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Spin qubits defined by valence band hole states are attractive for quantum information processing due to their inherent coupling to electric fields, enabling fast and scalable qubit control. Heavy holes in germanium are particularly promising, with recent demonstrations of fast and high-fidelity qubit operations. However, the mechanisms and anisotropies that underlie qubit driving and decoherence remain mostly unclear. Here we report the highly anisotropic heavy-hole g -tensor and its dependence on electric fields, revealing how qubit driving and decoherence originate from electric modulations of the g -tensor. Furthermore, we confirm the predicted Ising-type hyperfine interaction and show that qubit coherence is ultimately limited by 1/ f charge noise, where f is the frequency. Finally, operating the qubit at low magnetic field, we measure a dephasing time of T 2 *  = 17.6 μs, maintaining single-qubit gate fidelities well above 99% even at elevated temperatures of T  > 1 K. This understanding of qubit driving and decoherence mechanisms is key towards realizing scalable and highly coherent hole qubit arrays. The authors report the sweet-spot operation of germanium hole spin qubits, exploring the optimization of the external magnetic field orientation, the g -tensor and its electric tunability, and hyperfine interactions.

The common black box nature of machine learning models is an obstacle to their application in health care context. Their widespread application is limited by a significant “lack of trust.” So, the main goal of this work is the development of an evaluation approach that can assess, simultaneously, trust and performance. Trust assessment is based on (i) model robustness (stability assessment), (ii) confidence (95% CI of geometric mean), and (iii) interpretability (comparison of respective features ranking with clinical evidence). Performance is assessed through geometric mean. For validation, in patients’ stratification in cardiovascular risk assessment, a Portuguese dataset ( N =1544) was applied. Five different models were compared: (i) GRACE score, the most common risk assessment tool in Portugal for patients with acute coronary syndrome; (ii) logistic regression; (iii) Naïve Bayes; (iv) decision trees; and (v) rule-based approach, previously developed by this team. The obtained results confirm that the simultaneous assessment of trust and performance can be successfully implemented. The rule-based approach seems to have potential for clinical application. It provides a high level of trust in the respective operation while outperformed the GRACE model’s performance, enhancing the required physicians’ acceptance. This may increase the possibility to effectively aid the clinical decision. Graphical abstract

In semiconductor hole spin qubits, low magnetic field ( B ) operation extends the coherence time ( T 2 * ) but proportionally reduces the gate speed. In contrast, singlet-triplet (ST) qubits are primarily controlled by the exchange interaction (  J ) and can thus maintain high gate speeds even at low B . However, a large J introduces a significant charge component to the qubit, rendering ST qubits more vulnerable to charge noise when driven. Here, we demonstrate a highly coherent ST hole spin qubit in germanium, operating at both low B and low J . By modulating J , we achieve resonant driving of the ST qubit, obtaining an average gate fidelity of 99.68% and a coherence time of T 2 * = 1.9 μ s . Moreover, by applying the resonant drive continuously, we realize a dressed ST qubit with a tenfold increase in coherence time ( T 2 ρ * = 20.3 μ s ). Frequency modulation of the driving signal enables universal control, with an average gate fidelity of 99.63%. Our results demonstrate the potential for extending coherence times while preserving high-fidelity control of germanium-based ST qubits, paving the way for more efficient operations in semiconductor-based quantum processors. Hole spin qubits in germanium have seen significant advancements, though improving control and noise resilience remains a key challenge. Here, the authors realize a dressed singlet-triplet qubit in germanium, achieving frequency-modulated high-fidelity control and a tenfold increase in coherence time.

Background:Perseverance in pharmacological treatment for osteoporosis is a key factor in fracture prevention. Denosumab has demonstrated superior persistence compared to other anti-osteoporotic drugs in previous studies. Patient-related factors may influence treatment persistence.Objectives:To describe the characteristics of a cohort of patients undergoing denosumab treatment. To assess clinical and/or demographic characteristics that are significantly associated with treatment persistence.Methods:Patients diagnosed with osteoporosis aged over 50, visited in Rheumatology outpatient clinics of three hospitals in Tarragona, who were prescribed denosumab between January 2013 and December 2023 and had received at least two doses of denosumab. Clinical and demographic data were collected from the patients’ medical records. Logistical regression analysis was conducted to examine the relationship between different factors and treatment persistence. The variables studied included age, gender, polypharmacy, Charlson index, cognitive status, fracture risk, use of psychoactive drugs, previous osteoporotic fractures and previous osteoporosis treatments.Results:A total of 854 patients were recruited. Patients lost to treatment due to death (130 patients) and withdrawal due to improvement according to medical criteria (108) were excluded. 616 patients were analyzed. The characteristics of these patients are shown in Table 1. A total of 468 patients continued with treatment (76%) while 148 discontinued it (24%). The mean follow-up time was 59 months (minimum 12 – maximum 144). Variables significantly associated with lower treatment discontinuation were previous osteoporosis treatment (OR=0.67; CI: 0.48-0.93); polypharmacy with 5-10 drugs (OR 0.66; CI 0.45-0.95); polypharmacy with more than 10 drugs (OR 0.6; CI 0.37-0.97). The variable significantly associated with higher discontinuation was dementia (OR 1.96; CI 1.34-2.89).Conclusion:The studied cohort comprises an aging population with high comorbidity, a significant presence of dementia, and polypharmacy. Denosumab treatment persistence is significantly influenced by patient’s cognitive status, use of more than 5 drugs, and having received previous osteoporosis treatments. These factors should be considered when initiating long-term treatments, reevaluating the type of treatment, and reinforcing follow-up for these patients.Table 1.Characteristics of the analyzed populationN = 616Age (median, IQR)81 (74 – 87)Sex (n women, %)560, 90.90%Cognitive state (n, %) Good470, 76.30% Mild dementia115, 18.66% Moderate dementia30, 4.87%Densitometry at diagnosis (yes, %)416, 67.53%Column densitometry values T-score (median, IQR)-3.10 (-3.70 - -2.37)Hip densitometry values T-score (median, IQR)-2.50 (-2.90 - -1.90)Vitamin D values before starting treatment ng/dl (median, IQR)33.80 (28 – 44)Osteoporosis risk (n, %) High263, 42.69% Very high353, 57.31%Charlson index (median, IQR)4 (3 – 6)Psychoactive drugs (yes, %)311, 50.49%Corticoids (n, %) Up to 5 mg prednisone63, 10.22% More than 5 mg prednisone27, 4.38% No524, 85.06%Polypharmacy (n, %) Up to 5 different drugs205, 33.28% Between 5 and 10293, 47.56% More than 10116, 18.83%Previous osteoporotic fracture (n, %) Other fractures23, 3.73% Hip122, 19.81% Vertebral204, 33.11% No186, 30.19%Previous osteoporosis treatment (n, %) IV Bisphosphonates25, 4.06% Oral bisphosphonates213, 34.58% Teriparatide102, 16.56% No274, 44.48%REFERENCES:[1]   Reyes C, et al. One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. Osteoporos Int. 2017 Oct;28(10):2997-3004.[2]   Llop C, et al. Cumplimiento y permanencia de los tratamientos para la osteoporosis en pacientes con fractura de cadera. Aten primaria 2020;52(9):659-660.Acknowledgements:NIL.Disclosure of Interests:Silvia Paredes Galapagos, Novartis, Lilly, Amgen, Abbvie, Delia Taverner Janssen, Galapagos, Abbvie, Novartis, Ester Costa Janssen, Galapagos, Anna Pàmies Lilly, Galapagos, Amgen y Novartis, Carles Tomas: None declared, Didac Llop: None declared, Carles Llop: None declared.

Artificial intelligence (AI) has achieved notable performances in many fields and its research impact in healthcare has been unquestionable. Nevertheless, the deployment of such computational models in clinical practice is still limited. Some of the major issues recognized as barriers to a successful real-world machine learning applications include lack of: transparency; reliability and personalization. Actually, these aspects are decisive not only for patient safety, but also to assure the confidence of professionals. Explainable AI aims at to achieve solutions for artificial intelligence transparency and reliability concerns, with the capacity to better understand and trust a model, providing the ability to justify its outcomes, thus effectively assisting clinicians in rationalizing the model prediction. This work proposes an innovative machine learning based approach, implementing a hybrid scheme, able to combine in a systematic way knowledge-driven and data-driven techniques. In a first step a global set of interpretable rules is generated, founded on clinical evidence. Then, in a second phase, a machine learning model is trained to select, from the global set of rules, the subset that is more appropriate for a given patient, according to his particular characteristics. This approach addresses simultaneously three of the central requirements of explainable AI—interpretability, personalization, and reliability—without impairing the accuracy of the model’s prediction. The scheme was validated with a real dataset provided by two Portuguese Hospitals, the Santa Cruz Hospital, Lisbon, and the Santo André Hospital, Leiria, comprising a total of N = 1111 patients that suffered an acute coronary syndrome event, where the 30 days mortality was assessed. When compared with standard black-box structures (e.g. feedforward neural network) the proposed scheme achieves similar performances, while ensures simultaneously clinical interpretability and personalization of the model, as well as provides a level of reliability to the estimated mortality risk.

Melatonin and serotonin rhythms, which exhibit a close association with the endogenous circadian component of sleep, are attenuated with increasing age. This decrease seems to be linked to sleep alterations in the elderly. Chrononutrition is a field of chronobiology that establishes the principle of consuming foodstuffs at times of the day when they are more useful for health, improving, therefore, biorhythms and physical performance. Our aim was to analyze whether the consumption of cereals enriched with tryptophan, the precursor of both serotonin and melatonin, may help in the reconsolidation of the sleep/wake cycle and counteract depression and anxiety in 35 middle-aged/elderly (aged 55–75 year) volunteers in a simple blind assay. Data were collected for 3 weeks according to the following schedule: The control week participants consumed standard cereals (22.5 mg tryptophan in 30 g cereals per dose) at breakfast and dinner; for the treatment week, cereals enriched with a higher dose of tryptophan (60 mg tryptophan in 30 g cereals per dose) were eaten at both breakfast and dinner; the posttreatment week volunteers consumed their usual diet. Each participant wore a wrist actimeter that logged activity during the whole experiment. Urine was collected to analyze melatonin and serotonin urinary metabolites and to measure total antioxidant capacity. The consumption of cereals containing the higher dose in tryptophan increased sleep efficiency, actual sleep time, immobile time, and decreased total nocturnal activity, sleep fragmentation index, and sleep latency. Urinary 6-sulfatoxymelatonin, 5-hydroxyindoleacetic acid levels, and urinary total antioxidant capacity also increased respectively after tryptophan-enriched cereal ingestion as well as improving anxiety and depression symptoms. Cereals enriched with tryptophan may be useful as a chrononutrition tool for alterations in the sleep/wake cycle due to age.

BackgroundRheumatoid arthritis (RA) causes problems beyond the joints such as cardiovascular (CV) disease. It is estimated that the risk of developing CV disease in RA patients is approximately 50% higher than that in the general population[1]. The formation of atherosclerotic plaques is the main mechanism of the development of CV disease in RA patients[2]. The pathogenesis of atherosclerotic plaques is multifactorial and includes vascular, metabolic and inflammatory components[3]. In this regard, miRNA-24, 146 and Let7a have previously been associated with the presence of carotid plaques in RA patients[4].ObjectivesGiven that there is a strong relationship between the chronic inflammatory state of RA and arteriosclerosis, we evaluated, individually and globally, whether miRNA-24, 146 and Let7a were involved in the inflammatory state of RA and could link inflammation and arteriosclerosis.MethodsA total of 199 patients with RA were included. Inflammatory variables such as disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR) were quantified. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models were used for analysis. An expression score was created to evaluate all the miRNAs conjunctively.ResultsThe multivariate models showed that miRNA-146 was significantly associated with DAS28 (β = -0.15), and miRNAs 24, 146 and Let7a were significantly associated with ESR (β = -5.17, β = -5.29 and β = -6.47, respectively) in the overall cohort. When miRNAs were evaluated globally, they were also significantly associated with DAS28 and ESR in the overall cohort (β = 0.41 and β = 14.23, respectively). Sex-stratified analyses also showed different associations of these miRNAs with the inflammatory variables (Table 1).ConclusionPlasmatic expressions of miRNA-24, 146 and Let7a were associated with inflammatory markers of RA. These miRNAs are associated with both inflammation and atherosclerosis, which could link these processes, and are potential therapeutic targets for RA.References[1]Castañeda S, Martín-Martínez MA, González-Juanatey C, Llorca J, García-Yébenes MJ, Pérez-Vicente S, et al. Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: Baseline data of the CARMA Project. Semin Arthritis Rheum. 2015;44:618–26.[2]Ambrosino P, Lupoli R, Di Minno A, Tasso M, Peluso R, Di Minno MND. Subclinical atherosclerosis in patients with rheumatoid arthritis. A meta-analysis of literature studies. Thromb Haemost. 2015;113:916–30.[3]Wolf D, Ley K. Immunity and Inflammation in Atherosclerosis. Circ Res. 2019;124:315–27.[4]Llop D, Ibarretxe D, Plana N, Rosales R, Taverner D, Masana L, et al. A panel of plasma microRNAs improves the assessment of surrogate markers of cardiovascular disease in rheumatoid arthritis patients. Rheumatology (Oxford). 2022.Table 1.Summaries of the multivariate lineal regression models to estimate the associations between miRNAs and DAS28 and ESR in the overall cohort and stratified by sex. Basal models are adjusted for age, sex, body mass index, disease onset, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, corticosteroids and biological drugs. β = beta coefficient, p = p-value.MiRNAs association with DAS28 and ESRβpR2 (%)DAS28OVERALL COHORTBasal Model12.75+ miRNA – 146-0.150.0414.16+ Expression Score0.410.04915.30MENBasal Model13.91+ miRNA – 146-0.230.0222.06+ Expression Score0.780.0126.34ESROVERALL COHORTBasal Model10.57+ miRNA – 24-5.170.00215.25+ miRNA – 146-5.290.000316.41+ miRNA – Let7a-6.470.000516.15+ Expression Score14.23<0.000118.63MENBasal Model15.73+ miRNA – 24-5.180.0323.16+ miRNA – 146-5.010.0124.84+ miRNA – Let7a-6.540.0224.03+ Expression Score14.790.0126.37WOMENBasal Model9.95+ miRNA – 24-5.290.0213.97+ miRNA – 146-5.550.00814.82+ miRNA – Let7a-6.370.0114.48+ Expression Score15.260.00817.29AcknowledgementsWe would like to thank all the patients for their essential collaboration.Disclosure of InterestsSILVIA PAREDES Speakers bureau: Lilly, Bristol, Amgen, Consultant of: Galapagos, Sanofi, Bristol, Didac Llop: None declared, Daiana Ibarretxe Speakers bureau: Sanofi, Sobi, Genzyme, Rubio, Delia Taverner Speakers bureau: Galapagos, Amgen, Roser Rosales: None declared, Nuria Plana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Luis Masana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Amgen, Joan Carles Vallve: None declared.

BackgroundFatigue is a common symptom in chronic inflammatory diseases. The mechanism by which fatigue occurs is multidimensional. Previous studies suggested that several factors, including physiology, psychology and behavior, may contribute to its pathogenesis.Fatigue is considered one of the most common symptoms in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) with an incidence of 50–70%.Fatigue is a major factor contributing to unsatisfactory treatment outcome and poor quality of life, or even disability. Therefore, from a clinical point of view, how to improve the symptom of fatigue remains a challenge. Identifying factors related to fatigue could be a key to the management of this complex symptom.ObjectivesTo compare fatigue and its associated factors in patients with PsA and AS from two university hospitals.MethodsA cross-sectional analysis was performed in 105 patients (May – December 2022)Fatigue was assessed using 3 instruments: the fatigue subscale of the Short-form 36 survey (fatigue-SF36), the Visual Analogue scale of fatigue (VASf) and the Functional Assessment of chronic illness Therapy Fatigue Scale (FACIT-F). T-test was used to compare mean fatigue between PsA and AS patients.To determine in each patient group the relationship between fatigue (assessed by FACIT-F) and the other variables (DAPSA or ASDAS, CPR, ESR, hemoglobin, HAQ, Hospital Anxiety and depression Scale [HAD] and Brief Pain Inventory [BPI]) a Spearman correlation was performed. A value of p < 0.05 was accepted as statistically significant.ResultsA total of 105 patients were included, 55 (52.4%) PsA patients and 50 (47.6%) AS patients.We found that mean fatigue (using 3 instruments) had not significant differences in patients with PsA and AS (Table 1).In patients with PsA and AS, fatigue correlated to HAD, HAQ and pain, but not with CRP, ESR and hemoglobin (Table 2).In AS patients, high disease activity (assess by ASDAS) correlated with high levels of fatigue (lower levels on FACIT-F). However, in patients with PsA, fatigue and disease activity (DAPSA) were not related.ConclusionIn PsA and AS patients, fatigue seems to be related to subjective but not with objective (analytical) variables. In patients with AS, fatigue was related to disease activity, but in patients with PsA we found no correlation.References[1]Li, Aissaoui N et al. Fatigue in patients with ankylosing spondylitis: prevalence and relationships with disease-specific variables, psychological status, and sleep disturbance. Rheumatol Int. 2012 Jul;32:2117-24.[2]Conaghan PG et al Relationship of pain and fatigue with health-related quality of life and work in patients with psoriatic arthritis on TNFi: results of a multi-national real-world study RMD Open 2020;6:e001240.Table 1.Mean of fatigue in PsA and AS patientsPsA Mean (SD)AS Mean (SD)p-valueFACIT-F38.1 (10.3)37.7 (11.4)0.88VAS-F3.8 (2.5)4.29 (2.8)0.396SF36-Fatigue53.4 (22)56.7 (21.8)0.45Table 2.Fatigue correlations in PsA and AS patientsPsAp-valueASp-valueDisease activity-0.190.164-0.63<0.001PCR0.010.9470.010.30VSG0.050.6800.040.325Hemoglobin-0.130.337-0.150.46HAQ-0.50<0.001-0.67<0.001HAD depression-0.75<0.001-0.61<0.001HAD anxiety-0.70<0.001-0.47<0.001Pain (BPI)-0.64<0.001-0.71<0.001Acknowledgements:NIL.Disclosure of InterestsNone Declared.

In the present work, we evaluated the effect of the intake of a Jerte Valley cherry-based product (JVCP), compared to a placebo product, on sleep quality, urinary 6-sulfatoxymelatonin (aMT6-s) levels and the serum concentration of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8). This was a blind, placebo-controlled, randomized, crossover study. University of Extremadura (Spain). Ten young (20–30 years old), ten middle-aged (35–55 years old), and ten elderly (65–85 years old) participants. A placebo (Kool-Aid®) or JVCP (patent no. ES 2342141 B1) were consumed twice a day, as lunch and dinner desserts. Actigraphic monitoring was used to record and display the temporal patterns of the individuals' activity and rest. Urinary aMT6-s and serum cytokines (IL-1β, TNF-α and IL-8) were also determined. The consumption of the JVCP improved the nocturnal rest, measured by sleep efficiency, number of awakenings, total nocturnal activity, sleep latency, assumed sleep, actual sleep time and immobility. Moreover, it was detected an increase in both the levels of aMT6-s found in first-void morning urine and the concentrations of serum pro-somnogenic cytokines obtained from samples collected at the acrophase of the melatonin rhythm (1.00 am) in all experimental age groups after the JVCP consumption. Generally, better results were obtained with advancing age. The ingestion of the JVCP may contribute to establish a high-quality sleep and be used as a potential nutraceutical tool to prevent sleep disorders with the advance of age.

BackgroundPatients with rheumatoid arthritis (RA) present increased risk of cardiovascular (CV) disease compared to the general population. Moreover, CV risk factors that have causal relationship with atherosclerosis do not seem to fully explain the accelerated process that they exhibit[1]. Over the years, several serum growth factors have been associated with atherosclerosis and some of them have been targeted as potential immunotherapy targets for the treatment of CV disease[2,3]. However, very few studies have studied these associations in RA patients.ObjectivesWe evaluated the association of 8 plasmatic growth factors (angiopoietin-2, EGF, HB-EGF, PLGF, TGF-α, VEGFa, VEGFc, VEGFd) with surrogate markers of subclinical arteriosclerosis (carotid intima media thickness (cIMT), carotid plaque presence (cPP) and pulse wave velocity (PWV)) in a cohort of RA patients.MethodsA total of 199 patients with RA were included. Subclinical markers of arteriosclerosis, (cIMT, cPP and PWV) were measured with the My Lab 50 X-Vision sonogram. The different plasmatic growth factors were measured with Bio-Plex Pro Human Cancer Biomarker Panel 2, from BIO-RAD. Multivariate models and Partial Least Square Discriminant Analysis (PLS-DA) were used for analysis. Analyses were performed in the overall cohort and stratified by sex.ResultsThe multivariate models showed that angiopoietin-2 was significantly associated with cPP and PWV in the overall cohort. Moreover, VEGFc was also associated with PWV. Stratified analyses showed that VEGFa, VEGFd, EGF, PLGF, HB-EGF were associated with cPP in men patients. In this direction, PLS-DA analysis showed that the mentioned growth factors properly classified patients with and without cPP (Figure 1). Furthermore, angiopoietin-2, EGF, VEGFc, VEGFa, HB-EGF were associated with PWV. Regarding women, angiopoietin-2 was associated with PWV. Result from the lineal and logistic regressions are summarized in Table 1.ConclusionPlasmatic growth factors, especially in men, are highly associated with subclinical arteriosclerosis surrogate markers and could be potential predictors of CV disease in patients with RA.References[1]Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies. Arthritis Care Res. 2008;59:1690–7.[2]Mindur JE, Swirski FK. Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2019;39:1275–87.[3]Domouzoglou EM, Naka KK, Vlahos AP, Papafaklis MI, Michalis LK, Tsatsoulis A, et al. Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21. Am J Physiol - Hear Circ Physiol. 2015;309:H1029.Table 1.Summaries of the multivariate lineal and logistic regression models to estimate the associations between growth factors (GF) and cPP and PWV in the overall cohort and stratified by sex. Basal models are adjusted for age, sex, body mass index, disease onset, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, corticosteroids, biological drugs and DAS28. GF = growth factor, β = beta coefficient, OR = odds ratio, p = p-valueGF associations with subclinical arteriosclerosisORpR2 (%)cPPOVERALL COHORTBasal Model24+ angiopoietin-21.00050.0226MENBasal Model33+ VEGFa1.0020.0439+ VEGFd1.0020.0438+ EGF1.020.0240+ PLGF1.010.0339+ HB-EGF1.020.0438BpR2 (%)PWVOVERALL COHORTBasal Model32+ angiopoietin-20.00060.00136+ VEGFc0.00050.0434MENBasal Model33+ angiopoietin-20.00070.0240+ VEGFa0.0020.0239+ VEGFc0.0010.00841+ HB-EGF0.010.0438WOMENBasal Model36+ angiopoietin-20.00050.0139Figure 1.PLS-DA of men with cPP and without cPP, adjusted for the significant growth factors and age, body mass index, disease onset, disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs, corticosteroids, biological drugs and DAS. 28 0 = no cPP, 1 = cPPAcknowledgementsWe would like to thank all patients for their essential collaboration.Disclosure of InterestsANNA PAMIES CORTS Speakers bureau: Novartis, Galapagos, Didac Llop: None declared, Daiana Ibarretxe Speakers bureau: Sanofi, Sobi, Genzyme, Rubio, Delia Taverner Speakers bureau: Galapagos, Amgen, Roser Rosales: None declared, Nuria Plana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Luis Masana Speakers bureau: Amgen, Sanofi, Servier, Consultant of: Servier, Amgen, Joan Carles Vallve: None declared, Silvia Paredes Speakers bureau: Lilly, Bristol, Amgen, Consultant of: Galapagos, Sanofi, Bristol.