- 作者列表："Brown SGA","Ball EL","Perrin K","Asha SE","Braithwaite I","Egerton-Warburton D","Jones PG","Keijzers G","Kinnear FB","Kwan BCH","Lam KV","Lee YCG","Nowitz M","Read CA","Simpson G","Smith JA","Summers QA","Weatherall M","Beasley R","PSP Investigators.
BACKGROUND:Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown. METHODS:In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks. RESULTS:A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management. CONCLUSIONS:Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).
背景: 对于无并发症的、中到大的原发性自发性气胸，保守治疗是否是可接受的替代治疗。 方法: 在这项开放标签、多中心、非劣效性试验中，我们招募了 14 ~ 50 岁首次已知、单侧、中大型原发性自发性气胸的患者。患者被随机分配到气胸的即刻介入治疗 (干预组) 或保守观察方法 (保守管理组)，并随访 12 个月。主要结局是 8 周内肺再扩张。 结果: 共有 316 名患者接受随机分组 (154 名患者进入干预组，162 名患者进入保守管理组)。在保守管理组中，出于方案中预先规定的原因，25 例 (15.4%) 患者接受了治疗气胸的干预措施，137 例 (84.6%) 未接受干预措施。在一项完整的病例分析中，干预组 23 例患者和保守管理组 37 例患者的数据不可用, 129 例介入治疗患者中 131 例 (98.5%) 发生 8 周内再扩张，118 例保守治疗患者中 125 例 (94.4%) 发生 8 周内再扩张 (风险差异，-4.1 个百分点;95% 置信区间 [CI]，-8.6 ~ 0.5; 非劣效性 p = 0.02); 95% 置信区间的下界在预先设定的非劣效性范围内-9 个百分点。在一项敏感性分析中，56 天后的所有缺失数据都被归为治疗失败 (干预组 129 例患者中有 138 例患者 [93.5%] 重新扩张，118 例患者中有 143 例 [82.5%] 在保守-管理组中), -11.0 个百分点的风险差异 (95% CI，-18.4 ~-3.5)在预先设定的非劣效性边缘之外。保守治疗导致严重不良事件或气胸复发的风险低于介入治疗。 结论: 虽然主要结局对关于缺失数据的保守假设没有统计学意义，但该试验提供了适度的证据，即原发性自发性气胸的保守治疗不劣于介入治疗。具有较低的严重不良事件的风险。(由急救医学基金会等资助; PSP 澳大利亚新西兰临床试验注册号，actrn12611000184976。)。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.