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Searching for an Elusive Phantom - Targeting Estrogen in Pulmonary Hypertension. 寻找难以捉摸的幻影--肺动脉高压中的雌激素靶标
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202405-1029ED
Mark Toshner
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引用次数: 0
Pulmonary Hypertension and Anastrozole (PHANTOM): A Randomized, Double-Blind, Placebo-Controlled Trial. 肺动脉高压与阿那曲唑(PHANTOM):随机、双盲、安慰剂对照试验。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202402-0371OC
Steven M Kawut, Rui Feng, Susan S Ellenberg, Roham Zamanian, Todd Bull, Murali Chakinala, Stephen C Mathai, Anna Hemnes, Grace Lin, Margaret Doyle, Ruth Andrew, Margaret MacLean, Ioannis Stasinopoulos, Eric Austin, Angela DeMichele, Haochang Shou, Jasleen Minhas, Nianfu Song, Jude Moutchia, Corey E Ventetuolo

Rationale: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. Objectives: We aimed to determine whether anastrozole improved the 6-minute-walk distance (6MWD) at 6 months in pulmonary arterial hypertension (PAH). Methods: We performed a randomized, double-blind, placebo-controlled phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four postmenopausal women with PAH and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at 6 months. By intention-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. Measurements and Main Results: Forty-one subjects were randomized to placebo and 43 to anastrozole, and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued the study drug. There was no significant difference in the change in 6MWD at 6 months (placebo-corrected treatment effect, -7.9 m; 95% confidence interval, -32.7 to 16.9; P = 0.53). There was no difference in adverse events between the groups. Conclusions: Anastrozole did not show a significant effect on 6MWD compared with placebo in postmenopausal women with PAH and in men with PAH. Anastrozole was safe and did not have adverse effects. Clinical trial registered with www.clincialtrials.gov (NCT03229499).

理由:用阿那曲唑抑制芳香化酶可降低实验模型中的肺动脉高压:我们旨在确定阿那曲唑是否能改善肺动脉高压(PAH)患者六个月后的六分钟步行距离(6MWD):我们在七个中心对阿那曲唑进行了随机、双盲、安慰剂对照的II期临床试验。84名绝经后女性和男性 PAH 患者按 1:1 的比例被随机分配到每天口服阿那曲唑 1 毫克或安慰剂的治疗方案中,根据性别采用不同大小的置换区块进行分层。所有受试者和研究人员均蒙面。主要研究结果是 6 个月时 6MWD 与基线相比的变化。通过意向治疗分析,我们使用线性回归模型估算了阿那曲唑的治疗效果,并对性别和基线 6MWD 进行了调整。假设随访损失率为 10%,我们预计有 80% 的力量可以检测到 22 米的 6MWD 变化差异:41名受试者被随机分配到安慰剂组,43名受试者被随机分配到阿那曲唑组,所有受试者都接受了分配的治疗。安慰剂组和阿那曲唑组分别有 3 名和 2 名受试者停药。6个月时6MWD的变化无明显差异(安慰剂校正治疗效果-7.9米,95%CI -32.7 - 16.9,P = 0.53)。两组之间的不良反应没有差异:结论:与安慰剂相比,阿那曲唑对绝经后女性和男性 PAH 患者的 6MWD 没有显著影响。阿那曲唑安全且无不良反应。临床试验注册请访问 www.Clinicaltrials: gov,ID:NCT03229499。
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引用次数: 0
True Effect of Fludrocortisone for Septic Shock: Baseline Risk and Transitivity Concerns. 氟氢可的松治疗脓毒性休克的真实疗效:基线风险和转归问题。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202406-1104LE
Shodai Yoshihiro, Shunsuke Taito
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引用次数: 0
Elexacaftor/Tezacaftor/Ivacaftor Markedly Reduces Aspergillus fumigatus in Cystic Fibrosis. Elexacaftor/Tezacaftor/Ivacaftor能显著减少囊性纤维化中的曲霉菌。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202406-1128RL
Sarah J Morgan, David P Nichols, Windy Ni, Gina Hong, Stephen J Salipante, George M Solomon, Steven M Rowe, John P Clancy, Robert A Cramer, Pradeep K Singh
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引用次数: 0
IL-22Ra2 Levels Remain Elevated in People with Cystic Fibrosis despite Modulator Therapy. 尽管接受了调节剂治疗,囊性纤维化患者体内的 IL-22Ra2 水平仍然升高。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202402-0458RL
Christine M Bojanowski, Stella E Lee, Giraldina Trevejo-Nunez, Jennifer M Bomberger, Robert P Schleimer, Milene T Saavedra, Jay K Kolls
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引用次数: 0
Pulmonary Rehabilitation. 肺康复。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.210i9p3
Marilyn Moy, Christine Garvey, Suzanne Lareau
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引用次数: 0
Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers. 实现呼吸组学的承诺:发现和验证呼出挥发性生物标记物的考虑因素。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.202305-0868TR
Paul Brinkman, Michael Wilde, Waqar Ahmed, Ran Wang, Marc van der Schee, Shahd Abuhelal, Chad Schaber, Danen Cunoosamy, Graham W Clarke, Anke-Hilse Maitland-van der Zee, Sven-Erik Dahlén, Salman Siddiqui, Stephen J Fowler

The exhaled breath represents an ideal matrix for noninvasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review, we specifically address volatile organic compounds in the breath, with a view toward fulfilling the promise of these as actionable biomarkers, in particular, for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

呼出的气体是发现无创生物标记物的理想基质,呼出代谢组学有可能在精准医学时代发挥临床作用。在这篇简明的转化综述中,我们将特别讨论呼出气体中的挥发性有机化合物,以期实现将其作为可操作生物标记物的承诺,特别是肺部疾病。我们将回顾与呼吸研究重要里程碑相关的开创性工作;讨论呼吸生物标记物在不同疾病领域和医疗保健系统中的潜在应用,包括业界的观点;并概述研究设计的关键方面,如果呼吸分析要提供可靠、有效的生物标记物以满足未来临床实施的要求,那么任何关键性研究都需要考虑这些方面。
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引用次数: 0
November 1 Highlight. 11 月 1 日亮点
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-11-01 DOI: 10.1164/rccm.210i9xxviii
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引用次数: 0
Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study. 可能的慢性肺移植功能障碍的预后和风险:一项前瞻性多中心研究
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-10-29 DOI: 10.1164/rccm.202403-0568OC
Jamie L Todd, S Sam Weigt, Megan L Neely, Maria V Grau-Sepulveda, Kristen Mason, Michelle L Sever, Karen Kesler, Jerry Kirchner, Courtney W Frankel, Tereza Martinu, Michael Y Shino, Annette M Jackson, Elizabeth N Pavlisko, Nikki Williams, Mark A Robien, Lianne G Singer, Marie Budev, Wayne Tsuang, Pali D Shah, John M Reynolds, Laurie D Snyder, John A Belperio, Scott M Palmer

Rationale: Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain.

Objectives: Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort.

Methods: Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD.

Measurements and main results: Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar.

Conclusions: Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

理由慢性肺移植功能障碍(CLAD)阻碍了肺移植的成功。2019 年的一项共识完善了 CLAD 诊断,根据肺功能的持续下降引入了可能或明确的 CLAD。可能的 CLAD 的预后和风险仍不确定:在前瞻性多中心队列中确定可能的 CLAD 的预后和临床风险:器官移植临床试验-20》纳入了5个中心的745名符合CLAD条件的成年肺部受者,并采用严格的方法对可能的CLAD进行前瞻性判定。使用将 CLAD 视为时间依赖协变量的 Cox 模型确定了可能的 CLAD 对移植物损失的影响。使用带 LASSO 惩罚的正则化 Cox 模型来评估供体或受体特征以及移植后事件的发生和发生时间作为可能的 CLAD 风险。对明确的CLAD也进行了类似的分析:29.7%的患者在移植后3年发生了可能的CLAD,并显著增加了移植物丢失的风险(未经调整的HR为4.38,p为移植后90天),供体特异性抗体、急性排斥反应、急性肺损伤或组织性肺炎对可能的CLAD风险的独立信息贡献最大。明确的CLAD风险相似:结论:可能的CLAD可识别移植物丢失的高风险患者,支持前瞻性地识别这种情况,以尽早启动CLAD定向干预。需要采取更有效的策略来预防移植后巨细胞病毒、抑制异种特异性免疫和减少组织损伤,以减少可能的 CLAD 并提高肺部受体的存活率。
{"title":"Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.","authors":"Jamie L Todd, S Sam Weigt, Megan L Neely, Maria V Grau-Sepulveda, Kristen Mason, Michelle L Sever, Karen Kesler, Jerry Kirchner, Courtney W Frankel, Tereza Martinu, Michael Y Shino, Annette M Jackson, Elizabeth N Pavlisko, Nikki Williams, Mark A Robien, Lianne G Singer, Marie Budev, Wayne Tsuang, Pali D Shah, John M Reynolds, Laurie D Snyder, John A Belperio, Scott M Palmer","doi":"10.1164/rccm.202403-0568OC","DOIUrl":"10.1164/rccm.202403-0568OC","url":null,"abstract":"<p><strong>Rationale: </strong>Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain.</p><p><strong>Objectives: </strong>Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort.</p><p><strong>Methods: </strong>Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD.</p><p><strong>Measurements and main results: </strong>Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar.</p><p><strong>Conclusions: </strong>Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":""},"PeriodicalIF":19.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Airway Mucus Plugs on Chest Computed Tomography Are Associated with Exacerbations in COPD. 胸部计算机断层扫描显示的气道粘液塞与慢性阻塞性肺疾病的病情加重有关。
IF 19.3 1区 医学 Q1 CRITICAL CARE MEDICINE Pub Date : 2024-10-29 DOI: 10.1164/rccm.202403-0632OC
Emily Wan, Andrew Yen, Rim Elalami, Scott Grumley, Hrudaya P Nath, Wei Wang, Sharon Brouha, Padma P Manapragada, Mostafa Abozeed, Muhammad Usman Aziz, Mohd Zahid, Asmaa N Ahmed, Nina L Terry, Pietro Nardelli, James C Ross, Victor Kim, Sushilkumar Sonavane, Seth J Kligerman, Jørgen Vestbo, Alvar Agusti, Kangjin Kim, Raul San José Estépar, Edwin K Silverman, Michael H Cho, Alejandro A Diaz

Rationale/Objective: Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality. Whether mucus plugs are associated with prospective exacerbations has not been examined extensively.

Methods: Mucus plugs were visually-identified on baseline chest computed tomography (CT) scans from smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 2-4 COPD enrolled in two multicenter cohort studies: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and COPDGene. Associations between ordinal mucus plug score categories (0/1-2/≥3) and prospectively-ascertained AEs, defined as worsening respiratory symptoms requiring systemic steroids and/or antibiotics (moderate-to-severe) and/or ER/hospitalization (severe), were assessed using multivariable-adjusted zero-inflated Poisson regression; subjects were exacerbation-free at enrollment.

Results: Among 3,250 participants in COPDGene (mean±SD age 63.7±8.4 years, FEV1 50.6%±17.8% predicted, 45.1% female) and 1,716 participants in ECLIPSE (age 63.3±7.1 years, FEV1 48.3%±15.8% predicted, 36.2% female), 44.4% and 46.0% had mucus plugs, respectively. The incidence rates of AEs were 61.0 (COPDGene) and 125.7 (ECLIPSE) per 100 person-years. Relative to those without mucus plugs, the presence of 1-2 and ≥3 mucus plugs was associated with increased risk (adjusted rate ratio, aRR [95%CI]=1.07[1.05-1.09] and 1.15[1.1-1.2] in COPDGene; aRR=1.06[1.02-1.09] and 1.12[1.04-1.2] in ECLIPSE, respectively) for prospective moderate-to-severe AEs. The presence of 1-2 and ≥3 mucus plugs was also associated with increased risk for severe AEs during follow-up (aRR=1.05[1.01-1.08] and 1.09[1.02-1.18] in COPDGene; aRR=1.17[1.07-1.27] and 1.37[1.15-1.62] in ECLIPSE, respectively).

Conclusion: CT-based mucus plugs are associated with an increased risk for future COPD AEs.

理论依据/目的:慢性阻塞性肺疾病(COPD)的急性加重(AEs)与严重的发病率和死亡率有关。粘液栓是否与前瞻性加重有关尚未得到广泛研究:在两项多中心队列研究中,对全球慢性阻塞性肺病倡议(GOLD)2-4 级慢性阻塞性肺病吸烟者的基线胸部计算机断层扫描(CT)结果进行了粘液栓的视觉识别:这两项多中心队列研究分别是:慢性阻塞性肺病纵向评估以确定预测性替代终点(ECLIPSE)和慢性阻塞性肺病基因(COPDGene)。采用多变量调整零膨胀泊松回归法评估了粘液栓评分序数类别(0/1-2/≥3)与前瞻性确定的AEs(定义为需要使用全身类固醇和/或抗生素的呼吸道症状恶化(中度至重度)和/或急诊室/住院治疗(重度))之间的关系;受试者在入组时无病情加重:在COPDGene的3250名参与者(平均±SD年龄为63.7±8.4岁,FEV1预测值为50.6%±17.8%,女性占45.1%)和ECLIPSE的1716名参与者(年龄为63.3±7.1岁,FEV1预测值为48.3%±15.8%,女性占36.2%)中,分别有44.4%和46.0%的人有粘液栓。AE发生率分别为每100人年61.0例(COPDGene)和125.7例(ECLIPSE)。与没有粘液栓的患者相比,出现 1-2 个和≥3 个粘液栓与预期中度至重度 AE 风险增加有关(调整后比率比,aRR [95%CI]=1.07[1.05-1.09] 和 1.15[1.1-1.2](COPDGene;aRR=1.06[1.02-1.09]和 1.12[1.04-1.2](ECLIPSE))。1-2个和≥3个粘液栓的存在也与随访期间严重AEs风险的增加有关(COPDGene的aRR=1.05[1.01-1.08]和1.09[1.02-1.18];ECLIPSE的aRR=1.17[1.07-1.27]和1.37[1.15-1.62]):结论:基于 CT 的粘液栓与未来 COPD AE 风险的增加有关。
{"title":"Airway Mucus Plugs on Chest Computed Tomography Are Associated with Exacerbations in COPD.","authors":"Emily Wan, Andrew Yen, Rim Elalami, Scott Grumley, Hrudaya P Nath, Wei Wang, Sharon Brouha, Padma P Manapragada, Mostafa Abozeed, Muhammad Usman Aziz, Mohd Zahid, Asmaa N Ahmed, Nina L Terry, Pietro Nardelli, James C Ross, Victor Kim, Sushilkumar Sonavane, Seth J Kligerman, Jørgen Vestbo, Alvar Agusti, Kangjin Kim, Raul San José Estépar, Edwin K Silverman, Michael H Cho, Alejandro A Diaz","doi":"10.1164/rccm.202403-0632OC","DOIUrl":"10.1164/rccm.202403-0632OC","url":null,"abstract":"<p><p>Rationale/Objective: Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality. Whether mucus plugs are associated with prospective exacerbations has not been examined extensively.</p><p><strong>Methods: </strong>Mucus plugs were visually-identified on baseline chest computed tomography (CT) scans from smokers with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 2-4 COPD enrolled in two multicenter cohort studies: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and COPDGene. Associations between ordinal mucus plug score categories (0/1-2/≥3) and prospectively-ascertained AEs, defined as worsening respiratory symptoms requiring systemic steroids and/or antibiotics (moderate-to-severe) and/or ER/hospitalization (severe), were assessed using multivariable-adjusted zero-inflated Poisson regression; subjects were exacerbation-free at enrollment.</p><p><strong>Results: </strong>Among 3,250 participants in COPDGene (mean±SD age 63.7±8.4 years, FEV1 50.6%±17.8% predicted, 45.1% female) and 1,716 participants in ECLIPSE (age 63.3±7.1 years, FEV1 48.3%±15.8% predicted, 36.2% female), 44.4% and 46.0% had mucus plugs, respectively. The incidence rates of AEs were 61.0 (COPDGene) and 125.7 (ECLIPSE) per 100 person-years. Relative to those without mucus plugs, the presence of 1-2 and ≥3 mucus plugs was associated with increased risk (adjusted rate ratio, aRR [95%CI]=1.07[1.05-1.09] and 1.15[1.1-1.2] in COPDGene; aRR=1.06[1.02-1.09] and 1.12[1.04-1.2] in ECLIPSE, respectively) for prospective moderate-to-severe AEs. The presence of 1-2 and ≥3 mucus plugs was also associated with increased risk for severe AEs during follow-up (aRR=1.05[1.01-1.08] and 1.09[1.02-1.18] in COPDGene; aRR=1.17[1.07-1.27] and 1.37[1.15-1.62] in ECLIPSE, respectively).</p><p><strong>Conclusion: </strong>CT-based mucus plugs are associated with an increased risk for future COPD AEs.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":""},"PeriodicalIF":19.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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American journal of respiratory and critical care medicine
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