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MiR-1307-5p enhances fibroblast transdifferentiation to exacerbate chronic obstructive pulmonary disease through regulating FBXL16/HIF1α axis. MiR-1307-5p通过调节FBXL16/HIF1α轴增强成纤维细胞的转分化,从而加重慢性阻塞性肺病。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-17 DOI: 10.1186/s12931-024-03007-6
Li-Peng Yao, Zheng-Kai Wang, Xin-Qing Jiang, Beier Jiang, Si-Jia Chen, Zhi-Dan Hua, Dan-Dan Gao, Quan Zheng, Sheng-Mei Zhu, Mao-Xiang Qian, Feng Zhang, Li-Feng Xu, Cheng-Shui Chen, Fang Lu

Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive chronic inflammatory lung disease which affects millions of people worldwide. Activated fibroblasts are observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition. In this study, we identified that miR-1307-5p expression was significantly increased in lung fibroblasts derived from COPD patients. Mechanistically, we found that upregulation of miR-1307-5p promoted TGF-β induced lung fibroblast activation and transdifferentiation. We also identified FBXL16 as a direct target for miR-1307-5p mediated myofibroblast activation in COPD. Knockdown of FBXL16 by siRNA prominently increased the expression of myofibroblast markers in MRC-5 fibroblasts after TGF-β administration. Ectopic expression of FBXL16 in MRC-5 counteracted miR-1307-5p agomir-induced fibroblast transdifferentiation. Furthermore, We found that miR-1307-5p promoted pulmonary fibroblast transdifferentiation through FBXL16 regulated HIF1α degradation. In general, our findings indicate that miR-1307-5p is important for COPD pathogenesis, and may serve as a potential target for COPD treatment.

慢性阻塞性肺病(COPD)是一种不可逆的进行性慢性炎症性肺病,影响着全球数百万人。据观察,活化的成纤维细胞在慢性阻塞性肺病患者的肺部聚集,并通过细胞外基质(ECM)的异常沉积促进慢性阻塞性肺病的进展。在这项研究中,我们发现在慢性阻塞性肺病患者的肺成纤维细胞中,miR-1307-5p 的表达明显增加。从机理上讲,我们发现 miR-1307-5p 的上调促进了 TGF-β 诱导的肺成纤维细胞活化和转分化。我们还发现 FBXL16 是 miR-1307-5p 介导的慢性阻塞性肺疾病肌成纤维细胞活化的直接靶点。在给予 TGF-β 后,通过 siRNA 敲除 FBXL16 能显著增加 MRC-5 成纤维细胞中肌成纤维细胞标记物的表达。FBXL16 在 MRC-5 中的异位表达抵消了 miR-1307-5p agomir 诱导的成纤维细胞转分化。此外,我们还发现,miR-1307-5p 通过 FBXL16 调控 HIF1α 降解促进了肺成纤维细胞的转分化。总之,我们的研究结果表明,miR-1307-5p 对慢性阻塞性肺病的发病机制非常重要,可作为治疗慢性阻塞性肺病的潜在靶点。
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引用次数: 0
Effect of different CPAP levels on ultrasound-assessed lung aeration and gas exchange in neonates. 不同 CPAP 水平对新生儿超声评估肺通气和气体交换的影响。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-17 DOI: 10.1186/s12931-024-03010-x
Victor Sartorius, Barbara Loi, Laura Vivalda, Giulia Regiroli, Sofia De La Rubia-Ortega, Lucilla Pezza, Manon Midevaine, Shivani Shankar-Aguilera, Rafik Ben-Ammar, Daniele De Luca

Background: Respiratory distress syndrome (RDS) and transient tachypnoea (TTN) are the two commonest neonatal respiratory disorders. The optimal continuous positive airway pressure (CPAP) to treat them is unknown. We aim to clarify the effect of different CPAP levels on lung aeration and gas exchange in patients with RDS and TTN.

Methods: Prospective, observational, pragmatic, physiological cohort study. CPAP was sequentially increased from 4 to 6 and 8 cmH2O and backwards, with interposed wash-out periods. Lung aeration was assessed with a validated neonatal lung ultrasound score. Gas exchange was non-invasively evaluated with transcutaneous monitoring. Ultrasound score and PtcO2/FiO2 ratio were the co-primary outcomes. PtcCO2 and other oxygenation metrics were the secondary outcomes.

Results: 30 neonates with RDS and 30 with TTN were studied. Each CPAP increment significantly (overall always p < 0.001) improved both lung aeration and oxygenation, but the increase from 6 to 8 cmH2O achieved a small absolute benefit. In RDS patients, the absolute improvements were small and the diagnosis of TTN was significantly associated with greater improvement of lung aeration (β= -1.4 (95%CI: -2.4; -0.3), p = 0.01) and oxygenation (β = 39.6 (95%CI: 4.1; 75.1), p = 0.029). Aeration improved in 16 (53.3%) and 27 (90%) patients in the RDS and TTN groups, respectively (p = 0.034). Lung aeration showed significant hysteresis in TTN patients. Secondary outcomes gave similar results.

Conclusions: Increasing CPAP from 4 to 8 cmH2O improves ultrasound-assessed lung aeration and oxygenation in RDS and TTN. The absolute improvements are small when CPAP is beyond 6 cmH2O or for RDS patients.

背景:呼吸窘迫综合征(RDS)和一过性呼吸困难(TTN)是两种最常见的新生儿呼吸系统疾病。治疗这两种疾病的最佳持续气道正压(CPAP)尚不清楚。我们旨在明确不同 CPAP 水平对 RDS 和 TTN 患者肺通气和气体交换的影响:前瞻性、观察性、实用性、生理学队列研究。将 CPAP 从 4 cmH2O 顺序增加到 6 cmH2O 和 8 cmH2O,然后再向后增加,中间有一段冲洗期。通过有效的新生儿肺部超声评分评估肺通气情况。通过经皮监测对气体交换进行无创评估。超声评分和 PtcO2/FiO2 比率是共同的主要结果。PtcCO2和其他氧合指标为次要结果:研究对象包括 30 名患有 RDS 的新生儿和 30 名患有 TTN 的新生儿。CPAP 的每一增量都能明显(总体上总是 p 2O )获得微小的绝对益处。在 RDS 患者中,绝对改善程度较小,而 TTN 诊断与肺通气(β=-1.4 (95%CI: -2.4; -0.3),p = 0.01)和氧饱和度(β=39.6 (95%CI: 4.1; 75.1),p = 0.029)的改善程度显著相关。RDS 组和 TTN 组分别有 16 名(53.3%)和 27 名(90%)患者的通气状况有所改善(p = 0.034)。TTN患者的肺通气性显示出明显的滞后性。次要结果显示出相似的结果:将 CPAP 从 4 cmH2O 提高到 8 cmH2O 可改善 RDS 和 TTN 患者的超声评估肺通气和氧合情况。CPAP 超过 6 cmH2O 或 RDS 患者的绝对改善程度较小。
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引用次数: 0
Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO). 在实际临床实践中,双重支气管扩张剂疗法对慢性阻塞性肺病患者病情加重的益处:一项多中心验证研究(TOReTO)。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-17 DOI: 10.1186/s12931-024-02971-3
Yu-Ting Lai, Ying-Huang Tsai, Meng-Jer Hsieh, Ning-Hung Chen, Shih-Lung Cheng, Chi-Wei Tao, Yu-Feng Wei, Yao-Kuang Wu, Ming-Cheng Chan, Shih-Feng Liu, Wu-Huei Hsu, Tsung-Ming Yang, Ching-Lung Liu, Ping-Hung Kuo, Ming-Shian Lin

Background: Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups.

Methods: The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed.

Results: Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study.

Conclusions: The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

背景:事实证明,由长效β-受体激动剂(LABA)和长效毒蕈碱拮抗剂(LAMA)组成的双重支气管扩张剂疗法对慢性阻塞性肺病(COPD)患者有效。然而,目前仍不确定慢性阻塞性肺病患者中目前吸烟者和曾经吸烟者之间是否存在疗效差异。本研究旨在探讨 LABA/LAMA 疗法对这两类患者的疗效:TOReTO试验评估了肺功能、症状、健康状况、恶化发生率、临床显著恶化以及LABA/LAMA疗法的使用情况。这些疗法包括用于慢性阻塞性肺病患者的 Tio/Olo、优立定/维兰特罗(Umec/Vi)和优立定/维兰特罗(Umec/Vi)。该研究考察了当前吸烟者和曾经吸烟者的治疗效果差异。为了平衡基线特征,研究采用了倾向得分匹配法(PSM):研究收集了 967 名患者的数据。经过倾向得分匹配后,分别分析了三个治疗组的当前吸烟者首次急性加重的时间,结果发现他们之间存在显著差异(p = 0.0457)。其中,Umec/Vi 的急性加重发生率在治疗和吸烟状态之间存在差异(p = 0.0114)。LABA/LAMA 固定剂量组合的三个不同组别在治疗前吸烟者方面没有明显差异(p = 0.3079)。在整个治疗期间,慢性阻塞性肺疾病相关症状保持稳定。研究结束时,三组患者的症状评分(包括CAT和mMRC)无明显差异:结论:LABA/LAMA的三种固定剂量组合在减少曾经吸烟者的病情恶化方面没有差异,但在目前吸烟者中确实存在差异。这一趋势具有临床意义,今后的研究将通过控制影响变量来验证这一点。然而,由于该研究采用的是非随机研究设计,因此在解释这些结果时应谨慎。
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引用次数: 0
Survival, morbidity, and quality of life in pulmonary arterial hypertension patients: a systematic review of outcomes reported by population-based observational studies. 肺动脉高压患者的存活率、发病率和生活质量:基于人群的观察性研究报告结果的系统回顾。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-16 DOI: 10.1186/s12931-024-02994-w
Stefan Reinders, Eva-Maria Didden, Rose Ong

Background: Comprehensive summaries on real-world outcomes in pulmonary arterial hypertension (PAH)-a rare, incurable condition, are lacking. We conducted a systematic literature review to describe current survival, morbidity, and quality of life (QoL) outcomes in adult and pediatric PAH patients. We searched Medline and Embase electronic databases, clinicaltrials.gov, and encepp.eu entries, and grey literature to identify outcome estimates for right-heart catheterization-confirmed PAH patients from population-based observational studies (search date: 25 Nov 2021). Data were synthesized using a narrative approach and post-hoc subgroup meta-analyses were conducted to explore adult survival by region, disease severity, representativeness, and study period. The search yielded 7473 records. Following screening and full text review, 22 unique studies with 31 individual reports of outcomes were included. Studies were mostly national registries (n = 21), European (n = 13) and covering adults (n = 17); only six had systematic countrywide coverage of centers. Survival was the most frequently reported outcome (n = 22). Global adult 1-, 3-, and 5-year survival ranged from 85 to 99% (n = 15), 65 to 95% (n = 14), and 50 to 86% (n = 9), respectively. Subgroup meta-analysis showed that 1-, 3-, and 5-year survival in Europe was 90% (95% CI 86-94%; n = 8), 78% (95% CI 68-86%; n = 8), and 61% (95% CI 49-72%; n = 6), respectively; 1-year survival in North America was 88% (95% CI 83-93%; n = 3) and 3-year survival in Asia was 85% (95% CI 82-88%; n = 3). No difference in survival between regions was observed. Subgroup analysis suggested higher survival in patients with better baseline functional class; however, interpretation should be cautioned due to large subgroup heterogeneity and potential missingness of data.

Short conclusion: This review describes current disease outcomes based on well-defined and representative PAH populations. There is an overall lack of follow-up data for morbidity and QoL outcomes; survival estimates for pediatric patients are scarce and may not be generalizable to the current treatment era, although publications from large pediatric registries became available after our search date. This study demonstrated a remaining unmet need world-wide to improve long-term prognosis in PAH in the current era.

背景:肺动脉高压(PAH)是一种罕见的不治之症,目前尚缺乏对其实际治疗效果的全面总结。我们进行了一项系统性文献综述,以描述成人和儿童 PAH 患者目前的生存率、发病率和生活质量(QoL)结果。我们检索了 Medline 和 Embase 电子数据库、clinicaltrials.gov 和 encepp.eu 条目以及灰色文献,从基于人群的观察性研究(检索日期:2021 年 11 月 25 日)中确定了右心导管检查确诊的 PAH 患者的预后。我们采用叙述式方法对数据进行了综合,并进行了事后分组荟萃分析,以探讨不同地区、疾病严重程度、代表性和研究时期的成人存活率。搜索共获得 7473 条记录。经过筛选和全文审阅,共纳入了 22 项独特的研究和 31 份单独的结果报告。这些研究多为国家登记(21 项)、欧洲登记(13 项)和成人登记(17 项);只有六项研究对全国范围内的中心进行了系统性覆盖。存活率是最常报告的结果(22 例)。全球成人 1 年、3 年和 5 年生存率分别为 85% 至 99% (15 人)、65% 至 95% (14 人)和 50% 至 86% (9 人)。亚组荟萃分析显示,欧洲的 1 年、3 年和 5 年生存率分别为 90% (95% CI 86-94%; n = 8)、78% (95% CI 68-86%; n = 8) 和 61% (95% CI 49-72%; n = 6);北美的 1 年生存率为 88% (95% CI 83-93%; n = 3),亚洲的 3 年生存率为 85% (95% CI 82-88%; n = 3)。不同地区的存活率没有差异。亚组分析表明,基线功能分级较好的患者生存率较高;然而,由于亚组异质性较大且可能存在数据遗漏,因此在解释时应谨慎:简短结论:这篇综述描述了目前基于定义明确且具有代表性的 PAH 群体的疾病结果。简短结论:本综述描述了目前基于定义明确且具有代表性的 PAH 群体的疾病结果,但总体上缺乏发病率和 QoL 结果的随访数据;尽管在我们的搜索日期之后,大型儿科登记处的出版物可供使用,但儿科患者的生存率估计值很少,可能无法推广到当前的治疗时代。这项研究表明,在当今时代,全世界对改善 PAH 长期预后的需求仍未得到满足。
{"title":"Survival, morbidity, and quality of life in pulmonary arterial hypertension patients: a systematic review of outcomes reported by population-based observational studies.","authors":"Stefan Reinders, Eva-Maria Didden, Rose Ong","doi":"10.1186/s12931-024-02994-w","DOIUrl":"https://doi.org/10.1186/s12931-024-02994-w","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive summaries on real-world outcomes in pulmonary arterial hypertension (PAH)-a rare, incurable condition, are lacking. We conducted a systematic literature review to describe current survival, morbidity, and quality of life (QoL) outcomes in adult and pediatric PAH patients. We searched Medline and Embase electronic databases, clinicaltrials.gov, and encepp.eu entries, and grey literature to identify outcome estimates for right-heart catheterization-confirmed PAH patients from population-based observational studies (search date: 25 Nov 2021). Data were synthesized using a narrative approach and post-hoc subgroup meta-analyses were conducted to explore adult survival by region, disease severity, representativeness, and study period. The search yielded 7473 records. Following screening and full text review, 22 unique studies with 31 individual reports of outcomes were included. Studies were mostly national registries (n = 21), European (n = 13) and covering adults (n = 17); only six had systematic countrywide coverage of centers. Survival was the most frequently reported outcome (n = 22). Global adult 1-, 3-, and 5-year survival ranged from 85 to 99% (n = 15), 65 to 95% (n = 14), and 50 to 86% (n = 9), respectively. Subgroup meta-analysis showed that 1-, 3-, and 5-year survival in Europe was 90% (95% CI 86-94%; n = 8), 78% (95% CI 68-86%; n = 8), and 61% (95% CI 49-72%; n = 6), respectively; 1-year survival in North America was 88% (95% CI 83-93%; n = 3) and 3-year survival in Asia was 85% (95% CI 82-88%; n = 3). No difference in survival between regions was observed. Subgroup analysis suggested higher survival in patients with better baseline functional class; however, interpretation should be cautioned due to large subgroup heterogeneity and potential missingness of data.</p><p><strong>Short conclusion: </strong>This review describes current disease outcomes based on well-defined and representative PAH populations. There is an overall lack of follow-up data for morbidity and QoL outcomes; survival estimates for pediatric patients are scarce and may not be generalizable to the current treatment era, although publications from large pediatric registries became available after our search date. This study demonstrated a remaining unmet need world-wide to improve long-term prognosis in PAH in the current era.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A genome-wide association study of adults with community-acquired pneumonia. 社区获得性肺炎成人全基因组关联研究。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-16 DOI: 10.1186/s12931-024-03009-4
Eva Suarez-Pajes, Itahisa Marcelino-Rodriguez, Elisa Hernández Brito, Silvia Gonzalez-Barbuzano, Melody Ramirez-Falcon, Eva Tosco-Herrera, Luis A Rubio-Rodríguez, María Luisa Briones, Olga Rajas, Luis Borderías, Jose Ferreres, Antoni Payeras, Leonardo Lorente, Javier Aspa, Jose M Lorenzo Salazar, José Manuel Valencia-Gallardo, Nieves Carbonell, Jorge L Freixinet, Felipe Rodríguez de Castro, Jordi Solé Violán, Carlos Flores, Carlos Rodríguez-Gallego

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).

Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.

Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.

Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

背景:社区获得性肺炎(CAP)的发病率和住院率都很高。在传染病中,宿主遗传学在易感性和免疫反应中起着关键作用,所涉及的免疫途径高度依赖于微生物及其感染途径。在此,我们旨在通过病例对照全基因组关联研究(GWAS)确定 CAP 的遗传风险位点:我们对 3,765 名西班牙人进行了 GWAS 研究,其中包括 257 名住院治疗的 CAP 成年患者和 3,508 名人群对照。有 30% 的患者被证实患有肺炎球菌性 CAP,其余 70% 的患者是在微生物病因不明的患者中挑选出来的。我们使用逻辑回归法测试了 760 万个估算基因型。英国生物库细菌性肺炎 GWAS 用于结果验证。随后,我们根据贝叶斯精细图谱和功能证据对基因和可能的因果变异进行了优先排序。我们还对经典的HLA等位基因和氨基酸进行了推算和关联分析:六个独立的哨点变异达到了全基因组显著性(p -8),其中三个位于染色体 6p21.32,4q28.2、11p12 和 20q11.22 各一个。只有 6p21.32 上的一个变异在细菌性肺炎和肺炎球菌性肺炎的独立 GWAS 中得到了验证。我们的分析优先考虑了 4q28.2 上的 C4orf33、6p21.32 上的 TAPBP 和 20q11.22 上的 ZNF341。有趣的是,TAPBP 和 ZNF341 的遗传缺陷是以前已知的易患细菌性肺炎(包括肺炎球菌和流感嗜血杆菌)的先天性免疫错误。经典的 HLA 等位基因的相关性均不显著:我们完成了一项关于 CAP 的基因组学分析,发现了四个与 CAP 易感性有关的新风险位点。
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引用次数: 0
Development and evaluation of a questionnaire to capture environmental and occupational inhalational exposures in adults with fibrotic interstitial lung disease. 开发和评估调查问卷,以收集患有纤维化间质性肺病的成人的环境和职业吸入暴露情况。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-15 DOI: 10.1186/s12931-024-03000-z
Aparna C Swaminathan, Molly McFatrich, Laura Mkumba, Lauren Wright, Carrie A Redlich, Laurie D Snyder, Bryce B Reeve, Divya Patel, Mridu Gulati

Background: Identification of exposures in patients with interstitial lung diseases (ILDs) is essential for diagnosis and management and can be facilitated through the use of exposure questionnaires. However, for most ILDs, a patient-focused questionnaire is lacking. Cognitive interviewing is a methodology used to evaluate sources of understanding and misunderstanding in a questionnaire and to provide evidence of content validity. We developed and refined a new exposure questionnaire for patients with fibrotic ILDs by using cognitive interviewing to establish its understandability and content validity.

Methods: An exposure assessment questionnaire was developed by a multidisciplinary team. Cognitive interviews with 24 patients with fibrosing ILDs were conducted by trained interviewers over the phone or Zoom using a semi-structured interview guide. The questionnaire was amended based on the interviewers' interpretation of sources of misunderstanding. The revised questionnaire was tested in a second round of cognitive interviews with a different group of 24 patients.

Results: Among the 48 patients who completed interviews, mean age was 61 years, 58.3% were male and 75.0% were white. Based on the first round of cognitive interviews, the multidisciplinary team modified the questions, organization, and instructions of the questionnaire to facilitate recall, adjust for exposures that were frequently misunderstood or required clarification, and focus on clinically relevant exposures. The revised questionnaire performed well in the second round of interviews.

Conclusion: An exposure questionnaire, developed with input from patients, can be used to assess clinically relevant exposures in adults with fibrosing ILDs. This is the first questionnaire for all types of fibrosing ILD to have undergone content validation.

背景:间质性肺病(ILDs)患者的暴露识别对于诊断和管理至关重要,可通过使用暴露调查问卷来实现。然而,对于大多数 ILD 而言,缺乏以患者为中心的调查问卷。认知访谈是一种用于评估问卷中理解和误解来源并提供内容有效性证据的方法。我们采用认知访谈法为纤维化 ILD 患者开发并改进了一份新的暴露评估问卷,以确定其可理解性和内容有效性:方法:一个多学科团队开发了一份暴露评估问卷。由经过培训的访谈者通过电话或 Zoom 使用半结构化访谈指南对 24 名纤维化 ILD 患者进行认知访谈。根据访谈者对误解来源的解释,对问卷进行了修订。修订后的问卷在对另一组 24 名患者进行的第二轮认知访谈中进行了测试:在完成访谈的 48 名患者中,平均年龄为 61 岁,58.3% 为男性,75.0% 为白人。在第一轮认知访谈的基础上,多学科团队修改了问卷的问题、组织和说明,以方便回忆,调整经常被误解或需要澄清的暴露,并将重点放在与临床相关的暴露上。修订后的问卷在第二轮访谈中表现良好:结论:根据患者意见开发的暴露调查问卷可用于评估成人纤维性 ILD 患者的临床相关暴露。这是第一份经过内容验证的适用于所有类型纤维性 ILD 的问卷。
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引用次数: 0
Correction to: G12/13 signaling in asthma. 更正为哮喘中的 G12/13 信号传导。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1186/s12931-024-02985-x
Elizabeth L McDuffie, Reynold A Panettieri, Charles P Scott
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引用次数: 0
Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells. 鱼腥草素能防止气道平滑肌细胞的表型转换,从而减少卵清蛋白引发的气道重塑。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-14 DOI: 10.1186/s12931-024-03005-8
Yuanyuan Liu, Qiling Yin, Bin Liu, Zheng Lu, Meijun Liu, Ling Meng, Chao He, Jin Chang

Background: The transformation of airway smooth muscle cells (ASMCs) from a quiescent phenotype to a hypersecretory and hypercontractile phenotype is a defining feature of asthmatic airway remodeling. Fisetin, a flavonoid compound, possesses anti-inflammatory characteristics in asthma; yet, its impact on airway remodeling and ASMCs phenotype transition has not been investigated.

Objectives: This research seeked to assess the impact of fisetin on ovalbumin (OVA) induced asthmatic airway remodeling and ASMCs phenotype transition, and clarify the mechanisms through network pharmacology predictions as well as in vivo and in vitro validation.

Methods: First, a fisetin-asthma-ASMCs network was constructed to identify potential targets. Subsequently, cellular and animal studies were carried out to examine the inhibitory effects of fisetin on airway remodeling in asthmatic mice, and to detemine how fisetin impacts the phenotypic transition of ASMCs.

Results: Network analysis indicated that fisetin might affect asthma via mediating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway. Intraperitoneal administration of fisetin in vivo reduced airway inflammation and remodeling, as shown by reduced inflammatory cells, decreased T helper type 2 (Th2) cytokine release, diminished collagen accumulation, mitigated airway smooth muscle thickening, and decreased expression of osteopontin (OPN), collagen-I and α-smooth muscle actin (α-SMA). Moreover, fisetin suppressed the PI3K/AKT pathway in asthmatic lung tissue. According to the in vitro data, fisetin downregulated the expression of the synthetic phenotypic proteins OPN and collagen-I, contractile protein α-SMA, and inhibited cellular migration, potentially through the PI3K/AKT pathway.

Conclusion: These results suggest that fisetin inhibits airway remodeling in asthma by regulating ASMCs phenotypic shift, emphasizing that fisetin is a promising candidate for the treatment of airway smooth muscle remodeling.

背景:气道平滑肌细胞(ASMC)从静止表型转变为高分泌和高收缩表型是哮喘气道重塑的一个决定性特征。黄酮类化合物鱼腥草素在哮喘中具有抗炎特性,但其对气道重塑和 ASMC 表型转变的影响尚未得到研究:本研究旨在评估鱼腥草素对卵清蛋白(OVA)诱导的哮喘气道重塑和ASMCs表型转换的影响,并通过网络药理学预测以及体内、体外验证阐明其机制:方法:首先,构建了鱼腥草素-哮喘-ASMCs网络,以确定潜在靶点。方法:首先构建了鱼腥草素-哮喘-ASMCs网络,确定潜在靶点,然后进行细胞和动物实验,研究鱼腥草素对哮喘小鼠气道重塑的抑制作用,并确定鱼腥草素如何影响ASMCs的表型转变:结果:网络分析表明,鱼腥草素可能通过介导磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)通路影响哮喘。腹腔注射菲赛汀可减少气道炎症和重塑,具体表现为炎症细胞减少、T辅助2型细胞因子(Th2)释放减少、胶原堆积减少、气道平滑肌增厚减轻,以及骨生成素(OPN)、胶原蛋白-I和α-平滑肌肌动蛋白(α-SMA)表达减少。此外,鱼腥草素还能抑制哮喘肺组织中的 PI3K/AKT 通路。根据体外数据,鱼腥草素可能通过 PI3K/AKT 通路下调了合成表型蛋白 OPN 和胶原蛋白-I、收缩蛋白 α-SMA 的表达,并抑制了细胞迁移:这些结果表明,鱼腥草素通过调节 ASMCs 表型转变抑制了哮喘的气道重塑,强调了鱼腥草素是治疗气道平滑肌重塑的一种有前途的候选药物。
{"title":"Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells.","authors":"Yuanyuan Liu, Qiling Yin, Bin Liu, Zheng Lu, Meijun Liu, Ling Meng, Chao He, Jin Chang","doi":"10.1186/s12931-024-03005-8","DOIUrl":"https://doi.org/10.1186/s12931-024-03005-8","url":null,"abstract":"<p><strong>Background: </strong>The transformation of airway smooth muscle cells (ASMCs) from a quiescent phenotype to a hypersecretory and hypercontractile phenotype is a defining feature of asthmatic airway remodeling. Fisetin, a flavonoid compound, possesses anti-inflammatory characteristics in asthma; yet, its impact on airway remodeling and ASMCs phenotype transition has not been investigated.</p><p><strong>Objectives: </strong>This research seeked to assess the impact of fisetin on ovalbumin (OVA) induced asthmatic airway remodeling and ASMCs phenotype transition, and clarify the mechanisms through network pharmacology predictions as well as in vivo and in vitro validation.</p><p><strong>Methods: </strong>First, a fisetin-asthma-ASMCs network was constructed to identify potential targets. Subsequently, cellular and animal studies were carried out to examine the inhibitory effects of fisetin on airway remodeling in asthmatic mice, and to detemine how fisetin impacts the phenotypic transition of ASMCs.</p><p><strong>Results: </strong>Network analysis indicated that fisetin might affect asthma via mediating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway. Intraperitoneal administration of fisetin in vivo reduced airway inflammation and remodeling, as shown by reduced inflammatory cells, decreased T helper type 2 (Th2) cytokine release, diminished collagen accumulation, mitigated airway smooth muscle thickening, and decreased expression of osteopontin (OPN), collagen-I and α-smooth muscle actin (α-SMA). Moreover, fisetin suppressed the PI3K/AKT pathway in asthmatic lung tissue. According to the in vitro data, fisetin downregulated the expression of the synthetic phenotypic proteins OPN and collagen-I, contractile protein α-SMA, and inhibited cellular migration, potentially through the PI3K/AKT pathway.</p><p><strong>Conclusion: </strong>These results suggest that fisetin inhibits airway remodeling in asthma by regulating ASMCs phenotypic shift, emphasizing that fisetin is a promising candidate for the treatment of airway smooth muscle remodeling.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo. 人肺组织外植体在病毒和细菌感染早期的宿主转录组反应差异。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-12 DOI: 10.1186/s12931-024-02988-8
Aaqib Sohail, Fakhar H Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, Frank Pessler

Background: The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.

Results: Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77-82%; lncRNA 15-17%; pseudogenes 4-5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.

Conclusions: Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

背景:感染的头 24 小时是病原体与宿主组织相互作用的关键时间窗口。然而,由于临床上无法获得感染早期的组织,因此无法研究人体肺部自然感染的早期事件。因此,我们对肺气肿患者的体外培养人肺组织外植体(HLTE)进行了RNA测序,以研究在感染甲型流感病毒(IAV)、牛分枝杆菌卡介苗(BCG)和铜绿假单胞菌的最初24小时内,小非编码RNA、mRNA和长非编码RNA(lncRNA、lincRNA)种群的整体变化:结果:铜绿假单胞菌引起的表达变化最强,是唯一明显影响微RNA和PIWI相关RNA表达的病原体。在感染三种病原体后出现差异表达的RNA中,主要长RNA类别(> 100 nt)的代表性相似(mRNA 77-82%;lncRNA 15-17%;假基因 4-5%),但lnc-DDX60-1、RP11-202G18.1和lnc-THOC3-2是与IAV感染特别相关的RNA特征的一部分(此外还包括SNX10和SLC8A1)。IAV 感染诱导了快速的干扰素反应,CCL8 是上调最强烈的 mRNA。单细胞 RNA 测序确定气道上皮细胞和巨噬细胞是主要的 IAV 宿主细胞,但在表达很少或没有 IAV 转录本的细胞类型中也检测到了炎症反应。对大量和单细胞 RNAseq 数据的综合分析确定了一组 6 个 mRNA(IFI6、IFI44L、IRF7、ISG15、MX1、MX2)是对 IAV 感染的核心转录组反应。两种细菌病原体诱导的 mRNA 表达和预测的信号通路发生了非常相似的定性变化,但铜绿假单胞菌感染的变化幅度更大。GJB2、VNN1、DUSP4、SerpinB7和IL10的上调以及PKMYT1、S100A4、GGTA1P和SLC22A31的下调与细菌感染的关系最为密切:结论:人类肺组织对 IAV 感染的转录组反应与对卡介苗和铜绿假单胞菌感染的反应大不相同,而对这两种不同细菌病原体的反应却惊人地相似。在感染的早期阶段,这种 HLTE 模型应能在组织和单细胞水平上用于 RNA 引导的发病机制研究和组织生物标记物的发现。
{"title":"Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo.","authors":"Aaqib Sohail, Fakhar H Waqas, Peter Braubach, Laurien Czichon, Mohamed Samir, Azeem Iqbal, Leonardo de Araujo, Stephan Pleschka, Michael Steinert, Robert Geffers, Frank Pessler","doi":"10.1186/s12931-024-02988-8","DOIUrl":"https://doi.org/10.1186/s12931-024-02988-8","url":null,"abstract":"<p><strong>Background: </strong>The first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.</p><p><strong>Results: </strong>Pseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77-82%; lncRNA 15-17%; pseudogenes 4-5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.</p><p><strong>Conclusions: </strong>Human lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro. Aggregatibacter 与慢性气道疾病患者痰液中的炎症介质成反比,并能在体外减轻炎症。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-12 DOI: 10.1186/s12931-024-02983-z
Ellen Goeteyn, Steven L Taylor, Alison Dicker, Laura Bollé, Merel Wauters, Marie Joossens, Eva Van Braeckel, Jodie L Simpson, Lucy Burr, James D Chalmers, Geraint B Rogers, Aurélie Crabbé

Background: Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD.

Methods: Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients.

Results: We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability.

Conclusions: These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.

背景:慢性气道疾病(CAD)的特征是慢性气道炎症和促炎症病原体在肺部的定植。然而,虽然下气道中存在各种其他细菌种类,但人们对它们如何影响炎症尚未完全了解。我们的目的是鉴定存在于 CAD 患者下气道样本中的新型抗炎菌种:我们使用线性判别分析效应大小(LEfSE)和斯皮尔曼相关性分析法分析了三个独立队列(澳大利亚哮喘和支气管扩张症、苏格兰支气管扩张症)中成人 CAD 患者的配对痰微生物组和炎症标志物数据,以确定与患者低炎症特征相关的物种:结果:我们发现,在两个 CAD 队列(澳大利亚哮喘和支气管扩张)中,气道炎症标志物水平较低的患者中,Aggregatibacter 属的数量较多。此外,Aggregatibacter 的相对丰度与痰中 IL-8(澳大利亚支气管扩张症)和 IL-1β 水平(澳大利亚哮喘和支气管扩张症)成反比。随后使用生理相关的三维肺上皮细胞模型进行的体外测试表明,Aggregatibacter 菌属(即放线菌属(A. actinomycetemcomitans)和嗜水气单胞菌属(A. aphrophilus))及其无细胞上清液具有抗炎活性,且不会影响宿主细胞的活力:这些研究结果表明,Aggregatibacter 菌属可减轻 CAD 患者的气道炎症。
{"title":"Aggregatibacter is inversely associated with inflammatory mediators in sputa of patients with chronic airway diseases and reduces inflammation in vitro.","authors":"Ellen Goeteyn, Steven L Taylor, Alison Dicker, Laura Bollé, Merel Wauters, Marie Joossens, Eva Van Braeckel, Jodie L Simpson, Lucy Burr, James D Chalmers, Geraint B Rogers, Aurélie Crabbé","doi":"10.1186/s12931-024-02983-z","DOIUrl":"https://doi.org/10.1186/s12931-024-02983-z","url":null,"abstract":"<p><strong>Background: </strong>Chronic airway disease (CAD) is characterized by chronic airway inflammation and colonization of the lungs by pro-inflammatory pathogens. However, while various other bacterial species are present in the lower airways, it is not fully understood how they influence inflammation. We aimed to identify novel anti-inflammatory species present in lower airway samples of patients with CAD.</p><p><strong>Methods: </strong>Paired sputum microbiome and inflammatory marker data of adults with CAD across three separate cohorts (Australian asthma and bronchiectasis, Scottish bronchiectasis) was analyzed using Linear discriminant analysis Effect Size (LEfSE) and Spearman correlation analysis to identify species associated with a low inflammatory profile in patients.</p><p><strong>Results: </strong>We identified the genus Aggregatibacter as more abundant in patients with lower levels of airway inflammatory markers in two CAD cohorts (Australian asthma and bronchiectasis). In addition, the relative abundance of Aggregatibacter was inversely correlated with sputum IL-8 (Australian bronchiectasis) and IL-1β levels (Australian asthma and bronchiectasis). Subsequent in vitro testing, using a physiologically relevant three-dimensional lung epithelial cell model, revealed that Aggregatibacter spp. (i.e. A. actinomycetemcomitans, A. aphrophilus) and their cell-free supernatant exerted anti-inflammatory activity without influencing host cell viability.</p><p><strong>Conclusions: </strong>These findings suggest that Aggregatibacter spp. might act to reduce airway inflammation in CAD patients.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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