Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.

Ensaio clínico PROTEC, Protocolo nº 109MS408Abstract BACKGROUND: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. OBJECTIVE: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. METHODS: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. RESULTS: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. CONCLUSION: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708,info:eu-repo/semantics/publishedVersio

Star Formation in the Starburst Cluster in NGC 3603

We have used new, deep, visible and near infrared observations of the compact starburst cluster in the giant HII region NGC 3603 and its surroundings with the WFC3 on HST and HAWK-I on the VLT to study in detail the physical properties of its intermediate mass (~ 1 - 3 M_sun) stellar population. We show that after correction for differential extinction and actively accreting stars, and the study of field star contamination, strong evidence remains for a continuous spread in the ages of pre-main sequence stars in the range ~ 2 to ~ 30 Myr within the temporal resolution available. Existing differences among presently available theoretical models account for the largest possible variation in shape of the measured age histograms within these limits. We also find that this isochronal age spread in the near infrared and visible Colour-Magnitude Diagrams cannot be reproduced by any other presently known source of astrophysical or instrumental scatter that could mimic the luminosity spread seen in our observations except, possibly, episodic accretion. The measured age spread and the stellar spatial distribution in the cluster are consistent with the hypothesis that star formation started at least 20-30 Myrs ago progressing slowly but continuously up to at least a few million years ago. All the stars in the considered mass range are distributed in a flattened oblate spheroidal pattern with the major axis oriented in an approximate South-East - North-West direction, and with the length of the equatorial axis decreasing with increasing age. This asymmetry is most likely due to the fact that star formation occurred along a filament of gas and dust in the natal molecular cloud oriented locally in this direction.Comment: 21 pages, 19 figures, accepted for publication in Astrophysics & Space Scienc

Sodium intake and multiple sclerosis activity and progression in BENEFIT

OBJECTIVE: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. METHODS: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. RESULTS: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS: -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles. INTERPRETATION: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity

The Gaia -ESO Survey: Properties of newly discovered Li-rich giants

Aims. We report 20 new lithium-rich giants discovered within the Gaia-ESO Survey, including the first Li-rich giant with an evolutionary stage confirmed by CoRoT (Convection, Rotation and planetary Transits) data. We present a detailed overview of the properties of these 20 stars. Methods. Atmospheric parameters and abundances were derived in model atmosphere analyses using medium-resolution GIRAFFE or high-resolution UVES (Ultraviolet and Visual Echelle Spectrograph) spectra. These results are part of the fifth internal data release of the Gaia-ESO Survey. The Li abundances were corrected for non-local thermodynamical equilibrium effects. Other stellar properties were investigated for additional peculiarities (the core of strong lines for signs of magnetic activity, infrared magnitudes, rotational velocities, chemical abundances, and Galactic velocities). We used Gaia DR2 parallaxes to estimate distances and luminosities. Results. The giants have A(Li) &gt; 2.2 dex. The majority of them (14 of 20 stars) are in the CoRoT fields. Four giants are located in the field of three open clusters, but are not members. Two giants were observed in fields towards the Galactic bulge, but likely lie in the inner disc. One of the bulge field giants is super Li-rich with A(Li) = 4.0 dex. Conclusions. We identified one giant with infrared excess at 22 μm. Two other giants, with large v sin i, might be Li-rich because of planet engulfment. Another giant is found to be barium enhanced and thus could have accreted material from a former asymptotic giant branch companion. Otherwise, in addition to the Li enrichment, the evolutionary stages are the only other connection between these new Li-rich giants. The CoRoT data confirm that one Li-rich giant is at the core-He burning stage. The other giants are concentrated in close proximity to the red giant branch luminosity bump, the core-He burning stages, or the early-asymptotic giant branch. This is very clear from the Gaia-based luminosities of the Li-rich giants. This is also seen when the CoRoT Li-rich giants are compared to a larger sample of 2252 giants observed in the CoRoT fields by the Gaia-ESO Survey, which are distributed throughout the red giant branch in the Teff-log g diagram. These observations show that the evolutionary stage is a major factor for the Li enrichment in giants. Other processes, such as planet accretion, contribute at a smaller scale.</jats:p

Young [alpha/Fe]-enhanced stars discovered by CoRoT and APOGEE: What is their origin?

We report the discovery of a group of apparently young CoRoT red-giant stars exhibiting enhanced [_/Fe] abundance ratios (as determined from APOGEE spectra) with respect to solar values. Their existence is not explained by standard chemical evolution models of the Milky Way, and shows that the chemical-enrichment history of the Galactic disc is more complex. We find similar stars in previously published samples for which isochrone-ages could be reliably obtained, although in smaller relative numbers. This might explain why these stars have not previously received attention. The young [_/Fe]-rich stars are much more numerous in the CoRoT APOGEE (CoRoGEE) inner-field sample than in any other high-resolution sample available at present because only CoRoGEE can explore the inner-disc regions and provide ages for its field stars. The kinematic properties of the young [_/Fe]-rich stars are not clearly thick-disc like, despite their rather large distances from the Galactic mid-plane. Our tentative interpretation of these and previous intriguing observations in the Milky Way is that these stars were formed close to the end of the Galactic bar, near corotation – a region where gas can be kept inert for longer times than in other regions that are more frequently shocked by the passage of spiral arms. Moreover, this is where the mass return from older inner-disc stellar generations is expected to be highest (according to an inside-out disc-formation scenario), which additionally dilutes the in-situ gas. Other possibilities to explain these observations (e.g., a recent gas-accretion event) are also discussed

Galactic archaeology with asteroseismology and spectroscopy: Red giants observed by CoRoT and APOGEE

With the advent of the space missions CoRoT and Kepler, it has recently become feasible to determine precise asteroseismic masses and relative ages for large samples of red giant stars. We present the CoRoGEE dataset, obtained from CoRoT light curves for 606 red giants in two fields of the Galactic disc that have been co-observed by the Apache Point Observatory Galactic Evolution Experiment (APOGEE). We used the Bayesian parameter estimation code PARAM to calculate distances, extinctions, masses, and ages for these stars in a homogeneous analysis, resulting in relative statistical uncertainties of ≲2% in distance, ~4% in radius, ~9% in mass and ~25% in age. We also assessed systematic age uncertainties stemming from different input physics and mass loss. We discuss the correlation between ages and chemical abundance patterns of field stars over a broad radial range of the Milky Way disc (5 kpc <RGal< 14 kpc), focussing on the [α/Fe]-[Fe/H]-age plane in five radial bins of the Galactic disc. We find an overall agreement with the expectations of pure chemical-evolution models computed before the present data were available, especially for the outer regions. However, our data also indicate that a significant fraction of stars now observed near and beyond the solar neighbourhood migrated from inner regions. Mock CoRoGEE observations of a chemodynamical Milky Way disc model indicate that the number of high-metallicity stars in the outer disc is too high to be accounted for even by the strong radial mixing present in the model. The mock observations also show that the age distribution of the [α/Fe]-enhanced sequence in the CoRoGEE inner-disc field is much broader than expected from a combination of radial mixing and observational errors. We suggest that a thick-disc/bulge component that formed stars for more than 3 Gyr may account for these discrepancies. Our results are subject to future improvements due to (a) the still low statistics, because our sample had to be sliced into bins of Galactocentric distances and ages; (b) large uncertainties in proper motions (and therefore guiding radii); and (c) corrections to the asteroseismic mass-scaling relation. The situation will improve not only upon the upcoming Gaia data releases, but also with the foreseen increase in the number of stars with both seismic and spectroscopic information

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. OBJECTIVE: To validate the proposed genetic markers and to identify new markers. METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15). CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies

The Updated BaSTI Stellar Evolution Models and Isochrones: I. Solar Scaled Calculations

We present an updated release of the BaSTI (a Bag of Stellar Tracks and Isochrones) stellar model and isochrone library for a solar scaled heavy element distribution. The main input physics changed from the previous BaSTI release include the solar metal mixture, electron conduction opacities, a few nuclear reaction rates, bolometric corrections, and the treatment of the overshooting efficiency for shrinking convective cores. The new model calculations cover a mass range between 0.1 and 15 Msun, 22 initial chemical compositions between [Fe/H]=-3.20 and +0.45, with helium to metal enrichment ratio dY /dZ=1.31. The isochrones cover an age range between 20 Myr and 14.5 Gyr, take consistently into account the pre-main sequence phase, and have been translated to a large number of popular photometric systems. Asteroseismic properties of the theoretical models have also been calculated. We compare our isochrones with results from independent databases and with several sets of observations, to test the accuracy of the calculations. All stellar evolution tracks, asteroseismic properties and isochrones are made available through a dedicated Web site

Nuclear astrophysics: the unfinished quest for the origin of the elements

Half a century has passed since the foundation of nuclear astrophysics. Since then, this discipline has reached its maturity. Today, nuclear astrophysics constitutes a multidisciplinary crucible of knowledge that combines the achievements in theoretical astrophysics, observational astronomy, cosmochemistry and nuclear physics. New tools and developments have revolutionized our understanding of the origin of the elements: supercomputers have provided astrophysicists with the required computational capabilities to study the evolution of stars in a multidimensional framework; the emergence of high-energy astrophysics with space-borne observatories has opened new windows to observe the Universe, from a novel panchromatic perspective; cosmochemists have isolated tiny pieces of stardust embedded in primitive meteorites, giving clues on the processes operating in stars as well as on the way matter condenses to form solids; and nuclear physicists have measured reactions near stellar energies, through the combined efforts using stable and radioactive ion beam facilities. This review provides comprehensive insight into the nuclear history of the Universe and related topics: starting from the Big Bang, when the ashes from the primordial explosion were transformed to hydrogen, helium, and few trace elements, to the rich variety of nucleosynthesis mechanisms and sites in the Universe. Particular attention is paid to the hydrostatic processes governing the evolution of low-mass stars, red giants and asymptotic giant-branch stars, as well as to the explosive nucleosynthesis occurring in core-collapse and thermonuclear supernovae, gamma-ray bursts, classical novae, X-ray bursts, superbursts, and stellar mergers.Comment: Invited Review. Accepted for publication in "Reports on Progress in Physics" (version with low-resolution figures

Consensus statement on the use of alemtuzumab in daily clinical practice in Spain

Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europeade Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosismúltiple remitente recurrente.Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español.Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, admi-nistración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitualtIntroduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective: A consensus document was drafted on the management of alemtuzumab in routineclinical practice in Spain. Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug’s efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recom-mendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practiceLa elaboración de este manuscrito ha sido financiada por Sanofi-Genzym