Developing and validating prediction models for severe exacerbations and readmissions in patients hospitalised for COPD exacerbation (SERCO) in China: a prospective observational study.

BACKGROUND: There is a lack of individualised prediction models for patients hospitalised with chronic obstructive pulmonary disease (COPD) for clinical practice. We developed and validated prediction models of severe exacerbations and readmissions in patients hospitalised for COPD exacerbation (SERCO). METHODS: Data were obtained from the Acute Exacerbations of Chronic Obstructive Pulmonary Disease Inpatient Registry study (NCT02657525) in China. Cause-specific hazard models were used to estimate coefficients. C-statistic was used to evaluate the discrimination. Slope and intercept were used to evaluate the calibration and used for model adjustment. Models were validated internally by 10-fold cross-validation and externally using data from different regions. Risk-stratified scoring scales and nomograms were provided. The discrimination ability of the SERCO model was compared with the exacerbation history in the previous year. RESULTS: Two sets with 2196 and 1869 patients from different geographical regions were used for model development and external validation. The 12-month severe exacerbations cumulative incidence rates were 11.55% (95% CI 10.06% to 13.16%) in development cohorts and 12.30% (95% CI 10.67% to 14.05%) in validation cohorts. The COPD-specific readmission incidence rates were 11.31% (95% CI 9.83% to 12.91%) and 12.26% (95% CI 10.63% to 14.02%), respectively. Demographic characteristics, medical history, comorbidities, drug usage, Global Initiative for Chronic Obstructive Lung Disease stage and interactions were included as predictors. C-indexes for severe exacerbations were 77.3 (95% CI 70.7 to 83.9), 76.5 (95% CI 72.6 to 80.4) and 74.7 (95% CI 71.2 to 78.2) at 1, 6 and 12 months. The corresponding values for readmissions were 77.1 (95% CI 70.1 to 84.0), 76.3 (95% CI 72.3 to 80.4) and 74.5 (95% CI 71.0 to 78.0). The SERCO model was consistently discriminative and accurate with C-indexes in the derivation and internal validation groups. In external validation, the C-indexes were relatively lower at 60-70 levels. The SERCO model discriminated outcomes better than prior severe exacerbation history. The slope and intercept after adjustment showed close agreement between predicted and observed risks. However, in external validation, the models may overestimate the risk in higher-risk groups. The model-driven risk groups showed significant disparities in prognosis. CONCLUSION: The SERCO model provides individual predictions for severe exacerbation and COPD-specific readmission risk, which enables identifying high-risk patients and implementing personalised preventive intervention for patients with COPD.

Abnormal heart rate responses to exercise in non-severe COPD: relationship with pulmonary vascular volume and ventilatory efficiency.

BACKGROUND: Despite being a prognostic predictor, cardiac autonomic dysfunction (AD) has not been well investigated in chronic obstructive pulmonary disease (COPD). We aimed to characterise computed tomography (CT), spirometry, and cardiopulmonary exercise test (CPET) features of COPD patients with cardiac AD and the association of AD with CT-derived vascular and CPET-derived ventilatory efficiency metrics. METHODS: This observational cohort study included stable, non-severe COPD patients. They underwent clinical evaluation, spirometry, CPET, and CT. Cardiac AD was determined based on abnormal heart rate responses to exercise, including chronotropic incompetence (CI) or delayed heart rate recovery (HRR) during CPET. RESULTS: We included 49 patients with FEV1 of 1.2-5.0 L (51.1-129.7%), 24 (49%) had CI, and 15 (31%) had delayed HRR. According to multivariate analyses, CI was independently related to reduced vascular volume (VV; VV ≤ median; OR [95% CI], 7.26 [1.56-33.91]) and low ventilatory efficiency (nadir VE/VCO2 ≥ median; OR [95% CI], 10.67 [2.23-51.05]). Similar results were observed for delayed HRR (VV ≤ median; OR [95% CI], 11.46 [2.03-64.89], nadir VE/VCO2 ≥ median; OR [95% CI], 6.36 [1.18-34.42]). CONCLUSIONS: Cardiac AD is associated with impaired pulmonary vascular volume and ventilatory efficiency. This suggests that lung blood perfusion abnormalities may occur in these patients. Further confirmation is required in a large population-based cohort.

Efficacy and safety of a music-therapy facilitated pulmonary telerehabilitation program in COPD patients: the COPDMELODY study protocol.

Despite considerable evidence for the benefit in chronic obstructive pulmonary disease (COPD), the implementation of pulmonary rehabilitation (PR) is insufficient. However, music therapy may help address this gap due to its unique benefits. Therefore, we aimed to develop a music-therapy facilitated pulmonary telerehabilitation program based on rhythm-guided walking, singing, and objective telemonitoring. A supervised, parallel-group, single-blinded, randomized controlled clinical trial will be conducted, including 75 patients with COPD anticipated to be randomized in a 1:1:1 ratio into three groups. The intervention groups will receive a 12-week remotely monitored rehabilitation program, while the usual care group will not receive any rehabilitation interventions. Of the two intervention groups, the multi-module music therapy group will contain rhythm-guided walking and singing training, while the rhythm-guided walking group will only include music tempo-guided walking. The primary outcome is the distance of the incremental shuttle walking test. Secondary outcomes include respiratory muscle function, spirometry, lower extremity function, symptoms, quality of life, anxiety and depression levels, physical activity level, training adherence, and safety measurements. The results of this study can contribute to develop and evaluate a home-based music-facilitated rehabilitation program, which has the potential to act as a supplement and/or substitute (according to the needs) for traditional center-based PR in patients with stable COPD. Clinical trial registration: https://classic.clinicaltrials.gov/, NCT05832814.

Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testing: a retrospective study.

BACKGROUND: The recommended delivery mode for bronchodilators in bronchodilator responsiveness (BDR) testing remains controversial. OBJECTIVE: To compare the efficacy of salbutamol administration using a nebulizer versus a metered-dose inhaler (MDI) with spacer in BDR testing. DESIGN: A retrospective study. METHODS: This study examined the data of patients with chronic obstructive pulmonary disease who completed BDR testing between 1 December 2021 and 30 June 2022, at Xiangya Hospital, Central South University. After administering 400 µg of salbutamol through an MDI with spacer or 2.5 mg using a nebulizer, the changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were analyzed in patients with moderate-to-very severe spirometric abnormalities [pre-bronchodilator FEV1 percentage predicted values (FEV1%pred) ⩽59%]. Significant responsiveness was assessed as >12% and >200 mL improvement in FEV1 and/or FVC or >10% increase in FEV1%pred or FVC percentage predicted values (FVC%pred) from pre- to post-bronchodilator administration. RESULTS: Of the enrolled 894 patients, 83.2% were male (median age, 63 years). After propensity score matching, 240 pairs of patients were selected. The increment in FEV1 and increased FEV1 relative to the predicted value (ΔFEV1%pred) were significantly higher in patients <65 years and those with severe spirometric abnormalities in the nebulization group than patients in the MDI group (all p < 0.05). Compared with MDI with spacer, patients who used nebulization had a 30 mL greater increase in ΔFEV1 (95% CI: 0.01-0.05, p = 0.004) and a 1.09% greater increase in ΔFEV1%pred (95% CI: 0.303-1.896, p = 0.007) from baseline. According to the > 12% and >200 mL increase criterion, the significant BDR rate with nebulization was 1.67 times higher than that with an MDI with spacer (OR = 1.67, 95% CI: 1.13-2.47, p = 0.009). CONCLUSION: Salbutamol delivered using a nebulizer may be preferable to an MDI with spacer in certain circumstances. Nebulization has the potential to increase responsiveness to salbutamol in BDR testing.

Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testingBronchodilator responsiveness testing is commonly undertaken as an important part of spirometry testing to determine the degree of volume and airflow improvement after bronchodilator administration. BDR testing results may affect patients' diagnosis and treatment. This study compared the effects of two delivery models (a metered dose inhaler (MDI) with spacer and nebulization) on responsiveness to bronchodilators and the results of bronchodilator responsiveness testing among patients with chronic obstructive pulmonary disease. We found that the increment in forced expiratory volume in one second were significantly higher in patients aged <65 years and in those with severe spirometric abnormalities in the nebulization group than in those in the MDI group. The study provides evidence that salbutamol delivered by a nebulizer is preferable to an MDI with spacer in patients <65 years and in those with severe spirometric abnormalities and could increase positive responsiveness to bronchodilators. The study will assist in clinical decision-making by selecting the appropriate dosing regimen for different patients.

Associations of medication regimen complexity with medication adherence and clinical outcomes in patients with chronic obstructive pulmonary disease: a prospective study.

BACKGROUND: High medication burdens are common in patients with chronic obstructive pulmonary disease (COPD). This study aimed to explore the associations of medication regimen complexity index (MRCI) with medication adherence and clinical outcomes among patients with acute exacerbations of COPD (AECOPD) after hospital discharge. METHODS: Data were obtained from a nationwide cohort study of inpatients with AECOPD in China. MRCI scores were calculated using the medication list 30 days after discharge and separated into COPD-specific and non-COPD MRCI scores. Medication adherence was measured by the withdrawal rate of COPD or inhaled long-acting bronchodilators 6 months after discharge. Clinical outcomes included re-exacerbations and COPD-related readmissions during the 30-day to 6-month follow-up period. The associations of MRCI with medication withdrawal and clinical outcomes were evaluated using univariate and multivariate logistic regressions. Potential covariates included sociodemographic factors, year of COPD diagnosis, post-bronchodilator percentage predicted forced expiratory volume in 1 s, mMRC score, CAT score, and comorbidities. RESULTS: Among the 2853 patients included, the median total MRCI score was 7 [interquartile range (IQR), 7-13]. A high MRCI score (>7) was presented in 1316 patients (46.1%). Of the MRCI score, 91% were COPD specific. The withdrawal rates of the COPD and inhaled long-acting bronchodilators were 24.2% and 24.4%, respectively. Re-exacerbation and COPD-related readmission rates were 10.2% and 7.5%, respectively. After adjusting for covariates, patients with high total MRCI scores were less likely to discontinue COPD drugs [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.52-0.74] and inhaled long-acting bronchodilators (OR, 0.68; 95%CI, 0.57-0.81); conversely, these patients were more likely to experience re-exacerbation (OR, 1.64; 95% CI, 1.27-2.11) and readmission (OR, 1.57; 95% CI, 1.17-2.10). CONCLUSION: MRCI scores were relatively low among post-hospitalized patients with AECOPD in China. Higher MRCI scores were positively associated with adherence to COPD or inhaled medications, and risk of re-exacerbation and readmission. REGISTRATION: ClinicalTrials.gov identifier: NCT02657525.

Re-exacerbation within 30 days of discharge is associated with poor prognosis in the following year among patients hospitalised with exacerbation of chronic obstructive pulmonary disease: a clinical cohort study.

BACKGROUND: Exacerbation of chronic obstructive pulmonary disease (ECOPD) is a complex phenomenon, with marked heterogeneity in the aetiology, pathophysiology and clinical manifestations. This study aimed to evaluate the clinical characteristics and long-term outcomes of patients with 30-day exacerbation among those hospitalised with ECOPD in China. METHODS: Data from the Acute Exacerbations of Chronic Obstructive Pulmonary Disease Inpatient Registry were used in this study. The patients were divided into re-event and non-event groups based on the incidence of re-exacerbation within 30 days of discharge. Exacerbation, severe exacerbation and all-cause readmissions in the following 12 months were the outcomes of interest. The cumulative incidence rates and incidence densities were calculated. Multivariate hazard function models were used to determine the association between 30-day re-exacerbation and the long-term outcomes after accounting for the competing risk of death. RESULTS: Re-exacerbation within 30 days of discharge was observed in 4.9% (n=242) of the patients (n=4963). The cumulative incidence rates and incidence densities of exacerbation, severe exacerbation and all-cause readmissions in the event group were significantly higher than those in the non-event group. After adjustment, re-exacerbation within 30 days of discharge was associated with increased risks of exacerbation, severe exacerbation and all-cause readmissions in the following 12 months (adjusted HR: 3.85 (95% CI: 3.09 to 4.80), 3.46 (2.66 to 4.50) and 3.28 (2.52 to 4.25) accordingly). CONCLUSION: Re-exacerbation of COPD within 30 days of discharge is a significant predictor of long-term prognosis. In clinical practice, short-term re-exacerbation is a significant clinical phenotype of ECOPD that requires careful management at the earliest.

Influenza and pneumococcal vaccination coverage and associated factors in patients hospitalized with acute exacerbations of COPD in China: Findings from the real-world data.

BACKGROUND: Influenza and pneumococcal vaccination are a priority in patients with chronic obstructive pulmonary disease (COPD). However, limited information is available on vaccination coverage among patients with acute exacerbations of COPD (AECOPD) in China. This study aimed to determine the rates and associated factors of influenza and pneumococcal vaccination in patients hospitalized with AECOPD. METHODS: Baseline data from a national, multicenter, hospital-based study that included adult inpatients with AECOPD between 2017 and 2021 were analyzed. The outcomes of interest were the influenza vaccination in the past year and the pneumococcal vaccination in the past 5 years. To ensure national representativeness, rates were weighted according to the distribution of hospital levels and types enrolled in this study. Multivariable Poisson regression based on mixed-effects models were used to determine the associated factors. The independent variables included the region and hospital features where the participants were located, sociodemographic characteristics (age, sex, rural/urban residence, education, etc.), and clinical indicators (COPD disease history, lung function parameters, comorbidities, etc.). The treatment profiles of the vaccinated and unvaccinated participants were compared. RESULTS: Of 6949 eligible participants, the weighted rates of influenza/pneumococcal, influenza, and pneumococcal vaccination were 2.72% (95% confidence interval [CI]: 2.34-3.10%), 2.09% (95% CI: 1.76-2.43%), and 1.25% (95% CI: 0.99-1.51%), respectively. In multivariable models, age ≥60 years (60-69 years, odds ratio [OR]: 1.90, 95% CI: 1.11-3.25; ≥80 years, OR: 2.00, 95% CI: 1.06-3.78), geographical regions (Northern China relative to Eastern China, OR: 5.09, 95% CI: 1.96-13.21), urban residence (OR: 1.69, 95% CI: 1.07-2.66), a higher education level (junior high school, OR: 1.77, 95% CI: 1.21-2.58; senior high school or above, OR: 2.61, 95% CI: 1.69-4.03), former smoking (OR: 1.79, 95% CI: 1.15-2.79), and regular inhaled medication treatment (OR: 3.28, 95% CI: 2.29-4.70) were positively associated with vaccination. Patients who had experienced severe exacerbations in the past year were less likely to be vaccinated (OR: 0.65, 95% CI: 0.45-0.96). Compared with unvaccinated participants, vaccinated participants adhered better to pharmacological and non-pharmacological treatment. CONCLUSIONS: Influenza and pneumococcal vaccination coverage are extremely low. Urgent measures are necessary to increase vaccination coverage among inpatients with AECOPD in China.

Mortality and readmission risk for hospitalised patients with acute exacerbation of COPD with and without spirometric obstruction: a longitudinal observational study in China.

OBJECTIVE: To compare the clinical features and outcomes in patients with pre-chronic obstructive pulmonary disease (COPD) and COPD hospitalised for confirmed or suspected acute exacerbation of COPD (AECOPD). DESIGN: A multicentre, longitudinal observational cohort study. SETTING: Data were obtained from the AECOPD Inpatient Registry Study in China. PARTICIPANTS: 5896 patients hospitalised for AECOPD between 2017 and 2021. OUTCOMES: Patients were divided into the COPD (n=5201) and pre-COPD (n=695) groups according to the lung function test results. The outcomes of interest included all-cause, respiratory disease-related and cardiovascular disease-related deaths as well as readmissions within 30 days and 12 months after discharge. Cumulative incidence functions were used to estimate the risk of cause-specific mortality and readmission. Multivariate hazard function models were used to determine the association between lung function and outcomes. RESULTS: There were significant between-group differences in the symptoms at admission and medication use during hospitalisation. However, there was no significant between-group difference in the 30-day all-cause mortality (0.00 vs 2.23/1000 person-month (pm), p=0.6110) and readmission (33.52 vs 30.64/1000 pm, p=0.7175). Likewise, the 30-day and 12-month cause-specific outcomes were not significantly different between groups (30-day readmission with acute exacerbation (AE): 26.07 vs 25.11/1000 pm; 12-month all-cause mortality: 0.20 vs 0.93/1000 pm; all-cause readmission: 11.49 vs 13.75/1000 pm; readmission with AE: 9.15 vs 11.64/1000 pm, p>0.05 for all comparisons). Cumulative incidence curves revealed no significant between-group differences in the 30-day and 12-month prognosis (p>0.05). Multivariate analysis revealed no significant association of lung function categories with 30-day and 12-month mortality or readmission (p>0.05 for all effect estimations). CONCLUSIONS: Patients with pre-COPD have mild symptoms and similar risks for mortality and readmission during follow-up as patients with COPD. Patients with pre-COPD should receive optimal therapies before the occurrence of irreversible damage.

MASH1 induces neuron transdifferentiation of adrenal medulla chromaffin cells. / MASH1ä»‹å¯¼è‚¾ä¸Šè ºé«“è´¨å—œé“¬ç»†èƒžå‘ç”Ÿç¥žç»å ƒè½¬åˆ†åŒ–.

OBJECTIVES: Nerve growth factor (NGF) induces neuron transdifferentiation of adrenal medulla chromaffin cells (AMCCs) and consequently downregulates the secretion of epinephrine (EPI), which may be involved in the pathogenesis of bronchial asthma. Mammalian achaete scute-homologous 1 (MASH1), a key regulator of neurogenesis in the nervous system, has been proved to be elevated in AMCCs with neuron transdifferentiation in vivo. This study aims to explore the role of MASH1 in the process of neuron transdifferentiation of AMCCs and the mechanisms. METHODS: Rat AMCCs were isolated and cultured. AMCCs were transfected with siMASH1 or MASH1 overexpression plasmid, then were stimulated with NGF and/or dexamethasone, PD98059 (a MAPK kinase-1 inhibitor) for 48 hours. Morphological changes were observed using light and electron microscope. Phenylethanolamine-N-methyltransferase (PNMT, the key enzyme for epinephrine synthesis) and tyrosine hydroxylase were detected by immunofluorescence. Western blotting was used to test the protein levels of PNMT, MASH1, peripherin (neuronal markers), extracellular regulated protein kinases (ERK), phosphorylated extracellular regulated protein kinases (pERK), and JMJD3. Real-time RT-PCR was applied to analyze the mRNA levels of MASH1 and JMJD3. EPI levels in the cellular supernatant were measured using ELISA. RESULTS: Cells with both tyrosine hydroxylase and PNMT positive by immunofluorescence were proved to be AMCCs. Exposure to NGF, AMCCs exhibited neurite-like processes concomitant with increases in pERK/ERK, peripherin, and MASH1 levels (all P<0.05). Additionally, impairment of endocrine phenotype was proved by a signifcant decrease in the PNMT level and the secretion of EPI from AMCCs (all P<0.01). MASH1 interference reversed the effect of NGF, causing increases in the levels of PNMT and EPI, conversely reduced the peripherin level and cell processes (all P<0.01). MASH1 overexpression significantly increased the number of cell processes and peripherin level, while decreased the levels of PNMT and EPI (all P<0.01). Compared with the NGF group, the levels of MASH1, JMJD3 protein and mRNA in AMCCs in the NGF+PD98059 group were decreased (all P<0.05). After treatment with PD98059 and dexamethasone, the effect of NGF on promoting the transdifferentiation of AMCCs was inhibited, and the number of cell processes and EPI levels were decreased (both P<0.05). In addition, the activity of the pERK/MASH1 pathway activated by NGF was also inhibited. CONCLUSIONS: MASH1 is the key factor in neuron transdifferentiation of AMCCs. NGF-induced neuron transdifferentiation is probably mediated via pERK/MASH1 signaling.

ID2 inhibits lung adenocarcinoma cell malignant behaviors by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway.

Lung cancer is the most common cancer and one of the main causes of cancer-related deaths, presenting in most cases as metastatic disease. Given the frequent gene mutation and/or signaling deregulation in lung adenocarcinoma, identifying novel factors or agents that target these signaling pathways may be promising strategies for lung adenocarcinoma therapy. Herein, we identified inhibitor of DNA binding 2 (ID2) as an aberrantly downregulated gene in lung adenocarcinoma. ID2 overexpression not only suppressed the viability, colony formation ability, and migration ability of lung adenocarcinoma cells but also decreased the protein levels of N-cadherin, MMP2, MMP9 and the phosphorylation levels of AKT and mTOR. The effects of PI3K/AKT/mTOR signaling agonist on lung adenocarcinoma cells were opposite to those of ID2 overexpression, partially reversing the effects of ID2 overexpression. In these experimental tissue samples, ID2 protein levels and mRNA expression were also down-regulated compared with those in adjacent non-cancerous tissues. Altogether, these findings indicated that ID2 exerts its tumor-suppressive effects on the malignant behavior of lung adenocarcinoma cells by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. Restoration of ID2 expression in lung adenocarcinoma cells may improve the therapeutic efficacy of lung adenocarcinoma therapies.

Robotic-assisted thoracic surgery following neoadjuvant chemoimmunotherapy in patients with stage III non-small cell lung cancer: A real-world prospective cohort study.

Objective: Stage III non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases. For this subset of patients, clinical management is still under debate and prognosis remains poor so far. In the present study, we aimed to evaluate the feasibility and safety of robotic-assisted thoracic surgery after neoadjuvant chemoimmunotherapy in stage III NSCLC. Methods: A real-world prospective cohort study was performed in a single-center setting from April 2021 to May 2022. Patients who were diagnosed with resectable or potentially resectable stage IIIA-B NSCLC and received neoadjuvant chemoimmunotherapy followed by robotic-assisted thoracic surgery were enrolled. Pathological response to neoadjuvant chemoimmunotherapy, treatment-related adverse events, and surgical outcomes of these patients were evaluated. Results: A total of 44 patients who underwent robotic-assisted thoracic surgery after three doses of neoadjuvant chemoimmunotherapy were included in this study. Of these, 36 of 44 (81.8%) patients had a major pathological response, and 26 (59.1%) had a pathological complete response based on pathological examination of surgical specimen. Eight patients (18.2%) suffered grade 3 treatment-related adverse events, including neutropenia (n = 4), increased aminotransferases (n = 3), anemia (n = 1), and cutaneous capillary endothelial proliferation (n = 1). Robotic-assisted thoracic surgery was performed subsequently, and R0 resection was achieved in all patients. Only two (4.5%) patients required conversion to thoracotomy. Surgical complications occurred in five (11.4%) patients, including air leak (n = 3), chylothorax (n = 2), and surgical site infection (n = 1). There was no re-surgery or postoperative mortality within 90 days. Conclusion: Robotic-assisted thoracic surgery following neoadjuvant chemoimmunotherapy showed good feasibility and safety in stage III NSCLC. It was not associated with unexpected perioperative morbidity or mortality and may be a promising therapeutic option in stage III NSCLC. These results need further confirmation by more large-scale clinical trials.

Analysis of Clinical Features and Risk Factors in Pregnant Women With Miliary Pulmonary Tuberculosis After In Vitro Fertilization Embryo Transfer.

Purpose: Miliary pulmonary tuberculosis (TB) among pregnant women after in vitro fertilization embryo transfer (IVF-ET) causes poor outcomes but is rarely reported. This study analyzed the clinical characteristics and risk factors of these patients to provide hints for further studies. Method: The demographic characteristics, clinical manifestations, radiologic features, treatment, and outcomes of six patients diagnosed from May 2012 to August 2021 in Xiangya Hospital and 69 patients that were reported in English or Chinese literature from January 1980 to August 2021 were retrospectively analyzed. Continuous variables were compared between groups by t-test or Mann-Whitney U test, and categorical variables were compared between groups by chi-square test or Fisher exact test. Univariate and multiple logistic regression analyses were used to determine the predictors of respiratory failure. Results: A total of 75 patients were included. The average age of patients was about 30 years. All patients had tubal obstruction; 5 of them were diagnosed with pelvic TB before. Thirteen cases had a history of pulmonary or extrapulmonary TB, six out of them without any antituberculosis treatment history. All patients were in their first or second trimester during the onset of symptoms. The average interval between onset of symptoms and radiologic examination was about 21 days. The most common abnormalities on chest computed tomography scan were multiple nodules, pulmonary infiltrate, and consolidation. Merely 10 patients obtained bacteriological diagnosis by Mycobacterium tuberculosis culture or polymerase chain reaction test. The other patients were clinically diagnosed. All the patients received antituberculosis treatment. Although 44% of patients had fatal complications, all cases were cured or improved after antituberculosis treatment. Unfortunately, only eight fetuses survived (10.6%). The most frequent and severe complication was type I respiratory failure (20%). Patients with expectoration, dyspnea, coarse breath sounds, ground-glass opacity, and pulmonary infiltrate or consolidation were more likely to have respiratory failure (P < 0.05). Ground-glass opacity (OR = 48.545, 95% CI = 2.366-995.974, P = 0.012) and pulmonary infiltrate or consolidation (OR = 19.943, 95% CI = 2.159-184.213, P = 0.008) were independent predictors for respiratory failure. Conclusion: Tube infertility with underscreened or untreated TB is a risk factor for miliary TB during pregnancy after IVF-ET. Ground-glass opacity and pulmonary infiltrate or consolidation are predictors of respiratory failure. We demonstrate risk factors for incidence and complications to supply clues for future intervention and improve patient prognosis.

Aberrant Methylation of Aging-Related Genes in Asthma.

Background: Asthma is a complex pulmonary inflammatory disease which is common among older adults. Aging-related alterations have also been found in structural cells and immune cells of asthma patients. Nonetheless, the underlying mechanism by which differenced aging-related gene contributes to asthma pathology remains unclear. Of note, DNA methylation (DNAm) has been proven to play a critical mechanism for age-related gene expression changes. However, the methylation changes of aging-related genes in asthma patients are still obscure. Methods: First, changes in DNAm and gene expression were detected with multiple targeted bisulfite enrichment sequencing (MethTarget) and qPCR in peripheral blood of 51 healthy controls (HCs) and 55 asthmatic patients. Second, the correlation between the DNAm levels of specific altered CpG sites and the pulmonary function indicators of asthma patients was evaluated. Last, the receiver operator characteristic (ROC) curve and principal component analysis (PCA) were used to identify the feasibility of the candidate CpG sites as biomarkers for asthma. Results: Compared with HCs, there was a differential mRNA expression for nine aging-related genes in peripheral blood of asthma patients. Besides, the methylation levels of the nine aging-related genes were also altered in asthma patients, and a total of 68 CpG sites were associated with the severity of asthma. Notably, 9 of the 68 CpG sites were significantly associated with pulmonary function parameters. Moreover, ROC curve and PCA analysis showed that the candidate differential methylation sites (DMSs) can be used as potential biomarkers for asthma. Conclusions: In summary, this study confirmed the differentially expressed mRNA and aberrant DNAm level of aging-related genes in asthma patients. DMSs are associated with the clinical evaluation indicators of asthma, which indicate the involvement of aging-related genes in the pathogenesis of asthma and provide some new possible biomarkers for asthma.

Neutrophil Extracellular Trapping Network Promotes the Pathogenesis of Neutrophil-associated Asthma through Macrophages.

Asthma is a complex airway inflammatory disease that can be roughly classified into eosinophilic phenotype and non-eosinophilic phenotype. Most of the latter manifested as airway inflammation dominated by neutrophil infiltration, namely neutrophil-dominated asthma (NA). Neutrophil extracellular trapping (NETs) is a newly discovered antimicrobial mechanism of neutrophils; however, NETs can not only resist killing pathogenic microorganisms, but also promote tissue damage and autoimmune response. In the present study, we successfully established NA model in C57BL/6 mice and observed the increased formation of NETs. In NA mice, the free DNA abundance, the airway resistance, the cell numbers (total cell number, macrophage number, and neutrophil number), and inflammatory cytokine levels were significantly increased while the lung dynamic compliance was significantly reduced. After DNase I treatment, the above indexes in NA mice were all improved. In NA mice, either treatment with macrophage scavenger or IL-1ß neutralizing antibody also improved the above-described indexes. In vitro, in human peripheral blood-derived neutrophils, PMA treatment significantly increased the formation of NETs. Furthermore, in macrophages differentiated from THP-1 monocytes, LPS or isolated NETs both significantly increased the levels of cytokines. In conclusion, NETs can stimulate macrophages to secrete IL-1ß, which promotes neutrophils infiltration in the airway; infiltrated neutrophils, in turn, generates NETs, which can amplify the tissue damage caused by NETs and macrophages, inducing and aggravating NA.

Respiratory syncytial virus infection-induced mucus secretion by down-regulation of miR-34b/c-5p expression in airway epithelial cells.

Severe RSV infection is the main cause of hospitalization to children under the age of five. The regulation of miRNAs on the severity of RSV infection is unclear. The aim of the study was to identify the critical differential expression miRNAs (DE miRNAs) that can regulate the pathological response in RSV-infected airway epithelial cells. In this study, miRNA and mRNA chips of RSV-infected airway epithelia from Gene Expression Omnibus (GEO) were screened and analysed, separately. DE miRNAs-targeted genes were performed for further pathway and process enrichment analysis. DE miRNA-targeted gene functional network was constructed on the basis of miRNA-mRNA interaction. The screened critical miRNA was also investigated by bioinformatics analysis. Then, RSV-infected human bronchial epithelial cells (HBECs) were constructed to verify the expression of the DE miRNAs. Finally, specific synthetic DE miRNAs mimics were used to confirm the effect of DE miRNAs on the RSV-infected HBECs. 45 DE miRNAs were identified from GEO62306 dataset. Our results showed that hsa-mir-34b-5p and hsa-mir-34c-5p decreased significantly in HBECs after RSV infection. Consistent with the biometric analysis, hsa-mir-34b/c-5p is involved in the regulation of mucin expression gene MUC5AC. In RSV-infected HBECs, the inducement of MUC5AC production by decreased hsa-mir-34b/c-5p was partly mediated through activation of c-Jun. These findings provide new insights into the mechanism of mucus obstruction after RSV infection and represent valuable targets for RSV infection and airway obstruction treatment.

Variable DNA methylation of aging-related genes is associated with male COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease which has a close relationship with aging. Genome-wide analysis reveals that DNA methylation markers vary obviously with age. DNA methylation variations in peripheral blood have the potential to be biomarkers for COPD. However, the specific DNA methylation of aging-related genes in the peripheral blood of COPD patients remains largely unknown. METHODS: Firstly, 9 aging-related differentially expressed genes (DEGs) in COPD patients were screened out from the 25 aging-related genes profile through a comprehensive screening strategy. Secondly, qPCR and multiple targeted bisulfite enrichment sequencing (MethTarget) were used to detect the mRNA level and DNA methylation level of the 9 differentially expressed genes in the peripheral blood of 60 control subjects and 45 COPD patients. The candidate functional CpG sites were selected on the basis of the regulation ability of the target gene expression. Thirdly, the correlation was evaluated between the DNA methylation level of the key CpG sites and the clinical parameters of COPD patients, including forced expiratory volume in one second (FEV1), forced expiratory volume in one second as percentage of predicted volume (FEV1%), forced expiratory volume/ forced vital capacity (FEV/FVC), modified British medical research council (mMRC) score, acute exacerbation frequency and the situation of frequent of acute aggravation (CAT) score. Lastly, differentially methylated CpG sites unrelated to smoking were also determined in COPD patients. RESULTS: Of the 9 differentially expressed aging-related genes, the mRNA expression of 8 genes were detected to be significantly down-regulated in COPD group, compared with control group. Meanwhile, the methylated level of all aging-related genes was changed in COPD group containing 219 COPD-related CpG sites in total. Notably, 27 CpG sites of FOXO3 gene showed a lower False Discovery Rate (FDR) and higher methylation difference values. Also, some variable DNA methylation is associated with the severity of COPD. Additionally, of the 219 COPD-related CpG sites, 147 CpG sites were not related to smoking. CONCLUSION: These results identified that the mRNA expression and DNA methylation level of aging-related genes were changed in male COPD patients, which provides a molecular link between aging and COPD. The identified CpG markers are associated with the severity of COPD and provide new insights into the prediction and identification of COPD.

Suicidality among patients with asthma: A systematic review and meta-analysis.

BACKGROUND: Asthma is associated with multiple psychiatric comorbidities. However, the relationship between asthma and suicidality has not be well established. METHODS: According to the PRISMA guidelines, protocol of the study was registered in the PROSPERO database (CRD42019123150). A systematic search of the PubMed, Embase and PsycINFO databases was performed for relevant studies published from its inception to January 25, 2019. Studies that reported the risk of suicidal ideation, attempts and mortality in asthmatics compared with non-asthmatics were included. A random-effects model was used to synthesize the estimates and the quality of the included studies was assessed under the Newcastle-Ottawa Scale. RESULTS: Twenty-eight studies including 2,759,841 asthmatic patients and 16,290,362 non-asthmatic controls were pooled and analyzed in the current study. The pooled data showed that asthmatic patients had increased risk of exhibiting suicidal ideation (OR, 1.52; 95%CI, 1.37-1.70), suicide attempts (OR, 1.60; 95%CI, 1.33-1.92) and suicide mortality (OR, 1.31; 95%CI, 1.11-1.55) compared to non-asthmatic controls. Noticeably, adolescent asthmatic patients had a more than 2-fold risk of suicide mortality compared to non-asthmatic controls (OR, 2.14; 95%CI, 1.61-2.83). LIMITATIONS: The limitations of the present study were variability in study designs and various measures of asthma and suicidality, which possibly contribute to notable heterogeneity. CONCLUSIONS: Patients with asthma have a significantly increased risk of suicidal ideation, suicide attempts and suicide mortality. Clinical physicians should pay more attention to the increased risk of suicidality in asthmatics, screen for these suicidal thoughts and behaviors, and make appropriate mental health referrals when necessary.

The Safety and Efficacy of Anti-IL-13 Treatment with Tralokinumab (CAT-354) in Moderate to Severe Asthma: A Systematic Review and Meta-Analysis.

BACKGROUND: Several clinical studies have evaluated the use of tralokinumab (CAT-354) administration in patients with moderate to severe asthma; no consensus on tralokinumab efficacy and safety was reached. Thus, further analysis is required on the efficacy and safety of tralokinumab as an asthma biologic. OBJECTIVE: To assess the efficacy and safety of subcutaneous injection of tralokinumab in patients with moderate to severe asthma. METHODS: Clinical trials were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to November 4, 2018. Only randomized clinical trials (RCTs) with tralokinumab versus placebo treatment in patients with moderate to severe asthma were evaluated. Efficacy and safety outcomes were extracted, and a meta-analysis was performed using a random-effects model. The Cochrane Collaboration's risk-of-bias assessment tool was used to assess the risk of bias. RESULTS: Five studies describing 6 RCTs (including 2928 adults with moderate to severe asthma) were pooled and analyzed in this study. Absolute FEV1 was statistically improved in patients receiving tralokinumab at 300 mg every 2 weeks (mean difference [MD], 0.14 L; 95% CI, 0.08-0.21) and 600 mg every 2 weeks (MD, 0.20 L; 95% CI, 0.01-0.39), as well as FEV1% changes (MD, 5.82%, 95% CI, 3.58-8.06, and MD, 11.8%, 95% CI, 0.79-22.81, respectively). Also, absolute forced vital capacity volume changes (MD, 0.11 L; 95% CI, 0.01-0.21) and percentage changes (MD, 4.44%; 95% CI, 0.84-8.04) improved in tralokinumab at 300 mg every 2 weeks. Asthma Quality of Life Questionnaire scores were not significantly different, and absolute Asthma Control Questionnaire 6 scores were statistically improved but did not reach the clinically meaningful difference. Tralokinumab treatment did not decrease annualized asthma exacerbation rate in unselected patients with moderate to severe asthma, but it was associated with improved annualized asthma exacerbation rate in patients with severe asthma with high fractional exhaled nitric oxide levels (rate ratio, 0.72; 95% CI, 0.53-0.97). Tralokinumab was not associated with an increased incidence of serious adverse events, but it did show an increase in mild injection-site reactions (odds ratio, 5.92; 95% CI, 1.61-21.76). CONCLUSION: This pooled analysis of 6 RCTs suggested that tralokinumab was well tolerated and it modestly improved FEV1 and forced vital capacity in patients with moderate to severe asthma. It did not render clinically important improvements in asthma-related quality of life, and nor did it reduce asthma exacerbations.

Analysis of the Clinical Features of Tracheobronchial Fungal Infections with Tumor-Like Lesions.

BACKGROUND: Tracheobronchial fungal infections (TBFI) cause life-threatening complications in immunocompromised hosts but are rarely reported. Misdiagnosis and delayed antifungal treatment are associated with the high mortality rate of patients with TBFI. OBJECTIVES: This study analyzed the bronchoscopic features of TBFI and their roles in the early diagnosis of TBFI. METHODS: The demographic, clinical, radiologic, and bronchoscopic data of 53 patients diagnosed with TBFI in our department during a 15-year period were retrospectively analyzed. RESULTS: Most of the TBFI patients were male, and mass was the most common radiologic abnormality. Obvious predilection in primary bronchus distributions was observed. 41.9% of the 43 Aspergillus tracheobronchitis (AT) patients, 70% of the 10 tracheobronchial mucormycosis (TM) patients, and 100% of the 3 endobronchial cryptococcosis patients had been misdiagnosed as having cancer on bronchoscopy because of the presence of tumor-like lesions. The most common features of AT were bronchial occlusion with a mass or mucosal necrosis, bronchial stenosis with mucosal hyperplasia, or uneven mucosa. The main descriptions of TM were bronchial stenosis or obstruction due to mucosal necrosis, uneven mucosa, or a mass. The endoscopic characteristics of endobronchial cryptococcosis included occlusion due to uneven mucosa or mass, or external compressive stricture. CONCLUSION: Immunocompromised patients and immunocompetent patients with underlying disease displaying tumor-like lesions on bronchoscopy should be differentially diagnosed with cancer. Bronchial biopsy is indispensable for the early diagnosis of TBFI.

GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

BACKGROUND: Previous studies have demonstrated that glucocorticoid-induced transcript 1 gene (GLCCI1) rs37973 mutant genotype is associated with poor inhaled corticosteroid (ICS) response in asthmatics. As human airway relaxation is regulated by circulation epinephrine, which can be enhanced by corticosteroid. It is unknown whether or not GLCCI1 rs37973 is associated with circulation epinephrine and cortisol concentrations in asthma. The aim of this study is to evaluate these relationships. METHODS: A total of 182 asthmatics and 180 healthy controls were recruited for the study. 30 mild-to-moderate asthmatics received fluticasone propionate (125 µg, bid) treatment for 12 weeks. GLCCI1 rs37973 genotyping was performed with the iPlex MassARRAY genotyping platform. The plasma concentrations of cortisol and epinephrine of each participant were detected by enzyme linked immunosorbent assay (ELISA) kits. RESULTS: GLCCI1 rs37973 homozygotes mutant genotype GG had a higher plasma epinephrine concentration (median concentration 27.032 pg/ml, nGG = 36; median concentration 23.149 pg/ml, nAA+AG = 146; P = 0.015) and cortisol concentration (median concentration 1.141 ng/ml, nGG = 36; median concentration 0.921 ng/ml, nAA+AG = 146; P = 0.013). Both epinephrine concentration and cortisol concentration in plasma were positively correlated with FEV1 (r = 0.889 and r = 0.821, respectively. nasthma = 182). For asthmatics treated with ICS, rs37973 was associated with change in plasma epinephrine and cortisol concentration in a recessive model (AA + AG vs GG), with GG had less improvement in epinephrine concentration [ΔEPIAA+AG = 6.843 (9.26) pg/ml, nAA+AG = 26; ΔEPIGG = -1.666 (6.52) pg/ml, nGG = 4; P = 0.018] and cortisol concentration [ΔCORAA+AG = 0.3040 (0.21) ng/ml, nAA+AG = 26; ΔCORGG = -0.066 (0.24) ng/ml, nGG = 4; P = 0.009]. CONCLUSIONS: Our study suggested that the poor ICS response in GLCCI1 rs37973 mutant genotype might be related to the less increased amplitudes of plasma epinephrine and cortisol in asthmatic patients. TRIAL REGISTRATION: ChiCTR-RCC-13003634 www.chictr.org.cn. Active since September 27, 2013.