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Airway epithelial cell response to RSV is mostly impaired in goblet and multiciliated cells in asthma. 在哮喘患者中,气道上皮细胞对 RSV 的反应主要在鹅口疮细胞和多纤毛细胞中受损。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-220230
Aurore C A Gay, Martin Banchero, Orestes Carpaij, Tessa M Kole, Leonie Apperloo, Djoke van Gosliga, Putri Ayu Fajar, Gerard H Koppelman, Louis Bont, Rudi W Hendriks, Maarten van den Berge, Martijn C Nawijn

Background: In patients with asthma, respiratory syncytial virus (RSV) infections can cause disease exacerbation by infecting the epithelial layer of the airways, inducing subsequent immune response. The type I interferon antiviral response of epithelial cells upon RSV infection is found to be reduced in asthma in most-but not all-studies. Moreover, the molecular mechanisms causing the differences in the asthmatic bronchial epithelium in response to viral infection are poorly understood.

Methods: Here, we investigated the transcriptional response to RSV infection of primary bronchial epithelial cells (pBECs) from patients with asthma (n=8) and healthy donors (n=8). The pBECs obtained from bronchial brushes were differentiated in air-liquid interface conditions and infected with RSV. After 3 days, cells were processed for single-cell RNA sequencing.

Results: A strong antiviral response to RSV was observed for all cell types, for all samples (p<1e-48). Most (1045) differentially regulated genes following RSV infection were found in cells transitioning to secretory cells. Goblet cells from patients with asthma showed lower expression of genes involved in the interferon response (false discovery rate <0.05), including OASL, ICAM1 and TNFAIP3. In multiciliated cells, an impairment of the signalling pathways involved in the response to RSV in asthma was observed.

Conclusion: Our results highlight that the response to RSV infection of the bronchial epithelium in asthma and healthy airways was largely similar. However, in asthma, the response of goblet and multiciliated cells is impaired, highlighting the need for studying airway epithelial cells at high resolution in the context of asthma exacerbation.

背景:在哮喘患者中,呼吸道合胞病毒(RSV)感染可通过感染气道上皮细胞层引起疾病恶化,并诱发随后的免疫反应。大多数研究发现,哮喘患者在感染 RSV 后上皮细胞的 I 型干扰素抗病毒反应会降低,但并非所有研究都发现了这一点。此外,造成哮喘支气管上皮细胞对病毒感染反应差异的分子机制还不甚明了。方法:在此,我们研究了哮喘患者(8 人)和健康供体(8 人)的原发性支气管上皮细胞(pBECs)对 RSV 感染的转录反应。从支气管刷状细胞中获得的 pBECs 在空气-液体界面条件下分化并感染 RSV。3 天后,对细胞进行单细胞 RNA 测序:结果:在所有细胞类型、所有样本(pOASL、ICAM1 和 TNFAIP3)中都观察到了对 RSV 的强烈抗病毒反应。在多纤毛细胞中,观察到哮喘患者对 RSV 反应的信号通路受损:我们的研究结果表明,哮喘和健康气道的支气管上皮细胞对 RSV 感染的反应基本相似。然而,在哮喘中,鹅口疮细胞和多纤毛细胞的反应受到损害,这突出表明在哮喘恶化的情况下需要对气道上皮细胞进行高分辨率研究。
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引用次数: 0
Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals. 单核细胞 NLRP3 炎性体和白细胞介素-1β的激活受α-1 抗胰蛋白酶缺乏症患者的治疗调节。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-221071
Debananda Gogoi, Howard Yu, Michelle Casey, Rory Baird, Azeez Yusuf, Luke Forde, Michael E O' Brien, Jesse R West, Tammy Flagg, Noel G McElvaney, Edward Eden, Christian Mueller, Mark L Brantly, Patrick Geraghty, Emer P Reeves

Introduction: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.

Methods: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1β secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors.

Results: C3d acting via CR3 induces NLRP3 and pro-IL-1β production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1β secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1β (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation.

Discussion: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

导言:据报道,α-1抗胰蛋白酶(AAT)缺乏症(AATD)患者的补体成分3(C3)活化发生了改变。为了解其对炎症过程的潜在影响,本研究旨在探讨 C3d(C3 的一种裂解产物)是否会通过激活 NOD-、LRR- 和含吡咯啉结构域蛋白 3(NLRP3)炎性体来触发白细胞介素(IL)-1β 的分泌。该研究旨在探讨AAT增强疗法对AATD患者单核细胞C3d/补体受体3(CR3)信号轴和循环促炎标志物的影响:方法:检测 AATD 患者(28 人)和接受增强疗法的 AATD 患者(19 人)血液中的炎症介质。在CR3或NLRP3抑制剂存在或不存在的情况下,对AATD患者的单核细胞以及C3d刺激后的单核细胞进行了炎症体激活和IL-1β分泌测定:结果:C3d通过CR3诱导NLRP3和促IL-1β产生,并通过诱导内质网(ER)应激和钙通量,引发caspase-1活化和IL-1β分泌。用AAT疗法治疗AATD患者可降低血浆中C3d的水平(分别为3.0±1.2 µg/mL vs 1.3±0.5 µg/mL, pDiscussion):这些结果为了解与AATD相关的补体驱动炎症机制提供了有力的启示。虽然所述的C3d和NLRP3活化差异在AAT增强治疗后有所下降,但结果显示C3d和单核细胞ER应激持续存在,这对新疗法和临床实践具有重要意义。
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引用次数: 0
Antibiotic pharmacokinetics in infected pleural effusions. 感染性胸腔积液中的抗生素药代动力学。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-220402
David T Arnold, Liam Read, Oliver Waddington, Fergus W Hamilton, Sonia Patole, Jessica Hughes, Alice Milne, Alan Noel, Mark Bayliss, Nicholas A Maskell, Alasdair MacGowan

Pleural infection is usually treated with empirical broad-spectrum antibiotics, but limited data exist on their penetrance into the infected pleural space. We performed a pharmacokinetic study analysing the concentration of five intravenous antibiotics across 146 separate time points in 35 patients (amoxicillin, metronidazole, piperacillin-tazobactam, clindamycin and cotrimoxazole). All antibiotics tested, apart from co-trimoxazole, reach pleural fluid levels equivalent to levels within the blood and well above the relevant minimum inhibitory concentrations. The results demonstrate that concerns about the penetration of commonly used antibiotics, apart from co-trimoxazole, into the infected pleural space are unfounded.

胸膜感染通常采用经验性广谱抗生素进行治疗,但有关抗生素在受感染胸膜腔内渗透的数据却很有限。我们进行了一项药代动力学研究,分析了 35 名患者在 146 个不同时间点静脉注射五种抗生素(阿莫西林、甲硝唑、哌拉西林-他唑巴坦、克林霉素和复方新诺明)的浓度。除联合新诺明外,所有接受测试的抗生素在胸腔积液中的浓度水平都与血液中的浓度水平相当,并远高于相关的最低抑菌浓度。结果表明,除联合新诺明外,人们对常用抗生素渗入受感染胸膜腔的担忧是没有根据的。
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引用次数: 0
TB PCR in BAL and EBUS-TBNA samples for the diagnosis of pulmonary and mediastinal lymph node TB: retrospective TRiBE study. 用于肺和纵隔淋巴结结核诊断的 BAL 和 EBUS-TBNA 样本中的结核病 PCR:TRiBE 回顾性研究。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-220647
Mirae Park, Kartik Kumar, Meg Coleman, Laura Martin, Georgina Russell, Pauline Scheelbeek, Ajit Lalvani, Giovanni Satta, Onn Min Kon

Introduction: The role of Xpert Ultra in bronchoalveolar lavage (BAL) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) samples for pulmonary and mediastinal lymph node tuberculosis (TB) remains unclear.

Methods: This was a retrospective observational service evaluation at a tertiary TB centre in a low-incidence setting. The diagnostic indices of Xpert Ultra, smear and culture (with cytology for EBUS-TBNA samples) were compared with culture positivity or a composite reference standard of clinical TB diagnosis. Trace readouts, a new category of results for Xpert Ultra indicating low bacillary load, were analysed in two ways as a true positive or true negative result. 282 BAL and 139 EBUS-TBNA samples were included in the analysis.

Results: BAL: sensitivity with 95% CI against culture-confirmed pulmonary TB from BAL samples for Xpert Ultra (trace as positive) was 0.91 (0.82 to 0.98), Xpert Ultra (trace as negative) was 0.76 (0.69 to 0.83), smear was 0.38 (p=0.0009) and culture was 1.00 (0.91 to 1.00). Specificities for all the tests were ≥0.99 (0.98 to 1.00). The addition of smear to Xpert Ultra did not improve the diagnostic accuracy.EBUS-TBNA: sensitivity against culture-confirmed TB from EBUS-TBNA samples for Xpert Ultra (trace as positive) was 0.71 (0.63 to 0.78), Xpert Ultra (trace as negative) was 0.59 (0.54 to 0.63), smear was 0.12 (p=0.002), culture was 1.00 (0.89 to 1.00), cytology was 0.87 (0.76 to 0.98) and rapid on-site evaluation of cytology (ROSE) was 0.92 (0.78 to 1.00). Specificities were 0.99 (0.97 to 1.00), 0.99 (0.97 to 1.00), 1.00 (0.98 to 1.00), 1.00 (0.98 to 1.00), 0.67 (0.67 to 0.68) and 0.42, respectively.

Conclusion: Xpert Ultra had a significantly higher sensitivity compared with smear in both BAL and EBUS-TBNA samples. Xpert Ultra had a lower sensitivity compared with culture but comparable specificity with results being available within <24 hours. Trace readings in our low-incidence setting were associated with culture positivity in all BAL samples.

简介:Xpert Ultra 在支气管肺泡灌洗(BAL)和支气管内超声引导下经支气管针吸(EBUS-TBNA)样本检测肺结核和纵隔淋巴结结核(TB)中的作用尚不明确:这是一项在低发病率地区的三级结核病中心进行的回顾性观察服务评估。将 Xpert Ultra、涂片和培养(EBUS-TBNA 样本需进行细胞学检查)的诊断指标与培养阳性或临床结核病诊断的综合参考标准进行了比较。痕量读数是 Xpert Ultra 的一种新结果类别,表示结核菌载量较低,有两种分析方法,即真阳性或真阴性结果。分析包括 282 份 BAL 和 139 份 EBUS-TBNA 样本:BAL:Xpert Ultra(微量为阳性)对培养证实的肺结核的敏感性(95% CI)为 0.91(0.82 至 0.98),Xpert Ultra(微量为阴性)为 0.76(0.69 至 0.83),涂片为 0.38(p=0.0009),培养为 1.00(0.91 至 1.00)。所有检测的特异性均≥0.99(0.98 至 1.00)。EBUS-TBNA:Xpert Ultra(以微量为阳性)对 EBUS-TBNA 样本中经培养确诊的结核病的敏感性为 0.71(0.63 至 0.78),Xpert Ultra(以微量为阳性)对 EBUS-TBNA 样本中经培养确诊的结核病的敏感性为 0.73(0.91 至 1.00)。78),Xpert Ultra(微量为阴性)为 0.59(0.54 至 0.63),涂片为 0.12(P=0.002),培养为 1.00(0.89 至 1.00),细胞学为 0.87(0.76 至 0.98),细胞学快速现场评估(ROSE)为 0.92(0.78 至 1.00)。特异性分别为 0.99(0.97 至 1.00)、0.99(0.97 至 1.00)、1.00(0.98 至 1.00)、1.00(0.98 至 1.00)、0.67(0.67 至 0.68)和 0.42:结论:在 BAL 和 EBUS-TBNA 样本中,Xpert Ultra 的灵敏度明显高于涂片。与培养相比,Xpert Ultra 的灵敏度较低,但特异性不相上下,可在以下时间内得到结果
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引用次数: 0
Cause or consequence in idiopathic pulmonary fibrosis: using genetic data to back the right horse. 特发性肺纤维化的原因或结果:利用基因数据来支持正确的马。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2024-222011
Louise V Wain
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引用次数: 0
Rectal organoid morphometric analysis (ROMA)-re: optimising measurements automatically. 直肠器官形态分析(ROMA):自动重新优化测量。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2024-221829
Shafagh Waters, Peter G Middleton
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引用次数: 0
Risk of hypersensitivity pneumonitis and other interstitial lung diseases following organic dust exposure. 接触有机粉尘后患超敏性肺炎和其他间质性肺病的风险。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-221275
Inge Brosbøl Iversen, Jesper Medom Vestergaard, Ioannis Basinas, Johan Ohlander, Susan Peters, Elisabeth Bendstrup, Jens Peter Ellekilde Bonde, Vivi Schlünssen, Finn Rasmussen, Zara Ann Stokholm, Michael Brun Andersen, Hans Kromhout, Henrik Albert Kolstad

Background: Organic dust is associated with hypersensitivity pneumonitis, and associations with other types of interstitial lung disease (ILD) have been suggested. We examined the association between occupational organic dust exposure and hypersensitivity pneumonitis and other ILDs in a cohort study.

Methods: The study population included all residents of Denmark born in 1956 or later with at least 1 year of gainful employment since 1976. Incident cases of hypersensitivity pneumonitis and other ILDs were identified in the Danish National Patient Register 1994-2015. Job exposure matrices were used to assign individual annual levels of exposure to organic dust, endotoxin and wood dust from 1976 to 2015. We analysed exposure-response relations by different exposure metrics using a discrete-time hazard model.

Results: For organic dust, we observed increasing risk with increasing cumulative exposure with incidence rate ratios (IRR) per 10 unit-years of 1.19 (95% CI 1.12 to 1.27) for hypersensitivity pneumonitis and 1.04 (95% CI 1.02 to 1.06) for other ILDs. We found increasing risk with increasing cumulative endotoxin exposure for hypersensitivity pneumonitis and other ILDs with IRRs per 5000 endotoxin units/m3-years of 1.55 (95% CI 1.38 to 1.73) and 1.09 (95% CI 1.00 to 1.19), respectively. For both exposures, risk also increased with increasing duration of exposure and recent exposure. No increased risks were observed for wood dust exposure.

Conclusion: Exposure-response relations were observed between organic dust and endotoxin exposure and hypersensitivity pneumonitis and other ILDs, with lower risk estimates for the latter. The findings indicate that organic dust should be considered a possible cause of any ILD.

Trial registration number: j.no.: 1-16-02-196-17.

背景:有机粉尘与超敏性肺炎有关,也有人认为有机粉尘与其他类型的间质性肺病(ILD)有关。我们在一项队列研究中考察了职业性有机粉尘暴露与超敏性肺炎和其他间质性肺病之间的关系:研究对象包括所有 1956 年或以后出生、1976 年以来至少从事过一年有酬工作的丹麦居民。超敏性肺炎和其他 ILD 的发病病例在 1994-2015 年丹麦全国患者登记册中进行了确认。1976 年至 2015 年期间,我们使用工作暴露矩阵来确定个人每年暴露于有机粉尘、内毒素和木屑的水平。我们使用离散时间危害模型,根据不同的暴露指标分析了暴露-反应关系:对于有机粉尘,我们观察到随着累积暴露量的增加,风险也在增加,超敏性肺炎的每 10 单位年发病率比(IRR)为 1.19(95% CI 1.12 至 1.27),其他 ILD 为 1.04(95% CI 1.02 至 1.06)。我们发现,随着内毒素累积暴露量的增加,超敏性肺炎和其他 ILD 的风险也会增加,每 5000 个内毒素单位/立方米-年的 IRR 分别为 1.55(95% CI 1.38 至 1.73)和 1.09(95% CI 1.00 至 1.19)。对于这两种接触,风险也随着接触时间的延长和近期接触的增加而增加。木屑接触的风险没有增加:结论:有机粉尘和内毒素暴露与超敏性肺炎和其他 ILD 之间存在暴露-反应关系,后者的风险估计值较低。研究结果表明,有机粉尘应被视为任何 ILD 的可能诱因。
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引用次数: 0
Angiosarcoma of the pulmonary artery as an unexpected evolution of an apparent pulmonary thromboembolism. 肺动脉血管肉瘤是明显肺血栓栓塞症的意外演变。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-221041
Angela Bronte, Sofia González-Ibán, Elia Lecumberri de Fuentes, Héctor Lajusticia
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引用次数: 0
Rectal organoid morphology analysis (ROMA) as a novel physiological assay for diagnostic classification in cystic fibrosis. 直肠类器官形态分析(ROMA)作为一种新型生理检测方法,用于囊性纤维化的诊断分类。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2023-220964
Senne Cuyx, Anabela Santo Ramalho, Steffen Fieuws, Nikky Corthout, Marijke Proesmans, Mieke Boon, Kaline Arnauts, Marianne S Carlon, Sebastian Munck, Lieven Dupont, Kris De Boeck, François Vermeulen

Background: Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing CFTR variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive.

Methods: Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen.

Results: Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%).

Discussion: ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis.

背景:囊性纤维化(CF)的诊断并不总是那么简单,尤其是当汗液氯化物浓度(SCC)处于中间值且发现 CFTR 变异时。指南中提出的 CFTR 生理检测方法--鼻电位差和肠电流测量--并非在所有年龄段都可获得或可行。直肠类器官形态分析(ROMA)先前已被证明可根据一个明显的表型差异来区分有无CF患者的类器官:与非CF类器官相比,CF类器官形状不规则且缺乏可见的管腔。目前的研究旨在进一步探讨ROMA在CF诊断不确定时的作用:方法:使用之前制定的 ROMA 方案分析类器官形态。方法:使用之前建立的 ROMA 方案分析器质性组织形态,计算两个指数:圆度指数用于量化器质性组织的圆度,强度比用于衡量是否存在中心管腔:结果:对 116 名受试者的直肠器官组织进行了培养,并与之前研究中的 189 名受试者一起进行了分析。ROMA几乎完全区分了CF和非CF。ROMA指数与SCC、胰腺状态和遗传学相关,显示了趋同有效性。对于根据现行指南无法确定诊断结果的病例,ROMA提供了额外的诊断信息,24例病例中有18例(75%)通过ROMA进行了诊断分类:讨论:当SCC和遗传学不足以进行诊断分类时,ROMA可为CF诊断提供额外信息支持。ROMA是标准化的,可以集中管理,在诊断不明确时可作为首选生理检测方法纳入诊断工作。
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引用次数: 0
IgG and plasma viscosity as markers of disease activity in primary Sjogren's syndrome-related lymphocytic interstitial pneumonia. IgG和血浆粘度是原发性Sjogren综合征相关淋巴细胞性间质性肺炎疾病活动性的标志物。
IF 9 1区 医学 Q1 RESPIRATORY SYSTEM Pub Date : 2024-08-19 DOI: 10.1136/thorax-2024-221495
Sughra Alawi, Giles Dixon, Nidhi Bhatt, Huzaifa I Adamali, Harsha Gunawardena
{"title":"IgG and plasma viscosity as markers of disease activity in primary Sjogren's syndrome-related lymphocytic interstitial pneumonia.","authors":"Sughra Alawi, Giles Dixon, Nidhi Bhatt, Huzaifa I Adamali, Harsha Gunawardena","doi":"10.1136/thorax-2024-221495","DOIUrl":"10.1136/thorax-2024-221495","url":null,"abstract":"","PeriodicalId":23284,"journal":{"name":"Thorax","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620978","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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