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Editorial

Chest. 2017;151(3):523-524. doi:10.1016/j.chest.2016.09.018
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Acute exacerbations of COPD are responsible for 1.5 million emergency visits and 700,000 hospitalizations per year in the United States. Although most exacerbations are thought to be triggered by microbial agents, approximately 25% to 50% are thought to be noninfectious events, driven by diverse etiologies including air pollution, acute heart failure, ischemic heart disease, and anxiety. Early identification of these noninfectious events is important because standard antiexacerbation therapies including systemic corticosteroids and antibiotics are unlikely to be clinically useful for these etiologies and, of importance, may result in delays in the diagnosis and treatment of noninfectious causes of exacerbation such as acute coronary syndromes or congestive heart failure, leading to poor clinical outcomes.

Chest. 2017;151(3):525-526. doi:10.1016/j.chest.2016.10.053
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Following the publication of the National Lung Screening Trial (NLST), evaluation by the US Preventive Service Task Force, and approval for reimbursement by the Center for Medicare Services, low-dose CT for lung cancer screening is rapidly being adopted across the United States.,, Because lung cancer screening is a relatively new service, has the potential to cause harm as well as benefit, and has societal costs, there are published guidelines for how to set up, run, report, and properly maintain a screening program., A critical part of the screening process is the reporting and management of screen-detected findings, most notably but not limited to lung nodules. In this issue of CHEST, Mehta et al point out a potential pitfall in the reporting process.

Chest. 2017;151(3):527-528. doi:10.1016/j.chest.2017.01.007
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Jockeys hoping to squeeze more out of an exhausted thoroughbred at the end of a race often whip the horse’s thigh with a riding crop. By that point, the poor beast often has nothing left to give. After the recent publication by Nathan et al in the Lancet Respiratory Medicine, any additional pooled or meta-analyses of the impact of pirfenidone on 52-week mortality in patients with idiopathic pulmonary fibrosis (IPF) will be similarly futile. The issue is settled. It is time to move on.

Giants in Chest Medicine

Chest. 2017;151(3):529-530. doi:10.1016/j.chest.2016.07.023
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Editorials: Point and Counterpoint

Chest. 2017;151(3):531-532. doi:10.1016/j.chest.2016.11.021
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The inferior vena cava (IVC), a capacitance reservoir leading directly to the heart, encodes valuable hemodynamic information. When examined throughout the respiratory cycle, dynamic changes in the IVC diameter (ΔIVC) can guide fluid resuscitation,, akin to other dynamic predictors such as pulse pressure variation and respiration-related changes in stroke volume, arterial flow velocity, and ventricular outflow tract velocity time integrals. During positive pressure ventilation of the passive patient, inspiration raises the pleural, juxtacardiac, and right atrial pressures much more than abdominal pressure, transiently depressing venous return to the heart and tending to distend the IVC. The magnitude of this cardiopulmonary interaction depends on IVC compliance, the rise in pleural pressure, and whether the heart is on the steep portion of the cardiac function curve.

Chest. 2017;151(3):533-536. doi:10.1016/j.chest.2016.11.017
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The goal of fluid resuscitation in shock is to improve organ perfusion while avoiding the harms of excess fluid administration. Fluids lead to harm unless: (1) the tissue hypoxia results from inadequate oxygen delivery rather than mitochondrial or microvascular dysfunction; and (2) fluid administration leads to an increase in tissue oxygen delivery.,, Previous debates and investigations have focused on optimal methods for differentiating between states of inadequate oxygen delivery and mitochondrial dysfunction.,, The role of IVC ultrasound in fluid resuscitation focuses on its ability to predict whether fluids will increase cardiac output, a condition known as fluid responsiveness (FR).

Chest. 2017;151(3):536-537. doi:10.1016/j.chest.2016.11.019
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For a patient in shock, ultrasound of the IVC is a fundamental component of the intensivist’s assessment. Dr Kory argues that IVC diameter and its variation cannot be reliably assessed, but most intensivists find that the longitudinal, subcostal examination is easily learned. Interrater reliability is known to be high,, and, with careful attention to methodology, errors are uncommon. Facility with trans-hepatic (and occasionally trans-splenic) sonographic windows makes the examination applicable for nearly every critically ill patient.

Chest. 2017;151(3):537-538. doi:10.1016/j.chest.2016.11.020
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I appreciate and commend Dr Schmidt’s succinct review of the physiology underlying cardiac filling and output. He accurately observes that IVC distention has a strong correlation with FR. He neglects to mention, however, that IVC distention is found in such rare circumstances, it could never serve as the primary guide to fluid resuscitation unless we heavily sedated, paralyzed, and overinflated our intubated patients, an approach violating some of the most beneficial patient care practices we know of today (ie, low-tidal volume ventilation, avoiding delirium, increasing mobility). Thus, the debate rests almost entirely on the predictive merits of the most common respirophasic IVC variation encountered, which is IVC collapse.

Commentary

Chest. 2017;151(3):539-543. doi:10.1016/j.chest.2016.07.028
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Lung cancer screening using low-dose CT scanning reduces lung-cancer-specific and overall mortality in high-risk patients. A significant limitation of lung cancer screening is the false-positive rate. The American College of Radiology Lung Imaging Reporting and Data System (Lung-RADS) was designed to standardize reporting of low-dose lung cancer screening results and to decrease the false-positive rate without significantly compromising sensitivity. Implementing Lung-RADS can also improve cost-effectiveness. However, Lung-RADS has never been studied in a prospective fashion. It also does not have a specific reporting category for patients with isolated hilar and mediastinal adenopathy or pleural effusion in the absence of lung nodules. We report four such cases from our lung cancer screening program. We believe that this is a significant limitation of Lung-RADS and should be revised in its new version.

Original Research: COPD

Chest. 2017;151(3):544-554. doi:10.1016/j.chest.2016.07.034

Background  Patients with COPD experience episodes of increased inflammation, so-called acute exacerbations of COPD (AE-COPD). In 30% of AE-COPD cases, no clear cause is found. Since there is well-known cross talk between inflammation and thrombosis, the objectives of this study were to determine the prevalence, embolus localization, clinical relevance, and clinical markers of pulmonary embolism (PE) in unexplained AE-COPD.

Methods  A systematic search was performed using MEDLINE and EMBASE platforms from 1974 to October 2015. Prospective and cross-sectional studies that included patients with AE-COPD and used pulmonary CT-angiography for diagnosis of PE were included.

Results  The systematic search resulted in 1,650 records. The main reports of 22 articles were reviewed, and 7 studies were included. The pooled prevalence of PE in unexplained AE-COPD was 16.1% (95% CI, 8.3%-25.8%) in a total of 880 patients. Sixty-eight percent of the emboli found were located in the main pulmonary arteries, lobar arteries, or interlobar arteries. Mortality and length of hospital admission seemed to be increased in patients with unexplained AE-COPD and PE. Pleuritic chest pain and cardiac failure were more frequently reported in patients with unexplained AE-COPD and PE. In contrast, signs of respiratory tract infection was less frequently related to PE.

Conclusions  PE is frequently seen in unexplained AE-COPD. Two-thirds of emboli are found at locations that have a clear indication for anticoagulant treatment. These findings merit clinical attention. PE should receive increased awareness in patients with unexplained AE-COPD, especially when pleuritic chest pain and signs of cardiac failure are present, and no clear infectious origin can be identified.

Chest. 2017;151(3):555-563. doi:10.1016/j.chest.2016.10.058
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Background  Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.

Methods  Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers.

Results  Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (–8.33 ± 0.172 logM vs –8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003).

Conclusions  GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD.

Trial Registry  ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov

Original Research: Lung Cancer

Chest. 2017;151(3):564-571. doi:10.1016/j.chest.2016.10.025

Background  The benefits of a diagnostic workup for occult cancer in patients with VTE are controversial. Our aim was to provide and validate a risk score for occult cancer in patients with VTE.

Methods  We designed a nested case-control study in a cohort of patients with VTE included in the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry from 2001 to 2014. Cases included cancer detected beyond the first 30 days and up to 24 months after VTE. Control subjects were defined as patients with VTE with no cancer in the same period.

Results  Of 5,863 eligible patients, 444 (7.6%; 95% CI, 6.8%-8.2%) were diagnosed with occult cancer. On multivariable analysis, variables selected were male sex, age > 70 years, chronic lung disease, anemia, elevated platelet count, prior VTE, and recent surgery. We built a risk score assigning points to each variable. Internal validity was confirmed using bootstrap analysis. The proportion of patients with cancer who scored ≤ 2 points was 5.8% (241 of 4,150) and that proportion in those who scored ≥ 3 points was 12% (203 of 1,713). We also identified scores divided by sex and age subgroups.

Conclusions  This is the first risk score that has identified patients with VTE who are at increased risk for occult cancer. Our score needs to be externally validated.

Chest. 2017;151(3):572-578. doi:10.1016/j.chest.2016.10.027

Background  Lung cancer screening is a complex balance of benefits and harms. A counseling and shared decision-making visit has been mandated to assist patients with the decision about participation in screening. To our knowledge, the impact of this visit on patient understanding and decisions has not been studied.

Methods  We developed a centralized counseling and shared decision-making visit for our lung cancer screening program. The visit included confirmation of eligibility for screening, education supported by a narrated slide show, individualized risk assessment with a decision aid, time for answering questions, and data collection. We surveyed consecutive patients prior to the visit, immediately after the visit, and 1 month after the visit to determine the impact of the visit on their knowledge.

Results  Twenty-three of 423 patients (5.4%) who had a visit did not proceed to the screening CT scan. One hundred twenty-five consecutive patients completed the initial survey, 122 completed the postvisit survey, and 113 completed the 1-month follow-up survey. Prior to the visit, the patients had a poor level of understanding about the age and smoking eligibility criteria (8.8% and 13.6% correct, respectively) and the benefits and harms of screening (55.2% and 38.4% correct, respectively). There was a significant improvement in knowledge noted after the visit for all questions (P = .03 to P < .0001). Knowledge waned by the 1-month follow-up but remained higher than it was before the visit.

Conclusions  A centralized counseling and shared decision-making visit impacts the patient's knowledge about the eligibility criteria, benefits, and harms of lung cancer screening with LDCT, helping patients make value-based decisions.

Original Research: Critical Care

Chest. 2017;151(3):579-585. doi:10.1016/j.chest.2016.10.035

Background  Overuse of arterial blood gas (ABG) determinations leads to increased costs, inefficient use of staff work hours, and patient discomfort and blood loss. We developed guidelines to optimize ABG use in the ICU.

Methods  ABG use guidelines were implemented in all adult ICUs in our institution: three medical, two trauma-surgery, one cardiovascular, and one neurosurgical ICU. Although relying on pulse oximetry, we encouraged the use of ABG determination after an acute respiratory event or for a rational clinical concern and discouraged obtaining ABG measurements for routine surveillance, after planned changes of positive end-expiratory pressure or Fio2 on the mechanical ventilator, for spontaneous breathing trials, or when a disorder was not suspected. ABG measurements and global ICU metrics were collected before (year 2014) and after (year 2015) the intervention.

Results  We saw a reduction of 821.5 ± 257.4 ABG determinations per month (41.5%), or approximately one ABG determination per patient per mechanical ventilation (MV) day for each month (43.1%), after introducing the guidelines (P < .001). This represented 49 L of saved blood, a reduction of $39,432 in the costs of ICU care, and 1,643 staff work hours freed for other tasks. Appropriately indicated tests rose to 83.4% from a baseline 67.5% (P = .002). Less than 5% of inappropriately indicated ABG determinations changed patient management in the postintervention period. There were no significant differences in MV days, severity of illness, or ICU mortality between the two periods.

Conclusions  The large scale implementation of guidelines for ABG use reduced the number of inappropriately ordered ABG determinations over seven different multidisciplinary ICUs, without negatively impacting patient care.

Chest. 2017;151(3):586-596. doi:10.1016/j.chest.2016.10.057

Background  A proposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome (SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA) score of ≥ 2, and conceived “qSOFA” (quick SOFA) as a bedside indicator of organ dysfunction. We aimed to (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis-2) and revised (Sepsis-3) definitions for organ dysfunction in ED patients with infection.

Methods  Consecutive ED patients admitted with presumed infection were prospectively enrolled over 3 years. Sufficient observational data were collected to calculate SIRS, qSOFA, SOFA, comorbidity, and mortality.

Results  We enrolled 8,871 patients, with SIRS present in 4,176 (47.1%). SIRS was associated with increased risk of organ dysfunction (relative risk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2). SIRS and qSOFA showed similar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72 vs 0.73). qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively). Mortality for patients with organ dysfunction was similar for Sepsis-2 and Sepsis-3 (12.5% and 11.4%, respectively), although 29% of patients with Sepsis-3 organ dysfunction did not meet Sepsis-2 criteria. Increasing numbers of Sepsis-2 organ system dysfunctions were associated with greater mortality.

Conclusions  SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature. A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as a bedside screening method. Although mortality for organ dysfunction was comparable between Sepsis-2 and Sepsis-3, more prognostic and clinical information is conveyed using Sepsis-2 regarding number and type of organ dysfunctions. The SOFA score may require recalibration.

Original Research: Sleep Disorders

Chest. 2017;151(3):597-611. doi:10.1016/j.chest.2016.12.005

Background  Surgical patients with OSA are at increased risk for perioperative complications. Postoperative supplemental oxygen is commonly used, but it may contribute to respiratory depression in patients with OSA receiving opioids. The objective of the study is to investigate the effect of postoperative supplemental oxygen on arterial oxygen saturation (Sao2), sleep respiratory events, and CO2 level in patients with untreated OSA.

Methods  Consented patients with an apnea hypopnea index (AHI) > 5 events per hour on a preoperative polysomnography were randomized (1:1) to oxygen (O2 group) or no oxygen (control group). The O2 group received oxygen at 3 L/min via nasal prongs for three postoperative nights. The primary outcomes were polysomnographic parameters measuring Sao2, sleep respiratory events, and Pco2 measured by transcutaneous CO2 monitor (PtcCO2) on nights 1 through 3. The intention-to-treat and per protocol analysis were completed.

Results  There were 123 patients randomized (O2 group: n = 62; control group: n = 61). On night 3, the O2 vs control group had a higher average Sao2 (95.2% ± 3% vs 91.4% ± 4%, respectively; P < .001) and lower oxygen desaturation index (median, 2.3; 25th-75th percentile, 0.2-13.8 vs median, 18.5; 25th-75th percentile, 8.2-45.9 events per hour, respectively; P < .0001). The O2 group had a decreased AHI (median, 8.0; 25th-75th percentile, 2.1-19.9 vs median, 15.6; 25th-75th percentile, 9.5-45.8, respectively; P = .016), hypopnea index (P < .001), and central apnea index (P = .026) and a shortened longest apnea hypopnea duration (P = .002). Although time percentage with PtcCO2 ≥ 55 mm Hg ≥ 10% on postoperative night 1, 2, or 3 was found in 11.4% patients, there was no difference in PtcCO2 between the groups.

Conclusions  Postoperative supplemental oxygen was found to improve oxygenation and decrease the AHI without increasing the duration of apnea-hypopnea event or PtcCO2 level. A small number of patients had significant CO2 retention while receiving supplemental oxygen.

Trial Registry  ClinicalTrials.gov; No.: NCT01552304; URL: www.clinicaltrials.gov

Original Research: Asthma

Chest. 2017;151(3):612-618. doi:10.1016/j.chest.2016.10.028
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Background  The importance of balance between controller and reliever medications in asthma is recognized. However, to our knowledge, the extent to which real-world practice has caught up with evidence-based guidelines has not been studied.

Methods  This was a retrospective cohort study of individuals 15 to 67 years of age who satisfied a validated case definition of asthma in the administrative health database of British Columbia, Canada between 2002 and 2013. Each patient-year was assessed for inappropriate and excessive prescription of short-acting beta-agonists (SABAs) and the balance between controller and reliever medications. Trends on three time axes were evaluated: calendar time, time course of asthma, and age. Poisson regression was used to test for a linear trend.

Results  Three hundred fifty-six thousand, one hundred twelve patients (56.5% female sex; mean age, 30.5 years) contributed 2.6 million patient-years. In 7.3% of the patient-years, SABAs were prescribed inappropriately. This proportion dropped by a relative rate of 5.3% per year (P < .001). In the first year of asthma, 6.3% of patients had indicators of inappropriate SABA use, which dropped within the first 3 years but increased thereafter. Excessive prescription of SABAs increased rapidly during the time course of asthma (change of 23.3% per year; P < .001) and by age (change of 5.1% per year; P < .001).

Conclusions  Despite overwhelming evidence regarding the risks, inappropriate prescription for SABAs was prevalent. Excessive SABA use might explain high asthma mortality in older patients. Inappropriate prescriptions declined over the study period but increased over the time course of asthma. These trends might have contributed to the declining asthma hospitalization rates in British Columbia, but there remain gaps in care and potential for improvement in asthma outcomes.

Original Research: Diffuse Lung Disease

Chest. 2017;151(3):619-625. doi:10.1016/j.chest.2016.10.029

Background  The treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP.

Methods  Patients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use.

Results  Seventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco) % predicted were declining at a mean rate of 0.12% (P < .001) and 0.10% (P < .001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in Dlco of 4.2% (P < .001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).

Conclusions  Treatment with MMF or AZA is associated with improvements in Dlco in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.

Original Research: Pulmonary Procedures

Chest. 2017;151(3):626-635. doi:10.1016/j.chest.2016.10.052

Background  The indwelling pleural catheter (IPC), which was initially introduced for the management of recurrent malignant effusions, could be a valuable management option for recurrent benign pleural effusion (BPE), replacing chemical pleurodesis. The purpose of this study is to analyze the efficacy and safety of IPC use in the management of refractory nonmalignant effusions.

Methods  We conducted a systematic review and meta-analysis on the published literature. Retrospective cohort studies, case series, and reports that used IPCs for the management of pleural effusion were included in the study.

Results  Thirteen studies were included in the analysis, with a total of 325 patients. Congestive heart failure (49.8%) was the most common cause of BPE requiring IPC placement. The estimated average rate of spontaneous pleurodesis was 51.3% (95% CI, 37.1%-65.6%). The estimated average rate of all complications was 17.2% (95% CI, 9.8%-24.5%) for the entire group. The estimated average rate of major complications included the following: empyema, 2.3% (95% CI, 0.0%-4.7%); loculation, 2.0% (95% CI, 0.0%-4.7%); dislodgement, 1.3% (95% CI, 0.0%-3.7%); leakage, 1.3% (95% CI, 0.0%-3.5%); and pneumothorax, 1.2% (95% CI, 0.0%-4.1%). The estimated average rate of minor complications included the following: skin infection, 2.7% (95% CI, 0.6%-4.9%); blockage and drainage failure, 1.1% (95% CI, 0.0%-3.5%); subcutaneous emphysema, 1.1% (95% CI, 0.0%-4.0%); and other, 2.5% (95% CI, 0.0%-5.2%). One death was directly related to IPC use.

Conclusions  IPCs are an effective and viable option in the management of patients with refractory BPE. The quality of evidence to support IPC use for BPE remains low, and high-quality studies such as randomized controlled trials are needed.

Chest. 2017;151(3):636-642. doi:10.1016/j.chest.2016.10.005

Background  Endobronchial ultrasonographically guided transbronchial needle aspiration (EBUS-TBNA) of thoracic structures is a commonly performed tissue sampling technique. The use of an inner-stylet in the EBUS needle has never been rigorously evaluated and may be unnecessary.

Methods  In a prospective randomized single-blind controlled clinical trial, patients with a clinical indication for EBUS-TBNA underwent lymph node sampling using both with-stylet and without-stylet techniques. Sample adequacy, diagnostic yield, and various cytologic quality measures were compared.

Results  One hundred twenty-one patients were enrolled, with 194 lymph nodes sampled, each using both with-stylet and without-stylet techniques. There was no significant difference in sample adequacy or diagnostic yield between techniques. The without-stylet technique resulted in adequate samples in 87% of the 194 study lymph nodes, which was no different from the with-stylet adequacy rate (82%; P = .371). The with-stylet technique resulted in a diagnosis in 50 of 194 samples (25.7%), which was similar to the without-stylet group (49 of 194 [25.2%]; P = .740). There was a high degree of concordance in the determination of adequacy (84.0%; 95% CI, 78.1-88.9) and diagnostic sample generation (95.4%; 95% CI, 91.2-97.9) between the two techniques. A similar qualitative number of lymphocytes, malignant cells, and bronchial respiratory epithelia were recovered using each technique.

Conclusions  Omitting stylet use during EBUS-TBNA does not affect diagnostic outcomes and reduces procedural complexity.

Trial Registry  ClinicalTrials.Gov: No. NCT 02201654; URL:www.clinicaltrials.gov.

Original Research: Pulmonary Vascular Disease

Chest. 2017;151(3):643-649. doi:10.1016/j.chest.2016.10.002
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Background  Balloon pulmonary angioplasty (BPA) in chronic thromboembolic pulmonary hypertension (CTEPH) improves hemodynamics and exercise capacity. However, its effect on respiratory function is unclear. Our objective was to investigate the effect of BPA on respiratory function.

Methods  We enrolled patients with inoperable CTEPH who underwent BPA primarily in lower lobe arteries (first series) and upper and middle lobe arteries (second series). We compared changes in hemodynamics and respiratory function between different BPA fields.

Results  Sixty-two BPA sessions were performed in 13 consecutive patients. Mean pulmonary arterial pressure and pulmonary vascular resistance significantly improved from 44 ± 8 to 23 ± 5 mm Hg and 818 ± 383 to 311 ± 117 dyne/s/cm−5. The percent predicted diffusion capacity of lung for carbon monoxide (Dlco) decreased after BPA in the lower lung field (from 60% ± 8% to 54% ± 8%) with no recovery. Percent Dlco increased after BPA in the upper middle lung field (from 53% ± 6% to 58% ± 6%) and continued to improve during the follow-up (from 58% ± 6% to 64% ± 11%). The ventilation/Co2 production (e/co2) slope significantly improved after BPA in the lower lung field (from 51 ± 13 to 41 ± 8) and continued to improve during the follow-up (from 41 ± 8 to 35 ± 7); however, the e/co2 slope remained unchanged after BPA in the upper/middle lung field. Changes in % Dlco and the e/co2 slope differed significantly between lower and upper/middle lung fields.

Conclusions  The effect of BPA on respiratory function in patients with CTEPH differed depending on the lung field.

Original Research: Tobacco Cessation and Prevention

Chest. 2017;151(3):650-657. doi:10.1016/j.chest.2016.12.008

Background  Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β2-adrenoceptor-mediated vasodilation in smokers and never smokers.

Methods  In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived.

Results  Albuterol induced a substantial drop in mean (± SE) PVR (–67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (–28.6% ± 3% vs –3.1% ± 6%; P < .02).

Conclusions  These results are consistent with a dysfunction in a β2-adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium.

Original Research: Occupational and Environmental Lung Disease

Chest. 2017;151(3):658-667. doi:10.1016/j.chest.2016.10.030
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Background  The synthetic peptide solnatide is a novel pharmacologic agent that reduces extravascular lung water, blunts reactive oxygen species production, and improves lung function due to its ability to directly activate the epithelial sodium channel. The goal of this study was to investigate the effect of solnatide in pulmonary edema induced by acute hypobaric hypoxia and exercise in rats, which is considered a model for high-altitude pulmonary edema.

Methods  Sprague-Dawley rats were assigned to low-altitude control and eight treatment groups. Animals of all groups were subjected to exhaustive exercise in a hypobaric hypoxic environment simulating an altitude of 4,500 meters, followed by simulated ascent to 6,000 meters. After 48 h at 6,000 meters, rats were given sodium chloride, dexamethasone, aminophylline, p38 mitogen activated protein kinase inhibitor, and NOD-like receptor containing a pyrin domain 3 inhibitor, or one of three different doses of solnatide, once daily for 3 consecutive days. After 3 days, arterial blood gas, BAL fluid, lung water content, and histologic and ultra-microstructure analyses were performed. Tight junction protein occludin was assayed by using immunohistochemistry.

Results  Rats treated with solnatide had significantly lower BAL fluid protein and lung water content than high-altitude control rats. Lungs of solnatide-treated rats were intact and showed less hemorrhage and disruption of the alveolar-capillary barrier than those of high-altitude control animals. Occludin expression was significantly higher in solnatide-treated animals, compared with high-altitude control, dexamethasone-, and aminophylline-treated animals.

Conclusions  Solnatide reduced pulmonary edema, increased occludin expression, and improved gas-blood barrier function during acute hypobaric hypoxia and exercise in rats. These results provide a rationale for the clinical application of solnatide to patients with pulmonary edema and exposure to a high-altitude hypoxic environment.

Translating Basic Research Into Clinical Practice

Chest. 2017;151(3):668-673. doi:10.1016/j.chest.2016.09.030

Dendritic cells (DCs) are potent antigen-presenting cells. Because of their particular ability to initiate and regulate cell mediated and humoral immune responses, there is considerable interest in the role that DCs play in the pathogenesis of various lung diseases, especially those in which there is an excessive immune response to specific antigens (as in asthma) or a deficient immune response (as in lung cancer). A number of DC subpopulations have been defined in the lungs, including myeloid or conventional DCs that initiate T-cell immunity and antibody production and plasmacytoid DCs that have an important role in antiviral immunity and immune tolerance. Although an extensive body of literature has documented the role that DCs play in experimental models of lung disease, this review will highlight recent advances in our understanding of DC function in human disease, including asthma, COPD, antimicrobial immunity, and lung cancer. The future is likely to see new approaches whereby antigens and small molecules are targeted to receptors on particular DC subpopulations in order to modify pulmonary immune responses.

Recent Advances in Chest Medicine

Chest. 2017;151(3):674-685. doi:10.1016/j.chest.2016.05.025
OPEN ACCESS

The detection of peripheral lung nodules is increasing because of the expanded use of CT imaging and implementation of lung cancer screening recommendations. Although surgical resection of malignant nodules remains the treatment modality of choice at present, many patients are not surgical candidates, thus prompting the need for other therapeutic options. Stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation are emerging as viable alternatives to surgical resection. For safety, efficacy, and cost-effectiveness purposes, however, alternative bronchoscopic methods for treatment of peripheral lung cancer are currently under active exploration.

We searched the Cochrane Library and MEDLINE from 1990 to 2015 to provide the most comprehensive review of bronchoscopic treatment of malignant lung nodules. We used the following search terms: bronchoscopy, lung nodule, peripheral lung lesion, and bronchoscopic treatment. We focused on peripheral pulmonary nodules that are confirmed or highly likely to be malignant. Seventy-one articles were included in this narrative review. We have provided an overview of advanced bronchoscopic modalities that have been used or are under active investigation for definitive treatment of malignant pulmonary nodules. We have concisely discussed the use of direct intratumoral chemotherapy or gene therapies, transbronchial brachytherapy, bronchoscopy-guided radiofrequency ablation (RFA), placement of markers to guide real time-radiation and surgery, cryotherapy, and photodynamic therapy. We have also briefly reported on emerging technologies such as vapor ablation of lung parenchyma for lung cancers. Advances in bronchoscopic therapy will bring additional treatment options to patients with peripheral lung malignancies, with putative advantages over other minimally invasive modalities.

Special Features

Chest. 2017;151(3):686-696. doi:10.1016/j.chest.2016.10.031
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COPD is a highly debilitating disease that represents a substantial and growing health burden in women. There is increasing evidence for sex-related differences in COPD risk, progression, and outcomes. However, the disease receives scant attention as a women’s health issue. Thus, a multifaceted approach is required to address COPD in women, including greater awareness, minimization of risk, and further elucidation of the sex-specific factors (biological and cultural) that affect risk, disease progression, and treatment success. This article reviews the current literature on the topic and provides suggestions for achieving better outcomes for the millions of women with COPD worldwide.

Contemporary Reviews in Critical Care Medicine

Chest. 2017;151(3):697-706. doi:10.1016/j.chest.2016.10.040

Neuromuscular blockings agents (NMBAs) have a controversial role in the ventilatory and medical management of critical illness. The clinical concern surrounding NMBA-induced complications stems from evidence presented in the 2002 clinical practice guidelines, but new evidence from subsequent randomized trials and studies provides a more optimistic outlook about the application of NMBAs in the ICU. Furthermore, changes in the delivery of critical care, such as protocolized care pathways, minimizing or interrupting sedation, increased monitoring techniques, and overall improvements in reducing immobility, have created a modern, 21st century ICU environment whereby NMBAs may be administered safely. In this article we start with a review of the mechanism of action, side effects, and pharmacology of commonly used NMBAs. We then address the rationale for NMBA use for an expanding number of indications (endotracheal intubation, acute respiratory distress syndrome, status asthmaticus, increased intracranial and intra-abdominal pressure, and therapeutic hypothermia after cardiac arrest), with an emphasis on NMBA use in facilitating lung-protective ventilation for respiratory failure. We end with an appraisal over the importance of monitoring depth of paralysis and the concerns of complications, such as prolonged skeletal muscle weakness. In the context of adequate sedation and analgesia, monitored NMBA use (continuous or bolus administration) can be considered for the small number of clinical indications in critically ill patients for which evidence currently exists.

Contemporary Reviews in Sleep Medicine

Chest. 2017;151(3):707-719. doi:10.1016/j.chest.2016.11.049

CPAP is the first-line treatment for moderate to severe OSA syndrome. Up to 25% of patients with OSA syndrome discontinue CPAP treatment due to side effects. Unintentional leakage and its associated annoying consequences are the most frequently reported adverse effects of CPAP. Successive technological improvements have not succeeded in addressing this issue. A systematic review was conducted (1) to assess the impact of different technological advances on unintentional leaks and (2) to determine if any patient characteristics have already been identified as determinants of unintentional leakage. No CPAP modality was superior to another in reducing unintentional leaks and, surprisingly, oronasal masks were associated with higher unintentional leaks. Nasal obstruction, older age, higher BMI, central fat distribution, and male sex might be associated with an increased risk of unintentional leakage. Such leaks remain an important problem. Further studies are needed to improve the understanding of underlying clinical factors so that patients at risk of unintentional leaks may be identified and individualized solutions applied.

Pectoriloquy

Chest. 2017;151(3):720. doi:10.1016/j.chest.2016.08.1456
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    You play this game around the kitchen table, the big, round, white laminated table.

    You listen carefully while your father presents the case.

    The symptoms are some of the clues you must use to solve the mystery

    (electrolytes out of whack, fatigue),

    Along with the presentation of the patient your father enacts (morose),

    The cadence of the voice (deep and slow),

    Description of the face (eyes downcast, droopy),

    The gait (slow),

    The family input (a change, a loss).

    The false diagnoses that had led to the consultation with the expert, your father

    (drugs, kidney disease).

    What would it be this time?

    Good guesses are surreptitious vomiting (now called bulimia),

    or hypothyroidism, my favorites.

    Outcome of the game:

    three out of four children who play this game will go to medical school,

    inspired by the mystery and theatricality of their father’s game,

    by his coming alive as he solves the mysteries that save lives.

    The fourth will become a psychologist,

    fascinated by the self-destructive aspects in her father’s stories,

    then she will become a writer,

    realizing that it is the stories themselves that make her come alive.

Chest. 2017;151(3):721. doi:10.1016/j.chest.2016.08.1450
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    When the surgeon
    opens my chest
    to remove
    the ground glass nodule,
    he will find

    no coal dust,
    no tobacco,
    just a trace of grass.

    Some sadness and some guilt
    tied up in gossamer,
    a miniature Ruth Asawa sculpture,
    finely woven.

    I lie awake, exhaling.
    I hear the tumor’s whisper,
    a baby ready to come into the world.

    I wonder how it grew,
    no love child.

    A transparent oval gestated
    from small sins or bad karma,
    invisible on x rays,
    innocently curled up on my left lung.

    A tiny ghost escaping just in time,
    two days before Halloween,
    it will slip from the doctor’s hands
    in search of another crevice to haunt.

    Or float freely
    on the cool autumn breeze,
    unnoticed,
    among thousands of falling leaves.

Correspondence

Chest. 2017;151(3):722. doi:10.1016/j.chest.2016.10.045
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I read with great interest the retrospective study by Mayo Clinic researchers Ussavarungsi and colleagues, on transbronchial cryobiopsies for the diagnosis of diffuse parenchymal lung diseases (DPLDs), in a recent issue of CHEST (February 2017). Transbronchial cryobiopsies have emerged as an exciting diagnostic alternative for patients with DPLD, being less invasive than surgical lung biopsies but with a reported safety profile similar to that of conventional transbronchial biopsies. While the yield reported by the Mayo Clinic investigators is lower than those reported in previous studies, diagnostic yield remains an elusive end point in the absence of the comparative “gold standard” of surgical lung biopsy.

Chest. 2017;151(3):722-723. doi:10.1016/j.chest.2016.10.046
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We appreciate the insightful comments by Dr Maldonado regarding our study. As reported, our study demonstrated a diagnostic yield of 51%, which was lower than those reported previously. The diagnostic yield of transbronchial cryobiopsy has varied in studies published to date. This likely reflects the experience of bronchoscopists and pathologists as well as the technique used (ie, size of cryoprobe, freezing time, site and number of biopsy samples, etc.). Aside from the size of cryobiopsy specimens, pathologists likely have differing thresholds in diagnosing histopathologic patterns such as usual interstitial pneumonia (UIP) on bronchoscopic biopsy specimens. Thus, some authors have employed terms such as “possible UIP” and “probable UIP” in the interpretation of cryobiopsy specimens. Furthermore, it is notable that the portion of transbronchial cryobiopsy specimens that were interpreted to show a UIP pattern has varied widely in prior studies.,,,, Substantial interobserver variability among pathologists has been demonstrated even in the interpretation of surgical lung biopsies in patients with idiopathic interstitial pneumonias.,

Chest. 2017;151(3):723-724. doi:10.1016/j.chest.2016.10.062
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In a recent issue (December 2016) of CHEST, Gupta et al clearly describe the epidemiology of culture negative severe sepsis (CNSS). Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the presence of proven or suspected infection. However in 40% to 50% of patients, cultures are negative., Most clinicians will not be surprised by these data. SIRS criteria are met by many critically ill patients. Severe pancreatitis; major trauma; severe hemorrhage; major surgery; infections with viral, fungal, or bacterial pathogens; and autoimmune diseases all can elicit SIRS symptoms. If we cannot detect 1 of these causes, it is convenient to blame an unidentified pathogen and call it CNSS. It is an ancient human habit to give something a name and then feel master of it. (Genesis 2-19: Now the LORD God had formed out of the ground all the wild animals and all the birds in the sky. He brought them to the man to see what he would name them; and whatever the man called each living creature, that was its name.)

Chest. 2017;151(3):724. doi:10.1016/j.chest.2016.11.023
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We appreciate the comments by Drs. Meurs et al on our study detailing the epidemiology and outcomes of culture negative severe sepsis. We agree with the authors that systemic inflammatory response syndrome (SIRS) symptoms can be elicited by not only infections (identified or unidentified), but also other inflammatory conditions. It is, however, important to understand that these patients who qualify for the definition of severe sepsis but are in fact culture negative (ie, have culture negative severe sepsis) are a distinct cohort of patients with worse outcomes and therefore need to be looked at more carefully during evaluations. Our study provides an important groundwork for designing future studies to investigate and improve outcomes for this distinct population. It will also be important to see how this cohort changes with the adoption of the new definition of sepsis. Rather than defining a new term, the aim of our study was to describe and direct attention toward this vulnerable population. We would, therefore, propose to avoid using the new terminology of SIRS-unknown origin as suggested by the authors, especially because SIRS criteria are going out of favor for more updated definitions of sepsis.

Chest. 2017;151(3):724-725. doi:10.1016/j.chest.2016.10.065
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We read with interest the recent article from Bafadhel et al published in CHEST (August 2016) and the more recent article from Couillard et al (published in CHEST October 2016) examining the possible role of eosinophils as markers of disease severity and clinical outcome in exacerbations of COPD. The report by Bafadhel et al suggests that patients presenting to a hospital with an eosinophilic exacerbation of COPD had a shorter length of stay. However, in this study, the authors also reported that readmission rates at 1 year were similar in eosinophilic and noneosinophilic exacerbations. The subsequent study by Couillard et al suggests that eosinophilia was associated with an increased risk of 12-month COPD related readmission.

Chest. 2017;151(3):725-726. doi:10.1016/j.chest.2016.12.032
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We read with great interest the paper by Akizuki et al in this issue of CHEST. They reported that in patients with chronic thromboembolic pulmonary hypertension (CTEPH), diffusing capacity for carbon monoxide (Dlco) decreased after balloon pulmonary angioplasty (BPA), for mainly the lower lung lobes, and increased after BPA for upper lung lobes. They attributed these changes to the difference in the ventilation/perfusion ratio (V˙ /Q˙ ) between the upper and lower lobes. They hypothesized that BPA of the lower lobes, which have a low V˙ /Q˙ , further led to a decrease in the ratio, which in turn decreased the Dlco. We would like to add some points to this discussion.
Chest. 2017;151(3):726-727. doi:10.1016/j.chest.2017.01.022
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First, we would like to thank Dr Takei and colleagues for their sincere comments. In their letter to the editor regarding our recent paper, they made two important suggestions about analyzing the dead-space/tidal volume (Vd/Vt) and shunt fraction (Qs/Qt) to distinguish the amelioration of high ventilation/perfusion (V˙ /Q˙ ) and deterioration of low V˙ /Q˙  in different lung lobes. We agree that other objective evaluation methods for determining a change in V˙ /Q˙  would aid in supporting our hypothesis that the effect of balloon pulmonary angioplasty (BPA) differs between the upper and lower lobes due to a difference in the V˙ /Q˙ .
Chest. 2017;151(3):727-728. doi:10.1016/j.chest.2016.11.032
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We read with interest the study by Jara-Palomares and colleagues in this issue of CHEST. The article describes a score for identifying patients at higher risk of having an occult cancer identified after first presenting with VTE. We have previously published a study describing a similar predictive score and using similar methodology.

Chest. 2017;151(3):728-729. doi:10.1016/j.chest.2016.11.038
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We thank Drs Ferreyro et al for their interest in our article, their insightful comments, and the opportunity to reply. Ferreyro et al published a prognostic score with a final sample of 540 patients with VTE in 2013. Of these patients, 349 (two-thirds) composed the derivation cohort and 191 patients the validation cohort. In the derivation cohort, there were 32 cancers (9.2%) diagnosed during 1 year of follow-up. Moreover, they included a secondary analysis evaluating a combined outcome of cancer or death to address the possibility that death might occur before the identification of an occult cancer. In our opinion, this analysis should be taken with caution, because it is very difficult to assume that all deaths are secondary to occult cancer. In our study, 444 patients (7.6%; 95% CI, 6.90-8.28) were diagnosed with cancer beyond the first 30 days with a follow-up 2 years. One of the major differences with the study by Ferreyro et al is the sample size. As we know, the choice of an adequate sample size for a Cox regression analysis is generally based on the rule of thumb derived from simulation studies of a minimum of 10 events per variable. In the multivariate model, the authors included 3 variables, obtaining for previous VTE ß: 64 (95 CI%, 7.07-579). This large CI suggests that these data are not robust, mostly resulting from few events.

Erratum

Chest. 2017;151(3):730. doi:10.1016/j.chest.2017.01.016
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The authors have reported to CHEST that an error appeared in the figures in “Omalizumab Treatment Response in a Population With Severe Allergic Asthma and Overlapping COPD” (Chest. 2017;151(1):78-89).

Ultrasound Corner

Chest. 2017;151(3):e49-e51. doi:10.1016/j.chest.2016.07.048
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The patient is a 26-year-old man with a history of epidermolysis bullosa and extensive skin lesions complicated by squamous cell carcinoma in multiple sites, status post left above knee amputation with a percutaneous endoscopic jejunostomy tube placement for enteral nutrition, which was complicated by frequent dislodgment. The patient was initially admitted for aspiration pneumonia and sepsis that led to prolonged mechanical ventilation and subsequent tracheostomy.

Chest. 2017;151(3):e53-e56. doi:10.1016/j.chest.2016.07.047
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A 46-year-old man was brought to the ED with severe acute dyspnea and signs of systemic hypoperfusion that had evolved for the previous 2 hours. He also manifested abdominal and chest pain. His medical history revealed active smoking; family medical history was unremarkable.

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2017;151(3):e57-e62. doi:10.1016/j.chest.2017.01.023
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Case Presentaion  A 63-year-old woman visited our hospital for a further evaluation of progressive dyspnea. She had developed a progressive airflow obstruction after 3 years’ remission of non-Hodgkin’s lymphoma (follicular mixed cell type), which had been treated with chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The patient’s primary care physician had diagnosed her as having COPD and bronchial asthma and had treated her with medications including inhaled corticosteroids, tiotropium, and oral erythromycin. Her dyspnea had gradually worsened, however, and she had a score of 4 on the modified Medical Research Council dyspnea scale at the time of admission to our hospital.

Chest. 2017;151(3):e63-e68. doi:10.1016/j.chest.2016.09.006
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Case Presentaion  A 42-year-old woman with mixed connective tissue disease-associated interstitial lung disease underwent bilateral lung transplantation. She had an uneventful surgery and was extubated 3 h later. Induction immunosuppression therapy included methylprednisolone 500 mg intraoperatively, basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation, and methylprednisolone 125 mg intravenously bid for 2 days following surgery. Maintenance immunosuppression therapy consisted of prednisone 20 mg daily, mycophenolate mofetil 750 mg bid, and enteral tacrolimus 0.5 mg bid. Both the donor and the recipient were seropositive for cytomegalovirus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim-sulfamethoxazole, and voriconazole.

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