Experimental and theoretical studies on the effect of the oxo group in 1,4-benzodiazepines

Two families of regioisomeric 1,4-benzodiazepines, 4-benzyl-3H-benzo[e][1,4]diazepin-5-ones and 4-benzoyl-4,5-dihydro-3H-benzo[e][1,4]diazepines, have been synthesized through a similar Ugi/reduction cyclization sequence. Their conformation and stability depend on the position of the tautomeric imine/enamine equilibrium present in the diazepine nucleus, which in turn depends on the relative position of the carbonyl group adjacent to the nitrogen at the 4-position in the benzodiazepine system. Moreover, the electrophilic center on the imine tautomer is essential for the antitumor activity of some benzodiazepines as a DNA binding position. The mechanism of tautomerization in the presence or absence of the oxo group has been studied computationally using DFT methods (B3LYP/6-31G** level).Ministerio de Economía y Competitividad, Spain (project CTQ2012- 31611), from Ministerio de Ciencia e Innovación, Spain and Fondo de Desarrollo Regional (project MAT2011-22781), as well as from Junta de Castilla y León, Consejería de Educación y Cultura y Fondo Social Europeo (project ref. BU246A12-1 and BU327A11-2)

Tensiones y transiciones en las relaciones internacionales

Este libro reúne 12 textos en torno a la realidad internacional con­temporánea, que se presentan a modo de reflexiones, investigacio­nes empíricas y análisis conceptuales, elaborados por académicos y egresados de la Licenciatura de Relaciones Internacionales del ITESO, en el marco de la celebración del 20 aniversario de esta espe­cialidad, que nació en 1997 con el fin de formar profesionales capa­ces de analizar el panorama mundial y de establecer puentes entre las esferas local, nacional y global, para contribuir a la construcción de una sociedad más justa y equitativa. Dividida en cuatro apartados, esta obra busca mostrar una radio­grafía del complicado entramado que enfrentan las relaciones inter­nacionales en el dinámico y desafiante entorno mundial, lo que le convierte en un material de consulta de interés para todo estudiante y profesional en la materia, así como para todo aquel lector que busque conocer mejor los elementos, el funcionamiento, las interac­ciones y transiciones de las estructuras que rigen al mundo.ITESO, A.C

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Posibles impactos en el sector salud por el ingreso de Chile al NAFTA

Tesis (Ingeniería Comercial)Chile durante los últimos años ha desarrollado una estrategia de apertura comercial unilateral, sin embargo, recientemente se han presentado oportunidades que apuntan hacia la incorporación a acuerdos multilaterales. Es así, como los países de América del Norte, miembros de la mayor área de libre comercio en el mundo (357,25 millones de personas), han invitado a Chile para que se incorpore a este acuerdo comercial. Esta invitación trae consigo, implícitamente, un largo período de negociaciones que no será del todo fácil, pero que posiblemente puede traer para nuestro país grandes beneficios en todos o casi todos los sectores productivos de nuestra economía y que, por lo tanto, se podría ver reflejado en el bienestar de la población y crecimiento económico. A la vez, la incorporación al acuerdo presentará ciertas dificultades y desafios a superar, tales como ajustes a las normativas exigidas en el NAFTA y mejoras en la competitividad de las empresas nacionales. Es por esta razón que en el presente seminario analizaremos los posibles impactos que un acuerdo de esta naturaleza tendría sobre el Sector Salud, en especial por la desorganización que ha denotado durante los últimos años, así como la falta de visión por parte de la autoridad para llegar a una solución eficiente en la administración del sector y la utilización de los recursos disponibles. Además éste, por distintas razones, ha estado en tela de juicio y ha sido causa de discusión nacional y dudas respecto del real avance alcanzado por nuestro país. Así resulta obvio preguntarse, ¿ Qué podría aportar la adhesión al Acuerdo de Libre Comercio de América del Norte (NAFTA), en materia de salud, que el crecimiento económico alcanzado por nuestro país no haya logrado incluir hasta este momento?; pregunta que trataremos de dilucidar en el presente trabajo. Además creemos importante analizar las repercusiones en la salud, puesto que ésta ya no es sólo uno de los fines últimos del crecimiento económico, sino que a pasado a ser una condición esencial de éste y, a la vez, un elemento indispensable para la sociedad. La entrega de salud constituye uno de los mecanismos más importantes y significativos de la redistribución del ingreso, factor que se podría beneficiar con la adhesión al tratado

Prognosis impact of diabetes in elderly women and men with non-ST elevation acute coronary syndrome

Few studies have addressed to date the interaction between sex and diabetes mellitus (DM) in the prognosis of elderly patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Our aim was to address the role of DM in the prognosis of non-selected elderly patients with NSTEACS according to sex. A retrospective analysis from 11 Spanish NSTEACS registries was conducted, including patients aged ≥70 years. The primary end point was one-year all-cause mortality. A total of 7211 patients were included, 2,770 (38.4%) were women, and 39.9% had DM. Compared with the men, the women were older (79.95 ± 5.75 vs. 78.45 ± 5.43 years, p < 0.001) and more often had a history of hypertension (77% vs. 83.1%, p < 0.01). Anemia and chronic kidney disease were both more common in women. On the other hand, they less frequently had a prior history of arteriosclerotic cardiovascular disease or comorbidities such as peripheral artery disease and chronic pulmonary disease. Women showed a worse clinical profile on admission, though an invasive approach and in-hospital revascularization were both more often performed in men (p < 0.001). At a one-year follow-up, 1090 patients (15%) had died, without a difference between sexes. Male sex was an independent predictor of mortality (HR = 1.15, 95% CI 1.01 to 1.32, p = 0.035), and there was a significant interaction between sex and DM (p = 0.002). DM was strongly associated with mortality in women (HR: 1.45, 95% CI = 1.18-1.78; p < 0.001), but not in men (HR: 0.98, 95% CI = 0.84-1.14; p = 0.787). In conclusion, DM is associated with mortality in older women with NSTEACS, but not in men

Comentarios del Comité Español Interdisciplinario de Prevención Cardiovascular (CEIPC) a las Guías Europeas de Prevención Cardiovascular 2012

Resumen: Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad. Abstract: Based on the two main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions — such as smoking ban in public areas or the elimination of trans fatty acids from the food chain — are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses. Palabras clave: Prevención cardiovascular, Riesgo cardiovascular, Enfermedades cardiovasculares, Guías de práctica clínica, Keywords: Cardiovascular prevention, Cardiovascular risk, Cardiovascular diseases, Clinical practice guideline

Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines

Based on the 2 main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions—such as smoking ban in public areas or the elimination of trans fatty acids from the food chain—are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85 mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses. Resumen: Las guías europeas de prevención cardiovascular contemplan 2 sistemas de evaluación de la evidencia (SEC y GRADE) y recomiendan combinar las estrategias poblacional y de alto riesgo, interviniendo en todas las etapas de la vida, con la dieta como piedra angular de la prevención. La valoración del riesgo cardiovascular (RCV) incorpora los niveles de HDL y los factores psicosociales, una categoría de muy alto riesgo y el concepto edad-riesgo. Se recomienda el uso de métodos cognitivo-conductuales (entrevista motivadora, intervenciones psicológicas), aplicados por profesionales sanitarios, con la participación de familiares de los pacientes, para contrarrestar el estrés psicosocial y reducir el RCV mediante dietas saludables, entrenamiento físico, abandono del tabaco y cumplimiento terapéutico. También se requieren medidas de salud pública, como la prohibición de fumar en lugares públicos o eliminar los ácidos grasos trans de la cadena alimentaria. Otras novedades consisten en desestimar el tratamiento antiagregante en prevención primaria y la recomendación de mantener la presión arterial dentro del rango 130-139/80-85 mmHg en pacientes diabéticos o con RCV alto. Se destaca el bajo cumplimiento terapéutico observado, porque influye en el pronóstico de los pacientes y en los costes sanitarios. Para mejorar la prevención cardiovascular se precisa una verdadera alianza entre políticos, administraciones, asociaciones científicas y profesionales de la salud, fundaciones de salud, asociaciones de consumidores, pacientes y sus familias, que impulse la estrategia tanto poblacional como individual mediante el uso de toda la evidencia científica disponible, desde ensayos clínicos hasta estudios observacionales y modelos matemáticos para evaluar intervenciones a nivel poblacional, incluyendo análisis de coste-efectividad. Keywords: Cardiovascular prevention, Cardiovascular risk, Cardiovascular diseases, Clinical practice guidelines, Palabras clave: Prevención cardiovascular, Riesgo cardiovascular, Enfermedades cardiovasculares, Guías de práctica clínic

Simulations of Transport in Hard Particle Systems

We thank G. Gallavotti, J.L. Lebowitz and J. del Pozo for illuminating discussions. Financial support from Spanish Ministry MINECO Project FIS2017-84256-P is also acknowledged. We are also grateful for the computational resources and assistance provided by PROTEUS, the supercomputing center of the Institute Carlos I for Theoretical and Computational Physics at the University of Granada, Spain

Produção, composição e rendimento em queijo do leite de ovelhas Santa Inês tratadas com ocitocina Effects of oxytocin on milk yield and composition of Santa Inês ewes

Objetivou-se avaliar a produção, a composição e o rendimento (na fabricação de queijos) do leite de ovelhas Santa Inês tratadas ou não com ocitocina. Os animais foram mantidos em regime de confinamento e receberam uma dieta com 12% de PB e 65% de NDT. As ovelhas foram distribuídas em dois tratamentos: ordenha manual com injeção endovenosa de três UI de ocitocina e ordenha manual sem injeção de ocitocina (grupo controle). Realizou-se uma ordenha diária, de modo que, até a desmama, as ovelhas permaneceram diariamente com os cordeiros durante 14 horas. Os cordeiros foram desmamados aos 60 dias e as ovelhas continuaram sendo ordenhadas uma vez ao dia até o final da lactação. Foram coletadas amostras de leite para análise dos teores de gordura, de sólidos totais e de sólidos desengordurados. A duração média da lactação foi de 225&plusmn;27,24 e 210&plusmn;38,77 dias para as ovelhas controle e tratadas com ocitocina, respetivamente. Até os 133 dias de lactação, o tratamento com ocitocina (141,63&plusmn;51,52 kg) foi superior ao controle (89,39&plusmn;16,65 kg), entretanto, durante todo o período de lactação, não diferiu (169,64 &plusmn; 71,05) do controle (119,72&plusmn;32,73). As porcentagens de gordura (5,84&plusmn;0,44 e 4,96&plusmn;0,47), sólidos totais (17,40&plusmn;0,42 e 16,18&plusmn;0,57) e sólidos desengordurados (11,57&plusmn;0,15 e 11,22&plusmn;0,25) no leite foram influenciadas pela aplicação de ocitocina. Os resultados revelaram diferença significativa para as ovelhas tratadas com ocitocina, as quais apresentaram maior produtividade e, inclusive, melhor composição química do leite. A aplicação de ocitocina é recomendada para animais não adaptados à rotina de ordenha. O leite das ovelhas Santa Inês apresentou rendimentos de 4,80; 8,29 e 5,99 L/kg para os queijos tipo azeitão, pecorino e roquefort, respectivamente.<br>The objective of this trial was to investigate the effects of oxytocin on milk yield and composition and on cheese yield of Santa Inês sheep receiving a diet containing 12% CP and 65% TDN. Animals were maintained in pens and were assigned to one of the following two treatments: hand milking plus an intravenous injection of 3 IU of oxytocin or hand milking without oxytocin injection (control group). Ewes were milked daily and remained with their lambs for a daily period of 14 hours until weaning; lambs were weaned at 60 days of age and ewes still milked once a day until the end of lactation. Milk samples were collected for analysis of fat, total solids, and solids non-fat. Lactation length averaged 225&plusmn;27.24 and 210&plusmn;38.77 for control and oxytocin-treated ewes, respectively. Ewes receiving oxytocin yielded more milk (141.63&plusmn;51.52 kg) than those on the control group (89.39&plusmn;16.65 kg) until 133 days of lactation; however, total milk yield on the entire lactation did not differ significantly comparing oxyitocin-treated (169.64 &plusmn; 71.05) with control (119.72&plusmn;32.73) animals. Milk contents of fat (5.84&plusmn;0.44 and 4.96&plusmn;0.47), total solids (17.40&plusmn;0.42 and 16.18&plusmn;0.57) and solids non-fat (11.57&plusmn;0.15 and 11.22&plusmn;0.25) differed between both groups of animals, respectively. Results showed improved milk yield and composition on oxytocin-injected ewes; therefore, it is recommended the use of oxytocin to facilitate milk ejection on ewes not adapted to the milking routine. Yields of cheese (L of milk/kg of cheese) averaged 4.80, 8.29 and 5.99 L/kg for azeitão, pecorino, and roquefort cheeses, respectively