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.

Solitärer fibröser Tumor der Orbita: klinische, radiologische, histologische Merkmale und Differenzialdiagnose eines ungewöhnlichen Tumors

BACKGROUND: Solitary fibrous tumours (SFT) are mesenchymal neoplasias rarely found in the orbit. Due to their sharp delineation they are frequently mistaken for various benign neoplasma, such as cavernous hemangiomas, neurinomas and pleomorphic adenomas. We present two cases of SFT in the orbit and one in the lacrimal sac and discuss the radiological and histological differential diagnosis. PATIENTS AND METHODS: Among 9 patients diagnosed and operated in our department between 2008 and 2010 with an orbital tumour, three had the histological diagnosis of a solitary fibrous tumour. In 5 cases an MRI scan was performed preoperatively, in 4 cases a CT scan. RESULTS: Histology showed 2 pleomorphic adenomas, 2 cavernous hemangiomas, 2 neurinomas and 3 SFT. All SFT were intraoperatively well circumscribed and enucleated, showing histologically incomplete resection. No further treatment was given. There is no recurrence in any of the patients in the follow up of an average of 10 months (range 1 - 30 months). CONCLUSIONS: SFT are rare mesenchymal tumours of the orbit. The radiological differential diagnosis is difficult and they can be mistaken for more common tumours. The SFT has a wide range of histological appearances. Long term clinical follow-up is mandatory in all cases of SFT

Inter-observer agreement for spectral- and time-domain optical coherence tomography image grading: a prospective study

The purpose of this study was to compare inter-observer agreement of Stratus™ OCT versus Spectralis™ OCT image grading in patients with neovascular age-related macular degeneration (AMD). Thirty eyes with neovascular AMD were examined with Stratus™ OCT and Spectralis™ OCT. Four different scan protocols were used for imaging. Three observers graded the images for the presence of various pathologies. Inter-observer agreement between OCT models was assessed by calculating intra-class correlation coefficients (ICC). In Stratus™ OCT highest interobserver agreement was found for subretinal fluid (ICC: 0.79), and in Spectralis™ OCT for intraretinal cysts (IRC) (ICC: 0.93). Spectralis™ OCT showed superior interobserver agreement for IRC and epiretinal membranes (ERM) (ICC(Stratus™): for IRC 0.61; for ERM 0.56; ICC(Spectralis™): for IRC 0.93; for ERM 0.84). Increased image resolution of Spectralis™ OCT did improve the inter-observer agreement for grading intraretinal cysts and epiretinal membranes but not for other retinal changes

Rapid Remeasure of Dense Civilian Networks as a Game‐Changer Tool for Surface Deformation Monitoring: The Case Study of the M w 6.4 2020 Petrinja Earthquake, Croatia

International audienc

On the usability of Lombardi graph drawings

A recent line of work in graph drawing studies Lombardi drawings, i.e., drawings with circular-arc edges and perfect angular resolution at vertices. Little is known about the effects of curved edges versus straight edges in typical graph reading tasks. In this paper we present the first user evaluation that empirically measures the readability of three different layout algorithms (traditional spring embedder and two recent near-Lombardi force-based algorithms) for three different tasks (shortest path, common neighbor, vertex degree). The results indicate that, while users prefer the Lombardi drawings, the performance data do not present such a positive picture

HUWE1 employs a giant substrate-binding ring to feed and regulate its HECT E3 domain

HUWE1 is a universal quality-control E3 ligase that marks diverse client proteins for proteasomal degradation. Although the giant HECT enzyme is an essential component of the ubiquitin–proteasome system closely linked with severe human diseases, its molecular mechanism is little understood. Here, we present the crystal structure of Nematocida HUWE1, revealing how a single E3 enzyme has specificity for a multitude of unrelated substrates. The protein adopts a remarkable snake-like structure, where the C-terminal HECT domain heads an extended alpha-solenoid body that coils in on itself and houses various protein–protein interaction modules. Our integrative structural analysis shows that this ring structure is highly dynamic, enabling the flexible HECT domain to reach protein targets presented by the various acceptor sites. Together, our data demonstrate how HUWE1 is regulated by its unique structure, adapting a promiscuous E3 ligase to selectively target unassembled orphan proteins