CHEST publishes select peer-reviewed, accepted manuscripts Online First each week. The media embargo is lifted on the date of Online First publication. Final, edited versions will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication.

original research 
Souheil El-Chemaly, MD; Angelo Taveira-Dasilva, MD; Hilary J. Goldberg, MD; Elizabeth Peters, RN; Mary Haughey, RN; Don Bienfang, MD; Amanda M. Jones, RN; Patricia Julien-Williams, RN; Ye Cui, PhD; Julian A. Villalba, MD; Shefali Bagwe, MBBS; Rie Maurer, PhD; Ivan O. Rosas, MD; Joel Moss, MD; Elizabeth P. Henske, MD
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Background  Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxycholoroquine (an autophagy inhibitor) at 2 different dose levels is safe and well tolerated. Secondary endpoints included changes in lung function.

Methods  This 48-week, two-center Phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100–200 mg) given twice a day in combination with sirolimus to eligible patients ≥18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase off study drugs for an additional 24 weeks.

Results  Fourteen patients provided written, informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400 mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary endpoints showed improvement in lung function at 24 weeks, with decrease in lung function at the 48 week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV1 and FVC remained stable at 48 weeks, but the 6 minute walk distance showed a decrease towards baseline.

Conclusions  The combination of sirolimus and hydroxychloroquine is well tolerated with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials.

original research 
Claudia Mannini, M.D.; Federico Lavorini, M.D; Alessandro Zanasi, M.D; Federico Saibene, M.D; Luigi Lanata, M.D; Giovanni Fontana, M.D
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Background  Cough is produced by the same neuronal pool implicated in respiratory rhythm generation and antitussive drugs acting at the central level, such as the opioids, may depress ventilation. Levodropropizine is classified as a non-opioid, peripherally-acting antitussive drug acting at the level of airway sensory nerves. However, the lack of a central action by Levodropropizine remains to be fully established. We set out to compare the effects of Levodropropizine and the opioid antitussive agent Dihydrocodeine on the respiratory responses to a conventional CO2 re-breathing test in patients with chronic cough of any origin.

Methods  Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg Levodropropizine, or 15 mg Dihydrocodeine or matching placebo. Subsequently, patients breathed, for 5 min, a mixture of 93% oxygen and 7% CO2. Fractional end-tidal CO2 (FETCO2) and inspiratory minute ventilation (VI) were continuously monitored. Changes in breathing pattern variables were also assessed.

Results  At variance with Dihydrocodeine, Levodropropizine and placebo did not affect respiratory responses to hypercapnia (P<0.01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern.

Conclusion  The results are consistent with a peripheral action by Levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussives.

original research 
A.J.N. Raymakers, MSc; M. Sadatsafavi, PhD; D.D. Sin, MD; M.A. De Vera, PhD; L.D. Lynd, PhD
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Background  Patients with chronic obstructive disease (COPD) are often prescribed statins due to the increased prevalence of cardiovascular disease (CVD). There is considerable debate about the benefits conferred by statins in patients with COPD. This study evaluates the association of statin use with all-cause and pulmonary-related mortality in COPD patients.

Methods  This study uses population-based administrative data for the province of British Columbia, Canada. A cohort of COPD patients was identified based on individual patients’ prescription records. Statin exposure was ascertained in the 1-year period after COPD ‘diagnosis’. The primary and secondary outcomes, all-cause and pulmonary-related mortality, respectively, were evaluated in the 1-year period thereafter using multivariate Cox proportional hazards models and several definitions of medication exposure.

Results  There were 39,678 COPD patients that met the study inclusion criteria. Of these, 7,775 (19.6%) had received at least one statin dispensed in the exposure ascertainment window. There were 1446 all-cause deaths recorded within the cohort in the 1-year period after exposure ascertainment. In multivariate analysis, the estimated hazard ratio for statin exposure was 0.79 (95% CI: 0.67-0.92, p=0.0016) suggesting a 21% reduction in the risk from statin use on all-cause mortality. For pulmonary-related mortality, there was also a considerable reduction in the risk all-cause mortality from statin use (HR: 0.55, 95: CI: 0.32-0.93, p=0.02454). These results were robust to different specifications of the exposure ascertainment window.

Conclusions  This study shows that statin use in a population-based cohort of COPD patients may confer benefits in terms of reduced pulmonary-related and all-cause mortality.

contemporary reviews in sleep medicine 
Simon A. Joosten, MBBS, PhD; Garun S. Hamilton, MBBS, PhD; Matthew T. Naughton, MD

The interaction between obesity and obstructive sleep apnea (OSA) is complex. Whilst it is often assumed that obesity is the major cause of OSA, and that treatment of the OSA might mitigate further weight gain, new evidence is emerging that suggest these statements may not be the case. Obesity explains about 60% of the variance of the apnea hypopnea index definition of OSA, mainly in those < 50 years and less so in the elderly. Moreover, long term treatment of OSA with continuous positive airway pressure is associated with small but significant weight gain. This weight gain effect may result from abolition of the increased work of breathing associated with OSA. Weight loss, by either medical or surgical techniques, which often cures type 2 diabetes, has a beneficial effect upon sleep apnoea unfortunately in a minority of patients. A short jaw length may be predictive of a better outcome. The slight fall in the overall apnea hypopnea index with weight loss, however may be associated with a larger drop in the non-supine apnea hypopnea index, thus converting some patients from non-positional to positional (ie supine only) OSA. Importantly, patients undergoing surgical weight loss need close monitoring to prevent complications. Finally, in patients with moderate to severe obesity related OSA, the combination of weight loss with CPAP appears more beneficial than either treatment in isolation.

original research 
Eric Kuhn, MD; Esther I. Schwarz, MD; Daniel J. Bratton, PhD; Valentina A. Rossi, MD; Malcolm Kohler, MD
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Background  Untreated obstructive sleep apnea (OSA) is associated with impaired health-related quality of life (QoL) and excessive daytime sleepiness which have been shown to improve with treatment. The aim was to compare the effects of continuous positive airway pressure (CPAP) and mandibular advancement devices (MAD) on health-related QoL in OSA.

Methods  MEDLINE and Cochrane Library were searched up to November 2015. Randomized controlled trials (RCTs) comparing the effect of CPAP, MADs or an inactive control on health-related QoL assessed by the 36-item short form (SF-36) in OSA. Extraction of study characteristics, quality and bias assessment were independently performed by three authors. A network meta-analysis using multivariate random-effects meta-regression was performed to assess treatment effects on the mental (MCS) and physical (PCS) component summary scores of the SF-36.

Results  Of 1491 identified studies, 23 RCTs were included in the meta-analysis (2342 patients). Compared with an inactive control, CPAP was associated with a 1.7 point (95%CI 0.1-3.2, p=0.036) improvement in the MCS and a 1.7 point (95%CI 0.5-2.9, p=0.005) improvement in the PCS. MAD was associated with a 2.4 points (95%CI 0.0-4.9, p=0.053) and a 1.5 point (95%CI -0.2-3.2, p=0.076) improvement in the MCS and PCS, respectively, compared to inactive controls. There were no statistically significant differences in treatment effects on the SF-36 scores between CPAP and MAD.

Conclusions  CPAP is effective in improving health-related quality of life in OSA, and MADs may be just as effective but further RCTs comparing the two treatments are required.

translating basic research into clinical practice 
Brittany M. Salter, PhD; Roma Sehmi, PhD

Airway eosinophilia is a hallmark of allergic asthma and understanding mechanisms that promote increases in lung eosinophil numbers is important for effective pharmaco-therapeutic development. It has become evident that expansion of hemopoietic compartments in the bone marrow promotes differentiation and trafficking of mature eosinophils to the airways. Hematopoietic progenitor cells egress the bone marrow and home to the lungs, where in-situ differentiative processes within the tissue provide an ongoing source of pro-inflammatory cells. In addition, hematopoietic progenitor cells in the airways can respond to locally-derived alarmins, to produce a panoply of cytokines thereby themselves acting as effector pro-inflammatory cells that potentiate type 2 responses in eosinophilic asthma. In this review, we will provide evidence for these findings and discuss novel targets for modulating eosinophilopoietic processes, migration and effector function of precursor cells.

evidence-based medicine  FREE TO VIEW
John J. Mullon, M.D.; Kristin M. Burkart, M.D., M.Sc.; Gerard Silvestri, M.D.; D. Kyle Hogarth, M.D.; Francisco Almeida, M.D.; David Berkowitz, M.D.; George Eapen, M.D.; David Feller-Kopman, M.D.; Henry E. Fessler, MD; Erik Folch, M.D.; Colin Gillespie, M.D.; Andrew Haas, M.D.; Shaheen Islam, M.D.; Carla Lamb, M.D.; Stephanie M. Levine, M.D.; Adnan Majid, M.D.; Fabien Maldonado, M.D.; Ali Musani, M.D.; Craig Piquette, MD; Cynthia Ray, M.D.; Chakravarthy Reddy, M.D.; Otis Rickman, D.O.; Michael Simoff, M.D.; Momen M. Wahidi, M.D., M.B.A.; Hans Lee, M.D.
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Interventional Pulmonology (IP) is a rapidly evolving subspecialty of pulmonary medicine. In the last ten years formal IP fellowships have increased substantially in number from just five to now over thirty. The vast majority of IP fellowship trainees are selected through the National Residency Matching Program, and validated in-service and certification exams for IP exist. Practice standards and training guidelines for IP fellowship programs have been published, however considerable variability in the environment, curriculum, and experience offered by the various fellowship programs still exists and there is currently no formal accreditation process in place to standardize IP fellowship training. Recognizing the need for more uniform training across the various fellowship programs, a multi-society accreditation committee was formed with the intent to establish common accreditation standards for all IP fellowship programs in the United States. This article provides a summary of those standards and can serve as an accreditation template for training programs and their offices of graduate medical education as they move through the accreditation process.

evidence-based medicine  FREE TO VIEW
Anne B. Chang, FRACP, PhD; John J. Oppenheimer, MD; Miles Weinberger, MD, FCCP; Bruce K. Rubin, MD, FRCPC; Cameron C. Grant, FRACP, PhD; Kelly Weir, PhD; Richard S. Irwin, MD, Master FCCP
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Background  Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews relating to the management of chronic wet cough in children (aged ≤14-years) based on key questions (KQ1)-how effective are antibiotics in improving the resolution of cough? If so, what and for how long? and; (KQ2)-when should children be referred for further investigations?

Methods  We used the CHEST expert cough panel’s protocol for the systematic reviews and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients’ values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made.

Results  Combining data from the systematic reviews, we found high quality evidence in children aged ≤14-years with chronic (>4-weeks duration) wet/productive cough that using appropriate antibiotics improves cough resolution and; further investigations (e.g. flexible bronchoscopy, chest CTs and immunity tests) should be undertaken when specific cough pointers (e.g. digital clubbing) are present. When the wet cough does not improve following 4-weeks of antibiotics there is moderate quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis.

Conclusion  Compared to the 2006 Cough Guidelines, there is now high quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies particularly in primary health are required.

contemporary reviews in sleep medicine 
Sogol Javaheri, MD, MPH; Susan Redline, MD, MPH
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Insomnia is the most prevalent sleep disorder in the United States and is highly comorbid with a number of cardiovascular diseases. In the last decade a number of observational studies have demonstrated an association between insomnia and incident cardiovascular disease (CVD) morbidity and mortality, including hypertension, coronary heart disease, and heart failure. Despite some inconsistencies in the literature, likely due to variation in how insomnia is defined and measured, the existing data suggest that insomnia, especially when accompanied by short sleep duration, is associated with increased risk for hypertension, coronary heart disease and recurrent acute coronary syndrome, and heart failure. Purported mechanisms likely relate to dysregulation of the hypothalamic pituitary axis, increased sympathetic nervous system activity, and increased inflammation. This paper reviews the most recent studies of insomnia and CVD, the potential pathophysiologic mechanisms underlying this relationship, and highlights the need for randomized trials to further elucidate the nature of the relationship between insomnia and CVD.

evidence-based medicine  FREE TO VIEW
Alex Molassiotis, RN, PhD; Jaclyn A. Smith, MBChB, MRCP, PhD; Peter Mazzone, MD, MPH; Fiona Blackhall, FRCP, PhD; Richard S. Irwin, MD, Master FCCP
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Background  Cough among patients with lung cancer is a common but often undertreated symptom. We have used a recent Cochrane systematic review, among other sources of evidence, to update the recommendations and suggestions of the CHEST 2006 guideline on this topic.

Methods  The American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on data from the Cochrane systematic review on the topic, uncontrolled studies, case studies, and the clinical context. Final grading was reached by consensus according to Delphi methodology.

Results  The Cochrane systematic review identified 17 trials of primarily low quality evidence. Such evidence was related to both non-pharmacological (cough suppression) and pharmacological treatments (demulcents, opioids, peripherally-acting antitussives or local anesthetics) as well as endobronchial brachytherapy.

Conclusions  Compared with the 2006 CHEST Cough Guidelines, the current recommendations and suggestions are more specific and follow a step-up approach to the management of cough among patients with lung cancer, acknowledging the low quality evidence in the field and the urgent need to develop more effective, evidence-based interventions through high quality research.

original research 
Piergiuseppe Agostoni, MD, PhD; Carlo Vignati, MD; Piero Gentile, MD; Costanza Boiti, MD; Stefania Farina, MD; Elisabetta Salvioni, PhD; Massimo Mapelli, MD; Damiano Magrì, MD, PhD; Stefania Paolillo, MD; Nicoletta Corrieri, MD; Gianfranco Sinagra, MD; Gaia Cattadori, MD
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Aims  Cardiac output (Q) is a key parameter in the assessment of cardiac function, its measurement being crucial for the diagnosis, treatment and prognostic evaluation of all heart diseases. Until recently, Q determination at peak exercise has been possible through invasive methods, so that normal values were obtained in studies based on small populations.

Methods and Results  Nowadays, peak Q can be measured noninvasively by means of inert gas rebreathing technique (IGR). The present study was undertaken to provide reference values for peak Q in the normal general population and to obtain a formula able to estimate peak exercise Q from measured peak oxygen uptake (VO2).We studied 500 normal subjects (age 44.9±1.5 years, range 18-77, 260 males, 240 females) who underwent a maximal cardiopulmonary exercise test with peak Q measurement by IGR.In the overall study sample, peak Q was 13.2±3.5 L/min (males: 15.3±3.3 L/min; females: 11.0±2.0 L/min, p<0.001) and peak VO2 was 95±18% of the maximum predicted value (male: 95± 19%; female: 95±18%). Peak VO2 and peak Q progressively decreased with age (R2: 0.082, p<0.001 and R2: 0.144, p< 0.001, respectively). The VO2-derived formula to measure Q at peak exercise was (4.4 x peak VO2) + 4.3 in the overall study cohort, (4.3 x peak VO2) + 4.5 in males and (4.9 x peak VO2) + 3.6 in females.

Conclusions  The simultaneous measurement of Q and VO2 at peak exercise in a large sample of healthy subjects provided an equation to predict peak Q from peak VO2 values.

original research 
Peter Hou, MD; Michael Filbin, MD; Henry Wang, MD; Long Ngo, PhD; David T. Huang, MD; William C. Aird, MD; Donald M. Yealy, MD; Derek C. Angus, MD MPH; John A. Kellum, MD; Nathan I. Shapiro, MD MPH
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Background  We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine: the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis, and; the association between biomarkers and mortality.

Methods  Prospective study of biomarkers of endothelial cell permeability (vegf, sflt-1, ang-2) and hemostasis (vwf, thrombomodulin, tpa) in 605 of the 1341 ProCESS participants in a derivation cohort and 305 in validation. Analyses assess: 1) impact of varying resuscitation strategies on biomarker profiles; and, 2) association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 United States EDs in adult septic shock patients. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, 6, and 24 hours.

Results  There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and SFLT-1) and hemostasis (vwf, thrombomodulin, tpa) biomarkers were higher and VEGF levels were lower in non-survivors (P<0.05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation AUC=0.74; validation=0.70), similar to lactate (AUC=0.74) and SOFA score (AUC=0.73). In an analysis including all time points and adjusted for age, cancer, and Charlson, sFLT-1 adjusted AUC was 0.80.

Conclusions  We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did identify that elevated levels of Endothelial Cell biomarkers of permeability and hemostasis were associated with increased mortality.

original research 
Nichole T. Tanner; Alexander Porter; Michael Gould; Xiao-Jun Li; Anil Vachani; Gerard A. Silvestri
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Background  The annual incidence of pulmonary nodules is estimated at 1.57 million. Guidelines recommend utilizing an initial assessment of nodule probability for malignancy (pCA). A previous study found that despite this recommendation, physicians did not follow guidelines.

Methods  Physician (n= 337) and two previously validated risk model assessment of cancer pre-test probability were evaluated for performance in 337 patients with pulmonary nodules based on final diagnosis and compared. Physician assessed pCA was categorized into low, intermediate and high risk and the next test ordered was evaluated.

Results  The prevalence of malignancy was 47% (n=158) at one year. Physician assessed pCA performed better than nodule prediction calculators (AUC 0.85 vs 0.75, p<0.001 and 0.78, p=0.0001). Physicians did not follow indicated guidelines when selecting the next test in 61% of cases (n=205). Despite recommendations for serial CT imaging in those with low pCA, 52%(n=13) were managed more aggressively with PET imaging or biopsy; 12%(n=3) had biopsy for benign disease. Alternatively, in the high risk category, the majority (n=103, 75%) were managed more conservatively. Stratified by diagnosis, 92% (n=22) with benign disease underwent more conservative management with CT scan (20%), PET scan(15%), or biopsy(8%) though 3(8%) had surgery.

Conclusions  Physician assessment as a means for predicting malignancy in pulmonary nodules is more accurate than previously validated nodule prediction calculators. Despite the accuracy of clinical intuition, physicians did not follow guideline based recommendations when selecting the next diagnostic test. To provide optimal patient care, focus in the areas of guideline refinement, implementation and dissemination is needed.

original research 
Kathleen J. Ramos, MD; Bradley S. Quon, MD, MSc, MBA; Sonya L. Heltshe, PhD; Nicole Mayer-Hamblett, PhD; Erika D. Lease, MD; Moira L. Aitken, MD; Noel S. Weiss, MD, DrPH; Christopher H. Goss, MD, MSc, FCCP
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Background  Lung transplantation (LTx) is frequently considered for patients with cystic fibrosis (CF) when FEV1 reaches <30%. This study estimated transplant-free survival for CF patients and FEV1 <30% and identified predictors of death without LTx.

Methods  We conducted a retrospective cohort study using the CF Foundation Patient Registry, 1/1/2003-12/31/2013. Adult patients (≥18 years) with FEV1 <30% prior to LTx were included. We performed Kaplan-Meier survival estimates censored at LTx. Multivariable Cox proportional hazard regression identified predictors of mortality.

Results  There were 3,340 patients with FEV1 <30%. Death without LTx occurred in 1,250 (37.4%); 951 (28.5%) underwent LTx; 918 (27.5%) remained alive without LTx at the end of follow-up; 221 (6.6%) were lost to follow-up. Median transplant-free survival after FEV1 <30% was 6.6 years (95% CI 5.9-7.0). Adjusted predictors of death without LTx included (HR, 95% CI): supplemental oxygen use (2.1, 1.7-2.6), B. cepacia infection (1.8, 1.3-2.6), BMI ≤18 (1.6, 1.3-1.9), female sex (1.6, 1.2-2.0), CF-related diabetes on insulin (1.4, 1.2-1.8), and ≥1 exacerbations per year (1.7, 1.3-2.2; vs. 0 exacerbations).

Conclusions  Median survival is over 6.5 years for CF patients with FEV1 <30%, exceeding prior survival estimates. There is substantial heterogeneity in survival, with some CF patients dying soon after reaching this lung function threshold and others living for many years. For this reason, we conclude that FEV1 <30% remains an important marker of disease severity for CF patients. Patients with a supplemental oxygen requirement or frequent exacerbations should have prompt referral because of their increased risk of death.

original research 
Rafael Mesquita, MSc, PT; Nienke Nakken, MSc; Daisy J.A. Janssen, MD, PhD; Esther H.A. van den Bogaart, MSc; Jeannet M.L. Delbressine, BSc; Johannes M.N. Essers, MSc; Kenneth Meijer, PhD; Monique van Vliet, MD; Geeuwke J. de Vries, MD, PhD; Jean W.M. Muris, MD, PhD; Fabio Pitta, PhD, PT; Emiel F.M. Wouters, MD, PhD, FERS; Martijn A. Spruit, PhD, PT, FERS
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Background  Resident loved ones of patients with COPD can play an important role in helping patients to engage in physical activity. We aimed to compare activity levels and exercise motivation between COPD patients and their resident loved ones; to compare the same outcome measures in patients after stratification for the physical activity level of the loved ones; and to predict the likelihood of being physically active in patients with a physically active resident loved one.

Methods  125 patient-loved one dyads were cross-sectionally and simultaneously assessed. Sedentary behaviour, light activities and moderate-to-vigorous physical activity (MVPA) were measured with a triaxial accelerometer during free-living conditions for at least 5 days. Five exercise motivation constructs were investigated: amotivation, external regulation, introjected regulation, identified regulation, and intrinsic regulation.

Results  Patients spent more time in sedentary behaviour and less time in physical activity than their loved ones (P<0.0001). More intrinsic regulation was observed in loved ones compared to patients (P=0.003), with no differences in other constructs. Despite similar exercise motivation, patients with an active loved one spent more time in MVPA (mean (95% CI) 31 (24, 38) vs 18 (14, 22) min·day-1; P=0.002) and had a higher likelihood of being active (OR (95% CI) 4.36 (1.41, 13.30); P=0.01) than patients with an inactive loved one after controlling for age, body mass index and degree of airflow limitation.

Conclusions  COPD patients are more physically inactive and sedentary than their loved ones, despite relatively similar exercise motivation. Nevertheless, patients with an active loved one are more active themselves and have a higher likelihood of being active.

original research 
Anthony De Soyza; Melissa J. McDonnell, MD; Pieter C. Goeminne, MD, PhD; Stefano Aliberti, MD, PhD; Sara Lonni, MD; John Davison, RN; Lieven J. Dupont, MD, PhD; Thomas C. Fardon, MD; Robert M. Rutherford, MD; Adam T. Hill, MD; James D. Chalmers, MD PhD
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Introduction  We studied if Bronchiectasis (BR) and Rheumatoid arthritis (RA) when manifesting as an overlap syndrome (BROS) was associated with worse outcomes than other BR aetiologies applying the Bronchiectasis Severity Index (BSI).

Methods  We interrogated the Bronchiectasis Severity Index (BSI) databases of 1716 patients across 6 centres: Edinburgh, UK (608 patients), Dundee, UK (N=286), Leuven, Belgium (N=253), Monza, Italy (N=201), Galway Ireland (N=242) and Newcastle, UK (N=126). Patients were categorised as BROS (those with RA and Bronchiectasis without interstitial lung disease), idiopathic bronchiectasis, Bronchiectasis-COPD overlap syndrome (BCOS) and “other” BR aetiologies. Mortality rates, hospitalisation and exacerbation frequency were recorded.

Results  We identified 147 patients with BROS (8.5% of cohort). There was a statistically significant relationship between BROS and mortality although this was not associated with higher rates of bronchiectasis exacerbations or bronchiectasis-related hospitalisations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with “other” causes of BR, 18% for RA and 28.5% for BCOS. Mortality was statistically higher in BROS and BCOS compared with all other aetiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS when compared to idiopathic BR (BSI mean 7.7 vs. 7.1 respectively, p <0.05). BCOS had significantly higher BSI scores (mean 10.4), Pseudomonas aeruginosa colonization rates (24%) and prior hospitalisation rates (58%).

Conclusions  Both BROS and BCOS groups have an excess of mortality -the mechanisms for this may be complex but these data highlight that these subgroups require additional study to understand this excess mortality.

evidence-based medicine  FREE TO VIEW
Anne B. Chang, FRACP, PhD; John J. Oppenheimer, MD; Miles M. Weinberger, MD, FCCP; Bruce K. Rubin, FRCPC, MD; Kelly Weir, PhD; Cameron C. Grant, FRACP, PhD; Richard S. Irwin, MD, Master FCCP

Background  Using management algorithms or pathways potentially improves clinical outcomes. We undertook systematic reviews to examine various aspects in the generic approach (use of cough algorithms and tests) to the management of chronic cough in children (aged ≤14-years) based on key questions using the PICO format.

Methods  We used the CHEST expert cough panel’s protocol for the systematic reviews and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients’ values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain the final grading.

Results  Combining data from systematic reviews addressing 5 key questions, we found high quality evidence that a systematic approach to the management of chronic cough improves clinical outcomes. While there was evidence from several pathways, the highest evidence was from the use of the CHEST approach. However, there was no or little evidence to address some of the key questions posed.

Conclusion  Compared to the 2006 Cough Guidelines, there is now high quality evidence that in children aged ≤14 years with chronic cough (>4 weeks duration); the use of cough management protocols (or algorithms) improves clinical outcomes and; cough management or testing algorithm should differ depending on the associated characteristics of the cough and clinical history. A chest radiograph and, when age appropriate, spirometry (pre and post β2 agonist) should be undertaken. Other tests should not be routinely performed and undertaken in accordance to the clinical setting and the child’s clinical symptoms and signs (e.g. tests for tuberculosis when child has been exposed).

original research 
James D. Mancuso, M.D., Dr.P.H.; Rupal M. Mody, M.D.; Cara H. Olsen, Dr.P.H.; Lee H. Harrison, M.D.; Mathuram Santosham, M.D.; Naomi E. Aronson, M.D.
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Background  Bacille Calmette-Guérin vaccination (BCG) is known to cause false positive tuberculin skin test (TST) results from cross-reactions to mycobacterial antigens. However, the duration of BCG influence on the TST is poorly characterized. The objective of the study was to assess the long-term effect of BCG vaccination on TST reactivity.

Methods  Data on TST reactivity were prospectively collected during 1935-47 as part of a clinical trial among American Indians / Alaskan Natives and retrospectively thereafter between 1948 and 1998. TST induration of > 10 millimeters was defined as positive. Kaplan-Meier and multivariate Cox regression were used to compare the time to TST conversion and reversion between the BCG and placebo groups.

Results  BCG vaccination after infancy was associated with an increased risk of TST reactivity in the first 15 years after vaccination (adjusted Hazard Ratio=2.33). This association remained during the interval 16-55 years after vaccination, although the effect was attenuated (adjusted Hazard Ratio=1.26). Age at vaccination modestly impacted the effect of BCG on TST in the first 15 years. Positive TSTs among the BCG-vaccinated group were more likely to revert to negative during the first 15 years but not in the latter period.

Conclusions  This study provides evidence that BCG vaccination after infancy may influence the TST beyond the 10-year period conventionally accepted by the Centers for Disease Control and Prevention (CDC), extending up to 55 years after vaccination. This suggests that BCG vaccination should be taken into account when interpreting TST results regardless of time elapsed since vaccination.

contemporary reviews in sleep medicine 
Jagan A. Pillai, MBBS, PhD; James B. Leverenz, MD
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Sleep abnormalities are clearly recognized as distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep related symptoms has a positive impact on the quality of life of patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes among common neurodegenerative diseases with a focus on Alzheimer’s disease and synucleinopathies (i.e., Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy) that have been better studied. Sleep changes may also serve as markers to identify patients in the preclinical stage of some neurodegenerative disorders. A hypothetical model is postulated founded on the conjecture that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, could be a surrogate marker reflecting pathophysiological processes related to neurodegenerative disorders. This provides a clinical strategy for the screening of patients in the preclinical stages of neurodegenerative disorders to enable therapeutic trials to establish efficacy of neuroprotective agents to prevent or delay the development of symptoms and functional decline. It is unclear if sleep disturbance directly impacts neurodegenerative processes or is a secondary outcome of neurodegeneration; this is an active area of research. The clinical importance of recognizing and managing sleep changes in neurodegenerative disorders is beyond doubt.

original research 
Huimin Wu, MD; Robert A. Wise, MD; Ann E. Medinger, MD
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Background  Guidelines recommend the confirmation of a COPD diagnosis with spirometry. ICD-9-CM diagnostic codes are used frequently to identify patients with COPD for administrative purposes. However, coding the diagnosis of COPD does not require spirometric confirmation. The purpose of this study was to determine how often the discharge diagnoses of COPD is supported by spirometric measurements in the VA health system.

Methods  We reviewed records of patients hospitalized for COPD in a VA teaching hospital between 2005 and 2015. Individuals were counted once; rehospitalizations for COPD in the same time frame were excluded. Patients’ records were assessed for presence of spirometric measurements and for spirometric evidence of COPD.

Results  There were 1278 discharges with the principal diagnosis of COPD and allied conditions in the time frame. A total of 826 discharged-patients were included. Among them, 21% had no spirometric measurements, 12% were unable to perform the breathing maneuvers correctly, 56% had spirometric evidence of airways obstruction and 11% had normal pre or post bronchodilator FEV1/FVC measurements. Older patients were more likely to fail the spirometry or have no documented spirometry. Younger patients were more likely to have the first spirometry after their COPD hospitalizations.

Conclusions  Caution must be taken when using the discharge diagnosis database to measure health care outcomes and determine resource management. Efforts are needed to assure that patients clinically suspected to have COPD are tested with spirometry to improve the accuracy of diagnosis of COPD.

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