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.

Optimising the rotational classifier to process Eucla Basin mineral sands

Abstract not available

Scale-up and take-off development for rotary classification in the minerals industry

Abstract not available

Development of optimized vascular fractal tree models using level set distance function

Using the concepts of fractal scaling and constrained constructive optimization (CCO), a branching tree model, which has physiologically meaningful geometric properties, can be constructed [12-14]. A vascular branching tree model created in this way, although statistically correct in representing the vascular physiology, still does not possess a physiological correct arrangement of the major arteries. A distance-function based technique for 'staged growth' of vascular models has been developed in this work to address this issue. Time-dependent constraints based on a signed-distance level set function have been added, so that the tree models will first be grown near the designated surface(s) and, then, gradually allowed to penetrate into the enclosed volume. The proposed technique has been applied to construct a model of the human cerebral vasculature, which is characterized by the above-mentioned distribution of the arteries

Multiscale modeling of cerebral blood flow

A multiscale model of the human cerebral vasculature has been developed which includes a three-dimensional (3D) CFD model of the circle of Willis (CoW) and fractal tree models of all regions of small cerebral vasculature, namely Anterior, Middle and Posterior Cerebral Arteries (ACA, MCA, PCA). The realistic 3D CoW model was constructed from the medical imaging data with the use of 3D Slicer segmentation software. The flow model in the fractal tree models of ACA, MCA and PCA has been developed with the effects of blood vessel structural property, arterial size-dependent blood viscosity and nonparabolic velocity profile incorporated. The coupling of the CFD model (solved with ANSYS CFX) and the fractal tree models (solved with Matlab mathematic library) has been extended from one-way to two-way method in this work. The coupled model has been used to predict the transient blood flow in cerebral arteries and study the effect of occlusion on flow distribution in the brain

Modelling of embolus transport and embolic stroke

Cerebral microembolism may lead to the restriction of blood supply due to damaged blood vessel tissue (focal ischemia) which is increasingly seen as the cause of cognitive deterioration including Alzheimer's disease and vascular dementia. The flow through fractal models of the peripheral vasculature of the Anterior Cerebral Arteries (ACA) and Middle Cerebral Arteries (MCA) was modelled. The multi-scale model of the cerebral vasculature was coupled with blood flow and embolus transport models. The model incorporated asymmetric bifurcation trees, embolus-vascular interactions and autoregulation. Simulations were carried out where the embolus deposition rate, embolus diameter and embolus introduction rate were varied. Increasing the embolus diameter and embolus introduction rate increased the number of blocked terminal arteries to a quasi steady-state. For a low embolus deposition rate the MCA and ACA territory had the same embolization dynamics, even though, the MCA was larger than the ACA. It was also found for a higher embolus deposition rate the MCA, due to its more expansive structure, was less prone to occlusion than the ACA. The results also showed the effect of a single blockage is expected to be less severe in asymmetric flow than symmetric flow. This model will assist in developing a better understanding into embolic stroke and effect of microembolism and on the alteration of blood flow distribution in the circle of Willis

Transport by pulsatile flow in a branching network of cerebral vasculature

The supply of oxygen and glucose by blood flow is vital to the normal function of the brain and the deficit of either of these metabolism elements can cause severe degradation of the brain functionality. The transport of materials in the complex multi-branching structure of the cerebral vasculature is investigated to predict the brain oxygenation under normal conditions. A mathematical model of material transport due to pulsatile flow in a complex dichotomous branching tree network was developed which incorporated material-geometry interaction and diffusion across the blood vessel wall. Unlike previous work, this modelling work includes the full network structure and incorporates time-dependent flow. The predicted results indicate some effect of the flow transients on the propagation of the material introduced at the root segment in the vascular network. The effect was more pronounced in the case of constant blood viscosity. The transport model addressed the issue of oxygen transport in the cerebral vascular branching network with the inclusion of red blood cell (RBC) separation at bifurcation points. The predicted results indicate the significance of the vascular network geometry and RBC-bifurcation point interaction in defining the homogeneity of flow and oxygenation by the fractal vasculature. The simulations are found to be able to provide insights into the transport of materials by the blood circulation in the cerebral vasculature and the various factors which may affect the process. The separation of RBCs at branching points has a profound effect on the haemoglobin transport and, consequently, oxygen distribution in the vascular branching network