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• FOXA2 expression was decreased, and senescence markers were overexpressed in lungs of CS-exposed mice. • Upregulation of FOXA2 suppressed CSE-induced senescence and inflammatory cytokine expression in bronchial epithelial cells. • Upregulation of FOXA2 prevents CS-induced cell senescence and inflammation in mice. • FOXA2 downregulation activates the MAPK pathway. Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses varying degrees of chronic obstructive bronchitis and emphysema. Our previous study showed that Forkhead box protein A2 (FOXA2) is involved in cigarette smoke (CS)-induced squamous metaplasia. However, the contribution of FOXA2 activity to CS-induced cellular senescence and lung inflammation remains largely unknown. Here, we report that FOXA2 was underexpressed in CS-exposed mouse lungs, and decreased expression of FOXA2 was related to cell senescence and inflammation. Subsequent investigation suggested that FOXA2 is an anti-senescence factor in lung that is involved in inflammatory responses. Furthermore, FOXA2 overexpression delayed CSE-induced senescence and inflammation, which correlated with regulation of the p38 and Erk1/2 MAPK signaling pathways by CSE-induced FOXA2 downregulation. Collectivelly, these findings reveal a protective role for FOXA2 as a regulator of cell senescence and inflammation during COPD. [ABSTRACT FROM AUTHOR]

MicroRNA-501-3p (miR-501-3p) has been reported to play tumor-suppressive roles in different cancers; however, its expression pattern and biological function in non–small cell lung cancer (NSCLC) remain unknown. In this study, we noted downregulation of miR-501-3p in NSCLC tissues and cell lines. Functional assays showed that overexpression of miR-501-3p suppressed NSCLC cell proliferation, clonogenicity, migration, and invasion. Moreover, miR-501-3p overexpression attenuated in vivo tumor growth in a nude mouse model. In terms of the mechanism, RAP1A was identified as a novel target of miR-501-3p. Overexpression of RAP1A strongly attenuated the inhibitory effects of miR-501-3p on the capacity of NSCLC cells for proliferation and motility. In the clinical samples of NSCLC, miR-501-3p levels negatively correlated with RAP1A expression, which was upregulated in NSCLC. Collectively, these results indicate that miR-501-3p acts as a tumor suppressor in NSCLC by directly targeting RAP1A mRNA and may serve as a theranostic biomarker for patients with NSCLC. • MiR-501-3p expression is low in NSCLC tissues and cell lines. • miR-501-3p suppresses NSCLC cell proliferation and invasion in vitro. • MiR-501-3p directly targets the 3′-UTR of RAP1A mRNA. • MiR-501-3p suppresses the proliferation and invasiveness of NSCLC cells by repressing RAP1A expression. • MiR-501-3p suppresses tumor growth in vivo. [ABSTRACT FROM AUTHOR]

Background: It is known that small airway disease is present across all asthma severities; however, its prevalence and clinical characteristics in cough variant asthma (CVA) have not been fully illuminated. Methods: A total of 77 CVA patients with preserved proximal airway function (FEV1/FVC > 70%) were enrolled in this study. The correlation between forced expiratory flow at 50% (FEF50%) and FEF25–75% in the CVA population was first evaluated. FEF50% was determined to be an easy and feasible parameter for identifying small airway disease. CVA with small airway disease is defined as FEF50% < 70%, whereas CVA with normal small airways is identified as FEF50% > 70%. Demographic features, clinical characteristics, lung function and induced sputum test results were determined at the initial visit and at the final visit 1 year later. Results: FEF50% is a good marker for small airway disease. The cutoff value of 70% is more sensitive than the previously published 60% for identifying more patients with small airway problems early. Nearly half of the CVA population (45.4%) in our cohort had small airway disease. In both group, symptoms improved greatly after anti-asthmatic treatment. Interestingly, the changes in symptom scores [Asthma Control Test (ACT) and ACQ] were even greater in the CVA with small airway disease group than in the control group because of the higher medication usage in this subpopulation in real life. However anti-asthmatic therapy can not reverse small airway dysfunction. At last visit, FEF50% of CVA with small airway diseases was 57.2% ± 10.5%, still much lower than the control group (FEF50% = 92.6% ± 16.5%). Conclusions: In our cohort, nearly half of the CVA population had small airway disease. Their demographic features, clinical characteristics, airway eosinophils and drug responsiveness were quite similar between two groups, which means these indices can not be used as markers to identify small airway obstruction. We found FEF50% is an easy and feasible marker for early identification. Regular anti-asthmatic medication helped to improve clinical scores in patients with small airway disease, but the obstruction could not be reversed over 1-year period. [ABSTRACT FROM AUTHOR]

Purpose: To explore symptom clusters and interrelationships using a network analysis approach among symptoms in patients with lung tumors who underwent computed tomography (CT)-guided microwave ablation (MWA)., Methods: A longitudinal study was conducted, and 196 lung tumor patients undergoing MWA were recruited and were measured at 24 h, 48 h, and 72 h after MWA. The Chinese version of the MD Anderson Symptom Inventory and the Revised Lung Cancer Module were used to evaluate symptoms. Network analyses were performed to explore the symptom clusters and interrelationships among symptoms., Results: Four stable symptom communities were identified within the networks. Distress, weight loss, and chest tightness were the central symptoms. Distress, and weight loss were also the most key bridge symptoms, followed by cough. Three symptom networks were temporally stable in terms of symptom centrality, global connectivity, and network structure., Conclusion: Our findings identified the central symptoms, bridge symptoms, and the stability of symptom networks of patients with lung tumors after MWA. These network results will have important implications for future targeted symptom management intervention development. Future research should focus on developing precise interventions for targeting central symptoms and bridge symptoms to promote patients' health., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To evaluate the predictive value of sICAM-1 and sP-Selectins in the risk of death in a prospective cohort of adult acute respiratory distress syndrome (ARDS)., Methods: Adult ARDS patients were included. Plasma sICAM-1, sP-Selectins, and inflammatory cytokines (TNF-α, IL-1b, IL-6, IL-8, and IL-17A) were detected in ARDS subjects. The correlation between different factors and the potential of sICAM-1 and sP-Selectins as endothelial markers to predict the risk of deathfrom ARDS was analyzed., Competing Interests: All the authors declare that they have no conflict of interest in this work.Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2024 Pan Jing, Chaomin Wu, Chunling Du, Lei Zhou, Liang Gu, published by CEON/CEES.)

Background: Effective monitoring and management are crucial during long-term home noninvasive positive pressure ventilation (NPPV) in patients with hypercapnic chronic obstructive pulmonary disease (COPD). This study investigated the benefit of Internet of Things (IOT)-based management of home NPPV., Methods: This multicenter, prospective, parallel-group, randomized controlled non-inferiority trial enrolled patients requiring long-term home NPPV for hypercapnic COPD. Patients were randomly assigned (1:1), via a computer-generated randomization sequence, to standard home management or IOT management based on telemonitoring of clinical and ventilator parameters over 12 months. The intervention was unblinded, but outcome assessment was blinded to management assignment. The primary outcome was the between-group comparison of the change in health-related quality of life, based on severe respiratory insufficiency questionnaire scores with a non-inferiority margin of -5. This study is registered with Chinese Clinical Trials Registry (No. ChiCTR1800019536)., Findings: Overall, 148 patients (age: 72.7 ± 6.8 years; male: 85.8%; forced expiratory volume in 1 s: 0.7 ± 0.3 L; PaCO 2 : 66.4 ± 12.0 mmHg), recruited from 11 Chinese hospitals between January 24, 2019, and June 28, 2021, were randomly allocated to the intervention group (n = 73) or the control group (n = 75). At 12 months, the mean severe respiratory insufficiency questionnaire score was 56.5 in the intervention group and 50.0 in the control group (adjusted between-group difference: 6.26 [95% CI, 3.71-8.80]; P < 0.001), satisfying the hypothesis of non-inferiority. The 12-month risk of readmission was 34.3% in intervention group compared with 56.0% in the control group, adjusted hazard ratio of 0.56 (95% CI, 0.34-0.92; P = 0.023). No severe adverse events were reported., Interpretation: Among stable patients with hypercapnic COPD, using IOT-based management for home NPPV improved health-related quality of life and prolonged the time to readmission., Funding: Air Liquide Healthcare (Beijing) Co., Ltd., Competing Interests: The authors declare that they have no conflicts of interest. Air Liquide Healthcare (Beijing) Co., Ltd. funded the study, including providing ventilators, oxygen concentrators, related accessories and services, as well as the manuscript editing services. Air Liquide Healthcare (Beijing) Co., Ltd. was not involved in trial design, patient recruitment, data collection, analysis or interpretation; preparation, review, or approval of the manuscript; or the decision to submit for publication. The authors had complete independence and control over their research and findings. The authors have not been paid to write this article. The corresponding author had full access to all data in the study and was responsible for deciding when to submit the report for publication., (© 2024 The Authors.)

Background: Psychological workplace violence (WPV) is the primary form of workplace violence suffered by nursing interns. Psychological WPV not only damages the physical and mental health of nursing interns, but also has a negative impact on their work quality and career choice., Aim: To investigate the characteristics and types of psychological WPV suffered by nursing interns in China, analyze the influencing factors of psychological WPV among nursing interns, and explore the influence of psychological WPV on the professional commitment of nursing interns., Methods: The subjects were 1,095 nursing interns from 14 medical colleges in Shandong Province. The data were collected electronically using the psychological WPV against nursing interns questionnaire and the professional commitment scale of nursing. The frequency and component ratio were used to describe the incidence and characteristics of psychological WPV. Binary logistic regression was used to analyze the influencing factors of psychological WPV, and linear regression investigated the influence of psychological WPV on the professional commitment of nursing interns., Results: In the study, 45.0% ( n = 493) of nursing interns suffered at least one incidence of psychological WPV during clinical practice, mainly discrimination and verbal abuse. Patients and their relatives were the main perpetrators of psychological WPV. Discrimination and lack of trust were the two main reasons behind psychological WPV. Furthermore, 75.9% of psychological WPV incidents were not effectively reported. Logistic regression showed that clinical internship duration, place of family residence, and hospital level were the influencing factors of psychological WPV among nursing interns. Linear regression results showed that psychological WPV had a negative effect on nursing interns' professional commitment., Conclusion: Psychological WPV against nursing interns is highly prevalent in China, negatively impacting their professional commitment. It is suggested that colleges should introduce courses for nursing interns to understand and cope with psychological WPV before entering clinical practice, and hospitals should establish a mechanism to prevent, cope with, report, and deal with psychological WPV to effectively reduce the incidence of psychological WPV against nursing interns, improve their ability to cope with psychological WPV, and enhance their professional commitment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Kong, Li, Zhang, Guo, Xie, Gao, Luan, Zhuang, Du and Liu.)

Purpose: To evaluate the effects of multidisciplinary collaborative empowerment education on psychological distress and quality of life (QoL) in patients with colorectal cancer undergoing chemotherapy., Methods: A quasi-experimental study was conducted using repeated measures at pre- and post-intervention in the fourth chemotherapy cycle. Sixty patients with colorectal cancer aged 36-84 years were allocated to the intervention and control groups. The intervention group received multidisciplinary empowerment education, while the control group received routine health education. Psychological distress involving depression and anxiety symptoms was assessed using The Kessler Psychological Distress Scale (K10) and QoL was measured using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTCQLQ-C30). Repeated-measures analysis of variance was used to examine intervention effects. Statistical analyses were performed using the SPSS software (version 26.0)., Results: Psychological distress was considerably lower and QoL was considerably better in patients following multidisciplinary empowerment education in the intervention group than those in the control group. In addition, psychological distress significantly decreased and QoL improved in the intervention group compared to baseline., Conclusion: Multidisciplinary collaborative empowerment education was effective in improving the psychological distress and QoL among patients with colorectal cancer undergoing chemotherapy. These findings suggest that the establishment of multidisciplinary collaborative empowerment education might be considered as an innovative means of clinical patient education during combination chemotherapy to improve health outcomes in patients with colorectal cancer. However, our results should be interpreted with caution because of the small sample size. Further validation in a larger sample or randomized controlled design is necessary in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Poor control of asthma results from many factors, partly due to inadequate knowledge towards asthma among patients. It is necessary to know patients' knowledge level before education. However, there is no accepted instrument to evaluate knowledge of asthma in Chinese patients with asthma. The study aims to develop a Chinese version of Patient-completed Asthma Knowledge Questionnaire (PAKQ) to assess its reliability, validity, and responsiveness for testing its clinical application in Chinese adult patients with asthma., Methods: After translation, back-translation, and cross-cultural adaptation of the PAKQ into Chinese version, a survey of patients with asthma (n=464) in China was conducted. Demographics and clinical data were collected in addition to questionnaires concerning cognition of asthma, education, history, and asthma control test score. The PAKQ was then completed. 14±4 days after the initial assessment, the participants completed the retested questionnaire and again completed the questionnaire immediately after education. The reliability and the construct validity were evaluated. The optimal cut-off points for predicting disease knowledge among asthma patients were determined using the Youden index method., Results: The Chinese version of PAKQ showed high internal consistency (Cronbach's alpha =0.888) at baseline and an acceptable 2-week test-retest reliability (ICC =0.932, r=0.874). On the basis of large modification indices (>10), this four-factor questionnaire was found to fit the data satisfactorily (χ 2 /df =1.695, RMSEA =0.039, GFI =0.856, CFI =0.885, and SRMR =0.058). Paired t -tests showed significant changes on pre-educational and post-educational tests (t=22.83, df=463, P<0.0001). The optimal cut-off value of the PAKQ total score for assessing patients' knowledge level was 35 points (AUC =0.757)., Conclusions: The Chinese version of the PAKQ questionnaire was developed and validated in terms of reliability and validity as an effective instrument for the insight into asthma knowledge of adult patients with asthma in China. Future research will evaluate the utility of the instrument in clinical practice., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1604/coif). DZ is a current employee of Medical Affair of Joincare Pharmaceutical Group Industry Co., Ltd. and this work was supported by the company. The other authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Background: Fatigue is prevalent in breast cancer patients undergoing postoperative chemotherapy, which seriously affects physical and mental health. The present study aimed to investigate the relevance of fatigue, the self-efficacy of managing chronic disease (SEMCD), and the dual-mode of self-control (DMSC) in patients., Methods: Three hundred and seventy six breast cancer patients undergoing postoperative chemotherapy participated in this cross-sectional study. The General Information Questionnaire, Fatigue Scale-14 (FS-14), SEMCD-Scale (SEMCD-S), and DMSC-Scale (DMSC-S) were utilized to survey. Pearson correlation analysis and structural equation modeling were used for the statistical analysis of the correlation between the variables and mediating effects., Results: A total of 372 valid questionnaires (98.94%) were returned. The total fatigue score of FS-14 was (10.84 ± 1.80), the SEMCD-S score (30.05 ± 15.18), and the DMSC-Scale score (73.35 ± 9.49). Furthermore, physical fatigue was negatively correlated with the SEMCD-S and problem solving (r = -0.764 ~ -0.680, P < 0.01). Mental fatigue correlated positively with poor delay of gratification (r = 0.134, P < 0.05), and the SEMCD-S was also negatively correlated with the impulsivity, distractibility, and poor delay of gratification dimensions (r =-0.229~-0.130, P < 0.05). SEMCD correlated positively with problem-solving and future time perspective (r = 0.695~0.790, P < 0.001). In addition, SEMCD partially mediated the effect between the DMSC and fatigue (β = -0.335, P < 0.01), with the mediating effect accounting for 51.25%., Conclusion: Through SEMCD measure, it was found that DMSC indirectly influences fatigue levels in breast cancer patients undergoing postoperative chemotherapy., Competing Interests: None

Background: Chronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease. Circular RNAs (circRNAs) are associated with inflammation regulation; therefore, we examined distinct effects of circRNA FOXO3 (circFOXO3) against pneumonic inflammatory processes in COPD., Methods: We first quantified and localized circFOXO3 in mouse lung epithelial cell line MLE12 by quantitative reverse-transcription PCR and in situ hybridization. Next, circFOXO3 was suppressed by therapeutic administration of circFOXO3 knockdown lentivirus in mice exposed to air or cigarette smoke (CS) for 12 weeks, and several hallmarks of COPD were evaluated., Results: We noticed that circFOXO3 is upregulated in CS-exposed lungs and cigarette smoke extract (CSE)-treated murine alveolar epithelial cells. Knockdown of circFOXO3 attenuated the release of CXCL1 and IL-6 as well as inflammatory processes in the lungs of CS-exposed mice. In addition, we identified miR-214-3p as a circFOXO3-targeted microRNA. MiR-214-3p overexpression exerted protective effects against pneumonic inflammation after CS exposure. Silencing of circFOXO3 downregulated IKK-β mRNA (miR-214-3p's target), resulting in the dysfunction of the NF-κB signaling pathway and attenuation of CSE-induced inflammatory-cytokine expression., Conclusions: Collectively, these findings reveal a crucial function of circFOXO3 in the pathological remodeling related to CS-induced inflammatory processes. Hence, circFOXO3 might be a good target for the treatment of inflammatory disorders similar to CS-induced lung inflammation., (© 2021. The Author(s).)

Objective: The present study compared the effectiveness of asthma control test (ACT)-guided treatment vs. usual care (UC) in patients with asthma from China., Methods: This prospective, phase IV, multicenter, cluster-randomized, open-label 24-week study was conducted in China; patients were randomized to either ACT-guided treatment or UC group. The patients recorded peak expiratory flow, symptoms, and medication in a diary card every day and completed ACT at every clinic visit. For the UC group, patients completed ACT after the physician's treatment decision., Results: In total, 83.6% patients (n = 443/530; ACT: n = 209, UC: n = 234) completed the study. A significantly higher proportion of patients (adjusted OR [95% CI]: 7.87 (1.29, 48.11; p = 0.027) responded to the treatment and had ACT total score ≥20 or demonstrated an improvement of >3 points in ACT total score in ≥1 post-baseline assessment in the ACT-guided treatment vs. UC group. A higher proportion of patients had an ACT total score ≥20 and an improvement of >3 points in ACT total score at Week 24 in the ACT-guided treatment vs. the UC group (adjusted OR (95% CI):2.28 (1.07, 4.85; p = 0.036). A significant difference (p = 0.005) in change from baseline in ACT total score was observed in ACT-guided treatment vs. UC group at Week 24. The mean annual exacerbation rate was similar in both the groups., Conclusions: ACT-guided treatment was more effective in achieving ACT total score ≥20 or showing an improvement of >3 points in the ACT total score and well tolerated compared with UC treatment in the 24-week treatment period., Trial Registration: Clinical trials.gov Identifier: NCT02868281, https://clinicaltrials.gov/; GlaxoSmithKline study ID: 201097, https://www.gsk-studyregister.com/., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder caused by dysfunction of the cilia and flagella; however, causative genetic defects have not been detected in all patients with PCD. Seven Chinese Han patients with Kartagener syndrome were enrolled onto the present study. Transmission electron microscopy (TEM) was performed to evaluate the cilial defects and whole‑exome sequencing was used to analyze relevant genetic variations in all patients. In two of the seven patients with PCD, four novel dynein axonemal assembly factor 1 (DNAAF1) mutations were identified (NM&#95;178452.6:c.3G>A, c.124+1G>C, c.509delG and c.943A>T) in three alleles. Both of these patients had long‑standing infertility. Their chest computed tomography results showed bronchiectasis, lung infections and situs inversus, and paranasal computed tomography revealed sinusitis. Semen analysis of the male patient showed poor sperm motility. TEM showed defects in the inner and outer dynein arms in both patients. The DNAAF1 sequences of family members were then analyzed. Bioinformatics analysis indicated that these mutations may be the cause of the cilial defects in these two probands. Thus, the present study identified novel PCD‑causing mutations in DNAAF1 in two patients with PCD. These genetic variations were predicted to alter DNAAF1 amino acid residues and lead to loss of function, thereby inhibiting cilia‑mediated motility. Accordingly, the two probands had PCD symptoms, and one of them died due to PCD‑associated complications.

Background: The impact of corticosteroid therapy on outcomes of patients with coronavirus disease 2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without., Methods: In this single-center retrospective observational study, patients with ARDS caused by COVID-19 between January 20, 2020, and February 24, 2020, were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality., Results: A total of 382 patients [60.7 ± 14.1 years old (mean ± SD), 61.3% males] were analyzed. The median of sequential organ failure assessment (SOFA) score was 2.0 (IQR 2.0-3.0). Of these cases, 94 (24.6%) patients had invasive mechanical ventilation. The number of patients received systemic corticosteroids was 226 (59.2%), and 156 (40.8%) received standard treatment. The maximum dose of corticosteroids was 80.0 (IQR 40.0-80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0-12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, SOFA score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (HR 0.42; 95% CI 0.21, 0.85; p = 0.0160). Corticosteroids were not associated with delayed viral RNA clearance in our cohort., Conclusion: In this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed ARDS.

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.

Introduction: To investigate the risk factors for the death in patients with COVID-19 with type 2 diabetes mellitus (T2DM)., Research Design and Methods: We retrospectively enrolled inpatients with COVID-19 from Wuhan Jinyintan Hospital (Wuhan, China) between December 25, 2019, and March 3, 2020. The epidemiological and clinical data were compared between non-T2DM and T2DM or between survivors and non-survivors. Univariable and multivariable Cox regression analyses were used to explore the effect of T2DM and complications on in-hospital death., Results: A total of 1105 inpatients with COVID-19, 967 subjects with without T2DM (n=522 male, 54.0%) and 138 subjects with pre-existing T2DM (n=82 male, 59.4%) were included for baseline characteristics analyses. The complications were also markedly increased in patients with pre-existing T2DM, including acute respiratory distress syndrome (ARDS) (48.6% vs 32.3%, p<0.001), acute cardiac injury (ACI) (36.2% vs 16.7%, p<0.001), acute kidney injury (AKI) (24.8% vs 9.5%, p<0.001), coagulopathy (24.8% vs 11.1%, p<0.001), and hypoproteinemia (21.2% vs 9.4%, p<0.001). The in-hospital mortality was significantly higher in patients with pre-existing T2DM compared with those without T2DM (35.3% vs 17.4%, p<0.001). Moreover, in hospitalized patients with COVID-19 with T2DM, ARDS and coagulopathy were the main causes of mortality, with an HR of 7.96 (95% CI 2.25 to 28.24, p=0.001) for ARDS and an HR of 2.37 (95% CI 1.08 to 5.21, p=0.032) for coagulopathy. This was different from inpatients with COVID-19 without T2DM, in whom ARDS and cardiac injury were the main causes of mortality, with an HR of 12.18 (95% CI 5.74 to 25.89, p<0.001) for ARDS and an HR of 4.42 (95% CI 2.73 to 7.15, p<0.001) for cardiac injury., Conclusions: Coagulopathy was a major extrapulmonary risk factor for death in inpatients with COVID-19 with T2DM rather than ACI and AKI, which were well associated with mortality in inpatients with COVID-19 without T2DM., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lung cancer is a devastating cancer with high morbidity and mortality. Ubiquitin‑specific protease (USP) is a type of deubiquitinating enzyme (DUB) that has been implicated in numerous cancers, including colorectal, myeloma and breast. In the present study, the expression of USP51 was determined in the lung cancer cell line A549 and cisplatin (also known as DDP)‑resistant lung cancer strain A549/DDP. The expression of zinc‑finger E‑box binding homeobox 1 (ZEB1), a transcriptional repressor, was also examined. The effects of USP51 knockdown or overexpression on proliferation and apoptosis, as well as the impact of ZEB1 overexpression and USP51 interference on apoptosis and ubiquitination were then assessed. Notably, increased expression of USP51 and ZEB1 in A549/DDP cells was observed, and treatment with DDP significantly inhibited proliferation in A549/DDP cells. In addition, knockdown of USP51 in A549/DDP cells significantly induced apoptosis, decreased ZEB1 expression and increased cleaved poly ADP‑ribose polymerase 1 (PARP1) and cleaved caspase‑3 levels. Consistently, USP51 overexpression in A549 cells displayed the opposite effects and potently attenuated DDP‑induced apoptosis. Notably, overexpression of ZEB1 in A549/DDP cells potently attenuated the effects of USP51 knockdown on apoptosis, and co‑IP experiments further demonstrated interaction between USP51 and ZEB. Lastly, knockdown of USP51 promoted ZEB1 ubiquitination, leading to ZEB1 degradation. Collectively, the present findings demonstrated that USP51 inhibition attenuated DDP resistance in A549/DDP cells via ubiquitin‑mediated degradation of ZEB1. Hence, targeting USP51 may serve as a novel therapeutic target for DDP resistance in lung cancer.

Importance: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated., Objective: To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died., Design, Setting, and Participants: Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020., Exposures: Confirmed COVID-19 pneumonia., Main Outcomes and Measures: The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed., Results: Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72)., Conclusions and Relevance: Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

Background: Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown., Methods: We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 patients with severe asthma, and 12 control subjects). H 2 O 2 was used to stimulate the human macrophage line U937 to mimic the oxidative stress status in severe asthma. The ability of candidate compounds, namely, azithromycin, PI3K inhibitors (BEZ235 and LY294002) and a p38 MAPK inhibitor (BIRB796), to ameliorate GC insensitivity in severe asthma was evaluated., Results: PBMCs from patients with severe asthma exhibited dose-dependent and time-dependent GC insensitivity, which correlated with reduced activity of histone deacetylase 2 (HDAC2) (p < 0.05) and elevated expression of proinflammatory genes [nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)] (p < 0.01) compared with these parameters in the control group. The PI3K inhibitors (BZE235 and LY294002) significantly restored the GC sensitivity of PBMCs from patients with severe asthma. In vitro, the PI3K inhibitors (BZE235 and LY294002) ameliorated GC insensitivity in H 2 O 2 /TNFα-induced IL-8 release from U937 cells by independently restoring the activity of HDAC2 or inhibiting the activation of transcription factors., Conclusions: This study demonstrates that PI3K inhibitors ameliorate GC insensitivity in severe asthma by restoring HDAC2 activity and inhibiting the phosphorylation of nuclear signaling transcription factors.

Socio-ecological damage from climate-related disasters has increased worldwide, including a type of cold-season disaster (dzud) that is unique to the Eurasian steppes, notably Mongolia. During 2000-2014, dzuds killed approximately 30 million livestock and impacted the Mongolian socio-economy. The contributions of both natural and social processes to livestock mortality were not previously considered across Mongolia. Here, we consider the contribution of both multiple climate hazards (drought, cold temperatures and snow), and socioeconomic vulnerability (herders' livestock and coping-capacity) to mortality risk. We performed multi-regression analyses for each province using meteorological, livestock and socioeconomic datasets. Our results show that 93.5% of mortality within Mongolia was caused by a combination of multi-hazards (47.3%) and vulnerability (46.2%), suggesting dzuds were both climate- and man-made. However, in high-mortality hotspots, mortality was primarily caused by multi-hazards (drought-induced pasture deficiency and deep-snow). Livestock overpopulation and a lack of coping capacities that caused inadequate preparedness (e.g., hay/forage) were the main vulnerability factors. Frequent and severe multi-hazards greatly increased the mortality risk, while increased vulnerability caused by socioeconomic changes in Mongolia since the 1990s tended to amplify the effects of multi-hazards. Thus, reductions in herder vulnerability within high-mortality hotspots would likely be an effective means of mitigating the risk of future dzuds.

High mammalian gene expression was obtained for more than twenty different proteins in different cell types by just a few laboratory scale stable gene transfections for each protein. The stable expression vectors were constructed by inserting a naturally-occurring 1.006 kb or a synthetic 0.733 kb DNA fragment (including intron) of extremely GC-rich at the 5' or/and 3' flanking regions of these protein genes or their gene promoters. This experiment is the first experimental evidence showing that a non-coding extremely GC-rich DNA fragment is a super "chromatin opening element" and plays an important role in mammalian gene expression. This experiment has further indicated that chromatin-based regulation of mammalian gene expression is at least partially embedded in DNA primary structure, namely DNA GC-content.

Collagen is a popular biomaterial in many specific biological interactions as well as a structural element. In this work, the recombinant collagen-like proteins were synthesized using Escherichia coli expression system. A foldon sequence, GYIPEAPRDGQAYVRKDG EWVLLSTFL, derived from the native T4 phage fibritin was incorporated at the C-terminal of collagen-like protein molecules to stabilize the triple helix formed in the proteins. The differential scanning calorimetry and thermogravimetric analysis measurements showed that the thermostability of the recombinant collagen-like proteins was significantly improved when compared with those without the foldon sequence at the C-terminal. Fourier transform infrared and scanning electron microscopy observations indicated that the collagen-like proteins forms the triple helix structure and prefer to aggregate as fibrils, same as the native collagen. Moreover, the mice fibroblasts L929 cells could attach and grew very well on the recombinant collage-like proteins. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the cell biocompatibility of collagen-like proteins produced in this work was even better than that of native collagen, suggesting that the collagen-like proteins may be a satisfactory candidate for the future applications as a biomaterial.

To investigate the effect of the Ginkgo Biloba Extract (GBE) on the asthma and examine its possible mechanisms, 75 asthma patients were divided into 4 groups and the patients were respectively treated with fluticasone propionate for 2 weeks or 4 weeks, or treated with fluticasone propionate plus GBE for 2 weeks or 4 weeks. Fifteen healthy volunteers served as healthy controls. Sputum inhalation with inhaling hypertonic saline (4%-5%) was performed. Lung ventilatory function and forced expiratory volume in one second (FEV1) were measured. The numbers of different cells in induced sputum were calculated. The expression of PKCalpha in the cells was immunocytochemically detected and the percentages of positive cells in different cells were counted. Interleukin-5 (IL-5) in sputum supernatants was detected with enzyme-linked immunosorbent assay. The percentage of eosinophils, lymphocytes, PKCalpha positive inflammatory cells and the concentration of IL-5 in asthmatic patients were higher than those in the controls (P<0.05), and the eosinophils, lymphocytes, positive expression of PKCalpha and the level of IL-5 were significantly decreased in asthmatic patients after they were treated with fluticasone propionate or fluticasone propionate plus GBE. However, they were still significantly higher than those of the controls. Compared to the group treated with glucocorticosteroid for 2 weeks, no significant decrease was found in the percentage of eosinophils, lymphocytes, PKCalpha positive inflammatory cells and the IL-5 in the supernatant of induced sputum. Compared with the group treated with glucocorticosteroid for 2 or 4 weeks, significant decrease in the same parameters was observed in the group treated with fluticasone propionate and GBE for 4 weeks. The IL-5 level in the supernatant of induced sputum was positively correlated with the percentage of PKCalpha-positive inflammatory cells and the percentage of eosinophils in the induced sputum in asthma patient groups respectively (n=150, r= 0.83, P<0.01; n=150, r=0.76, P<0.01). The FEV1 was negatively correlated with the percentage of PKCalpha-positive inflammatory cells and the IL-5 levels in supernatant of induced sputum in asthma patients respectively (n=150, r=-0.77, P<0.01; n=150, r= -0.64, P<0.01). It is concluded that GBE could significantly decrease the infiltration of inflammatory cells such as eosinophils and lymphocytes in the asthmatic airway and relieve the airway inflammation. GBE may decrease the activation of the PKCalpha in the inflammatory cells and thereby decrease the IL-5 level in induced sputum. GBE may be used as a complement to the glucocorticosteroid therapy for asthma.