Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD. Methods: Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases. Results: A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1. Conclusions: Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.

Association between long-term ozone exposure and readmission for chronic obstructive pulmonary disease exacerbation.

The relationship between long-term ozone (O3) exposure and readmission for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains elusive. In this study, we collected individual-level information on AECOPD hospitalizations from a standardized electronic database in Guangzhou from January 1, 2014, to December 31, 2015. We calculated the annual mean O3 concentration prior to the dates of the index hospitalization for AECOPD using patients' residential addresses. Employing Cox proportional hazards models, we assessed the association between long-term O3 concentration and the risk of AECOPD readmission across several time frames (30 days, 90 days, 180 days, and 365 days). We estimated the disease and economic burden of AECOPD readmissions attributable to O3 using a counterfactual approach. Of the 4574 patients included in the study, 1398 (30.6%) were readmitted during the study period, with 262 (5.7%) readmitted within 30 days. The annual mean O3 concentration was 90.3 µg/m3 (standard deviation [SD] = 8.2 µg/m3). A 10-µg/m3 increase in long-term O3 concentration resulted in a hazard ratio (HR) for AECOPD readmission within 30 days of 1.28 (95% confidence interval [CI], 1.09 to 1.49), with similar results for readmission within 90, 180, and 365 days. Older patients (aged 75 years or above) and males were more susceptible (HR, 1.33; 95% CI, 1.10-1.61 and HR, 1.29; 95% CI, 1.09-1.53, respectively). The population attributable fraction for 30-day readmission due to O3 exposure was 29.0% (95% CI, 28.4%-30.0%), and the attributable mean cost per participant was 362.3 USD (354.5-370.2). Long-term exposure to elevated O3 concentrations is associated with an increased risk of AECOPD readmission, contributing to a significant disease and economic burden.

Butyrylcholinesterase-Activated Near-Infrared Fluorogenic Probe for In Vivo Theranostics of Alzheimer's Disease.

Butyrylcholinesterase (BChE) is a promising biomarker and effective therapeutic target for Alzheimer's disease (AD). Herein, we designed a BChE-activated near-infrared (NIR) probe, DTNP, which could be activated by BChE and inhibit its enzymatic activity. DTNP is composed of a cyclopropane moiety as the recognition unit, a NIR fluorophore hemicyanine as the NIR reporter, and a BChE inhibitor as the therapeutic unit. DTNP specifically binds BChE with high sensitivity and exhibits strong "turn-on" NIR fluorescence as well as nerve cell protection. In vivo imaging shows DTNP has favorable blood-brain barrier permeability and long-term tracking ability with preliminary competence in AD diagnosis. DTNP can significantly inhibit BChE activity, promote the release of ACh, and rescue learning deficits and cognitive impairment. Therefore, DTNP, the first reported and partially validated theranostic probe for the detection of BChE in AD, may provide a foundation and inspiration for imaging and therapy in AD.

Clinical characterization and outcomes of impulse oscillometry-defined bronchodilator response: an ECOPD cohort-based study.

BACKGROUND: The clinical significance of the impulse oscillometry-defined small airway bronchodilator response (IOS-BDR) is not well-known. Accordingly, this study investigated the clinical characteristics of IOS-BDR and explored the association between lung function decline, acute respiratory exacerbations, and IOS-BDR. METHODS: Participants were recruited from an Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort subset and were followed up for two years with visits at baseline, 12 months, and 24 months. Chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio < 0.70. IOS-BDR was defined as meeting any one of the following criteria: an absolute change in respiratory system resistance at 5 Hz ≤ - 0.137 kPa/L/s, an absolute change in respiratory system reactance at 5 Hz ≥ 0.055 kPa/L/s, or an absolute change in reactance area ≤ - 0.390 kPa/L. The association between IOS-BDR and a decline in lung function was explored with linear mixed-effects model. The association between IOS-BDR and the risk of acute respiratory exacerbations at the two-year follow-up was analyzed with the logistic regression model. RESULTS: This study involved 466 participants (92 participants with IOS-BDR and 374 participants without IOS-BDR). Participants with IOS-BDR had higher COPD assessment test and modified Medical Research Council dyspnea scale scores, more severe emphysema, air trapping, and rapid decline in FVC than those without IOS-BDR over 2-year follow-up. IOS-BDR was not associated with the risk of acute respiratory exacerbations at the 2-year follow-up. CONCLUSIONS: The participants with IOS-BDR had more respiratory symptoms, radiographic structural changes, and had an increase in decline in lung function than those without IOS-BDR. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer's Disease.

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

Sono-Immunotherapy Mediated Controllable Composite Nano Fluorescent Probes Reprogram the Immune Microenvironment of Hepatocellular Carcinoma.

Background: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy. Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety. Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype. Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.

Characteristics of inflammatory phenotypes in patients with chronic obstructive pulmonary disease: a cross-sectional study.

BACKGROUND: The relationship between airway inflammation in chronic obstructive pulmonary disease (COPD) and clinical characteristics remains unclear. This study aimed to investigate the airway inflammatory phenotypes in COPD and their association with clinical characteristics. METHODS: 895 patients with COPD were recruited from Guangdong Province, China in this study. Each patient underwent questionnaire interviews, spirometry testing, CT scans and induced sputum examination. Classification of airway inflammation phenotypes was based on sputum inflammatory cell counts. Covariance analysis was applied to assess associations with airway inflammation phenotypes. RESULTS: In this study, we found that neutrophilic phenotype (NP, 58.0%) was the most common airway inflammation phenotype in patients with COPD, followed by mixed granulocytic phenotype (MGP, 32.6%), eosinophilic phenotype (EP, 5.4%) and paucigranulocytic phenotype (PP, 4.0%). Compared with NP patients, those with MGP exhibited more frequent chronic respiratory symptoms, and a higher proportion of individuals classified under Global Initiative for Chronic Obstructive Lung Disease stages 3 and 4. After adjusting for confounding factors, MGP patients had lower lung function, and more severe emphysema and air trapping. On the contrary, patients with PP had the best pulmonary function and less emphysema and air trapping. CONCLUSIONS: NP was the most common airway inflammation phenotype in patients with COPD. Patients with MGP had more respiratory symptoms, greater loss of lung function, and more severe emphysema and gas trapping compared with those with NP. Meanwhile, PP may be a phenotype of mild damage to lung structure in patients with COPD.

Efficacy of online cognitive behavioral therapy for nonorganic erectile dysfunction in reproductive-age males during the COVID-19 pandemic: a randomized wait list-controlled trial.

BACKGROUND: Previous research has documented the impact of the COVID-19 pandemic on male sexual and mental health. However, no prior study has evaluated the efficacy of online cognitive behavioral therapy (CBT) during the COVID-19 pandemic for treating nonorganic erectile dysfunction (ED) by improving negative emotions and self-esteem. AIM: To test the efficacy of online CBT for nonorganic ED during the COVID-19 pandemic in Shanghai, China. METHODS: A randomized controlled trial was conducted during the COVID-19 pandemic. Paired t-tests and 1-way analysis of variance were used to analyze and compare erectile functioning, self-esteem, and emotional state between and within groups. OUTCOMES: The main outcome measures included scores on the 5-item International Index of Erectile Function, Rosenberg Self-esteem Scale, 9-item Patient Health Questionnaire, and 7-item Generalized Anxiety Disorder scale to evaluate erectile functioning, self-esteem, depression, and anxiety, respectively. RESULTS: In the CBT group, erectile functioning, intercourse satisfaction, orgasmic functioning, sexual desire, and overall satisfaction were significantly improved at posttreatment as compared with pretreatment (P < .05). After treatment, group differences in emotional state and self-esteem were observed between the CBT group and the control group. Results revealed that the CBT group had significantly better scores than the control group at posttreatment on the Rosenberg Self-esteem Scale (mean ± SD, 30.43 ± 6.51 vs 22.67 ± 10.74), Patient Health Questionnaire (7.07 ± 2.74 vs 11.07 ± 4.41), and Generalized Anxiety Disorder scale (8.36 ± 1.97 vs 11.13 ± 3.94; P < .05). CLINICAL IMPLICATIONS: This study represents an important advance in understanding of the efficacy of online CBT for treating nonorganic ED in reproductive-age males during the COVID-19 pandemic. STRENGTHS AND LIMITATIONS: The study participants, treatment modality, and COVID-19 pandemic background of this study are innovative and therefore strengths. However, our study has several limitations-namely, its sample size and use of self-report data to measure erectile functioning due to the pandemic. Further studies should incorporate sexual functioning-monitoring instruments as well as self-report data to measure erectile function. CONCLUSION: Online CBT clearly improved the emotional state and self-esteem of patients with ED during the COVID-19 pandemic.

Clinical features and 1-year outcomes of chronic bronchitis in participants with normal spirometry: results from the ECOPD study in China.

BACKGROUND: Evidence regarding clinical features and outcomes of individuals with non-obstructive chronic bronchitis (NOCB) remains scarce, especially in never-smokers. We aimed to investigate the clinical features and 1-year outcomes of individuals with NOCB in the Chinese population. METHODS: We obtained data on participants in the Early Chronic Obstructive Pulmonary Disease Study who had normal spirometry (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ≥0.70). NOCB was defined as chronic cough and sputum production for at least 3 months for two consecutive years or more at baseline in participants with normal spirometry. We assessed the differences in demographics, risk factors, lung function, impulse oscillometry, CT imaging and frequency of acute respiratory events between participants with and without NOCB. RESULTS: NOCB was present in 13.1% (149/1140) of participants with normal spirometry at baseline. Compared with participants without NOCB, those with NOCB had a higher proportion of men and participants with smoke exposure, occupational exposure, family history of respiratory diseases and worse respiratory symptoms (all p<0.05), but there was no significant difference in lung function. Never-smokers with NOCB had higher rates of emphysema than those without NOCB, but airway resistance was similar. Ever-smokers with NOCB had greater airway resistance than those without NOCB, but emphysema rates were similar. During 1-year follow-up, participants with NOCB had a significantly increased risk of acute respiratory events compared with participants who did not have NOCB, after adjustment for confounders (risk ratio 2.10, 95% CI 1.32 to 3.33; p=0.002). These results were robust in never-smokers and ever-smokers. CONCLUSIONS: Never-smokers and ever-smokers with NOCB had more chronic obstructive pulmonary disease-related risk factors, evidence of airway disease and greater risk of acute respiratory events than those without NOCB. Our findings support expanding the criteria defining pre-COPD to include NOCB.

Inter-relationships among neutrophilic inflammation, air trapping and future exacerbation in COPD: an analysis of ECOPD study.

BACKGROUND: The inter-relationships among neutrophilic airway inflammation, air trapping and future exacerbation in chronic obstructive pulmonary disease (COPD) remain unclear. OBJECTIVE: To evaluate the associations between sputum neutrophil proportions and future exacerbation in COPD and to determine whether these associations are modified by significant air trapping. METHODS: Participants with completed data were included and followed up to the first year in the Early Chronic Obstructive Pulmonary Disease study (n=582). Sputum neutrophil proportions and high-resolution CT-related markers were measured at baseline. Sputum neutrophil proportions were dichotomised based on their median (86.2%) to low and high levels. In addition, subjects were divided into the air trapping or non-air trapping group. Outcomes of interest included COPD exacerbation (separately any, severe and frequent exacerbation, occurring in the first year of follow-up). Multivariable logistic regressions were performed to examine the risk of severe exacerbation and frequent exacerbation with either neutrophilic airway inflammation groups or air trapping groups. RESULTS: There was no significant difference between high and low levels of sputum neutrophil proportions in the exacerbation in the preceding year. After the first year of follow-up, subjects with high sputum neutrophil proportions had increased risks of severe exacerbation (OR=1.68, 95% CI: 1.09 to 2.62, p=0.020). Subjects with high sputum neutrophil proportions and significant air trapping had increased odds of having frequent exacerbation (OR=3.29, 95% CI: 1.30 to 9.37, p=0.017) and having severe exacerbation (OR=2.72, 95% CI: 1.42 to 5.43, p=0.003) when compared with those who had low sputum neutrophil proportions and non-air trapping. CONCLUSIONS: We found that subjects with high sputum neutrophil proportions and significant air trapping are prone to future exacerbation of COPD. It may be a helpful predictor of future exacerbation.

The Short-term Efficacy of Contrast-enhanced Ultrasound (CEUS) and Gd-EOB-DTPA-enhanced Magnetic Resonance Imaging (MRI) Fusion Imaging-guided Radiofrequency Ablation (RFA) for Colorectal Liver Metastasis (CRLM).

OBJECTIVE: This study is to explore the efficacy of contrast-enhanced ultrasound (CEUS) / Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) fusion imaging-guided（fusion group）radiofrequency ablation (RFA) versus conventional ultrasound imaging-guided (conventional group) RFA for colorectal cancer liver metastases (CRLM) in a short-term. METHODS: From December 2020 to December 2021, patients who underwent imaging-guided RFA of CRLM at our hospital with available CT/MRI images were enrolled consecutively. 22 patients with 46 lesions had undergone conventional group RFA whereas 29 patients with 63 lesions had undergone fusion group RFA. The lesion detection rate, technical success, local tumor progression (LTP) and complications were calculated. RESULT: In this retrospective study, 51 patients with 130 lesions were diagnosed with CRLM. However, there were 12 lesions and 9 lesions invisible in the conventional group and fusion group, respectively. The lesion detection rate on the fusion imaging was significantly higher than on the US or CEUS in the fusion group (P＜0.05). There were no significant differences of the detection rate between the conventional group and the fusion group (P=0.207). In both groups, the technical success rate was 100%. For local tumor progression (LTP), there were no significant differences between the two groups (P＞0.05). The complications after ablation had no significant differences between the two groups (P=0.97). CONCLUSION: CEUS/ Gd-EOB-DTPA-enhanced MRI fusion imaging is a safe and effective method for RFA in the management of CRLM patients, and it may improve the therapeutic effect by detecting small lesions early.

Impaired exercise capacity in individuals with non-obstructive small airway dysfunction.

Background: Whether individuals with non-obstructive spirometry-defined small airway dysfunction (SAD) have impaired exercise capacity is unclear, particularly in never-smokers. This study clarifies the degree of impaired exercise capacity and its potential cause in individuals with non-obstructive SAD. Methods: This community-based, multiyear cross-sectional study analyzed data collected in Guangdong, China from 2012-2019 by the National Science and Technology Support Plan Program. Measurements of exercise capacity [peak work rate and peak oxygen uptake ( V ˙ O 2peak )] in participants with non-obstructive spirometry-defined SAD (n=157) were compared with those in controls (n=85) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) I patients (n=239). Subgroup analyses were performed by smoking status. Results: The risk of impaired exercise capacity was significantly higher in participants with non-obstructive SAD [ V ˙ O 2peak <84%predicted, adjusted odds ratio (aOR) =2.53; 95% confidence interval (CI): 1.42-4.52] than in controls but was not significantly different from that in GOLD I patients. Results were consistent within subgroups of smoking status (ever-smokers: non-obstructive SAD vs. controls, aOR =2.44; 95% CI: 1.08-5.51; never-smokers: non-obstructive SAD vs. controls, aOR =2.38, 95% CI: 1.02-5.58). Participants with non-obstructive SAD had a significantly lower peak work rate (ß=-10.5; 95% CI: -16.3 to -4.7) and V ˙ O 2peak (%predicted, ß=-4.0; 95% CI: -7.7 to -0.2) and tended to have higher ventilatory equivalents for carbon dioxide at the ventilatory threshold ( V ˙ E / V ˙ CO 2AT , ß=1.1; 95% CI: -0.1 to 2.3) when compared with controls. Both peak work rate and V ˙ O 2peak were negatively correlated with V ˙ E / V ˙ CO 2AT . Conclusions: Although not meeting the current criteria for chronic obstructive pulmonary disease, individuals with non-obstructive SAD have impaired exercise capacity that may be associated with ventilatory inefficiency regardless of smoking status.

Clinical characteristics of airway impairment assessed by impulse oscillometry in patients with chronic obstructive pulmonary disease: findings from the ECOPD study in China.

BACKGROUND: The role of airway impairment assessed by impulse oscillometry (IOS) in patients with chronic obstructive pulmonary disease (COPD) remains unclear. Therefore, this study aimed to analyze the proportion and clinical characteristics of airway impairment assessed by IOS across COPD severities, and explore whether airway impairment is a subtype of COPD. METHODS: This study was based on cross-sectional data from the ECOPD cohort in Guangdong, China. Subjects were consecutively recruited from July 2019 to August 2021. They filled out questionnaires and underwent lung function tests, IOS and computed tomography (CT). COPD was defined as post-bronchodilator forced expiratory volume in one second/forced vital capacity < lower limit of normal (LLN). Meanwhile, airway impairment was defined as IOS parameters > upper limit of normal or < LLN. On the one hand, Poisson regression was employed to analyze the associations between acute exacerbations of COPD (AECOPD) in the previous year and airway impairment. On the other hand, logistic regression was used to assess differences in CT imaging between patients with IOS parameters' abnormalities and patients with normal IOS parameters. RESULTS: 768 COPD subjects were finally enrolled in the study. The proportion of airway impairment assessed by R5, R20, R5-R20, X5, AX, and Fres was 59.8%, 29.7%, 62.5%, 52.9%, 60.9% and 67.3%, respectively. Airway impairment assessed by IOS parameters (R5, R5-R20, X5, AX, and Fres) in patients with COPD was present across all severities of COPD, particularly in GOLD 3-4 patients. Compared with patients with normal IOS parameters, patients with IOS parameters' abnormalities had more respiratory symptoms, more severe airway obstruction and imaging structural abnormalities. Patients with IOS parameters' abnormalities assessed by R5 [risk ratio (RR): 1.58, 95% confidential interval (CI): 1.13-2.19, P = 0.007], R5-R20 [RR: 1.73, 95%CI: 1.22-2.45, P = 0.002], X5 [RR: 2.11, 95%CI: 1.51-2.95, P < 0.001], AX [RR: 2.20, 95%CI: 1.53-3.16, P < 0.001], and Fres [RR: 2.13, 95%CI: 1.44-3.15, P < 0.001] had a higher risk of AECOPD in the previous year than patients with normal IOS parameters. CONCLUSIONS: Airway impairment assessed by IOS may be a subtype of COPD. Future studies are warranted to identify the underlying mechanisms and longitudinal progression of airway impairment.

Prediction of pathological complete response to neoadjuvant chemotherapy in patients with breast cancer using a combination of contrast-enhanced ultrasound and dynamic contrast-enhanced magnetic resonance imaging.

This study aimed to evaluate the value of dynamic contrast-enhanced ultrasound (CEUS) combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting pathological complete response (pCR) in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). Fifty-seven female patients with breast cancer (mean age, 50.46 years; range, 32-66 years) scheduled for NAC were recruited. CEUS and DCE-MRI were performed before and after NAC. Imaging features and their changes were compared with postoperative pathological results. After the clinical differences were balanced using propensity score matching, univariate and multiple logistic regression analyses were used to derive the characteristics independently associated with pCR. Receiver operating characteristic curve analysis was performed to assess diagnostic performance. After six to eight cycles of NAC, 24 (42.1%) patients achieved pCR, while 33 (57.9%) did not. Multivariate analysis showed that enhancement order on CEUS and DCE-MRI before NAC, reduction in diameter and enhancement shape on CEUS, maximum diameter on DCE-MRI, and the type of progressive dynamic contrast enhancement after NAC were independently associated with pCR after NAC. The area under the receiver operating characteristic curve for CEUS+DCE-MRI was 0.911 (95% confidence interval, 0.826-0.997), and the specificity and positive predictive values were 87.0% and 87.5%. CEUS and DCE-MRI have the potential for assessing the pathological response to NAC in patients with breast cancer; their combination showed the best diagnostic performance. CEUS+DCE-MRI has proved beneficial for comprehensive assessment and personalizing treatment strategies for patients with breast cancer.

Preserved ratio impaired spirometry is associated with small airway dysfunction and reduced total lung capacity.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) refers to decreased forced expiratory volume in 1 s (FEV1) in the setting of preserved ratio. Little is known about the role of PRISm and its complex relation with small airway dysfunction (SAD) and lung volume. Therefore, we aimed to investigate the associations between PRISm and SAD and lung volume. METHODS: We conducted a cross-sectional community-dwelling study in China. Demographic data, standard respiratory epidemiology questionnaire, spirometry, impulse oscillometry (IOS) and computed tomography (CT) data were collected. PRISm was defined as post-bronchodilator FEV1/FVC ≥ 0.70 and FEV1 < 80% predicted. Spirometry-defined SAD was defined as at least two of three of the post-bronchodilator maximal mid-expiratory flow (MMEF), forced expiratory flow 50% (FEF50), and forced expiratory flow 75% (FEF75) less than 65% of predicted. IOS-defined SAD and CT-defined gas trapping were defined by the fact that the cutoff value of peripheral airway resistance R5-R20 > 0.07 kPa/L/s and LAA- 856>20%, respectively. Analysis of covariance and logistic regression were used to determine associations between PRISm and SAD and lung volume. We then repeated the analysis with a lower limit of normal definition of spirometry criteria and FVC definition of PRISm. Moreover, we also performed subgroup analyses in ever smoker, never smoker, subjects without airway reversibility or self-reported diagnosed asthma, and subjects with CT-measured total lung capacity ≥70% of predicted. RESULTS: The final analysis included 1439 subjects. PRISm had higher odds and more severity in spirometry-defined SAD (pre-bronchodilator: odds ratio [OR]: 5.99, 95% confidence interval [95%CI]: 3.87-9.27, P < 0.001; post-bronchodilator: OR: 14.05, 95%CI: 8.88-22.24, P < 0.001), IOS-defined SAD (OR: 2.89, 95%CI: 1.82-4.58, P < 0.001), and CT-air trapping (OR: 2.01, 95%CI: 1.08-3.72, P = 0.027) compared with healthy control after adjustment for confounding factors. CT-measured total lung capacity in PRISm was lower than that in healthy controls (4.15 ± 0.98 vs. 4.78 ± 1.05 L, P < 0.05), after adjustment. These results were robust in repeating analyses and subgroup analyses. CONCLUSION: Our finding revealed that PRISm was associated with SAD and reduced total lung capacity. Future studies to identify the underlying mechanisms and longitudinal progression of PRISm are warranted.

The association between small airway dysfunction and aging: a cross-sectional analysis from the ECOPD cohort.

BACKGROUND: Aging has been evidenced to bring about some structural and functional lung changes, especially in COPD. However, whether aging affects SAD, a possible precursor of COPD, has not been well characterized. OBJECTIVE: We aimed to comprehensively assess the relationship between aging and SAD from computed tomography, impulse oscillometry, and spirometry perspectives in Chinese. METHODS: We included 1859 participants from ECOPD, and used a linear-by-linear association test for evaluating the prevalence of SAD across various age subgroups, and multivariate regression models for determining the impact of age on the risk and severity of SAD. We then repeated the analyses in these subjects stratified by airflow limitation. RESULTS: The prevalence of SAD increases over aging regardless of definitional methods. After adjustment for other confounding factors, per 10-yrs increase in age was significantly associated with the risk of CT-defined SAD (OR 2.57, 95% CI 2.13 to 3.10) and the increase in the severity of air trapping (ß 2.09, 95% CI - 0.06 to 4.25 for LAA-856), airway reactance (ß - 0.02, 95% CI - 0.04 to - 0.01 for X5; ß 0.30, 95% CI 0.13 to 0.47 for AX; ß 1.75, 95% CI 0.85 to 2.66 for Fres), as well as the decrease in expiratory flow rates (ß - 3.95, 95% CI - 6.19 to - 1.71 for MMEF%predicted; ß - 5.42, 95% CI - 7.88 to - 2.95 for FEF50%predicted) for SAD. All these associations were generally maintained in SAD defined by IOS or spirometry. After stratification of airflow limitation, we further found that the effect of age on LAA-856 was the most significant among almost all subgroups. CONCLUSIONS: Aging is significantly associated with the prevalence, increased risk, as well as worse severity of SAD. CT may be a more optimal measure to assess aging-related SAD. The molecular mechanisms for the role of aging in SAD need to be explored in the future. Trial registration Chinese Clinical Trial Registry ChiCTR1900024643. Registered on 19 July 2019.

Predictors of High Sputum Eosinophils in Chronic Obstructive Pulmonary Disease.

Background: Eosinophils are involved in the development of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroid responsiveness. We evaluated clinical predictors of high sputum eosinophil levels in a COPD cohort in China. Methods: We conducted an observational, prospective, population-based, cross-sectional study. Participants were tested for COPD and underwent spirometry, computed tomography scans, and a blood test. Participants also produced induced sputum and responded to an information-gathering questionnaire. High sputum eosinophils were defined as ≥3.0%. Multivariate logistic regression was used to identify predictors of high sputum eosinophil levels. Results: We recruited 895 patients with complete and quality control data. The median percentage of sputum eosinophil abundance was 2.00% (interquartile range: 0.75-5.00) and the prevalence of COPD with high sputum eosinophils was 38.0%. Covariance analysis indicated that the high sputum eosinophil group had lower lung function, more severe emphysema, and air trapping. Multivariate logistic regression indicated that high blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases were associated with high sputum eosinophil levels. Conclusion: High blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases may be predictors of high sputum eosinophil levels in Chinese COPD patients. High sputum eosinophils were associated with lower lung function, more emphysema, and gas trapping.

Discordant Spirometry and Impulse Oscillometry Assessments in the Diagnosis of Small Airway Dysfunction.

Background and objective: Spirometry is commonly used to assess small airway dysfunction (SAD). Impulse oscillometry (IOS) can complement spirometry. However, discordant spirometry and IOS in the diagnosis of SAD were not uncommon. We examined the association between spirometry and IOS within a large cohort of subjects to identify variables that may explain discordant spirometry and IOS findings. Methods: 1,836 subjects from the ECOPD cohort underwent questionnaires, symptom scores, spirometry, and IOS, and 1,318 subjects were examined by CT. We assessed SAD with R5-R20 > the upper limit of normal (ULN) by IOS and two of the three spirometry indexes (maximal mid-expiratory flow (MMEF), forced expiratory flow (FEF)50%, and FEF75%) < 65% predicted. Multivariate regression analysis was used to analyze factors associated with SAD diagnosed by only spirometry but not IOS (spirometry-only SAD) and only IOS but not spirometry (IOS-only SAD), and line regression was used to assess CT imaging differences. Results: There was a slight agreement between spirometry and IOS in the diagnosis of SAD (kappa 0.322, p < 0.001). Smoking status, phlegm, drug treatment, and family history of respiratory disease were factors leading to spirometry-only SAD. Spirometry-only SAD had more severe emphysema and gas-trapping than IOS-only SAD in abnormal lung function. However, in normal lung function subjects, there was no statistical difference in emphysema and gas-trapping between discordant groups. The number of IOS-only SAD was nearly twice than that of spirometry. Conclusion: IOS may be more sensitive than spirometry in the diagnosis of SAD in normal lung function subjects. But in patients with abnormal lung function, spirometry may be more sensitive than IOS to detect SAD patients with clinical symptoms and CT lesions.

Association Between Serum Total Bilirubin Level and Lung Function Decline in Patients with COPD: Results from a Pooled Study.

Background: Serum total bilirubin has been reported to have antioxidant properties against chronic respiratory diseases. The objective of our study is to evaluate the association of total bilirubin (TB) with annual lung function decline in COPD patients with different GOLD stages. Methods: This study used pooled data from two observational and prospective cohorts of 612 COPD patients whose TB levels were measured at baseline. The associations between TB and postbronchodilator FEV1, FEV1pred, FVC, FVCpred, FEV1/FVC, and the rate of their decline were all determined using linear regression models in the total population and strata of GOLD stages. Results: Serum TB was positively related to FEV1 and FVC in the total group (ß 0.02, 95% CI 0.001~0.02, P = 0.025 and ß 0.02, 95% CI 0.002~0.03, P = 0.022, respectively). Additionally, TB was inversely associated with the annual decline in FEV1 and FEV1pred (ß 4.91, 95% CI 1.68~8.14, P = 0.025 and ß 0.21, 95% CI 0.06~0.36, P = 0.022, respectively) when adjusted for multivariables. After stratification, the significant associations merely persisted in COPD patients with GOLD 2 and GOLD 3-4. Conclusion: Increased TB level was related to less annual decline in FEV1 as well as FEV1pred in moderate-to-severe COPD but not mild COPD, which indicated the different status of TB in different COPD severity and the possible role as potential biomarker merely in moderate-to-severe COPD. Future researches to determine whether TB could be served as biomarker for COPD and the mechanisms should be focused on some target patients with a certain disease severity.