Internal rotation and chlorine nuclear quadrupole coupling in 2-chloro-4-fluorotoluene explored by microwave spectroscopy and quantum chemistry.

2-Chloro-4-fluorotoluene was investigated using a combination of molecular jet Fourier transform microwave spectroscopy in the frequency range from 5 to 21 GHz and quantum chemistry. The molecule experiences an internal rotation of the methyl group, which causes fine splittings of all rotational transitions into doublets with separation on the order of a few tens of kHz. In addition, hyperfine effects originating from the chlorine nuclear quadrupole moment coupling its nuclear spin to the end-over-end rotation of the molecule are observed. The torsional barrier was derived using both the rho and the combined-axis-method, giving a value of 462.5(41) cm-1. Accurate rotational constants and quadrupole coupling constants were determined for the 35Cl and 37Cl isotopologues and compared with Bailey's semi-experimental quantum chemical predictions. The gas phase molecular structure was deduced from the experimental rotational constants supplemented with those calculated by quantum chemistry at various levels of theory. The values of the methyl torsional barrier and chlorine nuclear quadrupole coupling constants were compared with the theoretical predictions and with those of other chlorotoluene derivatives.

Serum IgG Levels and Risk of COPD Hospitalization: A Pooled Meta-analysis.

BACKGROUND: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations. RESEARCH QUESTION: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD. STUDY DESIGN AND METHODS: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status. RESULTS: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001. INTERPRETATION: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions.

Electron-withdrawing effects on the molecular structure of 2- and 3-nitrobenzonitrile revealed by broadband rotational spectroscopy and their comparison with 4-nitrobenzonitrile.

The rotational spectra of 2- and 3-nitrobenzonitrile were recorded via chirped-pulse Fourier transform microwave spectroscopy in the frequency range of 2-8 GHz. These molecules each display large dipole moments, making them viable candidates for deceleration and trapping experiments with AC-electric fields. For both molecules, the main isotopologues and all isotopologues of the respective 13C-, 15N-, 18O-monosubstituted species in their natural abundance were assigned. These assignments allowed for the structural determination of 2- and 3-nitrobenzonitrile via Kraitchman's equations as well as a mass-dependent least-squares fitting approach. The experimentally determined structural parameters are then compared to those obtained from quantum-chemical calculations for these two molecules and 4-nitrobenzonitrile. Structural changes caused by steric interaction and competition for the electron density of the phenyl ring highlight how these strong electron-withdrawing substituents affect one another according to their respective positions on the phenyl ring.

Smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years.

BACKGROUND: Cigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the development of structural lung disease, airflow obstruction and functional outcomes is not known. METHODS: We analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV1/FVC); secondary outcomes included five additional measures of disease: FEV1, CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George's Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years. RESULTS: 10 187 subjects were included. For FEV1/FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P<0.001). After categorisation, there was a linear increase in adjusted means FEV1/FVC with increase in pack-years (regression coefficient ß=-0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (ß=-0.041±0.004; P<0.001) but a relatively flat slope for cigarettes/day across all ranges of smoking duration (ß=-0.009±0.0.009; P=0.34). Strength of association of duration was similarly greater than pack-years for emphysema, gas trapping, FEV1, 6MWD and SGRQ. CONCLUSION: Smoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years. TRIAL REGISTRATION NUMBER: Post-results; NCT00608764.

The Relationships of Expectancies With E-cigarette Use Among Hospitalized Smokers: A Prospective Longitudinal Study.

Background: Expectancies demonstrate cross-sectional associations with e-cigarette use, but the prospective relationships between expectancies and e-cigarette use are unknown. This study examined the longitudinal associations of expectancies with e-cigarette use among hospitalized tobacco cigarette smokers. Methods: E-cigarette expectancies (e-cigarette-specific Brief Smoking Consequences Questionnaire-Adult [BSCQ-A]), tobacco cigarette expectancies (tobacco-specific BSCQ-A), and number of days used e-cigarettes in the past 30 days were assessed at baseline hospitalization, 6-months post-hospitalization, and 12-months post-hospitalization among 978 hospitalized tobacco cigarette smokers. Expectancy difference scores (e-cigarette-specific expectancies minus tobacco-specific expectancies) were computed for each of the 10 BSCQ-A scales. Cross-lagged panel models tested the relationships between expectancy difference scores and number of days used e-cigarettes in the past 30 days for each of the 10 BSCQ-A scales. Results: Though some models revealed partial associations between expectancies and e-cigarette use, only one yielded results consistent with hypotheses. Greater e-cigarette use at baseline predicted greater expectancies that e-cigarettes taste pleasant as compared to tobacco cigarettes at 6 months, which then predicted greater e-cigarette use at 12 months. To a lesser degree greater expectancies that e-cigarettes taste pleasant as compared to tobacco cigarettes at baseline predicted greater e-cigarette use at 6 months, which then predicted greater expectancies that e-cigarettes taste pleasant as compared to tobacco cigarettes at 12 months. Conclusions: Expectancies that e-cigarettes provide similar or more pleasant taste sensations as compared to tobacco cigarettes may be both a cause and consequence of e-cigarette use. Focusing on the taste experience may prove most effective in modifying e-cigarette use behavior. Implications: The current study offers the first longitudinal examination of expectancies and e-cigarette use. Results suggest expectancies that e-cigarettes provide similar or more pleasant taste sensations relative to tobacco cigarettes are both a cause and consequence of e-cigarette use. Efforts that focus on the e-cigarette taste experience may prove most effective in modifying e-cigarette use behavior.

The Long-Term Oxygen Treatment Trial for Chronic Obstructive Pulmonary Disease: Rationale, Design, and Lessons Learned.

The Long-Term Oxygen Treatment Trial demonstrated that long-term supplemental oxygen did not reduce time to hospital admission or death for patients who have stable chronic obstructive pulmonary disease and resting and/or exercise-induced moderate oxyhemoglobin desaturation, nor did it provide benefit for any other outcome measured in the trial. Nine months after initiation of patient screening, after randomization of 34 patients to treatment, a trial design amendment broadened the eligible population, expanded the primary outcome, and reduced the goal sample size. Within a few years, the protocol underwent minor modifications, and a second trial design amendment lowered the required sample size because of lower than expected treatment group crossover rates. After 5.5 years of recruitment, the trial met its amended sample size goal, and 1 year later, it achieved its follow-up goal. The process of publishing the trial results brought renewed scrutiny of the study design and the amendments. This article expands on the previously published design and methods information, provides the rationale for the amendments, and gives insight into the investigators' decisions about trial conduct. The story of the Long-Term Oxygen Treatment Trial may assist investigators in future trials, especially those that seek to assess the efficacy and safety of long-term oxygen therapy. Clinical trial registered with clinicaltrials.gov (NCT00692198).

Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study.

BACKGROUND: Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD METHODS: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia. RESULTS: Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05-22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58-0.85), self-reported heart failure (OR 6.92, 95%CI 1.56-30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17-6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38-7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up. CONCLUSIONS: Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia. TRIAL REGISTRATION: COPDGene is registered at ClinicalTrials.gov: NCT00608764 (Registration Date: January 28, 2008).

Withdrawal exposure with withdrawal regulation training for smoking cessation: a randomized controlled pilot trial.

INTRODUCTION: Although withdrawal processes form a key motivational basis for cigarette use, smoking cessation treatments appear to exert only modest effects on withdrawal. One treatment option for further reducing withdrawal severity would be to provide smokers with withdrawal regulation training. The objective of this study was to pilot a smoking cessation intervention comprising withdrawal exposure with withdrawal regulation training. METHODS: Adult smokers (N=80) were randomized to one of two conditions: 1) Withdrawal Exposure with Withdrawal Regulation Training (WT), which included the development and application of individualized withdrawal regulation strategies over four separate sessions that spanned the first four hours of abstinence; 2) or Relaxation Control (RC) training, which controlled for the therapeutic contact of WT. All sessions occurred before the quit date, after which differential treatment was discontinued and all participants received brief counseling, nicotine replacement therapy, and self-help literature. Biochemically-confirmed (CO≤3) seven-day point-prevalence abstinence was assessed at Months 2 and 3 after end-of-treatment. RESULTS: Treatment completion and ratings of credibility and efficacy were high and equivalent across conditions. 22.2% of participants in the WT condition were abstinent at both time points, whereas 0% and 4.2% of participants in the RC condition were abstinent at Months 2 and 3 (Month 3 OR=6.5 [0.73, 59.19]). In-session withdrawal ratings suggested WT improved regulation of withdrawal symptoms, which were in turn associated with abstinence. CONCLUSIONS: This small pilot study suggests that WT promotes abstinence by enhancing withdrawal regulation. Results warrant further investigation of this innovative treatment approach.

ß-Blockers are associated with a reduction in COPD exacerbations.

BACKGROUND: While some retrospective studies have suggested that ß-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful. METHODS: Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by ß-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe ß-blockers. RESULTS: 3464 subjects were included. During a median of 2.1 years of follow-up, ß-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of ß-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with ß-blocker use. CONCLUSIONS: ß-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial. TRIAL REGISTRATION NUMBER: (ClinicalTrials.gov NCT00608764).

A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

RATIONALE: Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively. OBJECTIVES: We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation. METHODS: We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups. CONCLUSIONS: Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).

Clinical and Radiologic Disease in Smokers With Normal Spirometry.

IMPORTANCE: Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free. OBJECTIVE: To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0. DESIGN, SETTING, AND PARTICIPANTS: Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011. MAIN OUTCOMES AND MEASURES: Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life. RESULTS: One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George's Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease. CONCLUSIONS AND RELEVANCE: Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.

The Impact of Parent's Health Literacy on Pediatric Asthma Outcomes.

Background: Health literacy has been associated with health disparities in many disease outcomes, including children's asthma. Parents are responsible for most of children's healthcare. Therefore, parents' health literacy may impact children's health outcomes, including asthma control. This study sought to determine the association between parent health literacy and children's asthma control among a cohort of predominately minority urban children aged between 6 and 12 years. Methods: This cross-sectional study assessed children with asthma and their parents at a single outpatient visit. English-speaking parents and their children, aged between 6 and 12 years with physician-diagnosed asthma, were eligible for this study. Healthcare providers assessed asthma control and severity, and parents completed demographic, health literacy, asthma control, and asthma knowledge measures. Children completed a pulmonary function test as part of the Asthma Control Questionnaire (ACQ) scoring. Results: A total of 281 parent-child dyads provided data, with the majority of parents being mothers and African American, with a high school level education or less. Lower parent health literacy was associated with worse asthma control as rated both by the provider (p=0.007) and the ACQ (p=0.013), despite only moderate concordance between ratings (ρ=0.408, p<0.0001). Lower parent health literacy also was associated with less asthma knowledge, which was associated with worse asthma control. Conclusions: Higher parent health literacy was associated with more parent asthma knowledge and better child asthma control. Pediatric providers should consider tailoring education or treatment plans or utilizing universal precautions for low health literacy.

Hospitalized smokers' expectancies for electronic cigarettes versus tobacco cigarettes.

INTRODUCTION: The objectives of the current study were to compare hospitalized smokers' expectancies for electronic cigarettes (e-cigarettes) against their expectancies for tobacco cigarettes and evaluate relationships between e-cigarette expectancies and intention to use e-cigarettes. METHODS: Analysis of baseline data from a one-year longitudinal observational study. The setting was a tertiary care academic center hospital in the Southeastern U.S. Participants were 958 hospitalized tobacco cigarette smokers. A questionnaire of e-cigarette expectancies based on the Brief Smoking Consequences Questionnaire-Adult (BSCQ-A) was developed and administered along with the original, tobacco-specific, BSCQ-A. Intention to use e-cigarettes was assessed with a single 10-point Likert scale item. RESULTS: Participants reported significantly weaker expectancies for e-cigarettes relative to tobacco cigarettes on all 10 BSCQ-A scales. Participants held sizably weaker expectancies that e-cigarettes pose health risks (p<.001, Cohen's d=-2.07), relieve negative affect (p<.001, Cohen's d=-1.01), satisfy the desire for nicotine (p<.001, Cohen's d=-.83), and taste pleasant (p<.001, Cohen's d=-.73). Among the strongest predictors of intention to use e-cigarettes were greater expectancies that e-cigarettes taste pleasant (p<.001, adjusted ß=.34), relieve negative affect (p<.001, adjusted ß=.32), and satisfy the desire for nicotine (p<.001, adjusted ß=.31). CONCLUSIONS: Hospitalized tobacco smokers expect fewer negative and positive outcomes from e-cigarettes versus tobacco cigarettes. This suggests that e-cigarettes might be viable though imperfect substitutes for tobacco cigarettes.

Differences in Electronic Cigarette Awareness, Use History, and Advertisement Exposure Between Black and White Hospitalized Cigarette Smokers.

E-cigarette use has increased rapidly over the past decade. There is growing concern about e-cigarette use and advertising given limited regulation of these products. This cross-sectional study reports on data collected at baseline from hospitalized cigarette smokers (N=944) recruited in monthly cohorts between December 2012 and September 2013. Participants were queried regarding e-cigarette awareness and use, and number and sources of e-cigarette advertisement exposures in the previous 6 months. Most Whites (99%) reported ever hearing of an e-cigarette compared to 96% of Blacks (p<0.001). Over two thirds (64%) of Whites reported ever using an e-cigarette compared to 30% of Blacks (p<0.001). There were significant trends in increasing e-cigarette use for both racial groups with an average increase of 13% each month (p<0.005) and in increasing e-cigarette advertisement exposure reported for the previous 6 months, with a 14% increase each month (p<0.0001). Whites reported 56% greater advertisement exposure than Blacks (mean=25 vs. 8 in month 1 to 79 vs. 45 in month 9, respectively; p<0.0001). For Blacks, advertisement exposure was significantly associated with e-cigarette use (p<0.001). Whites reported more advertisement exposure from stores and the Internet, and Blacks reported more advertisement exposure from radio or television. Results suggest that e-cigarette marketing is beginning to breach the Black population who are, as a consequence, "catching up" with Whites with regard to e-cigarette use. Given the significant disparities for smoking-related morbidity and mortality between Blacks and Whites, these findings identify new areas for future research and policy.

NIH electronic cigarette workshop: developing a research agenda.

BACKGROUND: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

Radiological correlates and clinical implications of the paradoxical lung function response to ß2 agonists: an observational study.

BACKGROUND: Bronchodilator response has been noted in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response to ß2 agonists resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely to be far more common than is symptomatic bronchoconstriction with ß2 agonists, but no systematic studies have been done. We assessed the prevalence of paradoxical response in current and former smokers with and without COPD, and its radiological correlates and clinical implications. METHODS: Non-Hispanic white and African-American patients (aged 45-80 years) from a large multicentre study COPDGene were classified into two groups on the basis of a paradoxical response, defined as at least a 12% and 200 mL reduction in forced expiratory volume in 1 sec (FEV1) or forced vital capacity (FVC), or both, after administration of a shortacting ß2 agonist (180 µg salbutamol). FINDINGS: Patients were recruited from January, 2008, to June, 2011. 9986 (96%) of 10,364 patients enrolled in the COPDGene study were included in the analysis population (mean age 59·6 years [SD 9·0]). Paradoxical response was noted in 453 (5%) of 9986 patients and the frequency was similar in patients with COPD (198 [4%] of 4439) and smokers without airflow obstruction (255 [5%] of 5547). Compared with white patients, a paradoxical response was twice as common in African-American patients (227 [7%] of 3282 vs 226 [3%] of 6704; p<0·0001). In the multivariate analyses, African-American ethnic origin (adjusted odds ratio 1·89, 95% CI 1·50-2·39; p<0·0001), less emphysema (0·96, 0·92-0·99; p=0·023), and increased wall-area percentage of the segmental airways (1·04, 1·01-1·08; p=0·023) were independently associated with a paradoxical response. A paradoxical response was independently associated with worse dyspnoea (adjusted ß for Modified Medical Research Council Dyspnoea Scale 0·12 [95% CI 0·00 to 0·24]; p=0·05), lower 6 min walk distance (-45·8 [-78·5 to -13·2]; p=0·006), higher Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index (0·31 [0·19 to 0·43]; p<0·0001), and a greater frequency of severe exacerbations (increased by a factor of 1·35, 1·00-1·81; p=0·048). INTERPRETATION: Paradoxical response to ß2 agonists is associated with respiratory morbidity and is more common in African-Americans. These findings might have implications for the use of ß2agonists in some patients. FUNDING: National Institutes of Health.

Simvastatin for the prevention of exacerbations in moderate-to-severe COPD.

BACKGROUND: Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS: We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS: A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89). CONCLUSIONS: Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Electronic cigarette awareness, use history, and expected future use among hospitalized cigarette smokers.

INTRODUCTION: E-cigarette use has surged during the past few years while the debate about the product's safety and efficacy for smoking cessation continues. Little is known about the characteristics that distinguish users from nonusers; in this study, we aimed to elucidate these characteristics among hospitalized smokers, a heretofore unstudied population. METHODS: Cross-sectional data were collected from cigarette smokers via hospital bedside interviews. Participants reported e-cigarette use status, reasons for use (if used), e-cigarette advertising exposure, expected likelihood of future e-cigarette use, desire to quit smoking, and demographic characteristics. RESULTS: Of the 657 English-speaking hospitalized smokers who provided data, 97% reported awareness of e-cigarettes and 46.4% reported e-cigarette use, with 20% reporting use in the previous 30 days. Previous e-cigarette use was significantly more likely among those who were White (odds ratio [OR] = 4.7; confidence interval [CI] = 3.2-6.7), were married/had a domestic partner (OR = 1.5; CI = 1.0-2.2), had more than a high school education (OR = 1.7; CI = 1.1-2.7), had e-cigarette advertising exposure (OR = 1.6; CI = 1.1-2.4), and were younger (OR = 1.3; CI = 1.1-1.5). Expected likelihood of future e-cigarette use was high and positively correlated with desire to quit smoking (Spearman's ρ = .18, p < .0001). CONCLUSIONS: Rates of awareness and use of e-cigarettes may be elevated among hospitalized smokers, with more use reported among those who were White, younger, more educated, in a relationship, and exposed to e-cigarette advertising. The association between desire to quit smoking and expected likelihood of future e-cigarette use suggests that cigarette smokers may perceive e-cigarettes as a useful cessation aid.

FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices.

RATIONALE: FVC is a difficult maneuver for many patients, and forced expiratory volume in 6 seconds (FEV6) has been proposed as a surrogate for FVC for the diagnosis of chronic obstructive pulmonary disease (COPD). Previous studies have performed head-to-head comparisons of these thresholds but did not examine their relationships with structural lung disease, symptoms, or exacerbations. OBJECTIVES: To compare FEV1/FEV6 with FEV1/FVC in the diagnosis of COPD-related morbidity and structural lung disease as assessed by CT. METHODS: We analyzed data from a large multicenter cohort study (COPDGene) that included current and former smokers (age 45-80 yr). Accuracy and concordance between the two ratios in diagnosing structural COPD was compared using CT measures of emphysema and airway disease and COPD-related morbidity to assess how the two ratios compare in defining disease. RESULTS: A total of 10,018 subjects were included. FEV1/FEV6 showed excellent accuracy in diagnosing airflow obstruction using FEV1/FVC < 0.70 as a reference (area under curve, 0.99; 95% confidence interval [CI], 0.989-0.992; P < 0.001). FEV1/FEV6 < 0.73 had the best sum of sensitivity (92.1%; 95% CI, 90.8-92.4) and specificity (97.3%; 95% CI, 97.3-98.1). There was excellent agreement between the two diagnostic cutoffs (κ = 0.90; 95% CI, 0.80-0.91; P < 0.001). In comparison with control subjects and those positive by FEV1/FVC alone, subjects positive by FEV1/FEV6 alone had greater gas trapping and airway wall thickness, worse functional capacity, and a greater number of exacerbations on follow-up. These relationships held true when disease definitions were made using the lower limits of normal. CONCLUSIONS: FEV1/FEV6 can be substituted for FEV1/FVC in diagnosing airflow obstruction and may better predict COPD-related pathology and morbidity.

Parent report and electronic medical record agreement on asthma education provided and children's tobacco smoke exposure.

OBJECTIVE: To examine the concordance between parent report and electronic medical record documentation of asthma health education provided during a single clinic visit and second-hand tobacco smoke exposure among children with asthma. METHODS: Parents of children with asthma were recruited from two types of clinics using different electronic medical record systems: asthma-specialty or general pediatric health department clinics. After their child's outpatient visit, parents were interviewed by trained study staff. Interview data were compared to electronic medical records for agreement in five categories of asthma health education and for the child's environmental tobacco smoke exposure. Kappa statistics were used to identify strength of agreement. Chi square and t-tests were used to examine differences between clinic types. RESULTS: Of 255 parents participating in the study 90.6% were African American and 96.1% were female. Agreement was poor across all clinics but was higher within the asthma specialty clinics than the health department clinics for smoke exposure (κ = 0.410 versus 0.205), asthma diagnosis/disease process (κ = 0.213 versus -0.016) and devices reviewed (κ = 0.253 versus -0.089) with parents generally reporting more education provided. For the 203 children with complete medical records, 40.5% did not have any documentation regarding smoking exposure in the home and 85.2% did not have any documentation regarding exposure elsewhere. CONCLUSIONS: We found low concordance between the parent's report and the electronic medical record for smoke exposure and asthma education provided. Un- or under-documented smoke exposure and health education have the potential to affect continuity of care for pediatric patients with asthma.