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Challenging the gold standard: the limitations of molecular assays for detection of Mycobacterium tuberculosis heteroresistance. 挑战金标准:检测结核分枝杆菌异抗性的分子测定的局限性。
IF 9 1区 医学 Q1 Medicine Pub Date : 2024-06-14 DOI: 10.1136/thorax-2023-220202
Sarah N Danchuk, Ori E Solomon, Thomas Andreas Kohl, Viola Dreyer, Ivan Barilar, Christian Utpatel, Stefan Niemann, Dick van Soolingen, Richard Anthony, Jakko van Ingen, Joy S Michael, Marcel A Behr

Objectives: Heteroresistant infections are defined as infections in which a mixture of drug-resistant and drug-susceptible populations are present. In Mycobacterium tuberculosis (M. tb), heteroresistance poses a challenge in diagnosis and has been linked with poor treatment outcomes. We compared the analytical sensitivity of molecular methods, such as GeneXpert and whole genome sequencing (WGS) in detecting heteroresistance when compared with the 'gold standard' phenotypic assay: the agar proportion method (APM).

Methods: Using two rounds of proficiency surveys with defined monoresistant BCG strains and mixtures of susceptible/resistant M. tb, we determined the limit of detection (LOD) of known resistance associated mutations.

Results: The LOD for rifampin-R (RIF-R) detection was 1% using APM, 60% using GeneXpert MTB/RIF, 10% using GeneXpert MTB/RIF Ultra and 10% using WGS. While WGS could detect mutations beyond those associated with RIF resistance, the LOD for these other mutations was also 10%. Additionally, we observed instances where laboratories did not report resistance in the majority population, yet the mutations were present in the raw sequence data.

Conclusion: The gold standard APM detects minority resistant populations at a lower proportion than molecular tests. Mycobacterium bovis BCG strains with defined resistance and extracted DNA from M. tb provided concordant results and can serve in quality control of laboratories offering molecular testing for resistance. Further research is required to determine whether the higher LOD of molecular tests is associated with negative treatment outcomes.

目的:异质性耐药感染是指耐药和易感人群混合存在的感染。在结核分枝杆菌(M. tb)中,杂合耐药性给诊断带来了挑战,并与治疗效果不佳有关。我们比较了 GeneXpert 和全基因组测序(WGS)等分子方法与 "黄金标准 "表型检测法--琼脂比例法(APM)--在检测异抗性方面的分析灵敏度:方法:通过对确定的单耐药卡介苗菌株和易感/耐药结核杆菌混合物进行两轮能力调查,我们确定了已知耐药性相关突变的检测限(LOD):结果:使用 APM 检测利福平-R (RIF-R) 的 LOD 为 1%,使用 GeneXpert MTB/RIF 为 60%,使用 GeneXpert MTB/RIF Ultra 为 10%,使用 WGS 为 10%。虽然 WGS 可以检测到与 RIF 抗性相关的突变之外的其他突变,但这些其他突变的 LOD 也是 10%。此外,我们还观察到实验室未报告多数人群耐药的情况,但原始序列数据中却存在突变:结论:金标准 APM 检测出少数耐药人群的比例低于分子检测。具有明确耐药性的牛分枝杆菌卡介苗菌株和从结核分枝杆菌中提取的 DNA 可提供一致的结果,可用于对提供耐药性分子检测的实验室进行质量控制。还需要进一步研究,以确定分子检测的 LOD 值较高是否与治疗效果不佳有关。
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引用次数: 0
Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry. 带有种系 DICER1 致病性/可能致病性变异的青少年和成人肺囊肿患病率:美国国立卫生研究院和国际胸膜肺大疱瘤/DICER1 登记处的报告。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-06-14 DOI: 10.1136/thorax-2023-221024
Alexander T Nelson, Lauren M Vasta, Dave Watson, Jung Kim, Anne K Harris, Ana F Best, Laura A Harney, Ann G Carr, Nicole Frederickson, Louis P Dehner, Christian P Kratz, Kelly N Hagedorn, William A Mize, Alexander Ling, Yoav H Messinger, D Ashley Hill, Kris Ann P Schultz, Douglas R Stewart

Background: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants.

Methods: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis.

Results: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB.

Conclusion: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

背景:胸膜肺泡瘤(PPB)是与 DICER1 相关肿瘤易感性有关的标志性肿瘤,其特征是与年龄有关,从囊性病变(I 型)发展为具有囊性和实性混合特征的高级别肉瘤(II 型)或纯实性病变(III 型)。并非所有的囊性 PPB 都会发展;Ir 型(退行性)假定代表退行性或未发展的 I 型 PPB,是一种充满空气的囊性病变,缺乏原始肉瘤成分。本研究旨在评估通过 CT 扫描检测到的带有 DICER1 致病性/可能致病性(P/LP)种系变异的青少年和成人非进展性肺囊肿的患病率:美国国立癌症研究所DICER1综合征自然史研究、国际PPB/DICER1登记处和/或国际卵巢和睾丸间质瘤登记处都登记了患者。本分析选取了12岁或12岁以上首次接受胸部CT检查的DICER1 P/LP种系变异患者:结果:在合并的数据库中,确定了 110 名在 12 岁或 12 岁以后首次接受胸部 CT 检查的种系 DICER1 P/LP 变异个体。38%的患者(42/110)发现了肺部囊性病变,共检测出 72 例囊性病变。肺囊肿患者与无肺囊肿患者在人口统计学上无差异。5例囊肿被切除,其中4例经中央复查为Ir型PPB:结论:肺囊肿常见于有 DICER1 基因变异的青少年和成人。需要进一步研究以了解儿童肺囊肿不进展或消退的机制,从而指导进行明智的干预。
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引用次数: 0
Transbronchial cryoablation in peripheral lung parenchyma with a novel thin cryoprobe and initial clinical testing. 使用新型超薄冷冻探针在外周肺实质进行经支气管冷冻消融术和初步临床试验。
IF 9 1区 医学 Q1 Medicine Pub Date : 2024-06-14 DOI: 10.1136/thorax-2023-220227
Chuanjia Gu, Haibin Yuan, Chi Yang, Fangfang Xie, Junxiang Chen, Lei Zhu, Yifeng Jiang, Jiayuan Sun

Background: Transbronchial cryoablation shows potential as a local therapy for inoperable peripheral lung cancer. However, its clinical application for peripheral pulmonary lesions has not been reported yet.

Methods: An improved cryoprobe with an 8-mm-long, 1.9-mm-wide cryotip was used. Initially, the safety and effectiveness of this cryoprobe were assessed in an in vivo porcine model. Transbronchial cryoablation with 2 or 3 freeze-thaw cycles (10 min or 15 min in each freezing time) was performed in 18 pigs under CT monitoring. Radiological and pathological examinations were performed to evaluate the extent of cryoablation. Subsequently, nine patients with stage IA peripheral lung cancer or metastases underwent transbronchial cryoablation with this cryoprobe under the guidance of navigation bronchoscopy and cone-beam CT. Technical success, safety and outcomes were assessed.

Results: 36 cryoablation procedures were performed successfully without any major complications in the porcine model. The extent of cryoablation increased with freezing time and the number of freeze-thaw cycles, which peaked at 24 hours and then gradually decreased. Pathological results showed a change from massive haemorrhage at 24 hours to fibrous hyperplasia with chronic inflammation after 4 weeks. In the clinical trial, 10 cryoablations were performed on 9 tumours with a technical success rate of 100%. One mild treatment-related complication occurred. Of the nine tumours, seven achieved complete ablation, while two exhibited incomplete ablation and subsequent local progression at 6 months.

Conclusion: Our initial experience indicated that transbronchial cryoablation was a safe and feasible procedure for non-surgical peripheral stage IA lung cancer or pulmonary metastases.

Trial registration number: ChiCTR2200061544.

背景:经支气管低温消融术作为一种局部疗法,可治疗无法手术的周围型肺癌。然而,其在肺外周病变方面的临床应用尚未见报道:方法:使用了一种改进的冷冻探针,带有一个 8 毫米长、1.9 毫米宽的冷冻片。方法:使用了一种改进的冷冻探针,该探针带有一个 8 毫米长、1.9 毫米宽的冷冻尖端。最初,在一个猪体内模型中对这种冷冻探针的安全性和有效性进行了评估。在 CT 监测下,对 18 头猪进行了经支气管冷冻消融术,冷冻消融周期为 2 或 3 次(每次冷冻时间为 10 分钟或 15 分钟)。通过放射学和病理学检查来评估冷冻消融的范围。随后,在导航支气管镜和锥形束 CT 的引导下,9 名患有 IA 期周围型肺癌或转移灶的患者接受了经支气管冷冻消融术。对技术成功率、安全性和结果进行了评估:结果:在猪模型中成功进行了 36 次冷冻消融手术,未出现任何重大并发症。冷冻消融的范围随着冷冻时间和冷冻-解冻循环次数的增加而增大,在24小时内达到峰值,然后逐渐减小。病理结果显示,24 小时时大量出血,4 周后纤维增生并伴有慢性炎症。在临床试验中,对 9 个肿瘤进行了 10 次冷冻消融,技术成功率为 100%。发生了一起与治疗相关的轻微并发症。在这 9 个肿瘤中,7 个实现了完全消融,2 个出现了不完全消融,并在 6 个月后出现局部进展:我们的初步经验表明,经支气管低温消融术是一种安全可行的非手术治疗外周IA期肺癌或肺转移瘤的方法:ChiCTR2200061544。
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引用次数: 0
To progress or not to progress: new insights into the evolution of pleuropulmonary blastomas come from studying lung cysts in adolescents and adults with DICER1-related tumour predisposition. 进展或不进展:通过研究具有 DICER1 相关肿瘤易感性的青少年和成年人的肺囊肿,对胸膜肺泡瘤的演变有了新的认识。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-06-14 DOI: 10.1136/thorax-2024-221459
Eric Santoni-Rugiu
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引用次数: 0
Comprehensive analysis of environmental exposure to hazardous trace elements and lung function: a national cross-sectional study. 有害微量元素环境暴露与肺功能综合分析:一项全国性横断面研究。
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-06-14 DOI: 10.1136/thorax-2022-219839
Yun-Jiang Yu, Tong Zheng, Jennifer L Perret, Yajing Han, Hongyan Li, Wenjie Meng, Dinh Bui, Qi-Zhen Wu, Chenyin Dong, Qiu-Ling Fang, Zhenchi Li, Hongxuan Kuang, Xiaowen Chen, Mingdeng Xiang, Xiaodi Qin, Shyamali C Dharmage, Guang-Hui Dong, Yang Zhou

Background: There is growing interest in the joint effects of hazardous trace elements (HTEs) on lung function deficits, but the data are limited. This is a critical research gap given increased global industrialisation.

Methods: A national cross-sectional study including spirometry was performed among 2112 adults across 11 provinces in China between 2020 and 2021. A total of 27 HTEs were quantified from urine samples. Generalised linear models and quantile-based g-computation were used to explore the individual and joint effects of urinary HTEs on lung function, respectively.

Results: Overall, there were negative associations between forced expiratory volume in 1 s (FEV1) and urinary arsenic (As) (z-score coefficient, -0.150; 95% CI, -0.262 to -0.038 per 1 ln-unit increase), barium (Ba) (-0.148, 95% CI: -0.258 to -0.039), cadmium (Cd) (-0.132, 95% CI: -0.236 to -0.028), thallium (Tl) (-0.137, 95% CI: -0.257 to -0.018), strontium (Sr) (-0.147, 95% CI: -0.273 to -0.022) and lead (Pb) (-0.121, 95% CI: -0.219 to -0.023). Similar results were observed for forced vital capacity (FVC) with urinary As, Ba and Pb and FEV1/FVC with titanium (Ti), As, Sr, Cd, Tl and Pb. We found borderline associations between the ln-quartile of joint HTEs and decreased FEV1 (-20 mL, 95% CI: -48 to +8) and FVC (-14 mL, 95% CI: -49 to+2). Ba and Ti were assigned the largest negative weights for FEV1 and FVC within the model, respectively.

Conclusion: Our study investigating a wide range of HTEs in a highly polluted setting suggests that higher urinary HTE concentrations are associated with lower lung function, especially for emerging Ti and Ba, which need to be monitored or regulated to improve lung health.

背景:人们对有害微量元素(HTEs)对肺功能缺陷的共同影响越来越感兴趣,但相关数据却很有限。鉴于全球工业化程度的提高,这是一个关键的研究缺口:方法:2020 年至 2021 年期间,在中国 11 个省的 2112 名成年人中开展了一项包括肺活量测定在内的全国性横断面研究。从尿液样本中共量化了 27 种 HTE。研究采用广义线性模型和基于量纲的g计算方法,分别探讨了尿液中HTEs对肺功能的个体影响和联合影响:总体而言,1 秒用力呼气容积(FEV1)与尿砷(As)(z-score coefficient,-0.150;95% CI,-0.262 至 -0.038,每增加 1 ln-单位)、钡(Ba)(-0.148,95% CI:-0.258至-0.039)、镉(Cd)(-0.132,95% CI:-0.236至-0.028)、铊(Tl)(-0.137,95% CI:-0.257至-0.018)、锶(Sr)(-0.147,95% CI:-0.273至-0.022)和铅(Pb)(-0.121,95% CI:-0.219至-0.023)。尿液中的砷、钡和铅以及钛(Ti)、砷、锶、镉、碲和铅对用力呼吸容量(FVC)和 FEV1/FVC 的影响也有类似的结果。我们发现,关节 HTE 的 ln-quartile 值与 FEV1(-20 mL,95% CI:-48 至 +8)和 FVC(-14 mL,95% CI:-49 至 +2)下降之间存在边缘关联。在模型中,Ba 和 Ti 分别被赋予 FEV1 和 FVC 的最大负权重:我们在高污染环境中对各种 HTE 进行的研究表明,尿液中 HTE 浓度越高,肺功能越差,尤其是新出现的 Ti 和 Ba,需要对其进行监测或调节,以改善肺部健康。
{"title":"Comprehensive analysis of environmental exposure to hazardous trace elements and lung function: a national cross-sectional study.","authors":"Yun-Jiang Yu, Tong Zheng, Jennifer L Perret, Yajing Han, Hongyan Li, Wenjie Meng, Dinh Bui, Qi-Zhen Wu, Chenyin Dong, Qiu-Ling Fang, Zhenchi Li, Hongxuan Kuang, Xiaowen Chen, Mingdeng Xiang, Xiaodi Qin, Shyamali C Dharmage, Guang-Hui Dong, Yang Zhou","doi":"10.1136/thorax-2022-219839","DOIUrl":"10.1136/thorax-2022-219839","url":null,"abstract":"<p><strong>Background: </strong>There is growing interest in the joint effects of hazardous trace elements (HTEs) on lung function deficits, but the data are limited. This is a critical research gap given increased global industrialisation.</p><p><strong>Methods: </strong>A national cross-sectional study including spirometry was performed among 2112 adults across 11 provinces in China between 2020 and 2021. A total of 27 HTEs were quantified from urine samples. Generalised linear models and quantile-based g-computation were used to explore the individual and joint effects of urinary HTEs on lung function, respectively.</p><p><strong>Results: </strong>Overall, there were negative associations between forced expiratory volume in 1 s (FEV<sub>1</sub>) and urinary arsenic (As) (z-score coefficient, -0.150; 95% CI, -0.262 to -0.038 per 1 ln-unit increase), barium (Ba) (-0.148, 95% CI: -0.258 to -0.039), cadmium (Cd) (-0.132, 95% CI: -0.236 to -0.028), thallium (Tl) (-0.137, 95% CI: -0.257 to -0.018), strontium (Sr) (-0.147, 95% CI: -0.273 to -0.022) and lead (Pb) (-0.121, 95% CI: -0.219 to -0.023). Similar results were observed for forced vital capacity (FVC) with urinary As, Ba and Pb and FEV<sub>1</sub>/FVC with titanium (Ti), As, Sr, Cd, Tl and Pb. We found borderline associations between the ln-quartile of joint HTEs and decreased FEV<sub>1</sub> (-20 mL, 95% CI: -48 to +8) and FVC (-14 mL, 95% CI: -49 to+2). Ba and Ti were assigned the largest negative weights for FEV<sub>1</sub> and FVC within the model, respectively.</p><p><strong>Conclusion: </strong>Our study investigating a wide range of HTEs in a highly polluted setting suggests that higher urinary HTE concentrations are associated with lower lung function, especially for emerging Ti and Ba, which need to be monitored or regulated to improve lung health.</p>","PeriodicalId":23284,"journal":{"name":"Thorax","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139933033","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
Lung allocation: a vexed, complex multifaceted challenge 肺分配:一个棘手、复杂的多方面挑战
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-06-02 DOI: 10.1136/thorax-2024-221747
Andrew Fisher, Jasvir Parmar
We read with interest the paper from Roussel et al .1 In this study, the authors examine the outcomes for lung transplant recipients who were allocated donor organs in two very different healthcare systems. Their findings raise the complex and vexed question of what the fairest system for the allocation donor lungs is, especially for those candidates identified as being at the highest risk of waiting list mortality. There are a myriad of different allocation systems in operation across the world, which highlights the complex interplay between medical need, the ethical, legal and societal issues that shape national organ allocation policies.2 3 The paper examines two large national databases over a 10-year period to compare lung transplant outcomes in the French and US systems. The French national lung allocation programme is similar to the UK lung allocation …
我们饶有兴趣地阅读了 Roussel 等人的论文1 。在这项研究中,作者考察了在两种截然不同的医疗体系中分配到供体器官的肺移植受者的结果。他们的研究结果提出了一个复杂而棘手的问题:什么是最公平的捐肺分配系统,尤其是对于那些被确定为等待名单上死亡风险最高的候选者而言。全世界有无数种不同的分配制度,这凸显了医疗需求、伦理、法律和社会问题之间复杂的相互作用,这些问题决定了国家器官分配政策的制定。法国的国家肺分配计划与英国的肺分配计划类似,都是通过肺移植来满足医疗需求。
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引用次数: 0
Correction: British Thoracic Society Winter Meeting 2023 更正:英国胸科学会 2023 年冬季会议
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1136/thorax-2023-btsabstracts-corr1
BMJ Publishing Group Ltd and British Thoracic Society
Abstract withdrawn as it was not presented at the Meeting S45 - Forced Oscillometry Technique in Children with Preschool Wheeze: Feasibility and Relationship to Clinical Parameters P89 - The burden and impact of NTM-LD and perspectives on care, UK data from a European patient survey (ENPADE) P97 - CPET’s utility in understanding unexplained exertional dyspnoea in military personnel. Amendments to author list M7 – Improving the use of Treatment Escalation Plans in the care of respiratory inpatients in a large tertiary centre. R Meharry, K Hamilton. Queen Elizabeth University Hospital, Glasgow, UK. Amendment to text in abstract P43 – …
S45 - 学龄前喘息儿童的强迫振荡测量技术:P89 - NTM-LD 的负担和影响以及对护理的看法,来自欧洲患者调查 (ENPADE) 的英国数据 P97 - CPET 在了解军人不明原因的用力性呼吸困难方面的作用。对作者名单的修改 M7 - 改善治疗升级计划在大型三级中心呼吸科住院患者护理中的应用。R Meharry,K Hamilton。英国格拉斯哥伊丽莎白女王大学医院。摘要 P43 中文本的修正--...
{"title":"Correction: British Thoracic Society Winter Meeting 2023","authors":"BMJ Publishing Group Ltd and British Thoracic Society","doi":"10.1136/thorax-2023-btsabstracts-corr1","DOIUrl":"https://doi.org/10.1136/thorax-2023-btsabstracts-corr1","url":null,"abstract":"Abstract withdrawn as it was not presented at the Meeting S45 - Forced Oscillometry Technique in Children with Preschool Wheeze: Feasibility and Relationship to Clinical Parameters P89 - The burden and impact of NTM-LD and perspectives on care, UK data from a European patient survey (ENPADE) P97 - CPET’s utility in understanding unexplained exertional dyspnoea in military personnel. Amendments to author list M7 – Improving the use of Treatment Escalation Plans in the care of respiratory inpatients in a large tertiary centre. R Meharry, K Hamilton. Queen Elizabeth University Hospital, Glasgow, UK. Amendment to text in abstract P43 – …","PeriodicalId":23284,"journal":{"name":"Thorax","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074272","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
Journal club 期刊俱乐部
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1136/thorax-2024-221678
Neda Akhtar Hasan
IPF is a progressive fibrotic lung disease with a median survival of 3–5 years post-diagnosis. Fifty cases are diagnosed per 100 000 people in the UK. The incidence has been rising over the last two decades, with no cure at present. Furthermore, considerable heterogeneity exists within the disease course, making management and prognostication challenging. Kraven et al (DOI: 10.1136/thoraxjnl-2021–218563) have identified 3 IPF endotypes, termed clusters, that exhibit statistically significant differences in the GAP index (gender-age-physiology index), mortality and gas transfer (DLCO). 220 patients were identified from three pooled, publicly available blood transcriptomic datasets found on the Gene Expression Omnibus, where intermittently, data such as force vital capacity (FVC) was missing. Cluster one heavily displayed genes correlating to electron transport, cellular respiration and TGFβ. Cluster two demonstrated genes related to DNA repair, cell cycle, and apoptosis. Cluster three expressed genes corresponding to immune responses. Cluster 2 patients had the most favourable outcomes, achieving higher DLCO values, and lower GAP scores. Cluster one had the highest GAP score. Cluster three had the poorest prognosis, being 3.59 times more likely to die than patients in cluster 2. Following this discovery phase, the authors created a validated …
IPF 是一种进行性纤维化肺病,确诊后的中位生存期为 3-5 年。在英国,每 10 万人中就有 50 例确诊病例。在过去的二十年里,发病率一直在上升,目前还没有治愈的方法。此外,病程中存在相当大的异质性,使得管理和预后具有挑战性。Kraven 等人(DOI: 10.1136/thoraxjnl-2021-218563)发现了 3 种 IPF 内型,称为群组,它们在 GAP 指数(性别-年龄-生理学指数)、死亡率和气体转移(DLCO)方面表现出显著的统计学差异。我们从基因表达总库(Gene Expression Omnibus)上公开发布的三个集合血液转录组数据集中确定了 220 名患者,这些数据集间歇性地缺失了力量生命容量(FVC)等数据。第一组大量显示了与电子传递、细胞呼吸和 TGFβ 相关的基因。第二组显示了与 DNA 修复、细胞周期和细胞凋亡有关的基因。第三组显示了与免疫反应相关的基因。第二组患者的预后最理想,DLCO值较高,GAP评分较低。第一组的 GAP 评分最高。第三组患者的预后最差,死亡几率是第二组患者的 3.59 倍。在这一发现阶段之后,作者创建了一个经过验证的...
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引用次数: 0
COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors. 慢性阻塞性肺病基底细胞的分泌细胞与多纤毛细胞失衡,导致对环境压力的恢复能力增强。
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-05-20 DOI: 10.1136/thorax-2022-219958
Mircea Gabriel Stoleriu, Meshal Ansari, Maximilian Strunz, Andrea Schamberger, Motaharehsadat Heydarian, Yaobo Ding, Carola Voss, Juliane Josephine Schneider, Michael Gerckens, Gerald Burgstaller, Alejandra Castelblanco, Teresa Kauke, Jan Fertmann, Christian Schneider, Juergen Behr, Michael Lindner, Elvira Stacher-Priehse, Martin Irmler, Johannes Beckers, Oliver Eickelberg, Benjamin Schubert, Stefanie M Hauck, Otmar Schmid, Rudolf A Hatz, Tobias Stoeger, Herbert B Schiller, Anne Hilgendorff

Introduction: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised.

Methods: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation.

Results: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells.

Conclusion: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

导言:环境污染物会伤害粘膜升降器,从而导致慢性阻塞性肺病(COPD)的病情恶化。人们对健康和疾病中上皮对环境纳米粒子的恢复机制知之甚少:我们研究了流行污染物(如碳和氧化锌纳米粒子)对来自慢性阻塞性肺病晚期(COPD-IV,n=4)、疾病早期(COPD-II,n=3)和肺健康个体(n=4)的原代人类支气管上皮细胞(pHBECs)的细胞功能和后代的影响。pHBECs 在空气-液体界面接触纳米粒子后,细胞培养物通过功能测定、转录组和蛋白质分析进行表征,并对 pHBEC 培养物的序列样本进行单细胞分析,重点关注基础细胞分化:结果:COPD-IV 的特征是分泌表型(MUC5AC+增加了两倍),而多纤毛上皮(Ac-Tub+减少了三倍)则是以牺牲多纤毛上皮为代价的,这导致其对颗粒诱导的细胞损伤的恢复能力增强(跨上皮电阻减少了五倍),环境中大量的氧化锌纳米颗粒就是例证。将 COPD-II 培养物暴露于香烟烟雾提取物会诱发 COPD-IV 特征性的前分泌表型。时间分辨单细胞转录组学揭示了潜在的 COPD-IV 独特基底细胞状态,其特征是 KRT5+ (P=0.018) 和 LAMB3+ (P=0.050) 表达量增加了两倍,Wnt 特异性基因 (P=0.014) 和 Notch 特异性基因 (P=0.021) 被显著激活,尤其是在基底细胞和分泌细胞的前体中:我们在基底细胞中发现了慢性阻塞性肺疾病阶段特异性基因改变,这些改变影响支气管提升器的细胞组成,并可能控制疾病特异性上皮复原机制,以应对环境纳米颗粒。所发现的现象可能会为治疗和预防策略提供依据。
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引用次数: 0
Improved childhood asthma control after exposure reduction interventions for desert dust and anthropogenic air pollution: the MEDEA randomised controlled trial. 对沙漠尘埃和人为空气污染采取减少暴露干预措施后,儿童哮喘控制率有所提高:MEDEA 随机对照试验。
IF 1 1区 医学 Q1 Medicine Pub Date : 2024-05-20 DOI: 10.1136/thorax-2023-220877
Panayiotis Kouis, Emmanouil Galanakis, Eleni Michaelidou, Paraskevi Kinni, Antonis Michanikou, Constantinos Pitsios, Julietta Perez, Souzana Achilleos, Nicos Middleton, Pinelopi Anagnostopoulou, Helen Dimitriou, Efstathios Revvas, Gerasimos Stamatelatos, Haris Zacharatos, Chrysanthos Savvides, Emily Vasiliadou, Nikos Kalivitis, Andreas Chrysanthou, Filippos Tymvios, Stefania I Papatheodorou, Petros Koutrakis, Panayiotis K Yiallouros

Introduction: Elevated particulate matter (PM) concentrations of anthropogenic and/or desert dust origin are associated with increased morbidity among children with asthma.

Objective: The Mitigating the Health Effects of Desert Dust Storms Using Exposure-Reduction Approaches randomised controlled trial assessed the impact of exposure reduction recommendations, including indoor air filtration, on childhood asthma control during high desert dust storms (DDS) season in Cyprus and Greece.

Design, participants, interventions and setting: Primary school children with asthma were randomised into three parallel groups: (a) no intervention (controls); (b) outdoor intervention (early alerts notifications, recommendations to stay indoors and limit outdoor physical activity during DDS) and (c) combined intervention (same as (b) combined with indoor air purification with high efficiency particulate air filters in children's homes and school classrooms. Asthma symptom control was assessed using the childhood Asthma Control Test (c-ACT), spirometry (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)) and fractional exhaled nitric oxide (FeNO).

Results: In total, 182 children with asthma (age; mean=9.5, SD=1.63) were evaluated during 2019 and 2021. After three follow-up months, the combined intervention group demonstrated a significant improvement in c-ACT in comparison to controls (β=2.63, 95% CI 0.72 to 4.54, p=0.007), which was more profound among atopic children (β=3.56, 95% CI 0.04 to 7.07, p=0.047). Similarly, FEV1% predicted (β=4.26, 95% CI 0.54 to 7.99, p=0.025), the need for any asthma medication and unscheduled clinician visits, but not FVC% and FeNO, were significantly improved in the combined intervention compared with controls.

Conclusion: Recommendations to reduce exposure and use of indoor air filtration in areas with high PM pollution may improve symptom control and lung function in children with asthma.

Trial registration number: NCT03503812.

导言:人为和/或沙漠沙尘造成的颗粒物(PM)浓度升高与哮喘儿童发病率增加有关:利用减少接触方法减轻沙漠沙尘暴对健康的影响随机对照试验评估了减少接触建议(包括室内空气过滤)对塞浦路斯和希腊沙漠沙尘暴高发季节儿童哮喘控制的影响:患有哮喘的小学生被随机分为三个平行组:(a) 无干预组(对照组);(b) 户外干预组(早期警报通知,建议在沙漠沙尘暴期间待在室内并限制户外体育活动);(c) 综合干预组(与(b)组相同,同时在儿童家中和学校教室使用高效微粒空气过滤器进行室内空气净化)。哮喘症状控制情况通过儿童哮喘控制测试(c-ACT)、肺活量测定(1 秒内用力呼气容积(FEV1)、用力肺活量(FVC))和呼出一氧化氮分数(FeNO)进行评估:在2019年和2021年期间,共对182名哮喘儿童(平均年龄=9.5岁,SD=1.63)进行了评估。经过三个月的随访,与对照组相比,联合干预组的 c-ACT 有显著改善(β=2.63,95% CI 0.72 至 4.54,p=0.007),特应性儿童的改善幅度更大(β=3.56,95% CI 0.04 至 7.07,p=0.047)。同样,与对照组相比,联合干预措施显著改善了预测 FEV1%(β=4.26,95% CI 0.54 至 7.99,p=0.025)、对任何哮喘药物的需求和非计划就诊率,但 FVC% 和 FeNO 没有改善:结论:建议在可吸入颗粒物污染严重的地区减少接触并使用室内空气滤清,可改善哮喘儿童的症状控制和肺功能:NCT03503812。
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