Maximizing the statistical diversity of an ensemble of bred vectors by using the geometric norm

It is shown that the choice of the norm has a great impact on the construction of ensembles of bred vectors. The geometric norm maximizes (in comparison with other norms such as the Euclidean one) the statistical diversity of the ensemble while at the same time it enhances the growth rate of the bred vector and its projection on the linearly most unstable direction (i.e., the Lyapunov vector). The geometric norm is also optimal in providing the least fluctuating ensemble dimension among all the spectrum of norms studied. The results are exemplified with numerical integrations of a toy model of the atmosphere (the Lorenz-96 model), but these findings are expected to be generic for spatially extended chaotic systems.D.P. acknowledges support by CSIC under the Junta de Ampliación de Estudios Programme (JAE-Doc). Financial support from the Ministerio de Ciencia e Innovacioón (Spain) under Projects FIS2009-12964-C05-05 and CGL2010-21869 is acknowledged

Spatio-temporal evolution of perturbations in ensembles initialized by bred, Lyapunov and singular vectors

We study the evolution of finite perturbations in the Lorenz ?96 model, a meteorological toy model of the atmosphere. The initial perturbations are chosen to be aligned along different dynamic vectors: bred, Lyapunov, and singular vectors. Using a particular vector determines not only the amplification rate of the perturbation but also the spatial structure of the perturbation and its stability under the evolution of the flow. The evolution of perturbations is systematically studied by means of the so-called mean-variance of logarithms diagram that provides in a very compact way the basic information to analyse the spatial structure. We discuss the corresponding advantages of using those different vectors for preparing initial perturbations to be used in ensemble prediction systems, focusing on key properties: dynamic adaptation to the flow, robustness, equivalence between members of the ensemble, etc. Among all the vectors considered here, the so-called characteristic Lyapunov vectors are possibly optimal, in the sense that they are both perfectly adapted to the flow and extremely robust.DP acknowledges the support by CSIC under the Junta de Ampliación de Estudios Programme (JAE-Doc). Financial support from the Ministerio de Educación y Ciencia (Spain) under projects FIS2006-12253-C06-04 and CGL2007-64387/CLI is acknowledged

Propuesta de Supply Chain Management y Logística para la empresa Riopaila Castilla S.A.

A proposal for "Supply Chain Management and Logistics" is presented to the company Riopaila Castilla S.A., it is necessary to deepen issues such as the management of flows in the supply chain that the company has adopted and the results obtained, as well as the management of their inventories, the supply of raw materials and the distribution of the finished product. With the knowledge of the strategies and methodologies implemented inside and outside the company, to carry out all its logistics stages, we can propose improvements in the layout, in inventory management and the selection of suppliers that allow the company business growth and market positioning, this diploma chapter presents each link in the supply chain and the strategies implemented by the company, always seeking collaboration in the continuous improvement of the logistics processes necessary for the proper flow of the supply chain.Para permitirnos presentar una propuesta de “Supply Chain Management y Logística”, a la empresa Riopaila Castilla S.A., es necesario la profundización en temas como el manejo de los flujos en la cadena de suministro que la empresa ha adoptado y los resultados obtenidos, así como el manejo de sus inventarios, el suministro de materias primas y la distribución del producto terminado. Con el conocimiento de las estrategias y metodologías implementadas dentro y fuera de la compañía, para llevar a cabo todas sus etapas de la logística, podemos proponer mejoras en el layout, en el manejo de inventarios y la selección de proveedores que le permitan a la compañía el crecimiento empresarial y el posicionamiento en el mercado, el presente diplomado presenta por capítulos cada eslabón de la cadena de suministro y las estrategias implementadas por la compañía, buscando siempre la colaboración en la mejora continua de los procesos de la logística necesaria para el flujo adecuado de la cadena de suministro.A proposal for "Supply Chain Management and Logistics" is presented to the company Riopaila Castilla S.A., it is necessary to deepen issues such as the management of flows in the supply chain that the company has adopted and the results obtained, as well as the management of their inventories, the supply of raw materials and the distribution of the finished product. With the knowledge of the strategies and methodologies implemented inside and outside the company, to carry out all its logistics stages, we can propose improvements in the layout, in inventory management and the selection of suppliers that allow the company business growth and market positioning, this diploma chapter presents each link in the supply chain and the strategies implemented by the company, always seeking collaboration in the continuous improvement of the logistics processes necessary for the proper flow of the supply chain

Recommendations for the Treatment of Anti-Melanoma Differentiation-Associated Gene 5-positive Dermatomyositis-Associated Rapidly Progressive Interstitial Lung Disease

Objectives: The study aimed to develop evidence-based recommendations for the treatment of rapidly progressive interstitial lung disease (RPILD) associated with the anti-Melanoma Differentiation-Associated Gene 5-positive dermatomyositis (DM) syndrome. Methods: The task force comprised an expert panel of specialists in rheumatology, intensive care medicine, pulmonology, immunology, and internal medicine. The study was carried out in two phases: identifying key areas in the management of DM-RPILD syndrome and developing a set of recommendations based on a review of the available scientific evidence. Four specific questions focused on different treatment options were identified. Relevant publications in English, Spanish or French up to April 2018 were searched systematically for each topic using PubMed (MEDLINE), EMBASE, and Cochrane Library (Wiley Online). The experts used evidence obtained from these studies to develop recommendations. Results: A total of 134 studies met eligibility criteria and formed the evidentiary basis for the recommendations regarding immunosuppressive therapy and complementary treatments. Overall, there was general agreement on the initial use of combined immunosuppressive therapy. Combination of high-dose glucocorticoids and calcineurin antagonists with or without cyclophosphamide is the first choice. In the case of calcineurin antagonist contraindication or treatment failure, switching or adding other immunosuppressants may be individualized. Plasmapheresis, polymyxin B hemoperfusion and/or intravenous immunoglobulins may be used as rescue options. ECMO should be considered in life-threatening situations while waiting for a clinical response or as a bridge to lung transplant. Conclusions: Thirteen recommendations regarding the treatment of the anti-MDA5 positive DM-RPILD were developed using research-based evidence and expert opinion.This project was supported by Spanish Rheumatology Society and Spanish Society of Internal Medicine (GEAS, Study Group on Autoimmune Diseases)

Morbid liver manifestations are intrinsically bound to metabolic syndrome and nutrient intake based on a machine-learning cluster analysis

Metabolic syndrome (MetS) is one of the most important medical problems around the world. Identification of patient ' s singular characteristic could help to reduce the clinical impact and facilitate individualized management. This study aimed to categorize MetS patients using phenotypical and clinical variables habitually collected during health check-ups of individuals considered to have high cardiovascular risk. The selected markers to categorize MetS participants included anthropometric variables as well as clinical data, biochemical parameters and prescribed pharmacological treatment. An exploratory factor analysis was carried out with a subsequent hierarchical cluster analysis using the z-scores from factor analysis. The first step identified three different factors. The first was determined by hypercholesterolemia and associated treatments, the second factor exhibited glycemic disorders and accompanying treatments and the third factor was characterized by hepatic enzymes. Subsequently four clusters of patients were identified, where cluster 1 was characterized by glucose disorders and treatments, cluster 2 presented mild MetS, cluster 3 presented exacerbated levels of hepatic enzymes and cluster 4 highlighted cholesterol and its associated treatments Interestingly, the liver status related cluster was characterized by higher protein consumption and cluster 4 with low polyunsaturated fatty acid intake. This research emphasized the potential clinical relevance of hepatic impairments in addition to MetS traditional characterization for precision and personalized management of MetS patients

Applied diagnostics in liver cancer. Efficient combinations of sorafenib with targeted inhibitors blocking AKT/mTOR

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. There is increasing interest in developing specific markers to serve as predictors of response to sorafenib and to guide targeted therapy. Using a sequencing platform designed to study somatic mutations in a selection of 112 genes (HepatoExome), we aimed to characterize lesions from HCC patients and cell lines, and to use the data to study the biological and mechanistic effects of case-specific targeted therapies used alone or in combination with sorafenib. We characterized 331 HCC cases in silico and 32 paired samples obtained prospectively from primary tumors of HCC patients. Each case was analyzed in a time compatible with the requirements of the clinic (within 15 days). In 53% of the discovery cohort cases, we detected unique mutational signatures, with up to 34% of them carrying mutated genes with the potential to guide therapy. In a panel of HCC cell lines, each characterized by a specific mutational signature, sorafenib elicited heterogeneous mechanistic and biological responses, whereas targeted therapy provoked the robust inhibition of cell proliferation and DNA synthesis along with the blockage of AKT/mTOR signaling. The combination of sorafenib with targeted therapies exhibited synergistic anti-HCC biological activity concomitantly with highly effective inhibition of MAPK and AKT/mTOR signaling. Thus, somatic mutations may lead to identify case-specific mechanisms of disease in HCC lesions arising from multiple etiologies. Moreover, targeted therapies guided by molecular characterization, used alone or in combination with sorafenib, can effectively block important HCC disease mechanisms.FUNDING: Grants from ISCIII, co-financed by the European Union (FEDER) (PI16/00156), Ramón and Cajal research program from MINECO (RYC-2013-14097) and FUNDACIÓN LUCHAMOS POR LA VIDA to JPV. Grants from ISCIII (RD06/0020/0107-RD012/0036/0060) to MAP. Grant from ISCIII (Ref. PIE15/00079) to JC & JPV. NGD is a recipient of a UC-IDIVAL pre-doctoral fellow. I.V. was also supported by the Ramón and Cajal research program

Long daytime napping is associated with increased adiposity and type 2 diabetes in an elderly population with metabolic syndrome

Research examining associations between objectively-measured napping time and type 2 diabetes (T2D) is lacking. This study aimed to evaluate daytime napping in relation to T2D and adiposity measures in elderly individuals from the Mediterranean region. A cross-sectional analysis of baseline data from 2190 elderly participants with overweight/obesity and metabolic syndrome, in the PREDIMED-Plus trial, was carried out. Accelerometer-derived napping was measured. Prevalence ratios (PR) and 95% confidence intervals (CI) for T2D were obtained using multivariable-adjusted Cox regression with constant time. Linear regression models were fitted to examine associations of napping with body mass index (BMI) and waist circumference (WC). Participants napping ≥90 min had a higher prevalence of T2D (PR 1.37 (1.06, 1.78)) compared with those napping 5 to <30 min per day. Significant positive associations with BMI and WC were found in those participants napping ≥30 min as compared to those napping 5 to <30 min per day. The findings of this study suggest that longer daytime napping is associated with higher T2D prevalence and greater adiposity measures in an elderly Spanish population at high cardiovascular risk

Intermittent hypoxia is associated with high hypoxia inducible factor-1α but not high vascular endothelial growth factor cell expression in tumors of cutaneous melanoma patients

Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1α and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1α were performed, and the percentage of positive cells (0, 75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1α expression, respectively. Cases with HIF-1α expression >6% (high expression) were compared with those 75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1α were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1α was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1α expression. Thus, IH emerges as an independent risk factor for higher HIF-1α expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators

Predictive Power of the "Trigger Tool" for the detection of adverse events in general surgery: a multicenter observational validation study

Background In spite of the global implementation of standardized surgical safety checklists and evidence-based practices, general surgery remains associated with a high residual risk of preventable perioperative complications and adverse events. This study was designed to validate the hypothesis that a new “Trigger Tool” represents a sensitive predictor of adverse events in general surgery. Methods An observational multicenter validation study was performed among 31 hospitals in Spain. The previously described “Trigger Tool” based on 40 specific triggers was applied to validate the predictive power of predicting adverse events in the perioperative care of surgical patients. A prediction model was used by means of a binary logistic regression analysis. Results The prevalence of adverse events among a total of 1,132 surgical cases included in this study was 31.53%. The “Trigger Tool” had a sensitivity and specificity of 86.27% and 79.55% respectively for predicting these adverse events. A total of 12 selected triggers of overall 40 triggers were identified for optimizing the predictive power of the “Trigger Tool”. Conclusions The “Trigger Tool” has a high predictive capacity for predicting adverse events in surgical procedures. We recommend a revision of the original 40 triggers to 12 selected triggers to optimize the predictive power of this tool, which will have to be validated in future studies

Isotemporal substitution of inactive time with physical activity and time in bed: cross-sectional associations with cardiometabolic health in the PREDIMEDPlus study

Background: This study explored the association between inactive time and measures of adiposity, clinical parameters, obesity, type 2 diabetes and metabolic syndrome components. It further examined the impact of reallocating inactive time to time in bed, light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) on cardio-metabolic risk factors, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Methods: This is a cross-sectional analysis of baseline data from 2189 Caucasian men and women (age 55-75 years, BMI 27-40 Kg/m2) from the PREDIMED-Plus study (http://www.predimedplus.com/). All participants had ≥3 components of the metabolic syndrome. Inactive time, physical activity and time in bed were objectively determined using triaxial accelerometers GENEActiv during 7 days (ActivInsights Ltd., Kimbolton, United Kingdom). Multiple adjusted linear and logistic regression models were used. Isotemporal substitution regression modelling was performed to assess the relationship of replacing the amount of time spent in one activity for another, on each outcome, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Results: Inactive time was associated with indicators of obesity and the metabolic syndrome. Reallocating 30 min per day of inactive time to 30 min per day of time in bed was associated with lower BMI, waist circumference and glycated hemoglobin (HbA1c) (all p-values < 0.05). Reallocating 30 min per day of inactive time with 30 min per day of LPA or MVPA was associated with lower BMI, waist circumference, total fat, visceral adipose tissue, HbA1c, glucose, triglycerides, and higher body muscle mass and HDL cholesterol (all p-values < 0.05). Conclusions: Inactive time was associated with a poor cardio-metabolic profile. Isotemporal substitution of inactive time with MVPA and LPA or time in bed could have beneficial impact on cardio-metabolic health