Many definitions of COPD exacerbations are reported. The choice for a definition determines the number of exacerbations observed. However, the effect of different definitions on the effect sizes of randomized controlled trials is unclear. This article provides an overview of the large variation of definitions of COPD exacerbations from the literature. Furthermore, the effect of using different definitions on effect sizes (relative risk and hazard ratio) was investigated in a randomized controlled discontinuation trial of inhaled corticosteroids. The following definitions were applied: (1) unscheduled medical attention, (2) a course of oral corticosteroids/antibiotics, (3) deterioration in two major or one major and one minor symptom according to Anthonisen (referenced later), (4) a change in one or more symptoms, (5) a change in two or more symptoms, and (6) a combination of numbers 2 and 4. Relative risks for the exacerbation rate ranged from 1.19 to 1.49, and hazard ratios for time to first exacerbation ranged from 1.36 to 1.84 for the various definitions, varying from nonsignificant to significant. Because the definition of a COPD exacerbation has an impact on the effect size of interventions, there is an urgent need for concerted attempts to reach agreement on a definition of an exacerbation. Also, the exact definition to be used in a study should be specified in the protocol.

Although the insulating properties of asbestos have been known for millennia, the link between asbestos exposure and mesothelioma was not recognized until 1960, when it was first described in South African asbestos miners. The incidence of mesothelioma parallels asbestos usage with a latency of 20 to 40+ years; thus, patient numbers are declining in the United States but rising in the developing world. Radiation, genetics, and possibly simian virus 40 are less common causes. Diagnosis can be challenging, since the results of pleural fluid cytology testing are often negative despite repeated sampling. No staging system adequately predicts prognosis in the unresected patient. Newly described biomarkers, including soluble mesothelin-related peptide, megakaryocyte potentiation factor, and osteopontin, may predict which asbestos-exposed individuals will develop mesothelioma, and may prove useful in assessing response to treatment. Since surgery cannot eradicate all residual microscopic disease, a multimodality approach is encouraged. Metaanalysis suggests that pleurectomy/decortication may achieve outcomes similar to those of extrapleural penumonectomy. The standard first-line chemotherapy for unresectable disease is pemetrexed plus cisplatin. This combination improves response, survival, time to progression, pulmonary function, and disease-related symptoms. Carboplatin is often substituted, with similar results. Other active agents include raltitrexed, gemcitabine, and vinorelbine. Novel agents in clinical trials include inhibitors of the epidermal growth factor receptor, vascular endothelial growth factor, mesothelin, and histone deacetylases. Although disappointing results of early trials did not confirm promising preclinical data, recent studies have suggested that some novel agents may be effective. As we learn more about mesothelioma biology, molecularly targeted agents may become treatment options.

COPD is a highly prevalent disorder that results from the interplay of genetic susceptibility and environmental exposures. Over the past 2 decades, significant technological advances have been made in genetic investigations of complex diseases, yet limited progress has been made in the identification of additional COPD susceptibility genes. Genetic and phenotypic heterogeneity, limited power due to modest study population sizes, and significant modification of genetic effects by environmental factors pose significant challenges in COPD and emphysema genetic studies. More refined characterization of the emphysema and airway components of COPD can now be obtained through the systematic use of CT scans. These improved phenotypes can be applied in genome-wide association studies and will likely lead to the discovery of additional susceptibility loci and therapeutic targets.

Skeletal muscle weakness and its impact on exercise tolerance in many people with COPD provide a rationale for the intervention of progressive resistance exercise during pulmonary rehabilitation. To optimize rehabilitation outcomes, clinicians prescribing resistance programs require up-to-date information on effectiveness, safety, and feasibility. Therefore, the review aimed to update the current evidence for progressive resistance exercise for people with COPD.

Epidemiologic studies have identified an increased risk of asthma with acetaminophen use, but the results have been conflicting. We sought to quantify the association between acetaminophen use and the risk of asthma in children and adults.

Spirometry is a useful test of pulmonary function and can be safely performed in a variety of clinical situations. Although the technique for performing the maneuver is straightforward, there are many sources of variability in results. Specific criteria must be met in order for the test to be considered valid. For the best results, proper instruction and coaching is essential, and patient understanding and effort must be maximized. Appropriate interpretation of spirometry requires several steps, including recognition and reporting of technically sound maneuvers, comparison to an appropriate reference population, and finally application of a well-developed interpretation scheme utilized in the context of patient symptoms and findings. Failure at any point along this path from performance to interpretation can yield misleading results that may ultimately poorly impact patient care. A clear understanding by the provider of proper coding and billing for spirometry is necessary to receive appropriate reimbursement from payers.

To our knowledge, there are no specific and validated measures of quality of life (QoL) or degree of disability for pulmonary arterial hypertension (PAH). A review of the literature shows that, with the exception of one recently designed specifically for pulmonary hypertension, QoL questionnaires used in PAH studies are generic measures. These are selected because of shared symptoms that do not necessarily correlate well with functional or physiologic measures and have not been validated for applicability in PAH. In this review, we present the available QoL tools for pulmonary artery hypertension and describe the need for more specific instruments that consider the physical and emotional implications of the diseases associated with PAH and the impact of various treatment options. We also discuss the impact of PAH on work ability and the need for provisions to address medical disability status and Social Security benefit status.

With vastly heterogeneous morphologic manifestations, sarcoidosis is one of the "great imitators" of medicine. Because there is no specific confirmatory test, the diagnosis rests on clinical acumen coupled with supportive information from tissue or blood evaluation and the exclusion of other diseases. The characteristic histologic pattern of noncaseating, epithelioid cell granulomas is not always present in skin lesions, which may be visually distinctive or diverse in appearance. As a result of their high incidence of respiratory disease, patients with sarcoidosis frequently seek care from pulmonologists who may become their primary health-care providers. Physicians who treat patients with sarcoidosis should be aware of the disease's diverse organ manifestations, but particularly those appearing on the skin because these can be disfiguring, have prognostic importance, and may not be readily diagnosed even by skin specialists. In this comprehensive review, we sought to illustrate this diversity and to update the diagnostic approach, histologic spectrum, and therapeutic strategies involved in cutaneous sarcoidosis.

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by ineffective clearance of surfactant by alveolar macrophages. Through recent studies with genetically altered mice, the etiology of this idiopathic disease is becoming clearer. Functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to contribute to disease pathogenesis because mutant mice deficient in GM-CSF or its receptor spontaneously develop PAP. Recent human studies further suggest a connection between PAP and defective GM-CSF activity because inactivating anti-GM-CSF autoantibodies are observed in all patients with idiopathic PAP, and additional rare cases of PAP in children have been accompanied by genetic defects in the alpha chain of the GM-CSF receptor. In patients and mouse models of PAP, deficient GM-CSF activity appears to result in defective alveolar macrophages that are unable to maintain pulmonary surfactant homeostasis and display defective phagocytic and antigen-presenting capabilities. The most recent studies also suggest that neutrophil dysfunction additionally contributes to the increased susceptibility to lung infections seen in PAP. Because the phenotypic and immunologic abnormalities of PAP in mouse models can be corrected by GM-CSF reconstituting therapies, early clinical trials are underway utilizing administration of GM-CSF to potentially treat human PAP. The development of novel treatment approaches for PAP represents a dramatic illustration in pulmonary medicine of the "bench-to-bedside" process, in which basic scientists, translational researchers, and clinicians have joined together to rapidly take advantage of the unexpected observations frequently made in the modern molecular biology research laboratory.

Current guidelines recommend the use of inhaled corticosteroids (ICSs) added to long-acting beta(2)-agonists (LABAs) for treatment of symptomatic patients with severe and very severe COPD. However, the evidence has been inconclusive. The aim of this review was to assess the safety and efficacy of LABAs/ICSs compared with LABA monotherapy for patients with moderate-to-very severe COPD.

Little is known about the optimal management of impending paradoxical embolism (IPDE), a biatrial thromboembolus caught in transit across a patent foramen ovale. Our aim was to review observational studies on this subject to identify prognostic factors and to compare mortality and systemic embolism between treatments.

Patients in the ICU are known to have severely disrupted sleep with disturbed circadian pattern, decreased nocturnal sleep time, abnormally increased stages 1 and 2 sleep, and reduced or absent deep sleep. Recent data reveal that a subpopulation of critically ill patients manifests unique EEG sleep patterns. The etiology of sleep disruption in the ICU includes the inherent nature of the environment, medications, ventilator-patient interaction, and the effect of acute illness. How sleep disruption contributes to outcomes in critically ill patients, such as recovery time and weaning from mechanical ventilation, is unknown. This article reviews the literature describing sleep in ICU patients, including recent investigations in patients who require mechanical ventilation, factors that affect sleep in critically ill patients, and the potential mechanisms and clinical implications of disturbed sleep in the ICU setting with directions to consider for future investigations.

The International Association for the Study of Lung Cancer (IASLC) has conducted an extensive initiative to inform the revision of the lung cancer staging system. This involved development of an international database along with extensive analysis of a large population of patients and their prognoses. This article reviews the recommendations of the IASLC International Staging Committee for the definitions for the TNM descriptors and the stage grouping in the new non-small cell lung cancer staging system.

We have come to appreciate that scientific misconduct is often not intuitively obvious to those who perpetrate it. Therefore, this commentary has been written to review what we know about the role of conflict of interest (COI) in the reporting of scientific information and to challenge those of us in educator roles to do a better job in mentoring our trainees, junior faculty, and associates on what is right and wrong; what is ethical and unethical. The review addresses the following questions: (1) Why has the public trust in the clinical research industry been eroded? (2) How often is the ethical concept of equipoise violated in industry-sponsored randomized controlled clinical trials? (3) How often are negative trials underreported and favorable trials selectively or redundantly over-reported in industry-sponsored randomized controlled clinical trials? (4) What is being done to restore the public trust? While there are multiple strategies to mitigate COI in the reporting of scientific information, we have come to appreciate that the disclosure of potential conflicts of interest is not enough. It is our hope that this article and its contents can serve as a stimulus for the development and incorporation of an educational series in all training programs on what is ethical and unethical in the conducting and reporting of scientific studies.

Inconsistent information exists about factors associated with daytime hypercapnia in obese patients with obstructive sleep apnea (OSA). We systematically evaluated these factors in this population.

Despite 20 years of debate, several US Food and Drug Administration (FDA) hearings, black-box warnings, and many descriptive articles and metaanalyses, controversy regarding the safety of long-acting beta-agonist (LABA) treatment in asthma patients continues. This has resulted in a recent call for another large and definitive safety study. This commentary focuses first on data provided in the metaanalysis recently undertaken by the FDA of safety outcomes among 60,954 individuals in 110 LABA trials, and second on the sample size that would be required for a new definitive study of LABA safety in the presence of mandatory treatment with an inhaled corticosteroid (ICS). A critical stratified analysis in the FDA report involving 15,192 individuals indicates that a LABA used with mandatory ICS therapy was not associated with an increased risk of asthma-related mortality, intubations, or exacerbations (risk difference [RD], 0.25 per 1,000 individuals; 95% confidence interval [CI], -1.69 to 2.18). Using the same stratified data to calculate the sample size required to prove or disprove an association between the use of LABA with mandatory ICS therapy and adverse outcomes, assuming the RD is exactly 0.25, and ignoring the 95% CI, which includes 0.0 or even a negative risk, such a study is both logistically and scientifically impossible. A new study is not practicable, nor is one needed in the light of current analyses of existing data. It is time to learn from the past, to rigorously avoid LABA monotherapy in asthma, and to use a LABA (when indicated) always in mandatory combination with appropriate doses of an ICS.

Pain in patients who are critically ill remains undertreated despite decades of research, guideline development and distribution, and intense educational efforts. By nature of their complex medical conditions, these patients present unique challenges to the delivery of optimal pain treatment. Outdated clinical practices and faulty systems, such as a formulary that allows dangerous prescriptions, present additional obstacles. A multidisciplinary and patient-centered continuous quality improvement process is essential to identifying barriers and implementing evidence-based solutions to the problem of undertreated pain in hospital ICUs. This article addresses barriers common to the ICU setting and presents a number of structured approaches that have been shown to be successful in improving pain treatment in patients who are critically ill.

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.