Publications

New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.

INTRODUCTION

Tobacco manufacturers' aggressive promotion of new smokeless tobacco products such as snus warrants a timely and effective public health response. This study tested potential countermarketing messages to discourage current and former smokers from becoming dual users of smokeless tobacco and cigarettes.

METHODS

In a pretest-post-test experiment, 1836 adult current and recently former smokers from a national sample were randomised to view one of six antismokeless tobacco ads followed by a snus ad, to view a control ad followed by a snus ad; or to view two control ads. Perceived effectiveness of ads and actual changes in attitudes and openness to snus were compared across groups using analyses of variance.

RESULTS

Some ads that were perceived as most effective did not change attitudes or openness to trying snus, and conversely, some ads not perceived as effective changed attitudes and openness to snus. Ads portraying the negative health effects of smokeless tobacco were perceived as most effective, but ads with antitobacco industry themes significantly decreased favourable attitudes toward snus. Responses to ads were different for smokers who had ever used smokeless tobacco: for this group health effects and humorous/testimonial ads were effective.

CONCLUSIONS

Measures of perceived effectiveness of antitobacco ads need to be augmented with measures of actual effectiveness to assess countermarketing messages. Some of the developed ads, such as ads with anti-industry themes, were effective for the overall population of smokers whereas humorous/testimonial and health effects ads were particularly effective in changing attitudes of past users of smokeless tobacco.

John Widdicombe has made substantial contributions to respiratory physiology and to the field of cough particularly. He was one of the first to characterise Aδ-myelinated fibres in the airways that could mediate cough and increased breathing. Later on, he initiated the series of international London Cough Symposia that gathered researchers and clinicians on a two-yearly basis to discuss recent results and concepts regarding cough. John Widdicombe was interested in all aspects of cough from the definition to potential new antitussives. This article will focus on his contributions and on his generous personality through reminiscences from three friends.

BACKGROUND

Cadmium (Cd) is an important metal with both common occupational and environmental sources of exposure. Although it is likely to cause adverse respiratory effects, relevant human data are relatively sparse.

METHODS

A cross-sectional study of 133 workers in jewellery workshops using Cd under poor hygienic conditions and 54 referent jewellery sales staffs was performed. We assessed symptoms, performed spirometry, measured urinary Cd levels in all study subjects and quantified airborne total oxidant contents for 35 job areas in which the studied workforce was employed. We tested the association of symptoms with exposure relative to the unexposed referents using logistic regression analysis, and tested the association between urinary Cd levels and lung function using multiple regression analysis, adjusting for demographics, smoking and area-level airborne oxidants.

RESULTS

Exposed workers had 10 times higher urinary Cd values than referents (geometric mean 5.8 vs 0.41 µg/dl; p<0.01). Of the exposed subjects, 75% reported respiratory tract symptoms compared with 33% of the referents (OR=3.1, 95% CI 1.4 to 7.3). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were also lower among the exposed workers than the referents (>600 ml decrement for each, p<0.001). For every 1 µg increase in urinary Cd there was a 34 ml decrement in FVC and a 39 ml decrement in FEV1 (p<0.01), taking into account other covariates including workplace airborne oxidant concentrations.

CONCLUSIONS

This cohort of heavily exposed jewellery workers experienced frequent respiratory symptoms and manifested a marked deficit in lung function, demonstrating a strong response to Cd exposure.