Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Technical Approach Determines Inflammatory Response after Surgical and Transcatheter Aortic Valve Replacement

To investigate the periprocedural inflammatory response in patients with isolated aortic valve stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) with different technical approaches.Patients were prospectively allocated to one of the following treatments: SAVR using conventional extracorporeal circulation (CECC, n = 47) or minimized extracorporeal circulation (MECC, n = 15), or TAVI using either transapical (TA, n = 15) or transfemoral (TF, n = 24) access. Exclusion criteria included infection, pre-procedural immunosuppressive or antibiotic drug therapy and emergency indications. We investigated interleukin (IL)-6, IL-8, IL-10, human leukocyte antigen (HLA-DR), white blood cell count, high-sensitivity C-reactive protein (hs-CRP) and soluble L-selectin (sCD62L) levels before the procedure and at 4, 24, and 48 h after aortic valve replacement. Data are presented for group interaction (p-values for inter-group comparison) as determined by the Greenhouse-Geisser correction.SAVR on CECC was associated with the highest levels of IL-8 and hs-CRP (p<0.017, and 0.007, respectively). SAVR on MECC showed the highest descent in levels of HLA-DR and sCD62L (both p<0.001) in the perioperative period. TA-TAVI showed increased intraprocedural concentration and the highest peak of IL-6 (p = 0.017). Significantly smaller changes in the inflammatory markers were observed in TF-TAVI.Surgical and interventional approaches to aortic valve replacement result in inflammatory modulation which differs according to the invasiveness of the procedure. As expected, extracorporeal circulation is associated with the most marked pro-inflammatory activation, whereas TF-TAVI emerges as the approach with the most attenuated inflammatory response. Factors such as the pre-treatment patient condition and the extent of myocardial injury also significantly affect inflammatory biomarker patterns. Accordingly, TA-TAVI is to be classified not as an interventional but a true surgical procedure, with inflammatory biomarker profiles comparable to those found after SAVR. Our study could not establish an obvious link between the extent of the periprocedural inflammatory response and clinical outcome parameters

Observation of Marfes in the Wendelstein 7-X stellarator with inboard limiters

In the first operational campaign of the Wendelstein 7-X (W7-X) stellarator we observed Marfe-like radiation belts at the plasma edge. We describe and analyze the behaviour of these radiation belts, especially with respect to the high density inside the belt, with a set of suitable diagnostics. We present evidence suggesting that these Marfe-like radiation belts are triggered by a drop of the edge temperature below 30 eV. From this observation we draw the conclusion that the physical cause of Marfes in tokamaks and Marfe-like radiation belts in W7-X is the same, namely radiative condensation. Furthermore, both exhibit the device symmetry, i.e. axisymmetry in a tokamak and the fivefold stellarator symmetry in W7-X.This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 under grant agreement No 633053

Incidental findings on craniomaxillofacial cone beam computed tomography in orthodontic patients

Purpose: Cone beam computed tomography (CBCT) in orthodontics is increasingly used for detecting impacted or ectopic teeth or for orthognathic and cleft lip and palate treatment. Incidental findings (IFs) are frequently encountered and often relevant. The aim of this study was to detect the prevalence of relevant pathologies on CBCT scans of orthodontic patients. Methods: Over a 6-year period, incidental imaging findings were analyzed in 345 CBCT scans (181 men; 164 women; age 163 +/- 8.4 years), and subdivided into dental (Group 1), skeletal (Group 2), sinunasa I (Group 3), and infrequent other pathologies (Group 4). Results: A total of 502 IFs were detected in 345 patients (1.4 IFs per patient, on average). Most IFs were found in Group 1 (358 IFs; 713%), followed by Group 2 (129 IFs; 25.7%), Group 3 (14 IFs; 2.8%), and Group 4 (1 IF; 0.2%). There were 119 (34.5%) patients with a missing wisdom tooth, 94 (27.3%) with dental aplasia, 71 (20.6%) with dislocations, 33 (9.6%) with partial opacifications, and 27 (7.8%) with signs of sinusitis. Conclusions: This study found that IFs in orthodontic CBCT scans are frequently encountered, even in younger orthodontic patients. When interpreting CBCT scans, orthodontists should be aware of potential relevant IFs that may require further investigation, change patients' treatment or affect their quality of life

Biochemical markers of inflammatory response II.

<p>The table indicates p-values as a result of comparisons within different time points as determined by Wilcoxon test with Bonferroni adjustment. Group interaction indicates p values for inner-subject effects as determined by Greenhouse-Geisser (ANOVA on ranks with Bonferroni adjustment). Data are expressed as mean ± standard error of mean (SEM). <u>Legend</u>: TF-TAVI indicates transcatheter transfemoral aortic valve replacement; TA-TAVI, transcatheter transapical aortic valve replacement; MECC, minimized extracorporeal circulation; CECC, conventional extracorporeal circulation; WBC, white blood cells; CRP, high-sensitivity C-reactive protein; sCD62L, soluble CD62L.</p