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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.

evidence-based medicine  FREE TO VIEW
Gerard J. Criner, MD, FCCP; Jean Bourbeau, MD, FCCP, FRCPC; Rebecca L. Diekemper, MPH; Daniel R. Ouellette, MD, FCCP; Donna Goodridge, RN, PhD; Paul Hernandez, MDCM, FRCPC; Kristen Curren, MA; Meyer S. Balter, MD, FCCP, FRCPC; Mohit Bhutani, MD, FCCP, FRCPC; Pat G. Camp, PT, PhD; Bartolome R. Celli, MD, FCCP; Gail Dechman, PT, BScPT, PhD; Mark T. Dransfield, MD; Stanley B. Fiel, MD, FCCP; Marilyn G. Foreman, MD, FCCP; Nicola A. Hanania, MBBS, FCCP; Belinda K. Ireland, MD, MSc; Nathaniel Marchetti, DO, FCCP; Darcy D. Marciniuk, MD, FCCP; Richard A. Mularski, MD, FCCP; Joseph Ornelas, MS, PhD(c); Jeremy D. Road, MD, FRCPC; Michael K. Stickland, PhD
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Chronic obstructive pulmonary disease (COPD) is a common disease with substantial associated morbidity and mortality. Patients with COPD usually have a progression of airflow obstruction that is not fully reversible and can lead to a history of progressive worsening breathlessness that can impact daily activities and health-related quality of life. COPD is the fourth leading cause of death in Canadian men and women and the third in the U.S., it claimed 133,965 U.S. lives in 2009. In 2011, 12.7 million U.S. adults were estimated to have COPD. However, approximately 24 million U.S. adults have evidence of impaired lung function, indicating an under diagnosis of COPD. While 4% of Canadians aged 35 to 79 self-reported being diagnosed with COPD, direct measurements of lung function from the Canadian Health Measures Survey (CHMS) indicate that 13% of Canadians had a lung function score indicative of COPD.

evidence-based medicine  FREE TO VIEW
Gerard J. Criner, MD, FCCP; Jean Bourbeau, MD, FCCP, FRCPC; Rebecca L. Diekemper, MPH; Daniel R. Ouellette, MD, FCCP; Donna Goodridge, RN, PhD; Paul Hernandez, MDCM, FRCPC; Kristen Curren, MA; Meyer S. Balter, MD, FCCP, FRCPC; Mohit Bhutani, MD, FCCP, FRCPC; Pat G. Camp, PT, PhD; Bartolome R. Celli, MD, FCCP; Gail Dechman, PT, BScPT, PhD; Mark T. Dransfield, MD; Stanley B. Fiel, MD, FCCP; Marilyn G. Foreman, MD, FCCP; Nicola A. Hanania, MD, MS, FCCP, FRCPC; Belinda K. Ireland, MD, MSc; Nathaniel Marchetti, DO, FCCP; Darcy D. Marciniuk, MD, FCCP; Richard A. Mularski, MD, MSHS, MCR, FCCP; Joseph Ornelas, MS, PhD(c); Jeremy D. Road, MD, FRCPC; Michael K. Stickland, PhD
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Background:  Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the United States as well as the rest of the world. An exacerbation of COPD, periodic escalations of symptoms of cough, dyspnea and sputum production, is a major contributor to the worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and costs of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has recently accumulated about the prevention of acute exacerbations.

Methods:  In recognition of the importance of the prevention of exacerbations in the life of a COPD patient, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. The 3 key clinical questions were developed using the PICO (population, intervention, comparator, and outcome of interest) format, that addressed the prevention of acute exacerbations of COPD were non-pharmacologic therapies, inhaled therapies, and oral therapies. We utilized recognized document evaluation tools to allow us to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendation in each PICO category in a balanced and unbiased fashion.

Results:  The AECOPD Guideline is unique not only for the topic of the guideline, prevention of acute COPD exacerbations, but also for the first-in-kind partnership between two of the largest thoracic societies of North America. The Guidelines Oversight Committee (GOC) of the American College of Chest Physicians in partnership with the COPD Clinical Assembly of the Canadian Thoracic Society launched this project with the objective that a systematic review and critical evaluation of the published literature that was conducted by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the COPD patient.

Conclusion:  This guideline is unique because it provides an up-to-date, rigorous evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.

original research 
Meeta Prasad Kerlin, MD, MSCE; Michael O. Harhay, MPH; Jeremy M. Kahn, MD, MSc; Scott D. Halpern, MD, PhD
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Background:  Evidence regarding nighttime physician staffing of intensive care units (ICUs) is suboptimal. We aimed to determine how nighttime physician staffing models influence patient outcomes.

Methods:  We performed a multicenter retrospective cohort study in a multicenter registry of US ICUs. The exposure variable was the ICU’s nighttime physician staffing model. The primary outcome was hospital mortality. Secondary outcomes included new limitations on life support, ICU length-of-stay, hospital length-of-stay, and duration of mechanical ventilation. Daytime physician staffing was studied as a potential effect modifier.

Results:  The study included 270,742 patients in 143 ICUs. Compared to nighttime staffing with an attending intensivist, nighttime staffing without an attending intensivist was not associated with hospital mortality (OR 1.03; 95% CI 0.92, 1.15; p=0.65). This relationship was not modified by daytime physician staffing (interaction p=0.19). When nighttime staffing was subcategorized, neither attending non-intensivist nor physician trainee staffing was associated with hospital mortality, compared to attending intensivist staffing. However, nighttime staffing without any physician was associated with reduced odds of hospital mortality (OR 0.79; 95% CI 0.68, 0.91; p=0.002) and new limitations on life support (OR 0.83; 95% CI 0.75, 0.93; p=0.001). Nighttime staffing was not associated with ICU or hospital length-of-stay. Nighttime staffing with an attending non-intensivist was associated with a slightly longer duration of mechanical ventilation (HR 1.05; 95% CI 1.02, 1.09; p<0.001).

Conclusions:  We found little evidence that nighttime physician staffing models impact patient outcomes. ICUs without physicians at night may exhibit reduced hospital mortality, possibly attributable to differences in end-of-life care practices.

original research 
John D. Brannan, PhD; Johan Bood, PhD; Ahmad Alkhabaz, MD; David Balgoma, PhD; Joceline Otis, BSc; Ingrid Delin, BSc; Barbro Dahlén, MD, PhD; Craig E. Wheelock, PhD; Parameswaran Nair, MD, PhD; Sven-Erik Dahlén, MD, PhD; Paul M. O’Byrne, MB
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Background:  Omega-3 fatty acid supplements have been reported to inhibit exercise-induced bronchospasm (EIB). It has not been determined if omega-3 supplements inhibit airway sensitivity to inhaled mannitol, a test for bronchial hyperresponsiveness (BHR) and model for EIB in persons with mild-moderate asthma.

Methods:  In a double-blind, crossover trial, asthmatic subjects who had BHR to inhaled mannitol (n=23, 14 males, mean age 28, half taking regular inhaled corticosteroids) were randomized to omega-3 supplements (4.0g/day eicosapentaenoic acid and 2.0g/day docosahexaenoic acid) or matching placebo for 3-weeks, separated by a 3-week washout. The primary outcome was the provoking dose of mannitol (mg) required to cause a 15% fall in FEV1 (PD15). Secondary outcomes were sputum eosinophil counts, spirometry, asthma control questionnaire (ACQ), serum triacylglycerides and lipid mediator profile in urine and serum.

Results:  PD15 (geometric mean, 95% CI) to mannitol following supplementation with omega-3s (78 mg, 51-119) was not different to placebo (88mg, 56-139)(p=0.5). There were no changes in sputum eosinophils (mean±SD) in a sub-group of subjects (omega-3s;8.4±8.2%: placebo;7.8±11.8%,p=0.9)(n=11). At the end of each treatment period there were no differences in FEV1 (% predicted)(omega-3s;85±13%: placebo;84±11%,p=0.9) or ACQ (omega-3s;1.1±0.5%: placebo;1.1±0.5%,p=0.9)(n=23). Omega-3s caused significant lowering of blood triglycerides and expected shifts in serum fatty acids and eicosanoid metabolites, confirming adherence to the supplements; however, no changes were observed in urinary mast cell mediators.

Conclusion:  Three weeks of omega-3 supplements does not improve BHR to mannitol, decrease sputum eosinophils or inhibit urinary excretion of mast cell mediators in persons with mild-moderate asthma indicating that dietary omega-3 supplementation is not useful in the short-term treatment of asthma.

Clinical Trial Registration:  URL: http://www.clinicaltrials.gov (Identifier Number NCT00526357).

original research 
Gustavo J. Rodrigo, MD; José A. Castro-Rodríguez, MD, PhD
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Background.  The role of tiotropium for the treatment of asthma has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium in asthma patients.

Methods.  Randomized, placebo-controlled trials were included. Primary outcomes were peak and trough forced expiratory volume in the first second (FEV1), and morning and evening peak expiratory flow (PEF).

Results.  Thirteen studies (4,966 patients) were included. Three different therapeutic protocols were identified. Tiotropium as add-on to inhaled corticosteroids (ICS) showed statistically and clinically significant increases in PEF (22-24 L/min) and FEV1 (140-150 mL). Also, tiotropium decreased the rate of exacerbations (Number need to treat for benefit [NNTB] = 36) and improved asthma control. The use of tiotropium in patients poorly controlled despite the use of medium to high doses of ICS was not inferior to salmeterol. Finally, the use of tiotropium as add-on ICS/salmeterol combination increased pulmonary function in a clinically significant magnitude, reduced asthma exacerbations (Relative risk = 0.70; 95% CI: 0.53 to 0.94, p<0.02, I2=0%, NNTB = 17), and improved asthma control compared with ICS/salmeterol. Tiotropium was well tolerated and no potential safety signals were observed.

Conclusions.  Tiotropium resulted non-inferior to salmeterol and superior to placebo in patients with moderate-severe asthma who were not adequately controlled by ICS or ICS/salmeterol. Major benefits were concentrated in the increase in lung function, and in the case of severe asthmatics, in the reduction of exacerbations.

editorials 
Derek C. Angus, M.D., M.P.H; Clifford S. Deutschman, M.S., M.D; Jesse B. Hall, M.D; Kevin C. Wilson, M.D; Cindy L. Munro, APRN-BC, Ph.D; Nicholas S. Hill, M.D
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Overuse of medical tests and treatments wastes health care resources and leads to unnecessary complications, while underuse results in delayed or missed diagnoses and treatment opportunities. Such problems are well recognized and there have been multiple attempts to correct inappropriate diagnostic testing and treatment over the past several decades. However, sustainable solutions have proven to be elusive.

original research 
Amelia Shoemark; Mellisa Dixon; Philip Beales; Claire Hogg
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  Cilia line the surface of the respiratory tract and beat in a coordinated wave to protect the lungs against infection. Bardet Biedl Syndrome (BBS) is rare condition attributed to cilia dysfunction. Murine models of BBS suggest a respiratory phenotype, however, no reports have studied the translation of these findings in patients.

  We assessed clinical symptoms of motile cilia dysfunction and histology of ciliated respiratory epithelium in patients with BBS.

  We report an increased prevalence of neonatal respiratory distress at birth (12%), GP diagnosed asthma (21%), otitis media (33%) and rhinitis (36%) in patients with BBS. These symptoms, however, occurred at a significantly reduced incidence compared to patients with known motile cilia dysfunction (Primary Ciliary Dyskinesia, PCD). Respiratory epithelial assessment revealed cellular damage, significant ciliary depletion (on 60% ciliated cells) and goblet cell hyperplasia in patients with BBS (50% goblet cells). These findings were quantifiably similar to that of patients with asthma (p>0.05). Surprisingly motile cilia function and ultrastructure was grossly normal with the exception of occasional unique inclusions within the ciliary membrane.

  In conclusion motile ciliary structure and function is essentially normal in patients with BBS.

original research 
Cindy L. Munro, RN, ANP, PhD, FAANP, FAAN, FAAAS; Mary Jo Grap, RN, PhD, FAAN; Curtis N. Sessler, MD, FCCP; R.K. Elswick, Jr, PhD; Devanand Mangar, MD, FCCP; Rachel Karlnoski-Everall, PhD; Paula Cairns, RN, BSN
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Introduction  Daily application of oral chlorhexidine gluconate (CHX) following intubation to reduce risk of ventilator-associated pneumonia (VAP) is now standard of care in many intensive care units. This randomized clinical trial evaluated the benefit of adding a pre-intubation CHX dose to the known benefit of post-intubation CHX to reduce risk of early onset VAP. A secondary aim was to test the effect of a pre-intubation oral application of CHX on early endotracheal tube (ETT) colonization.

Methods  Subjects (n=314) were recruited from two teaching hospitals and randomly assigned to oral application of 5 ml CHX 0.12% solution pre-intubation (intervention group, n=157), or to a control group (n=157) who received no CHX pre-intubation. All subjects received CHX twice daily after intubation. Groups were compared using a repeated measures model with Clinical Pulmonary Infection Score (CPIS) as the response variable. In a planned subset of subjects, ETT were cultured at extubation.

Results  Application of a pre-intubation dose of CHX did not provide benefit over the intervention period beyond that afforded by daily oral CHX following intubation. ETT colonization at extubation was less than 20% in both groups (no statistically significant difference). Mean CPIS remained below 6 (VAP threshold score) in both groups.

Conclusions  Although it is feasible to deliver CHX prior to intubation (including emergent or urgent intubation), the results suggest that pre-intubation CHX may be inconsequential when the ventilator bundle, including daily oral CHX, is in place. During the pre-intubation period, providers should focus their attention on other critical activities.

Clinical Trial Registration:  ClinicalTrials.gov NCT00893763

original research 
Vignesh Raman, B.S.; Caitlyn E. MacGlaflin, M.S.; Cherie P. Erkmen, M.D.
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Background:  Respiratory complications occur in 20-65% of esophagectomy patients. While non-invasive positive pressure ventilation (NPPV) is associated with fewer complications than endotracheal intubation (ET), it is relatively contraindicated after esophagectomy due to potential injury to the anastomosis. We created an ex vivo and in vivo pig model to determine the pressure tolerance of an esophagectomy anastomosis and compare it to esophageal pressure during NPPV.

Methods:  We created a stapled side-to-side, functional end-to-end esophagogastric anastomosis. With continuous intraluminal pressure monitoring, we progressively insufflated the anastomosis with a syringe until we detected an anastomotic leak, and recorded the maximum pressure before leakage. We performed this experiment in 10 esophageal specimens and 10 live pigs. We then applied a laryngeal mask airway (LMA) to five live pigs and measured the pressure in the proximal esophagus with increasing ventilatory pressures.

Results:  The perforation was always at the anastomosis. The ex vivo and in vivo anastomoses tolerated a mean of 101±44 cm H2O (95% CI) and 84±38 cm H2O before leak, respectively. There was no significant difference between the pressure thresholds of ex vivo and in vivo anastomoses (p=0.51). When 20, 30, and 40 cm H2O of positive pressure via LMA were delivered, the esophagus sensed 5±4 cm H2O (25%), 11±11 cm H2O (37%), and 15±9 cm H2O (38%), respectively.

Conclusions:  Our pig model suggests that an esophagectomy anastomosis can tolerate a considerably higher pressure than is transmitted to the esophagus during NPPV. NPPV may be a safe alternative to ET after esophagectomy.

original research 
Jonathan H. Chung; Ashish Chawla; Anna L. Peljto; Carlyne Cool; Steve D. Groshong; Janet L. Talbert; David McKean; Kevin K. Brown; Tasha E. Fingerlin; Marvin I. Schwarz; David A. Schwartz; David A. Lynch
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Background:  The current UIP/IPF CT classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable CT UIP on histology, and to determine the effect of the promoter polymorphism in the MUC5B gene (rs35705950) on histologic and CT UIP diagnosis.

Methods:  The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within one year of chest CT. UIP diagnosis on CT was categorized as inconsistent with, indeterminate, probable, or definite UIP by 2-3 pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N=200) were genotyped for rs35705950.

Results:  The proportion of CT diagnoses were as follows: inconsistent with 69/201 (34.3%), indeterminate 72/201 (35.8%), probable 34/201 (16.9%), and definite 26/201 (12.9%) UIP. Subjects with probable CT UIP were more likely to have histologic probable/definite UIP than subjects with indeterminate CT UIP (82.4% [28/34] versus 54.2% [39/72]; p-value 0.01). CT and microscopic honeycombing were not associated with each other (p-value 0.76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT and histologic UIP diagnosis (p-value: 0.03).

Conclusions:  Probable CT UIP is associated with a higher rate of histologic UIP than indeterminate CT UIP suggesting that they are distinct groups and should not be combined into a single CT category as currently recommended by guidelines. CT and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT and histology.

original research 
Robert P. Frantz, MD; Robert J. Schilz, DO, PhD; Murali M. Chakinala, MD; David B. Badesch, MD; Adaani E. Frost, MD; Vallerie V. McLaughlin, MD; Robyn J. Barst, MD; Daniel M. Rosenberg, PhD; Dave P. Miller, MS; Brian K. Hartline, MD; Wade W. Benton, PharmD; Harrison W. Farber, MD
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Background:  Few studies have prospectively reported outcomes in pulmonary arterial hypertension (PAH) patients treated with epoprostenol in the modern-day era of oral therapy and combination treatments. The Registry to PROSPECTively Describe Use of Epoprostenol for Injection [Veletri, prolonged Room Temperature Stable Epoprostenol (RTS-Epo)] in Patients with Pulmonary Arterial Hypertension (PROSPECT) was established to prospectively describe the course of PAH in patients prescribed RTS-Epo.

Methods:  PROSPECT is a multicenter, US-based drug registry of primarily Group I PAH patients treated with RTS-Epo who were parenteral-naïve or parenteral-transitioned at enrollment. Patients were followed until discontinuation of RTS-Epo, withdrawal, loss to follow-up, death, or end of study (maximum 1 year). One-year freedom from hospitalization (FH) and survival estimates were summarized by prostacyclin history (parenteral-naïve or parenteral-transitioned), gender, and chronic renal insufficiency (CRI).

Results:  A total of 336 patients were included. The overall one-year FH estimate was 51.0% ±2.8% and was lower in parenteral-naive patients than parenteral-transitioned patients (42.8% ±4.3% vs. 57.1% ±3.7%, respectively; p=0.002). FH estimates were lower in male patients than female patients (38.3% ±5.9% vs. 54.6% ±3.2%, respectively; p<0.015) and in patients with CRI than patients without CRI (17.0% ±8.4% vs. 53.7% ±2.9%, respectively; p<0.001). The overall one-year survival estimate was 84.0% ±2.1%. Survival was poorer in parenteral-naive patients, male patients, and patients with CRI.

Conclusions:  Risk of hospitalization and mortality remain high in PAH patients. In particular, patients who are parenteral-naïve at initiation of RTS-Epo therapy, male patients, and patients with CRI require close monitoring and aggressive clinical management.

original research 
Jose Leonidas Alves, Jr, MD; Francisca Gavilanes, MD; Carlos Jardim, MD, PhD; Caio Julio Cesar dos Santos Fernandes, MD, PhD; Luciana Tamie Kato Morinaga, MD; Bruno Dias, MD, PhD; Susana Hoette, MD, PhD; Marc Humbert, MD, PhD; Rogerio Souza, MD, PhD
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Background:  Pulmonary arterial hypertension (PAH) is a rare and ultimately fatal disorder of the pulmonary vasculature. There is increasing interest in the worldwide characteristics of PAH patients, although data coming from the southern hemisphere remain scarce. The objective of this study was to describe a cohort of incident PAH patients from a large reference center in Brazil.

Methods:  All consecutive patients diagnosed with PAH by right heart catheterization between 2008 and 2013 were included in the study.

Results:  A total of 178 newly diagnosed PAH patients were enrolled in the study (mean age of 46 yr, female/male ratio of 3.3:1 and 45.5% in functional class III or IV). IPAH, CTD and Sch-PAH accounted for 28.7, 25.8 and 19.7% of all cases, respectively. The patients were treated with PDE5 inhibitors (66%), ERAs (27%) or a combination of both (5%). For the PAH group as a whole, the estimated survival rate 3 years after diagnosis was 73.9%. The prognosis for the CTD patients was worse than that for the IPAH and Sch-PAH patients (p=0.03).

Conclusions:  The distribution of PAH etiologies and the baseline characteristics in our registry clearly differ from the previously published European and USA-based registries. These differences highlight the importance of regional registries and also raise questions regarding the need to better account for such differences in future clinical trials.

original research 
Annette Kristiansen, MD; Linn Brandt, MD; Pablo Alonso-Coello, MD, PhD; Thomas Agoritsas, MD; Elie A. Akl, MD, MPH, PhD; Tara Conboy, RGN, BSc, MSc; Mahmoud Elbarbary, MD, MSc, PhD, EDIC; Mazen Ferwana, MD, PhD; Wedad Medani, MSc; Mohammad Hassan Murad, MD, MPH; David Rigau, MD; Sarah Rosenbaum, PhD; Frederick A. Spencer, MD; Shaun Treweek, Prof; Gordon Guyatt, MD, FCCP; Per Olav Vandvik, MD, PhD

Background:  Bridging the gap between clinical research and everyday healthcare practice requires effective communication strategies. To address current shortcomings in conveying practice recommendations and supporting evidence, we are creating and testing presentation formats for clinical practice guidelines (CPGs).

Methods:  We carried out multiple cycles of brainstorming and sketching, developing a prototype. Physicians participating in the user testing viewed CPG formats linked to clinical scenarios and engaged in semi-structured interviews applying a think-aloud method for exploring important aspects of user experience.

Results:  We developed a multilayered presentation format that allows clinicians to successively view more in depth information. Starting with the recommendations clinicians can on demand access a rationale and a key information section containing statements on quality of the evidence, balance between desirable and undesirable consequences, values and preferences, and resource considerations. We collected feedback from 27 stakeholders and performed user testing with 47 practicing physicians from six countries. Advisory group feedback and user testing of the first version revealed problems with conceptual understanding of underlying CPG methodology, as well as difficulties with the complexity of the layout and content. Extensive revisions made before the second round of user testing resulted in most participants expressing overall satisfaction with the final presentation format.

Conclusion:  We have developed an electronic multilayered CPG format that enhances the usability of CPGs for front-line clinicians. We have implemented the format in electronic guideline tools which guideline organizations can now use when authoring and publishing their guidelines.

original research 
Eva Rivas, MD; Ebymar Arismendi, MD; Alvar Agustí, MD, FERS; Marcelo Sanchez, MD; Salvadora Delgado, MD; Concepción Gistau, MsC; Peter D. Wagner, MD; Roberto Rodriguez-Roisin, MD, FERS
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BACKGROUND.  Obesity is a global and growing public health problem. Bariatric surgery (BS) is indicated in patients with morbid obesity. The effects of morbid obesity and BS upon ventilation-perfusion (VA/Q) ratio distributions using the multiple inert gas elimination technique have never been explored before.

METHODS.  We compared respiratory and inert gas (VA/Q ratio distributions) pulmonary gas exchange, both breathing ambient air and 100% oxygen, in 19 morbidly obese women (body mass index [BMI], 45 Kg/m2), both before and one year after BS, and 8 normal weight never-smokers, age-matched healthy females.

RESULTS.  Before BS, morbidly obese individuals had reduced arterial PO2 (76±2 mmHg) and increased alveolar-arterial PO2 difference (AaPO2, 27±2 mmHg) caused by small amounts of shunt (4.3±1.1% of QT) along with abnormally broadly unimodal blood flow dispersion (Log SDQ, 0.83±0.06). During 100% oxygen breathing, shunt increased two-fold in parallel with a reduction of blood flow to low VA/Q units, suggesting the development of reabsorption atelectasis without reversion of hypoxic pulmonary vasoconstriction. After BS, body weight was reduced significantly (BMI, 31 Kg/m2) and pulmonary gas exchange abnormalities were decreased.

CONCLUSIONS.  Morbid obesity is associated with mild-to-moderate shunt and VA/Q imbalance. These abnormalities are reduced after BS.

original research 
Christine G. Kohn, PharmD; Elizabeth L. Mearns, PharmD; Matthew W. Parker, MD; Adrian V. Hernandez, MD, PhD; Craig I. Coleman, PharmD
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Background:  Studies suggest outpatient treatment or early discharge of acute pulmonary embolism (aPE) is reasonable for those deemed to be at low-risk of early mortality. We sought to determine clinical prediction rule (CPR) accuracy for identifying aPE patients at low-risk for mortality.

Methods:  We performed a literature search of Medline and Embase from January 2000-March 2014, along with a manual search of references. We included studies deriving/validating a CPR for early post-aPE all-cause mortality and providing mortality data over at least the index aPE hospitalization but ≤90-days. A bivariate model was used to pool sensitivity and specificity estimates using a random-effects approach. Traditional random-effects meta-analysis was performed to estimate the weighted proportion of patients deemed at low-risk for early mortality and their odds ratios for death compared to high-risk patients.

Results:  Forty studies (52 cohort-CPR analyses) reporting on 11 CPRs were included. The highest sensitivities were observed with the Global Registry of Acute Coronary Events (GRACE)(0.99, 95%CI=0.89-1.00), Aujesky 2006 (0.97, 95%CI=0.95-0.99), simplified Pulmonary Embolism Severity Index (sPESI)(0.92, 95%CI=0.89-0.94), PESI (0.89, 95%CI=0.87-0.90) and European Society of Cardiology (ESC)(0.88, 95%CI=0.77-0.94) tools; with remaining CPR sensitivities ranging from 0.41-0.82. Of these 5 CPRs with the highest sensitivities, none had a specificity >0.48. They suggested anywhere from 22%-45% of aPE patients were at low-risk; and that low-risk patients had a 77%-97% lower odds of death compared to those at high-risk.

Conclusions:  Numerous CPRs for prognosticating early mortality in aPE patients are available, but not all demonstrate the high sensitivity needed to reassure clinicians.

original research 
Laurie L. Carr, MD; Jonathan H. Chung, MD; Rosane Duarte Achcar, MD; Zoran Lesic, MD; Ji Y. Rho, MD; Kunihiro Yagihashi, MD; Robert M. Tate, MD; Jeffrey J. Swigris, DO, MS; Jeffrey A. Kern, MD

Background:  Current understanding of the clinical course of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed, as respiratory symptoms are ascribed to other lung conditions.

Objectives:  To collect and analyze longitudinal clinical data: pulmonary physiology, chest high-resolution computed tomography (HRCT) imaging, and therapies to better delineate the course of disease.

Methods:  We established a cohort of patients (N=30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model percent predicted one-second forced expiratory volume (FEV1%) over time.

Results:  All subjects were female who presented with longstanding cough and dyspnea. The majority of subjects had a FEV1% <50 at the time of diagnosis. Forty percent of subjects were diagnosed with asthma as the cause for physiological obstruction. The mean FEV1% for the entire cohort showed no statistically significant decline over time, but 26% of subjects experienced a 10% decline in FEV1 within two years. Among pathology samples available for review, 28% (5 of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT, transbronchial and surgical lung biopsy data.

Conclusions:  DIPNECH is a female-predominant lung disease manifested by dyspnea and cough, physiological obstruction and nodules on HRCT. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria.

original research 
Sunyoung Lee, MD; Ho Yun Lee, MD; Kyung Soo Lee, MD; Miyeon Yie, MD; Jaeil Zo, MD; Young Mog Shim, MD; Joungho Han, MD; Joong Hyun Ahn, MS
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Background:  With International Association for the Study of Lung Cancer (IASLC) lymph node (LN) map, some tumors previously staged as N2 disease with Mountain Dresler-American Thoracic Society (MD-ATS) map, are staged as N1. We aimed to evaluate the effectiveness of IASLC LN map in stratifying patient prognosis in patients with non-small cell lung cancer (NSCLC) and LN metastasis in nodal station 4 or 10.

Methods:  Of 2,086 patients undergoing curative surgical resection for NSCLC, we searched patients who had cancer cell-harboring LNs in nodal station 10 or 4 (n = 531), and reclassified them into three different subgroups (N1 [N1 in both MD-ATS and IASLC maps], in-between [N2 with MD-ATS but N1 in IASLC map], and N2 [N2 in both maps]) based on histopathologic results. We compared disease-free survivals (DFSs) among three subgroups by using Kaplan Meier method and log-rank analysis.

Results:  Of 531 patients, 295 patients belonged to N1 group, 66 patients belonged to in-between group, and 170 patients belonged to N2 group according to the IASLC map. The cumulative DFS rates at 5 years of N1, in-between, and N2 groups were 47%, 39%, and 29%, respectively. In multivariate analysis, LN ratio was identified as significant independent prognostic factor (HR : 2.877, 95% CI : 1.391-5.950, P = .004).

Conclusions:  Changed definition between N1 and N2 diseases by IASLC LN map works well as expected in stratifying patient prognosis. Positive LN ratio may be more valuable than nodal stations involved in predicting patient survival in resectable NSCLC.

original research 
Daniel H. Sterman, MD; Thomas Keast; Lav Rai; Jason Gibbs; Henky Wibowo; Jeff Draper; Felix J. Herth, MD; Gerard A. Silvestri, MD, MS
Topics: , ,

Introduction:  Bronchoscopic Trans-Parenchymal Nodule Access (BTPNA) is a novel approach to accessing pulmonary nodules (PN). This real-time, image-guided approach was evaluated for safety, accuracy, and yield in the healthy canine model.

Methods:  A novel, inorganic model of sub-centimeter pulmonary nodules (PN) was developed, consisting of 0.25 cc aliquots of calcium hydroxylapatite (Radiesse) implanted via trans-bronchial access in airways seven generations beyond the main bronchi to represent targets for evaluation of accuracy and yield. Thoracic computed tomography (CT) scans were acquired for each subject, and from these CT scans LungPoint Virtual Bronchoscopic Navigation software provided guidance to the region of interest, and novel Trans-Parenchymal Nodule Access (TPNA) software algorithms automatically generated point-of-entry (POE) recommendations, registered CT and real-time fluoroscopic images, and overlaid guidance onto live bronchoscopic and fluoroscopic video to achieve a vessel-free, straight-line path from a central airway through parenchymal tissue for access to peripheral lesions.

Results:  In a 9 canine cohort, the BTPNA procedure was performed to sample 31 implanted Radiesse targets, implanted to simulate PNs, via biopsy forceps through a specially designed sheath. The mean length of the 31 tunnels was 35mm (20.5 to 50.3 mm range). Mean tunnel creation time was 16:52 minutes and diagnostic yield was 90.3% (28/31). No significant adverse events were noted in any of the canine subject’s status post BTPNA with no pneumothoraces and minimal bleeding (all bleeding events less than 2 milliliters in volume).

Conclusion:  These canine studies demonstrate that BTPNA has the potential to achieve the high yield of Transthoracic Needle Aspiration (TTNA) with the low complication profile associated with traditional bronchoscopy. These results merit further study in humans.

original research 
Anna L. Peljto; Moises Selman; Dong Soon Kim; Elissa Murphy; Laura Tucker; Annie Pardo; Jung Su Lee; Wonjun Ji; Marvin I. Schwarz; Ivana V. Yang; David A. Schwartz; Tasha E. Fingerlin
Topics: , , ,

Background:  Polymorphisms in the MUC5B promoter, TOLLIP gene, and nine additional genetic loci have been associated with idiopathic pulmonary fibrosis (IPF) within non-Hispanic white populations. It is unknown whether these variants account for risk of IPF in other racial/ethnic populations. We conducted a candidate SNP association study in cohorts of Mexican and Korean IPF patients.

Methods:  We chose 12 SNPs from 11 loci that are associated with IPF among non-Hispanic whites and genotyped these SNPs in cohorts of Mexican (83 cases, 111 controls) and Korean (239 cases, 87 controls) subjects. Each SNP was tested for association with IPF, after adjusting for age and sex.

Results:  The MUC5B promoter SNP rs35705950 was associated with IPF in the Mexican (OR=7.36, p-value=1.1x10-4), but not the Korean (p-value=.99) cohort. The SNP in the IVD gene (chromosome15, rs2034650) was significantly associated with pulmonary fibrosis in both the Mexican (OR=0.40, p-value=0.01) and Korean (OR=0.13, p-value=8.1x10-4) cohorts. In the Korean cohort, there were no other variants associated with disease. In the Mexican cohort, SNPs on chromosomes 3, 4, and 11 were also associated with disease.

Conclusions:  The strongest identified genetic risk factor for IPF among the non-Hispanic white population, the MUC5B promoter polymorphism, is also a strong risk factor in a Mexican population, but is very rare in a Korean population. The majority of genetic variants that account for risk of IPF in groups other than non-Hispanic whites are unknown. Hispanic and Asian populations should be studied separately to identify genetic risk loci for IPF.

original research 
Rachel O’Conor, MPH; Michael S. Wolf, PhD, MPH; Samuel G. Smith, PhD; Melissa Martynenko, MPH; Daniel P. Vicencio, MD; Mary Sano, MD; Juan P. Wisnivesky, MD, DrPH; Alex D. Federman, MD, MPH
Topics: , , ,

Background:  We sought to investigate the degree to which cognitive skills explain associations between health literacy and asthma-related medication use among older adults with asthma.

Methods:  Patients aged 60 years and older receiving care at 8 outpatient clinics (primary care, geriatrics, pulmonology, allergy and immunology) in New York, NY and Chicago, IL were recruited to participate in structured, in-person interviews as part of the Asthma Beliefs and Literacy in the Elderly (ABLE) study (n=425). Behaviors related to medication use were investigated, including adherence to prescribed regimens, metered dose inhaler (MDI) technique, and dry powder inhaler (DPI) technique. Health literacy was measured using the Short Test of Functional Health Literacy in Adults (S-TOFHLA). Cognitive function was assessed in terms of fluid (working memory, processing speed, executive function) and crystallized (verbal) ability.

Results:  The mean age of participants was 68 years; 40% were Hispanic, 30% African American. More than a third (38%) were adherent to their controller medication, 53% demonstrated proper DPI technique, and 38% demonstrated correct MDI technique. In multivariable analyses, limited literacy was associated with poorer adherence to controller medication (OR, 2.3; 95% CI, 1.29-4.08), incorrect DPI (OR, 3.51; 95% CI, 1.81-6.83) and MDI techniques (OR, 1.64; 95% CI, 1.01-2.65). Fluid and crystallized abilities were independently associated with medication behaviors. However, when fluid abilities were added to the model, literacy associations were reduced.

Conclusion:  Among older asthmatics, interventions to promote proper medication use should seek to simplify tasks and patient roles in order to overcome cognitive load and suboptimal performance in self-care.

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