I.G.), Fundació Roses Contra el Càncer (J.B.-B.), Ministerio de Universidades FPU Fellowship (FPU 18/00069) (P.T.), MICIN-Agencia Estatal de Investigación Fellowships (PRE2020-093032 and BES-2017-080415) (P.M. and E. Cintado, respectively), Ministerio de Ciencia, Innovación y Universidades-E050251 (PID2019-110292RB-I00) (J.L.T.), FCT (PTDC/MED-ONC/32222/2017) (C.C.F.), Fundação Millennium bcp (C.C.F.), private donations (C.C.F.) and the Foundation for Applied Cancer Research in Zurich (E.L.R. and M.W.)

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3 years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0 years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013

Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation. the GLORIA-AF registry

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007