Corticosteroids for the treatment of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. Untreated, this incurable disease, which has an X-linked recessive inheritance, is characterised by muscle wasting and loss of walking ability, leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is a major aim of treatment. Evidence from randomised controlled trials (RCTs) indicates that corticosteroids significantly improve muscle strength and function in boys with DMD in the short term (six months), and strength at two years (two-year data on function are very limited). Corticosteroids, now part of care recommendations for DMD, are largely in routine use, although questions remain over their ability to prolong walking, when to start treatment, longer-term balance of benefits versus harms, and choice of corticosteroid or regimen.We have extended the scope of this updated review to include comparisons of different corticosteroids and dosing regimens. OBJECTIVES: To assess the effects of corticosteroids on prolongation of walking ability, muscle strength, functional ability, and quality of life in DMD; to address the question of whether benefit is maintained over the longer term (more than two years); to assess adverse events; and to compare efficacy and adverse effects of different corticosteroid preparations and regimens. SEARCH METHODS: On 16 February 2016 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, and LILACS. We wrote to authors of published studies and other experts. We checked references in identified trials, handsearched journal abstracts, and searched trials registries. SELECTION CRITERIA: We considered RCTs or quasi-RCTs of corticosteroids (e.g. prednisone, prednisolone, and deflazacort) given for a minimum of three months to patients with a definite DMD diagnosis. We considered comparisons of different corticosteroids, regimens, and corticosteroids versus placebo. DATA COLLECTION AND ANALYSIS: The review authors followed standard Cochrane methodology. MAIN RESULTS: We identified 12 studies (667 participants) and two new ongoing studies for inclusion. Six RCTs were newly included at this update and important non-randomised cohort studies have also been published. Some important studies remain unpublished and not all published studies provide complete outcome data. PRIMARY OUTCOME MEASURE: one two-year deflazacort RCT (n = 28) used prolongation of ambulation as an outcome measure but data were not adequate for drawing conclusions. SECONDARY OUTCOME MEASURES: meta-analyses showed that corticosteroids (0.75 mg/kg/day prednisone or prednisolone) improved muscle strength and function versus placebo over six months (moderate quality evidence from up to four RCTs). Evidence from single trials showed 0.75 mg/kg/day superior to 0.3 mg/kg/day on most strength and function measures, with little evidence of further benefit at 1.5 mg/kg/day. Improvements were seen in time taken to rise from the floor (Gowers' time), timed walk, four-stair climbing time, ability to lift weights, leg function grade, and forced vital capacity. One new RCT (n = 66), reported better strength, function and quality of life with daily 0.75 mg/kg/day prednisone at 12 months. One RCT (n = 28) showed that deflazacort stabilised muscle strength versus placebo at two years, but timed function test results were too imprecise for conclusions to be drawn.One double-blind RCT (n = 64), largely at low risk of bias, compared daily prednisone (0.75 mg/kg/day) with weekend-only prednisone (5 mg/kg/weekend day), finding no overall difference in muscle strength and function over 12 months (moderate to low quality evidence). Two small RCTs (n = 52) compared daily prednisone 0.75 mg/kg/day with daily deflazacort 0.9 mg/kg/day, but study methods limited our ability to compare muscle strength or function. ADVERSE EFFECTS: excessive weight gain, behavioural abnormalities, cushingoid appearance, and excessive hair growth were all previously shown to be more common with corticosteroids than placebo; we assessed the quality of evidence (for behavioural changes and weight gain) as moderate. Hair growth and cushingoid features were more frequent at 0.75 mg/kg/day than 0.3 mg/kg/day prednisone. Comparing daily versus weekend-only prednisone, both groups gained weight with no clear difference in body mass index (BMI) or in behavioural changes (low quality evidence for both outcomes, one study); the weekend-only group had a greater linear increase in height. Very low quality evidence suggested less weight gain with deflazacort than with prednisone at 12 months, and no difference in behavioural abnormalities. Data are insufficient to assess the risk of fractures or cataracts for any comparison.Non-randomised studies support RCT evidence in showing improved functional benefit from corticosteroids. These studies suggest sustained benefit for up to 66 months. Adverse effects were common, although generally manageable. According to a large comparative longitudinal study of daily or intermittent (10 days on, 10 days off) corticosteroid for a mean period of four years, a daily regimen prolongs ambulation and improves functional scores over the age of seven, but with a greater frequency of side effects than an intermittent regimen. AUTHORS' CONCLUSIONS: Moderate quality evidence from RCTs indicates that corticosteroid therapy in DMD improves muscle strength and function in the short term (twelve months), and strength up to two years. On the basis of the evidence available for strength and function outcomes, our confidence in the effect estimate for the efficacy of a 0.75 mg/kg/day dose of prednisone or above is fairly secure. There is no evidence other than from non-randomised trials to establish the effect of corticosteroids on prolongation of walking. In the short term, adverse effects were significantly more common with corticosteroids than placebo, but not clinically severe. A weekend-only prednisone regimen is as effective as daily prednisone in the short term (12 months), according to low to moderate quality evidence from a single trial, with no clear difference in BMI (low quality evidence). Very low quality evidence indicates that deflazacort causes less weight gain than prednisone after a year's treatment. We cannot evaluate long-term benefits and hazards of corticosteroid treatment or intermittent regimens from published RCTs. Non-randomised studies support the conclusions of functional benefits, but also identify clinically significant adverse effects of long-term treatment, and a possible divergence of efficacy in daily and weekend-only regimens in the longer term. These benefits and adverse effects have implications for future research and clinical practice

Four new black hole candidates identified in M31 globular clusters with Chandra and XMM-Newton

We have identified four new black hole candidates in M31 globular clusters using 123 Chandra, and 4 XMM-Newton observations of the M31 central region. The X-ray source associated with Bo 163 (XB163) is a recurrent transient, with the highest luminosity ~1.4E+38 erg/s, considerably brighter than any outbursts from the neutron star transients Aql X-1 or 4U 1608-452; the outburst apparently started ~45 days earlier than the observed peak, hence the luminosity could have been considerably higher. We identified XB082, XB153 and XB185 as BHCs by observing "low state" emission spectra at luminosities that exceed the threshold for neutron star binaries. The probability that these are neutron star systems with anisotropic emission beamed toward us is <4E-4, and their variability suggests emission from a single source. We therefore conclude that these systems likely contain black holes rather than neutron stars. We have now identified 4 persistently bright BHCs in the region; the probability that these are all background AGN is <1E-20. According to theory, the donors could be tidally captured main sequence stars, or white dwarves in ultra-compact binaries. We find that GCs that are particularly massive (XB082) or metal rich (XB144) can host bright X-ray sources in addition to those that are both (XB163). Our method may reveal BHCs in other bright X-ray sources.Comment: Accepted for publication in ApJ. 17 pages, 5 figure

3D ensemble-based online oceanic flow field estimation for underwater glider path planning

Estimating ocean flow fields in 3D is a critical step in enabling the reliable operation of underwater gliders and other small, low-powered autonomous marine vehicles. Existing methods produce depth-averaged 2D layers arranged at discrete vertical intervals, but this type of estimation can lead to severe navigation errors. Based on the observation that real-world ocean currents exhibit relatively low velocity vertical components, we propose an accurate 3D estimator that extends our previous work in estimating 2D flow fields as a linear combination of basis flows. The proposed algorithm uses data from ensemble forecasting to build a set of 3D basis flows, and then iteratively updates basis coefficients using point measurements of underwater currents. We report results from experiments using actual ensemble forecasts and synthetic measurements to compare the performance of our method to the direct 3D extension of the previous work. These results show that our method produces estimates with dramatically lower error metrics, with and without measurement noise.Comment: Submitted to IROS 202

GODAE systems in operation

During the last 15 years, operational oceanography systems have been developed in several countries around the world. These developments have been fostered primarily by the Global Ocean Data Assimilation Experiment (GODAE), which coordinated these activities, encouraged partnerships, and facilitated constructive competition. This multinational coordination has been very beneficial for the development of operational oceanography. Today, several systems provide routine, real-time ocean analysis, forecast, and reanalysis products. These systems are based on (1) state-of-the-art Ocean General Circulation Model (OGCM) configurations, either global or regional (basin-scale), with resolutions that range from coarse to eddy-resolving, and (2) data assimilation techniques ranging from analysis correction to advanced three- or four-dimensional variational schemes. These systems assimilate altimeter sea level anomalies, sea surface temperature data, and in situ profiles of temperature and salinity, including Argo data. Some systems have implemented downscaling capacities, which consist of embedding higher-resolution local systems in global and basin-scale models (through open boundary exchange of data), especially in coastal regions, where small scale-phenomena are important, and also increasing the spatial resolution for these regional/coastal systems to be able to resolve smaller scales (so-called downscaling). Others have implemented coupling with the atmosphere and/or sea ice. This paper provides a short review of these operational GODAE systems.Published76-914.6. Oceanografia operativa per la valutazione dei rischi in aree marineN/A or not JCRope

Status and future of global and regional ocean prediction systems

Operational evolution of global and regional ocean forecasting systems has been extremely significant in recent years. GODAE (Global Ocean Data Assimilation Experiment) Oceanview supports the national research groups providing them with coordination and sharing expertise among the partners. Several systems have been set up and developed pre-operationally and the majority of these are now fully operational; at the present time, they provide medium- and long-term forecasts of the most relevant ocean physical variables. These systems are based on ocean general circulation models (OGCMs) and data assimilation techniques that are able to correct the model with the information inferred from different types of observations. A few systems also incorporate a biogeochemical component coupled with the physical system while others are based on coupled ocean-wave-ice-atmosphere models. The products are routinely validated with observations in order to assess their quality. Data and products implementation and organization, as well as service for the users has been well tried and tested and most of the products are now available  to the users. The interaction with different users is an important factor in the development process. This paper provides a synthetic overview of the GODAE Oceanview prediction systems

GODAE systems in operation

During the last 15 years, operational oceanography systems have emerged in several countries around the world. This emergence has been largely fostered by the GODAE experiment, during which each nation engaged in this activity have organised partnership and constructive competition. This trans-national coordination was very beneficial for the development of operational oceanography, leading to economies of scales and more targeted actions. Today, several systems provide routine real-time ocean analysis and forecast and/or reanalysis products. They are all based on (i) state-of-the-art primitive equation baroclinic Ocean General Circulation Model (OGCM) configurations, either global or regional (basin-scale), with resolutions that range from coarse to eddy resolving and (ii) data assimilation techniques whose complexity ranges from simple analysis correction to advanced 4D variational schemes. They assimilate altimeter sea level anomalies, remotely sensed SST such as GHRSST products and in situ profiles of T and S, including ARGO. Some systems have implemented downscaling capacities in specific regions of interest including shelf/coastal seas. Some also have implemented coupling with the atmosphere and/or the prognostic sea ice in polar regions. They are the GODAE system in operation. They are reviewed in this paper. The GODAE system discussed here include: (1) BLUElink OceanMAPS, (2) C-NOOFS, , (3) ECCO, (4) FOAM, (5) HYCOM/NCODA, (6) MERCATOR, (7) MFS, (8) MOVE/MRI.COM, (9) NLOM/NCOM, (10) NMEFC, (11) RTOFS and (12) TOPAZ.SubmittedNice, France3.11. Oceanografia Operativaope

Status and future of global and regional ocean prediction systems

Operational evolution of global and regional ocean forecasting systems has been extremely significant in recent years. GODAE (Global Ocean Data Assimilation Experiment) Oceanview supports the national research groups providing them with coordination and sharing expertise among the partners. Several systems have been set up and developed pre-operationally and the majority of these are now fully operational; at the present time, they provide medium- and long-term forecasts of the most relevant ocean physical variables. These systems are based on ocean general circulation models (OGCMs) and data assimilation techniques that are able to correct the model with the information inferred from different types of observations. A few systems also incorporate a biogeochemical component coupled with the physical system while others are based on coupled ocean-wave-ice-atmosphere models. The products are routinely validated with observations in order to assess their quality. Data and products implementation and organization, as well as service for the users has been well tried and tested and most of the products are now available  to the users. The interaction with different users is an important factor in the development process. This paper provides a synthetic overview of the GODAE Oceanview prediction systems.Publisheds201-s2204A. Clima e OceaniJCR Journalope

GODAE systems in operation

During the last 15 years, operational oceanography systems have been developed in several countries around the world. These developments have been fostered primarily by the Global Ocean Data Assimilation Experiment (GODAE), which coordinated these activities, encouraged partnerships, and facilitated constructive competition. This multinational coordination has been very beneficial for the development of operational oceanography. Today, several systems provide routine, real-time ocean analysis, forecast, and reanalysis products. These systems are based on (1) state-of-the-art Ocean General Circulation Model (OGCM) configurations, either global or regional (basin-scale), with resolutions that range from coarse to eddy-resolving, and (2) data assimilation techniques ranging from analysis correction to advanced three- or four-dimensional variational schemes. These systems assimilate altimeter sea level anomalies, sea surface temperature data, and in situ profiles of temperature and salinity, including Argo data. Some systems have implemented downscaling capacities, which consist of embedding higher-resolution local systems in global and basin-scale models (through open boundary exchange of data), especially in coastal regions, where small scale-phenomena are important, and also increasing the spatial resolution for these regional/coastal systems to be able to resolve smaller scales (so-called downscaling). Others have implemented coupling with the atmosphere and/or sea ice. This paper provides a short review of these operational GODAE systems

The Marketing Firm: Retailer and consumer contingencies

acceptedVersionpublishedVersio