Associations of Air Pollution and Pediatric Asthma in Cleveland, Ohio.

Air pollution has been associated with poor health outcomes and continues to be a risk factor for respiratory health in children. While higher particulate matter (PM) levels are associated with increased frequency of symptoms, lower lung function, and increase airway inflammation from asthma, the precise composition of the particles that are more highly associated with poor health outcomes or healthcare utilization are not fully elucidated. PM is measured quantifiably by current air pollution monitoring systems. To better determine sources of PM and speciation of such sources, a particulate matter (PM) source apportionment study, the Cleveland Multiple Air Pollutant Study (CMAPS), was conducted in Cleveland, Ohio, in 2009-2010, which allowed more refined assessment of associations with health outcomes. This article presents an evaluation of short-term (daily) and long-term associations between motor vehicle and industrial air pollution components and pediatric asthma emergency department (ED) visits by evaluating two sets of air quality data with healthcare utilization for pediatric asthma. Exposure estimates were developed using land use regression models for long-term exposures for nitrogen dioxide (NO2) and coarse (i.e., with aerodynamic diameters between 2.5 and 10 µm) particulate matter (PM) and the US EPA Positive Matrix Factorization receptor model for short-term exposures to fine (<2.5 µm) and coarse PM components. Exposure metrics from these two approaches were used in asthma ED visit prevalence and time series analyses to investigate seasonal-averaged short- and long-term impacts of both motor vehicles and industry emissions. Increased pediatric asthma ED visits were found for LUR coarse PM and NO2 estimates, which were primarily contributed by motor vehicles. Consistent, statistically significant associations with pediatric asthma visits were observed, with short-term exposures to components of fine and coarse iron PM associated with steel production. Our study is the first to combine spatial and time series analysis of ED visits for asthma using the same periods and shows that PM related to motor vehicle emissions and iron/steel production are associated with increased pediatric asthma visits.

High-dose and low-dose varenicline for smoking cessation in adolescents: a randomised, placebo-controlled trial.

BACKGROUND: Although cigarette smoking typically begins in adolescence, evidence for successful pharmacological smoking cessation interventions for this population is scarce. In adult smokers, varenicline is the most effective single pharmacotherapy. The aim of this study was to assess the efficacy and tolerability of varenicline for smoking cessation in adolescents. METHODS: We did a randomised, placebo-controlled trial with adolescent smokers aged 12-19 years who were seeking treatment to quit at 57 outpatient centres (in the USA, Russia, South Korea, Taiwan, Canada, and Georgia). Participants were randomly assigned (1:1:1) to receive 12 weeks of high-dose varenicline (1 mg twice daily; 0·5 mg twice daily if bodyweight ≤55 kg), low-dose varenicline (0·5 mg twice daily; 0·5 mg once daily if bodyweight ≤55 kg), or placebo, then followed up for 40 additional weeks. At all visits, participants received brief, developmentally tailored smoking cessation counselling (<10 min per session) delivered by a trained counsellor. The primary efficacy outcome was continuous abstinence from weeks 9 to 12, measured via a Nicotine Use Inventory and confirmed by urine cotinine testing. The primary tolerability outcome was frequency of treatment-emergent adverse events, including neuropsychiatric adverse events, occurring after the first dose and within 30 days of the last dose of study medication. This trial is registered with ClinicalTrials.gov, NCT01312909. FINDINGS: Between April 26, 2011, and Jan 18, 2018, 312 participants were enrolled and completed participation in the study: 109 in the high-dose varenicline group, 103 in the low-dose varenicline group, and 100 in the placebo group. The continuous abstinence rates from week 9 to 12 were 20% (22 of 109) in the high-dose varenicline group, 27% (28 of 103) in the low-dose varenicline group, and 18% (18 of 100) in the placebo group. Abstinence rates between high-dose varenicline and placebo groups (odds ratio [OR] 1·18 [95% CI 0·59-2·37]; p=0·63) and between low-dose varenicline and placebo groups (1·73 [0·88-3·39]; p=0·11) did not differ significantly. Treatment-emergent adverse events occurred in 65 (60%) of 108 participants in the high-dose group, 53 (53%) of 100 in the low-dose group, and 52 (53%) of 99 in the placebo group, and most were rated as mild. Neuropsychiatric treatment-emergent adverse events occurred in 18 (17%) of 108 participants in the high-dose group, 11 (11%) of 100 in the low-dose group, and 12 (12%) of 99 in the placebo group, and none was rated as severe. INTERPRETATION: This trial did not show an advantage in abstinence with varenicline compared with placebo among adolescent smokers. The rates of treatment-emergent adverse events were similar to those in previous trials of adult smokers, raising no new tolerability signals. These findings do not support the use of varenicline as a first-line pharmacotherapy for smoking cessation in adolescents. FUNDING: Pfizer.

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer's Disease.

OBJECTIVES: Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer's disease. DESIGN: Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan. METHODS: Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 µg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up. RESULTS: ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies. CONCLUSIONS: Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimer's disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease.

Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-ß (Aß) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3µg, 10µg, 30µg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aß IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30µg + QS-21; ACC-001 10µg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aß IgG titers compared with ACC-001 alone. Plasma Aßx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.