Background: Glucagon-like peptide 1 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. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There has been one previous population pharmacokinetic analysis of total melphalan given as a short infusion in 84 adults (mixed diagnoses) and creatinine clearance and body size were found to be important determinants of total melphalan clearance. Dose and exposure to total melphalan were found to correlate with the development of mucositis. WHAT THIS STUDY ADDS• This is the largest population pharmacokinetic study on melphalan conducted to date. It is the first conducted in a uniform patient population (patients with multiple myeloma) and the first in which both total and unbound melphalan pharmacokinetics are examined. Factors found to be important determinants of total and unbound plasma clearance of melphalan were creatinine clearance, fat free mass and haematocrit. Haematocrit has not previously been identified as an influential covariate in any previous study. The importance of total and unbound melphalan exposure on transplant outcome was demonstrated by preliminary pharmacodynamic results showing significant associations with melphalan-related toxicity. A preliminary analysis of the association with disease response showed promising trends, but will be examined in more detail with longer follow-up of the whole cohort. AIMSTo i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response. METHODSPopulation pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m -2 melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (Ն90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test. RESULTSA two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h -1 , respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l -1 h) and unbound AUC (range 1.0-6.5 mg l -1 h) were significantly higher in patients who had oral mucositis (Նgrade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l -1 h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l -1 h, P = 0.06), when assessed from pre-to post-melphalan. CONCLUSIONSCreatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising tren...

We study the statistical properties of spherical harmonic modes of temperature maps of the cosmic microwave background. Unlike other studies, which focus mainly on properties of the amplitudes of these modes, we look instead at their phases. In particular, we present a simple measure of phase correlation that can be diagnostic of departures from the standard assumption that primordial density fluctuations constitute a statistically homogeneous and isotropic Gaussian random field, which should possess phases that are uniformly random on the unit circle. The method we discuss checks for the uniformity of the distribution of phase angles using a non‐parametric descriptor based on the use of order statistics, which is known as Kuiper's statistic. The particular advantage of the method we present is that, when coupled to the judicious use of Monte Carlo simulations, it can deliver very interesting results from small data samples. In particular, it is useful for studying the properties of spherical harmonics at low l for which there are only a small number of independent values of m and which therefore furnish only a small number of phases for analysis. We apply the method to the COBE Differential Microwave Radiometer (DMR) and Wilkinson Microwave Anisotropy Probe (WMAP) sky maps, and find departures from uniformity in both. In the case of WMAP, our results probably reflect Galactic contamination or the known variation of signal‐to‐noise ratio across the sky rather than primordial non‐Gaussianity.

Neopterin has a short half-life and was useful for monitoring inflammation activity in a patient with relapsing-remitting encephalitis. CSF neopterin is a useful marker of inflammation in a broad range of acute and chronic CNS disorders, and is a significantly more sensitive marker of inflammation than CSF pleocytosis.