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1.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Background
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
Objective
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Design
Cross-sectional population-based study of adults age 45-84 years in the United States
Measurements
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
Results
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
Conclusions
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
doi:10.1136/thoraxjnl-2012-202116
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
2.  Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome 
Thorax  2014;69(7):623-629.
Rationale
Acute respiratory distress syndrome (ARDS) affects over 200,000 people annually in the US. Despite causing severe, and often refractory, hypoxemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined.
Methods
Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls.
Main results
Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex-vivo with GM-CSF were retained on first-pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to PAF were initially retained, but subsequently released such that only 14% remained in the lungs at 40 minutes. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS, compared to both perioperative control and septic patients.
Conclusions
We have demonstrated minimal delay or retention of un-primed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then ‘de-prime’ and are re-released into the systemic circulation. Further, we show that this physiological de-priming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.
doi:10.1136/thoraxjnl-2013-204742
PMCID: PMC4055272  PMID: 24706039
Acute respiratory distress syndrome (ARDS); multi-organ dysfunction; neutrophils
3.  The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults 
Thorax  2007;63(3):208-214.
Background
A reduced dietary intake of n-3 fatty acids, in association with increased n-6 fatty acid intake, has been proposed as a potential aetiological factor for chronic obstructive pulmonary disease (COPD) and asthma. However, the relative importance of individual fatty acids within the n-3 and n-6 categories on this effect has not been widely investigated. We have studied the relation between individual fatty acid intakes, lung function and self-reported respiratory symptoms and diagnoses in a representative sample of more than 13 000 Dutch adults.
Methods
Intake of individual fatty acids was estimated by a food frequency questionnaire and analysed in relation to measures of forced expiratory volume in 1 s (FEV1) and to questionnaire reported wheeze, asthma and COPD symptoms.
Results
After adjusting for confounding, we found no protective association between individual n-3 fatty acid intakes and FEV1. Higher intakes of some n-6 fatty acids were associated with lower FEV1, this effect being most marked for c22:4 n-6 docosatetraenoic acid (reduction in FEV1 between the highest and lowest quintile of intake 54.5 ml (95% CI –81.6 to –27.4)). Most of the n-6 fatty acid effects interacted significantly with smoking, their effects being strongest in current smokers. Individual n-3 fatty acid intakes were generally associated with a higher risk of wheeze in the past year, but otherwise there was little or no association between fatty acid intake and wheeze, doctor diagnosed asthma or other respiratory symptoms.
Conclusions
A high intake of n-3 fatty acids does not appear to protect against COPD or asthma, but a high intake of several n-6 fatty acids is associated with a significant reduction in FEV1, particularly in smokers. These findings indicate that high dietary intake of n-6 fatty acids, rather than reduced n-3 intake, may have an adverse effect on lung health.
doi:10.1136/thx.2007.090399
PMCID: PMC3979330  PMID: 17901161
4.  Hygiene, atopy and wheeze–eczema–rhinitis symptoms in schoolchildren from urban and rural Ecuador 
Thorax  2013;69(3):232-239.
Background
Rural residence is protective against atopy and wheeze–rhinitis–eczema symptoms in developed countries, an effect attributed to farming and poor hygiene exposures. There are few data from developing countries addressing this question. We compared atopy and wheeze–rhinitis–eczema symptoms between urban and rural Ecuador, and explored the effects of farming and poor hygiene exposures.
Methods
We performed cross sectional studies of schoolchildren living in rural and urban Ecuador. Data on symptoms and farming/hygiene exposures were collected by parental questionnaire, atopy by allergen skin prick test reactivity and geohelminth infections by stool examinations.
Results
Among 2526 urban and 4295 rural schoolchildren, prevalence was: atopy (10.0% vs 12.5%, p=0.06), wheeze (9.4% vs 10.1%, p=0.05), rhinitis (8.1% vs 6.4%, p=0.02) and eczema (5.9% vs 4.7%, p=0.06). A small proportion of symptoms were attributable to atopy (range 3.9–10.7%) with greater attributable fractions for respiratory symptoms observed in urban schoolchildren. Respiratory symptoms were associated with poor hygiene/farming exposures: wheeze with lack of access to potable water; and rhinitis with household pets, no bathroom facilities and contact with large farm animals. Birth order was inversely associated with respiratory symptoms. Area of residence and atopy had few effects on these associations.
Conclusions
Urban schoolchildren living in Ecuador have a similar prevalence of atopy, eczema and wheeze but a higher prevalence of rhinitis compared with rural children. Some farming and poor hygiene exposures were associated with an increase in the prevalence of wheeze or rhinitis while birth order was inversely associated with these symptoms.
doi:10.1136/thoraxjnl-2013-203818
PMCID: PMC3932750  PMID: 24105783
Wheeze-Rhinitis-Eczema; Atopy; Hygiene; Farming; Urban-Rural
5.  Survival of patients with small cell lung cancer undergoing lung resection in England, 1998–2009 
Thorax  2013;69(3):269-273.
Introduction
Chemotherapy or chemoradiotherapy is the recommended treatment for small cell lung cancer (SCLC), except in stage I disease where clinical guidelines state there may be a role for surgery based on favourable outcomes in case series. Evidence supporting adjuvant chemotherapy in resected SCLC is limited but this is widely offered.
Methods
Data on 359 873 patients who were diagnosed with a first primary lung cancer in England between 1998 and 2009 were grouped according to histology (SCLC or non-SCLC (NSCLC)) and whether they underwent a surgical resection. We explored their survival using Kaplan–Meier analysis and Cox regression, adjusting for age, sex, comorbidity and socioeconomic status.
Results
The survival of 465 patients with resected SCLC was lower than patients with resected NSCLC (5-year survival 31% and 45%, respectively), but much higher than patients of either group who were not resected (3%). The difference between resected SCLC and NSCLC diminished with time after surgery. Survival was superior for the subgroup of 198 ‘elective’ SCLC cases where the diagnosis was most likely known before resection than for the subgroup of 267 ‘incidental’ cases where the SCLC diagnosis was likely to have been made after resection.
Conclusions
These data serve as a natural experiment testing the survival after surgical management of SCLC according to NSCLC principles. Patients with SCLC treated surgically for early stage disease may have survival outcomes that approach those of NSCLC, supporting the emerging clinical practice of offering surgical resection to selected patients with SCLC.
doi:10.1136/thoraxjnl-2013-203884
PMCID: PMC3932952  PMID: 24172710
Lung Cancer; Small Cell Lung Cancer
6.  Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema 
Thorax  2013;69(3):223-231.
Rationale
Alveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), αCTF and βCTF, through protease mediated ectodomain shedding.
Objective
To explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells.
Methods and results
Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of αCTF.
Conclusions
CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.
doi:10.1136/thoraxjnl-2013-203867
PMCID: PMC3933066  PMID: 24092566
Airway Epithelium; Emphysema
7.  Fungi and pollen exposure in the first months of life and risk of early childhood wheezing 
Thorax  2009;64(4):10.1136/thx.2007.090241.
BACKGROUND
Many studies have found that risk of childhood asthma varies by month of birth, but few have examined ambient aeroallergens as an explanatory factor.
OBJECTIVE
To examine whether birth during seasons of elevated ambient fungal spore or pollen concentrations is associated with risk of early wheezing or blood levels of Th1- and Th2-type cells at 24 months of age.
METHODS
514 children were enrolled before birth and followed to 24 months of age. Early wheezing was determined from medical records and Th1 and Th2-type cells were measured in peripheral blood using flow cytometry. Ambient aeroallergen concentrations were measured throughout the study period and discrete seasons of high spore and pollen concentrations were defined.
RESULTS
A seasonal pattern was observed, with birth in the fall-winter (the fungal spore season) associated with increased odds of early wheezing (adjusted odds ratio = 3.1; 95% confidence interval: 1.3, 7.4). Increasing mean daily concentrations of basidiospores and ascospores in the first three months of life were associated with increased odds of wheeze, as were increasing mean daily concentrations of total and specific pollen types. Levels of Th1 cells at age 24 months were positively associated with mean fungal spore concentrations and negatively associated with mean pollen concentrations in the first three months of life.
CONCLUSIONS
Children with higher exposure to fungal spores and pollen in the first three months of life were at increased risk of early wheezing. This association was independent of other seasonal factors, including ambient PM2.5 levels and lower respiratory infections.
doi:10.1136/thx.2007.090241
PMCID: PMC3882001  PMID: 19240083
asthma; wheeze; birth season; mold; pollen; epidemiology
8.  Incremental value of T-SPOT.TB for diagnosis of active pulmonary tuberculosis in children in a high-burden setting: a multivariable analysis 
Thorax  2013;68(9):860-866.
Introduction
Interferon γ release assays (IGRAs) are increasingly used for tuberculosis (TB) infection, but their incremental value beyond patient demographics, clinical signs and conventional tests for active disease has not been evaluated in children.
Methods
The incremental value of T-SPOT.TB was assessed in 491 smear-negative children from two hospitals in Cape Town, South Africa. Bayesian model averaging was used to select the optimal set of patient demographics and clinical signs for predicting culture-confirmed TB. The added value of T-SPOT.TB over and above patient characteristics and conventional tests was measured using statistics such as the difference in the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI).
Results
Cough longer than 2 weeks, fever longer than 2 weeks, night sweats, malaise, history of household contact and HIV status were the most important predictors of culture-confirmed TB. Binary T-SPOT.TB results did not have incremental value when added to the baseline model with clinical predictors, chest radiography and the tuberculin skin test. The AUC difference was 3% (95% CI 0% to 7%). Using risk cut-offs of <10%, 10–30% and >30%, the NRI was 7% (95% CI −8% to 31%) but the CI included the null value. The IDI was 3% (95% CI 0% to 11%), meaning that the average predicted probability across all possible cut-offs improved marginally by 3%.
Conclusions
In a high-burden setting, the T-SPOT.TB did not have added value beyond clinical data and conventional tests for diagnosis of TB disease in smear-negative children.
doi:10.1136/thoraxjnl-2012-203086
PMCID: PMC3862980  PMID: 23674550
Clinical Epidemiology; Tuberculosis
9.  Low levels of tissue factor lead to alveolar hemorrhage, potentiating murine acute lung injury and oxidative stress 
Thorax  2012;67(12):1032-1039.
Background
Systemic blockade of Tissue Factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown.
Hypothesis
We used mice with complete knockout of mouse TF and low levels (~1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury.
Methods
LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal (IT) injection and studied at 24 hours.
Results
Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4 × 105 WT LPS versus 3.3 × 105 LTF LPS, p=0.947) and protein (493 μg/ml WT LPS versus 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS versus LTF LPS) and histology compared to wild type mice. LTF mice also had increased hemorrhage and free hemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F2-Isoprostanes and Isofurans).
Conclusions
These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar hemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit tissue factor may be deleterious in patients with ALI.
doi:10.1136/thoraxjnl-2012-201781
PMCID: PMC3652432  PMID: 23033361
Coagulation; free hemoglobin; acute lung injury; acute respiratory distress syndrome; alveolar hemorrhage
10.  THE RELATIONSHIP BETWEEN MATERNAL ADIPOSITY AND INFANT WEIGHT GAIN AND CHILDHOOD WHEEZE AND ATOPY 
Thorax  2013;68(4):372-379.
Background
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Methods
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Results
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Discussion
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
doi:10.1136/thoraxjnl-2012-202556
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
11.  Progress in cystic fibrosis and the CF Therapeutics Development Network 
Thorax  2012;67(10):882-890.
Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.
doi:10.1136/thoraxjnl-2012-202550
PMCID: PMC3787701  PMID: 22960984
12.  Thunderstorm-associated asthma in Atlanta, Georgia 
Thorax  2008;63(7):659-660.
doi:10.1136/thx.2007.092882
PMCID: PMC3766719  PMID: 18587040
asthma; thunderstorms; Southeast USA
13.  Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation 
Thorax  2011;67(1):12-18.
Background
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.
Methods
A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.
Results
The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.
Conclusions
In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904
doi:10.1136/thoraxjnl-2011-200393
PMCID: PMC3746507  PMID: 21825083
14.  Mutations of DNAH11 in Primary Ciliary Dyskinesia Patients with Normal Ciliary Ultrastructure 
Thorax  2011;67(5):433-441.
Rationale
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterized by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognized to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in DNAH11.
Objectives
In order to test further for mutant DNAH11 as a cause of PCD, we sequenced DNAH11 in patients with a PCD clinical phenotype, but no known genetic etiology.
Methods
We sequenced 82 exons and intron/exon junctions in DNAH11 in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer ± inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, we sequenced DNAH11 in 13 patients with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Results
Of the 58 unrelated PCD patients with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; plus, 2 PCD patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or Ioss-of-function splice-site mutations.
Conclusions
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
doi:10.1136/thoraxjnl-2011-200301
PMCID: PMC3739700  PMID: 22184204
Cilia; Dynein; Kartagener syndrome; Dextrocardia; Heterotaxy
15.  Wingless: developmentally important genes that respond adversely to smoking 
Thorax  2013;68(8):703-704.
doi:10.1136/thoraxjnl-2013-203249
PMCID: PMC3726201  PMID: 23611881
16.  Smoking in movies and adolescent smoking: cross-cultural study in six European countries 
Thorax  2011;66(10):875-883.
Aim
To investigate whether the association between exposure to smoking in movies and smoking among youth is independent of cultural context.
Method
Cross-sectional survey of 16 551 pupils recruited in Germany, Iceland, Italy, the Netherlands, Poland and Scotland with a mean age of 13.4 years (SD=1.18) and an equal gender distribution. School-based surveys were conducted between November 2009 and June 2010. Using previously validated methods, exposure to movie smoking was estimated from the 250 top-grossing movies of each country (years 2004–2009) and related to ever smoking.
Results
Overall, 29% of the sample had tried smoking. The sample quartile (Q) of movie smoking exposure was significantly associated with the prevalence of ever smoking: 14% of adolescents in Q1 had tried smoking, 21% in Q2, 29% in Q3 and 36% in Q4. After controlling for age, gender, family affluence, school performance, television screen time, number of movies seen, sensation seeking and rebelliousness and smoking within the social environment (peers, parents and siblings), the adjusted ORs for having tried smoking in the entire sample were 1.3 (95% CI 1.1 to 1.5) for adolescents in Q2, 1.6 (95% CI 1.4 to 1.9) for Q3 and 1.7 (95% CI 1.4 to 2.0) for Q4 compared with Q1. The adjusted relationship between ever smoking and higher movie smoking exposure levels was significant in all countries with a non-linear association in Italy and Poland.
Conclusions
The link between smoking in movies and adolescent smoking is robust and transcends different cultural contexts. Limiting young people's exposure to movie smoking could have important public health implications.
doi:10.1136/thoraxjnl-2011-200489
PMCID: PMC3719161  PMID: 21873322
17.  Exposure to smoking in films and own smoking among Scottish adolescents: a cross-sectional study 
Thorax  2011;66(10):866-874.
Background
Evidence of high exposure of UK youth to images of smoking in films has led to calls for an 18 rating for films with smoking to reduce smoking in youth. However, the only study to date in the UK to test for an association showed no relation between film-smoking exposure and smoking among young adults.
Objective
To assess whether there is an association between exposure to film images of smoking and own smoking among UK adolescents and whether repeated viewings of films has an impact.
Design
Cross-sectional study.
Participants
1999 pupils aged 15–16 years from 13 Scottish schools.
Outcome
Smoked tobacco in the past year.
Exposure measure
Film-smoking exposure was assessed using the Beach method; account for repeated viewings of films was then used to modify estimated exposure. Covariates included: media usage, parental restriction on and context of TV/film viewing, family connectedness, parental monitoring and friends' smoking.
Results
Most (71%) students had not smoked in the past year. About half reported no parental restrictions on TV/film viewing. Many reported repeated viewings of films; accounting for this more than doubled exposure estimates and strengthened the association with smoking. Adolescents with high exposure to film smoking were more likely to have smoked than those with low exposure (adjusted odds ratio (AOR) 2.08, 95% CI 1.22 to 3.55). Additionally, adolescents who reported parental rules about TV/film watching were less likely to smoke (AOR 0.37 (0.27 to 0.52)) than those who did not. Adolescents who mainly watched films with friends had higher exposure to film smoking and were more likely to smoke (AOR 2.19 (1.10 to 4.38)).
Conclusions
Exposure to film smoking is associated with smoking among Scottish adolescents. These data lend support to calls for an 18 rating for films with images of smoking.
doi:10.1136/thoraxjnl-2011-200095
PMCID: PMC3719166  PMID: 21764893
18.  Relationship between Quantitative CT Metrics and Health Status and Bode in COPD 
Thorax  2012;67(5):399-406.
Background
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
Methods
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
Results
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Conclusion
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
doi:10.1136/thoraxjnl-2011-201185
PMCID: PMC3719874  PMID: 22514236
Imaging; COPD; emphysema
19.  Key Observations from the NHLBI Asthma Clinical Research Network 
Thorax  2012;67(5):450-455.
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
doi:10.1136/thoraxjnl-2012-201876
PMCID: PMC3709602  PMID: 22514237
20.  Development and validity testing of an IPF-specific version of the St George's Respiratory Questionnaire 
Thorax  2010;65(10):921-926.
Rationale
The St George's Respiratory Questionnaire (SGRQ) is often applied to assess health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). Some SGRQ items will inevitably have weaker measurement properties than others when applied to this population. This study was conducted to develop an IPF-specific version of the SGRQ.
Methods
Data from a recently completed trial that enrolled subjects with IPF (n=158) who completed the SGRQ and other measures were analysed at baseline and 6 months. There were four phases to the study: (1) removing items with missing responses and using Rasch analysis on retained items to identify fit and refine item response categories; (2) development of a new scoring scheme; (3) testing agreement between original and revised versions and testing construct validity of the revised SGRQ; and (4) rewording to finalise the IPF-specific version (SGRQ-I).
Results
Items were removed due to missing responses (6 items) and misfit to the Rasch model (10 items); 34 items from the original 50 were retained. For certain items, disordered response thresholds were identified and corrected by collapsing response categories. A scoring algorithm was developed to place SGRQ-I scores on a scale with SGRQ scores. For any given outcome measure (eg, forced vital capacity (% predicted) and lung carbon monoxide transfer factor (% predicted), 6-min walk distance and patient-reported questionnaires), Pearson correlations were similar between pairs that included original SGRQ scores and corresponding pairs that included SGRQ-I scores. Internal reliability (Cronbach α) for each SGRQ-I component was comparable to the original SGRQ (Symptoms 0.62; Activities 0.80; Impacts 0.85).
Conclusions
The SGRQ-I contains items from the original SGRQ that are the most reliable for measuring health-related quality of life in patients with IPF.
doi:10.1136/thx.2010.139121
PMCID: PMC3697105  PMID: 20861296
21.  Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years 
Thorax  2010;65(12):1099-1106.
Background
Little is known about whether patterns of growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at age 3 years
Methods
Birth weight and length were measured in 1548 children born at term. Conditional fetal head and abdominal circumference growth velocities were calculated from antenatal ultrasound measurements. Conditional postnatal growth velocities were calculated from infant weight, length and adiposity data. .Measures of size and conditional growth were related to parentally-reported infant and early childhood wheeze and to atopic status at age 3.
Results
Atopy risk increased by 46% per standard deviation (SD) increase in abdominal circumference growth velocity from 11-19 weeks’ gestation but by 20% per SD decrease in abdominal growth velocity from 19-34 weeks (p=0.007 and p=0.011). Atopic wheeze risk increased by 20% per SD decrease in 19-34 week abdominal growth (p=0.046). Non-atopic wheeze risk increased by 10% per SD decrease in 11-19 week head circumference growth. Greater relative infant weight and adiposity gains were associated with both atopic and non-atopic wheeze.
Conclusions
Rapid growth during 11-19 weeks’ gestation followed by growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development. A lower early fetal growth trajectory is associated with non-atopic wheeze, possibly reflecting an association with smaller airways. An association between postnatal adiposity gain and wheeze may partly reflect prenatal influences that cause fetal growth to falter but are then followed by postnatal adiposity gain.
doi:10.1136/thx.2010.134742
PMCID: PMC3685135  PMID: 20956394
asthma; preschool-wheeze; allergic sensitisation; growth; nutrition
22.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Background
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
Objective
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Methods
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
Results
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
Conclusions
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
doi:10.1136/thoraxjnl-2012-201888
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
23.  Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia 
Thorax  2012;67(6):533-539.
Rationale
Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied.
Objective
This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia.
Methods and results
Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2.
Conclusions
Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.
doi:10.1136/thoraxjnl-2011-201176
PMCID: PMC3358432  PMID: 22250097
24.  Exercise peripheral oxygen saturation (SpO2) accurately reflects arterial oxygen saturation (SaO2) and predicts mortality in systemic sclerosis 
Thorax  2009;64(7):626-630.
Background
Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD).
Methods
83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (SpO2) and arterial oxygen saturation (SaO2) was examined and survival differences between subgroups of subjects stratified on SpO2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of SpO2.
Results
At maximal exercise the mean (SD) difference between SpO2 and SaO2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise SpO2 (SpO2max) fell below 89% or whose SpO2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose SpO2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose SpO2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02).
Conclusion
In patients with SSc-ILD, SpO2 is an adequate reflection of SaO2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, SpO2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.
doi:10.1136/thx.2008.111393
PMCID: PMC3667987  PMID: 19359269
25.  Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset 
Thorax  2012;67(12):1061-1066.
Background
Eosinophilic inflammation is implicated in asthma. Eotaxin 1–3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed.
Objective
To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma.
Methods
Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1–3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation.
Results
Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma.
Conclusions
Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.
doi:10.1136/thoraxjnl-2012-201634
PMCID: PMC3652589  PMID: 23015684

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