ABSTRACT
Introduction: Airflow obstruction (AO) is evidenced by reduced forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) with the threshold for diagnosis often being set at <0.7. However, currently the ATS/ERS standards for interpretation of lung function tests recommend the lower limit of normal (LLN), calculated by reference equations of the Global Lung Initiative from 2012 (GLI-12), as a threshold for AO diagnosis. The present study aims to investigate phenotypes, with focus on hyperinflation, which influence AO prevalence defined by FEV1/FVC < LLN when compared to the fixed 0.7 threshold. Methods: Data from 3,875 lung function tests (56.4% men, aged 18-95) including 3,824 body plethysmography recordings performed from July 2021 to June 2022 were analysed. The difference between both classifiers was quantified, before and after stratification by sex, age, and hyperinflation. Results: AO diagnosis was significantly less frequent with the LLN threshold (18.2%) compared to the fixed threshold (28.0%) (p < 0.001) with discordance rate of 10.5%. In the presence of mild or moderate hyperinflation, there was substantial agreement (Cohen's kappa: 0.616, 0.718) between the classifiers compared to near perfect agreement in the presence of severe hyperinflation (Cohen's kappa: 0.896). In addition, subgroup analysis after stratification for sex, age, and hyperinflation showed significant differences between both classifiers. Conclusion: The importance of using the LLN threshold instead of the fixed 0.7 threshold for the diagnosis of AO is highlighted. When using the fixed threshold AO, misdiagnosis was more common in the presence of mild to moderate hyperinflation.
ABSTRACT
Blood gas analysis is part of the diagnostic work-up for pulmonary hypertension (PH). Although some studies have found that the partial pressure of carbon dioxide (PaCO2) is an independent marker of mortality in individuals with pulmonary arterial hypertension (PH Group 1), there is a lack of data regarding the significance of PaCO2 in individuals with different types of PH based on the new 2022 definitions. Therefore, this study analyzed data from 157 individuals who were undergoing PH work-up, including right heart catheterization, using PH definitions from the 2022 European Society of Cardiology/European Respiratory Society guidelines. At diagnosis, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels were significantly higher, but the time-course of NT-pro-BNP levels during treatment was significantly more favorable in individuals with pulmonary arterial hypertension (PH Group 1) who did versus did not have hypocapnia (p = 0.026 and p = 0.017, respectively). These differences based on the presence of hypocapnia were not seen in individuals with PH Groups 2, 3, or 4. In conclusion, using the new definition of PH, hypocapnia may correlate with worse risk stratification at diagnosis in individuals with pulmonary arterial hypertension. However, hypocapnic individuals with pulmonary arterial hypertension may benefit more from disease-specific therapy than those without hypocapnia.
ABSTRACT
The combination of neoadjuvant chemotherapy, radiochemotherapy, and maintenance therapy with interferon beta (IFNß) has led to superior results in the treatment of children and adolescents with nasopharyngeal carcinoma (NPC). However, nothing is known about the mechanism of the antitumor activity of IFNß in NPC. Here, we investigate the role of IFNß on apoptosis in NPC cells. Six NPC cell lines, one patient-derived NPC xenograft (PDX) and one SV40-transformed nasoepithelial cell line were used. Induction of apoptosis by IFNß was measured by flow cytometric analysis of subG1-DNA-content, Hoechst 33258 staining and activation of caspase-3. Dissection of death ligand signaling pathways included measuring surface expression of its components by flow cytometry, activation by death ligands and neutralization with specific antibodies and siRNA. IFNß induced apoptosis at concentrations achievable in humans in five of six NPC cell lines and in PDX cells but not in nasoepithelial cells. Inhibition of caspases-3 and -8 abrogated this effect suggesting IFNß promoted apoptosis through the extrinsic pathway. IFNß induced surface expression of TRAIL and TRAIL-R2 and the addition of an anti-TRAIL-antibody or transfection with TRAIL-siRNA blocked IFNß-induced apoptosis. No induction of TRAIL-expression was noted in the IFNß-resistant cell line. In conclusion, IFNß leads to apoptosis in NPC cells in an autocrine way via the induction of TRAIL expression and subsequent activation of the TRAIL-signaling pathway. The mechanism described could at least partly explain the clinical benefit of IFNß in the treatment of NPC. Further studies in a mouse-xenograft model are warranted to substantiate this effect in vivo.
