Hot off the presses! Sep 16 Lancet

The Sep 16 issue of the Lancet is now up on Pubget (About Lancet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Time for action in New York on non-communicable diseases
  - Lancet 378(9795):961 (2011)
  
• COPD—more vigorous research needed
  - Lancet 378(9795):962 (2011)
  
• Ethical behaviour in clinical research—a lesson from the past
  - Lancet 378(9795):962 (2011)
  
• Personalised medicine for asthma management in pregnancy
  - Lancet 378(9795):963-964 (2011)
  
• Lifetime risk of COPD: what will the future bring?
  - Lancet 378(9795):964-965 (2011)
  
• Lung-volume reduction by airway bypass
  - Lancet 378(9795):966-967 (2011)
  
• Successfully mapping novel asthma loci by GWAS
  - Lancet 378(9795):967-968 (2011)
  
• High-concentration oxygen therapy in COPD
  - Lancet 378(9795):969-970 (2011)
  
• Global anti-smoking campaigns urgently needed
  - Lancet 378(9795):970-971 (2011)
  
• Offline: From August 6 to March 11
  - Lancet 378(9795):972 (2011)
  
• Smoking in Russia: will old habits die hard?
  - Lancet 378(9795):973-974 (2011)
  
• The Lancet Technology: September, 2011
  - Lancet 378(9795):975 (2011)
  
• Bracelets from cluster bombs
  - Lancet 378(9795):976 (2011)
  
• Klaus Rabe: incoming President of the ERS
  - Lancet 378(9795):977 (2011)
  
• Paul Meier
  - Lancet 378(9795):978 (2011)
  
• Dexamethasone in community-acquired pneumonia
  - Lancet 378(9795):979 (2011)
  
• Dexamethasone in community-acquired pneumonia
  - Lancet 378(9795):979-980 (2011)
  
• Dexamethasone in community-acquired pneumonia
  - Lancet 378(9795):980 (2011)
  
• Dexamethasone in community-acquired pneumonia
  - Lancet 378(9795):980 (2011)
  
• Dexamethasone in community-acquired pneumonia – Authors' reply
  - Lancet 378(9795):981 (2011)
  
• Aerosol drug delivery: developments in device design and clinical use
  - Lancet 378(9795):981-982 (2011)
  
• Aerosol drug delivery: developments in device design and clinical use
  - Lancet 378(9795):982 (2011)
  
• Aerosol drug delivery: developments in device design and clinical use – Authors' reply
  - Lancet 378(9795):982 (2011)
  
• Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial
  - Lancet 378(9795):983-990 (2011)
  Background Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (FENO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on FENO and symptoms would reduce asthma exacerbations. Methods We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks' gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or FENO concentrations (active intervention group) used to uptitrate (FENO >29 ppb) or downtitrate (FENO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting β2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when FENO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482. Findings 111 women were randomly assigned to the FENO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the FENO group than in the control group (0·288 vs 0·615 exacerbations per pregnancy; incidence rate ratio 0·496, 95% CI 0·325–0·755; p=0·001). The number needed to treat was 6. In the FENO group, quality of life was improved (score on short form 12 mental summary was 56·9 [95% CI 50·2–59·3] in FENO group vs 54·2 [46·1–57·6] in control group; p=0·037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0·046). Interpretation Asthma exacerbations during pregnancy can be significantly reduced with a validated FENO-based treatment algorithm. Funding National Health and Medical Research Council of Australia.
• Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study
  - Lancet 378(9795):991-996 (2011)
  Background Although chronic obstructive pulmonary disease (COPD) is one of the most deadly, prevalent, and costly chronic diseases, no comprehensive estimates of the risk of developing COPD in the general population have been published. We aimed to quantify the lifetime risk of developing physician-diagnosed COPD in a large, multicultural North American population. Methods We did a retrospective longitudinal cohort study using population-based health administrative data from Ontario, Canada (total population roughly 13 million). All individuals free of COPD in 1996 were monitored for up to 14 years for three possible outcomes; diagnosis of COPD by a physician, reached 80 years of age, or death. COPD was identified with a previously validated case definition based on COPD health services claims. The cumulative incidence of physician-diagnosed COPD over a lifetime adjusted for the competing risk of death was calculated by a modified survival analysis technique. Results were stratified by sex, socioeconomic status, and whether individuals lived in a rural or urban setting. Findings A total of 579 466 individuals were diagnosed with COPD by a physician over the study period. The overall lifetime risk of physician-diagnosed COPD at age 80 years was 27·6%. Lifetime risk was higher in men than in women (29·7% vs 25·6%), individuals of lower socioeconomic status than in those of higher socioeconomic status (32·1% vs 23·0%), and individuals who lived in a rural setting than in those who lived in an urban setting (32·4% vs 26·7%). Interpretation About one in four individuals are likely to be diagnosed and receive medical attention for COPD during their lifetime. Clinical evidence-based approaches, public health action, and more research are needed to identify effective strategies to prevent COPD and ensure that those with the disease have the highest quality of life possible. Funding Government of Ontario, Canada.
• Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial
  - Lancet 378(9795):997-1005 (2011)
  Background Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. Methods We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that ai! rway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. Findings All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). Interpretation Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. Funding Broncus Technologies.
• Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
  - Lancet 378(9795):1006-1014 (2011)
  Background We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. Methods We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Findings Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p=2·4×10−8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. Interpretation The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. Funding National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.
• New insights into the immunology of chronic obstructive pulmonary disease
  - Lancet 378(9795):1015-1026 (2011)
  Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative ! stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation.
• The future of chronic obstructive pulmonary disease treatment—difficulties of and barriers to drug development
  - Lancet 378(9795):1027-1037 (2011)
  Although chronic obstructive pulmonary disease (COPD) is a major global health problem with a rising incidence and morbidity, few pharmacotherapeutic advances have been made over the past several decades. The challenges of development of such agents are multifactorial and include rudimentary understanding of the biological genesis of human disease, inadequate in-vitro and in-vivo models, unvalidated biomarkers, inefficient physiological and clinical endpoints, and variable regulatory review worldwide. Blockade of various inflammatory pathways and mediators is a reasonable therapeutic strategy to alter the natural history of COPD. Substantial heterogeneity is evident with respect to clinical presentation, physiology, imaging, response to therapy, decline in lung function, and survival. Numerous endpoints have been proposed for clinical studies in COPD, with new approaches under study. The novel strategy that seems most promising is the use of biomarkers. We hope that wi! th these approaches novel pharmacotherapies will be developed in the near future.
• Controversies in treatment of chronic obstructive pulmonary disease
  - Lancet 378(9795):1038-1047 (2011)
  Chronic obstructive pulmonary disease (COPD) is a chronic disorder with substantial comorbidity and major effects attributable to the high morbidity and mortality rates. Despite an increasing evidence base, some important controversies in COPD management still exist. The classic way to define COPD has been based on spirometric criteria, but more relevant diagnostic methods are needed that can be used to describe COPD severity and comorbidity. Initiation of interventions earlier in the natural history of the disease to slow disease progression is debatable, there are many controversies about the role of inhaled corticosteroids in the management of COPD, and long-term antibiotics for prevention of exacerbation have had a resurgence in interest. Novel therapeutic drugs are urgently needed for optimum management of the acute COPD exacerbation. COPD is a complex disease and consists of several clinically relevant phenotypes that in future will guide its management.
• Something in the air
  - Lancet 378(9795):1048 (2011)