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original research 
Shigeki Sawada, MD, PhD; Natsumi Yamashita, MD, PhD; Ryujiro Sugimoto, MD, PhD; Tsuyoshi Ueno, MD, PhD; Motohiro Yamashita, MD, PhD
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Background  The long-term outcomes of follow-up care for ground-glass opacity (GGO) need to be clarified.

Methods  Between 2000 and 2005, 226 patients with pure or mixed GGOs of 3 cm or smaller in size were registered. The CT findings and changes in the findings during the follow-up period and the outcomes of the 226 patients were subsequently reviewed.

Results  Overall, 124 patients underwent resections, 57 did not receive follow-up examinations after 68 months because of stable disease or disease reduction and 45 were continuing to receive follow-up examinations. Thirty-nine patients showed tumor growth during the follow-up period. Among the patients with a ratio of the diameter of consolidation relative to the tumor diameter (CTR) >0, all the cases with tumor growth were identified within 3 years; meanwhile, more than 3 years were required to identify tumor growth in 16% of the patients with a CTR =0. Aggressive cancer occurred in 4% of the patients with a CTR =0 and in 70% of the patients with a CTR >25%. Aggressive cancer was observed in 46% of the patients whose CTR increased during the follow-up period and in 8% of the patients whose tumors increased in size.

Conclusion  A higher CTR and an increase in the CTR during the follow-up were associated with invasive cancer. A follow-up period of 3 years is considered to be adequate for judging tumor growth in patients with a CTR >0, while a longer follow-up period might be needed for patients with a CTR =0.

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No abstract is available for this article
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No abstract is available for this article
editorial 
Harold J. Farber, MD, MSPH, FCCP
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No abstract is available for this article
original research 
Katherine O’Neill, PhD; Michael M. Tunney, PhD; Elinor Johnston, PhD; Stephen Rowan, PhD, MD; Damian G. Downey, MD; Jacqueline Rendall, MD; Alastair Reid, MD; Ian Bradbury, PhD; J. Stuart Elborn, PhD, MD; Judy. M. Bradley, PhD
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Background  Lung clearance index (LCI) has good clinimetric properties and an acceptable feasibility profile as a surrogate endpoint in Cystic Fibrosis (CF). Although most studies to date have been in children, increasing numbers of adults with CF also have normal spirometry. Further study of LCI as an endpoint in CF adults is required. Therefore, the purpose of this study was to determine the clinimetric properties of LCI over the complete age range of people with CF.

Methods  Clinically stable adults and children with CF and age matched healthy controls were recruited.

Results  LCI and spirometry data for 110 CF subjects and 61 controls were collected at a stable visit. CF Questionnaire-Revised (CFQ-R) was completed by 80/110 CF subjects. Fifty-six CF subjects completed a second stable visit. The LCI CV% was 4.1% in adults and 6.3% in children with CF. The coefficient of repeatability of LCI was 1.2 in adults and 1.3 in children. In both adults and children, LCI (AUCROC=0.93 and 0.84) had greater combined sensitivity and specificity to discriminate between people with CF and controls compared to FEV1 (AUCROC=0.88 and 0.60) and FEF25-75 (AUCROC=0.87 and 0.68). LCI correlated significantly with the CFQ-R treatment burden in adults (r=-0.37; p<0.01) and children (r=-0.50; p<0.01). Washout tests were successful in 90% of CF subjects and were perceived as comfortable and easy to perform in both adults and children.

Conclusions  These data support the use of LCI as a surrogate outcome measure in CF clinical trials in adults as well as children.

original research 
Danielle F. Wurzel, PhD; Julie M. Marchant, PhD; Stephanie T. Yerkovich, PhD; John W. Upham, PhD; Helen L. Petsky, PhD; Heidi Smith-Vaughan, PhD; Brent Masters, PhD; Helen Buntain, PhD; Anne B. Chang, PhD
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Background  Protracted bacterial bronchitis (PBB) and bronchiectasis are distinct diagnostic entities that share common clinical and laboratory features. It is postulated, but remains unproven, that PBB precedes a diagnosis of bronchiectasis in a subgroup of children. In a cohort of children with PBB, our objectives were to: (a) determine the medium-term risk of bronchiectasis and (b) identify risk factors for bronchiectasis and recurrent episodes of PBB.

Methods  161 children with PBB and 25 controls were prospectively recruited to this cohort study. A subset of 106 children was followed for 2 years. Flexible bronchoscopy, BAL and basic immune function tests were performed. CT chest was undertaken if clinical features were suggestive of bronchiectasis.

Results  Of 161 children with PBB (66% male), 13 (8.1%) were diagnosed with bronchiectasis over the study period. Almost half (43.5%) with PBB had recurrent episodes (>3/year). Major risk factors for bronchiectasis included: H. influenzae lower airway infection (in BAL) (p=0.013) and recurrent episodes of PBB (p=0.003). H. influenzae infection conferred >7 times higher risk of bronchiectasis [HR 7.55 (95%CI 1.66 - 34.28), p=0.009] compared to absence of H. influenzae. The majority of isolates (82%) were nontypeable H. influenzae. No risk factors for recurrent PBB were identified.

Conclusions  PBB is associated with a future diagnosis of bronchiectasis in a subgroup of children. H. influenzae lower airway infection and recurrent PBB are significant predictors. Clinicians should be cognisant of the relationship between PBB and bronchiectasis and appropriate follow-up measures should be taken in those with risk factors.

original research 
Anja Frei, PhD; Lara Siebeling, PhD; Callista Wolters, MD; Leonhard Held, Prof; Patrick Muggensturm, MD; Alexandra Strassmann, MSc; Marco Zoller, MD; Gerben ter Riet, PhD; Milo A. Puhan, Prof
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Background  COPD exacerbation incidence rates are often ascertained retrospectively, through patient recall and self-reports. We compared exacerbation ascertainment through patient self-reports and single physician chart review to central adjudication by a committee and explored determinants and consequences of misclassification.

Methods  Self-reported exacerbations (event-based definition) in 409 primary care COPD patients participating in the ICE COLD ERIC cohort were ascertained 6-monthly over 3 years. Exacerbations were adjudicated by single experienced physicians and an adjudication committee who had information from patient charts. We assessed the accuracy (sensitivities and specificities) of self-reports and single physician chart review against a central adjudication committee (reference standard). We used multinomial logistic regression and bootstrap stability analyses to explore determinants of misclassifications.

Results  The adjudication committee identified 648 exacerbations, corresponding with an incidence rate of 0.60±0.83 exacerbations/patient-year and a cumulative incidence proportion of 58.9%. Patients self-reported 841 exacerbations (incidence rate 0.75±1·01, incidence proportion 59.7%). Sensitivity/specificity of self-reports were 84%/76%, those of single physician chart review between 89-96% and 87-99%. The multinomial regression model and bootstrap selection showed that having experienced more exacerbations was the only factor consistently associated with under- and over-reporting of exacerbations (under-reporters: relative risk ratio 2.16, 95% CI 1.76-2.65; over-reporters: relative risk ratio 1.67, 95% CI 1.39-2.00).

Conclusions  Patient 6-month recall of exacerbation events are inaccurate. This may lead to inaccurate estimates of incidence measures and underestimation of treatment effects. The use of multiple data sources combined with event adjudication could substantially reduce sample size requirements and possibly cost of studies.

contemporary reviews in critical care medicine 
Eric L. Scholten, MD; Jeremy R. Beitler, MD, MPH; G. Kim Prisk, PhD, DSc; Atul Malhotra, MD
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Prone positioning was first proposed in the 1970s as a method to improve gas exchange in the acute respiratory distress syndrome (ARDS). Subsequent observations of dramatic improvement in oxygenation with simple patient rotation motivated the next several decades of research. This work elucidated the physiology mechanisms underlying changes in gas exchange and respiratory mechanics with prone ventilation. However, translating physiological improvements into a clinical benefit has proven challenging; several contemporary trials showed no major clinical benefits with proning. By optimizing patient selection and treatment protocols, the most recent Proning Severe ARDS Patients (PROSEVA) trial demonstrated a significant mortality benefit with prone ventilation. This trial, and subsequent meta-analyses, support the role of prone positioning as an effective therapy to reduce mortality in severe ARDS, particularly when applied early with other lung-protective strategies. This review discusses the physiological principles, clinical evidence, and practical application of prone ventilation in ARDS.

editorial 
Miles Weinberger, MD
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No abstract is available for this article
recent advances in chest medicine 
Edward M. Wolin, MD

Neuroendocrine tumors (NET) are a rare, heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. Despite increasing incidence, awareness of lung NET remains low among thoracic specialists who are often involved in assessment and early treatment for these patients. Successful treatment requires accurate and timely diagnosis; however, classification can be challenging, particularly for well-differentiated and intermediate-differentiated lung NET types (typical carcinoids [TC] and atypical carcinoids [AC]). Diagnosis and management of lung NET are further complicated by the nonspecificity of symptoms, variable natural history, and lack of high-level clinical evidence requiring a multidisciplinary approach, which has been shown to improve prognosis. Currently, surgery remains the only curative option for TC/AC. Inconsistencies between guideline recommendations for systemic therapies, especially radiation and chemotherapy, result in a lack of consensus on a standardized treatment for unresectable disease. Recent data from the phase 3 RADIANT-4 trial, which contained a large population of patients with advanced, well-differentiated, nonfunctional lung NET in addition to those with gastrointestinal NET, showed a reduced risk of disease progression and death with everolimus compared with placebo, leading to US approval of everolimus in these patient populations. This is the first high-level therapeutic evidence in patients with TC/AC, and everolimus is currently the only agent approved for TC/AC treatment. Increased awareness, prompt diagnosis, and additional adequately powered controlled clinical trials of patients with well-differentiated and intermediate-differentiated lung NET are needed to further improve evidence-based care.

recent advances in chest medicine 
Poushali Bhattacharjee, MD; Dana P. Edelson, MD, MS; Matthew M. Churpek, MD, MPH, PhD
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Sepsis contributes to up to half of all deaths in hospitalized patients, and early interventions, such as appropriate antibiotics, have been shown to improve outcomes. Most research has focused on early identification and treatment of septic patients in the emergency department and the intensive care unit; however, many patients develop sepsis on the general wards. The goal of this review is to discuss recent advances in sepsis detection in patients on the hospital wards. It will discuss data highlighting the benefits and limitations of the systemic inflammatory response syndrome (SIRS) criteria for screening septic patients, such as its low specificity, as well as newly described scoring systems, including the proposed role of the quick Sepsis-related Organ Failure Assessment (qSOFA) score. Challenges specific to detecting sepsis on the wards will be discussed, and future directions that utilize big data approaches and automated alert systems will be highlighted.

original research 
Barret Rush, MD; Paul Hertz, MD; Alexandra Bond, MD; Robert McDermid, MD; Leo Anthony Celi, MD MPH MS
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Objective  To investigate the use of palliative care (PC) in patients with end-stage chronic obstructive pulmonary disease (COPD) on home oxygen hospitalized for an exacerbation

Methods  Retrospective nationwide cohort analysis utilising the Nationwide Inpatient Sample (NIS). All patients >18 years of age with a diagnosis of COPD on home oxygen admitted for an exacerbation were included.

Results  55,208,382 hospitalizations from the 2006-2012 NIS samples were examined. There were 181,689 patients with COPD on home oxygen admitted for an exacerbation, 3,145 (1.7%) patients also had a palliative care contact. There was a 4.5-fold relative increase in PC referral from 2006 (0.45%) to 2012 (2.56%, p<0.01). Patients receiving palliative care consultations compared to those who did not were: older (75.0 years SD 10.9 vs 70.6 years SD 9.7, p<0.01), had longer hospitalizations (4.9 days IQR 2.6-8.2 vs 3.5 days IQR 2.1-5.6) and more likely to die in hospital (32.1% vs 1.5%, p<0.01). Race was significantly associated with referral to palliative care, with White patients referred more often than minorities (p<0.01). Factors associated with PC referral were: age (OR 1.03, 95% CI 1.02-1.04, p<0.01), metastatic cancer (OR 2.40, 95% CI 2.02-2.87, p<0.01), non-metastatic cancer (OR 2.75, 95% CI 2.43-3.11, p<0.01), invasive mechanical ventilation (OR 4.89, 95% CI 4.31-5.55, p<0.01), non-invasive mechanical ventilation (OR 2.84, 95% CI 2.58-3.12, p<0.01), and DNR status (OR 7.95, 95% CI 7.29-8.67, p<0.01).

Conclusions  The use of PC increased dramatically during the study period, however PC contact occurs only in a minority of end-stage COPD patients admitted with an exacerbation.

original research 
N. Gupta, MSc; L. Pinto, MD; A. Benedetti, PhD; P.Z. Li, MSc; W. Tan, MD; S. Aaron, MD; K.R. Chapman, MD; J.M. FitzGerald, MD; P. Hernandez, MD; D. Marciniuk, MD; F. Maltais, MD; D. O'Donnell, MD; D. Sin, MD; B. Walker, MD; J. Bourbeau, MD
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Background  The COPD Assessment Test (CAT) is a valid disease specific questionnaire measuring health status. However, knowledge concerning its use regarding patient and disease characteristics remains limited. Our main objective was to assess the degree to which the CAT score varies and can discriminate between specific patient population groups.

Methods  The Canadian Cohort Obstructive Lung Disease (CanCOLD) is a random-sampled population-based, multicenter prospective cohort that includes subjects with COPD: GOLD 1 to 3. The CAT questionnaire was administered at three visits (baseline, 1.5 and 3 years). The CAT total score was determined for sex, age groups, smoking status, GOLD classification, exacerbations and comorbidities.

Results  716 subjects with COPD were included in the analysis. The majority of subjects (72.5%) were not previously diagnosed with COPD. The mean FEV1/FVC ratio was 61.1 ± 8.1% with a mean FEV1 % predicted of 82.3 ± 19.3%. The mean CAT scores were 5.8 ± 5.0, 9.6 ± 6.7 and 16.1 ± 10.0 for GOLD 1, 2, and 3 and higher, respectively. Higher CAT scores were observed in women, current smokers, ever-smokers and in subjects with previous diagnosis of COPD. The CAT was also able to distinguish between subjects who experience exacerbations versus no-exacerbations.

Conclusions  These results suggest that the CAT, originally designed for use in clinically symptomatic COPD patients, can also be used in individuals with mild airflow obstruction and newly diagnosed COPD. In addition, the CAT was able to discriminate between genders and subjects who experience frequent and infrequent exacerbations.

original research 
Thomas S. Valley, MD, MSc; Michael W. Sjoding, MD, MSc; Zachary D. Goldberger, MD, MS; Colin R. Cooke, MD, MSc, MS
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Background  Quality of care for acute myocardial infarction (AMI) and heart failure (HF) varies across hospitals, but factors driving variation are incompletely understood. We evaluated the relationship between a hospital’s intensive care unit (ICU) or coronary care unit (CCU) admission rate and quality of care provided to patients with AMI or HF.

Methods  A retrospective cohort study of Medicare beneficiaries hospitalized in 2010 with AMI or HF was performed. Hospitals were grouped into quintiles by their risk- and reliability-adjusted ICU admission rates for AMI or HF. We examined the rates that hospitals failed to deliver standard AMI or HF processes of care (process measure failure rates), 30-day mortality, 30-day readmissions, and Medicare spending after adjusting for patient and hospital characteristics.

Results  Hospitals in the lowest quintile had ICU admission rates < 29% for AMI or < 8% for HF. Hospitals in the top quintile had rates > 61% for AMI or > 24% for HF. Hospitals in the highest quintile had higher process measure failure rates for some but not all process measures. Hospitals in the top quintile had greater 30-day mortality (14.8% vs. 14.0%, p=0.002 for AMI; 11.4% vs. 10.6%, p<0.001 for HF), but no differences in 30-day readmissions or Medicare spending when compared to hospitals in the lowest quintile.

Conclusions  Hospitals with the highest rates of ICU admission for patients with AMI or HF delivered lower quality of care and had higher 30-day mortality for these conditions. High ICU use hospitals may be targets to improve care delivery.

ahead of the curve 
Xianglan Yao, M.D., Ph.D.; Elizabeth M. Gordon, Ph.D.; Amisha V. Barochia, M.B.B.S.; Alan T. Remaley, M.D., Ph.D.; Stewart J. Levine, M.D.
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New treatments are needed for asthmatics who are refractory to standard therapies, such as individuals with a phenotype of “type 2 low” inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. Apolipoprotein A-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent HDL particles. The ability of the apoA-I/ABCA1 pathway to efflux cholesterol from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have demonstrated that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in asthmatics. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for severe asthmatics who are unresponsive to other therapies.

original research 
Sameer S. Kadri, MD, MS; Andrew C. Miller, MD; Samuel Hohmann, PhD; Stephanie Bonne, MD; Carrie Nielsen, MA; Carmen Wells, RN; Courtney Gruver, RN; Sadeq A. Quraishi, MD, MHA, MMSc; Junfeng Sun, PhD; Rongman Cai, PhD; Peter E. Morris, MD; Bradley D. Freeman, MD; James H. Holmes, MD; Bruce A. Cairns, MD; Anthony F. Suffredini, MD
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Background  Mortality after smoke inhalation-associated acute lung injury (SI-ALI) remains substantial. Age and burn surface area are risk factors of mortality, while the impact of patient and center-level variables and treatments on survival are unknown.

Methods  We performed a retrospective cohort study of burn and non-burn centers at 68 United States academic medical centers from 2011-2014. Adult SI-ALI inpatients were identified using an algorithm based on a billing code for respiratory conditions from smoke inhalation who were mechanically ventilated by hospital day 4, with either a length-of-stay ≥ 5-days or death within 4 days of hospitalization. Predictors of in-hospital mortality were identified using logistic regression. The primary outcome was the odds ratio for in-hospital mortality.

Results  769 patients (52.9 ± 18.1 years) with SI-ALI were analyzed. In-hospital mortality was 26% in the SI-ALI cohort and 50% in patients with ≥20% surface burns. In addition to age > 60 years (OR 5.1, 95%CI 2.53-10.26) and ≥20% burns (OR 8.7, 95%CI 4.55-16.75), additional risk factors of in-hospital mortality included initial vasopressor use (OR 5.0, 95%CI 3.16-7.91), higher DRG-based risk-of-mortality assignment and lower hospital bed capacity (OR 2.3, 95%CI 1.23-4.15). Initial empiric antibiotics (OR 0.93, 95%CI 0.58-1.49) did not impact survival. These new risk factors improved mortality prediction (ΔAUC) by 9.9%(p<0.001).

Conclusions  In addition to older age and major surface burns, mortality in SI-ALI is predicted by initial vasopressor use, higher DRG-based risk-of-mortality assignment and care at centers with <500 beds, but not by initial antibiotic therapy.

translating basic research in clinical practice 
Greer Arthur, PhD; Peter Bradding, DM, FRCP
No abstract is available for this article
original research 
Alejandro A. Diaz, MD, M.PH; Hans Petersen, MS; Paula Meek, PhD, RN; Akshay Sood, MD, MPH, FCCP; Bartolome Celli, MD, FCCP; Yohannes Tesfaigzi, PhD
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Introduction  Smoking is associated with impaired health-related quality of life (HRQL) across all populations. Because decline in lung function and risk for COPD are lower in New Mexican Hispanic smokers compared to their non-Hispanic White (NHW) counterparts, we investigated whether HRQL differs between these two racial-ethnic groups and determined the factors that contribute to this difference.

Methods  We compared the score results of the Medical Outcomes Short-Form 36 Health Survey (SF-36) and St George’s Respiratory Questionnaire (SGRQ) in 378 Hispanics and 1,597 non-Hispanic whites (NHW) enrolled into the Lovelace Smokers’ Cohort (LSC) from New Mexico. The associations of race-ethnicity with SGRQ and SF-36 were assessed using multivariable regression.

Results  Physical functioning (difference -4.5, P=0.0008) but not mental health or role emotional domains of the SF-36 was worse in Hispanic smokers than their NWH counterparts in multivariable analysis. SGRQ total score and activity and impact subscores were worse in Hispanic (vs. NHW) smokers after adjustment for education level, current smoking, pack-years smoked, body mass index, number of comorbidities, and forced expiratory volume in one second % predicted (difference range, 2.9 to 5.0, all comparisons P≤0.001). While the difference in the SGRQ activity domain was above the clinically important difference of 4 units, the total score was not.

Conclusion  New Mexican Hispanic smokers have clinically relevant lower HRQL than their NHW counterparts. A perception of diminished physical functioning and impairment in daily-life activities contribute to the poorer HRQL among Hispanics.

original research 
Martha E. Billings, MD, MSc; Dayna Johnson, PhD, MPH, MS; Guido Simonelli, MD; Kari Moore, MS; Sanjay R. Patel, MD, MS; Ana V. Diez Roux, MD, PhD; Susan Redline, MD, MPH
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Background  There has been growing interest in understanding how neighborhoods may relate to cardiovascular risk. Neighborhood effects on sleep apnea may be one contributing mechanism. We investigated whether neighborhood walking environment and personal activity levels are related to obstructive sleep apnea.

Methods  We analyzed data from a subpopulation of the Multi-Ethnic Study of Atherosclerosis (MESA), including subjects who participated in both MESA Sleep and Neighborhood studies (n=1,896). Perceived neighborhood walking environment and subjects’ objective activity were evaluated in multivariate, multi-level models for an association with sleep apnea severity as defined by the apnea hypopnea index. Sex, race/ethnicity and obesity were examined as moderators.

Results  Residing in the lowest quartile walking environment neighborhoods (score <3.75) was associated with more severe sleep apnea [mean 2.7 events/hr greater AHI, 95% CI (0.7, 4.6)], after adjusting for demographics, body mass index, co-morbidities, health behaviors, neighborhood socio-economic status and site. Associations were stronger among obese and male individuals. Approximately one standard deviation greater objective activity in men, was associated with a lower AHI [mean -2.4 95% CI (-3.5, -1.3) events/hr]. This association was partially mediated by body mass index (P<0.001).

Conclusions  Living in neighborhoods with a low walking environment score is associated with greater sleep apnea severity, especially in male and obese individuals. In men, greater activity level is associated with less severe sleep apnea, independent of body mass index, co-morbidities and socio-economics. Neighborhood-level interventions that increase walkability and enable increased physical activity may potentially reduce sleep apnea severity.

recent advances in chest medicine 
Hossein-Ardeschir Ghofrani, MD; Marc Humbert, MD; David Langleben, MD; Ralph Schermuly, MD; Johannes-Peter Stasch, PhD; Martin R. Wilkins, MD; James R. Klinger, MD
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Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure and increased pulmonary vascular resistance. If untreated, they can result in death due to right heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. Here we describe in detail the role of the nitric oxide–sGC–cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH, and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and the pivotal Phase III randomized clinical trials in PAH and CTEPH.

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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543