Exchange-Rate Pass-Through to Import Prices in the Euro Area

This paper presents an empirical analysis of transmission rates from exchange rate movements to import prices, across countries and product categories, in the euro area over the last fifteen years. Our results show that the transmission of exchange rate changes to import prices in the short run is high, although incomplete, and that it differs across industries and countries; in the long run, exchange rate pass-through is higher and close to one. We find no strong statistical evidence that the introduction of the euro caused a structural change in this transmission. Although estimated point elasticities seem to have declined since the introduction of the euro, we find little evidence of a structural break in the transmission of exchange rate movements except in the case of some manufacturing industries. And since the euro was introduced, industries producing differentiated goods have been more likely to experience reduced rates of exchange rate pass-through to import prices. Exchange rate changes continue to lead to large changes in import prices across euro-area countries.

How cyclical do cyclically-adjusted balances remain? An EU study

Observed budget balances are an imperfect indicator of the fiscal policy stance, because fluctuations in economic activity induce automatic changes in the balance, hence the use of cyclically-adjusted balances (CAB). However, this paper shows that CABs (as measured through one of the two methods currently used by the Commission) tend to be systematically overestimated during downturns and underestimated during expansions. The dominant source of this distortion arises from the filtering of revenues deemed to be cyclical, possibly signalling a problem with the computation of elasticities. The effect of the items which are assumed not to move with the cycle is non significant, but this overall result conceals offseting effects: public investment turns to be significantly procyclical and interest payments and transfers to firms are countercyclical. Classification-JEL : H6, E6.. cyclically adjusted balances, fiscal policy, EU.

Indicadores de calidad en cardiología. Principales indicadores para medir la calidad de los resultados (indicadores de resultados) y parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). INCARDIO (Indicadores de Calidad en Unidades Asistenciales del Área del Corazón): Declaración de posicionamiento de consenso de SEC/SECTCV

ResumenLa práctica clínica cardiológica requiere una organización compleja que influya en los resultados globales y puede diferir sustancialmente entre distintos hospitales y comunidades. El objetivo de este documento de consenso es definir indicadores de calidad en cardiología, incluidos los indicadores para medir la calidad de los resultados (indicadores de resultados) y los parámetros de calidad relacionados con mejores resultados en la práctica clínica (indicadores de práctica asistencial). El documento está destinado principalmente al sistema de asistencia sanitaria de España y puede servir de base para documentos similares en otros países.AbstractCardiology practice requires complex organization that impacts overall outcomes and may differ substantially among hospitals and communities. The aim of this consensus document is to define quality markers in cardiology, including markers to measure the quality of results (outcomes metrics) and quality measures related to better results in clinical practice (performance metrics). The document is mainly intended for the Spanish health care system and may serve as a basis for similar documents in othe rcountries

Lifestyles, arterial aging, and its relationship with the intestinal and oral microbiota (MIVAS III study): a research protocol for a cross-sectional multicenter study

The microbiota is increasingly recognized as a significant factor in the pathophysiology of many diseases, including cardiometabolic diseases, with lifestyles probably exerting the greatest influence on the composition of the human microbiome. The main objectives of the study are to analyze the association of lifestyles (diet, physical activity, tobacco, and alcohol) with the gut and oral microbiota, arterial aging, and cognitive function in subjects without cardiovascular disease in the Iberian Peninsula. In addition, the study will examine the mediating role of the microbiome in mediating the association between lifestyles and arterial aging as well as cognitive function.Methods and analysisMIVAS III is a multicenter cross-sectional study that will take place in the Iberian Peninsula. One thousand subjects aged between 45 and 74 years without cardiovascular disease will be selected. The main variables are demographic information, anthropometric measurements, and habits (tobacco and alcohol). Dietary patterns will be assessed using a frequency consumption questionnaire (FFQ) and the Mediterranean diet adherence questionnaire. Physical activity levels will be evaluated using the International Physical Activity Questionnaire (IPAQ), Marshall Questionnaire, and an Accelerometer (Actigraph). Body composition will be measured using the Inbody 230 impedance meter. Arterial aging will be assessed through various means, including measuring medium intimate carotid thickness using the Sonosite Micromax, conducting analysis with pulse wave velocity (PWA), and measuring pulse wave velocity (cf-PWV) using the Sphygmocor System. Additional cardiovascular indicators such as Cardio Ankle Vascular Index (CAVI), ba-PWV, and ankle-brachial index (Vasera VS-2000®) will also be examined. The study will analyze the intestinal microbiota using the OMNIgene GUT kit (OMR−200) and profile the microbiome through massive sequencing of the 16S rRNA gene. Linear discriminant analysis (LDA), effect size (LEfSe), and compositional analysis, such as ANCOM-BC, will be used to identify differentially abundant taxa between groups. After rarefying the samples, further analyses will be conducted using MicrobiomeAnalyst and R v.4.2.1 software. These analyses will include various aspects, such as assessing α and β diversity, conducting abundance profiling, and performing clustering analysis.DiscussionLifestyle acts as a modifier of microbiota composition. However, there are no conclusive results demonstrating the mediating effect of the microbiota in the relationship between lifestyles and cardiovascular diseases. Understanding this relationship may facilitate the implementation of strategies for improving population health by modifying the gut and oral microbiota

Novel variants in GALE cause syndromic macrothrombocytopenia by disrupting glycosylation and thrombopoiesis

Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, is involved in galactose metabolism and protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, and jaundice. Whole-exome sequencing revealed 4 variants that affect GALE, 3 of those previously unreported (Pedigree A, p.Lys78ValfsX32 and p.Thr150Met; Pedigree B, p.Val128Met; and p.Leu223Pro). Platelet phenotype analysis showed giant and/or grey platelets, impaired platelet aggregation, and severely reduced alpha and dense granule secretion. Enzymatic activity of the UDP-galactose-4-epimerase enzyme was severely decreased in all patients. Immunoblotting of platelet lysates revealed reduced GALE protein levels, a significant decrease in N-acetyl-lactosamine (LacNAc), showing a hypoglycosylation pattern, reduced surface expression of gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex and mature β1 integrin, and increased apoptosis. In vitro studies performed with patients-derived megakaryocytes showed normal ploidy and maturation but decreased proplatelet formation because of the impaired glycosylation of the GPIbα and β1 integrin, and reduced externalization to megakaryocyte and platelet membranes. Altered distribution of filamin A and actin and delocalization of the von Willebrand factor were also shown. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasizes the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function.This work was supported by grants from Instituto de Salud Carlos III (ISCIII) & Feder (PI17/01966, PI20/00926) and cofunded by European Union (ERDF/ESF, “Investing in your future”), Gerencia Regional de Salud (GRS2061/A/2019, GRS2135/A/2020, GRS2314/A/2021), Fundación Mutua Madrileña (FMM, AP172142019), Sociedad Española de Trombosis y Hemostasia (SETH-FETH; Premio López Borrasca 2019 and Ayuda a Grupos de Trabajo en Patología Hemorrágica 2020 and 2021), Fundación Castellano Leonesa de Hematología y Hemoterapia (FUCALHH 2020), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD12/0036/0069), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233). Progetti di ricerca di rilevante interesse Nazionale (PRIN 2017Z5LR5Z), and the European Commission (H2020-FETOPEN-1-2016-2017-SilkFusion ID 767309). The author´s research on Inherited Platelet Disorders is conducted in accordance with the aims of the multicentric project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” of Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC). A.M.-Q. is fully supported by an “Ayuda predoctoral de la Junta de Castilla y León” by the Fondo Social Europeo (JCYL- EDU/556/2019 PhD scholarship) and received an “Ayuda para breves estancias formativas” from the Sociedad Española de Hematología y Hemoterapia (SEHH-FEHH), and from the Sociedad Española de Trombosis y Hemostasia (SETH-FETH); E.V. is fully supported by an “Ayuda para contratos predoctorales de la Universidad de Salamanca cofinanciadas por el banco Santander,” programa propio III convocatoria 2018; I.S.-G. is supported by a contract from the University of Salamanca cofinanced by the Junta de Castilla y León (Council of Education) and FEDER-European Union [ref. SA0118P20 (2)]; S.S.-M. and C.M.-G. received funding from the European Research Council (ERC) under the ERA-Per-Med programme (ERAPERMED2018-275) SYNtherapy and ISCIII (AC18/00093) cofunded by ERDF/ESF, “Investing in your future”; I.G.-T. and R.B. are supported by a grant from the Universidad de Salamanca (“Contrato postdoctoral Universidad de Salamanca programa propio II, 2019”)Peer reviewe

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006

TRAF3 alterations are frequent in del-3′IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3′IGH (del-3′IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3′IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3′IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3′IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3′IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3′IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.Funding information: Universidad de Salamanca; Fundación Española de Hematología y Hemoterapia (FEHH); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Grant/Award Number: CB16/12/00233; Red Temática de Investigación Cooperativa en Cáncer (RTICC); “Fundación Memoria Don Samuel Solórzano Barruso”: FS/33–2020, Grant/Award Number: RD12/0036/0069; “Gerencia Regional de Salud, SACYL”:, Grant/Award Numbers: GRS2385/A/21, GRS2140/A/20; Consejería de Educación, Junta de Castilla y León, Grant/Award Number: SA118P20; European Regional Development Fund and Instituto de Salud Carlos III, Grant/Award Numbers: CD19/00222, FI19/00191; Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI21/00983, PI18/0150

Impact of operatoŕs experience on peri-procedural outcomes with Watchman FLX: Insights from the FLX-SPA registry

Background: The Watchman FLX is a device upgrade of the Watchman 2.5 that incorporates several design enhancements intended to simplify left atrial appendage occlusion (LAAO) and improve procedural outcomes. This study compares peri-procedural results of LAAO with Watchman FLX (Boston Scientific, Marlborough, Massachusetts) in centers with varying degrees of experience with the Watchman 2.5 and Watchman FLX. Methods: Prospective, multicenter, 'real-world' registry including consecutive patients undergoing LAAO with the Watchman FLX at 26 Spanish sites (FLX-SPA registry). Implanting centers were classified according to the center's prior experience with the Watchman 2.5. A further division of centers according to whether or not they had performed ≤ 10 or > 10Watchman FLX implants was prespecified at the beginning of the study. Procedural outcomes of institutions stratified according to their experience with the Watchman 2.5 and FLX devices were compared. Results: 359 patients [mean age 75.5 (SD8.1), CHA2DS2-VASc 4.4 (SD1.4), HAS-BLED 3.8(SD0.9)] were included. Global success rate was 98.6%, successful LAAO with the first selected device size was achieved in 95.5% patients and the device was implanted at first attempt in 78.6% cases. There were only 9(2.5%) major peri-procedural complications. No differences in efficacy or safety results according to the centeŕs previous experience with Watchman 2.5 and procedural volume with Watchman FLX existed. Conclusions: The Watchman FLX attains high procedural success rates with complete LAA sealing in unselected, real-world patients, along with a low incidence of peri-procedural complications, regardless of operatoŕs experience with its previous device iteration or the number of Watchman FLX devices implanted

Laying the Foundations for a Human-Predator Conflict Solution: Assessing the Impact of Bonelli's Eagle on Rabbits and Partridges

BACKGROUND: Predation may potentially lead to negative effects on both prey (directly via predators) and predators (indirectly via human persecution). Predation pressure studies are, therefore, of major interest in the fields of theoretical knowledge and conservation of prey or predator species, with wide ramifications and profound implications in human-wildlife conflicts. However, detailed works on this issue in highly valuable--in conservation terms--Mediterranean ecosystems are virtually absent. This paper explores the predator-hunting conflict by examining a paradigmatic, Mediterranean-wide (endangered) predator-two prey (small game) system. METHODOLOGY/PRINCIPAL FINDINGS: We estimated the predation impact ('kill rate' and 'predation rate', i.e., number of prey and proportion of the prey population eaten, respectively) of Bonelli's eagle Aquila fasciata on rabbit Oryctolagus cuniculus and red-legged partridge Alectoris rufa populations in two seasons (the eagle's breeding and non-breeding periods, 100 days each) in SE Spain. The mean estimated kill rate by the seven eagle reproductive units in the study area was c. 304 rabbits and c. 262 partridges in the breeding season, and c. 237 rabbits and c. 121 partridges in the non-breeding period. This resulted in very low predation rates (range: 0.3-2.5%) for both prey and seasons. CONCLUSIONS/SIGNIFICANCE: The potential role of Bonelli's eagles as a limiting factor for rabbits and partridges at the population scale was very poor. The conflict between game profitability and conservation interest of either prey or predators is apparently very localised, and eagles, quarry species and game interests seem compatible in most of the study area. Currently, both the persecution and negative perception of Bonelli's eagle (the 'partridge-eating eagle' in Spanish) have a null theoretical basis in most of this area