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

original research 
Takaya Maruyama, M.D., Ph.D.; Takao Fujisawa, M.D., Ph.D.; Shigeru Suga, M.D., Ph.D.; Haruna Nakamura, M.D.; Mizuho Nagao, M.D., Ph.D.; Kiyosu Taniguchi, M.D., Ph.D.; Kiyoyuki Tsutsui, M.D., Ph.D.; Toshiaki Ihara, M.D., Ph.D.; Michael S. Niederman, M.D.
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Background:  In Japan, routine use of early antiviral therapy for patients with influenza is standard.

Methods:  Multicenter prospective cohort evaluation of hospitalized patients with laboratory-confirmed influenza to identify prognostic factors among patients receiving antiviral therapy.

Results:  The population included 1345 influenza patients ( 766 pediatric and 579 adult), and excluding those < age 1(not approved for anti-viral therapy) , 97.7% (1224/1253) received antiviral therapy. Among 579 adult patients, 24 (4.1%) died within 30 days , while none of the 766 pediatric patients died. 528 of the adult patients (91.2%) had influenza A, 509 (87.9%) had a chronic underlying illness, 211 (36.4%) had radiographically confirmed pneumonia . 20 of the 24 patients who died, had pneumonia , and the etiologies were: Streptococcus pneumoniae (12.3%), Staphylococcus aureus (10.9%), including methicillin-resistant S. aureus (MRSA) (3.3%), Enterobacteriaceae (8.1%), and Pseudomonas aeruginosa (3.3%). Of these, 151 were classified as community-acquired pneumonia (CAP), and 60 as healthcare-associated pneumonia (HCAP). Inappropriate therapy was more common in HCAP than CAP ( 15.2% vs. 2%, p=0.001). Potential multidrug-resistant (MDR) pathogens were more common ( 21.7%vs 2.6%, p<0.001) in HCAP patients, particularly MRSA (10% vs 0.7%, p=0.002) and Pseudomonas aeruginosa (8.3% vs 1.3%, p=0.021). Using Cox proportional hazards modeling with prescribed independent variables, male gender, severity score, serum albumin (malnutrition), and pneumonia were associated with survival 30 -days from the onset of influenza.

Conclusions:  Among the prognostic factors, malnutrition and pneumonia are amenable to medical intervention. There is an opportunity to improve empiric therapy for patients with HCAP and influenza.

Trial registration:  Japan Medical Association Center for Clinical Trials JMA-IIA00123.

original research 
MAJ David C. Hostler, MD, MPH; Elizabeth S. Marx, MD; COL Lisa K. Moores, MD; CPT Sarah Petteys, MD; MAJ Jordanna Mae Hostler, MD; MAJ Joshua D. Mitchell, MD; Paul R. Holley, MS; LTC Jacob F. Collen, MD; CPT Brian Foster, DO; LTC Aaron B. Holley, MD

Objectives:  Recent guidelines recommend assessing medical inpatients for bleeding risk prior to providing chemical prophylaxis for venous thromboembolism (VTE). The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding risk score (BRS) was derived from a well defined population of medical inpatients but it has not been externally validated. We sought to externally validate the IMPROVE BRS.

Methods:  We prospectively collected characteristics on admission and VTE prophylaxis data each hospital day on all patients admitted for a medical illness to the Walter Reed Army Medical Center (WRAMC) over an 18 month period. We calculated the IMPROVE BRS for each patient using admission data and reviewed medical records to identify bleeding events.

Results:  From September 2009 through March 2011 there were 1668 inpatients who met the IMPROVE inclusion criteria. Bleeding events occurred during 45 (2.7%) separate admissions; 31 (1.9%) events were major and 14 (0.8%) were non-major but clinically relevant. 256 (20.7%) patients had an IMPROVE BRS ≥ 7.0. Kaplan-Meier curves showed a higher cumulative incidence of major (p=0.02) and clinically important (major plus clinically relevant non-major) (p=0.06) bleeding within 14 days in patients with an IMPROVE BRS ≥ 7.0. An IMPROVE BRS ≥ 7.0 was associated with major bleeding in Cox-regression analysis adjusted for administration of chemical prophylaxis (OR 2.6, 95% CI: 1.1-5.9; p=0.03); there was a trend toward significant association with clinically important bleeding (OR 1.9, 95% CI: 0.9-3.7; p=0.07).

Conclusions:  The IMPROVE BRS calculated at admission predicts major bleeding in medical inpatients. This model may help assess relative risks of bleeding and VTE before chemoprophylaxis is administered.

original research 
Roland W. Esser; M. Cornelia Stoeckel, PhD; Anne Kirsten, MD; Henrik Watz, MD; Karin Taube, MD; Kirsten Lehmann; Sibylle Petersen, PhD; Helgo Magnussen, MD; Andreas von Leupoldt, PhD
Topics: ,

Background:  Patients with Chronic Obstructive Pulmonary Disease (COPD) suffer from chronic dyspnea, which is commonly perceived as highly aversive and threatening. Moreover, COPD is often accompanied by disease-specific fears and avoidance of physical activity. However, little is known about structural brain changes in COPD patients and respective relations with disease duration and disease-specific fears.

Methods:  This study investigated structural brain changes in COPD patients and their relation with disease duration, fear of dyspnea, and fear of physical activity. We used voxel-based morphometric analysis of MRI images to measure differences in generalized cortical degeneration and regional gray matter between 30 patients with moderate-to-severe COPD and 30 matched healthy control subjects. Disease-specific fears were assessed by the COPD anxiety questionnaire.

Results:  COPD patients showed no generalized cortical degeneration, but decreased gray matter in posterior cingulate cortex (whole brain analysis) as well as in anterior and mid cingulate cortex, hippocampus, and amygdala (regions-of-interest analyses). Patients’ reductions in gray matter in anterior cingulate cortex were negatively correlated with disease duration, fear of dyspnea, and fear of physical activity. Mediation analysis revealed that the relation between disease duration and reduced gray matter of the anterior cingulate was mediated by fear of physical activity.

Conclusions:  COPD patients demonstrated gray matter decreases in brain areas relevant for the processing of dyspnea, fear, and antinociception. These structural brain changes were partly related to longer disease duration and greater disease-specific fears, which might contribute to a less favorable course of the disease.

original research 
Thomas K. Aldrich, MD; Pragya Gupta, MD; Sean Stoy, MD; Anthony Carlese, DO; Daniel J. Goldstein, MD
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Background:  Pulse oximetry fails when pulsations are weak or absent, common in patients with continuous flow left ventricular assist devices (LVADs). We developed a method to measure arterial oxygenation (SaO2) noninvasively in pulseless LVAD patients.

Methods:  The technique involves 5-10 second occlusions of radial and ulnar arteries on one hand. A fingertip is transilluminated alternately with LEDs emitting 660nm (red,R) and 905nm (infrared,IR). During the ∼1 second after release of occlusion, changing absorbance of each wavelength is measured and their ratio (R/IR) calculated.We studied five normal subjects breathing hyperoxic, normoxic, or hypoxic gas mixtures to establish a calibration curve, using standard pulse oximetry as gold standard. We also studied seven pulseless LVAD patients (two studied twice) at clinically-determined oxygenation.

Results:  Normal subject data showed close correlation of SpO2 with R/IR, [SpO2 =111-(26.7 x R/IR), R2=0.975]. For LVAD patients, predicted SaO2 (from the calibration curve) tended to underestimate measured SaO2 (from arterial blood) by a clinically-insignificant 1.1±1.6 percentage points (mean±SD), maximum 3.4 percentage points.

Conclusions:  Preliminary results in a small number of patients demonstrate that pulseless oximetry can be used to estimate arterial saturation with acceptable accuracy.

Clinical Implications:  A noninvasive oximeter that does not rely on pulsatile flow would be a valuable advance in assessing oxygenation in patients with LVADs, for whom the only current option is arterial puncture, which is painful, risks arterial injury, and only provides a snapshot evaluation of oxygenation.

original research 
Gurinder Singh, MD; Wei Zhang, MS; Yong-Fang Kuo, PhD; Gulshan Sharma, MD, MPH
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Background:  There is a growing understanding of the prevalence and impact of psychological disorders on chronic obstructive pulmonary disease (COPD). However, the role of these disorders in early readmission is unclear.

Methods:  We analyzed data from 5% fee-for-service Medicare beneficiaries diagnosed with COPD (ICD-9 code 491.xx, 492.xx,493.xx and 496.xx) between 2001 and 2011 who were hospitalized with a primary discharge diagnosis of COPD or a primary discharge diagnosis of respiratory failure (518.xx and 799.1) with secondary diagnosis for COPD. We hypothesized that such psychological disorders as depression, anxiety, psychosis, alcohol abuse and drug abuse are independently associated with an increased risk of 30-day readmission in patients hospitalized for COPD.

Results:  Between 2001 and 2011, 135,498 hospitalizations occurred for COPD in 80,088 fee-for-service Medicare beneficiaries. Of these, 30,218 (22.30%) patients had one or more psychological disorders. In multivariate analyses, odds of 30-day readmission were higher in patients with COPD who had depression [Odds Ratio (OR) 1.34, 95% Confidence Interval (CI), 1.29 - 1.39], anxiety (OR 1.43, 95% CI 1.37-1.50), psychosis (OR 1.18, 95% CI 1.10-1.27), alcohol abuse (OR 1.30, 95% CI 1.15-1.47) and drug abuse (OR 1.29, 95% CI 1.11-1.50) compared to those who did not have these disorders. These psychological disorders increased amount of variation in 30-day readmission attributed to patient characteristics by 37%.

Conclusion:  Psychological disorders like depression, anxiety, psychosis, alcohol abuse and drug abuse are independently associated with higher all cause 30-day readmission rates for Medicare beneficiaries with COPD.

original research 
Melissa A. Lyle, MD; Eric R. Fenstad, MD, MSc; Michael D. McGoon, MD; Robert P. Frantz, MD; Michael J. Krowka, MD; Garvan C. Kane, MD, PhD; Karen L. Swanson, DO
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Background:  A subset of patients with Hereditary Hemorrhagic Telangiectasia (HHT) develops pulmonary hypertension (PH) by mechanisms including pulmonary arterial hypertension, high flow, and elevated pulmonary arterial wedge pressure (PAWP). We aimed to describe echocardiographic and hemodynamic characteristics of patients with coexisting HHT and PH.

Methods:  Single center cohort study of patients with confirmed HHT who underwent right heart catheterization (RHC) and transthoracic 2D echocardiography for suspected PH between 6/1/2003-9/1/2013 at Mayo Clinic Rochester.

Results:  Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a MPAP ≥ 25 mmHg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and PVR, with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mmHg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mmHg, PAWP of 17 ± 10 mmHg, and PVR of 4.5 ± 4.2 Wood Units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine (32%) patients. The presence of PH trended towards worse survival (p = 0.06).

Conclusions:  PH in patients with HHT occurs by different mechanisms, and there is a trend towards worse survival in patients that develop PH despite the mechanism. The equal predilection towards all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.

original research 
Elizabeth L. Salsgiver, MPH; Aliza K. Fink, DSc; Emily A. Knapp, BA; John J. LiPuma, MD; Kenneth N. Olivier, MD; Bruce C. Marshall, MD; Lisa Saiman, MD, MPH
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Background:  Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions.

Methods:  We performed a retrospective analysis using data reported to the CF Foundation Patient Registry (CFFPR) from 2006-2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included P. aeruginosa, methicillin-susceptible S. aureus (MSSA), MRSA, Haemophilus influenzae, B. cepacia complex, Stenotrophomonas maltophilia and Achromobacter xylosoxidans. Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010-2012 when the CFFPR collected NTM species.

Results:  In 2012, the pathogens of highest prevalence and incidence were MSSA and P. aeruginosa, followed by MRSA. The prevalence of A. xylosoxidans and B. cepacia complex were relatively low. From 2006-2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P. aeruginosa and B. cepacia complex, but significantly increased for MRSA. From 2010-2012, the annual percent change in overall prevalence of NTM and M. avium complex increased.

Conclusions:  The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.

original research 
Marla K. Beauchamp, PhD; Samantha L. Harrison, PhD; Roger S. Goldstein, MD; Dina Brooks, PhD

Background:  Balance deficits and an increased fall risk are well documented in individuals with COPD. Despite evidence that balance training can improve performance on clinical balance tests their Minimal Clinically Important Difference (MCID) is unknown. The aim of this study was to determine the MCID of the Berg Balance Scale (BBS), Balance Evaluation Systems Test (BESTest) and Activities-specific Balance Confidence Scale (ABC) in COPD patients undergoing pulmonary rehabilitation.

Methods:  We performed a secondary analysis of data from two studies of balance training in COPD (n=55). The MCID for each balance measure was estimated using the following anchor and distribution-based approaches: 1) mean change scores on a patient-reported global change in balance scale; 2) optimal cut-point from receiver operating curves (ROC); and 3) the minimal detectable change with 95% confidence (MDC95).

Results:  Data from 55 patients with COPD (mean age 71.2 ± 7.1; mean FEV1 39.2 ± 15.8 percent predicted) were used in the analysis. The smallest estimate of MCID was from the ROC curve method. Anchor-based estimates of the MCID ranged from 3.5 to 7.1 for the BBS, 10.2 to 17.4 for the BESTest and 14.2 to 18.5 for the ABC scale; their MDC95 values were 5.0, 13.1 and 18.9, respectively.

Conclusion:  Among COPD patients undergoing pulmonary rehabilitation, a change of 5 to 7 points for the BBS, 13 to 17 points for the BESTest and 19 points for the ABC scale is required to be both perceptible to patients and beyond measurement error.

original research 
Emir Festic, MD, MS; Jose Soto Soto, MD; Lisa A. Pitre, MS; Marilu Leveton, MS; Danielle M. Ramsey, ARNP; William D. Freeman, MD; Michael G. Heckman, MS; Augustine S. Lee, MD, MS
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Background:  There is a need for improved clinical identification of hospitalized patients at risk of aspiration. We evaluated our novel phonetic test in a broad spectrum of intensive or intermediate care unit patients at risk for aspiration.

Methods:  We prospectively enrolled 60 hospitalized patients with aspiration risk, between December 2009 and September 2011, who subsequently underwent audio-recorded 3-component phonetic bedside evaluation. The recordings were scored by two blinded speech-language pathologists. The institutional “Dysphagia Admission Screening Test” was performed by a bedside nurse. The primary outcomes, dysphagia and aspiration, were assessed by videofluoroscopic swallowing study and/or fiberoptic endoscopic evaluation of swallowing. We assessed the short and long-term clinical outcomes (length of stay, subsequent aspiration pneumonia and respiratory failure, survival), and how these associated with the phonetic and swallow assessments.

Results:  Statistically significant linear associations with dysphagia were noted for all three individual phonetic components. Also, there were statistically significant linear associations with aspiration for diadochokinesis (P=0.050) and Consensus Auditory-Perceptual Evaluation of voice (P=0.025). Diadochokinesis alone predicted dysphagia (AUC: 0.74, P=0.001) and aspiration (AUC: 0.67, P=0.012). Its predictive ability improved when combined with normalized dysphagia admission screening test results (AUC: 0.79, P=0.001). The short and long-term clinical outcomes were adversely affected by the worse phonetic/swallowing scores, though not statistically different.

Conclusions:  Abnormal phonation among intensive and intermediate care unit patients is associated with dysphagia and aspiration. Future investigative efforts should uncover the most effective combination of evaluations for accurate bedside detection of dysphagia and aspiration risk in a broad spectrum of patients.

original research 
Cecilia Becattini, PhD; Alexander T. Cohen, PhD; Giancarlo Agnelli, MD; Luke Howard, PhD; Borja Castejón, MD; Javier Trujillo-Santos, PhD; Manuel Monreal, PhD; Arnaud Perrier, PhD; Roger D. Yusen, MD; David Jiménez, PhD
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Background:  For patients diagnosed with acute pulmonary embolism (PE), the prognostic significance of concomitant deep vein thrombosis (DVT) lacks clarity.

Methods:  We performed a meta-analysis of studies that enrolled patients with acute PE to assess the prognostic value of concomitant DVT for the primary outcome of 30-day all-cause mortality, and the secondary outcome of 90-day PE-related adverse events. We conducted unrestricted searches of Pubmed and Embase from 1980 through September 30, 2014 and used the terms “deep vein thrombosis”, “pulmonary embolism”, and “prognos*”. We used a random-effects model to pool study results; Begg rank correlation method to evaluate for publication bias; and I2 testing to assess for heterogeneity.

Results:  The meta-analysis included a total of 9 studies (10 cohorts, as one study had 2 cohorts) with 8,859 patients. Of the 7 cohorts with 7,868 participants that had PE and provided results on the primary outcome, 4,379 (56%) had concomitant DVT; 272 of 4,379 (6.2%) patients with concomitant DVT died 30-days after the diagnosis of PE compared with 133 of 3,489 (3.8%) without DVT. Concomitant DVT had a significant association with 30-day all-cause mortality in all patients (7 cohorts; odds ratio [OR], 1.9; 95% CI, 1.5 to 2.4; I2 = 0%). Concomitant DVT was not significantly associated with 90-day PE-related adverse outcomes (5 cohorts; OR, 1.6; 95% CI, 0.8 to 3.4; I2 = 75%).

Conclusions:  In patients diagnosed with acute symptomatic PE, concomitant DVT was significantly associated with an increased risk of death within 30 days of PE diagnosis.

original research 
Takashi Nojiri, MD, PhD; Kazuhiro Yamamoto, MD, PhD, FACC; Hajime Maeda, MD, PhD; Yukiyasu Takeuchi, MD, PhD; Naoko Ose, MD; Yoshiyuki Susaki, MD, PhD; Masayoshi Inoue, MD, PhD; Meinoshin Okumura, MD, PhD
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BACKGROUND:  We previously reported that patients with elevated preoperative B-type natriuretic peptide (BNP) levels have an increased risk for postoperative atrial fibrillation following lung cancer surgery. The present study evaluated whether the specific phosphodiesterase III inhibitor olprinone can reduce the incidence of postoperative atrial fibrillation in patients with elevated BNP levels undergoing pulmonary resection for lung cancer.

METHODS:  A prospective randomized study was conducted with 40 patients who had elevated preoperative BNP levels (≥30 pg/mL) and underwent scheduled lung cancer surgery. All patients were in sinus rhythm at surgery. Low-dose olprinone or placebo was continuously infused for 24 hours and started just before anesthesia induction. The primary endpoint was the incidence of postoperative atrial fibrillation. The secondary endpoints were perioperative hemodynamics and levels of BNP, white blood cell counts, and C-reactive protein.

RESULTS:  The incidence of postoperative atrial fibrillation was significantly lower in the olprinone group than in the placebo group (10% vs. 60%, p <0.001). Patients in the olprinone group showed significantly lower BNP, white blood cell counts, and C-reactive protein levels after surgery.

CONCLUSIONS:  Continuous infusion of olprinone during lung cancer surgery was safe and reduced the incidence of postoperative atrial fibrillation following pulmonary resection in patients with elevated preoperative BNP levels.

Trial Registration:  JPRN-UMIN2404

special features 
Paul H. Mayo, MD, FCCP; Mangala Narasimhan, DO, FCCP; Seth Koenig, MD, FCCP
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Critical care transesophageal echocardiography (TEE) has utility in characterizing shock states encountered by intensivists when transthoracic echocardiography (TTE) gives insufficient information, or when more detailed analysis of cardiac structures are needed. It is safe, feasible, easy to learn, and is a recommended component of advanced critical care echocardiography. This article will review critical care TEE in reference to training, equipment, comparison to TTE, indications, safety, and standard views of critical care TEE. It should be considered a companion article to a recent two part series in CHEST that focused on advanced critical care TTE. Included with this article is an online supplement that has a representative series of critical care TEE images with clinical commentary.

translating basic research into clinical practice 
Zbigniew Zaslona, Ph.D.; Marc Peters-Golden, M.D.
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Pathophysiologic gaps in the actions of currently available treatments for asthma and COPD include neutrophilic inflammation, airway remodeling, and alveolar destruction. All of these processes can be modulated by cyclic AMP-elevating prostaglandins E2 and I2 (also known as prostacyclin). These prostanoids have long been known to elicit bronchodilation and to protect against bronchoconstriction provoked by a variety of stimuli. Much less well known is their capacity to inhibit inflammatory responses involving activation of lymphocytes, eosinophils, and neutrophils as well as to attenuate epithelial injury and mesenchymal cell activation. This profile of actions identifies prostanoids as attractive candidates for exogenous administration in asthma. By contrast, excessive prostanoid production and signaling might contribute to both the increased susceptibility to infections which drive COPD exacerbations and the inadequate alveolar repair that characterizes emphysema. Inhibition of endogenous prostanoid synthesis or signaling thus has therapeutic potential for these types of patients. By virtue of their pleiotropic capacity to modulate numerous pathophysiologic processes relevant to the expression and natural history of airway diseases, prostanoids emerge as attractive targets for therapeutic manipulation.

original research 
Yugo Yamashita, MD; Yasuhiro Hamatani, MD; Masahiro Esato, MD, PhD; Yeong-Hwa Chun, MD, PhD; Hikari Tsuji, MD, PhD; Hiromichi Wada, MD, PhD; Koji Hasegawa, MD, PhD; Mitsuru Abe, MD, PhD; Gregory Y.H. Lip, MD; Masaharu Akao, MD, PhD
Topics: ,

Background:  Atrial fibrillation (AF) is increasingly prevalent with age, and increasing age is an independent risk factor for ischemic stroke. Oral anticoagulant (OAC) therapy use in the extreme elderly (age ≥85 years) is challenging.

Methods:  The Fushimi AF Registry is a community-based prospective study of Japanese AF patients (79 participating medical institutions in Fushimi-ku, Kyoto). The enrollment of patients was started in March 2011, and follow-up data were available for 3,304 patients as of July 2014. We compared clinical characteristics and outcomes between the extreme elderly group (n=479, 14.5%) and others.

Results:  The extreme elderly had a higher prevalence of major co-morbidities and risk scores for stroke, but received less OAC. After a mean follow-up of 2.0 years, endpoints in the extreme elderly group were as follows: all-cause death 17.6, stroke or systemic embolism (SE) 5.1, and major bleeding 2.0 per 100 person-years, respectively. The extreme elderly group was associated with a higher incidence of combined stroke/SE and all-cause death (hazard ratio (HR) 3.20, 95% confidence interval (CI) 2.66-3.84, p<0.01), higher incidences of stroke/SE (HR 2.57, 95% CI 1.77-3.65, p<0.01) and mortality (HR 3.48, 95% CI 2.84-4.25, p<0.01), compared with others (aged ≤84). The incidence of major bleeding was not significantly different (HR 1.40, 95% CI 0.78-2.36, p=0.25).

Conclusions:  In our community-based prospective cohort, Japanese extreme elderly AF patients had a higher incidence of stroke but similar major bleeding risks compared with the younger AF population.

Trial Registry:  UMIN Clinical Trials Registry; No.: UMIN000005834; URL: http://www.umin.ac.jp/ctr/index.htm

point and counterpoint  FREE TO VIEW
David M. Rapoport, MD
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Over the past 30 years, we have come to appreciate that during sleep there is a spectrum of obstructive breathing physiology ranging from mild snoring to severe obstructive sleep apnea syndrome. By some estimates significant abnormalities of breathing during sleep may affect as much as 15-20% of the adult population and 5-10% of children. The obesity epidemic makes it likely that these numbers will only increase.

point and counterpoint  FREE TO VIEW
Naresh M. Punjabi, MD
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Since the early clinical descriptions of obstructive sleep apnea in the 1970s, our understanding of the pathogenesis and adverse consequences of this chronic disease has advanced substantially. Initially, the primary focus was the recognition of sleep-related apneic events which were observed to severely fragment sleep, induce cardiovascular instability, and lead to excessive sleepiness during the day. Given the significant hemodynamic and sleep-related effects of obstructive apneas during sleep, it comes as no surprise that the “apnea index”, which tallies the number of apneas per hour of sleep, became the primary disease defining metric for obstructive sleep apnea. However, over time as the full spectrum of upper airway collapse during sleep became more apparent, the simple concept of only quantifying apneas quickly evolved into something more complex. It is now obvious that obstructive apneas, the original sine qua non for the disease, are not the only events of interest as obstructive hypopneas have similar effects (e.g., arousals, blood pressure swings). As the clinical impact of hypopneas became widely recognized, these events were incorporated in quantifying disease activity and the original “apnea-index” gave way to the now commonly used “apnea-hypopneas index” (AHI). Although defining hypopneas continues to be plagued with many challenges, the AHI has become a ubiquitous measure in sleep and respiratory medicine. In fact, the AHI is used not only to diagnose obstructive sleep apnea but also is central in assessing disease severity.

point and counterpoint  FREE TO VIEW
David M. Rapoport, MD
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In his editorial Dr. Punjabi points out intrinsic limitations of the AHI concept: the cycle rate of events does not capture physiological “severity” of each event (eg, quantitative flow reduction, event duration) or biological impact (eg. degree of desaturation, sympathetic activation); temporal distribution of events is not captured (eg clusters of apnea/hypopnea are counted equally to widely separated individual events); other essential aspects of sleep are ignored (eg total duration of sleep determines overall exposure to sleep disordered breathing). Thus, he argues AHI is an overly simplistic representation of the complex physiology of a 7 hour recording of the polysmonogram.

point and counterpoint  FREE TO VIEW
Naresh M. Punjabi, MD

It is quite reasonable to advocate that the apnea-hypopnea index (AHI) is a clinically valuable metric for obstructive sleep apnea (OSA) on the basis that patients with a high AHI have a higher prevalence of excessive sleepiness, hypertension, and cardiovascular disease compared to those with a lower AHI. Moreover, the contention that the AHI is a “marker of disease” is also sound given that clinical symptoms improve or resolve when the AHI decreases with treatment. However, these arguments only suggest that the AHI is, at best, a crude metric for OSA. Indeed, Dr. Rappaport’s conclusion that the AHI is useful in “defining the presence of obstructive sleep apnea if severely elevated and … the risk of obstructive sleep apnea is moderately increased” indicates that the AHI is not a metric with high fidelity. A high fidelity index of disease can identify the presence of that disease and also exhibit a dose-response association with relevant health outcomes. The lack of a strong association between increasing AHI and clinical consequences, such as daytime sleepiness and hypertension, points to its relative crude nature and rigorous consideration is thus required of alternative or complementary measures that can correlate with endpoints more precisely than the AHI.

translating basic research into clinical practice 
Dr Claire Rooney; Professor Tariq Sethi
Topics: , , ,

Lung cancer is the principal cause of cancer related mortality in the developed world, accounting for almost one quarter of all cancer deaths. Traditional treatment algorithms largely relied on histological subtype and comprised pragmatic chemotherapy regimes with limited efficacy. However, as our understanding of the molecular basis of disease in NSCLC has improved exponentially it has become apparent that NSCLC can be radically subdivided, or molecularly characterised on the basis of recurrent ‘driver’ mutations occurring in specific oncogenes. We know that the presence of such mutations leads to constitutive activation of aberrant signalling proteins that initiate, progress and sustain tumourigenesis. This persistence of the malignant phenotype is referred to as ‘oncogene addiction’. On this basis a paradigm shift in treatment approach has occurred. Rational, targeted therapies have been developed, the first being tyrosine kinase inhibitors which first entered the clinical arena over 10 years ago. These were tremendously successful, significantly impacting on the natural history of NSCLC and improving patient outcomes. However the benefits of these drugs are limited somewhat by the emergence of adaptive resistance mechanisms, and efforts to tackle this phenomenon are ongoing. A better understanding of all types of oncogene driven NSCLC and the occurrence of TKI resistance will help us further develop 2nd and 3rd generation small molecule inhibitors and will expand our range of ‘precision therapies’ for this disease.

original research 
Devashri Salvi; Sneha Limaye; Veena Muralidharan; Jyoti Londhe; Sapna Madas; Sanjay Juvekar; Shyam Biswal; Sundeep Salvi
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Background:  An estimated 700 million people suffer from mosquito borne diseases worldwide. Various types of mosquito repellents are widely used to prevent mosquito bites.

Aims:  (a) To measure the indoor levels of PM2.5 and CO during the burning of Mosquito Coils (MCs) and study the impact of indoor ventilation patterns. (b) Study and compare the prevalence of respiratory ailments in homes using different types of mosquito repellents.

Methods:  Indoor PM2.5 and CO levels were measured inside a bedroom during the burning of MCs keeping the window and/or door open/closed over a six hour duration. A cross-sectional survey was conducted in 3 villages where 465 individuals were administered a questionnaire that captured demographic details, type and duration of mosquito repellents used and prevalence of respiratory symptoms and diseases.

Results:  53% of the subjects burnt MCs on most days of the week and 63% did so with their doors and windows closed. Burning of MCs produced very high levels of PM2.5 (1031 µg/m3 mean, 1613 µg/m3 peak ) and CO (6.50 ppm mean, 10.27 ppm peak) when both the door and window were closed. These levels reduced by around 50% when the window was opened and more than 95% when both the window and the door were opened. The prevalence rates of respiratory symptoms and diseases were higher in subjects using MCs although not statistically significant. Those living in smaller homes and using MCs had significantly greater morbidity.

Conclusion:  Burning of MC produces indoor levels of PM2.5 and CO that are higher than those reported during the burning of biomass fuels for cooking purposes and may be associated with respiratory morbidity.

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