The effect of damage control laparotomy on surgical-site infection risks after emergent intestinal surgery.

INTRODUCTION: Damage-control laparotomy has been widely used in general surgery. However, associated surgical-site infection risks have rarely been investigated. Damage-control laparotomy allows for additional opportunities for decontamination. We hypothesized that damage-control laparotomy would be associated with lower surgical-site infection risks compared with laparotomy with only primary fascial closure or with primary fascial and skin closure. METHODS: Patients admitted for emergent intestinal surgery from 2006 to 2021 were included. Multivariate analyses were performed to identify surgical-site infection-associated risk factors. Although variables like laparotomy type (damage-control laparotomy, primary fascial closure, and primary fascial and skin closure) were provided by National Surgical Quality Improvement Program, other variables such as number of operations were retrospectively collected. P < .05 was considered significant. RESULTS: Overall, 906 patients were included; 213 underwent damage-control laparotomy, 175 primary fascial closure, and 518 primary fascial and skin closure. Superficial, deep, and organ-space surgical-site infection developed in 66, 6, and 97 patients, respectively. Compared with primary fascial and skin closure, both damage-control laparotomy (odds ratio, 0.30 [95% CI, 0.13-0.73], P = .008) and primary fascial closure (odds ratio, 0.09 [95% CI, 0.02-0.37], P = .001) were associated with lower superficial incisional surgical-site infection but not organ-space surgical-site infection risk (odds ratio, 0.80 [95% CI, 0.29-2.19] P = .667 and odds ratio, 0.674 [95% CI, 0.21-2.14], P = .502, respectively). Body mass index was associated with increased risk of superficial incisional surgical-site infection (odds ratio, 1.06 [95% CI, 1.03-1.09], P < .001) whereas frailty was associated with organ space surgical-site infection (odds ratio, 3.28 [95% CI, 1.29-8.36], P = .013). For patients who underwent damage-control laparotomy, the number of operations did not affect risk of either superficial incisional surgical-site infection or organ space SSI. CONCLUSION: Herein, compared with primary fascial and skin closure, both damage-control laparotomy and primary fascial closure were associated with lower superficial but not organ space surgical-site infection risks. For patients who underwent damage-control laparotomy, number of operations did not affect surgical-site infection risks.

Lung tumor discrimination by deep neural network model CanDo via DNA methylation in bronchial lavage.

Bronchoscopic-assisted discrimination of lung tumors presents challenges, especially in cases with contraindications or inaccessible lesions. Through meta-analysis and validation using the HumanMethylation450 database, this study identified methylation markers for molecular discrimination in lung tumors and designed a sequencing panel. DNA samples from 118 bronchial washing fluid (BWF) specimens underwent enrichment via multiplex PCR before targeted methylation sequencing. The Recursive Feature Elimination Cross-Validation and deep neural network algorithm established the CanDo classification model, which incorporated 11 methylation features (including 8 specific to the TBR1 gene), demonstrating a sensitivity of 98.6% and specificity of 97.8%. In contrast, bronchoscopic rapid on-site evaluation (bronchoscopic-ROSE) had lower sensitivity (87.7%) and specificity (80%). Further validation in 33 individuals confirmed CanDo's discriminatory potential, particularly in challenging cases for bronchoscopic-ROSE due to pathological complexity. CanDo serves as a valuable complement to bronchoscopy for the discriminatory diagnosis and stratified management of lung tumors utilizing BWF specimens.

Inverted Placement of Endoscopic One-Way Endobronchial Valve Combined with Gelfoam in the Closure of Bronchopleural Fistula with Empyema in a Mechanically Ventilated Patient: A Case Report.

Bronchopleural fistula (BPF) with empyema caused by severe necrotizing pulmonary infection is a complicated clinical problem that is often associated with poor general condition so surgical interventions cannot be tolerated in most cases. Here, we present the successful management of multiple BPF with empyema in a mechanically ventilated patient with aspiration lung abscess. Occlusion utilizing Gelfoam followed by endobronchial valves (EBVs) implanted inverted via bronchoscope decreased the air leaking significantly and made intrapleural irrigation for empyema achievable and safe. This is the first report of a novel way of EBV placement and the combination use with other occlusive substances in BPF with empyema in a patient on mechanical ventilation. This method may be an option for refractory BPF cases with pleural infection.

Associations between short-term exposure to ambient air pollution and lung function in adults.

BACKGROUND: Evidence of the acute effects of high-level air pollution on small airway function and systemic inflammation in adults is scarce. OBJECTIVE: To examined the associations of short-term (i.e., daily) exposure to multiple air pollutants with lung function and inflammatory markers. METHODS: We assessed short-term (daily) effects of air pollutants, including particulate matter with aerodynamic diameter less than 2.5 µm (PM2.5) and 10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO), on lung function and peripheral immune cell counts over various lag times using generalized linear regression models. RESULTS: A total of 4764 adults were included from the general community-dwelling population in Shanghai, China. Exposure to air pollutants and lung function were negatively correlated. Decline in FEF between 25% and 75% of vital capacity (FEF25-75%) were found associated with PM2.5, SO2, and CO, and decline in forced expiratory volume in 3 s (FEV3) to forced vital capacity (FVC) ratio were associated with all examined pollutants, indicating obstruction in small airways. Obstructed airflow in large and middle airways as indicated by decline in FEV1/FVC were also associated with all pollutants. In subgroup analysis, significant negative associations between the five pollutants and SAD parameters were found only in males but not in females. The difference in the associations of SO2 with FEF75% between males and females achieved statistical significance. Additionally, all examined pollutants were significantly associated with lower peripheral neutrophil count. IMPACT STATEMENT: Acute exposure to air pollutants were associated with airflow-limitation. Both small airways and proximal airways were affected. Acute exposure to air pollutants were accompanied with a lower neutrophil count.

Complement and complement regulatory proteins are upregulated in lungs of COVID-19 patients.

We explored the pathological changes and the activation of local complement system in COVID-19 pneumonia. Lung paraffin sections of COVID-19 infected patients were analyzed by HE (hematoxylin-eosin) staining. The deposition of complement C3, the deposition of C3b/iC3b/C3d and C5b-9, and the expression of complement regulatory proteins, CD59, CD46 and CD55 were detected by immunohistochemistry. In COVID-19 patients' lung tissues, fibrin exudation, mixed with erythrocyte, alveolar macrophage and shed pneumocyte are usually observed in the alveoli. The formation of an "alveolar emboli" structure may contribute to thrombosis and consolidation in lung tissue. In addition, we also found that compared to normal tissue, the lung tissues of COVID-19 patients displayed the hyper-activation of complement that is represented by extensive deposition of C3, C3b/iC3b/C3d and C5b-9, and the increased expression level of complement regulatory proteins CD55, and especially CD59 but not CD46. The thrombosis and consolidation in lung tissues may contribute to the pathogenesis of COVID-19. The increased expression of CD55 and CD59 may reflect a feedback of self-protection on the complement hyper-activation. Further, the increased C3 deposition and the strongly activated complement system in lung tissues may suggest the rationale of complement-targeted therapeutics in conquering COVID-19.

Utility of cell-free DNA from bronchial washing fluid in diagnosis and genomic determination for radiology-suspected pulmonary nodules.

BACKGROUND: Bronchial washing fluid (BWF) is a less-invasive specimen. Due to the limited sensitivity of BWF cellular component diagnosis, the aim of this study was to explore the potential role of BWF supernatant as a source of liquid biopsy of lung cancer. METHODS: This prospective study enrolled 76 suspected and 5 progressed lung cancer patients. Transbronchial biopsy tissues, BWF supernatant (BWF_Sup) and BWF precipitant (BWF_Pre) were tested by a targeted panel of 1021 genes. RESULTS: BWF_Sup cell-free DNA (cfDNA) was superior to tissue biopsy and BWF_Pre in determining mutational allele frequency, tumour mutational burden, and chromosomal instability. Moreover, BWF_Sup and BWF_Pre achieved comparable efficacy to tissue samples in differentiating malignant and benign patients, but only BWF_Sup persisted differentiated performance after excluding 55 malignancies pathologically diagnosed by bronchoscopic biopsy. Among 67 malignant patients, 82.1% and 71.6% of tumour-derived mutations (TDMs) were detected in BWF_Sup and BWF_Pre, respectively, and the detectability of TDMs in BWF_Sup was independent of the cytological examination of BWF. BWF_Sup outperformed BWF_Pre in providing more subclonal information and thus might yield advantage in tracking drug-resistant markers. CONCLUSIONS: BWF_Sup cfDNA is a reliable medium for lung cancer diagnosis and genomic profiles and may provide important information for subsequent therapeutic regimens.

A Classifier for Improving Early Lung Cancer Diagnosis Incorporating Artificial Intelligence and Liquid Biopsy.

Lung cancer is the leading cause of cancer-related deaths worldwide and in China. Screening for lung cancer by low dose computed tomography (LDCT) can reduce mortality but has resulted in a dramatic rise in the incidence of indeterminate pulmonary nodules, which presents a major diagnostic challenge for clinicians regarding their underlying pathology and can lead to overdiagnosis. To address the significant gap in evaluating pulmonary nodules, we conducted a prospective study to develop a prediction model for individuals at intermediate to high risk of developing lung cancer. Univariate and multivariate logistic analyses were applied to the training cohort (n = 560) to develop an early lung cancer prediction model. The results indicated that a model integrating clinical characteristics (age and smoking history), radiological characteristics of pulmonary nodules (nodule diameter, nodule count, upper lobe location, malignant sign at the nodule edge, subsolid status), artificial intelligence analysis of LDCT data, and liquid biopsy achieved the best diagnostic performance in the training cohort (sensitivity 89.53%, specificity 81.31%, area under the curve [AUC] = 0.880). In the independent validation cohort (n = 168), this model had an AUC of 0.895, which was greater than that of the Mayo Clinic Model (AUC = 0.772) and Veterans' Affairs Model (AUC = 0.740). These results were significantly better for predicting the presence of cancer than radiological features and artificial intelligence risk scores alone. Applying this classifier prospectively may lead to improved early lung cancer diagnosis and early treatment for patients with malignant nodules while sparing patients with benign entities from unnecessary and potentially harmful surgery. Clinical Trial Registration Number: ChiCTR1900026233, URL: http://www.chictr.org.cn/showproj.aspx?proj=43370.

Genetic Alteration Profiling of Chinese Lung Adenocarcinoma and Its Effect on Targeted Therapy Efficacy.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a highly heterogeneous disease with a diversity of phenotypes and genotypes in different populations. The purpose of this study is to investigate oncogenic alterations of lung adenocarcinoma (LUAD) in eastern China and their significance in targeted therapies. METHODS: This study enrolled 101 LUAD patients and used a customized DNA panel to detect molecular alterations. Comprehensive analysis of mutations and clinical application of genomic profiling was carried out. RESULTS: The most commonly mutated genes were epidermal growth factor receptor (EGFR) (53%) and tumor protein p53 (TP53) (32%). The less frequently mutated genes were erb-b2 receptor tyrosine kinase 2 (ERBB2) (25%), ATR serine/threonine kinase (ATR) (20%), CCAAT enhancer binding protein alpha (CEBPA) (16%), RB transcriptional corepressor 1 (RB1) (16%), transcription factor 7 like 2 (TCF7L2) (14%), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) (12%) and spectrin alpha, erythrocytic 1 (SPTA1) (12%). Among them, the frequency of ERBB2, ATR, CEBPA, RB1 and TCF7L2 mutations was much higher than that in the databases. Seventy percent of the patients harbored at least one actionable alteration according to the OncoKB evidence. CEBPA mutations affected the efficacy of EGFR-tyrosine kinase inhibitors. ERBB2, CEBPA and TCF7L2 mutated tumors tend to have higher tumor mutation burden (TMB). CONCLUSIONS: LUAD patients from eastern China have a unique profile of mutations. The targeted DNA panel is helpful for personalized treatment decision of LUAD patients, and specific mutations may affect the efficacy of targeted therapies.

Rapid discrimination between tuberculosis and sarcoidosis using next-generation sequencing.

OBJECTIVES: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), has similar clinical, radiological, and histopathological characteristics to sarcoidosis (SA). Accurately distinguishing SA from TB remains a clinical challenge. METHODS: A total of 44 TB patients and 47 SA patients who were clinically diagnosed using chest radiography, pathological examination, routine smear microscopy, and microbial culture were enrolled in this study. The MTB genome was captured and sequenced directly from tissue specimens obtained upon operation or biopsy, and the feasibility of next-generation sequencing (NGS) for the MTB genome in the differential diagnosis of TB from SA was evaluated. RESULTS: Using a depth >10× and coverage >15% of the sequencing data, TB patients were identified via the NGS approach directly using operation or biopsy specimens without clinical pretreatment. The sensitivity, specificity, and concordance of the NGS method were 81.8% (36/44), 95.7% (45/47), and 89.0% (81/91), respectively (kappa = 0.78, 95% confidence interval 0.65-0.91; P<0.001). CONCLUSIONS: This study established an improved NGS strategy for rapidly distinguishing patients with TB from those with SA and has potential clinical benefits.

Bronchial Washing Fluid Versus Plasma and Bronchoscopy Biopsy Samples for Detecting Epidermal Growth Factor Receptor Mutation Status in Lung Cancer.

BACKGROUND: Bronchial washing fluid (BWF) is a common specimen collected during bronchoscopy and has been suggested to contain both tumor cells and cell-free DNA. However, there is no consensus on the feasibility of BWF in epidermal growth factor receptor (EGFR) genetic analysis because of the limited sample size and varying results in previous studies. This study compared the feasibility, sensitivity, and specificity of detecting EGFR mutation using BWF, bronchoscopy biopsy, and plasma samples in patients with lung cancer (LC). MATERIALS AND METHODS: A total of 144 patients (110 with LC and 34 without LC) were enrolled in the study. During diagnostic bronchoscopy for suspected LC lesions, bronchial washing with saline was performed directly or through a guide sheath. BWF was collected as well as paired bronchoscopy biopsy and plasma samples, and EGFR mutation testing was performed via highly sensitive blocker polymerase chain reaction. The EGFR mutation status of histologic samples was set as the standard reference. RESULTS: Compared with the histologic samples, the sensitivity, specificity, and concordance rate of EGFR mutation detected in BWF samples were 92.5%, 100%, and 97.9%, respectively. Moreover, BWF showed a higher sensitivity in EGFR mutation testing than both plasma (100% [8/8] vs. 62.5% [5/8], p = 0.095) and bronchoscopy biopsy samples (92.5% [37/40] vs. 77.5% [31/40], p = 0.012) and identified EGFR mutations in 6 cases whose biopsy failed to establish an LC diagnosis. The diameter of the target lesion and its contact degree with BWF were positive predictive factors for EGFR testing results. CONCLUSIONS: BWF yields a high sensitivity in EGFR mutation testing, having high concordance with histologic samples, and presenting the benefit of rapid EGFR mutation detection in LC patients.

Circulating Genetically Abnormal Cells Add Non-Invasive Diagnosis Value to Discriminate Lung Cancer in Patients With Pulmonary Nodules ≤10 mm.

BACKGROUND: Lung cancer screening using low-dose computed tomography (LDCT) often leads to unnecessary biopsy because of the low specificity among patients with pulmonary nodules ≤10 mm. Circulating genetically abnormal cells (CACs) can be used to discriminate lung cancer from benign lung disease. To examine the diagnostic value of CACs in detecting lung cancer for patients with malignant pulmonary nodules ≤10 mm. METHODS: In this prospective study, patients with pulmonary nodules ≤10 mm who were detected at four hospitals in China from January 2019 to January 2020 were included. CACs were detected using fluorescence in-situ hybridization. All patients were confirmed as lung cancer or benign disease by further histopathological examination. Multivariable logistic regression models were established to detect the presence of lung cancer using CACs and other associated characteristics. Receiver operating characteristic analysis was used to evaluate the performance of CACs for lung cancer diagnosis. RESULTS: Overall, 125 patients were included and analyzed. When the cutoff value of CACs was >2, the sensitivity and specificity for lung cancer were 70.5 and 86.4%. Male (OR = 0.330, P = 0.005), maximum solid nodule (OR = 2.362, P = 0.089), maximum nodule located in upper lobe (OR = 3.867, P = 0.001), and CACs >2 (OR = 18.525, P < 0.001) met the P < 0.10 criterion for inclusion in the multivariable models. The multivariable logistic regression model that included the dichotomized CACs (>2 vs. ≤2) and other clinical factors (AUC = 0.907, 95% CI = 0.842-0.951) was superior to the models that only considered dichotomized CACs or other clinical factors and similar to the model with numerical CACs and other clinical factors (AUC = 0.913, 95% CI = 0.850-0.956). CONCLUSION: CACs presented a significant diagnostic value in detecting lung cancer for patients with pulmonary nodules ≤10 mm.

Selectivity and Sensitivity of Near-Infrared Spectroscopic Sensing of ß-Hydroxybutyrate, Glucose, and Urea in Ternary Aqueous Solutions.

The next-generation artificial pancreas is under development with the goal to enhance tight glycemic control for people with type 1 diabetes. Such technology requires the integration of a chemical sensing unit combined with an insulin infusion device controlled by an algorithm capable of autonomous operation. The potential of near-infrared spectroscopic sensing to serve as the chemical sensing unit is explored by demonstrating the ability to quantify multiple metabolic biomarkers from a single near-infrared spectrum. Independent measurements of ß-hydroxy-butyrate, glucose, and urea are presented based on analysis of near-infrared spectra collected over the combination spectral range of 5000-4000 cm-1 for a set of 50 ternary aqueous standard solutions. Spectra are characterized by a 1 µAU root-mean-square (RMS) noise for 100% lines with a resolution of 4 cm-1 and an optical path length of 1 mm. Calibration models created by the net analyte signal (NAS) and the partial least squares (PLS) methods provide selective measurements for each analyte with standard errors of prediction in the upper micromolar concentration range. The NAS method is used to determine both the selectivity and sensitivity for each analyte and their values are consistent with these standard errors of prediction. The NAS method is also used to characterize the background spectral variance associated with instrumental and environmental variations associated with buffer spectra collected over a multiday period.

Iron metabolism regulation of epithelial-mesenchymal transition in idiopathic pulmonary fibrosis.

BACKGROUND: Iron overload has been found in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and is thought to be involved in disease progression; however, the underlying mechanism is complex and not yet fully understood. We sought to assess the in vitro role of iron in the progression of fibrosis in lung epithelial cells, and examine the possible regulation of iron and IPF. METHODS: Erastin was used to establish a cell model of iron accumulation in mouse lung epithelial cell line 12 (MLE-12). A Cell Counting Kit-8 assay and annexin V staining were applied to measure cell viability and apoptosis, quantitative polymerase chain reaction (qPCR) and quantitative immunoblot analysis of the protein was conducted to analyze the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), Vimentin and ß-Actin. The autophagy was visualized by microtubule-associated protein 1A/1B-light chain 3 (LC3) staining and western blot. RESULTS: The results showed that cell proliferation was significantly inhibited and apoptotic and necrotic cells were significantly increased with 2 µM of erastin treatment. Western blotting showed that reactive oxygen species (ROS) production and the level of heme oxygenase-1 were increased in the cells. Epithelial-mesenchymal transition (EMT) represented by the suppression of E-cadherin and the upregulation of α-smooth muscle actin (α-SMA) and Vimentin was induced by erastin. Additionally, autophagy represented by activated LC3B and up-regulated Beclin-1 were also induced by erastin. To further ascertain the role of autophagy in erastin-induced EMT, chloroquine, which is an autophagy inhibitor, was employed, and was found to effectively reduce EMT in this process. CONCLUSIONS: These results support the role of the enhanced accumulation of iron as a mechanism for increasing the vulnerability of lung epithelial cells to iron-driven oxidant injury that triggers further autophagy during EMT.

Clinical predictors of COVID-19 disease progression and death: Analysis of 214 hospitalised patients from Wuhan, China.

INTRODUCTION: COVID-19 has spread rapidly worldwide and has been declared a pandemic. OBJECTIVES: To delineate clinical features of COVID-19 patients with different severities and prognoses and clarify the risk factors for disease progression and death at an early stage. METHODS: Medical history, laboratory findings, treatment and outcome data from 214 hospitalised patients with COVID-19 pneumonia admitted to Eastern Campus of Renmin Hospital, Wuhan University in China were collected from 30 January 2020 to 20 February 2020, and risk factors associated with clinical deterioration and death were analysed. The final date of follow-up was 21 March 2020. RESULTS: Age, comorbidities, higher neutrophil cell counts, lower lymphocyte counts and subsets, impairment of liver, renal, heart, coagulation systems, systematic inflammation and clinical scores at admission were significantly associated with disease severity. Ten (16.1%) moderate and 45 (47.9%) severe patients experienced deterioration after admission, and median time from illness onset to clinical deterioration was 14.7 (IQR 11.3-18.5) and 14.5 days (IQR 11.8-20.0), respectively. Multivariate analysis showed increased Hazards Ratio of disease progression associated with older age, lymphocyte count <1.1 × 109/L, blood urea nitrogen (BUN)> 9.5 mmol/L, lactate dehydrogenase >250 U/L and procalcitonin >0.1 ng/mL at admission. These factors were also associated with the risk of death except for BUN. Prediction models in terms of nomogram for clinical deterioration and death were established to illustrate the probability. CONCLUSIONS: These findings provide insights for early detection and management of patients at risk of disease progression or even death, especially older patients and those with comorbidities.

Construction of Potential miRNA-mRNA Regulatory Network in COPD Plasma by Bioinformatics Analysis.

Background: Chronic obstructive pulmonary disease (COPD) has become a major cause of morbidity and mortality worldwide. Increasing evidence indicates that aberrantly expressed microRNAs (miRNAs) are involved in the pathogenesis of COPD. However, an integrative exploration of miRNA-mRNA regulatory network in COPD plasma remains lacking. Methods: The microarray datasets GSE24709, GSE61741, and GSE31568 were downloaded from the GEO database and analyzed using GEO2R tool to identify differentially expressed miRNAs (DEMs) between COPD and normal plasma. The consistently changing miRNAs in the three datasets were screened out as candidate DEMs. Potential upstream transcription factors and downstream target genes of candidate DEMs were predicted by FunRich and miRNet, respectively. Next, GO annotation and KEGG pathway enrichment analysis for target genes were performed using DAVID. Then, PPI and DEM-hub gene network were constructed using the STRING database and Cytoscape software. Finally, GSE56768 was used to evaluate the hub gene expressions. Results: A total of nine (six upregulated and three downregulated) DEMs were screened out in the above three datasets. SP1 was predicted to potentially regulate most of the downregulated DEMs, while YY1 and E2F1 could regulate both upregulated and downregulated DEMs. 1139 target genes were then predicted, including 596 upregulated DEM target genes and 543 downregulated DEM target genes. Target genes of DEMs were mainly enriched in PI3K/Akt signaling pathway, mTOR signaling pathway, and autophagy. Through the DEM-hub gene network construction, most of the hub genes were found to be potentially modulated by miR-497-5p, miR-130b-5p, and miR-126-5p. Among the top 12 hub genes, MYC and FOXO1 expressions were consistent with that in the GSE56768 dataset. Conclusion: In the study, potential miRNA-mRNA regulatory network was firstly constructed in COPD plasma, which may provide a new insight into the pathogenesis and treatment of COPD.

Associations of long-term exposure to ambient fine particulate matter and nitrogen dioxide with lung function: A cross-sectional study in China.

BACKGROUND: Few studies have evaluated the effects of ambient air pollution exposure on lung function, especially in areas with high air pollution levels. OBJECTIVES: To investigate the associations of annual concentrations of particulate matter with diameters < 2.5 µm (PM2.5) and nitrogen dioxide (NO2) with adult lung function in Shanghai, China. METHODS: We included 5276 permanent residents aged ≥ 20 years. Annual residential exposure to PM2.5 and NO2 was estimated by validated satellite-based and land use regression models, respectively. The effects of PM2.5 and NO2 on lung function were estimated separately using multivariable linear regression, adjusting for potential confounders. RESULTS: Higher exposure to PM2.5 and NO2 was significantly associated with lower forced vital capacity (FVC), inspiration capacity (IC), and vital capacity (VC). An increase of 10 µg/m3 in the annual average PM2.5 exposure was associated with a 45.83 ml (95% CI: -82.59, -9.07) lower FVC, 1.36 (95% CI: -2.42, -0.29) lower FVC of % predicted (FVC%pred), 121.98 ml (95% CI: -164.38, -79.57) lower IC, and 89.12 ml (95% CI -124.94, -53.3) lower VC. For NO2, an increase of 10 µg/m3 in the annual average concentration was associated with 26.65 ml (95% CI: -46.29, -7.00) lower FVC, 0.70 (95% CI: -1.27, 0.13) lower FVC%pred, 65.26 ml (95% CI: -87.76, -42.76) lower IC, and 45.88 ml (95% CI: -65.03, -26.73) lower VC. The estimated effects on FEV1 were -10.25 ml (95% CI: -40.92, 20.42) and -0.29% (95% CI: -1.40, 0.82) per 10 µg/m3 increase in PM2.5 and -0.74 ml (95% CI: -17.13, 15.65) and 0.01% (95% CI: -0.58, 0.61) per 10 µg/m3 increase in NO2, which were not statistically significant. Stratified analysis showed that the estimated effects of PM2.5 were greater in the healthy subgroup than the COPD patients. Obese individuals were more susceptible to adverse effects of PM2.5 and NO2 on lung function. Education level showed no or only weak evidence of modification of the associations between air pollution and lung function. CONCLUSION: In this study, long-term exposure to ambient air pollutants was significantly associated with impaired lung function, presenting as restrictive ventilatory patterns.

Corticosteroid, oseltamivir and delayed admission are independent risk factors for prolonged viral shedding in patients with Coronavirus Disease 2019.

INTRODUCTION: Coronavirus Disease 2019 (COVID-19) has spread worldwide, and it has reached to more than 14.5 million cases. Although Hubei province is the epicenter of China, little is known about epidemiological and clinical features of COVID-19 in other areas in Hubei province around Wuhan. In addition, the virological data, particularly the factors associated with viral shedding of COVID-19 has not been well described. OBJECTIVE: To describe the epidemiological and clinical features of patients with COVID-19 in Tianmen city, and identify risk factors associated with prolonged viral shedding of COVID-19. METHODS: Inpatients with COVID-19 admitted before February 9, 2020 were included. Characteristics were compared between patients with early and late viral RNA shedding. Multivariate cox regression model was used to investigate variables associated with prolonged viral shedding. RESULTS: One hundred and eighty-three patients were included. About 8.2% patients were categorized as critical degree of severity. All patients received antiviral therapy, with arbidol and interferon being the commonest. About 38.3% and 16.9% patients were treated with corticosteroid and immunoglobulin, respectively. Time from onset to admission (HR = 0.829, P < 0.001), and administration of corticosteroid (HR = 0.496, P = 0.002), arbidol (HR = 2.605, P = 0.008) and oseltamivir (HR = 0.416, P < 0.001) were independently associated with duration of viral shedding. CONCLUSION: Symptoms of patients from Tianmen are relatively mild. Treatment should be started as early as possible, but corticosteroid and oseltamivir should be initiated with caution. In addition, clinical trials on arbidol should be conducted to demonstrate its effectiveness.

Clinical outcomes of patients with HER2-mutant advanced lung cancer: chemotherapies versus HER2-directed therapies.

BACKGROUND: Lung cancer is now the leading cause of cancer mortality worldwide for both men and women. In non-small cell lung cancer (NSCLC), matching a specifically targeted drug to the identified driver mutation in each patient resulted in dramatically improved therapeutic efficacy, often in conjunction with decreased toxicity. Mutations in HER2 have been identified as an oncogenic driver gene for NSCLC. This retrospective study was conducted to better understand the clinical outcomes of advanced lung cancer patients harboring HER2 mutations treated with chemotherapies and HER2-targeted agents, as well as the optimal clinical choice. METHODS: Patients who were diagnosed with advanced lung cancer (stage IIIB/IV) and had undergone molecular testing at Zhongshan Hospital, Fudan University, Shanghai, China from April 2016 to December 2018 were reviewed. For patients that had HER2 mutant advanced lung cancer, we analyzed their clinical and molecular features and clinical outcomes, including overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR). RESULTS: We identified 44 patients harboring HER2 mutations. Their median age was 56 years, with the majority being women (n = 24), never smokers (n = 32), and having the adenocarcinoma genotype (n = 42). Amongst the HER2 mutations present, a 12 base pair in-frame insertion in exon 20 with p.771insAYVM was the most common subtype in patients with known detail variants of HER2 mutation (9/27). The median OS from the date of advanced disease diagnosis was 9.9 months with 24 deaths, and a median follow-up of 12.7 months for survivors. For patients with a known HER2 exon 20 insertion mutation, OS tended to be superior (though not statistically) in the first-line HER2-TKI group to that in the group receiving chemotherapy (10.8 versus 9.8 months, p = 0.40). However, patients that received first-line chemotherapy had a median PFS of 5.9 months, numerically longer than that of the HER2-TKI group (4.6 months, p = 0.63). Patients who received HER2-targeted therapy as first-line therapy had an improved OS (10.8 versus 10.1 months, p = 0.30) and PFS (4.6 versus 2.8 months, p = 0.36) relative to those who received HER2-targeted therapy as subsequent-line therapy, although they did not meet the threshold for statistical significance. Furthermore, patients with AYVM mutation were associated with poor clinical outcomes. CONCLUSION: Pemetrexed-based chemotherapy remains an important component of care for patients with HER2-mutant NSCLC. HER2-TKI given as an initial therapy may bring more clinical benefits than when given as a subsequent-line therapy. Refining the patient population based on patterns of HER2 variants may help improve the efficacy of anti-HER2 treatment in lung cancer. Developing highly effective and tolerable HER2-targeted agents is urgently needed for this population.

CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A.

BACKGROUND: Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; however, its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action. METHODS: By using immunohistochemistry, the expression levels were evaluated in both cancer and non-cancerous tissues. Subsequently, CHD4 knockdown and overexpression strategies were employed to investigate the effects of CHD4 on cell proliferation, migration, along with the growth and formation of tumors in a xenografts mouse model. The protein expression levels of CHD4, PHF5A and ROCK/RhoA markers were determined by Western blot analysis. RESULTS: Compared with non-cancerous tissues, CHD4 was overexpressed in cancer tissues and CHD4 expression levels were closely related to clinical parameters of NSCLC patients. In H292 and PC-9 cell lines, CHD4 overexpression could promote the proliferative and migratory potential of NSCLC cells. Furthermore, down-regulation of CHD4 could reduce the proliferative and migratory ability in A549 and H1299 cell lines. Meanwhile, knockdown of CHD4 could decrease the tumorigenicity in nude mice. Finally, we demonstrated that one of the mechanisms underlying the promotive effect of CHD4 on NSCLC proliferation and migration may be through its interaction with PHD finger protein 5A (PHF5A) and subsequent activation of the RhoA/ROCK signaling pathway. CONCLUSIONS: CHD4, which is highly expressed in cancer tissue, could be an independent prognostic factor for NSCLC patients. CHD4 plays an important role in regulating the proliferative and migratory abilities of NSCLC via likely the RhoA/ROCK pathway by regulating PHF5A.