Dynamic Edematous Response of the Human Heart to Myocardial Infarction Implications for Assessing Myocardial Area at Risk and Salvage

BACKGROUND: Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment-elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model. METHODS: A total of 16 patients with anterior ST-segment-elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment-elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements. RESULTS: In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography. CONCLUSIONS: Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post-ST-segment-elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.This study was partially supported by a competitive grant from the Spanish Society of Cardiology (Proyectos de Investigacion Traslacional en Cardiologia de la Sociedad Espanola de Cardiologia 2015, for the project Caracterizacion tiSUlar miocaRdica con resonancia magnetica en pacientes tras inFarto agudo de mioCardio con elevacioN de ST sometidos a angloplastia Coronaria primaria. Estudio SURF-CNIC), by a competitive grant from the Carlos III Institute of Health-Fondo de Investigacion Sanitaria- and the European Regional Development Fund (ERDF/FEDER) (PI10/02268 and PI13/01979), the Spanish Ministry of economy, industry, and competitiveness (MEIC) and ERDF/FEDER SAF2013-49663-EXP. Dr Fernandez-Jimenez holds a FICNIC fellowship from the Fundacio Jesus Serra, the Fundacion Interhospitalaria de Investigacion Cardiovascular, and the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), and Dr Aguero is a FP7-PEOPLE-2013-ITN-Cardionext fellow. This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare, and is part of a bilateral research program between Hospital de Salamanca Cardiology Department and the CNIC. This research program is part of an institutional agreement between FIIS-Fundacion Jimenez Diaz and CNIC. The CNIC is supported by the MEIC and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).S

Band gap creation using quasiordered structures based on sonic crystals

It is well known that sonic crystals are periodic structures that present acoustic band gaps attenuation centered at frequencies related with the lattice constant of the structure. We present an approach based on genetic algorithms to create band gaps in a predetermined range of frequencies. The mechanism used by genetic algorithms to achieve this objective is the creation of vacancies in a starting sonic crystal, built with air-embedded rigid scatterers. As a result of the optimization process, we obtain quasiordered structures on which acoustic properties are based in the multiple scattering theory. (c) 2006 American Institute of Physics.Romero García, V.; Fuster García, E.; García-Raffi, LM.; Sánchez Pérez, EA.; Sopena Novales, M.; Llinares Galiana, J.; Sánchez Pérez, JV. (2006). Band gap creation using quasiordered structures based on sonic crystals. Applied Physics Letters. 88(17):1741041-1741043. doi:10.1063/1.2198012S174104117410438817Cervera, F., Sanchis, L., Sánchez-Pérez, J. V., Martínez-Sala, R., Rubio, C., Meseguer, F., … Sánchez-Dehesa, J. (2001). Refractive Acoustic Devices for Airborne Sound. Physical Review Letters, 88(2). doi:10.1103/physrevlett.88.023902Sanchis, L., Håkansson, A., Cervera, F., & Sánchez-Dehesa, J. (2003). Acoustic interferometers based on two-dimensional arrays of rigid cylinders in air. Physical Review B, 67(3). doi:10.1103/physrevb.67.035422Hughes, G., & Andújar, J. L. G. (1997). Simple rules with complex outcomes. Nature, 387(6630), 241-242. doi:10.1038/387241a0Sánchez-Pérez, J. V., Caballero, D., Mártinez-Sala, R., Rubio, C., Sánchez-Dehesa, J., Meseguer, F., … Gálvez, F. (1998). Sound Attenuation by a Two-Dimensional Array of Rigid Cylinders. Physical Review Letters, 80(24), 5325-5328. doi:10.1103/physrevlett.80.5325Montero de Espinosa, F. R., Jiménez, E., & Torres, M. (1998). Ultrasonic Band Gap in a Periodic Two-Dimensional Composite. Physical Review Letters, 80(6), 1208-1211. doi:10.1103/physrevlett.80.1208Caballero, D., Sánchez-Dehesa, J., Martínez-Sala, R., Rubio, C., Sánchez-Pérez, J. V., Sanchis, L., & Meseguer, F. (2001). Suzuki phase in two-dimensional sonic crystals. Physical Review B, 64(6). doi:10.1103/physrevb.64.064303Liu, Z. (2000). Locally Resonant Sonic Materials. Science, 289(5485), 1734-1736. doi:10.1126/science.289.5485.1734Hirsekorn, M., Delsanto, P. ., Batra, N. ., & Matic, P. (2004). Modelling and simulation of acoustic wave propagation in locally resonant sonic materials. Ultrasonics, 42(1-9), 231-235. doi:10.1016/j.ultras.2004.01.014Hirsekorn, M. (2004). Small-size sonic crystals with strong attenuation bands in the audible frequency range. Applied Physics Letters, 84(17), 3364-3366. doi:10.1063/1.1723688Umnova, O., Attenborough, K., & Linton, C. M. (2006). Effects of porous covering on sound attenuation by periodic arrays of cylinders. The Journal of the Acoustical Society of America, 119(1), 278-284. doi:10.1121/1.2133715Hu, X., Chan, C. T., & Zi, J. (2005). Two-dimensional sonic crystals with Helmholtz resonators. Physical Review E, 71(5). doi:10.1103/physreve.71.055601Tournat, V., Pagneux, V., Lafarge, D., & Jaouen, L. (2004). Multiple scattering of acoustic waves and porous absorbing media. Physical Review E, 70(2). doi:10.1103/physreve.70.026609Chen, Y.-Y., & Ye, Z. (2001). Theoretical analysis of acoustic stop bands in two-dimensional periodic scattering arrays. Physical Review E, 64(3). doi:10.1103/physreve.64.036616Sanchis, L., Cervera, F., Sánchez-Dehesa, J., Sánchez-Pérez, J. V., Rubio, C., & Martínez‐Sala, R. (2001). Reflectance properties of two-dimensional sonic band-gap crystals. The Journal of the Acoustical Society of America, 109(6), 2598-2605. doi:10.1121/1.1369784Håkansson, A., Sánchez-Dehesa, J., & Sanchis, L. (2004). Acoustic lens design by genetic algorithms. Physical Review B, 70(21). doi:10.1103/physrevb.70.214302Sanchis, L., Håkansson, A., López-Zanón, D., Bravo-Abad, J., & Sánchez-Dehesa, J. (2004). Integrated optical devices design by genetic algorithm. Applied Physics Letters, 84(22), 4460-4462. doi:10.1063/1.1738931Håkansson, A., Cervera, F., & Sánchez-Dehesa, J. (2005). Sound focusing by flat acoustic lenses without negative refraction. Applied Physics Letters, 86(5), 054102. doi:10.1063/1.185271

Lessons Learned From 10 Years of Preschool Intervention for Health Promotion: JACC State-of-the-Art Review.

Implementing a health promotion program for children is a complex endeavor. In this review, we outline the key lessons learned over 10 years of experience in implementing the SI! Program (Salud Integral-Comprehensive Health) for cardiovascular health promotion in preschool settings in 3 countries: Colombia (Bogotá), Spain (Madrid), and the United States (Harlem, New York). By matching rigorous efficacy studies with implementation science, we can help bridge the divide between science and educational practice. Achieving sustained lifestyle changes in preschool children through health promotion programs is likely to require the integration of several factors: 1) multidisciplinary teams; 2) multidimensional educational programs; 3) multilevel interventions; 4) local program coordination and community engagement; and 5) scientific evaluation through randomized controlled trials. Implementation of effective health promotion interventions early in life may induce long-lasting healthy behaviors that could help to curb the cardiovascular disease epidemic.This work is supported by the SHE Foundation and “la Caixa” Foundation (LCF/CE16/10700001). The project in Colombia was funded by Santo Domingo Foundation; the study in the United States (FAMILIA) was funded by the American Heart Association (grant no. 14SFRN20490315); and the study in Spain (SI! Program) was funded by the SHE Foundation, the research grant FIS-PI11/ 01885 (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III), and Fundació la Marató de TV3 (369/C/2016). Dr SantosBeneit is the recipient of grant LCF/PR/MS19/12220001 funded by “la Caixa” Foundation (ID 100010434). Dr Fernández-Jiménez is the recipient of grant PI19/01704 funded by the Fondo de Investigación Sanitaria–Instituto de Salud Carlos III and co-funded by the European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future.” The Centro Nacional de Investigaciones Cardiovasculares is supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review

[EN] Purpose: To systematically review evidence regarding the association of multi-parametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th , 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and high-risk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, alpha=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.This work was supported by the Spanish Ministry for Investigation, Development and Innovation project with identification number DPI2016-80054-R.Oltra-Sastre, M.; Fuster García, E.; Juan -Albarracín, J.; Sáez Silvestre, C.; Perez-Girbes, A.; Sanz-Requena, R.; Revert-Ventura, A.... (2019). 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Immunotherapy with CAR-T cells in paediatric haematology-oncology

Despite being a rare disease, cancer is the first cause of mortality due to disease during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CAR-T19 cells, has opened up a new scenario in the approach to haematology tumours like acute lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of identifying the centres most suitable for their administration, but also the need for these to undergo a profound change in order that their healthcare activity is extended, in some cases, to the ability for the in-house manufacture of these types of therapies. The hospitals specialised in paediatric haematology-oncology thus have the challenge of progressing towards a healthcare model that integrates cellular immunotherapy, having the appropriate capacity to manage all aspects relative to their use, manufacture, and administration of these new treatments.A pesar de ser una enfermedad rara, el cáncer es la primera causa de mortalidad por enfermedad durante la edad pediátrica en los países desarrollados. En este momento, la irrupción de nuevos tratamientos como la inmunoterapia constituye un nuevo paradigma clínico y regulatorio. Uno de estos tipos de inmunoterapia es la inmunoterapia celular. En particular, los medicamentos de terapia avanzada con receptores antigénicos quiméricos en los linfocitos T (CAR-T), y en concreto las células CAR-T19, han supuesto un nuevo escenario en el abordaje de los tumores hematológicos, como la leucemia aguda linfoblástica y los linfomas de células tipo B. La aprobación por las autoridades regulatorias de tisagenlecleucel y axicabtagene ciloleucel,ha impulsado la puesta en marcha del Plan Nacional de Terapias Avanzadas-Medicamentos CAR-T en España, evidenciándose no solo la conveniencia de identificar los centros más adecuados para su administración, sino la necesidad de que estos sufran una profunda transformación para que su actividad asistencial se extienda en algunos casos a la capacidad de fabricación propia de este tipo de terapias. Los hospitales especializados en hematooncología pediátrica tienen por tanto el reto de evolucionar hacia un modelo asistencial que integre la inmunoterapia celular,dotándose de capacidad propia para gestionar todos los aspectos relativos al uso, fabricación y administración de estos nuevos tratamientos.Fundación CRIS contra el cáncer

Combined fit to the spectrum and composition data measured by the Pierre Auger Observatory including magnetic horizon effects

The measurements by the Pierre Auger Observatory of the energy spectrum and mass composition of cosmic rays can be interpreted assuming the presence of two extragalactic source populations, one dominating the flux at energies above a few EeV and the other below. To fit the data ignoring magnetic field effects, the high-energy population needs to accelerate a mixture of nuclei with very hard spectra, at odds with the approximate E$^{-2}$ shape expected from diffusive shock acceleration. The presence of turbulent extragalactic magnetic fields in the region between the closest sources and the Earth can significantly modify the observed CR spectrum with respect to that emitted by the sources, reducing the flux of low-rigidity particles that reach the Earth. We here take into account this magnetic horizon effect in the combined fit of the spectrum and shower depth distributions, exploring the possibility that a spectrum for the high-energy population sources with a shape closer to E$^{-2}$ be able to explain the observations

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (X$_{max}$) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1-10 EeV, a new analysis technique has been developed by combining the FD-based measurement of X$_{max}$ with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy