The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis.

Hemodynamic assessment is a key component of the evaluation of the critically ill patients and has both diagnostic and prognostic utility. This review outlines a general approach to assessment of hemodynamics and perfusion, and then discusses various hemodynamic parameters: heart rate, BP, intravascular (central venous and pulmonary artery) pressures, cardiac output, and myocardial performance, within the context not only of how they are best measured but also how they should be used in a clinical context. Hemodynamics are best assessed using a combination of not only different hemodynamic parameters but also those with the inclusion of clinical indices of perfusion. The benefits of these techniques, as with all medical testing and interventions, must be weighed against any potential risks. Although what to measure and how to measure it is important, what is most important is how to use the information. Evaluating the response to therapeutic interventions is frequently the most useful way to employ hemodynamic monitoring techniques. For the practitioner, learning how to select from a robust set of hemodynamic tools and how to tailor their use to individual clinical settings will allow for optimal patient care.

COPD is a leading cause of morbidity and mortality worldwide and is now the third leading cause of death in the United States. Acute exacerbations of COPD (AECOPDs) are common events that often lead to hospitalization, and their frequency worsens with disease progression. AECOPDs are associated with worsened quality of life, increased health-care costs, and increased mortality. Accordingly, there is great interest in preventing AECOPDs to improve outcomes. Both pharmacologic and nonpharmacologic interventions alter the frequency of AECOPDs and COPD-related hospitalizations. To examine the best available evidence, we restricted this review to include studies that used randomized controlled designs lasting at least 6 months. Pharmacologic interventions discussed include inhaled corticosteroids, long-acting β-agonists, long-acting antimuscarinic agents, macrolide antibiotics, and phosphodiesterase-4 inhibitors. The nonpharmacologic interventions discussed include lung volume reduction surgery, pulmonary rehabilitation, and disease management programs.

The increase in total cross-sectional area in the distal airways of the human lung enhances the mixing of each tidal breath with end-expiratory gas volume by slowing bulk flow and increasing gas diffusion. However, this transition also favors the deposition of airborne particulates in this region because they diffuse 600 times slower than gases. Furthermore, the persistent deposition of toxic airborne particulates stimulates a chronic inflammatory immune cell infiltration and tissue repair and remodeling process that increases the resistance in airways <2 mm in diameter four to 40-fold in COPD. This increase was originally attributed to lumen narrowing because it increases resistance in proportion to the change in lumen radius raised to the fourth power. In contrast, removal of one-half the number of tubes arranged in parallel is required to double their resistance, and approximately 90% need to be removed to explain the increase in resistance measured in COPD. However, recent reexamination of this problem based on micro-CT imaging indicates that terminal bronchioles are both narrowed and reduced to 10% of the control values in the centrilobular and 25% in the panlobular emphysematous phenotype of very severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade IV) COPD. These new data indicate that both narrowing and reduction in numbers of terminal bronchioles contribute to the rapid decline in FEV₁ that leads to severe airway obstruction in COPD. Moreover, the observation that terminal bronchiolar loss precedes the onset of emphysematous destruction suggests this destruction begins in the very early stages of COPD.

Oxygen therapy is an integral part of the treatment of critically ill patients. Maintenance of adequate oxygen delivery to vital organs often requires the administration of supplemental oxygen, sometimes at high concentrations. Although oxygen therapy is lifesaving, it may be associated with deleterious effects when administered for prolonged periods at high concentrations. Here, we review the recent advances in our understanding of the molecular responses to hypoxia and high levels of oxygen and review the current guidelines for oxygen therapy in critically ill patients.

In 2008, lung cancer replaced liver cancer as the number one cause of death among people with malignant tumors in China. The registered lung cancer mortality rate increased by 464.84% in the past 3 decades, which imposes an enormous burden on patients, health-care professionals, and society. We performed a systematic review of the published data on lung cancer in China between 1990 and 2011 to analyze the incidence and mortality rates, economic burden, and risk factors of cancer and the effectiveness of interventions. Lung cancer incidence varies within China. People in eastern China, especially women, likely have a higher risk of developing lung cancer than those in western China. The crude mortality rates from lung cancer in 2008 were 47.51 per 100,000 men and 22.69 per 100,000 women. The crude mortality rate was highest in Shanghai (76.49 per 100,000 men and 35.82 per 100,000 women) and lowest in Tibet (25.14 per 100,000 men) and Ningxia (12.09 per 100,000 women). Smoking and environmental pollution are major risk factors for lung cancer in China. Continuous efforts should be concentrated on education of the general public regarding lung cancer to increase prevention and early detection. Specific interventions need to be implemented to reduce smoking rates and environmental risk factors. Standardized treatment protocols should be adapted in China.

Thromboembolic diseases are common. Heparins and the vitamin K antagonists have been the mainstay of therapy for &gt; 60 years, but both classes of agents have limitations. The "ideal" anticoagulant should be as effective and safe as heparin and vitamin K antagonists but should also be available in both a parenteral and an oral formulation, have predictable pharmacokinetics, and lack significant toxicities unrelated to the anticoagulant activity. Moreover, it should target a specific coagulation factor and have an antidote that leads to rapid reversal. There are now agents that fulfill some of these criteria. Here we review the pharmacology and effectiveness of the oral activated factor X inhibitors rivaroxaban and apixaban and the oral direct thrombin inhibitor dabigatran. These agents have undergone extensive phase 3 testing and are currently approved for various indications in the United States, Canada, or Europe. Rivaroxaban is approved in the United States for VTE prevention after major orthopedic surgery and for stroke prevention in atrial fibrillation and is approved in Europe and Canada for secondary prevention of VTE. Apixaban is currently under review by the US Food and Drug Administration for stroke prevention and is approved in Europe for VTE prevention following major orthopedic surgery. Dabigatran is approved in the United States for stroke prevention in nonvalvular atrial fibrillation and is being reviewed for secondary prevention of VTE.

The pathogenesis of chronic lung disorders is poorly understood but is often thought to arise because of repeated injuries derived from exposure to exogenous or endogenous stress factors. Protein-misfolding events have been observed in a variety of genetic and nongenetic chronic lung disorders and may contribute to both the initiation and the progression of lung disease through endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Evidence indicates that exposure to common lung irritants such as cigarette smoke, environmental pollutants, and infectious viral or bacterial agents can induce ER stress and protein misfolding. Although the UPR is thought to be a molecular mechanism involved in the repair and restoration of protein homeostasis or "proteostasis," prolonged activation of the UPR may lead to compromised cellular functions, cellular transformation, or cell death. Here, we review literature that associates protein-misfolding events with ER stress and UPR activation and discuss how this basic molecular repair mechanism may contribute to the initiation and progression of various genetic and nongenetic chronic lung diseases.

Two different regimens of enoxaparin (40 mg once daily or 30 mg bid) have been used as control arms in trials of new oral anticoagulants. The choice of enoxaparin comparator may influence the perceived relative efficacy and safety of the newer agents, and we aimed to identify any significant differences between the two enoxaparin regimens.

In this second part of a two-part series, we describe an algorithmic approach to the diagnosis of the solitary pulmonary nodule (SPN). An essential aspect of the evaluation of SPN is determining the pretest probability of malignancy, taking into account the significant medical history and social habits of the individual patient, as well as morphologic characteristics of the nodule. Because pretest probability plays an important role in determining the next step in the evaluation, we describe various methods the physician may use to make this determination. Subsequently, we outline a simple yet comprehensive algorithm for diagnosing a SPN, with distinct pathways for the solid and subsolid SPN.

The solitary pulmonary nodule (SPN) is frequently encountered on chest imaging and poses an important diagnostic challenge to clinicians. The differential diagnosis is broad, ranging from benign granulomata and infectious processes to malignancy. Important concepts in the evaluation of SPNs include the definition, morphologic characteristics via appropriate imaging modalities, and the calculation of pretest probability of malignancy. Morphologic differentiation of SPN into solid or subsolid types is important in the choice of follow-up and further management. In this first part of a two-part series, we describe the morphologic characteristics and various imaging modalities available to further characterize SPN. In Part 2, we will describe the determination of pretest probability of malignancy and an algorithmic approach to the diagnosis of SPN.

Interstitial lung disease (ILD) is one of the most serious pulmonary complications associated with connective tissue diseases (CTDs), resulting in significant morbidity and mortality. Although the various CTDs associated with ILD often are considered together because of their shared autoimmune nature, there are substantial differences in the clinical presentations and management of ILD in each specific CTD. This heterogeneity and the cross-disciplinary nature of care have complicated the conduct of prospective multicenter treatment trials and hindered our understanding of the development of ILD in patients with CTD. In this update, we present new information regarding the diagnosis and treatment of patients with ILD secondary to systemic sclerosis, rheumatoid arthritis, dermatomyositis and polymyositis, and Sjögren syndrome. We review information on risk factors for the development of ILD in the setting of CTD. Diagnostic criteria for CTD are presented as well as elements of the clinical evaluation that increase suspicion for CTD-ILD. We review the use of medications in the treatment of CTD-ILD. Although a large, randomized study has examined the impact of immunosuppressive therapy for ILD secondary to systemic sclerosis, additional studies are needed to determine optimal treatment strategies for each distinct form of CTD-ILD. Finally, we review new information regarding the subgroup of patients with ILD who meet some, but not all, diagnostic criteria for a CTD. A careful and systematic approach to diagnosis in patients with ILD may reveal an unrecognized CTD or evidence of autoimmunity in those previously believed to have idiopathic ILD.

It is now well established that cardiovascular disease contributes significantly to both morbidity and mortality in COPD. Shared risk factors for cardiovascular disease and COPD, such as smoking, low socioeconomic class, and a sedentary lifestyle contribute to the natural history of each of these conditions. However, it is now apparent that alternative, novel mechanisms are involved in the pathogenesis of cardiovascular disease, and these may play an important role in driving the increased cardiovascular risk associated with COPD. In this article, we discuss the potential mechanisms that link COPD to an increased risk of cardiovascular disease.

The objective of this study was to systematically review and quantitatively synthesize all randomized controlled trials (RCTs) that have compared important outcomes in critically ill patients who received an administration of probiotics.

The quality and potential impact of available clinical guidelines for asthma management have not been systematically evaluated. We, therefore, evaluated the quality of clinical practice guidelines (CPGs) for asthma.

The success of pulmonary rehabilitation (PR) is established, but how to sustain benefits over the long term is less clear. The aim of this systematic review was to determine the effect of supervised exercise programs after primary PR on exercise capacity and health-related quality of life (HRQL) in individuals with COPD.

The longitudinal associations between depression or anxiety and COPD, and their comorbid effect on prognosis, have not been adequately addressed by previous reviews. We aimed to systematically assess these associations to inform guidelines and practice.

Chronic insomnia (symptoms for ≥ 6 months) is the most common sleep disorder, affecting 6% to 10% of adults in the general population, with even higher rates in patients with comorbid conditions (eg, hypertension, 44%; cardiac disease, 44.1%; breathing problems, 41.5%). Traditionally, chronic insomnia occurring with another condition has been considered secondary and rarely received direct treatment because treatment of the primary condition was expected to improve the insomnia. However, this approach often failed because chronic insomnia is maintained by behaviors, cognitions, and associations that patients adopt as they attempt to cope with poor sleep but that end up backfiring (eg, increasing caffeine, spending more time in bed, trying harder to sleep). Cognitive behavioral treatment of insomnia (CBTi) targets those behaviors, cognitions, and associations and is effective across a variety of populations, including those with medical and psychologic comorbidities. Thus, in 2005, a National Institutes of Health expert consensus panel on chronic insomnia recommended dropping the term "secondary insomnia" in favor of the term "comorbid insomnia." Because CBTi does not carry the risks associated with some sleep medications (eg, dependency, polypharmacy, cognitive and psychomotor impairment), it is an attractive option for patients with other conditions. Through the Society of Behavioral Sleep Medicine (www.behavioralsleep.org) and the American Board of Sleep Medicine (www.absm.org), it is possible to find practitioners with expertise in CBTi (as well as other aspects of behavioral sleep medicine) and other behavioral sleep resources. Given the currently limited number of trained practitioners, exploration of alternative delivery methods (eg, briefer protocols, self-help, Internet) to improve access to this highly effective treatment and expanded training in these treatments are warranted.

Massive pulmonary emboli is a rare disease in children, with only 39 reported cases in the last 50 years. Almost 50% of the patients died suddenly without receiving medical treatment. Most of the patients who were managed medically (70% of the treated patients) underwent surgical pulmonary embolectomy with 80% survival. Surgical pulmonary embolectomy is a blind procedure that can be improved by using intraoperative angioscopy. This technique was reported in adults with good results. In this article, we describe two pediatric patients who underwent fiber-optic-guided surgical pulmonary embolectomy. To our knowledge, this technique has never been reported in the pediatric population.