Hot off the presses! Aug 29 Lancet

The Aug 29 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:

• COPD—more than just tobacco smoke
  - Lancet 374(9691):663 (2009)
  
• Self-plagiarism: unintentional, harmless, or fraud?
  - Lancet 374(9691):664 (2009)
  
• Revitalising health in Afghanistan
  - Lancet 374(9691):664 (2009)
  
• Phosphodiesterase-4 inhibition in COPD
  - Lancet 374(9691):665-667 (2009)
  
• From BODE to ADO to outcomes in multimorbid COPD patients
  - Lancet 374(9691):667-668 (2009)
  
• Inhaled corticosteroids in COPD and the risk of pneumonia
  - Lancet 374(9691):668-670 (2009)
  
• Time to define the disorders of the syndrome of COPD
  - Lancet 374(9691):670-672 (2009)
  
• Telemedicine for management of patients with COPD?
  - Lancet 374(9691):672-673 (2009)
  
• Sex, rights, and politics—from Cairo to Berlin
  - Lancet 374(9691):674-675 (2009)
  
• Elective caesarean sections—risks to the infant
  - Lancet 374(9691):675-676 (2009)
  
• Abortion ban leads to more maternal deaths in Nicaragua
  - Lancet 374(9691):677 (2009)
  
• Stretching the AIDS dollar
  - Lancet 374(9691):678 (2009)
  
• Leonardo Fabbri: investigating the complexity of COPD
  - Lancet 374(9691):679 (2009)
  
• Susan Spencer
  - Lancet 374(9691):680 (2009)
  
• Rivaroxaban versus enoxaparin after total knee arthroplasty
  - Lancet 374(9691):681 (2009)
  
• Rivaroxaban versus enoxaparin after total knee arthroplasty
  - Lancet 374(9691):681 (2009)
  
• Rivaroxaban versus enoxaparin after total knee arthroplasty
  - Lancet 374(9691):681-682 (2009)
  
• Rivaroxaban versus enoxaparin after total knee arthroplasty
  - Lancet 374(9691):682 (2009)
  
• Rivaroxaban versus enoxaparin after total knee arthroplasty – Authors' reply
  - Lancet 374(9691):683 (2009)
  
• On empathy: another perspective
  - Lancet 374(9691):683-684 (2009)
  
• Gestational diabetes and health promotion
  - Lancet 374(9691):684 (2009)
  
• Pricing of pneumococcal vaccines under advance market commitments
  - Lancet 374(9691):684 (2009)
  
• Department of Error
  - Lancet 374(9691):684 (2009)
  
• Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials
  - Lancet 374(9691):685-694 (2009)
  Background The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. Methods In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 μg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV1) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. Findings Patients were assigned to treatment, stratified according to smoking status and treatment with longacting β2 agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV1 increased by 48 mL with roflumilast compared with placebo (p<0·0001). The rate of exacerbations that were moderate or severe per patient per year was 1·14 with roflumilast and 1·37 with placebo (reduction 17% [95% CI 8–25], p<0·0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was −2·17 kg. Interpretation Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. Funding Nycomed.
• Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials
  - Lancet 374(9691):695-703 (2009)
  Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 μg or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1 s (FEV1). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV1 by 49 mL (p<0·0001) in patients treated with salmeterol, and 80 mL (p<0·0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV1 was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients. Funding Nycomed.
• Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index
  - Lancet 374(9691):704-711 (2009)
  Background The BODE index (including body-mass index, airflow obstruction, dyspnoea, and exercise capacity) was an important contribution to the prognostic assessment of patients with chronic obstructive pulmonary disease (COPD). However, no study has assessed whether the risk of mortality predicted by the BODE index matches the observed mortality in different populations. We assessed the calibration of the BODE index, updated it to improve its calibration, and developed and validated a simplified index for use in primary-care settings. Methods We included 232 patients from the Swiss Barmelweid cohort with longstanding and severe COPD and 342 patients from the Spanish Phenotype and Course of COPD cohort study who had had their first hospital admission due to moderate-to-severe COPD. In both cohorts we compared the observed 3-year risk of all-cause mortality with the risk predicted by the BODE index. We then updated the BODE index and developed a simplified ADO index (including age, dyspnoea, and airflow obstruction) from the Swiss cohort, and validated both in the Spanish cohort. Findings Calibration of the BODE index was poor, with relative underprediction of 3-year risk of mortality by 36% in the Swiss cohort (median predicted risk 21·7% [IQR 12·7–31·7] vs 34·1% observed risk; p=0·013) and relative overprediction by 39% in the Spanish cohort (16·7% [12·7–31·7] vs 12·0%; p=0·035). The 3-year risk of mortality predicted by both the updated BODE (median 10·7% [8·1–13·8]) and ADO indices (11·8% [9·1–14·3]) matched the observed mortality in the Spanish cohort well (p=0·99 and p=0.98, respectively). Interpretation Both the updated BODE and ADO indices could lend support to the prognostic assessment of patients with COPD in specialised and primary-care settings. Such assessment enhances the targeting of treatments to individual patients. Funding Swiss National Science Foundation; Klinik Barmelweid; Fondo de Investigación Sanitaria Ministry of Health, Spain; Agència d'Avaluació de Tecnologia i Recerca Mèdiques, Catalonia Government; Spanish Society of Pneumology and Thoracic Surgery; Catalan Foundation of Pneumology; Red RESPIRA; Red RCESP; Fondo de Investigación Sanitaria; Fondo de Investigación Sanitaria; Fundació La Marató de TV3; Novartis Farmacèutica, Spain.
• Budesonide and the risk of pneumonia: a meta-analysis of individual patient data
  - Lancet 374(9691):712-719 (2009)
  Background Concern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients. Methods We pooled patient data from seven large clinical trials of inhaled budesonide (320–1280 μg/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients' age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV1). Findings We analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1·05, 95% CI 0·81–1·37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0·92, 0·62–1·35), or for time to pneumonia as an adverse event (log-rank test 0·94) or a serious adverse event (0·61). Increasing age and decreasing percent of predicted FEV1 were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event. Interpretation Budesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients. Funding Michael Smith Foundation for Health Research.
• Caution: coloured medication and the colour blind
  - Lancet 374(9691):720 (2009)
  
• Screening for and early detection of chronic obstructive pulmonary disease
  - Lancet 374(9691):721-732 (2009)
  Chronic obstructive pulmonary disease (COPD) is a substantially underdiagnosed disorder, with the diagnosis typically missed or delayed until the condition is advanced. Spirometry is the most frequently used pulmonary function test and enables health professionals to make an objective measurement of airflow obstruction and assess the degree to which it is reversible. As a diagnostic test for COPD, spirometry is a reliable, simple, non-invasive, safe, and non-expensive procedure. Early diagnosis of COPD should provide support for smoking cessation initiatives and lead to reduction of the societal burden of the disease, but definitive confirmation of both proves elusive. Despite substantial effort and investment, implementation of quality spirometry is deficient because of several hurdles and limitations, described in this Review. All in all, spirometry is recognised as the essential test for diagnosis and monitoring of COPD.
• Chronic obstructive pulmonary disease in non-smokers
  - Lancet 374(9691):733-743 (2009)
  Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Tobacco smoking is established as a major risk factor, but emerging evidence suggests that other risk factors are important, especially in developing countries. An estimated 25–45% of patients with COPD have never smoked; the burden of non-smoking COPD is therefore much higher than previously believed. About 3 billion people, half the worldwide population, are exposed to smoke from biomass fuel compared with 1·01 billion people who smoke tobacco, which suggests that exposure to biomass smoke might be the biggest risk factor for COPD globally. We review the evidence for the association of COPD with biomass fuel, occupational exposure to dusts and gases, history of pulmonary tuberculosis, chronic asthma, respiratory-tract infections during childhood, outdoor air pollution, and poor socioeconomic status.
• New drugs for exacerbations of chronic obstructive pulmonary disease
  - Lancet 374(9691):744-755 (2009)
  Tobacco smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD), but viral and bacterial infections are the major causes of exacerbations in later stages of disease. Reactive oxygen species (ROS), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) activate families of pattern recognition receptors (PRRs) that include the toll-like receptors (TLRs). This understanding has led to the hypothesis that COPD is an archetypal disease of innate immunity. COPD is characterised by abnormal response to injury, with altered barrier function of the respiratory tract, an acute phase reaction, and excessive activation of macrophages, neutrophils, and fibroblasts in the lung. The activated non-specific immune system then mediates the processes of inflammation and repair, fibrosis, and proteolysis. COPD is also associated with corticosteroid resistance, abnormal macrophage and T-cell populations in the airway, a! utoinflammation and autoimmunity, aberrant fibrosis, accelerated ageing, systemic and concomitant disease, and defective regeneration. Such concepts have been used to generate a range of molecular targets, and clinical trials are taking place to identify effective drugs for the prevention and treatment of COPD exacerbations.
• A reason to panic in pregnancy
  - Lancet 374(9691):756 (2009)