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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 
Long Jiang, MD; Wenhua Liang, MD, PhD; Jianfei Shen, MD, PhD; Xiaofang Chen, PhD; Xiaoshun Shi, MD; Jiaxi He, MD, PhD; Chenglin Yang, MD, PhD; Jianxing He, MD, PhD, FACS
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Background:  Visceral pleural invasion (VPI) is considered an aggressive and invasive factor in Non-small-cell lung cancer (NSCLC). Recent studies found that VPI, dependent on tumor size, influenced T stage, but there is no consensus on whether VPI is important in node-negative NSCLC. In addition, its role in stage IB NSCLC is still uncertain. This meta-analysis sought to assess the role of VPI in node-negative NSCLC according to different tumor sizes and especially in stage IB disease.

Methods:  A systematic literature search was performed on four databases (EBSCO, Pubmed, OVID and Springer) to find relevant articles. The primary endpoint was 5-year overall survival. Pooled Odds ratios (ORs) were calculated using control as a reference group and significance was determined by the Z test.

Results:  Thirteen relevant studies with a total of 27171 patients were included in this study. The number of patients with VPI was 5821 (21%). VPI was proved a significant adverse prognostic factor in patients with tumor size≤3cm (OR 0.71,95% CI 0.64 to 0.79; p<0.001), tumor size>3, but≤5cm (OR 0.69, 95% CI 0.56 to 0.86; p<0.001) and tumor size>5, but≤7cm (OR 0.70, 95% CI 0.54 to 0.91; p=0.007). A further comparison was made with stage IB NSCLC. Tumor size≤3cm with VPI was found to have a better survival than tumor size>3, but≤5cm regardless of VPI (OR 1.31, 95% CI 1.19 to 1.45; p<0.001). Exploratory analysis found no survival benefit between tumor size≤3cm with VPI and tumor size>3, but≤5cm without VPI (OR 1.16, 95% CI 0.95 to 1.43; p=0.15); however, the prognosis for tumor size>3, but≤5cm with VPI was not as good as the prognosis of those with tumor size≤3cm with VPI.

Conclusion:  VPI together with tumor size has a synergistic effect on survival in node-negative NSCLC. Stage IB NSCLC patients with larger tumor size with VPI might be considered for adjuvant chemo after surgical resection and need carefully preoperative evaluation and postoperative follow-up. Further randomized clinical trials that can determinate the impact of adjuvant chemo on IB patients with VPI are warranted.

original research 
David M. Mannino, MD; Keiko Higuchi, MPH; Tzy-Chyi Yu, MHA, PhD; Huanxue Zhou, MS; Yangyang Li, MS; Haijun Tian, PhD; Kangho Suh, PharmD, MS
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Background:  The morbidity and mortality associated with chronic obstructive pulmonary disease (COPD) exacts a considerable economic burden. Comorbidities in COPD are associated with poor health outcomes and increased costs. Our objective was to assess the impact of comorbidities on COPD-associated costs in a large administrative claims dataset.

Methods:  This was a retrospective observational study of data from the Truven Health MarketScan Commercial Claims and Encounters and MarketScan Medicare Supplemental Databases from January 1, 2009, to September 30, 2012. Resource consumption was measured from the index date (date of first occurrence of non–rule-out COPD diagnosis) to 360 days after the index date. Resource utilization (all-cause and disease-specific [ie, COPD- or asthma-related] emergency room [ER] visits, hospitalizations, office visits, other outpatient visits, and total length of hospital stay) and healthcare costs (all-cause and disease-specific costs for ER visits, hospitalizations, office visits, other outpatient visits, and medical, prescription, and total healthcare costs) were assessed. Generalized linear models were used to evaluate the impact of comorbidities on total healthcare costs, adjusting for age, sex, geographic location, baseline healthcare utilization, employment status, and index COPD medication.

Results:  Among 183,681 COPD patients, the most common comorbidities were cardiovascular disease (34.8%), diabetes (22.8%), asthma (14.7%), and anemia (14.2%). Most patients (52.8%) had 1 or 2 comorbidities of interest. The average all-cause total healthcare costs from the index date to 360 days after the index date were highest for patients with chronic kidney disease ($41,288) and anemia ($38,870). The impact on total healthcare costs was greatest for anemia ($10,762 more on average than a patient with COPD without anemia).

Conclusions:  Our analysis demonstrated that high resource utilization and costs were associated with COPD and multiple comorbidities.

original research 
Julie V. Philley, MD; Richard J. Wallace, Jr., MD; Jeana L. Benwill, MD; Varsha Taskar, MD; Barbara A. Brown-Elliott, MS, MT (ASCP) SM; Foram Thakkar, MBBS; Timothy R. Aksamit, MD; David E. Griffith, MD
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  Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent MICs for Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM), especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for treatment of multi-drug resistant tuberculosis (MDR-TB), but has not been tested clinically for NTM disease.

  We describe a case series of off- label use of bedaquiline for treatment failure lung disease due to MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (6 MAC, 4 Mab) could obtain bedaquiline. The 10 patients had been treated for 1-8 years and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide resistant isolates (8/10). Patients were treated with the same bedaquiline dosage used in TB trials, and received the best available companion drugs (mean 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline.

  Common side effects included nausea (60%), arthralgias (40%), anorexia and subjective fever (30%). No abnormal EKG findings were observed with a mean QTc interval lengthening of 2.4 ms at 6 months. After 6 months of therapy, 60% (6/10) of patients had a microbiologic response with 50% (5/10) having one or more negative cultures.

  This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but requires confirmation with larger studies.

original research 
Nicholas A. Smyrnios, M.D.; Richard Lenard, RRT; Sunil Rajan, M.D.; Michael Newman, D. O.; Stephen P. Baker, MScPH; Nehal Thakkar, M.D.; Wahid Wassef, M.D.; Niraj Ajmere, M.D.; Richard S. Irwin, M.D.
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Objective:  To develop a mechanism of discovering misdirection into the airway of naso/orogastric tubes before they reach their full depth of placement in adults.

Design:  After a preliminary proof of concept animal study suggested the safety and feasibility of assessing tracheal or esophageal intubation with a self inflating bulb syringe, a prospective, observational study was performed in humans evaluating both the bulb syringe and a colorimetric CO2 detector.

Setting:  Medical ICUs of a tertiary care medical center

Subjects:  202 medical adult ICU patients whose bedside caregivers had determined a need for placement of a naso/orogastric tube

Intervention:  Measurement of reinflation of the self inflating bulb syringe and color change on the colorimetric CO2 detector when the tube was positioned at 30 cm. We compared these findings to a “standard” (i.e. end tidal CO2 results of a capnograph and the results of a chest radiograph performed at the completion of the tube placement).

Measurement and main results:  A prospective convenience sample of 257 tube placements in 199 patients was studied. On the first tube placement attempt in any patient the self inflating bulb syringe had a sensitivity of 91.5 % and a specificity of 87.0 % in detecting non-esophageal placement while the colorimetric device exhibited a 99.4 % sensitivity and a 91.3 % specificity. On subsequent insertions the bulb syringe showed 95.7% sensitivity and 100% specificity, while the colorimetric device exhibited 97.8% sensitivity and 100% specificity. The colorimetric device was 8 times more expensive than the bulb syringe.

Conclusions:  The self inflating bulb syringe and the colorimetric CO2 detector are very good at detecting naso/orogastric tube malpositioning into the airway although the colorimetric device is slightly more sensitive and specific. Neither method adds substantial time or difficulty to the insertion process. The colorimetric device is substantially more expensive. The decision as to which method to use may be based on local institutional factors such as expense.

evidence-based medicine  FREE TO VIEW
Armin Ernst, MD, FCCP; Momen M. Wahidi, MD, MBA, FCCP; Charles A. Read, MD, FCCP; John D. Buckley, MD, FCCP; Doreen J. Addrizzo-Harris, MD, FCCP; Pallav L. Shah, MD; Felix J.F. Herth, MD, FCCP; Alberto de Hoyos Parra, MD; Joseph Ornelas, MS; Lonny Yarmus, DO, FCCP; Gerard A. Silvestri, MD, MS, FCCP

Background / Introduction:  The determination of competency of trainees in programs performing bronchoscopy is quite variable. Some programs provide didactic lectures with hands-on supervision; other programs incorporate advanced simulation centers; while others have a checklist approach. Although no single method has been proven best, the variability alone suggests that outcomes are variable. Program directors and certifying bodies need guidance to create standards for training programs. Little well-developed literature on the topic exists.

Methodology:  To provide credible and trustworthy guidance, rigorous methodology has been applied to create this bronchoscopy consensus training statement. All panelists were vetted and approved by the CHEST Guidelines Oversight Committee. Each topic group drafted questions in a PICO (Population, Intervention, Comparator, Outcome) format. MEDLINE via PubMed and the Cochrane Library were systematically searched. Manual searches also supplemented the searches. All gathered references were screened for consideration based on inclusion criteria and all statements were designated as an “Ungraded Consensus-Based Statement”.

Results:  We suggest that professional societies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. Bronchoscopy training programs should incorporate multiple tools including simulation. We suggest that ongoing quality and process improvement systems be introduced and that certifying agencies move from a volume-based certification system to skill acquisition and knowledge-based competency assessment for trainees. We also suggest that assessment of skill maintenance and improvement in practice be evaluated on a regular basis with ongoing quality and process improvement systems after initial skill acquisitions are introduced.

Conclusions:  The current methods used for bronchoscopy competency with training programs are variable. We suggest that professional societies and certifying agencies move from a volume- based certification system to a standardized skill acquisition and knowledge-based competency assessment for pulmonary and thoracic surgery trainees.

original research 
Emanuele Pivetta, M.D.,M.Sc.; Alberto Goffi, M.D.; Enrico Lupia, M.D.,Ph.D.; Maria Tizzani, M.D.; Giulio Porrino, M.D.; Enrico Ferreri, M.D.; Giovanni Volpicelli, M.D.,FCCP; Paolo Balzaretti, M.D.; Alessandra Banderali, M.D.; Antonello Iacobucci, M.D.; Stefania Locatelli, M.D.; Giovanna Casoli, M.D.; Michael B. Stone, M.D.; Milena M. Maule, Ph.D.; Ileana Baldi, Ph.D.; Franco Merletti, M.D.; GianAlfonso Cibinel, M.D.; for the SIMEU Group for Lung Ultrasound in the Emergency Department in Piedmont
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Background.  Lung ultrasonography (LUS) has recently emerged as a non-invasive tool for the differential diagnosis of pulmonary diseases. However, its use for the diagnosis of acute decompensated heart failure (ADHF) still raises some concerns.Here, we tested the hypothesis that an integrated approach implementing LUS with the clinical assessment would have higher diagnostic accuracy than standard work-up in differentiating ADHF from non-cardiogenic dyspnea in the Emergency Department (ED).

Methods.  We conducted a multicenter prospective cohort study in seven Italian EDs. For patients presenting with acute dyspnea, the emergency physician was asked to categorize the diagnosis as ADHF or non-cardiogenic dyspnea a) after the initial clinical assessment, and b) after performing LUS (“LUS-implemented” diagnosis). All patients also underwent chest radiography. After discharge, the cause of patient’s dyspnea was determined by independent review of the entire medical records. The diagnostic accuracy of the different approaches was then compared.

Results.  One-thousand-five patients were enrolled. The LUS-implemented approach had a significantly higher accuracy (sensitivity 97%; 95% CI, 95-98.3%; specificity 97.4%; 95% CI 95.7-98.6%) in differentiating ADHF from non-cardiac causes of acute dyspnea than the initial clinical work-up (sensitivity 85.3%; 95% CI, 81.8-88.4%; specificity 90%; 95% CI, 87.2-92.4%), chest radiography alone (sensitivity 69.5%; 95% CI, 65.1-73.7%; specificity 82.1%; 95% CI, 78.6-85.2%), and natriuretic peptides (sensitivity 85%; 95% CI, 80.3-89%; specificity 61.7%; 95% CI, 54.6-68.3%; No.=486 patients). Net reclassification index of LUS-implemented approach compared to standard work-up was 19.1%.

Conclusions.  The implementation of LUS with the clinical evaluation may improve accuracy of ADHF diagnosis in patients presenting to the ED.

Clinical Trial Registration.  ClinicalTrials.gov number, NCT01287429 (http://clinicaltrials.gov/show/NCT01287429).

original research 
Annemarie L. Lee; Samantha L. Harrison; Roger S. Goldstein; Dina Brooks
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Background:  Pain is emerging as a clinical complication in chronic obstructive pulmonary disease (COPD), but the clinical impact of this comorbidity and the measurement properties of instruments used to assess pain requires evaluation.

Methods:  Electronic searches of five databases were performed up to September 2014 for the two phases of this review. To be included in phase 1, studies reported the clinical associations of pain and prevalence in individuals with COPD. To be included in phase 2, studies reported measurement properties of an instrument assessing pain in COPD. Two independent reviewers rated the quality of quantitative and qualitative evidence (phase 1) and the measurement properties using the 4-point COSMIN checklist (phase 2).

Results:  Of the 358 studies identified in the literature, nine met the inclusion criteria for phase 1 and five for phase 2. The mean (SD) quality score (out of 16) for the quantitative studies was 13.1(1.7). The pooled prevalence of pain in moderate to very severe COPD was 66% (95% CI 44% to 85%). Higher pain intensity was associated with increased dyspnea, fatigue, poorer quality of life and a greater quantity of specific comorbidities. Of the two identified instruments (Brief Pain Inventory and McGill Pain Questionnaire), the measurement properties analyzed were construct validity, internal consistency and criterion-predictive validity, with variable findings based on ‘fair’ or ‘poor’ quality studies.

Conclusions:  In people with COPD, pain has negative clinical associations with symptoms and quality of life measures. Further research exploring the measurement properties of instruments assessing pain is required.

original research 
Prof Metin Akgun, MD, FCCP; Assist Prof Omer Araz, MD; Assist Prof Elif Yilmazel Ucar, MD; Assist Prof. Adem Karaman, MD; Prof. Fatih Alper, MD, PhD; Prof. Metin Gorguner, MD; Kathleen Kreiss, MD
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Background:  The course of denim sandblasting silicosis is unknown. We aimed to reevaluate former sandblasters studied in 2007 for incident silicosis, radiographic progression, pulmonary function loss, and mortality, and to examine any associations between these outcomes and previously demonstrated risk factors for silicosis.

Methods:  We defined silicosis on chest radiograph as category 1/0 small opacity profusion using the International Labor Organization classification. We defined radiographic progression as a profusion increase of two or more subcategories, development of a new large opacity, or an increase in large opacity category. We defined pulmonary function loss as a 12% or more decrease in forced vital capacity.

Results:  Among the 145 former sandblasters studied in 2007, 83 were reassessed in 2011. In the four-year follow-up period, 9 (6.2%) had died at a mean age of 24 years. Of the 74 living sandblasters available for reexamination, the prevalence of silicosis increased from 55.4% to 95.9%. Radiographic progression, observed in 82%, was associated with younger age, never smoking, foreman work, and sleeping at the workplace. Pulmonary function loss, seen in 66%, was positively associated with never smoking and higher initial percent predicted forced vital capacity. Death was associated with never smoking, foreman work, number of different denim sandblasting places of work, sleeping at the workplace, and lower pulmonary functions, of which only the number of different places worked remained in multivariate analyses.

Conclusions:  This four-year follow up suggests that almost all former denim sandblasters may develop silicosis, despite short exposures and latency.

original research 
Kristin M. Jensen, MD, MSc; Carter J. Sevick, MS; Laura Seewald; Ann C. Halbower, MD; Matthew M. Davis, MD, MAPP; Edward RB. McCabe, MD, PhD; Allison Kempe, MD, MPH; Steven Abman, MD
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Background:  Children with Down syndrome (DS) are at high risk for obstructive sleep apnea (OSA). Increasing elevation is known to exacerbate underlying respiratory disorders and worsen sleep quality in non-DS persons, but whether altitude modulates the severity of OSA in DS is uncertain. In this study, we evaluate the impact of elevation (≤1500m vs. > 1500m) on the proportion of hospitalizations involving OSA in children with and without DS.

Methods:  Merging the 2009 Kids’ Inpatient Database with zip-code linked elevation data, we analyzed differences in the proportion of pediatric hospitalizations (ages 2-20 years) involving OSA, pneumonia, and congenital heart disease (CHD), with and without DS. We used multivariable logistic regression to evaluate the association of elevation with hospitalizations involving OSA and DS, adjusting for key comorbidities.

Results:  Proportionately more DS encounters involved OSA, CHD, and pneumonia within each elevation category than non-DS encounters. However, the risk difference for hospitalizations involving OSA and DS increased disproportionately at higher elevations (DS: 16.2% (95% CI 9.2%-23.2%); non-DS: 0.1% (95% CI -0.4%-0.7%)). Multivariable estimates of relative risk indicate increased risk of hospitalization involving OSA at higher elevations for persons with DS and in children age 2-4 years or with ≥2 chronic conditions.

Conclusion:  At elevations >1500m, children with DS and OSA have a disproportionately higher risk of hospitalizations than children with OSA without DS. This finding has not been described previously. With further validation, this finding suggests the need for greater awareness and earlier screening for OSA and its complications in patients with DS living at higher elevations.

original research 
Cristiane Hallal, PhD; Veridiana S. Chaves, MD; Gilberto C. Borges; Isabel C. Werlang, PhD; Fernanda U. Fontella, PhD; Ursula Matte, PhD; Marcelo Z. Goldani, PhD; Paulo R. Carvalho, PhD; Eliana A. Trotta, PhD; Jefferson P. Piva, PhD; Sergio G. S. Barros, PhD; Helena A. S. Goldani, MD, PhD
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Background:  Gastroesophageal reflux (GER) and pulmonary aspiration (PA) are frequent in intensive care unit (ICU) patients. The presence of pepsin in airways seems to be the link between them. However, pepsin isoforms A (gastric specific) and C (pneumocyte potentially derived) needs to be distinguished. This study aimed to evaluate GER patterns and to determine the presence of pepsin A and C in tracheal secretion of critically ill mechanically ventilated children.

Methods:  All patients underwent multichannel intraluminal impedance-pH monitoring (MII-pH). Tracheal secretion samples were collected to determine the presence of pepsin. Pepsin A and C were evaluated by Western-Blot. MII-pH parameters analyzed were number of GER episodes (NGER); acid, weakly acidic and weakly alkaline GER episodes; proximal and distal GER episodes.

Results:  Thirty-four patients, median age 4(1-174) months were included. MII-pH detected 2172 GER episodes, 77.0% were weakly acidic and 71.7% were proximal. Median(25th-75thpercentile) of NGER episodes/patient was 59.5(20.3-85.3). Weakly acidic GER episodes/patient were significantly more frequent than acid GER episodes/patient [median (25th-75th percentile) 43.5 (20.3 – 68.3) vs 1.0 (0 – 13.8), respectively], p<0.001. Only 3 patients had acid reflux index altered (44.9%, 12.7%, and 13.6%), all off antiacid drugs. Pepsin A was found in 100% of samples, pepsin C in 76.5%.

Conclusion:  The majority of GER episodes of ICU children were proximal and weakly acidic. All patients had aspiration of gastric contents detected by pepsin A in tracheal fluid. A specific pepsin assay should be performed to establish gastropulmonary aspiration since pepsin C was found in more than 70% of samples.

original research 
Zaid Zoumot, PhD; Antonella LoMauro; Andrea Aliverti, PhD; Christopher Nelson; Simon Ward; Simon Jordan, MD; Michael I. Polkey, PhD; Pallav L. Shah, MD; Nicholas S. Hopkinson, PhD
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Background:  Lung volume reduction (LVR) techniques improve lung function in selected patients with emphysema but the impact of LVR procedures on the asynchronous movement of different chest wall compartments, which is a feature of emphysema, is not known.

Methods:  We used optoelectronic plethysmography to assess the effect of surgical and bronchoscopic LVR on chest wall asynchrony. Twenty-six patients were assessed before and three months after LVR (surgical (n=9) or bronchoscopic (n=7)), or a sham/unsuccessful bronchoscopic treatment (controls, n=10). Chest wall volumes were divided into six compartments (left and right of each of pulmonary ribcage (Vrc,p), abdominal ribcage (Vrc,a) and abdomen (Vab)) and phase shift angles (θ) calculated for the asynchrony between Vrc,p and Vrc,a (θRC), and between Vrc,a and Vab (θDIA).

Results:  Participants had a forced expiratory volume in the 1st second of 34.6±18% predicted and a Residual Volume of 217.8±46.0 % predicted with significant chest wall asynchrony during quiet breathing at baseline (θRC 31.3±38.4° and θDIA -38.7±36.3°). Between group difference in the change in θRC and θDIA during quiet breathing following treatment was 44.3° (95% CI -78 to -10.6, p=0.003) and 34.5° (95% CI 1.4 to 67.5, p=0.007) towards 0° (representing perfect synchrony), respectively, favoring the LVR group. Changes in θRC and θDIA were statistically significant on the treated but not the untreated sides.

Conclusions:  Successful LVR significantly reduces chest wall asynchrony in patients with emphysema.

original research 
Matthew P. Buman, PhD; Christopher E. Kline, PhD; Shawn D. Youngstedt, PhD; Barbara Phillips, MD, MSPH, FCCP; Marco Tulio de Mello, PhD; Max Hirshkowitz, PhD
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Background:  Excess sitting is emerging as a novel risk factor for cardiovascular disease, diabetes, mental illness, and all-cause mortality. Physical activity, distinct from sitting, is associated with better sleep and lower risk for obstructive sleep apnea (OSA), yet relationships among sitting behaviors and sleep/OSA remain unknown. We examined whether total sitting time and sitting while viewing television were associated with sleep duration and quality, OSA risk, and sleepiness.

Methods:  The 2013 National Sleep Foundation Sleep in America Poll was a cross-sectional study of 1,000 adults aged 23-60 years. Total sitting time, time watching television while sitting, sleep duration and quality, OSA risk, and daytime sleepiness were assessed.

Results:  After adjusting for confounding factors (including body mass index [BMI] and physical activity), each additional hour per day of total sitting was associated with greater odds of poor sleep quality (OR [95% CI] = 1.06 [1.01, 1.11]), but not with other sleep metrics (including sleep duration), OSA risk, or daytime sleepiness. For television viewing while sitting, each additional hour per day was associated with greater odds of long sleep onset latency (≥ 30 m) (OR=1.15 [1.04, 1.27]), waking up too early in the morning (OR=1.12 [1.03, 1.23]), poor sleep quality (OR=1.12 [1.02, 1.24]), and ‘high risk’ for OSA (OR=1.15 [1.04, 1.28]). Based upon an interaction analysis, regular physical activity was protective against OSA risk associated with television viewing (p=0.04).

Conclusions:  Excess sitting was associated with relatively poor sleep quality. Sitting while watching television was associated with relatively poor sleep quality and OSA risk and may be an important risk factor for sleep disturbance and apnea risk.

original research 
Tomas Konecny, MD, PhD; Jeffrey B. Geske, MD; Ondrej Ludka, MD, PhD; Marek Orban, MD; Peter A. Brady, MD; Muaz M. Abudiab, MD; Felipe N. Albuquerque, MD; Alexander Placek, BSc; Tomas Kara, MD, PhD; Karine R. Sahakyan, MD, PhD; Bernard J. Gersh, MD, DPhil; A. Jamil Tajik, MD; Thomas G. Allison, PhD; Steve R. Ommen, MD; Virend K. Somers, MD, DPhil
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Background:  Mechanisms of decreased exercise capacity in patients with hypertrophic cardiomyopathy (HCM) are not well understood. Sleep disordered breathing (SDB) is a treatable and highly prevalent disorder in patients with HCM. The role of co-morbid SDB in the attenuated exercise capacity in HCM has not previously been studied.

Methods:  Overnight oximetry, cardiopulmonary exercise testing, and echocardiographic studies were performed in consecutive HCM patients seen at Mayo Clinic. SDB was considered present if oxygen desaturation index (number of ≥4% desaturations per hour) was ≥ 10. Peak oxygen consumption (pkVO2, the most reproducible and prognostic measure of cardiovascular fitness) was then correlated with the presence and severity of SDB.

Results:  A total of 198 HCM patients were studied (age 53±16 years; 122 male) of whom 32% met the criteria for the SDB diagnosis. Patients with SDB had decreased pkVO2 compared to those without SDB (16 vs 21 mlO2/kg/min; p<0.001). SDB remained significantly associated with pkVO2 after accounting for confounding clinical variables (p<0.001) including age, sex, body mass index, atrial fibrillation, and coronary artery disease.

Conclusions:  In patients with HCM, the presence of SDB is associated with decreased pkVO2. SDB may represent an important and potentially modifiable contributor to impaired exercise tolerance in this unique population.

original research 
Carlos H. Martinez, MD, MPH; David M. Mannino, MD; Jeffrey L. Curtis, MD; MeiLan K. Han, MD, MS; Alejandro A. Diaz, MD, MPH
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Background:  Understanding ethnic differences in health status (HS) could help to design culturally-appropriate interventions. We hypothesized that there are race/ethnic differences in HS between non-Hispanic whites and Mexican-Americans with obstructive lung disease (OLD), and that they are mediated by socioeconomic factors.

Methods:  We analyzed 826 U.S. adults 30 years of age and older self-identified as Mexican-Americans or non-Hispanic whites with spirometry-confirmed OLD (FEV1/FVC <0.7) who participated in the National Health and Nutrition Examination Survey 2007-2010. We assessed associations between Mexican-American ethnicity and self-reported HS using logistic regression models adjusted for demographics, smoking status, number of comorbidities, limitation for work, and lung function, and tested the contribution of education and healthcare access to ethnic differences in HS.

Results:  Among Mexican-American with OLD, worse (fair/poor) health status was more prevalent than among non-Hispanic Whites (weighted % [standard error], 46.6% [5.0] vs. 15.2% [1.6]; P<0.001). In bivariate analysis socioeconomic characteristics were associated with lower odds of reporting poor HS (high school graduation OR 0.24, 95%, CI 0.10-0.40; access to healthcare OR 0.50, 95% CI 0.30-0.80). In fully-adjusted models there was a strong association between Mexican-American ethnicity (vs. non-Hispanic white) and fair/poor HS (odds ratio [OR], 7.52 [95% CI, (4.43 – 12.78)]; P<0.001). Higher education and access to healthcare contributed to lower the Mexican-American ethnicity odds of fair/poor HS by 47% and 16%, respectively; and together they contributed 55% to reduce the differences in HS with non-Hispanic Whites.

Conclusion:  Mexican-Americans with OLD report poorer overall health status than non-Hispanic whites, and education and healthcare access are large contributors to the difference.

original research 
Marco Guazzi, MD, PhD, FACC; Robert Naeije, MD; Ross Arena, PhD; Ugo Corrà, MD; Stefano Ghio, MD; Paul Forfia, MD; Andrea Rossi, MD; Lawrence P. Cahalin, MD; Francesco Bandera, MD; Pierluigi Temporelli, MD
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Background:  Pulmonary hypertension is of poor prognosis in heart failure (HF), and this is related to right ventricular (RV) failure. Increased ventilatory response and exercise oscillatory ventilation (EOV) have also a negative impact. We hypothesized that severity classification of HF and risk prediction could be improved by combining functional capacity, with cardiopulmonary exercise testing (CPET) and RV-pulmonary circulation coupling, evaluated by the tricuspid annular plane systolic excursion (TAPSE)-pulmonary artery systolic pressure (PASP) relationship.

Methods:  459 HF patients were assessed with Doppler echocardiography and CPET and tracked for outcome. Subjects were followed for major cardiac events [cardiac mortality, left ventricular assist device (LVAD) implantation, or heart transplantation]. Cox regression and Kaplan-Meier analyses were performed with TAPSE and PASP as individual measures and combining them in a ratio form.

Results:  TAPSE/PASP was the strongest predictor whereas NYHA and EOV added predictive value. A 4-quadrant group prediction risk was created according to TAPSE (</≥16 mm) vs PASP (</≥40 mmHg) thresholds looking at CPET variables distribution within groups as follows: Group A (TAPSE> 16 mm and PASP < 40 mmHg) presented the lowest risk (HR: 0.17) and best ventilation; Group B exhibited a low risk (HR:0.88) with depressed TAPSE (< 16 mm) and normal PASP a preserved peak VO2 but high ventilation. Group C had an increased risk (HR: 1.3, TAPSE ≥ 16 mm, PASP ≥ 40 mmHg), reduced peak VO2 and high EOV prevalence. Group D had the highest risk (HR: 5.6), the worse RV-pulmonary pressure coupling (TAPSE< 16 and PASP≥ 40 mmHg), the lowest peak VO2 and the highest EOV rate.

Conclusions:  the TAPSE/PASP ratio combined with the exercise ventilation provides relevant clinical and prognostic insights in HF. A low TAPSE/PASP with EOV identifies patients at particular high risk of cardiac events.

original research 
Carolina Fernández, MD; Carlo Bova, MD; Olivier Sanchez, PhD; Paolo Prandoni, PhD; Mareike Lankeit, MD; Stavros Konstantinides, PhD; Simone Vanni, MD; Covadonga Fernández-Golfín, PhD; Roger D. Yusen, MD; David Jiménez, PhD
Topics: ,

Background:  For patients diagnosed with acute symptomatic pulmonary embolism (PE), the Bova score classifies their risk of developing PE-related complications within 30 days after PE diagnosis. The original Bova score study derived the model from 2,874 normotensive patients that had acute PE and participated in one of six prospective PE studies.

Methods:  We retrospectively assessed the validity of the Bova risk model in normotensive patients with acute PE diagnosed in an academic urban emergency department. Two clinician investigators used baseline data for the model’s 4 prognostic variables to stratify patients into the three Bova risk classes (I–III) for 30-day PE-related complications. Intraclass correlation coefficient (ICC) and the kappa statistic assessed inter-rater variability.

Results:  The Bova risk score classified the majority of the cohort of 1,083 patients into the lowest Bova risk stage (stage I, 80%; stage II, 15%; stage III, 5%), The primary endpoint occurred in 91 of the 1,083 (8.4%; 95% confidence interval [CI], 6.7-10%) patients during the 30 days after the PE diagnosis. Risk class correlated with the PE-related complication rate (class I 4.4%, class II 18%, and class III 42%; ICC 0.93 [95% CI, 0.92-0.94]; kappa statistic 0.80 [P < 0.001]), in-hospital complication rate (class I 3.7%, class II 15%, and class III 37%), and 30-day PE-related mortality (class I 3.1%, class II 6.8%, and class III 10.5%).

Conclusion:  The Bova risk score accurately stratifies normotensive patients with acute PE into stages of increasing risk of PE-related complications that occur within 30 days of PE diagnosis.

original research 
Chee M. Chan, MD, MPH; Christian J. Woods, MD; Theodore E. Warkentin, MD; Jo-Ann I. Sheppard, BSc; Andrew F. Shorr, MD, MPH
Topics: ,

Background:  Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin utilization. An enzyme-linked immunosorbent assay (ELISA) is usually performed to assist in the diagnosis of HIT. ELISAs tend to be sensitive but lack specificity. We sought to utilize a new cut-off to define a positive HIT ELISA.

Methods:  We conducted a prospective observational study of hospitalized patients undergoing ELISA testing. All patients who underwent ELISA testing were eligible for inclusion (n=496). Irrespective of the results, all subjects had confirmatory testing with a serotonin release assay (SRA). We compared a threshold optical density (OD)>1.00 to the current definition of a positive ELISA (OD>0.40) as a screening test for a positive SRA. We used sensitivity, specificity, and area under the receiver operating curve to determine whether an OD>1.00 would improve diagnostic accuracy for HIT.

Results:  The SRA was positive in 10 patients (prevalence: 2.0%). Adjusting the definition of a positive HIT ELISA to >1.00 maintained the sensitivity and negative predictive value at 100% in our cohort. The positive predictive value (PPV) of the higher cutoff OD was more than triple the PPV of an OD>0.40 (41.7% vs 13.3%). No patient with a positive SRA had an OD measurement <1.00.

Conclusions:  Increasing the OD threshold enhances specificity without noticeably compromising sensitivity. Altering the definition of the HIT ELISA could prevent unnecessary testing and/or treatment with non-heparin based anticoagulants in patients with possible HIT.

Clinical Trial Registration:  clinicaltrials.gov (NCT 00946400)

original research 
Rachel Gavish, MD, MPH; Amalia Levy, MPH, PhD; Or Kalchiem Dekel, MD; Erez Karp, MD; Nimrod Maimon, MD
Topics: , ,

Background:  The high frequency of readmissions in patients with chronic obstructive pulmonary disease (COPD) remains a significant problem. The impact of a pulmonologist follow-up visit during the month after discharge from hospital due to COPD exacerbation on reducing readmissions was examined. A profile of patients who did not attend the follow-up visits was built.

Methods:  Our population-based retrospective cohort study analyzed the data of all COPD patients who were treated at a lung institute in an Israeli hospital and were hospitalized between January 1, 2004, and December 31, 2010. Multivariate logistic regression was used to characterize the patient who did not attend the follow up visit and to examine the effect of lack of visit on rehospitalization within 90 days of discharge. Cox proportional hazards analysis was used to model the effect of lacking visit on additional hospitalization or death during the study period.

Results:  Of the 195 patients enrolled in the study, 44.1% had follow-up visits with pulmonologists within 30 days of discharge. Not attending the follow-up visit was associated with distant residence, higher number of hospitalizations in the previous year, lack of a recommendation in the discharge letter for a follow-up visit, and lower frequency of follow-up visits with pulmonologists in the previous year. Moreover, not attending the follow-up visit were associated with a significant increased risk for rehospitalization within 90 days from discharge (odd ratio [OR], 2.91; 95% confidence interval [CI], 1.06-8.01).

Conclusions:  Early follow-up visits with pulmonologists seem to reduce exacerbation related rehospitalization rates of COPD patients. We recommend that patients have early post-discharge follow-up visits with pulmonologists.

original research 
Eliana S. Mendes, M.D.; Lilian Cadet; Johana Arana; Adam Wanner, M.D.
Topics: , , ,

RATIONALE:  We have previously shown that in asthmatics a single dose of an inhaled glucocorticosteroid (ICS) acutely potentiates inhaled albuterol-induced airway vascular smooth muscle relaxation through a non-genomic action. An effect on airway smooth muscle was not seen, presumably because the patients had normal lung function. The purpose of the present study was to conduct a similar study in asthmatics with airflow obstruction to determine if an ICS could acutely also potentiate albuterol-induced airway smooth muscle relaxation in them.

METHODS:  In 15 adult asthmatics (mean±SE baseline FEV1 62±3%), the response to inhaled albuterol (180μg) was assessed by determining the change in FEV1(ΔFEV1) for airway smooth muscle and in airway blood flow (ΔQaw) for airway vascular smooth muscle measured 15 min after drug inhalation. Using a double-blind design, the patients inhaled a single dose of the ICS mometasone (400 μg) or placebo simultaneously with or 30 min before albuterol inhalation.

RESULTS:  After simultaneous drug administration, mean ΔFEV1 was 0.20±0.05L (10%) after placebo and 0.32±0.04L(19%) after mometasone (p<0.05); mean ΔQaw was -2% after placebo and 30% after mometasone (p<0.005). When mometasone or placebo were administered 30 min before albuterol, there was a lesser and insignificant difference in ΔFEV1 between the two treatments, while the difference in ΔQaw remained significant.

CONCLUSIONS:  This pilot study showed that in adult asthmatics with airflow obstruction, a single standard dose of an ICS can acutely increase the FEV1 response to a standard dose of inhaled albuterol administered simultaneously. The associated potentiation of albuterol-induced vasodilation in the airway was of greater magnitude and retained when the ICS was administered 30 min before albuterol. The clinical significance of this observation will have to be established by a study involving a larger patient cohort.

original research 
Charles R. Esther, Jr.; Raymond D. Coakley; Ashley G. Henderson; Yi-Hui Zhou; Fred A. Wright; Richard C. Boucher
Topics: , ,

Background:  Metabolomic evaluation of cystic fibrosis airway secretions could identify metabolites and metabolic pathways involved in neutrophilic airway inflammation that could serve as biomarkers and therapeutic targets.

Methods:  Mass spectrometry based metabolomics was performed on a discovery set of bronchoalveolar lavage fluid samples from 25 children with cystic fibrosis, and targeted mass spectrometric methods were utilized to identify and quantify metabolites related to neutrophilic inflammation. A biomarker panel of these metabolites was then compared to neutrophil counts and clinical markers in independent validation sets of lavage from children with cystic fibrosis and adults with chronic obstructive pulmonary disease compared to controls.

Results:  Of the 7791 individual peaks detected by positive mode mass spectrometric metabolomics discovery profiling, 338 were associated with neutrophilic inflammation. Targeted mass spectrometry determined that many of these peaks were generated by metabolites from pathways related to metabolism of purines, polyamines, proteins, and nicotinamide. Analysis of the independent validation sets verified that several metabolites, particularly those from purine metabolism and protein catabolism pathways, were strongly correlated to neutrophil counts and related to clinical markers including airway infection and lung function in subjects with cystic fibrosis or chronic obstructive pulmonary disease.

Conclusions:  Mass spectrometric metabolomics identified multiple metabolic pathways associated with neutrophilic airway inflammation. These findings provide insight into disease pathophysiology and can serve as the basis for developing disease biomarkers and therapeutic interventions for airways diseases.

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