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 Constraining Influence of the Revolutionary on the Growth of the Field

This article draws attention to a pattern of development within science and other intellectual research communities that has received virtually no mention. We propose that subsequent dominance of a research community by a figure responsible for significant innovation often delays progress in the field. During the period in which the revolutionary continues to influence research in a community, too frequently the effect is to freeze what Kuhn called normal science ‘puzzle solving’ into the limited directions which the revolutionary sanctions. This constrains theorizing to speculation of a type which the revolutionary advocates, and prevents attempts at reconceptualization almost entirely. Having made one revolutionary advance, the dominant figure effectively prevents subsequent progress until he or she either retires from the field or dies. “Science advances one funeral at a time” (Planck, 1949), After his or her initial contribution, the continued presence of an innovative or revolutionary figure frequently stifles progress rather than aids it. We document four cases of this phenomenon as of signal consequence in the history of science and philosophy. We stress at the outset that this is an overview, designed to press the plausibility of our thesis rather than examine it in complete and necessary historical detail. We proceed in section one with a more thorough explication of the problem. Section two examines four examples of just how these revolutionary thinkers often constrains development and growth. In section three we broaden our argument by demonstrating the breadth and general scope of the problem by sketching the import of this phenomenon at the intersection of sociology, philosophy, and psychology of science in light of prominent theories of scientific methodology, and the insufficiency of presumptive methodologies to explain such episodes

Psychology and Critique — Forms of Psychologization after 1945: An Introduction

Current psychology has gone to hell – according to some critical voices from within the discipline, which find a forum in the critical science blog Neuroskeptic (2012). The reason for this infernal location is the replication crisis that seized psychology in 2011 and which has since then led to ever more far-reaching controversies about psychological research methods. No less dramatic is another current critique of psychology which takes a completely different direction: Critics such as the German legal expert and social scientist Albert Krölls (2016) currently argue that psychology is the ‘modern opium of the people’

Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes

SummaryDocking, the initial association of secretory vesicles with the plasma membrane, precedes formation of the SNARE complex, which drives membrane fusion. For many years, the molecular identity of the docked state, and especially the vesicular docking protein, has been unknown, as has the link to SNARE complex assembly. Here, using adrenal chromaffin cells, we identify the vesicular docking partner as synaptotagmin-1, the calcium sensor for exocytosis, and SNAP-25 as an essential plasma membrane docking factor, which, together with the previously known docking factors Munc18-1 and syntaxin, form the minimal docking machinery. Moreover, we show that the requirement for Munc18-1 in docking, but not fusion, can be overcome by stabilizing syntaxin/SNAP-25 acceptor complexes. These findings, together with cross-rescue, double-knockout, and electrophysiological data, lead us to propose that vesicles dock when synaptotagmin-1 binds to syntaxin/SNAP-25 acceptor complexes, whereas Munc18-1 is required for the downstream association of synaptobrevin to form fusogenic SNARE complexes