3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

scopic evidence for high altitude aurora at Jupiter from Galileo extreme ultraviolet spectrometer and Hopkins ultraviolet telescope observations

The Galileo Extreme Ultraviolet Spectrometer (EUVS) and th

The Hot and Energetic Universe: Solar system and exoplanets

Supporting paper for the science theme "The Hot and Energetic Universe" to be implemented by the Athena+ X-ray observatory (http://www.the-athena-x-ray-observatory.eu). 8 pages, 6 figuresThe high resolution non-dispersive spectroscopy and unprecedented sensitivity of Athena+ will revolutionize solar system observing: the origin of the ions producing Jupiter's X-ray aurorae via charge exchange will be conclusively established, as well as their dynamics, giving clues to their acceleration mechanisms. X-ray aurorae on Saturn will be searched for to a depth unattainable by current Earth-bound observatories. The X-ray Integral Field Unit of Athena+ will map Mars' expanding exosphere, which has a line-rich solar wind charge exchange spectrum, under differing solar wind conditions and through the seasons; relating Mars' X-ray emission to its atmospheric loss will have significant impact also on the study of exoplanet atmospheres. Spectral mapping of cometary comae, which are spectacular X-ray sources with extremely line-rich spectra, will probe solar wind composition and speed at varying distances from the Sun. Athena+ will provide unique contributions also to exoplanetary astrophysics. Athena+ will pioneer the study of ingress/eclipse/egress effects during planetary orbits of hot-Jupiters, and will confirm/improve the evidence of Star-Planet Interactions (SPI) in a wider sample of planetary systems. Finally Athena+ will drastically improve the knowledge of the X-ray incident radiation on exoplanets, a key element for understanding the effects of atmospheric mass loss and of the chemical and physical evolution of planet atmospheres, particularly relevant in the case of young systems

Energy flux and characteristic energy of electrons over Jupiter's main auroral emission

Jupiter's powerful aurorae are caused by energetic electrons precipitating from the magnetosphere into the atmosphere where they excite the molecular hydrogen. These electrons are characterized over the auroral regions by the Jovian Auroral Distributions Experiment (JADE) and the Jupiter Energetic particle Detector Instrument (JEDI) on Juno. Derived energy spectra and pitch angle distributions help us understand how these aurorae are created and powered. Corresponding ultraviolet emissions from reconstructed images taken by the Ultraviolet Spectrograph (UVS) on Juno give us the context and allow us to match the electron observations with their impact on the atmosphere. In this study, we show how the electron energy flux and characteristic energy vary from the polar region, over the main emission, and equatorward of the main emission in relationship with the UV emissions. We focus on the closest passes which range from 1.25 to 2 RJ. We find that while the >30 keV electrons dominate the energy flux in the polar regions and equatorward of the main emission, there is a region near the maximum UV brightness where: i) the characteristic energy decreases from more than 100 keV to less than 10 keV and ii) the maximum contribution to, or a significant fraction of, the total downward energy flux comes from <30 keV electrons. This pattern is present in all eight perijove passes for which JADE and JEDI have the best pitch angle coverage. <P /

Systematic capture of MeV electron beams by MWR

Every ~ 53 days since August 2016, Juno swings by Jupiter and as the spacecraft spins along a polar orbit, measurements of Jupiter's microwave radiation are carried out at high data rates for several hours (~ 9 hours) with the Juno Microwave Radiometer (MWR). Within ~ 6 planetary radii (Rj) and from inside/outside the magnetospheric region, the thermal and synchrotron emissions are measured at high temporal and spatial resolutions. In this paper, we present a synthesis of the spatial distributions of the microwave radiation and discuss the similarities and differences observed at six wavelengths (1.3-50 cm). In addition to the thermal emission and synchrotron radiation from Jupiter's electron belt, unexpected signatures in MWR are either systematically or sporadically reported during perijove 1 (PJ1) and PJ3-PJ6. The preliminary results of a multi-instrument analysis of radio (MWR), extreme and far-ultraviolet auroral emissions (Juno UVS), field (Juno magnetometer), keV electrons (JEDI), and background radiation signatures in Juno's ASC and SRU instruments suggest that some of these signatures are consistent with the capture by MWR of synchrotron emission radiated by MeV electron beams, which may be associated with auroral activity. We subsequently describe in detail our data analysis and effort to model the synchrotron radiation from MeV electron beams to support our findings

High-latitude ion transport and energetic explorer (HI-LITE): a mission to investigate ion outflow from the high-latitude ionosphere

audience: researcher, professionalThe proposed HI-LITE Explorer will investigate the global ion outflow from the high-latitude ionosphere, its relationship to auroral features, and the consequences of this outflow on magnetospheric processes. The unique nature of the HI-LITE Explorer images will allow temporal and spatial features of the global ion outflow to be determined. The mission's scientific motivation comes from the fundamental role high-latitude ionospheric ions play in the dynamics of the solar wind driven magnetospheric-ionospheric system. These outflows are a major source of plasma for the magnetosphere and it is believed they play an important role in the triggering of substorms. In addition this paper describes the HI-LITE spacecraft and instruments

The Hot and Energetic Universe: A White Paper presenting the science theme motivating the Athena+ mission

This White Paper, submitted to the recent ESA call for science themes to define its future large missions, advocates the need for a transformational leap in our understanding of two key questions in astrophysics: 1) How does ordinary matter assemble into the large scale structures that we see today? 2) How do black holes grow and shape the Universe? Hot gas in clusters, groups and the intergalactic medium dominates the baryonic content of the local Universe. To understand the astrophysical processes responsible for the formation and assembly of these large structures, it is necessary to measure their physical properties and evolution. This requires spatially resolved X-ray spectroscopy with a factor 10 increase in both telescope throughput and spatial resolving power compared to currently planned facilities. Feedback from supermassive black holes is an essential ingredient in this process and in most galaxy evolution models, but it is not well understood. X-ray observations can uniquely reveal the mechanisms launching winds close to black holes and determine the coupling of the energy and matter flows on larger scales. Due to the effects of feedback, a complete understanding of galaxy evolution requires knowledge of the obscured growth of supermassive black holes through cosmic time, out to the redshifts where the first galaxies form. X-ray emission is the most reliable way to reveal accreting black holes, but deep survey speed must improve by a factor ~100 over current facilities to perform a full census into the early Universe. The Advanced Telescope for High Energy Astrophysics (Athena+) mission provides the necessary performance (e.g. angular resolution, spectral resolution, survey grasp) to address these questions and revolutionize our understanding of the Hot and Energetic Universe. These capabilities will also provide a powerful observatory to be used in all areas of astrophysics