Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Pulmonary Arterial Pruning and Longitudinal Change in Percent Emphysema and Lung Function: The Genetic Epidemiology of COPD Study.

BACKGROUND: Pulmonary endothelial damage has been shown to precede the development of emphysema in animals, and vascular changes in humans have been observed in COPD and emphysema. RESEARCH QUESTION: Is intraparenchymal vascular pruning associated with longitudinal progression of emphysema on CT imaging or decline in lung function over 5 years? STUDY DESIGN AND METHODS: The Genetic Epidemiology of COPD Study enrolled ever smokers with and without COPD from 2008 through 2011. The percentage of emphysema-like lung, or "percent emphysema," was assessed at baseline and after 5 years on noncontrast CT imaging as the percentage of lung voxels < -950 Hounsfield units. An automated CT imaging-based tool assessed and classified intrapulmonary arteries and veins. Spirometry measures are postbronchodilator. Pulmonary arterial pruning was defined as a lower ratio of small artery volume (< 5 mm2 cross-sectional area) to total lung artery volume. Mixed linear models included demographics, anthropomorphics, smoking, and COPD, with emphysema models also adjusting for CT imaging scanner and lung function models adjusting for clinical center and baseline percent emphysema. RESULTS: At baseline, the 4,227 participants were 60 ± 9 years of age, 50% were women, 28% were Black, 47% were current smokers, and 41% had COPD. Median percent emphysema was 2.1 (interquartile range, 0.6-6.3) and progressed 0.24 percentage points/y (95% CI, 0.22-0.26 percentage points/y) over 5.6 years. Mean FEV1 to FVC ratio was 68.5 ± 14.2% and declined 0.26%/y (95% CI, -0.30 to -0.23%/y). Greater pulmonary arterial pruning was associated with more rapid progression of percent emphysema (0.11 percentage points/y per 1-SD increase in arterial pruning; 95% CI, 0.09-0.16 percentage points/y), including after adjusting for baseline percent emphysema and FEV1. Arterial pruning also was associated with a faster decline in FEV1 to FVC ratio (-0.04%/y per 1-SD increase in arterial pruning; 95% CI, -0.008 to -0.001%/y). INTERPRETATION: Pulmonary arterial pruning was associated with faster progression of percent emphysema and more rapid decline in FEV1 to FVC ratio over 5 years in ever smokers, suggesting that pulmonary vascular differences may be relevant in disease progression. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

A controlled statistical study to assess measurement variability as a function of test object position and configuration for automated surveillance in a multicenter longitudinal COPD study (SPIROMICS).

PURPOSE: A test object (phantom) is an important tool to evaluate comparability and stability of CT scanners used in multicenter and longitudinal studies. However, there are many sources of error that can interfere with the test object-derived quantitative measurements. Here the authors investigated three major possible sources of operator error in the use of a test object employed to assess pulmonary density-related as well as airway-related metrics. METHODS: Two kinds of experiments were carried out to assess measurement variability caused by imperfect scanning status. The first one consisted of three experiments. A COPDGene test object was scanned using a dual source multidetector computed tomographic scanner (Siemens Somatom Flash) with the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) inspiration protocol (120 kV, 110 mAs, pitch = 1, slice thickness = 0.75 mm, slice spacing = 0.5 mm) to evaluate the effects of tilt angle, water bottle offset, and air bubble size. After analysis of these results, a guideline was reached in order to achieve more reliable results for this test object. Next the authors applied the above findings to 2272 test object scans collected over 4 years as part of the SPIROMICS study. The authors compared changes of the data consistency before and after excluding the scans that failed to pass the guideline. RESULTS: This study established the following limits for the test object: tilt index ≤0.3, water bottle offset limits of [-6.6 mm, 7.4 mm], and no air bubble within the water bottle, where tilt index is a measure incorporating two tilt angles around x- and y-axis. With 95% confidence, the density measurement variation for all five interested materials in the test object (acrylic, water, lung, inside air, and outside air) resulting from all three error sources can be limited to ±0.9 HU (summed in quadrature), when all the requirements are satisfied. The authors applied these criteria to 2272 SPIROMICS scans and demonstrated a significant reduction in measurement variation associated with the test object. CONCLUSIONS: Three operator errors were identified which significantly affected the usability of the acquired scan images of the test object used for monitoring scanner stability in a multicenter study. The authors' results demonstrated that at the time of test object scan receipt at a radiology core laboratory, quality control procedures should include an assessment of tilt index, water bottle offset, and air bubble size within the water bottle. Application of this methodology to 2272 SPIROMICS scans indicated that their findings were not limited to the scanner make and model used for the initial test but was generalizable to both Siemens and GE scanners which comprise the scanner types used within the SPIROMICS study.

Insight into Best Variables for COPD Case Identification: A Random Forests Analysis.

RATIONALE: This study is part of a larger, multi-method project to develop a questionnaire for identifying undiagnosed cases of chronic obstructive pulmonary disease (COPD) in primary care settings, with specific interest in the detection of patients with moderate to severe airway obstruction or risk of exacerbation. OBJECTIVES: To examine 3 existing datasets for insight into key features of COPD that could be useful in the identification of undiagnosed COPD. METHODS: Random forests analyses were applied to the following databases: COPD Foundation Peak Flow Study Cohort (N=5761), Burden of Obstructive Lung Disease (BOLD) Kentucky site (N=508), and COPDGene® (N=10,214). Four scenarios were examined to find the best, smallest sets of variables that distinguished cases and controls:(1) moderate to severe COPD (forced expiratory volume in 1 second [FEV1] <50% predicted) versus no COPD; (2) undiagnosed versus diagnosed COPD; (3) COPD with and without exacerbation history; and (4) clinically significant COPD (FEV1<60% predicted or history of acute exacerbation) versus all others. RESULTS: From 4 to 8 variables were able to differentiate cases from controls, with sensitivity ≥73 (range: 73-90) and specificity >68 (range: 68-93). Across scenarios, the best models included age, smoking status or history, symptoms (cough, wheeze, phlegm), general or breathing-related activity limitation, episodes of acute bronchitis, and/or missed work days and non-work activities due to breathing or health. CONCLUSIONS: Results provide insight into variables that should be considered during the development of candidate items for a new questionnaire to identify undiagnosed cases of clinically significant COPD.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care. METHODS: PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002-2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded. RESULTS: Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations. CONCLUSION: Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care.

Association between exposure to household cigarette smoking behavior and cigarette smoking in Hispanic adults: Findings from the Hispanic Community Health Study/Study of Latinos.

BACKGROUND: Cigarette smoking behavior is highly determined by social influences during childhood and adolescence. This phenomenon has not been fully evaluated in the Hispanic/Latino population. PURPOSE: To examine the association between exposure to household cigarette smoking behavior (HCSB) and adult cigarette smoking among a diverse Hispanic/Latino population living in four US urban centers. The effect of acculturation on cigarette smoking was also evaluated. METHODS: Data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=13,231, ages 18-74years, collected between March 2008 and June 2011) were analyzed using logistic regression. RESULTS: HCSB exposure was an independent risk factor for adult current cigarette smoking in Hispanic/Latinos (OR 1.7; 95% CI 1.4, 2.1) after controlling for relevant confounders including socio-demographic and cultural factors. Cubans and Puerto Ricans had the highest prevalence of HCSB exposure (59% and 47% respectively) and highest prevalence of current cigarette smoking (26% and 32%) compared with other Hispanic/Latino groups, (p<.01). CONCLUSIONS: Our data suggest that exposure to HCSB in Hispanics/Latinos living in the US is an independent predictor of adult cigarette smoking, and this association appears to be strongest in Cubans and Puerto Ricans.

Computed tomographic measures of airway morphology in smokers and never-smoking normals.

Bronchial wall area percent (WA% = 100 × wall area/total bronchial cross sectional area) is a standard computed tomographic (CT) measure of central airway morphology utilized in smokers with chronic obstructive pulmonary disease (COPD). Although it provides significant clinical correlations, the range of reported WA% is narrow. This suggests limited macroscopic change in response to smoking or that remodeling proportionally affects the airway wall and lumen dimensions such that their ratio is preserved. The objective of this study is to assess central airway wall area (WA), lumen area (Ai), and total bronchial area (Ao) from CT scans of 5,179 smokers and 92 never smoking normal subjects. In smokers, WA, Ai, and Ao were positively correlated with forced expiratory volume in 1 s (FEV1) expressed as a percent of predicted (FEV1%), and the WA% was negatively correlated with FEV1% (P < 0.0001 for all comparisons). Importantly, smokers with lower FEV1% tended to have airways of smaller cross-sectional area with lower WA. The increases in the WA% across GOLD stages of chronic obstructive pulmonary disease (COPD) can therefore not be due to increases in WA. The data suggest two possible origins for the WA% increases: 1) central airway remodeling resulting in overall reductions in airway caliber in excess of the decreased WA or 2) those with COPD had smaller native airways before they began smoking. In both cases, these observations provide an explanation for the limited range of values of WA% across stages of COPD.

Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables. METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Subclinical atherosclerosis, airflow obstruction and emphysema: the MESA Lung Study.

Airflow obstruction is an independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined whether an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations. The Multi-Ethnic Study of Atherosclerosis recruited participants aged 45-84 yrs without clinical cardiovascular disease. Spirometry, carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcium (CAC) were measured using standard protocols. Percentage of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors, including C-reactive protein. Decrements in forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity ratio were associated with greater internal carotid IMT, particularly among smokers (p=0.03 and p<0.001, respectively) whereas percentage emphysema was associated with reduced ABI regardless of smoking history (p=0.004). CAC was associated with neither lung function (prevalence ratio for the presence of CAC in severe airflow obstruction 0.99, 95% CI 0.91-1.07) nor percentage emphysema. An obstructive pattern of spirometry and emphysema were associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to CAC.

Randomised aspirin assignment and risk of adult-onset asthma in the Women's Health Study.

BACKGROUND: Randomised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin. The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma, but randomised data in women are lacking. A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women's Health Study. METHODS: A randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry. Female health professionals self-reported an asthma diagnosis on yearly questionnaires. RESULTS: Among 37 270 women with no reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group (hazard ratio 0.90; 95% CI 0.82 to 0.99; p = 0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, with no effect in women with a body mass index of >/=30 kg/m2. The effect of aspirin on adult-onset asthma was not significantly modified by age, smoking status, exercise levels, postmenopausal hormone use or randomised vitamin E assignment. CONCLUSIONS: In this large randomised clinical trial of apparently healthy adult women, administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma.

Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study.

BACKGROUND: Hemostatic factors and endothelial markers may play some role in racial/ethnic differences in cardiovascular disease (CVD) rates. However, little information exists on hemostatic factors and endothelial markers across racial/ethnic groups. OBJECTIVES: To describe, in four American racial/ethnic groups (Caucasian, Black, Hispanic, and Chinese), mean levels of selected hemostatic factors and endothelial markers. PATIENTS AND METHODS: Multi-ethnic Study of Atherosclerosis baseline data were used (participant age: 45-84 years). Sex-specific analysis of covariance models, and t-tests for pairwise comparisons, were used to compare means of factors and markers. Adjustments were made for demographics and traditional CVD risk factors. Differences were significant at P < 0.05. RESULTS: Blacks had the highest levels of factor VIII, D-Dimer, plasmin-antiplasmin (PAP), and von Willebrand factor, among the highest levels of fibrinogen and E-selectin (women only), but among the lowest levels of intercellular adhesion molecule 1 (ICAM-1), and, in men, the lowest levels of plasminogen activator inhibitor-1 (PAI-1). Whites and Hispanics tended to have intermediate levels of factors and markers, although they had the highest levels of ICAM-1, and Hispanics had the highest mean levels of fibrinogen and E-selectin (women only). Chinese participants had among the highest levels of PAI-1, but the lowest, or among the lowest, of all other factors and markers. No soluble thrombomodulin differences were observed. CONCLUSIONS: In this large cohort, hemostatic factor and endothelial marker mean levels varied by race/ethnicity, even after adjustment for traditional CVD risk factors.

Tiotropium for stable chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: A systematic review was undertaken to evaluate the efficacy of tiotropium, a long acting anticholinergic drug, on clinical events, symptom scales, pulmonary function, and adverse events in stable chronic obstructive pulmonary disease (COPD). METHODS: A systematic search was made of the Cochrane trials database, MEDLINE, EMBASE, CINAHL, and a hand search of 20 respiratory journals. Missing data were obtained from authors and the manufacturer. Randomised controlled trials of > or =12 weeks' duration comparing tiotropium with placebo, ipratropium bromide, or long acting beta2 agonists (LABA) were reviewed. Studies were pooled to yield odds ratios (OR) or weighted mean differences with 95% confidence intervals (CI). RESULTS: Nine trials (8002 patients) met the inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.73; 95% CI 0.66 to 0.81) and related hospitalisation (OR 0.68; 95% CI 0.54 to 0.84) but not pulmonary (OR 0.50; 95% CI 0.19 to 1.29) or all-cause (OR 0.96; 95% CI 0.63 to 1.47) mortality compared with placebo and ipratropium. Reductions in exacerbations and hospitalisations compared with LABA were not statistically significant. Similar patterns were evident for quality of life and symptom scales. Tiotropium yielded greater increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline to 6-12 months than did placebo, ipratropium, and LABA. Decline in FEV1 over 1 year was 30 ml (95% CI 7 to 53) slower with tiotropium than with placebo and ipratropium (data were not available for LABA). Reports of dry mouth and urinary tract infections were increased with tiotropium. CONCLUSIONS: Tiotropium reduced COPD exacerbations and related hospitalisations, improved quality of life and symptoms, and may have slowed the decline in FEV1. Long term trials are warranted to evaluate the effects of tiotropium on decline in FEV1 and to clarify its role compared with LABA.

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non-Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non-Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait-listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age-adjusted mortality rate was higher among non-Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06-1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06-1.56, p = 0.01) compared to non-Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non-Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98-1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99-1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.

Recent exposure to particulate matter and C-reactive protein concentration in the multi-ethnic study of atherosclerosis.

Ambient levels of particulate matter have been linked to cardiovascular disease. The mechanisms mediating these associations are poorly understood. One candidate mechanism is inflammation. Using data from the Multi-Ethnic Study of Atherosclerosis (2000-2002), the authors investigated the relation between exposure to particulate matter of less than or equal to 2.5 microm in diameter (PM2.5) and C-reactive protein concentration in 5,634 persons aged 45-84 years who were free of cardiovascular disease. Data from US Environmental Protection Agency monitors were used to estimate PM2.5 exposures for the prior day, prior 2 days, prior week, prior 30 days, and prior 60 days. Only the 30-day and 60-day mean exposures showed a weak positive association with C-reactive protein, and confidence intervals were wide: relative increases in C-reactive protein per 10 microg/m3 of PM2.5 adjusted for person-level covariates were 3% (95% confidence interval (CI): -2, 10) for a 30-day mean and 4% (95% CI: -3, 11.0) for a 60-day mean. The means of 7-day, 30-day, and 60-day exposures were weakly, positively, and nonsignificantly associated with the odds of C-reactive protein of greater than or equal to 3 mg/liter: adjusted odds ratios were 1.05 (95% CI: 0.96, 1.15), 1.12 (95% CI: 0.98, 1.29), and 1.12 (95% CI: 0.96, 1.32), respectively. Slightly stronger associations were observed in persons without other risk factors for elevated C-reactive protein, but this heterogeneity was not statistically significant. The authors' results are not compatible with strong effects of particulate matter exposures on population levels of C-reactive protein.

Inhaled tiotropium for stable chronic obstructive pulmonary disease.

BACKGROUND: Tiotropium is a new anticholinergic therapy for chronic obstructive pulmonary disease (COPD) that differs from ipratropium by its functional relative selectivity for muscarinic receptor subtypes and which allows once-per-day dosing. OBJECTIVES: To determine the efficacy of tiotropium on clinical endpoints such exacerbations and hospitalisations, symptom scales and pulmonary function compared to placebo and other bronchodilators used for stable COPD. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group Specialised Register, a compilation of systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and hand searching of 20 respiratory journals. Bibliographies from included studies and reviews were searched. The date of the last search was October 2004. SELECTION CRITERIA: Randomised clinical trials comparing tiotropium with placebo, ipratropium bromide, or long-acting ss2-agonists for greater than, or equal to, one month's duration. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data. Missing data were obtained from authors or the manufacturer of tiotropium. The data were analysed using the Cochrane Review Manager RevMan 4.2. Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (CI). MAIN RESULTS: From 69 identified references, nine RCTs (6,584 patients) met inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.74; 95% CI 0.66 to 0.83) and related hospitalisations (OR 0.64; 95% CI 0.51 to 0.82) compared to placebo or ipratropium. When applied to an annual baseline risk of 45% for exacerbations and 10% for hospitalisation, the number of patients needed to treat with tiotropium for one year were 14 (95% CI 11 to 22) to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one hospitalisation compared to placebo and ipratropium. Reductions in these endpoints compared to long-acting ss2-agonists were not statistically significant. Similar patterns were evident for quality-of-life and symptom scales. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium and long-acting ss2-agonists over 6 to 12 months. The decline in trough FEV1 from steady state was 30 ml (95% CI 7 to 53 ml) less with tiotropium than with placebo or ipratropium over one year; no data on decline in FEV1 from steady state were available for long-acting ss2-agonists. Dry mouth was increased by tiotropium. AUTHORS' CONCLUSIONS: Tiotropium reduced COPD exacerbations and related hospitalisations compared to placebo and ipratropium. It also improved health-related quality-of-life and symptom scores among patients with moderate and severe disease, and may have slowed decline in FEV1. Additional long-term studies are required to evaluate its effect on mortality and change in FEV1 to clarify its role in comparison to, or in combination with, long-acting ss2-agonists and to assess its effectiveness in mild and very severe COPD.

Effects of chewing gum on responses to routine painful procedures in children.

In infants, sweet taste and sucking on a pacifier both have analgesic effects. Animal studies suggest that sweet taste may involve opioids, while rhythmic oral movements, as with a pacifier, increase the release of serotonin, which is involved in the gating of nociceptive afferents. The present study was designed to see if these effects produce an analgesic effect in children. Two studies were performed, during blood draws in a pediatric test center in 7- to 12-year-old children, and during vaccination at school in 9- to 11-year-old children. Using unsweetened or sweetened chewing gum, there were four groups: control, sweet, chew, and sweet plus chew. Overall, there was no effect of either sweet taste or chewing on pain responses. However, in boys sweet taste tended to increase pain ratings, but only in conjunction with chewing, while in girls sweet taste tended to decrease pain ratings in conjunction with chewing and increased them in the absence of chewing. Ratings of pain intensity and affective state were correlated. Affective state before the painful stimulus was related to pain response in the girls and in the boys in the test center, but not in the schools. In the schools, the presence of peers may have influenced the ratings.

Methylxanthines for exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Most international guidelines currently recommend methylxanthines (e.g., theophylline, aminophylline) for severe exacerbations of chronic obstructive pulmonary disease (COPD), yet clinical trials underlying this recommendation have been small and underpowered. OBJECTIVES: To determine the benefit of methylxanthines compared to placebo for COPD exacerbations. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group COPD Register, a compilation of systematic searches of CINAHL, EMBASE, MEDLINE and CENTRAL and hand searching of 20 respiratory journals. Primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies and reviews were searched. SELECTION CRITERIA: Included studies were limited to RCTs of patients presenting with acute COPD exacerbations, treated with methylxanthines (oral or intravenous) or placebo plus standard care. Two reviewers independently selected articles for inclusion and assessed methodological quality. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed using the Cochrane Review Manager 4.1. Studies were pooled to yield weighted mean differences (WMD), standardised mean difference (SMD) or odds ratios (OR) and reported using 95% confidence intervals (95%CI). MAIN RESULTS: From 29 identified references, 4 RCTs met inclusion criteria (169 patients). Mean change in forced expiratory volume in one second (FEV1) at 2 hours was similar in methylxanthine and placebo groups. Data on clinical outcomes were sparse. Trends toward improvements in hospitalisation and length-of-stay were offset by a trend toward more relapses at one week. Changes in symptom scores were not significant. Methylxanthines caused more nausea and vomiting than placebo (OR: 4.6; 95% CI: 1.7 to 12.6) and trended toward more frequent tremor, palpitations, and arrhythmias. REVIEWER'S CONCLUSIONS: Given current evidence, methylxanthines should not be used for COPD exacerbations. Possible beneficial effects in lung function and clinical endpoints were modest and inconsistent, whereas adverse effects were significantly increased. More selective agents, tested in larger randomised trials, are necessary if methylxanthines are to have any role in the treatment of COPD exacerbations.

Methyl-xanthines for exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: International guidelines currently recommend the use of methyl-xanthines for exacerbations of chronic obstructive pulmonary disease (COPD) for patients who have incomplete responses to bronchodilators. However, available clinical trials are small and underpowered to evaluate the benefits and risks of methyl-xanthines in this acute setting. OBJECTIVES: To determine the benefit of methyl-xanthines compared to standard care for COPD exacerbations. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group COPD Register which is a compilation of systematic searches of CINAHL, EMBASE, MEDLINE and CENTRAL and hand searching of 20 respiratory journals. In addition, primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies, known reviews and texts were also searched. SELECTION CRITERIA: Only RCTs were eligible for inclusion. Studies were included if patients presented with acute COPD exacerbations and were treated with either methyl-xanthines (oral or intravenous) or placebo (with or without standard care) early in the acute treatment. Studies also needed to report either pulmonary function or admission results. Two reviewers independently selected potentially relevant articles and selected articles for inclusion. Methodological quality was independently assessed by two reviewers. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers if the authors were unable to verify the validity of information. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed using the Cochrane Review Manager 4.0.4 Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (95%CI). MAIN RESULTS: From 28 identified references, 4 RCTs met inclusion criteria (172 patients). Mean change in forced expiratory volume in one second (FEV1) at 2 hours was similar in methyl-xanthine and placebo groups (FEV1 WMD: -8 ml; 95% CI: -85 to 69 ml). The only study to report hospitalization rates showed a non-significant reduction with methyl-xanthines (OR: 0.3; 95% CI: 0.1 to 1.8) among 39 patients. Patients receiving methyl-xanthines had similar improvements in symptom scores, but reported more gastrointestinal side effects (OR: 5.3; 95% CI: 1.3 to 21.0) than patients receiving placebo. REVIEWER'S CONCLUSIONS: There is no evidence to support the routine use of methyl-xanthines for COPD exacerbations. Methyl-xanthines do not appreciably improve FEV1 during COPD exacerbations and cause adverse effects; evidence of their effect on admissions is limited.