Abstract: This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Abstract: Objective To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD). Methods Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis. Results Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p Conclusions We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD. Trial registration number NCT00403767; Post-results.

Abstract: Viral dynamic modeling has had a long history of providing insight into the dynamics of hepatitis C virus infection. This chapter reviews a model used to predict treatment outcomes for regimens including the direct-acting antiviral telaprevir. Challenges for modeling existing and upcoming regimens are also discussed.

Abstract: BACKGROUND Metastatic castration-resistant prostate cancer (mCRPC) is typically associated with declining health-related quality of life (HR-QoL). OBJECTIVE To assess patient experience with abiraterone acetate (hereafter abiraterone) plus prednisone longitudinally. METHODS COU-AA-302 was a phase 3, multinational, randomized, double-blind study that enrolled asymptomatic or mildly symptomatic, chemotherapy-naive patients with mCRPC. Patients were randomized to 1 g abiraterone daily plus 5 mg prednisone BID (n = 546) or placebo plus prednisone (n = 542) in continuous 28-day cycles. Patient-reported outcomes (PROs) were collected using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, consisting of 4 well-being subscales (physical, social/family, emotional, functional) and a prostate cancer-specific subscale (PCS). The trial outcome index (TOI) is a composite of the physical well-being, functional well-being, and PCS scores. Least squares mean change from baseline at each cycle up to 1 year (cycle13) was compared between treatment arms using a mixed-effects model for repeated measures, which assumed that data were "missing at random." A pattern-mixture model (PMM) with multiple imputation was performed to address the assumption that data were "missing not at random." RESULTS Significant differences favoring abiraterone-prednisone were observed for FACT-P total, TOI, and PCS scores, and for all well-being subscales except social/family well-being over the first year of treatment. These results were supported by the PMM with multiple imputation. LIMITATIONS Attrition after 1 year limited our ability to analyze the PRO data beyond that time point. CONCLUSIONS Abiraterone-prednisone confers sustained HR-QoL benefits over the course of treatment.

Abstract: Background Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. Objective We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. Methods We developed CD11c-specific autophagy-related gene 5 (Atg5) −/− mice and used several murine models to investigate the role of autophagy in asthmatic patients. Results For the first time, we found that deletion of the Atg5 gene specifically in CD11c + cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c + cells in wild-type mice. We further found that adoptive transfer of Atg5 −/− , but not wild-type, bone marrow–derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5 −/− mice is glucocorticoid resistant and IL-17A dependent. Conclusion Our results suggest that lack of autophagy in pulmonary CD11c + cells induces neutrophilic airway inflammation and hyperreactivity.

Abstract: Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate-the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the 'inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes-IMPA1 or SMIT1, both mimic several lithium's behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions, 3H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by ~50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP3 but not IP1 reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP3 receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP3 administration; IP3 administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.