Aims
To evaluate the safety and efficacy of once‐weekly dulaglutide 1.5 mg, a long‐acting glucagon‐like peptide‐1 receptor agonist, compared with placebo in patients with type 2 diabetes (T2D) on ...glimepiride monotherapy.
Methods
This phase III, randomized (4 : 1; dulaglutide:placebo), double‐blind, placebo‐controlled, 24‐week study compared the safety and efficacy of once‐weekly dulaglutide 1.5 mg with placebo in sulphonylurea‐treated (≥half‐maximal dose, stable ≥3 months) patients (N = 300) with T2D and inadequate glycaemic control glycated haemoglobin (HbA1c) ≥7.5 and ≤9.5% (≥58 mmol/mol and ≤80 mmol/mol). Analysis was carried out according to intention‐to‐treat.
Results
At baseline, the mean participant age was 58 years; mean HbA1c was 8.4% (68 mmol/mol) and mean weight was 85.5 kg. Dulaglutide 1.5 mg was superior to placebo at 24 weeks for HbA1c reduction from baseline with a between‐group HbA1c difference of −1.3% 95% confidence interval (CI) −1.6, −1.0 or ‐14 mmol/mol (95% CI −17, −11); p < 0.001. A greater proportion of participants in the dulaglutide group reached an HbA1c level of <7.0% (53 mmol/mol) compared with placebo (55.3% vs 18.9%; p < 0.001). Dulaglutide significantly decreased fasting serum glucose from baseline compared with placebo (between‐group difference −1.86 mmol/l (95% CI −2.58, −1.14) or −33.54 mg/dl (95% CI −46.55, −20.53); p < 0.001. Weight was decreased significantly from baseline in the dulaglutide group (p < 0.001); the between‐group difference was not significant. The most common treatment‐emergent adverse events for dulaglutide 1.5 mg were gastrointestinal: nausea (10.5%), diarrhoea (8.4%) and eructation (5.9%). Total hypoglycaemia was higher with dulaglutide 1.5 mg vs placebo (2.37 and 0.07 events/participant/year, respectively; p = 0.025). No severe hypoglycaemia was reported.
Conclusions
Once‐weekly dulaglutide 1.5 mg had a favourable benefit/risk profile when added to glimepiride monotherapy.
Aims
To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non‐alcoholic fatty ...liver/non‐alcoholic steatohepatitis.
Methods
A total of 1499 participants from AWARD‐1, AWARD‐5, AWARD‐8 and AWARD‐9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non‐alcoholic fatty liver/non‐alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma‐glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c, fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non‐alcoholic fatty liver/non‐alcoholic steatohepatitis subgroup.
Results
In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels vs placebo least squares mean treatment differences: –1.7 IU/l (95% CI –2.8, –0.6), P=0.003; –1.1 IU/l (95% CI –2.1, –0.1), P=0.037; –6.6 IU/l (95% CI –12.4, –0.8), P=0.025, respectively. In the subgroup with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (–8.8 IU/l vs –6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l).
Conclusions
Once‐weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon‐like peptide‐1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.
What's new?
Non‐alcoholic fatty liver disease is present in >75% of people with Type 2 diabetes.
Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of Type 2 diabetes.
This analysis evaluated the effects of dulaglutide on liver and glycaemic/metabolic measurements in a subgroup of people with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis and Type 2 diabetes.
Treatment response of dulaglutide in the subgroup was similar to that in the overall population.
Dulaglutide improved plasma aminotransferases and gamma‐glutamyl transpeptidase in a pattern consistent with liver fat reductions.
Oscillatory neural networks based on insulator to metal transition of VO 2 switches are implemented for image recognition. The VO 2 oscillators are fabricated on silicon in a CMOS compatible process. ...A fully-connected network of coupled oscillators is investigated using programmable resistors as coupling elements. In this approach, input of the image information and data processing is performed in the time domain. In particular, tuning the coupling resistors allows to control the phase-relation between the oscillators. This is used to memorize and recognize patterns in an analog circuit. The concept is demonstrated experimentally on a three-VO 2 oscillator network, whereas simulations are performed on a larger 9-oscillators circuit.
Background:
Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear ...understanding of its application and durability of effect in clinical practice has yet to evolve.
Objectives:
To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab.
Methods:
Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review.
Results:
One hundred patients were identified with a mean follow-up of 6.1 years (range 1–13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity.
Conclusion:
Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.
The Advanced LIGO detectors have recently completed their second observation run successfully. The run lasted for approximately 10 months and led to multiple new discoveries. The sensitivity to ...gravitational waves was partially limited by laser noise. Here, we utilize auxiliary sensors that witness these correlated noise sources, and use them for noise subtraction in the time domain data. This noise and line removal is particularly significant for the LIGO Hanford Observatory, where the improvement in sensitivity is greater than 20%. Consequently, we were also able to improve the astrophysical estimation for the location, masses, spins, and orbital parameters of the gravitational wave progenitors.
Extensional stress−strain measurements on a polyurea (PU) were carried out at strain rates up to 830 s−1, in combination with ex post facto small-angle X-ray scattering (SAXS) measurements and ...temperature-dependent SAXS. The elastomer is of interest because of its application as an impact-resistant coating. The highest strain rates used herein fall within the softening, or transition, zone of the viscoelastic spectrum and are thus relevant to the working hypothesis that the performance of a polyurea impact coating is related to its transition to the glassy state when strained very rapidly. While quasi-static and slow deformation of the PU gives rise to irrecoverable strain and anisotropic SAXS patterns, when stretched at high rates the PU recovers completely and the scattering is isotropic. Thus, the deformation of the hard domains observed at low rates is absent at high strain rates. Linear dynamic mechanical measurements were also carried out, with the obtained segmental relaxation times in good agreement with dielectric relaxation measurements on this material. The PU exhibits the usual breakdown of time−temperature superposition in the transition zone. This thermorheological complexity underlies the fact that published time−temperature shift factors for this material are unrelated to the segmental dynamics, and therefore use of these shift factors to predict the onset of glassy dynamics during impact loading of the PU will be in error.
Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could ...improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset.
Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA.
Education, but not ethnicity/race, influenced the reporting of postpartum depression difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01).
Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.
The objectives of this study were to (1) validate a method using refractometry to rapidly and accurately determine immunoglobulin (IgG) concentration in Jersey colostrum, (2) determine whether there ...should be different refractive index (nD) and %Brix cut points for Jersey colostrum, and (3) evaluate the effect of multiple freeze–thaw (FT) cycles on radial immunodiffusion (RID) and a digital refractometer to determine IgG concentration in Jersey colostrum. Samples (n=58; 3L) of colostrum were collected from a dairy in northwestern Iowa. Samples were analyzed within 2h of collection for IgG concentration by RID, %Brix, and nD by refractometer and an estimate of IgG by colostrometer. Samples were frozen, placed on dry ice, and transported to the laboratory at Iowa State University (Ames). Samples arrived frozen and were placed in a −20°C manual-defrost freezer until further analysis. On d 7 (1FT), d 14 (2FT), and 1yr (3FT) all samples were thawed, analyzed for IgG by RID, %Brix, nD by refractometer, and IgG estimate by colostrometer, and frozen until reanalysis at the next time point. Fresh colostrum had a mean (±SD) IgG concentration of 72.91 (±33.53) mg/mL, 21.24% (±4.43) Brix, and nD 1.3669 (±0.0074). Multiple FT cycles did affect IgG as determined by RID and colostrometer reading. The IgG concentrations were greater in fresh and 1FT samples as compared with 2FT and 3FT samples (72.91, 75.38, 67.20, and 67.31mg of IgG/mL, respectively). The colostrometer reading was lower in 1FT samples compared with fresh and 2FT samples. Multiple FT cycles had no effect on nD or %Brix reading. In fresh samples, IgG concentration was moderately correlated with nD (r=0.79), %Brix (r=0.79), and colostrometer reading (r=0.79). Diagnostic test characteristics using the recommended cut point of 1.35966 nD resulted in similar sensitivities for 1FT and 2 FT samples (94.87 and 94.74%, respectively). Cut points of 18 and 19% Brix resulted in the greatest sensitivities (92.31 and 84.62%) and specificity (94.74 and 94.74%, respectively). The 18% Brix cut point resulted in 94.83% of the samples being correctly classified based on IgG concentration. These data support the use of digital refractometer to accurately and rapidly determine IgG concentration in fresh Jersey colostrum. Additionally, these data suggest that IgG concentration determined by RID is affected by multiple FT cycles, whereas estimates obtained by refractometer are not affected by multiple FT cycles.
The little auk (
Alle alle
) is one of the most numerous seabirds in the world, but their winter prey selection has never been thoroughly studied. In the present study, we analyzed the proventricular ...contents of 205 little auks caught in coastal areas off southwest Greenland during December–February and off Newfoundland in March. Large Calanoid copepods are known to be the main prey during summer. We found krill to become the crucial winter prey in both areas, followed by
Themisto
spp. and young capelin (
Mallotus villosus
). No difference was found between the diet of juvenile and adult birds. Copepods constituted around 1 % of the diet and close to all copepods were in birds caught near Cape Farwell in December. These findings provide new and important insight into the forage ecology of the little auk, and they support other studies showing that large Calanoid copepods in the Arctic decent for winter hibernation at depths that are below the diving range of the little auks. More studies to determine offshore diet and annual variation are, however, needed in order to get a more complete picture.
We have implemented the sectional aerosol dynamics model SALSA (Sectional Aerosol module for Large Scale Applications) in the European-scale chemistry-transport model MATCH (Multi-scale Atmospheric ...Transport and Chemistry). The new model is called MATCH-SALSA. It includes aerosol microphysics, with several formulations for nucleation, wet scavenging and condensation. The model reproduces observed higher particle number concentration (PNC) in central Europe and lower concentrations in remote regions. The modeled PNC size distribution peak occurs at the same or smaller particle size as the observed peak at four measurement sites spread across Europe. Total PNC is underestimated at northern and central European sites and accumulation-mode PNC is underestimated at all investigated sites. The low nucleation rate coefficient used in this study is an important reason for the underestimation. On the other hand, the model performs well for particle mass (including secondary inorganic aerosol components), while elemental and organic carbon concentrations are underestimated at many of the sites. Further development is needed, primarily for treatment of secondary organic aerosol, in terms of biogenic emissions and chemical transformation. Updating the biogenic secondary organic aerosol (SOA) scheme will likely have a large impact on modeled PM2.5 and also affect the model performance for PNC through impacts on nucleation and condensation.
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