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The Predictive Value of Interferon-γ Release Assays and Tuberculin Skin Test
© 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-3077
References 1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e576S-e600S. 2. Koertke H, Minami K, Boethig D, et al. INR self-management permits lower anticoagulation levels after mechanical heart valve replacement. Circulation. 2003;108(suppl 1):1175-1178. 3. Dong L, Shi YK, Tian ZP, Ma JY, Wang X, Yi J. Low intensity anticoagulation therapy after mechanical heart valve replacement [in Chinese]. Zhonghua Wai Ke Za Zhi. 2003;41(4): 250-252.
Response To the Editor: We thank Drs Fu and colleagues for their letter regarding the applicability of the American College of Chest Physicians guidelines on antithrombotic and thrombolytic therapy for valvular disease to Chinese patients. To clarify, the guidelines on mechanical valves recommend the following1: 1. In patients with a mechanical aortic valve, we recommend VKA (vitamin K antagonist) therapy with a target of 2.5 (range, 2.0-3.0) over higher targets (Grade 1B). 2. In patients with a mechanical mitral valve, we suggest VKA therapy with a target of 3.0 (range, 2.5-3.5) over lower international normalized ratio (INR) targets (Grade 2C). 3. In patients with mechanical heart valves in both the aortic and the mitral positions, we suggest target INR 3.0 (range, 2.5-3.5) over target INR 2.5 (range, 2.0-3.0) (Grade 2C). However, the gist of the letter from West China Hospital is valid. INR targets in Chinese patients, and indeed in all patients, need higher-quality evidence than what currently exists. Differing INR targets based on thromboembolic risk is unique to heart valve therapy; for example, the INR target for a patient with atrial fibrillation and a CHA2DS2VASc stroke risk score of 8 is the same as that of a patient with a CHA2DS2VASc score of 3, despite higher thromboembolic risk.2 The evidence supporting such differing targets for heart valves is of moderate quality at best according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework,3 and begs for further studies. One such study, Lowering the Intensity of Oral Anticoagulant Therapy in Patients With Bileaflet Mechanical Aortic Valve Replacement (LOWERING-IT), also supports the approach of lower INR targets in low-risk mechanical aortic valves but needs validation in a larger trial.4 The ninth edition of the American College of Chest Physician guidelines presents an objective assessment of the available literature up to October 2009 that is based on the GRADE framework and the resultant recommendations. We look forward to reading publications from the West China Hospital based on its national database and will incorporate any new knowledge into future guidelines. Richard Whitlock, MD, PhD Matthew Danter, MD Hamilton, ON, Canada
Affiliations: From the Division of Cardiac Surgery, McMaster University. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Richard Whitlock, MD, PhD, Division of Cardiac Surgery, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4LB, Canada; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0557
References 1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest. 2012;141(2)(suppl): e576S-e600S. 2. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2)(suppl):e531S-e575S. 3. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650):924-926. 4. Torella M, Torella D, Chiodini P, et al. LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: results from the “LOWERING-IT” trial. Am Heart J. 2010;160(1):171-178.
The Predictive Value of Interferon-g Release Assays and Tuberculin Skin Test What About Those Not Vaccinated With Bacillus Calmette-Guérin? To the Editor, In a recent meta-analysis in CHEST (July 2012), Diel et al1 concluded that interferon-g release assays (IGRAs), including QuantiFERON-TB Gold (QFT-G) (Cellestis, a company of Qiagen GmBH), QuantiFERON-TB Gold In-Tube (QFT-GIT) (Cellestis, a company of Qiagen GmBH), and the T-SPOT.TB ELISPOT (Oxford Immunotec Ltd), have a higher positive predictive value (PPV) and negative predictive value (NPV) for progression to active TB compared with those of the tuberculin skin test (TST). The PPV and NPV in those not vaccinated with bacille Calmette-Guérin (BCG) was not shown because the majority of the study participants had a history of BCG vaccination. Therefore, the results should apply mostly to the BCG-vaccinated and not be generalized. A previous study in contacts of patients with TB by the same authors2 disregarded the analysis in the population at the highest risk of disease, that is, BCG-unvaccinated close contacts exposed to patients who tested positive on smear with pulmonary disease. But further analysis found that the PPVs of QFT-GIT and TST were not statistically different.3 This indicates that both tests may predict TB disease similarly in this population. This is probably one of the reasons why the use of TST continues in most lowburden settings where the BCG vaccine has been discontinued.
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Correspondence
The practice of latent TB infection (LTBI)-targeted screening using IGRAs is becoming more common, particularly for BCG-vaccinated immigrants living in low-burden settings where laboratory facilities are usually available and the government, medical plans, or research programs cover the cost of testing. However, if, in the real world of high-burden settings, the cost of screening with TST is high, then screening with IGRA is a luxury. Many IGRA research studies performed in high-burden settings frequently have to rely on the sponsor for total or partial funding, as was likely the case in many studies cited in this metaanalysis. Lowering the cost of IGRAs would encourage use by TB programs where they are more needed, identifying more BCG-vaccinated individuals with true infection and candidates for preventive treatment. In conclusion, further research is needed in BCG-unvaccinated close contacts of smear-positive patients to clearly establish similarities or differences in the PPV and NPV between IGRAs and TST, to determine whether there is any difference in the number of individuals identified for preventive treatment using each test, and to establish what the best costbenefit is in this population. Eduardo Hernández-Garduño, MD Gerardo G. Huitrón Bravo, MD Toluca, Mexico Affiliations: From the Centro de Investigación en Ciencias Médicas, Universidad Autónoma del Estado de México. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Eduardo Hernández-Garduño, MD, Centro de Investigación en Ciencias Médica, Jesús Carranza #200, Toluca, Estado de México, México, 50130; email: investigador.cicmed@ gmail.com. © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0055
by Drs Hernández-Garduño and Huitrón-Bravo is the advantage of interferon-g release assays (IGRAs) over the TST in people with nontuberculous mycobacteria infections, which are distributed worldwide. The TST, but not IGRAs, cross-react against most nontuberculous mycobacteria, irrespective of any simultaneous coverage with BCG.2 I certainly agree with the authors that lowering IGRA costs would probably encourage the implementation of preventive therapy (PT). With respect to the cost-effectiveness of PT, it should be kept in mind that IGRAs may dramatically reduce the number of falsely positive contact people wrongly considered for PT, which may at least partially compensate higher IGRA costs.3 In previous letters4,5 in reference to our predictive value study in Germany,6 Dr Hernández-Garduño suggested that both tests, IGRAs and the TST, may predict TB disease in high-risk contacts similarly. However, in our reply at that time,5 we demonstrated that the lack of statistical significance for different QuantiFERON-TB Gold In Tube-Test (QFT-GIT) (Cellestis, a company of Qiagen GmBH) and TST progression rates in subjects not vaccinated with BCG in two-tailed testing (although there was a significantly higher progression rate in favor of the QFT-GIT in one-tailed testing) is most likely explained by the small sample size. Thus, it would be incorrect to conclude that TST predictive value is similar to QFTGIT in the unvaccinated contacts. In addition, although the IGRAs have a fixed cutoff for test positivity, TST cutoffs in BCG vaccines and subsequently the number of contacts with presumed latent TB infection who eventually progress to active TB depend on differing opinions of national committees on what constitutes test positivity in the TST; cutoffs vary between induration sizes of 5 and 15 mm. Therefore, as the authors of this letter stress, in the “real world” of high-burden settings, where most people can be expected to be BCG vaccinated, we do not see the need for any further research in BCGunvaccinated close contacts of smear positive patients to clearly establish similarities or differences in the positive predictive value and negative predictive value between IGRAs and TST. Roland Diel, MD, MPH Hannover, Germany
References 1. Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-g release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest. 2012;142(1):63-75. 2. Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a wholeblood interferon-g release assay for developing active tuberculosis: an update. Am J Respir Crit Care Med. 2011;183(1): 88-95. 3. Hernández-Garduño E. An update: the predictive value of QuantiFERON-TB-Gold In-Tube assay and the tuberculin skin test. Am J Respir Crit Care Med. 2011;183(3):414.
Response To the Editor: I thank Drs Hernández-Garduño and Huitrón Bravo for addressing some important aspects of testing close contacts of patients with TB for latent TB infection. The authors point out that in highburden countries, where bacille Calmette-Guérin (BCG) vaccination is common,1 it is necessary to identify more vaccinated but truly infected individuals, and because of possibly false-positive cross-reactions this cannot be done effectively by testing with the tuberculin skin test (TST). Another important point not addressed
Affiliations: From the Department of Pulmonary Medicine, Medical School Hannover (MHH). Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Diel has received travel reimbursement and/or fees for speaking at symposia sponsored by Cellestis Ltd, Oxford Immunotec Ltd, and Pharmore Ltd (exclusive supplier of Tuberculin RT23 for Germany). Correspondence to: Roland Diel, MD, MPH, Medical School Hannover, Carl-Neuberg-Str 1, Hannover, Germany 30625; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0126
References 1. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011;8(3):e1001012. 2. Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-g release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest. 2012;142(1):63-75. 3. Diel R, Wrighton-Smith P, Zellweger JP. Cost-effectiveness of interferon-gamma release assay testing for the treatment of latent tuberculosis. Eur Respir J. 2007;30(2):321-332. 4. Hernández-Garduño E. Predictive value of the tuberculin skin test and the QuantiFERON-TB Gold In-Tube assay for
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Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 05/15/2013
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References 1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e576S-e600S. 2. Koertke H, Minami K, Boethig D, et al. INR self-management permits lower anticoagulation levels after mechanical heart valve replacement. Circulation. 2003;108(suppl 1):1175-1178. 3. Dong L, Shi YK, Tian ZP, Ma JY, Wang X, Yi J. Low intensity anticoagulation therapy after mechanical heart valve replacement [in Chinese]. Zhonghua Wai Ke Za Zhi. 2003;41(4): 250-252.
Response To the Editor: We thank Drs Fu and colleagues for their letter regarding the applicability of the American College of Chest Physicians guidelines on antithrombotic and thrombolytic therapy for valvular disease to Chinese patients. To clarify, the guidelines on mechanical valves recommend the following1: 1. In patients with a mechanical aortic valve, we recommend VKA (vitamin K antagonist) therapy with a target of 2.5 (range, 2.0-3.0) over higher targets (Grade 1B). 2. In patients with a mechanical mitral valve, we suggest VKA therapy with a target of 3.0 (range, 2.5-3.5) over lower international normalized ratio (INR) targets (Grade 2C). 3. In patients with mechanical heart valves in both the aortic and the mitral positions, we suggest target INR 3.0 (range, 2.5-3.5) over target INR 2.5 (range, 2.0-3.0) (Grade 2C). However, the gist of the letter from West China Hospital is valid. INR targets in Chinese patients, and indeed in all patients, need higher-quality evidence than what currently exists. Differing INR targets based on thromboembolic risk is unique to heart valve therapy; for example, the INR target for a patient with atrial fibrillation and a CHA2DS2VASc stroke risk score of 8 is the same as that of a patient with a CHA2DS2VASc score of 3, despite higher thromboembolic risk.2 The evidence supporting such differing targets for heart valves is of moderate quality at best according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework,3 and begs for further studies. One such study, Lowering the Intensity of Oral Anticoagulant Therapy in Patients With Bileaflet Mechanical Aortic Valve Replacement (LOWERING-IT), also supports the approach of lower INR targets in low-risk mechanical aortic valves but needs validation in a larger trial.4 The ninth edition of the American College of Chest Physician guidelines presents an objective assessment of the available literature up to October 2009 that is based on the GRADE framework and the resultant recommendations. We look forward to reading publications from the West China Hospital based on its national database and will incorporate any new knowledge into future guidelines. Richard Whitlock, MD, PhD Matthew Danter, MD Hamilton, ON, Canada
Affiliations: From the Division of Cardiac Surgery, McMaster University. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Richard Whitlock, MD, PhD, Division of Cardiac Surgery, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4LB, Canada; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0557
References 1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest. 2012;141(2)(suppl): e576S-e600S. 2. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2)(suppl):e531S-e575S. 3. Guyatt GH, Oxman AD, Vist GE, et al; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650):924-926. 4. Torella M, Torella D, Chiodini P, et al. LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: results from the “LOWERING-IT” trial. Am Heart J. 2010;160(1):171-178.
The Predictive Value of Interferon-g Release Assays and Tuberculin Skin Test What About Those Not Vaccinated With Bacillus Calmette-Guérin? To the Editor, In a recent meta-analysis in CHEST (July 2012), Diel et al1 concluded that interferon-g release assays (IGRAs), including QuantiFERON-TB Gold (QFT-G) (Cellestis, a company of Qiagen GmBH), QuantiFERON-TB Gold In-Tube (QFT-GIT) (Cellestis, a company of Qiagen GmBH), and the T-SPOT.TB ELISPOT (Oxford Immunotec Ltd), have a higher positive predictive value (PPV) and negative predictive value (NPV) for progression to active TB compared with those of the tuberculin skin test (TST). The PPV and NPV in those not vaccinated with bacille Calmette-Guérin (BCG) was not shown because the majority of the study participants had a history of BCG vaccination. Therefore, the results should apply mostly to the BCG-vaccinated and not be generalized. A previous study in contacts of patients with TB by the same authors2 disregarded the analysis in the population at the highest risk of disease, that is, BCG-unvaccinated close contacts exposed to patients who tested positive on smear with pulmonary disease. But further analysis found that the PPVs of QFT-GIT and TST were not statistically different.3 This indicates that both tests may predict TB disease similarly in this population. This is probably one of the reasons why the use of TST continues in most lowburden settings where the BCG vaccine has been discontinued.
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Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 05/15/2013
Correspondence
The practice of latent TB infection (LTBI)-targeted screening using IGRAs is becoming more common, particularly for BCG-vaccinated immigrants living in low-burden settings where laboratory facilities are usually available and the government, medical plans, or research programs cover the cost of testing. However, if, in the real world of high-burden settings, the cost of screening with TST is high, then screening with IGRA is a luxury. Many IGRA research studies performed in high-burden settings frequently have to rely on the sponsor for total or partial funding, as was likely the case in many studies cited in this metaanalysis. Lowering the cost of IGRAs would encourage use by TB programs where they are more needed, identifying more BCG-vaccinated individuals with true infection and candidates for preventive treatment. In conclusion, further research is needed in BCG-unvaccinated close contacts of smear-positive patients to clearly establish similarities or differences in the PPV and NPV between IGRAs and TST, to determine whether there is any difference in the number of individuals identified for preventive treatment using each test, and to establish what the best costbenefit is in this population. Eduardo Hernández-Garduño, MD Gerardo G. Huitrón Bravo, MD Toluca, Mexico Affiliations: From the Centro de Investigación en Ciencias Médicas, Universidad Autónoma del Estado de México. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Eduardo Hernández-Garduño, MD, Centro de Investigación en Ciencias Médica, Jesús Carranza #200, Toluca, Estado de México, México, 50130; email: investigador.cicmed@ gmail.com. © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0055
by Drs Hernández-Garduño and Huitrón-Bravo is the advantage of interferon-g release assays (IGRAs) over the TST in people with nontuberculous mycobacteria infections, which are distributed worldwide. The TST, but not IGRAs, cross-react against most nontuberculous mycobacteria, irrespective of any simultaneous coverage with BCG.2 I certainly agree with the authors that lowering IGRA costs would probably encourage the implementation of preventive therapy (PT). With respect to the cost-effectiveness of PT, it should be kept in mind that IGRAs may dramatically reduce the number of falsely positive contact people wrongly considered for PT, which may at least partially compensate higher IGRA costs.3 In previous letters4,5 in reference to our predictive value study in Germany,6 Dr Hernández-Garduño suggested that both tests, IGRAs and the TST, may predict TB disease in high-risk contacts similarly. However, in our reply at that time,5 we demonstrated that the lack of statistical significance for different QuantiFERON-TB Gold In Tube-Test (QFT-GIT) (Cellestis, a company of Qiagen GmBH) and TST progression rates in subjects not vaccinated with BCG in two-tailed testing (although there was a significantly higher progression rate in favor of the QFT-GIT in one-tailed testing) is most likely explained by the small sample size. Thus, it would be incorrect to conclude that TST predictive value is similar to QFTGIT in the unvaccinated contacts. In addition, although the IGRAs have a fixed cutoff for test positivity, TST cutoffs in BCG vaccines and subsequently the number of contacts with presumed latent TB infection who eventually progress to active TB depend on differing opinions of national committees on what constitutes test positivity in the TST; cutoffs vary between induration sizes of 5 and 15 mm. Therefore, as the authors of this letter stress, in the “real world” of high-burden settings, where most people can be expected to be BCG vaccinated, we do not see the need for any further research in BCGunvaccinated close contacts of smear positive patients to clearly establish similarities or differences in the positive predictive value and negative predictive value between IGRAs and TST. Roland Diel, MD, MPH Hannover, Germany
References 1. Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-g release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest. 2012;142(1):63-75. 2. Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a wholeblood interferon-g release assay for developing active tuberculosis: an update. Am J Respir Crit Care Med. 2011;183(1): 88-95. 3. Hernández-Garduño E. An update: the predictive value of QuantiFERON-TB-Gold In-Tube assay and the tuberculin skin test. Am J Respir Crit Care Med. 2011;183(3):414.
Response To the Editor: I thank Drs Hernández-Garduño and Huitrón Bravo for addressing some important aspects of testing close contacts of patients with TB for latent TB infection. The authors point out that in highburden countries, where bacille Calmette-Guérin (BCG) vaccination is common,1 it is necessary to identify more vaccinated but truly infected individuals, and because of possibly false-positive cross-reactions this cannot be done effectively by testing with the tuberculin skin test (TST). Another important point not addressed
Affiliations: From the Department of Pulmonary Medicine, Medical School Hannover (MHH). Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Diel has received travel reimbursement and/or fees for speaking at symposia sponsored by Cellestis Ltd, Oxford Immunotec Ltd, and Pharmore Ltd (exclusive supplier of Tuberculin RT23 for Germany). Correspondence to: Roland Diel, MD, MPH, Medical School Hannover, Carl-Neuberg-Str 1, Hannover, Germany 30625; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0126
References 1. Zwerling A, Behr MA, Verma A, Brewer TF, Menzies D, Pai M. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med. 2011;8(3):e1001012. 2. Diel R, Loddenkemper R, Nienhaus A. Predictive value of interferon-g release assays and tuberculin skin testing for progression from latent TB infection to disease state: a metaanalysis. Chest. 2012;142(1):63-75. 3. Diel R, Wrighton-Smith P, Zellweger JP. Cost-effectiveness of interferon-gamma release assay testing for the treatment of latent tuberculosis. Eur Respir J. 2007;30(2):321-332. 4. Hernández-Garduño E. Predictive value of the tuberculin skin test and the QuantiFERON-TB Gold In-Tube assay for
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 05/15/2013
CHEST / 143 / 5 / MAY 2013
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