The Numerical Solution of the External Dirichlet Generalized Harmonic Problem for a Sphere by the Method of Probabilistic Solution

In the present paper, an algorithm for the numerical solution of the external Dirichlet generalized harmonic problem for a sphere by the method of probabilistic solution (MPS) is given, where “generalized” indicates that a boundary function has a finite number of first kind discontinuity curves. The algorithm consists of the following main stages: (1) the transition from an infinite domain to a finite domain by an inversion; (2) the consideration of a new Dirichlet generalized harmonic problem on the basis of Kelvin’s theorem for the obtained finite domain; (3) the numerical solution of the new problem for the finite domain by the MPS, which in turn is based on a computer simulation of the Weiner process; (4) finding the probabilistic solution of the posed generalized problem at any fixed points of the infinite domain by the solution of the new problem. For illustration, numerical examples are considered and results are presented.Partial funding for open access charge: Universidad de Málag

Uncertainty analysis of a loss of cooling and loss of coolant accident in a spent fuel pool using TRACE

[EN] In this work the fundamentals and application results of an uncertainty analysis of a loss of coolant and loss of cooling accident in a spent fuel pool are presented. The spent fuel pool was modeled with TRACE V5.0 Patch 5 using a VESSEL 3D component in Cartesian coordinates. A more detailed nodalization was necessary as compared with a previous study of the same accident scenario to better develop the uncertainty analysis in the framework of the Best Estimate Plus Uncertainty (BEPU) approach. First, the model was calibrated using Main Yankee spent fuel pool experimental data of temperatures and flows measured in steady state conditions. Using the calibrated model, the analysis of the accident was performed considering uncertainty in boundary conditions and in all the coefficients included in the TRACE uncertainty quantification data module. The figure of merit selected in this work is the time at which the cladding oxidation reaches 0.17 times the cladding thickness before oxidation (CFR 50.46 b2). The uncertainty analysis was performed using Wilks' method and surrogate models. In particular, the Elastic Net surrogate model has demonstrated its potential not only to predict the evolution of the figure of merit in an appropriate way with lower computational effort than the Wilks' method but also its capability to identify the most relevant uncertain parameters, such as the fuel and cladding specific heats, rod internal pressure coefficient, burst temperature coefficient, a group of fluid regime heat transfer coefficients, the cladding metal-water reaction rate coefficient and the cladding tolerance for the average cores. In addition, the surrogate model provides more information of the distribution of the evolution of the figure of merit. The estimations of the 5/95 tolerance limits, both with the Wilks' method and with the surrogate models, are very similar, ranging from 30.432 to 30.461 h.The authors are grateful to the Spanish "Consejo de Seguridad Nuclear (CSN)" for the financial support they provided for Research MASA Project 2 and STN/4524/2015/640 (CAMP Project).Sanchez-Saez, F.; Carlos Alberola, S.; Villanueva López, JF.; Sánchez Galdón, AI.; Martorell Alsina, SS. (2020). Uncertainty analysis of a loss of cooling and loss of coolant accident in a spent fuel pool using TRACE. Progress in Nuclear Energy. 124:1-8. https://doi.org/10.1016/j.pnucene.2020.1033451812

Real-World Management and Clinical Outcomes of Stroke Survivors With Atrial Fibrillation: A Population-Based Cohort in Spain

Antiplatelets; Atrial fibrillation; Treatment strategiesAntiplaquetarios; Fibrilación auricular; Estrategias de tratamientoAntiplaquetàries; Fibril·lació auricular; Estratègies de tractamentObjective: Despite the continuous update of clinical guidelines, little is known about the real-world management of patients with atrial fibrillation (AF) who survived a stroke. We aimed to assess patterns of therapeutic management of stroke survivors with AF and clinical outcomes using data from routine practice in a large population-based cohort. Methods: A population-based retrospective cohort study of all patients with AF who survived a stroke, from January 2010 to December 2017 in the Valencia region, Spain (n = 10,986), was carried out. Treatment strategies and mean time to treatment initiation are described. Temporal trends are shown by the management pattern during the study period. Factors associated with each pattern (including no treatment) vs. oral anticoagulant (OAC) treatment were identified using logistic multivariate regression models. Incidence rates of clinical outcomes (mortality, stroke/TIA, GI bleeding, and ACS) were also estimated by the management pattern. Results: Among stroke survivors with AF, 6% were non-treated, 23% were prescribed antiplatelets (APT), 54% were prescribed OAC, and 17% received OAC + APT at discharge. Time to treatment was 8.0 days (CI 7.6–8.4) for APT, 9.86 (CI 9.52–10.19) for OAC, and 16.47 (CI 15.86–17.09) for OAC + APT. Regarding temporal trends, management with OAC increased by 20%, with a decrease of 50% for APT during the study period. No treatment and OAC + APT remained relatively stable. The strongest predictor of no treatment and APT treatment was having the same management strategy pre-stroke. Those treated with APT had the highest rates of GI bleeding and recurrent stroke/TIA, and untreated patients showed the highest rates of mortality. Conclusion: In this large population-based cohort using real-world data, nearly 30% of AF patients who suffered a stroke were untreated or treated with APT, which overall is not recommended. Treatment was started within 2 weeks as recommended, except for OAC + APT, which was started later. The strong association of APT treatment or non-treatment with the same treatment strategy before stroke occurrence suggests a strong therapeutic inertia and opposes recommendations. Patients under these two strategies had the highest rates of adverse outcomes. An inadequate prescription poses a great risk on patients with AF and stroke; thus monitoring their management is necessary and should be setting-specific.CR-B was funded at the start of this work by the Instituto de Salud Carlos III, Spanish Ministry of Health, co-financed by the European Regional Development Fund (grant number RD16/0001/0011) and currently through a competitive grant (Sara Borrell CD19/00137). FS-S was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health through the REDISSEC network (grant number RD16/0001/0011). The views presented here are those of the authors and not necessarily those of the FISABIO Foundation, the Valencia Ministry of Health or the study sponsors

Sustained Cytotoxic Response of Peripheral Blood Mononuclear Cells from Unvaccinated Individuals Admitted to the ICU Due to Critical COVID-19 Is Essential to Avoid a Fatal Outcome

The main objective of this study was to determine the influence of the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) on the outcome of unvaccinated individuals with critical COVID-19 admitted to the ICU. Blood samples from 23 individuals were collected upon admission and then every 2 weeks for 13 weeks until death (Exitus group) (n = 13) or discharge (Survival group) (n = 10). We did not find significant differences between groups in sociodemographic, clinical, or biochemical data that may influence the fatal outcome. However, direct cellular cytotoxicity of PBMCs from individuals of the Exitus group against pseudotyped SARS-CoV-2-infected Vero E6 cells was significantly reduced upon admission (−2.69-fold; p = 0.0234) and after 4 weeks at the ICU (−5.58-fold; p = 0.0290), in comparison with individuals who survived, and it did not improve during hospitalization. In vitro treatment with IL-15 of these cells did not restore an effective cytotoxicity at any time point until the fatal outcome, and an increased expression of immune exhaustion markers was observed in NKT, CD4+, and CD8+ T cells. However, IL-15 treatment of PBMCs from individuals of the Survival group significantly increased cytotoxicity at Week 4 (6.18-fold; p = 0.0303). Consequently, immunomodulatory treatments that may overcome immune exhaustion and induce sustained, efficient cytotoxic activity could be essential for survival during hospitalization due to critical COVID-19.This work was supported by the Coordinated Research Activities at the National Center of Microbiology (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00). The work of Guiomar Casado is financed by CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”. The work of Montserrat Torres is supported by Instituto de Salud Carlos III (COV20_00679). The work of Fernando Ramos Martín is financed by the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00). The work of Mario Manzanares is supported by a pre-doctoral grant from Instituto de Salud Carlos III (ISCIII-PFIS FI20CIII/00021). The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Sara Rodríguez-Mora is financed by NIH grant R01AI143567.N

Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Objective: glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance. Methods: we studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts. Results: we show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression. Conclusion: our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity

Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study

Background: Limited studies have evaluated the joint influence of redox-related metals and genetic variation on metabolic pathways. We analyzed the association of 11 metals with metabolic patterns, and the interacting role of candidate genetic variants, in 1145 participants from the Hortega Study, a population-based sample from Spain. Methods: Urine antimony (Sb), arsenic, barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V), and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured by ICP-MS and AAS, respectively. We summarized 54 plasma metabolites, measured with targeted NMR, by estimating metabolic principal components (mPC). Redox-related SNPs (N = 291) were measured by oligo-ligation assay. Results: In our study, the association with metabolic principal component (mPC) 1 (reflecting non-essential and essential amino acids, including branched chain, and bacterial co-metabolism versus fatty acids and VLDL subclasses) was positive for Se and Zn, but inverse for Cu, arsenobetaine-corrected arsenic (As) and Sb. The association with mPC2 (reflecting essential amino acids, including aromatic, and bacterial co-metabolism) was inverse for Se, Zn and Cd. The association with mPC3 (reflecting LDL subclasses) was positive for Cu, Se and Zn, but inverse for Co. The association for mPC4 (reflecting HDL subclasses) was positive for Sb, but inverse for plasma Zn. These associations were mainly driven by Cu and Sb for mPC1; Se, Zn and Cd for mPC2; Co, Se and Zn for mPC3; and Zn for mPC4. The most SNP-metal interacting genes were NOX1, GSR, GCLC, AGT and REN. Co and Zn showed the highest number of interactions with genetic variants associated to enriched endocrine, cardiovascular and neurological pathways. Conclusions: Exposures to Co, Cu, Se, Zn, As, Cd and Sb were associated with several metabolic patterns involved in chronic disease. Carriers of redox-related variants may have differential susceptibility to metabolic alterations associated to excessive exposure to metals.This work was supported by the Strategic Action for Research in Health sciences [CP12/03080, PI15/00071, PI10/0082, PI13/01848, PI14/00874, PI16/01402, PI21/00506 and PI11/00726], CIBER Fisio patología Obesidad y Nutrición (CIBEROBN) (CIBER-02-08-2009, CB06/03 and CB12/03/30,016), the State Agency for Research (PID2019-108973RB- C21 and C22), the Valencia Government (GRUPOS 03/101; PROMETEO/2009/029 and ACOMP/2013/039, IDI FEDER/2021/072 and GRISOLIAP/2021/119), the Castilla-Leon Government (GRS/279/A/08) and European Network of Excellence Ingenious Hypercare (EPSS-037093) from the European Commission. The Strategic Action for Research in Health sciences, CIBERDEM and CIBEROBN are initiatives from Carlos III Health Institute Madrid and cofunded with European Funds for Regional Development (FEDER). The State Agency for Research and Carlos III Health Institute belong to the Spanish Ministry of Science and Innovation. ADR received the support of a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MGP received the support of a fellowship from “la Caixa” Foundation (ID 100010434, fellowship code LCFLCF/BQ/DI18/11660001). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.S

Bootstrapped-ensemble-based Sensitivity Analysis of a trace thermal-hydraulic model based on a limited number of PWR large break loca simulations

[EN] The safety verification of nuclear systems can be done by analyzing the outputs of Best-Estimate Thermal-Hydraulic (BE-TH) codes, which allow predicting the system response under safe and accidental conditions with greater realism as compared to conservative TH codes. In this case, it is necessary to quantify and control the uncertainties in the analysis, which affect the estimated safety margins. This can be achieved by Sensitivity Analysis (SA) and Uncertainty Analysis (UA) techniques tailored to handle the large computational costs of TH codes. This work presents an Ensemble-Based Sensitivity Analysis (EBSA) based on Finite Mixture Model (FMM) as an effective solution to keep low the code runs and handle the uncertainty in the SA methods. The approach proposed is challenged against a situation of a very low number of code runs: the Bootstrap method is, then, used in support. Three different strategies based on EBSA and Bootstrap are set forth (i.e., bottom-up, all-out and filter strategies). An application is provided with respect to a Large Break Loss of Coolant Accident (LBLOCA) simulated by a TRACE model of the Zion 1 Nuclear Power Plant (NPP).Di Maio, F.; Bandini, A.; Zio, E.; Carlos Alberola, S.; Sanchez Saez, F.; Martorell Alsina, SS. (2016). Bootstrapped-ensemble-based Sensitivity Analysis of a trace thermal-hydraulic model based on a limited number of PWR large break loca simulations. Reliability Engineering & System Safety. 153:122-134. doi:10.1016/j.ress.2016.04.013S12213415

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use

Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years

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