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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

original research 
Carolina Fernández, MD; Carlo Bova, MD; Olivier Sanchez, PhD; Paolo Prandoni, PhD; Mareike Lankeit, MD; Stavros Konstantinides, PhD; Simone Vanni, MD; Covadonga Fernández-Golfín, PhD; Roger D. Yusen, MD; David Jiménez, PhD
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Background:  For patients diagnosed with acute symptomatic pulmonary embolism (PE), the Bova score classifies their risk of developing PE-related complications within 30 days after PE diagnosis. The original Bova score study derived the model from 2,874 normotensive patients that had acute PE and participated in one of six prospective PE studies.

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

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

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

original research 
Chee M. Chan, MD, MPH; Christian J. Woods, MD; Theodore E. Warkentin, MD; Jo-Ann I. Sheppard, BSc; Andrew F. Shorr, MD, MPH
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Background:  Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin utilization. An enzyme-linked immunosorbent assay (ELISA) is usually performed to assist in the diagnosis of HIT. ELISAs tend to be sensitive but lack specificity. We sought to utilize a new cut-off to define a positive HIT ELISA.

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

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

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

Clinical Trial Registration:  clinicaltrials.gov (NCT 00946400)

original research 
Rachel Gavish, MD, MPH; Amalia Levy, MPH, PhD; Or Kalchiem Dekel, MD; Erez Karp, MD; Nimrod Maimon, MD
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Background:  The high frequency of readmissions in patients with chronic obstructive pulmonary disease (COPD) remains a significant problem. The impact of a pulmonologist follow-up visit during the month after discharge from hospital due to COPD exacerbation on reducing readmissions was examined. A profile of patients who did not attend the follow-up visits was built.

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

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

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

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

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

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

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

original research 
Charles R. Esther, Jr.; Raymond D. Coakley; Ashley G. Henderson; Yi-Hui Zhou; Fred A. Wright; Richard C. Boucher
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Background:  Metabolomic evaluation of cystic fibrosis airway secretions could identify metabolites and metabolic pathways involved in neutrophilic airway inflammation that could serve as biomarkers and therapeutic targets.

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

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

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

original research 
Carlos Henrique G. Uchôa, PT; Naury de Jesus Danzi-Soares, RN, PhD; Flávia S. Nunes, MD, PhD; Altay A. L. de Souza; Flávia B. Nerbass, PT; Rodrigo P. Pedrosa, MD, PhD; Luiz Antonio M. César, MD, PhD; Geraldo Lorenzi-Filho, MD, PhD; Luciano F. Drager, MD, PhD
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Background:  The impact of Obstructive Sleep Apnea (OSA) on new cardiovascular events in patients undergoing coronary artery bypass graft (CABG) surgery is poorly explored.

Methods:  Consecutive patients referred for CABG underwent clinical evaluation and standard polysomnography in the preoperative period. CABG surgery data including percentage of off-pump and on-pump CABG, number of grafts, and intraoperative complications were collected. The primary endpoint was Major Adverse Cardiac or Cerebrovascular Events - MACCE (combined events of all-cause death, myocardial infarction, repeated revascularization and cerebrovascular events). Secondary endpoints included individual MACCE events, typical angina and arrhythmias. Patients were evaluated at 30 days (short-term) and long-term (up to 6.1 years) period after CABG.

Results:  We studied 67 patients (50 men; mean age: 58±8 years; mean body mass index: 28.5±4.1 kg/m2). OSA (apnea-hypopnea index ≥15 events/hour) was present in 56% of the population. The patients were followed for a mean of 4.5 years (range: 3.2 to 6.1 years). No differences were observed in the short-term follow-up. In contrast, MACCE (35% vs. 16%; p=0.02), new revascularization (19 vs. 0%; p=0.01), episodes of typical angina (30 vs. 7%; p=0.02) and atrial fibrillation (22 vs. 0%; p=0.0068) were more common in patients with than without OSA in the long-term follow-up. OSA was an independent factor associated with the occurrence of MACCE, repeated revascularization, typical angina, and atrial fibrillation in the multivariate analysis.

Conclusions:  OSA is independently associated with a higher rate of long-term cardiovascular events after CABG and may have prognostic and economical significance in CABG surgery.

original research 
Mariano Rinaudo, MD; Miquel Ferrer, MD, PhD; Silvia Terraneo, MD; Francesca De Rosa, MD; Rogelio Peralta, MD; Laia Fernández-Barat, PhD; Gianluigi Li Bassi, MD, PhD; Antoni Torres, MD, PhD
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Background:  Chronic obstructive pulmonary disease (COPD) seems related with poor outcome in patients with ventilator-associated pneumonia (VAP). However, many intensive care unit (ICU) patients with COPD do not require intubation but can also develop pneumonia in the ICU. We therefore compared the characteristics and outcomes of patients with ICU-acquired pneumonia (ICUAP) with and without underlying COPD.

Methods:  We prospectively assessed the characteristics, microbiology, systemic inflammatory response and survival of 279 consecutive patients with ICUAP clustered according to underlying COPD or not. The primary end-point was 90-day survival.

Results:  Seventy-one (25%) patients had COPD. The proportion of VAP was less frequent in patients with COPD, 30, 42%, compared with 126, 61% in patients without COPD (p=0.011). COPD patients were older, more frequently males, smokers and alcohol consumers, and they had more frequently previous use of non-invasive ventilation. The rate of microbiologic diagnosis was similar between groups, with a higher rate of Aspergillus spp. and a lower rate of Enterobacteriaceae in COPD patients. We found lower levels of Interleukin-6 and InterleukinL-8 in COPD patients without previous intubation. The 90-day mortality was higher in COPD patients (40, 57% vs. 74, 37% in non-COPD patients, p=0.003). Among others, COPD was independently associated with decreased 90-day survival in the overall population (adjusted hazard-ratio 1.94, 95% confidence interval 1.11-3.40, p=0.020); this association was observed only in patients with VAP, but not in those without previous intubation.

Conclusion:  COPD was independently associated with decreased 90-day survival; in patients with VAP but not in those without previous intubation.

original research 
Ciro Casanova, MD; Jose M. Marin, MD; Cristina Martinez-Gonzalez, MD; Pilar de Lucas-Ramos, MD; Isabel Mir-Viladrich, MD; Borja Cosio, MD; German Peces-Barba, MD; Ingrid Solanes-García, MD; Ramón Agüero, MD; Nuria Feu-Collado, MD; Miryam Calle-Rubio, MD; Inmaculada Alfageme, MD; Alfredo de Diego-Damia, MD; Rosa Irigaray, MD; Margarita Marín, MD; Eva Balcells, MD; Antonia Llunell, MD; Juan Bautista Galdiz, MD; Rafael Golpe; Celia Lacarcel; Carlos Cabrera; Alicia Marin; Joan B. Soriano, MD; Jose Luis Lopez-Campos, MD; Juan José Soler-Cataluña; Juan P. de-Torres, MD; for the COPD History Assessment In SpaiN (CHAIN) cohort
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Rationale:  The modified Medical Research Council (mMRC) dyspnea, the Chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), and the Clinical COPD Questionnaire (CCQ) have been interchangeably proposed by the GOLD initiative for assessing symptoms in COPD patients. However, there are no data on the prognostic value of these tools in terms of mortality.

Objectives:  To evaluate the prognostic value of the CAT and CCQ scores and compare with modified Medical Research Council (mMRC) dyspnea.

Methods:  We analyzed the ability of these tests to predict mortality in an observational cohort of 768 COPD patients (82% males; FEV1 60%) from the CHAIN study, a multicenter observational Spanish cohort who were monitored annually for a mean follow-up time of 38 months.

Measurements and Main Results:  Subjects who died (n=73; 9.5%) had higher CAT (14 vs. 11, p=0.022), CCQ (1.6 vs. 1.3, p=0.033), and mMRC dyspnea scores (2 vs. 1, p<0.001) than survivors. Receiver operating characteristic analysis showed that higher CAT, CCQ, and dyspnea scores were associated with higher mortality (area under the curve: 0.589, 0.588, and 0.649, respectively). CAT scores ≥17 and CCQ scores >2.5 provided a similar sensitivity than mMRC dyspnea scores ≥2 to predict all-cause mortality.

Conclusions:  The CAT and the CCQ have similar ability for predicting all-cause mortality in patients with chronic obstructive pulmonary disease, but were inferior to mMRC dyspnea scores. We suggest new thresholds for CAT and CCQ scores based on mortality risk that could be useful for the new GOLD grading classification.

  ClinicalTrials.gov Identifier: NCT01122758

original research 
Giora Landesberg, MD, DSc; Phillip D. Levin, MA, BA, BChir; Dan Gilon, MD, FACC; Sergey Goodman, MD; Milena Georgieva, MD; Charles Weissman, MD; Allan S. Jaffe, MD; Charles L. Sprung, MD; Vivian Barak, PhD
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Introduction:  In-vitro studies suggested that circulating inflammatory cytokines cause septic myocardial dysfunction. However, no in-vivo clinical study has investigated whether serum inflammatory cytokines concentrations correlate with septic myocardial dysfunction.

Methods:  Repeated echocardiograms and concurrent serum inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, IL-18, TNFα and MCP-1) and cardiac biomarkers (high-sensitivity troponin-T and NT-proBNP) were examined in 105 patients with severe sepsis and septic shock. Cytokines and biomarkers were tested for correlations with systolic and diastolic dysfunction, sepsis severity and mortality.

Results:  Systolic dysfunction defined as reduced left-ventricular ejection-fraction (LVEF) <50% or <55% and diastolic dysfunction defined as e’-wave <8 cm/sec on tissue-Doppler imaging (TDI) or E/e'-ratio were found in 13 (12%), 24 (23%), 53 (50%) and 26 (25%) patients, respectively. Forty-four (42%) patients died in-hospital. All cytokines, except IL-1, correlated with SOFA and APACHE-II scores and all cytokines predicted mortality. IL-10 and IL-18 independently predicted mortality among cytokines (odds ratio= 3.1 and 28.3, p=0.006 and <0.0001). However, none of the cytokines correlated with LVEF, end-diastolic volume index (EDVI), stroke-volume index (SVI) or s’-wave and e’-wave velocities on TDI (Pearson’s linear and Spearman’s rank (ρ) nonlinear correlations). Similarly, no differences were found in cytokine concentrations between patients dichotomized to high versus low LVEF, EDVI, SVI, s'-wave or e'-wave (Mann-Whitney U-tests). In contrast, NT-proBNP strongly correlated with both reduced LVEF and reduced e'-wave velocity and hs-troponin-T correlated mainly with reduced e'-wave.

Conclusions:  Unlike cardiac biomarkers, none of the measured inflammatory cytokines correlates with systolic or diastolic myocardial dysfunction in severe sepsis or septic shock.

original research 
Ozen K. Basoglu, M.D.; Peter J. Barnes, FRS.; Sergei A. Kharitonov, M.D.; Amir Pelleg, Ph.D.
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BACKGROUND:  Extracellular adenosine 5’-triphosphate (ATP) stimulates vagal C and Aδ fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers and patients with chronic obstructive pulmonary disease (COPD), and compared these responses to the effects of inhaled adenosine, the metabolite of ATP

METHODS:  We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity and ATP in exhaled breath condensate in healthy non-smokers (n=10), healthy smokers (n=14), and patients with COPD (n=7).

RESULTS:  In comparison with healthy subjects, ATP induced more dyspnea, cough and throat irritation in smokers and COPD patients and the effects of ATP were more pronounced than those of AMP. The concentration of ATP in the exhaled breath condensate of patients with COPD was elevated compared to those of healthy subjects.

CONCLUSIONS:  Smokers and patients with COPD manifest hypersensitivity to extracellular ATP, which may play a mechanistic role in COPD.

original research 
Richard I. Carter, PhD; Michael J. Ungurs, PhD; Anilkumar Pillai, MB, ChB; Richard A. Mumford, PhD; Robert A. Stockley, DSc
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Background  New markers of COPD and emphysema disease activity are urgently required since current measures of disease severity do not reflect the total disease burden nor predict disease progression. A recently described in vivo marker of neutrophil elastase activity (Aα-Val360) may be an effective marker of COPD and emphysema disease activity and the current study explores its use in patients with alpha-1-antitrypsin deficiency (AATD) across the disease severity spectrum with particular interest in whether it can be used as an early predictor of the need for intervention.

Methods  Cross-sectional and longitudinal relationships between Aα-Val360 and full lung function tests, CT densitometry, and other biomarkers were explored in this study of a registry of untreated patients with PiZZ AATD.

Results  The Aα-Val360 related cross-sectionally to physiological, radiological and symptomatic markers of disease severity though not disease progression. Similar cross sectional relationships were observed in subjects with mild physiological abnormalities, however in this subgroup baseline Aα-Val360 concentration did relate to subsequent disease progression.

Conclusions  In cross sectional studies Aα-Val360 reflects disease severity in AATD and may be a useful marker of disease activity in patients with early disease in whom therapeutic intervention may be indicated.

original research 
Clara Fontaine-Delaruelle; Pierre-Jean Souquet; Delphine Gamondes; Eric Pradat; Aurélie De Leusse; Gilbert R. Ferretti; Sébastien Couraud
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BACKGROUND:  CT-guided transthoracic core-needle biopsy (TTNB) is frequently used for the diagnosis of lung nodules, but the clinical value of negative results has not been sufficiently investigated. We sought to determine the negative predictive value (NPV) of TTNB and investigate predictive factors of negative results.

PATIENTS AND METHOD:  All consecutive TTNBs performed in three centers between 2006 and 2012 were included. The medical charts of patients with non-malignant TTNB results were reviewed and classified as true or false negatives. Binary logistic regression was used for multivariate analysis.

RESULTS:  Overall, 980 TTNB were included. Malignant disease was found in 79% (n=777) of the cases, non-malignant disease in 6% (n=54) and “negative” results in 15% (n=149). For the diagnosis of malignant disease, NPV was 51%. Estimated sensitivity, specificity and accuracy were respectively 89%, 99% and 90%. The complication rate was 34% (life-threatening complication in 6%). In multivariate analysis, predictive factors for a false-negative result were radiologist experience (AOR=0.996; 95% CI [0.994-0.998]), occurrence of a complication during the procedure (AOR=1.958 [1.202-3.187]), and moderate to high SUVmax on the PET scan (AOR=7.657 [1.737-33.763]). In 24 cases, a second TTNB was performed at the same target. The complication rate was 33% and TTNB provided diagnosis in 95% of cases with a 67% NPV.

CONCLUSION:  Half of all “negative” TTNBs are falsely negative for malignant diagnosis. A second TTNB at the same target provides a final diagnosis in most cases without increasing complication rates.

original research 
Jeffrey H. Jennings, MD; Krishna Thavarajah, MD; Michael Mendez, MD; Michael Eichenhorn, MD; Paul Kvale, MD; Lenar Yessayan, MD
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Background:  Hospital readmissions for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) pose burdens to the healthcare system and patients. A current gap in knowledge is whether a pre-discharge screening and educational tool, administered to patients with COPD, reduces readmissions and emergency department (ED) visits.

Methods:  A single center, randomized trial of patients admitted with AECOPD was conducted at Henry Ford Hospital between February 2010 and April 2013. One hundred seventy-two patients were randomized either to the control (standard care) or bundle group in which patients received smoking cessation counseling, screening for gastroesophageal reflux disease and depression or anxiety, standardized inhaler teaching, and a 48-hour post-discharge phone call. The primary endpoint was the difference in the composite risk of hospitalizations or ED visits for AECOPD between the 2 groups in the 30 days following discharge. A secondary endpoint included 90-day readmission rate.

Results:  Of the 172 patients, 18 of 79 in the control group (22.78%) and 18 of 93 in the bundle group (19.35%) were readmitted within 30 days. The risk of ED visits or hospitalizations within 30 days was not different between the groups (risk difference = -3.43%, 95% confidence interval = -15.68%−8.82%; p= 0.58). Overall, the time to readmission in 30 days and 90 days was similar between groups (log-rank test p= 0.71 and p= 0.88, respectively).

Conclusion:  A pre-discharge bundle intervention in AECOPD is not sufficient to reduce the 30-day risk of hospitalizations or ED visits. Increased resources may be needed to generate a measurable effect on readmission rates.

original research 
Sanjiva M. Lutchmedial, MD; Whitney G. Creed, BA; Alastair J. Moore, MD; Ryan R. Walsh, MD; George E. Gentchos, MD; David A. Kaminsky, MD
Topics: ,

Background:  COPD has traditionally been defined by the presence of irreversible airflow limitation on spirometry using either the GOLD or ATS/ERS criteria (lower limit of normal, LLN). We have observed that some patients with clinical COPD and emphysema on chest computerized tomography (CT) have no obstruction on spirometry. The purpose of this study was to assess the prevalence of obstruction by GOLD and LLN criteria in patients with emphysema on CT and determine which radiographic criteria were associated with a clinical diagnosis of COPD.

Methods:  We retrospectively analyzed the clinical records and spirometry of all patients who had radiographically defined emphysema on chest CT scans completed at the University of Vermont in 2011. We compared spirometric criteria and CT factors with the presence of clinical COPD based on chart review.

Results:  We identified 274 patients with CT defined emphysema. GOLD detected obstruction in 228 (83%) and LLN in 206 (75%) of patients. However, GOLD failed to correctly identify 19 (6.9%) patients and LLN 38 (13.9%) patients (average 10.4%) who had radiographic emphysema and a clinical diagnosis of COPD. Obese patients had a lower prevalence of obstruction whether classified by LLN or by GOLD. Among patients with spirometric obstruction, there were greater degrees of emphysema, and more severely increased airway wall thickness. Factors that were independently associated with clinical COPD were lower FVC % predicted, lower FEV1/FVC ratio and increasing airway wall thickness.

Conclusions:  Spirometry missed 10.4% of patients with clinical COPD who have significant emphysema on chest CT.

original research 
Jonathan K. Alder; Susan E. Stanley; Christa L. Wagner; Makenzie Hamilton; Vidya Sagar Hanumanthu; Mary Armanios
Topics: , ,

Short telomeres are a common defect in idiopathic pulmonary fibrosis, yet mutations in the telomerase genes account for only a subset of these cases. We identified a family with pulmonary fibrosis, idiopathic infertility and short telomeres. Exome sequencing of blood-derived DNA revealed two mutations in the telomere binding protein TINF2. The first was a 15 base pair deletion encompassing the exon 6 splice acceptor site, and the second was a missense mutation, Thr284Arg. Haplotype analysis indicated both variants fell on the same allele. However, lung-derived DNA showed predominantly the Thr284Arg allele indicating the deletion seen in the blood was acquired and may have a protective advantage since it diminished expression of the missense mutation. This mosaicism may represent functional reversion in telomere syndromes similar to what has been described for Fanconi anemia. No mutations were identified in over forty uncharacterized pulmonary fibrosis probands suggesting mutant TINF2 accounts for a small subset of familial cases. However, similar to affected individuals in this family, we identified a history of male and female infertility preceding the onset of pulmonary fibrosis in 11% of telomerase mutation carriers with TERT and TR mutations (5 of 45). Our findings identify TINF2 as a mutant telomere gene in familial pulmonary fibrosis, and suggest infertility may precede the presentation of pulmonary fibrosis in a small subset of adults with telomere syndromes.

original research 
María Luz Alonso-Álvarez, MD; Joaquin Terán-Santos, MD; Estrella Ordax Carbajo, MD, PhD; José Aurelio Cordero-Guevara, MD; Ana Isabel Navazo-Egüia, MD; Leila Kheirandish-Gozal, MD, MSc; David Gozal, MD, FCCP
Topics: , ,

Objective:  To evaluate the diagnostic reliability of home respiratory polygraphy (HRP) in children with a clinical suspicion of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS)

Methods:  A prospective blind evaluation was performed. Children between 2 to 14 years-old, with clinical suspicion of OSAS, who were referred to the Sleep Unit were included. An initial HRP followed by a ulterior date, same night, in-laboratory overnight respiratory polygraphy and polysomnography (PSG) in the Sleep Laboratory were performed. The AHI-HRP were compared to AHI-PSG, and therapeutic decisions based on AHI-HRP and AHI-PSG were analyzed using intraclass correlation coefficients (ICC), Bland-Altman plots and receiver operator curves (ROC).

Results:  27 boys and 23 girls, with a mean age of 5.3 ± 2.55 years were studied, and 66% were diagnosed with OSAS based on a PSG-defined obstructive RDI ≥3/hrTST. Based on the availability of concurrent HRP-PSG recordings, the optimal AHI-HRP corresponding to the PSG-defined OSAS criterion was established as ≥5.6/hr. The latter exhibited a sensitivity of 90.9% (95% CI: 79.6% -100%) and a specificity of 94.1% (95% CI: 80%-100%).

Conclusions:  Home respiratory polygraphic recordings emerge as a potentially useful and reliable approach for the diagnosis of OSAS in children, However, more research is required for the diagnosis of mild OSAS using HRP in children.

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