Understanding Uncertainties in Model-Based Predictions of Aedes aegypti Population Dynamics

Dengue is one of the most important insect-vectored human viral diseases. The principal vector is Aedes aegypti, a mosquito that lives in close association with humans. Currently, there is no effective vaccine available and the only means for limiting dengue outbreaks is vector control. To help design vector control strategies, spatial models of Ae. aegypti population dynamics have been developed. However, the usefulness of such models depends on the reliability of their predictions, which can be affected by different sources of uncertainty including uncertainty in the model parameter estimation, uncertainty in the model structure, measurement errors in the data fed into the model, individual variability, and stochasticity in the environment. This study quantifies uncertainties in the mosquito population dynamics predicted by Skeeter Buster, a spatial model of Ae. aegypti, for the city of Iquitos, Peru. The uncertainty quantification should enable us to better understand the reliability of model predictions, improve Skeeter Buster and other similar models by targeting those parameters with high uncertainty contributions for further empirical research, and thereby decrease uncertainty in model predictions

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.

Bladder Tissue Pharmacokinetics of Intravesical Mitomycin C and Suramin in Dogs

Suramin, at non-cytotoxic doses, reverses chemoresistance and enhances the activity of mitomycin C (MMC) in mice bearing human bladder xenograft tumors. The present study evaluated the pharmacokinetics of the intravesical suramin and MMC, alone or in combination, in dogs. Animals received either high dose suramin (20 mg/ml), low dose suramin (6 mg/ml), MMC (2 mg/ml), or combination of low dose suramin and MMC, instilled for 2 h. The dosing volume was 20 ml. All groups showed dilution of drug levels over time due to continued urine production. For single agent suramin, the results showed (a) 5% to 10% penetration into bladder tissues, (b) minimal and clinically insignificant systemic absorption (i.e., undetectable at low dose or a peak concentration that was 6,000× lower than urine concentrations), and (c) disproportionally higher drug penetration and concentrations in bladder tissues at the higher dose. Results for single agent MMC are consistent with our earlier observations. The co-administration of MMC did not alter the plasma, urine, or tissue pharmacokinetics of suramin. Adding suramin did not alter plasma or tissue pharmacokinetics of MMC, but lowered the MMC concentrations in urine by about 20%. This may be in part due to accelerated MMC degradation by co-incubation of suramin or due to variations in urine production rate (because animals were allowed for water during treatment). Suramin readily penetrates the urothelium and into deeper bladder tissues, indicating its potential utility in intravesical therapy