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1.  National Adolescent Treatment Trial for Obesity in Kuwait (NATTO): project design and results of a randomised controlled trial of a good practice approach to treatment of adolescent obesity in Kuwait 
Trials  2014;15:234.
Background
Few randomised controlled trials (RCTs) of interventions for the treatment of adolescent obesity have taken place outside the western world. This RCT tested whether a simple ‘good practice’ intervention for the treatment of adolescent obesity would have a greater impact on weight status and other outcomes than a referral to primary care (control) in adolescents in Kuwait City.
Methods
We report on an assessor-blinded RCT of a treatment intervention in 82 obese 10- to 14-year-olds (mean age 12.4, SD 1.2 years), randomised to a good practice treatment or primary care control group over 6 months. The good practice intervention was intended as relatively low intensity (6 hours contact over 24 weeks, group-based), aiming to change sedentary behaviour, physical activity, and diet. The primary outcome was a change in body mass index (BMI) Z score; other outcomes were changes in waist circumference and blood pressure.
Results
The retention of subjects to follow up was acceptable (n = 31 from the intervention group, and n = 32 from the control group), but engagement with both the intervention and control treatment was poor. Treatment had no significant effect on BMI Z score relative to control, and no other significant benefits to intervention were observed.
Conclusions
The trial was feasible, but highlights the need to engage obese adolescents and their families in the interventions being trialled. The trial should inform the development of future adolescent obesity treatment trials in the Gulf States with the incorporation of qualitative assessment in future intervention trials.
Trial registration
RCT Registered as National Adolescent Treatment Trial for Obesity in Kuwait (NATTO): http://www.controlled-trials.com/ISRCTN37457227, 1 December 2009.
doi:10.1186/1745-6215-15-234
PMCID: PMC4074381  PMID: 24943283
obesity; overweight; adolescents; treatment; BMI; randomised controlled trial
2.  Physical activity, diet and BMI in children aged 6–8 years: a cross-sectional analysis 
BMJ Open  2014;4(6):e005001.
Objective
To assess relationships between current physical activity (PA), dietary intake and body mass index (BMI) in English children.
Design and setting
Longitudinal birth cohort study in northeast England, cross-sectional analysis.
Participants
425 children (41% of the original cohort) aged 6–8 years (49% boys).
Main outcome measures
PA over 7 days was measured objectively by an accelerometer; three categories of PA were created: ‘active’ ≥60 min/day moderate-to-vigorous-intensity PA (MVPA); ‘moderately active’ 30–59 min/day MVPA; ‘inactive’ <30 min/day MVPA. Dietary intake over 4 days was measured using a prospective dietary assessment tool which incorporated elements of the food diary and food frequency methods. Three diet categories were created: ‘healthy’, ‘unhealthy’ and ‘mixed’, according to the number of portions of different foods consumed. Adherence to the ‘5-a-day’ recommendations for portions of fruit and vegetables was also assessed. Children were classified as ‘healthy weight’ or ‘overweight or obese’ (OW/OB) according to International Obesity Taskforce cutpoints for BMI. Associations between weight status and PA/diet categories were analysed using logistic regression.
Results
Few children met the UK-recommended guidelines for either MVPA or fruit and vegetable intake, with just 7% meeting the recommended amount of MVPA of 60 min/day, and 3% meeting the 5-a-day fruit and vegetable recommendation. Higher PA was associated with a lower OR for OW/OB in boys only (0.20, 95% CI 0.04 to 0.88). There was no association detected between dietary intake and OW/OB in either sex.
Conclusions
Increasing MVPA may help to reduce OW/OB in boys; however, more research is required to examine this relationship in girls. Children are not meeting the UK guidelines for diet and PA, and more needs to be done to improve this situation.
doi:10.1136/bmjopen-2014-005001
PMCID: PMC4054632  PMID: 24902732
Public Health; Epidemiology
3.  Correction: Predictive Validity and Classification Accuracy of ActiGraph Energy Expenditure Equations and Cut-Points in Young Children 
PLoS ONE  2014;9(1):10.1371/annotation/c26dd8e7-d512-4255-a80c-f3bf56c1ac0d.
doi:10.1371/annotation/c26dd8e7-d512-4255-a80c-f3bf56c1ac0d
PMCID: PMC3898872
4.  Health related quality of life of obese adolescents in Kuwait 
BMC Pediatrics  2013;13:105.
Background
Obesity impairs health related quality of life (HRQL) in adolescents, but most evidence in this area has mostly come from western societies. We wanted to test the hypothesis that obesity impairs HRQL in Kuwaiti adolescents, and to test for differences in HRQL assessed by self-report and parent-proxy report.
Methods
In 500 Kuwaiti 10–14 year olds HRQL was assessed using the Peds QLTM with both adolescent self-reports (n = 500) and parent-proxy reports (n = 374).
Results
Obesity was not significantly associated with HRQL in regression analysis. In a paired comparison of 98 pairs of obese adolescents vs. 98 healthy weight peers, impairment of HRQL reached significance only for physical score (95% CI = −1.5, -9.4), not for psychosocial score or total score. In a paired comparison of parent-proxy vs. self-reports for the obese adolescents, total score (95% CI = −4.9, -10.9), physical score (95% CI = −3.2, -11.0), and psychosocial score (95% CI = −4.2, -10.8) were all significantly lower in the parent reports.
Conclusions
Obesity is not associated with marked impairment of HRQL in adolescents in Kuwait, in contrast to studies in western societies. This may reflect cultural differences in attitudes towards obesity.
doi:10.1186/1471-2431-13-105
PMCID: PMC3710478  PMID: 23845118
Obesity; Adolescent; Health-related quality of life
5.  Evidence-Based Obesity Prevention in Childhood and Adolescence: Critique of Recent Etiological Studies, Preventive Interventions, and Policies123 
Advances in Nutrition  2012;3(4):636S-641S.
Prevention of obesity in childhood and adolescence remains a worthwhile and realistic goal, but preventive efforts have been beset by a number of problems, which are the subject of this review. The review draws on recent systematic reviews and evidence appraisals and has a United Kingdom (UK) perspective because there is a rich evidence base in the United Kingdom that may be helpful to obesity prevention researchers elsewhere. Recent evidence of a leveling off in child and adolescent obesity prevalence in some Western nations should not encourage the belief that the obesity prevention problem has been solved, although a better understanding of recent secular trends might be helpful for prevention strategy in future. An adequate body of evidence provides behavioral targets of preventive interventions, and there are frameworks for prioritizing these targets logically and models for translating them into generalizable interventions with a wide reach (e.g., school-based prevention interventions such as Planet Health). An improved understanding of the “energy gap” that children and adolescents experience would be helpful to the design of preventive interventions and to their tailoring to particular groups. In the United Kingdom, some recent etiological evidence has been taken as indicative of the need for paradigm shifts in obesity prevention, but this evidence from single studies has not been replicated, and paradigm shifts probably occur only rarely. Ensuring that the evidence base on etiology and prevention influences policy effectively remains one of the greatest challenges for childhood obesity researchers.
doi:10.3945/an.112.002014
PMCID: PMC3649738  PMID: 22798005
6.  Predictive Validity and Classification Accuracy of ActiGraph Energy Expenditure Equations and Cut-Points in Young Children 
PLoS ONE  2013;8(11):e79124.
Objectives
Evaluate the predictive validity of ActiGraph energy expenditure equations and the classification accuracy of physical activity intensity cut-points in preschoolers.
Methods
Forty children aged 4–6 years (5.3±1.0 years) completed a ∼150-min room calorimeter protocol involving age-appropriate sedentary, light and moderate-to vigorous-intensity physical activities. Children wore an ActiGraph GT3X on the right mid-axillary line of the hip. Energy expenditure measured by room calorimetry and physical activity intensity classified using direct observation were the criterion methods. Energy expenditure was predicted using Pate and Puyau equations. Physical activity intensity was classified using Evenson, Sirard, Van Cauwenberghe, Pate, Puyau, and Reilly, ActiGraph cut-points.
Results
The Pate equation significantly overestimated VO2 during sedentary behaviors, light physical activities and total VO2 (P<0.001). No difference was found between measured and predicted VO2 during moderate-to vigorous-intensity physical activities (P = 0.072). The Puyau equation significantly underestimated activity energy expenditure during moderate-to vigorous-intensity physical activities, light-intensity physical activities and total activity energy expenditure (P<0.0125). However, no overestimation of activity energy expenditure during sedentary behavior was found. The Evenson cut-point demonstrated significantly higher accuracy for classifying sedentary behaviors and light-intensity physical activities than others. Classification accuracy for moderate-to vigorous-intensity physical activities was significantly higher for Pate than others.
Conclusion
Available ActiGraph equations do not provide accurate estimates of energy expenditure across physical activity intensities in preschoolers. Cut-points of ≤25counts⋅15 s−1 and ≥420 counts⋅15 s−1 for classifying sedentary behaviors and moderate-to vigorous-intensity physical activities, respectively, are recommended.
doi:10.1371/journal.pone.0079124
PMCID: PMC3823763  PMID: 24244433
7.  Three-dimensional Airway Tree Architecture and Pulmonary Function 
Academic radiology  2012;19(11):1395-1401.
Rationale and Objectives
The airway tree is a primary conductive structure, and airways’ morphologic characteristics, or variations thereof, may have an impact on airflow, thereby affecting pulmonary function. The objective of this study was to investigate the correlation between airway tree architecture, as depicted on computed tomography, and pulmonary function.
Materials and Methods
A total of 548 chest computed tomographic examinations acquired on different patients at full inspiration were included in this study. The patients were enrolled in a study of chronic obstructive pulmonary disease (Specialized Center for Clinically Oriented Research) and underwent pulmonary function testing in addition to computed tomographic examinations. A fully automated airway tree segmentation algorithm was used to extract the three-dimensional airway tree from each examination. Using a skeletonization algorithm, airway tree volume–normalized architectural measures, including total airway length, branch count, and trachea length, were computed. Correlations between airway tree measurements with pulmonary function testing parameters and chronic obstructive pulmonary disease severity in terms of the Global Initiative for Obstructive Lung Disease classification were computed using Spearman’s rank correlations.
Results
Non-normalized total airway volume and trachea length were associated (P < .01) with lung capacity measures (ie, functional residual capacity, total lung capacity, inspiratory capacity, vital capacity, residual volume, and forced expiratory vital capacity). Spearman’s correlation coefficients ranged from 0.27 to 0.55 (P < .01). With the exception of trachea length, all normalized architecture-based measures (ie, total airway volume, total airway length, and total branch count) had statistically significant associations with the lung function measures (forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced expiratory vital capacity), and adjusted volume was associated with all three respiratory impedance measures (lung reactance at 5 Hz, lung resistance at 5 Hz, and lung resistance at 20 Hz), and adjusted branch count was associated with all respiratory impedance measures but lung resistance at 20 Hz. When normalized for lung volume, all airway architectural measures were statistically significantly associated with chronic obstructive pulmonary disease severity, with Spearman’s correlation coefficients ranging from −0.338 to −0.546 (P < .01).
Conclusions
Despite the large variability in anatomic characteristics of the airway tree across subjects, architecture-based measures demonstrated statistically significant associations (P < .01) with nearly all pulmonary function testing measures, as well as with disease severity.
doi:10.1016/j.acra.2012.06.007
PMCID: PMC3646411  PMID: 22884402
Airway tree architecture; chronic obstructive pulmonary disease; computed tomography; pulmonary function; lung diseases
8.  Randomized Trial of Zileuton for Treatment of COPD Exacerbations Requiring Hospitalization 
COPD  2011;8(1):21-29.
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 LTE4 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 LTE4 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.
doi:10.3109/15412555.2010.540273
PMCID: PMC3775706  PMID: 21299475
Chronic Obstructive Pulmonary Disease (COPD); Acute exacerbation of COPD (AECOPD); Leukotrienes; Zileuton; Clinical trial
9.  In Response: 
doi:10.1097/MPH.0b013e31829eedf8
PMCID: PMC3767275  PMID: 23823109
10.  The Influence of Minimum Sitting Period of the ActivPAL™ on the Measurement of Breaks in Sitting in Young Children 
PLoS ONE  2013;8(8):e71854.
Background
Sitting time and breaks in sitting influence cardio-metabolic health. New monitors (e.g. activPAL™) may be more accurate for measurement of sitting time and breaks in sitting although how to optimize measurement accuracy is not yet clear. One important issue is the minimum sitting/upright period (MSUP) to define a new posture. Using the activPAL™, we investigated the effect of variations in MSUP on total sitting time and breaks in sitting, and also determined the criterion validity of different activPAL™ settings for both constructs.
Methods
We varied setting of MSUP in 23 children (mean (SD) age 4.5 y (0.7)) who wore activPAL™ (24 hr/d) for 5–7 d. We first studied activPAL™ using the default setting of 10 s MSUP and then reduced this to 5 s, 2 s and 1 s. In a second study, in a convenience sample of 30 pre-school children (mean age 4.1 y (SD 0.5)) we validated the activPAL™ measures of sitting time and breaks in sitting at different MSUP settings against direct observation.
Results
Comparing settings of 10, 5, 2 and 1 s, there were no significant differences in sitting time (6.2 hr (1.0), 6.3 hr (1.0), 6.4 hr (1.0) and 6.3 hr (1.6), respectively) between settings but there were significant increases in the apparent number of breaks - (8(3), 14(2), 21(4) and 28 (6)/h) at 10, 5, 2 and 1 s settings, respectively. In comparison with direct observation, a 2 s setting had the smallest error relative to direct observation (95% limits of agreement: -14 to +17 sitting bouts/hr, mean difference 1.83, p = 0.2).
Conclusion
With activPAL™, breaks in sitting, but not total sitting time, are highly sensitive to the setting of MSUP, with 2 s optimal for young children. The MSUP to define a new posture will need to be empirically determined if accurate measurements of number of breaks in sitting are to be obtained.
doi:10.1371/journal.pone.0071854
PMCID: PMC3743753  PMID: 23977163
11.  The influence of the food environment on overweight and obesity in young children: a systematic review 
BMJ Open  2012;2(6):e001538.
Background and objective
The increasing prevalence of childhood obesity has led to interest in its prevention, particularly through school-based and family-based interventions in the early years. Most evidence reviews, to date, have focused on individual behaviour change rather than the ‘obesogenic environment’.
Objective
This paper reviews the evidence on the influence of the food environment on overweight and obesity in children up to 8 years.
Data sources
Electronic databases (including MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), DARE, CINAHL and Psycho-Info) and reference lists of original studies and reviews were searched for all papers published up to 31 August 2011.
Study selection
Study designs included were either population-based intervention studies or a longitudinal study. Studies were included if the majority of the children studied were under 9 years, if they related to diet and if they focused on prevention rather than treatment in clinical settings.
Data extraction
Data included in the tables were characteristics of participants, aim, and key outcome results. Quality assessment of the selected studies was carried out to identify potential bias and an evidence ranking exercise carried out to prioritise areas for future public health interventions.
Data synthesis
Thirty-five studies (twenty-five intervention studies and ten longitudinal studies) were selected for the review. There was moderately strong evidence to support interventions on food promotion, large portion sizes and sugar-sweetened soft drinks.
Conclusions
Reducing food promotion to young children, increasing the availability of smaller portions and providing alternatives to sugar-sweetened soft drinks should be considered in obesity prevention programmes aimed at younger children. These environment-level interventions would support individual and family-level behaviour change.
doi:10.1136/bmjopen-2012-001538
PMCID: PMC3532982  PMID: 23253872
Preventive Medicine; Public Health
12.  Incidence of obesity during childhood and adolescence in a large contemporary cohort☆ 
Preventive Medicine  2011;52(5):300-304.
Background and Aims
Timing of obesity development during childhood and adolescence is unclear, hindering preventive strategies. The primary aim of the present study was to quantify the incidence of overweight and obesity throughout childhood and adolescence in a large contemporary cohort of English children (the Avon Longitudinal Study of Parents and Children, ALSPAC; children born 1991–1992). A secondary aim was to examine the persistence of overweight and obesity.
Methods
Longitudinal data on weight and height were collected annually from age 7–15 years in the entire ALSPAC cohort (n = 4283), and from 3 to 15 years in a randomly selected subsample of the cohort (n = 549; ‘Children in Focus’ CiF). Incidence of overweight and obesity (BMI (Body mass index) at or above the 85th and 95th centiles relative to UK reference data) was calculated. Risk ratios (RR) for overweight and obesity at 15 years based on weight status at 3, 7, and 11 years were also calculated.
Results
In the entire cohort, four-year incidence of obesity was higher between ages 7 and 11 years than between 11 and 15 years (5.0% vs 1.4% respectively). In the CiF sub-sample, four-year incidence of obesity was also highest during mid-childhood (age 7–11 years, 6.7%), slightly lower during early childhood (3–7 years, 5.1%) and lowest during adolescence (11–15 years 1.6%). Overweight and obesity at all ages had a strong tendency to persist to age 15 years as indicated by risk ratios (95% CI (Confidence interval)) for overweight and obesity at 15 years from overweight and obesity (relative to healthy weight status) at 3 years (2.4, 1.8–3.1), 7 years (4.6, 3.6–5.8), and 11 years (9.3, 6.5–13.2).
Conclusion
Mid–late childhood (around age 7–11 years) may merit greater attention in future obesity prevention interventions.
doi:10.1016/j.ypmed.2011.02.014
PMCID: PMC3919170  PMID: 21371500
ALSPAC; Obesity; Aetiology; Prevention; Overweight; Children; Adolescents
13.  QUANTITATIVE CT ANALYSIS, AIRFLOW OBSTRUCTION AND LUNG CANCER IN THE PITTSBURGH LUNG SCREENING STUDY 
Background
To study the relationship between emphysema, airflow obstruction and lung cancer in a high risk population we performed quantitative analysis of screening computed tomography (CT) scans.
Methods
Subjects completed questionnaires, spirometry and low-dose helical chest CT. Analyses compared cases and controls according to automated quantitative analysis of lung parenchyma and airways measures.
Results
Our case-control study of 117 matched pairs of lung cancer cases and controls did not reveal any airway or lung parenchymal findings on quantitative analysis of screening CT scans that were associated with increased lung cancer risk. Airway measures including wall area %, lumen perimeter, lumen area and average wall HU, and parenchymal measures including lung fraction < −910 Hounsfield Units (HU), were not statistically different between cases and controls.
Conclusions
The relationship between visual assessment of emphysema and increased lung cancer risk could not be verified by quantitative analysis of low-dose screening CT scans in a high risk tobacco exposed population.
doi:10.1097/JTO.0b013e318219aa93
PMCID: PMC3157578  PMID: 21610523
14.  SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung Development 
Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.
Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.
Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.
Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.
Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
doi:10.1164/rccm.201010-1751OC
PMCID: PMC3137139  PMID: 21330457
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
15.  Radiographic Evaluation of the Potential Lung Volume Reduction Surgery Candidate 
Delineating the extent and distribution of emphysema is an essential component of the evaluation of candidates for lung volume reduction surgery (LVRS). Imaging also may identify contraindications to LVRS, including bronchiectasis and pleural scarring. The chest X-ray is of limited utility in LVRS evaluation. Chest computed tomography (CT) scanning is an essential component of the evaluation, demonstrating the presence of emphysema and its amount and distribution. Clinical experience has shown that a substantial minority of chest CT scans will also demonstrate pulmonary nodules, some of which represent lung cancers. Published series, including the National Emphysema Treatment Trial, consistently demonstrate that patients with upper lobe predominant or heterogeneous emphysema are most likely to benefit from LVRS. Heterogeneity and distribution can also be assessed by radionuclide ventilation perfusion scanning, but this modality adds little additional information to CT scanning.
doi:10.1513/pats.200802-017ET
PMCID: PMC2645313  PMID: 18453349
emphysema; lung volume reduction surgery; CT scanning; pulmonary nodule; preoperative evaluation
16.  The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection 
SUMMARY
Allograft rejection remains a major limitation to successful solid organ transplantation. Here, we investigated the biosynthesis and bioactions of the pro-resolving mediators lipoxin A4 and resolvin E1 in host responses to organ transplantation. In samples obtained during screening bronchoscopy after human lung transplantation, bronchoalveolar lavage fluid levels of lipoxin A4 were increased in association with the severity of allograft rejection that was graded independently by clinical pathology. Lipoxin A4 significantly inhibited calcineurin activation in human neutrophils, and lipoxin A4 stable analogs prevented acute rejection of vascularized cardiac and renal allografts. Transgenic animals expressing human lipoxin A4 receptors revealed important sites of action in host tissues for lipoxin A4’s protective effects. Resolvin E1 displays counter-regulatory actions for leukocytes, in part, via increased lipoxin A4 biosynthesis, yet RvE1 administered (1 µg, iv) to donor (days −1 and 0) and recipient mice (day −1, 0 and +4) was even more potent than a lipoxin stable analog (1 µg, iv) in prolonging renal allograft survival (median survival time = 74.0 days with RvE1 and 37.5 days with a LXA4 analog). Together, these results highlight the potential for pro-resolving mediators in prolonging survival of solid organ transplants.
doi:10.1016/j.plefa.2010.09.002
PMCID: PMC3019284  PMID: 20869861
17.  Research priorities for child and adolescent physical activity and sedentary behaviours: an international perspective using a twin-panel Delphi procedure 
Background
The quantity and quality of studies in child and adolescent physical activity and sedentary behaviour have rapidly increased, but research directions are often pursued in a reactive and uncoordinated manner.
Aim
To arrive at an international consensus on research priorities in the area of child and adolescent physical activity and sedentary behaviour.
Methods
Two independent panels, each consisting of 12 experts, undertook three rounds of a Delphi methodology. The Delphi methodology required experts to anonymously answer questions put forward by the researchers with feedback provided between each round.
Results
The primary outcome of the study was a ranked set of 29 research priorities that aimed to be applicable for the next 10 years. The top three ranked priorities were: developing effective and sustainable interventions to increase children’s physical activity long-term; policy and/or environmental change and their influence on children’s physical activity and sedentary behaviour; and prospective, longitudinal studies of the independent effects of physical activity and sedentary behaviour on health.
Conclusions
These research priorities can help to guide decisions on future research directions.
doi:10.1186/1479-5868-10-112
PMCID: PMC3853883  PMID: 24228891
Physical activity; Sedentary behaviour; Research priorities; Children; Adolescents
18.  Perfusion Scintigraphy and Patient Selection for Lung Volume Reduction Surgery 
Rationale: It is unclear if lung perfusion can predict response to lung volume reduction surgery (LVRS).
Objectives: To study the role of perfusion scintigraphy in patient selection for LVRS.
Methods: We performed an intention-to-treat analysis of 1,045 of 1,218 patients enrolled in the National Emphysema Treatment Trial who were non–high risk for LVRS and had complete perfusion scintigraphy results at baseline. The median follow-up was 6.0 years. Patients were classified as having upper or non–upper lobe–predominant emphysema on visual examination of the chest computed tomography and high or low exercise capacity on cardiopulmonary exercise testing at baseline. Low upper zone perfusion was defined as less than 20% of total lung perfusion distributed to the upper third of both lungs as measured on perfusion scintigraphy.
Measurements and Main Results: Among 284 of 1,045 patients with upper lobe–predominant emphysema and low exercise capacity at baseline, the 202 with low upper zone perfusion had lower mortality with LVRS versus medical management (risk ratio [RR], 0.56; P = 0.008) unlike the remaining 82 with high perfusion where mortality was unchanged (RR, 0.97; P = 0.62). Similarly, among 404 of 1,045 patients with upper lobe–predominant emphysema and high exercise capacity, the 278 with low upper zone perfusion had lower mortality with LVRS (RR, 0.70; P = 0.02) unlike the remaining 126 with high perfusion (RR, 1.05; P = 1.00). Among the 357 patients with non–upper lobe–predominant emphysema (75 with low and 282 with high exercise capacity) there was no improvement in survival with LVRS and measurement of upper zone perfusion did not contribute new prognostic information.
Conclusions: Compared with optimal medical management, LVRS reduces mortality in patients with upper lobe–predominant emphysema when there is low rather than high perfusion to the upper lung.
doi:10.1164/rccm.201001-0043OC
PMCID: PMC2970864  PMID: 20538961
perfusion; computed tomography; emphysema; mortality; lung volume reduction surgery
19.  Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene 
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
doi:10.1164/rccm.200910-1586OC
PMCID: PMC2937234  PMID: 20463177
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
20.  Relationship of Emphysema and Airway Disease Assessed by CT to Exercise Capacity in COPD 
Respiratory medicine  2010;104(8):1145-1151.
SUMMARY
Objective
To assess the association of emphysema and airway disease assessed by volumetric computed tomography (CT) with exercise capacity in subjects with chronic obstructive pulmonary disease (COPD).
Methods
We studied 93 subjects with COPD (Forced Expiratory Volume in 1 s [FEV1] %predicted mean ± SD 57.1 ± 24.3%, female gender = 40) enrolled in the Lung Tissue Research Consortium. Emphysema was defined as percentage of low attenuation areas less than a threshold of −950 Hounsfield units (%LAA-950) on CT scan. The wall area percentage (WA%) of the 3rd to 6th generations of the apical bronchus of right upper lobe (RB1) were analyzed. The six-minute walk distance (6MWD) test was used as a measure of exercise capacity.
Results
The 6MWD was inversely associated with %LAA-950 (r = −0.53, p<0.0001) and with the WA% of 6th generation of RB1 only (r = −0.28, p = 0.009). In a multivariate regression model including CT indices of emphysema and airway disease that were adjusted for demographic and physiologic variables as well as brand of CT scanner, only the %LAA-950 remained significantly associated with exercise performance. Holding other covariates fixed, this model showed that a 10% increase of CT emphysema reduced the distance walked in six minutes 28.6 meters (95% Confidence Interval = −51.2, −6.0, p = 0.01).
Conclusion
These results suggest that the extent of emphysema but not airway disease measured by volumetric CT contributes independently to exercise limitation in subjects with COPD.
doi:10.1016/j.rmed.2010.02.023
PMCID: PMC2904840  PMID: 20385477
COPD; CT; emphysema; airways; 6-minute walk test
21.  Peripheral blood gene expression profiles in COPD subjects 
To identify non-invasive gene expression markers for chronic obstructive pulmonary disease (COPD), we performed genome-wide expression profiling of peripheral blood samples from 12 subjects with significant airflow obstruction and an equal number of non-obstructed controls. RNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) and gene expression was assessed using Affymetrix U133 Plus 2.0 arrays.
Tests for gene expression changes that discriminate between COPD cases (FEV1< 70% predicted, FEV1/FVC < 0.7) and controls (FEV1> 80% predicted, FEV1/FVC > 0.7) were performed using Significance Analysis of Microarrays (SAM) and Bayesian Analysis of Differential Gene Expression (BADGE). Using either test at high stringency (SAM median FDR = 0 or BADGE p < 0.01) we identified differential expression for 45 known genes. Correlation of gene expression with lung function measurements (FEV1 & FEV1/FVC), using both Pearson and Spearman correlation coefficients (p < 0.05), identified a set of 86 genes. A total of 16 markers showed evidence of significant correlation (p < 0.05) with quantitative traits and differential expression between cases and controls. We further compared our peripheral gene expression markers with those we previously identified from lung tissue of the same cohort. Two genes, RP9and NAPE-PLD, were identified as decreased in COPD cases compared to controls in both lung tissue and blood. These results contribute to our understanding of gene expression changes in the peripheral blood of patients with COPD and may provide insight into potential mechanisms involved in the disease.
doi:10.1186/2043-9113-1-12
PMCID: PMC3164605  PMID: 21884629
Microarray; Biomarkers; PBMC
22.  Physiological and Computed Tomographic Predictors of Outcome from Lung Volume Reduction Surgery 
Rationale: Previous investigations have identified several potential predictors of outcomes from lung volume reduction surgery (LVRS). A concern regarding these studies has been their small sample size, which may limit generalizability. We therefore sought to examine radiographic and physiologic predictors of surgical outcomes in a large, multicenter clinical investigation, the National Emphysema Treatment Trial.
Objectives: To identify objective radiographic and physiological indices of lung disease that have prognostic value in subjects with chronic obstructive pulmonary disease being evaluated for LVRS.
Methods: A subset of the subjects undergoing LVRS in the National Emphysema Treatment Trial underwent preoperative high-resolution computed tomographic (CT) scanning of the chest and measures of static lung recoil at total lung capacity (SRtlc) and inspiratory resistance (Ri). The relationship between CT measures of emphysema, the ratio of upper to lower zone emphysema, CT measures of airway disease, SRtlc, Ri, the ratio of residual volume to total lung capacity (RV/TLC), and both 6-month postoperative changes in FEV1 and maximal exercise capacity were assessed.
Measurements and Main Results: Physiological measures of lung elastic recoil and inspiratory resistance were not correlated with improvement in either the FEV1 (R = −0.03, P = 0.78 and R = –0.17, P = 0.16, respectively) or maximal exercise capacity (R = –0.02, P = 0.83 and R = 0.08, P = 0.53, respectively). The RV/TLC ratio and CT measures of emphysema and its upper to lower zone ratio were only weakly predictive of postoperative changes in both the FEV1 (R = 0.11, P = 0.01; R = 0.2, P < 0.0001; and R = 0.23, P < 0.0001, respectively) and maximal exercise capacity (R = 0.17, P = 0.0001; R = 0.15, P = 0.002; and R = 0.15, P = 0.002, respectively). CT assessments of airway disease were not predictive of change in FEV1 or exercise capacity in this cohort.
Conclusions: The RV/TLC ratio and CT measures of emphysema and its distribution are weak but statistically significant predictors of outcome after LVRS.
doi:10.1164/rccm.200906-0911OC
PMCID: PMC2830400  PMID: 19965810
23.  Pulmonary Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema 
Rationale: Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema.
Objectives: We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization.
Methods: In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm2 (CSA<5) and 5 to 10 mm2 (CSA5−10), and calculated the percentage of total CSA for the lung area (%CSA<5 and %CSA5–10, respectively). The correlations of %CSA<5 and %CSA5–10 with pulmonary arterial mean pressure (\documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document}) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using \documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document} as the dependent outcome was also performed.
Measurements and Main Results: The %CSA<5 had a significant negative correlation with \documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document} (r = −0.512, P < 0.0001), whereas the correlation between %CSA5–10 and \documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document} did not reach statistical significance (r = −0.196, P = 0.083). Multiple linear regression analysis showed that %CSA<5 and diffusing capacity of carbon monoxide (DlCO) % predicted were independent predictors of \documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document} (r2 = 0.541): %CSA <5 (P < 0.0001), and DlCO % predicted (P = 0.022).
Conclusions: The %CSA<5 measured on CT images is significantly correlated to \documentclass[10pt]{article} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{pmc} \usepackage[Euler]{upgreek} \pagestyle{empty} \oddsidemargin -1.0in \begin{document} \begin{equation*}\overline{Ppa}\end{equation*}\end{document} in severe emphysema and can estimate the degree of pulmonary hypertension.
doi:10.1164/rccm.200908-1189OC
PMCID: PMC2817812  PMID: 19875683
chronic obstructive pulmonary disease; emphysema; pulmonary hypertension; CT
24.  Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD* 
Chest  2008;135(3):737-744.
Background
Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).
Methods
In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.
Results
In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.
Conclusions
In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.
doi:10.1378/chest.08-1993
PMCID: PMC2906241  PMID: 19017876
case-control studies; COPD; genetics; phenotype; single-nucleotide polymorphism
25.  Genetic association analysis of COPD candidate genes with bronchodilator responsiveness 
Respiratory medicine  2008;103(4):552-557.
Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV1, change in FEV1 as a percent of baseline FEV1, and change in FEV1 as a percent of predicted FEV1. Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes (EPHX1, SFTPB, TGFB1, SERPINE2, GSTP1, ADRB2). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 (p = 0.009 – 0.04), three SNPs in SERPINE2 (p = 0.004 – 0.05) and two SNPs in ADRB2 (0.04 – 0.05) were significantly associated with BDR phenotypes in NETT subjects. BDR. One SNP in EPHX1 (rs1009668, p = 0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB, TGFB1, and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.
doi:10.1016/j.rmed.2008.10.025
PMCID: PMC2745950  PMID: 19111454
bronchodilator responsiveness; chronic obstructive pulmonary disease; genetics; association analysis

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