Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

The hybridogenetic Rana (Pelophylax) esculenta complex studied in a molecular context

The study of hybridogenesis is expected to shed light on the role played by the so-called ‘asexual reproduction’ in vertebrate evolution, since hybridogenesis, gynogenesis and parthenogenesis are restricted to lower vertebrates. Hence, it seemed interesting to define the stage and time of germline differentiation in reproductively unstable organisms which, to accomplish functional gamete maturation, can change the normal approach to meiosis by means of unusual cytological steps, such as genome elimination and endoreduplication. The cytogenetic aspects of ‘asexual’ meiosis have already been thoroughly studied. At present, molecular investigations are in progress to characterise the single steps of germline differentiation in a hybridogenetic green frog system, and the results obtained so far can be considered promising, as shown in this work. Vasa, PL10 and Y-box homolog genes, first isolated in Rana (Pelophylax), are expressed during early phases of gametogenesis in R. (P.) ridibunda and R. (P.) lessonae (parental species), and R. (P.) esculenta (their natural hybrid), suggesting that gametogenesis, during the adult life, follows a unique genetic sequence in the two parental species as well as in hybridogenetic hybrids. Similar molecular investigations need to be carried out on larval stages prior to metamorphosis, when the genetic plasticity of gemline cells allows their commitment versus either the standard and/or hybridogenetic reproduction mode