Signaling Without Common Prior: An Experiment

The common prior assumption is pervasive in game-theoretic models with incomplete information. This paper investigates experimentally the importance of inducing a common prior in a two-person signaling game. For a specific probability distribution of the sender's type, the long-run behavior without an induced common prior is shown to be different from the behavior when a common prior is induced, while for other distributions behavior is similar under both regimes. We also present a learning model that allows players to learn about the other players' strategies and the prior distribution of the sender's type. We show that this learning model accurately accounts for all main features of the data.

Conjectural Variations and Evolutionary Stability: A New Rationale for Consistency

Adopting an evolutionary approach, we explain the conjectural variations Þrms may hold in duopoly. Given conjectures, Þrms play the market game rationally. Success in the market game determines Þtness in the evolutionary game. We show that the unique conjectures which are evolutionarily stable are consistent in that they anticipate rivals' behavior correctly

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease: A REALI European Pooled Data Analysis

INTRODUCTION: Management of type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiated in adults with inadequately controlled T2DM. METHODS: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60–89 (N = 786), 45–59 (N = 219), and 15–44 mL/min/1.73 m2 (N = 108). RESULTS: Compared to those with baseline eGFR ≥ 60 mL/min/1.73 m2, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24 weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (− 1.14% [− 1.28 to − 1.00], − 1.21% [− 1.34 to − 1.08], − 1.19% [− 1.36 to − 1.01], and − 0.99% [− 1.22 to − 0.76]) and the proportion of patients achieving HbA1c < 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60–89, 45–59, and 15–44 mL/min/1.73 m2 subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15–44 mL/min/1.73 m2 subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week 24. CONCLUSION: Although an eGFR of 15–44 mL/min/1.73 m2 was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR

Impact of Age on the Effectiveness and Safety of Insulin Glargine 300 U/mL: Results from the REALI European Pooled Data Analysis

Introduction: Patients aged ≥ 65&nbsp;years continue to be underrepresented in clinical studies related to type 2 diabetes mellitus (T2DM). Accordingly, the REALI pooled analysis was performed to evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) across different age subgroups, using data from 14 interventional and non-interventional studies. Methods: Pooled efficacy and safety data were collected from 8106 European patients with uncontrolled T2DM who were initiated on or switched to Gla-300 injected once daily for 24&nbsp;weeks. Patients were categorised into five age subgroups: &lt; 50 (N = 727), 50–59 (N = 2030), 60–69 (N = 3054), 70–79 (N = 1847) and ≥ 80&nbsp;years (N = 448). Results: Mean baseline haemoglobin A1c (HbA1c) decreased linearly from the youngest (9.10%) to the oldest (8.46%) age subgroup. Following Gla-300 initiation, there were similar HbA1c reductions across age groups, with a least squares mean (95% confidence interval) change in HbA1c from baseline to week 24 of − 1.09% (− 1.18 to − 1.00), − 1.08% (− 1.14 to − 1.03), − 1.12% (− 1.17 to − 1.07), − 1.18% (− 1.24 to − 1.12) and − 1.11% (− 1.23 to − 0.99) in the &lt; 50, 50–59, 60–69, 70–79 and ≥ 80&nbsp;years subgroups, respectively. The incidences and event rates of reported hypoglycaemia were overall low. Compared to younger age subgroups, lower incidences of symptomatic hypoglycaemia occurring at any time of the day (5.9 vs. 7.6–9.4% for the younger subgroups) or during the night (0.5 vs. 1.6–2.5%) were recorded in patients aged ≥ 80&nbsp;years. By contrast, the highest incidence of severe hypoglycaemia occurring any time of the day was reported in the subgroup aged ≥ 80&nbsp;years (1.1 vs. 0.1–0.6% for the younger age subgroups). Conclusion: Gla-300 initiated in patients with uncontrolled T2DM provides glycaemic improvement with a favourable safety profile across a wide range of ages

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease: A REALI European Pooled Data Analysis

Introduction: Management of type&nbsp;2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300&nbsp;U/mL (Gla-300) initiated in adults with inadequately controlled T2DM. Methods: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60–89 (N = 786), 45–59 (N = 219), and 15–44&nbsp;mL/min/1.73&nbsp;m2 (N = 108). Results: Compared to those with baseline eGFR ≥ 60&nbsp;mL/min/1.73&nbsp;m2, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24&nbsp;weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (−&nbsp;1.14% [−&nbsp;1.28 to −&nbsp;1.00], −&nbsp;1.21% [−&nbsp;1.34 to −&nbsp;1.08], −&nbsp;1.19% [−&nbsp;1.36 to −&nbsp;1.01], and −&nbsp;0.99% [−&nbsp;1.22 to −&nbsp;0.76]) and the proportion of patients achieving HbA1c &lt; 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60–89, 45–59, and 15–44&nbsp;mL/min/1.73&nbsp;m2 subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15–44&nbsp;mL/min/1.73&nbsp;m2 subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week&nbsp;24. Conclusion: Although an eGFR of 15–44&nbsp;mL/min/1.73&nbsp;m2 was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR

Efficacy and Safety of Ezetimibe Added to Atorvastatin Versus Atorvastatin Uptitration or Switching to Rosuvastatin in Patients With Primary Hypercholesterolemia

Hypercholesterolemic patients (n = 1,547) at high atherosclerotic cardiovascular disease risk with low-density lipoprotein cholesterol (LDL-C) levels 65100 and 64160 mg/dl while treated with atorvastatin 10 mg/day entered a multicenter, randomized, double-blind, active-controlled, clinical trial using two 6-week study periods. Period I compared the efficacy/safety of (1) adding ezetimibe 10 mg (ezetimibe) to stable atorvastatin 10 mg, (2) doubling atorvastatin to 20 mg, or (3) switching to rosuvastatin 10 mg. Subjects in the latter 2 groups who persisted with elevated LDL-C levels ( 65100 and 64160 mg/dl) after period I, entered period II; subjects on atorvastatin 20 mg had ezetimibe added to their atorvastatin 20 mg, or uptitrated their atorvastatin to 40 mg; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe or uptitrated their rosuvastatin to 20 mg. Some subjects on atorvastatin 10 mg plus ezetimibe continued the same treatment into period II. At the end of period I, ezetimibe plus atorvastatin 10 mg reduced LDL-C significantly more than atorvastatin 20 mg or rosuvastatin 10 mg (22.2% vs 9.5% or 13.0%, respectively, p <0.001). At the end of period II, ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg (17.4% vs 6.9%, p <0.001); switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg (17.1% vs 7.5%, p <0.001). Relative to comparative treatments, ezetimibe added to atorvastatin 10 mg (period I) or atorvastatin 20 mg (period II) produced significantly greater percent attainment of LDL-C targets <100 or <70 mg/dl, and significantly greater percent reductions in total cholesterol, non-high-density lipoprotein cholesterol, most lipid and lipoprotein ratios, and apolipoprotein B (except ezetimibe plus atorvastatin 20 vs atorvastatin 40 mg). Reports of adverse experiences were generally similar among groups. In conclusion, treatment of hypercholesterolemic subjects at high cardiovascular risk with ezetimibe added to atorvastatin 10 or 20 mg produced significantly greater improvements in key lipid parameters and significantly greater attainment of LDL-C treatment targets than doubling atorvastatin or switching to (or doubling) rosuvastatin at the compared doses

Design of small molecule-responsive microRNAs based on structural requirements for Drosha processing

MicroRNAs (miRNAs) are prevalent regulatory RNAs that mediate gene silencing and play key roles in diverse cellular processes. While synthetic RNA-based regulatory systems that integrate regulatory and sensing functions have been demonstrated, the lack of detail on miRNA structure–function relationships has limited the development of integrated control systems based on miRNA silencing. Using an elucidated relationship between Drosha processing and the single-stranded nature of the miRNA basal segments, we developed a strategy for designing ligand-responsive miRNAs. We demonstrate that ligand binding to an aptamer integrated into the miRNA basal segments inhibits Drosha processing, resulting in titratable control over gene silencing. The generality of this control strategy was shown for three aptamer–small molecule ligand pairs. The platform can be extended to the design of synthetic miRNAs clusters, cis-acting miRNAs and self-targeting miRNAs that act both in cis and trans, enabling fine-tuning of the regulatory strength and dynamics. The ability of our ligand-responsive miRNA platform to respond to user-defined inputs, undergo regulatory performance tuning and display scalable combinatorial control schemes will help advance applications in biological research and applied medicine

Antiepileptic drugs’ tolerability and safety – a systematic review and meta-analysis of adverse effects in dogs

<p>Various anti-epileptic drugs (AEDs) are used for the management of idiopathic epilepsy (IE) in dogs. Their safety profile is an important consideration for regulatory bodies, owners and prescribing clinicians. However, information on their adverse effects still remains limited with most of it derived from non-blinded non-randomized uncontrolled trials and case reports.</p><p><span>This poster won third place, which was presented at the Veterinary Evidence Today conference, Edinburgh November 1-3, 2016. </span></p><br /> <img src="https://www.veterinaryevidence.org/rcvskmod/icons/oa-icon.jpg" alt="Open Access" /

Enzymes for consumer products to achieve climate neutrality

29 pags., 4 figs., 3 tabs., 1 graf.Accumulated greenhouse gas emissions are expected to increase from 36.2 Giga-tons (Gt) to 60 Gt over the next three decades. The global surface temperature has increased by¿+¿1.09¿°C since 2001, and might increase by¿+¿2.2¿°C in 2100, +3.6¿°C in 2200 and +4.6¿°C in 2500. These emissions and temperature rises cannot be reduced in their entirety, but they can be lowered by using enzymes. Enzymes are proteins that catalyze biochemical reactions that make life possible since 3.8 billion years ago. Scientists have been able to "domesticate" them in such a way that enzymes, and their engineered variants, are now key players of the circular economy. With a world production of 117 Kilo-tons and a trade of 14.5 Billion-dollars, they have the potential to annually decrease CO2 emissions by 1 to 2.5 Billion-tons (Bt), the carbon demand to synthesise chemicals by 200 Million tons (Mt), the amount of chemicals by 90¿Mt, and the economic losses derived from global warming by 0.5%, while promoting biodiversity and our planet¿s health. Our success to increase these benefits will depend on better integration of enzymatic solutions in different sectors.This study was conducted under the auspices of the FuturEnzyme Project funded by the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 101000327. MF also acknowledges Grants PID2020-112758RB-I00, PDC2021-121534-I00, and TED2021-130544B-I00 from the MCIN/AEI/10.13039/501100011033 and the European Union (“NextGenerationEU/PRTR”)

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies

AIMS: Statins have modest adverse effects on glycaemic control. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers low-density lipoprotein cholesterol. This study assessed the effects of alirocumab on new-onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline. METHODS AND RESULTS: Pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) of 24–104 weeks duration. Six trials (n = 4211) were ≥52 weeks in length. Most patients received background maximally tolerated statin. Alirocumab effect on the rate of diabetes-related treatment-emergent adverse events (TEAEs), and/or fasting plasma glucose (FPG) and glycated haemoglobin A(1C) (HbA(1C)) was measured at baseline and every 12–24 weeks. Transition to diabetes analysis combined TEAE and FPG/HbA(1C) laboratory data. At baseline, 30.7% of individuals had diabetes and were excluded from the current analysis. The remaining 3448 individuals without diabetes had pre-diabetes (39.6%) or were normoglycaemic (29.7%). The hazard ratio (HR; 95% confidence interval) for diabetes-related TEAEs in alirocumab was 0.64 (0.36–1.14) vs. placebo and 0.55 (0.22–1.41) vs. ezetimibe. The HR associated for transition from pre-diabetes to new-onset diabetes for alirocumab was 0.90 (0.63–1.29) vs. placebo and 1.10 (0.57–2.12) vs. ezetimibe. Mean change in FPG/HbA(1C) over time showed no difference between treatment groups in patients without diabetes. CONCLUSIONS: There was no evidence of an effect of alirocumab on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6–18 months, compared to either placebo or ezetimibe. Longer follow-up with larger number of individuals is needed to conclusively rule out an effect