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.

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.

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.).

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, 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).

Pulmonary arterial enlargement and acute exacerbations of COPD.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. METHODS: We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. RESULTS: Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. CONCLUSIONS: Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.).

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.

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.

Azithromycin for prevention of exacerbations of COPD.

BACKGROUND: Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS: We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

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.

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.

Can a school-based hand hygiene program reduce asthma exacerbations among elementary school children?

BACKGROUND: Viral upper respiratory tract infections have been implicated as a major cause of asthma exacerbations among school-aged children. Regular hand washing is the most effective method to prevent the spread of viral respiratory tract infections, but effective hand-washing practices are difficult to establish in schools. OBJECTIVES: This randomized controlled trial evaluated whether a standardized regimen of hand washing plus alcohol-based hand sanitizer could reduce asthma exacerbations more than schools' usual hand hygiene practices. METHODS: This was a 2-year, community-based, randomized controlled crossover trial. Schools were randomized to usual care and then intervention (sequence 1) or intervention and then usual care (sequence 2). Intervention schools were provided with alcohol-based hand sanitizer, hand soap, and hand hygiene education. The primary outcome was the proportion of students experiencing an asthma exacerbation each month. Generalized estimating equations were used to model the difference in the marginal rate of exacerbations between sequences while controlling for individual demographic factors and the correlation within each student and between students within each school. RESULTS: Five hundred twenty-seven students with asthma were enrolled among 31 schools. The hand hygiene intervention did not reduce the number of asthma exacerbations compared with the schools' usual hand hygiene practices (P = .132). There was a strong temporal trend because both sequences experienced fewer exacerbations during year 2 compared with year 1 (P < .001). CONCLUSIONS: Although the intervention was not found to be effective, the results were confounded by the H1N1 influenza pandemic that resulted in substantially increased hand hygiene behaviors and resources in usual-care schools. Therefore these results should be viewed cautiously.

Long-term comparative immunogenicity of protein conjugate and free polysaccharide pneumococcal vaccines in chronic obstructive pulmonary disease.

BACKGROUND: Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years. METHODS: One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years. RESULTS: Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed. CONCLUSIONS: PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points. CLINICAL TRIALS REGISTRATION: NCT00457977.

Influence of lightweight ambulatory oxygen on oxygen use and activity patterns of COPD patients receiving long-term oxygen therapy.

Lightweight ambulatory oxygen devices are provided on the assumptions that they enhance compliance and increase activity, but data to support these assumptions are lacking. We studied 22 patients with severe chronic obstructive pulmonary disease receiving long-term oxygen therapy (14 men, average age = 66.9 y, FEV(1) = 33.6%pred, PaO(2) at rest = 51.7 torr) who were using E-cylinders as their portable oxygen. Subjects were recruited at 5 sites and studied over a 2-week baseline period and for 6 months after randomizing them to either continuing to use 22-lb E-cylinders towed on a cart or to carrying 3.6-lb aluminum cylinders. Utilizing novel electronic devices, ambulatory and stationary oxygen use was monitored continuously over the 2 weeks prior to and the 6 months following randomization. Subjects wore tri-axial accelerometers to monitor physical activity during waking hours for 2-3 weeks prior to, and at 3 and 6 months after, randomization. Seventeen subjects completed the study. At baseline, subjects used 17.2 hours of stationary and 2.5 hours of ambulatory oxygen daily. At 6 months, ambulatory oxygen use was 1.4 ± 1.0 hrs in those randomized to E-cylinders and 1.9 ± 2.4 hrs in those using lightweight oxygen (P = NS). Activity monitoring revealed low activity levels prior to randomization and no significant increase over time in either group. In this group of severe chronic obstructive pulmonary disease patients, providing lightweight ambulatory oxygen did not increase either oxygen use or activity. Future efforts might focus on strategies to encourage oxygen use and enhance activity in this patient group. This trial is registered at ClinicalTrials.gov (NCT003257540).

Redesigning a large school-based clinical trial in response to changes in community practice.

BACKGROUND: Asthma exacerbations are seasonal with the greatest risk in elementary-age students occurring shortly after returning to school following summer break. Recent research suggests that this seasonality in children is primarily related to viral respiratory tract infections. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections; unfortunately, achieving hand washing recommendations in schools is difficult. Therefore, we designed a study to evaluate the effect of hand sanitizer use in elementary schools on exacerbations among children with asthma. PURPOSE: To describe the process of redesigning the trial in response to changes in the safety profile of the hand sanitizer as well as changes in hand hygiene practice in the schools. METHODS: The original trial was a randomized, longitudinal, subject-blinded, placebo-controlled, community-based crossover trial. The primary aim was to evaluate the incremental effectiveness of hand sanitizer use in addition to usual hand hygiene practices to decrease asthma exacerbations in elementary-age children. Three events occurred that required major modifications to the original study protocol: (1) safety concerns arose regarding the hand sanitizer's active ingredient; (2) no substitute placebo hand sanitizer was available; and (3) community preferences changed regarding hand hygiene practices in the schools. RESULTS: The revised protocol is a randomized, longitudinal, community-based crossover trial. The primary aim is to evaluate the incremental effectiveness of a two-step hand hygiene process (hand hygiene education plus institutionally provided alcohol-based hand sanitizer) versus usual care to decrease asthma exacerbations. Enrollment was completed in May 2009 with 527 students from 30 schools. The intervention began in August 2009 and will continue through May 2011. Study results should be available at the end of 2011. LIMITATIONS: The changed design does not allow us to directly measure the effectiveness of hand sanitizer use as a supplement to traditional hand washing practices. CONCLUSIONS: The need to balance a rigorous study design with one that is acceptable to the community requires investigators to be actively involved with community collaborators and able to adapt study protocols to fit changing community practices.

Randomized trial of zileuton for treatment of COPD exacerbations requiring hospitalization.

RATIONALE: Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations. OBJECTIVE: We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization. METHODS: Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production. MAIN FINDINGS: Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75 +/- 2.19 vs. 3.86 +/- 3.06 days for zileuton vs. placebo, p = 0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p = 0.63) despite a decline in urinary LTE(4) levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine -1.38 +/- 1.19 vs. 0.14 +/- 1.51, p < 0.0001) and 72 hours (-1.32 +/- 2.08 vs. 0.26 +/- 1.93, p<0.006). Adverse events were similar in both groups. PRINCIPAL CONCLUSIONS: While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE(4) levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.

Cost-effectiveness of school-based asthma screening in an urban setting.

BACKGROUND: Much has been done to promote population-based childhood asthma screening; however, concerns remain regarding its cost-effectiveness. OBJECTIVES: To conduct a cost-effectiveness analysis of school-based asthma screening strategies. METHODS: A 5 health state Markov approach (symptom-free, symptom, exacerbation recovery, emergency department, and hospitalization day) was used to evaluate school-based screening in a simulated population of urban elementary-age school children. Two questionnaire and 2 multistage strategies incorporating spirometry or spirometry with exercise testing were evaluated from the societal perspective by using 365 daily cycles. The outcome was 2006 dollars per quality-adjusted life year (QALY). RESULTS: The most efficient strategy identified children with previously diagnosed but poorly controlled asthma at a cost of $150,000 per QALY (95% CI, $65,800-$318,000). Uncertainty surrounding the cost-effectiveness estimate was primarily a result of the symptom day preference weight estimate (44%), the probability of confirmation after screening (17%), the adequacy of asthma control in the population (9%), and the estimated treatment effect on symptoms (6%). Screening generated an additional 21 symptom-free day equivalents per child identified with previously diagnosed but not well controlled asthma and led to $85.55, $12.36, and $2.58 in additional screening, daily treatment, and indirect costs and $5.01 less in emergency department and hospitalization costs. CONCLUSION: Population-based asthma screening is not cost-effective at $50,000 per QALY and has only a 20% chance of being cost-effective at $100,000 per QALY. The most efficient approach is to screen for previously diagnosed but poorly controlled asthma. Linking screening with better treatment, and long-term adherence strategies might yield future cost-effective approaches.

A survey of clergy practices associated with premarital financial counseling.

The purpose of this exploratory study was to gain an understanding of the state of clergy-led premarital financial counseling. Clergy respondents (n = 223) indicated that they often include a financial component in their formal premarital counseling. The most frequently discussed financial topics are budgeting, managing debt and credit, and saving. The most frequently cited obstacles to providing premarital financial counseling are lack of time and lack of subject matter expertise.