Preclinical evaluation of triiodothyronine nanoparticles as a novel therapeutic intervention for resuscitation from cardiac arrest.

BACKGROUND: Given emerging evidence of rapid non-genomic cytoprotective effects of triiodothyronine (T3), we evaluated the resuscitative efficacy of two nanoparticle formulations of T3 (T3np) designed to prolong cell membrane receptor-mediated signaling. METHODS: Swine (n = 40) were randomized to intravenous vehicle (empty np), EPI (0.015 mg/kg), T3np (0.125 mg/kg), or T3np loaded with phosphocreatine (T3np + PCr; 0.125 mg/kg) during CPR following 7-min cardiac arrest (n = 10/group). Hemodynamics and biomarkers of heart (cardiac troponin I; cTnI) and brain (neuron-specific enolase; NSE) injury were assessed for up to 4-hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis. RESULTS: Compared with vehicle (4/10), the rate of ROSC was higher in swine receiving T3np (10/10; p < 0.01), T3np + PCr (8/10; p = 0.08) or EPI (10/10; p < 0.01) during CPR. Although time to ROSC and survival duration were comparable between groups, EPI was associated with a ∼2-fold higher post-ROSC concentration of cTnI vs T3np and T3np + PCr and the early post-ROSC rise in NSE and neuronal injury were attenuated in T3np-treated vs EPI-treated animals. Analysis of hippocampal ultrastructure revealed deterioration of mitochondrial integrity, reduced active zone length, and increased axonal vacuolization in EPI-treated animals vs controls. However, the frequency of these abnormalities was diminished in animals resuscitated with T3np. CONCLUSIONS: T3np achieved a ROSC rate and post-ROSC survival that was superior to vehicle and comparable to EPI. The attenuation of selected biomarkers of cardiac and neurologic injury at individual early post-ROSC timepoints in T3np-treated vs EPI-treated animals suggests that T3np administration during CPR may lead to more favorable outcomes in cardiac arrest.

Reductions in human papillomavirus-disease resource use and costs with quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccination: the FUTURE Study Economic Evaluation.

OBJECTIVE: To examine the short-term impact of quadrivalent human papillomavirus (HPV) (types 6/11/16/18) recombinant vaccination upon HPV disease-related health-care resource utilization and costs among young women. METHODS: We analyzed data from a randomized clinical trial comparing quadrivalent vaccination to placebo, among women (N = 7861) primarily 16 to 23 years of age at enrollment. HPV disease episodes, health-care resource utilization and costs associated with cervical, vaginal, and vulvar precancers, and anogenital warts were analyzed over a period of 2.5 years among women, regardless of baseline HPV status. RESULTS: Overall, there was a 25.9% (P < 0.001) reduction in total HPV disease-related health-care costs among women receiving vaccine versus placebo (absolute reduction $3939 per 100 trial enrollees). We observed similar overall reductions in HPV-disease episodes and resource utilization. There was a statistically significant reduction in HPV 6/11-related disease episode costs of 65.1% ($1837 per 100), and a reduction of 51.4% ($1781 per 100) in HPV 16/18-related episode costs. CONCLUSIONS: Quadrivalent HPV vaccination can reduce HPV disease events, resource use and costs when administered to a broad population of young women 16 to 23 years of age. Prevention of HPV types 6 and 11 yielded similar value in terms of HPV disease cost offsets, compared to protection against HPV 16 and 18, during the years initially after vaccination. Over the short-term, costs of vaccination exceed cost offsets associated with prevention of HPV disease; however, quadrivalent HPV vaccination has previously been shown to be cost-effective in the longer term, when fully accounting for health benefits and cost offsets.

Expected Mean Squares for Hierarchical Factorial Layouts with Population Imbalance.

We introduce an analysis of variance usable for two-factor hierarchical models where observations are incompletely sampled from unbalanced populations of finite effects. Our new approach enables unbiased estimation of the variance components for this type of model and allows hypothesis testing to identify significant effects/sub-class effects. An explanation of how these results can be generalized to factorial layouts with more than two factors is given.

Potential impact on cardiovascular public health of over-the-counter statin availability.

Over-the-counter (OTC) statin availability has been hypothesized to represent a strategy for treating consumers at moderate risk of coronary heart disease (CHD) who are currently not receiving drug therapy. The viability of this strategy has been questioned, particularly with respect to the public health benefit that can be obtained in an unsupervised treatment environment. The previously reported Consumer Use Study of Over-the-Counter Lovastatin (CUSTOM) examined consumer behavior in a simulated OTC setting in which 20 mg lovastatin could be purchased. Framingham CHD risk scores were calculated for 981 self-selected consumers who used OTC lovastatin in CUSTOM. Overall, this group had a median 10-year CHD risk of 10%, but with significant numbers of consumers with estimated risks of <5% and >20%. According to the risk profile of CUSTOM consumers, the use of 20 mg lovastatin for 10 years would be expected to prevent approximately 33,100 CHD events per 1 million users. This represents a 10-year number needed to treat of 30 consumers. This optimal benefit may be reduced because some higher risk consumers in CUSTOM used lovastatin rather than appropriate, more aggressive supervised care. On the basis of the frequencies of diversion from optimal care observed in CUSTOM, the number of events prevented might be reduced to 23,000 (number needed to treat 43 consumers). Sensitivity analyses have demonstrated that these estimates are robust and that the predicted public health benefit likely falls in the range of 23,000 to 33,000 CHD events prevented per 1 million treated for 10 years. In conclusion, on a population basis, OTC statin availability is likely to result in clinically meaningful reductions in CHD morbidity and mortality. The analyses also identified opportunities for optimizing the use of OTC statins in the marketplace.