Randomised Controlled Trials in Diabetes Research : A Pathway to Interpreting Published Results

Altres ajuts: Ferrer, GluSense, Zealand, Eli Lilly and Company, Novartis, Sanofi, Medtronic, MSD, Sandoz, Abbott Diabetes Care, AstraZeneca España, Boehringer Ingelheim España, GSK, Roche España, Novo NordiskKey Summary Points: Randomised controlled trials (RCTs) remain the gold standard for direct treatment comparisons. However, interpreting the results of RCTs and making judgements about the quality of evidence and how results may be applicable to diabetes management can be difficult for healthcare practitioners (HCPs). In this article, a checklist of the points that we consider most important when reading and interpreting RCT publications is summarised, and may serve as useful guidance for HCPs

Isotopic ratios of H, C, N, O, and S in comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy)

The apparition of bright comets C/2012 F6 (Lemmon) and C/2014 Q2 (Lovejoy) in March-April 2013 and January 2015, combined with the improved observational capabilities of submillimeter facilities, offered an opportunity to carry out sensitive compositional and isotopic studies of the volatiles in their coma. We observed comet Lovejoy with the IRAM 30m telescope between 13 and 26 January 2015, and with the Odin submillimeter space observatory on 29 January - 3 February 2015. We detected 22 molecules and several isotopologues. The H$_2^{16}$O and H$_2^{18}$O production rates measured with Odin follow a periodic pattern with a period of 0.94 days and an amplitude of ~25%. The inferred isotope ratios in comet Lovejoy are $^{16}$O/$^{18}$O = 499 $\pm$ 24 and D/H = 1.4 $\pm$ 0.4 $\times 10^{-4}$ in water, $^{32}$S/$^{34}$S = 24.7 $\pm$ 3.5 in CS, all compatible with terrestrial values. The ratio $^{12}$C/$^{13}$C = 109 $\pm$ 14 in HCN is marginally higher than terrestrial and $^{14}$N/$^{15}$N = 145 $\pm$ 12 in HCN is half the Earth ratio. Several upper limits for D/H or 12C/13C in other molecules are reported. From our observation of HDO in comet C/2014 Q2 (Lovejoy), we report the first D/H ratio in an Oort Cloud comet that is not larger than the terrestrial value. On the other hand, the observation of the same HDO line in the other Oort-cloud comet, C/2012 F6 (Lemmon), suggests a D/H value four times higher. Given the previous measurements of D/H in cometary water, this illustrates that a diversity in the D/H ratio and in the chemical composition, is present even within the same dynamical group of comets, suggesting that current dynamical groups contain comets formed at very different places or times in the early solar system.Comment: Accepted for publication in Astronomy and Astrophysic

Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures

Integrated safety and efficacy analysis of dasiglucagon for treatment of severe hypoglycaemia in individuals with type 1 diabetes

Aims To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). Materials and Methods An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. Results Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. Conclusions Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D

Fermi/LAT discovery of gamma-ray emission from a relativistic jet in the narrow-line quasar PMN J0948+0022

We report the discovery by the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope of high-energy gamma-ray emission from the peculiar quasar PMN J0948+0022 (z=0.5846). The optical spectrum of this object exhibits rather narrow Hbeta (FWHM(Hbeta) ~ 1500 km s^-1), weak forbidden lines and is therefore classified as a narrow-line type I quasar. This class of objects is thought to have relatively small black hole mass and to accrete at high Eddington ratio. The radio loudness and variability of the compact radio core indicates the presence of a relativistic jet. Quasi simultaneous radio-optical-X-ray and gamma-ray observations are presented. Both radio and gamma-ray emission (observed over 5-months) are strongly variable. The simultaneous optical and X-ray data from Swift show a blue continuum attributed to the accretion disk and a hard X-ray spectrum attributed to the jet. The resulting broad band spectral energy distribution (SED) and, in particular, the gamma-ray spectrum measured by Fermi are similar to those of more powerful FSRQ. A comparison of the radio and gamma-ray characteristics of PMN J0948+0022 with the other blazars detected by LAT shows that this source has a relatively low radio and gamma-ray power, with respect to other FSRQ. The physical parameters obtained from modelling the SED also fall at the low power end of the FSRQ parameter region discussed in Celotti & Ghisellini (2008). We suggest that the similarity of the SED of PMN J0948+0022 to that of more massive and more powerful quasars can be understood in a scenario in which the SED properties depend on the Eddington ratio rather than on the absolute power.Comment: 10 pages, 5 figures, accepted for publication on ApJ Main Journal. Corresponding author: L. Foschin

Fermi Large Area Telescope Bright Gamma-ray Source List

Following its launch in June 2008, the Fermi Gamma-ray Space Telescope (Fermi) began a sky survey in August. The Large Area Telescope (LAT) on Fermi in 3 months produced a deeper and better-resolved map of the gamma-ray sky than any previous space mission. We present here initial results for energies above 100 MeV for the 205 most significant (statistical significance greater than ~10-sigma) gamma-ray sources in these data. These are the best-characterized and best-localized point-like (i.e., spatially unresolved) gamma-ray sources in the early-mission data.Comment: Accepted by ApJS. Many helpful comments by referee incorporated 57 pages, 12 figure

Early Fermi Gamma-ray Space Telescope Observations of the Quasar 3C 454.3

This is the first report of Fermi Gamma-ray Space Telescope observations of the quasar 3C 454.3, which has been undergoing pronounced long-term outbursts since 2000. The data from the Large Area Telescope (LAT), covering 2008 July 7 - October 6, indicate strong, highly variable gamma-ray emission with an average flux of ~3 x 10^{-6} photons cm^{-2} s^{-1}, for energies above 100 MeV. The gamma-ray flux is variable, with strong, distinct, symmetrically-shaped flares for which the flux increases by a factor of several on a time scale of about three days. This variability indicates a compact emission region, and the requirement that the source is optically thin to pair-production implies relativistic beaming with Doppler factor delta > 8, consistent with the values inferred from VLBI observations of superluminal expansion (delta ~ 25). The observed gamma-ray spectrum is not consistent with a simple power-law, but instead steepens strongly above ~2 GeV, and is well described by a broken power-law with photon indices of ~2.3 and ~3.5 below and above the break, respectively. This is the first direct observation of a break in the spectrum of a high luminosity blazar above 100 MeV, and it is likely direct evidence for an intrinsic break in the energy distribution of the radiating particles. Alternatively, the spectral softening above 2 GeV could be due to gamma-ray absorption via photon-photon pair production on the soft X-ray photon field of the host AGN, but such an interpretation would require the dissipation region to be located very close (less than 100 gravitational radii) to the black hole, which would be inconsistent with the X-ray spectrum of the source.Comment: Accepted by the Astrophysical Journal; corresponding authors: Greg Madejski ([email protected]) and Benoit Lott ([email protected]

Continuous subcutaneous insulin infusion therapy is associated with reduced retinopathy progression compared with multiple daily injections of insulin

AIMS/HYPOTHESIS: We aimed to compare diabetic retinopathy outcomes in people with type 1 diabetes following introduction of continuous subcutaneous insulin infusion (CSII) therapy with outcomes in people receiving continuing therapy with multiple daily insulin injections (MDI). METHODS: This is a retrospective cohort study using the Scottish Care Information – Diabetes database for retinal screening outcomes and HbA(1c) changes in 204 adults commenced on CSII therapy between 2013 and 2016, and 211 adults eligible for CSII during the same period but who continued on MDI therapy. Diabetic retinopathy progression (time to minimum one-grade worsening in diabetic retinopathy from baseline grading) was plotted for CSII and MDI cohorts using Kaplan–Meier curves, and outcomes were compared using multivariate Cox regression analysis adjusting for age, sex, baseline HbA(1c), blood pressure, cholesterol, smoking status and socioeconomic quintile. Impact of baseline HbA(1c) and change in HbA(1c) on diabetic retinopathy progression was assessed within CSII and MDI cohorts. RESULTS: CSII participants were significantly younger, were from less socially deprived areas, and had lower HbA(1c) and higher diastolic BP at baseline. There was a larger reduction in HbA(1c) at 1 year in those on CSII vs MDI (−6 mmol/mol [−0.6%] vs −2 mmol/mol [−0.2%], p < 0.01). Diabetic retinopathy progression occurred in a smaller proportion of adults following commencement of CSII vs continued MDI therapy over mean 2.3 year follow-up (26.5% vs 18.6%, p = 0.0097). High baseline HbA(1c) (75 mmol/mol [9%]) was associated with diabetic retinopathy progression in the MDI group (p = 0.0049) but not the CSII group (p = 0.93). Change in HbA(1c) at follow-up, irrespective of baseline glycaemic status, did not significantly affect diabetic retinopathy progression in either group. CONCLUSIONS/INTERPRETATION: CSII was associated with reduced diabetic retinopathy progression compared with continued MDI therapy, and may be protective against diabetic retinopathy progression for those with high baseline HbA(1c). Progression of diabetic retinopathy over 3 years was not associated with a change in HbA(1c). GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05456-w