Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI)

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3–7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb/V and dialysis in Spanish clinical practice – preliminary data Vie-KinD study

Poster presentatio

Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials

[EN] Combining several theories this paper presents a general multiphysics framework applied to the study of coupled and active materials, considering mechanical, electric, magnetic and thermal fields. The framework is based on thermodynamic equilibrium and non-equilibrium interactions, both linked by a two-temperature model. The multi-coupled governing equations are obtained from energy, momentum and entropy balances; the total energy is the sum of thermal, mechanical and electromagnetic parts. The momentum balance considers mechanical plus electromagnetic balances; for the latter the Abraham rep- resentation using the Maxwell stress tensor is formulated. This tensor is manipulated to automatically fulfill the angular momentum balance. The entropy balance is for- mulated using the classical Gibbs equation for equilibrium interactions and non-equilibrium thermodynamics. For the non-linear finite element formulations, this equation requires the transformation of thermoelectric coupling and conductivities into tensorial form. The two-way thermoe- lastic Biot term introduces damping: thermomechanical, pyromagnetic and pyroelectric converse electromagnetic dynamic interactions. Ponderomotrix and electromagnetic forces are also considered. The governing equations are converted into a variational formulation with the resulting four-field, multi-coupled formalism implemented and val- idated with two custom-made finite elements in the research code FEAP. Standard first-order isoparametric eight-node elements with seven degrees of freedom (dof) per node (three displacements, voltage and magnetic scalar potentials plus two temperatures) are used. Non-linearities and dynamics are solved with Newton-Raphson and New- mark-b algorithms, respectively. Results of thermoelectric, thermoelastic, thermomagnetic, piezoelectric, piezomag- netic, pyroelectric, pyromagnetic and galvanomagnetic interactions are presented, including non-linear depen- dency on temperature and some second-order interactions.This research was partially supported by grants CSD2008-00037 Canfranc Underground Physics, Polytechnic University of Valencia under programs PAID 02-11-1828 and 05-10-2674. The first author used the grant Generalitat Valenciana BEST/2014/232 for the completion of this work.Pérez-Aparicio, JL.; Palma, R.; Taylor, R. (2016). Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials. Archives of Computational Methods in Engineering. 23:535-583. https://doi.org/10.1007/s11831-015-9149-9S53558323Abraham M (1910) Sull’elettrodinamica di Minkowski. 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Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Dietary α‐Linolenic Acid, Marine ω‐3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study

Background: Epidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω‐3 fatty acids (long‐chain n‐3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all‐cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long‐chain n‐3 polyunsaturated fatty acids (≥500 mg/day). Methods and Results: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable‐adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9‐y follow‐up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all‐cause mortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long‐chain n‐3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all‐cause mortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all‐cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all‐cause mortality, whereas protection from cardiac mortality is limited to fish‐derived long‐chain n‐3 polyunsaturated fatty acids. Clinical Trial Registration URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts