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Bin Hu,1 Jingchun Pei,1 Cheng Wan,1,2 Shuangshuang Liu,1 Zhe Xu,3,4 Yongwei Zou,1 Zhigao Li,1 Zhiwei Tang1 1Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 2Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, People’s Republic of China; 4School of Basic Medical Sciences, Qujing Medical College, Qujing, People’s Republic of ChinaCorrespondence: Zhiwei Tang, Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, People’s Republic of China, Email tangzhiwei7755@hotmail.comAbstract: Ischemic stroke constitutes a significant global health care challenge, and a comprehensive understanding of its recovery mechanisms is imperative for the development of innovative therapeutic strategies. Angiogenesis, a pivotal element of ischemic tissue repair, facilitates the restoration of blood flow to damaged regions, thereby promoting neuronal regeneration and functional recovery. Nevertheless, the mechanisms underlying postischemic stroke angiogenesis remain incompletely elucidated. This review meticulously examines the constituents of the neurovascular unit, ion channels, molecular mediators, and signaling pathways implicated in angiogenesis following stroke. Furthermore, it delves into prospective therapeutic strategies informed by these factors. Our objective is to provide detailed and exhaustive information on the intricate mechanisms governing postischemic stroke angiogenesis, thus providing a robust scientific foundation for the advancement of novel neurorepair therapies.Keywords: ischemic stroke, angiogenesis, signaling pathways

Weihua Han,1,* Peiyao Zhou,2,* Chun Chen,3,* Chunyang Wu,2 Li Shen,1 Cailing Wan,4 Yanghua Xiao,4 Jiao Zhang,2 Bingjie Wang,1 Junhong Shi,1 Xinru Yuan,1 Haojin Gao,1 Hongxiu Wang,1 Ying Zhou,1 Fangyou Yu1 1Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 4School of Public Health, Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying Zhou; Fangyou Yu, Email 18702195157@163.com; wzjxyfy@163.comBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a great threat to public health worldwide. Ceftazidime-avibactam (CZA) is an effective β-lactam/β-lactamase inhibitors against CRKP. However, reports of resistance to CZA, mainly caused by Klebsiella pneumoniae carbapenemase (KPC) variants, have increased in recent years. In this study, we aimed to describe the resistance characteristics of KPC-12, a novel KPC variant identified from a CZA resistant K. pneumoniae.Methods: The K. pneumoniae YFKP-97 collected from a patient with respiratory tract infection was performed whole-genome sequencing (WGS) on the Illumina NovaSeq 6000 platform. Genomic characteristics were analyzed using bioinformatics methods. Antimicrobial susceptibility testing was conducted by the broth microdilution method. Induction of resistant strain was carried out in vitro as previously described. The G. mellonella killing assay was used to evaluate the pathogenicity of strains, and the conjugation experiment was performed to evaluate plasmid transfer ability.Results: Strain YFKP-97 was a multidrug-resistant clinical ST11-KL47 K. pneumoniae confers high-level resistance to CZA (16/4 μg/mL). WGS revealed that a KPC variant, KPC-12, was carried by the IncFII (pHN7A8) plasmids (pYFKP-97_a and pYFKP-97_b) and showed significantly decreased activity against carbapenems. In addition, there was a dose-dependent effect of blaKPC-12 on its activity against ceftazidime. In vitro inducible resistance assay results demonstrated that the KPC-12 variant was more likely to confer resistance to CZA than the KPC-2 and KPC-3 variants.Discussion: Our study revealed that patients who was not treated with CZA are also possible to be infected with CZA-resistant strains harbored a novel KPC variant. Given that the transformant carrying blaKPC-12 was more likely to exhibit a CZA-resistance phenotype. Therefore, it is important to accurately identify the KPC variants as early as possible.Keywords: carbapenem-resistant Enterobacterales, Klebsiella pneumoniae, ceftazidime-avibactam, KPC-12, carbapenemase

Liyuan Qiao,1,2,&ast; Shulin Ding,2,&ast; Wanrui Ma,1 Chuanzhi Xu,3 Xiaoqing Zhang,3 Yuxi Liu,1,2 Chonghua Wan1,2 1The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, people’s republic of china; 2Key Laboratory for Quality of Life and Psychological Assessment and Intervention, School of Humanities and Management, Guangdong Medical University, Dongguan, people’s republic of china; 3School of Public Health, Kunming Medical University, Kunming, people’s republic of china&ast;These authors contributed equally to this workCorrespondence: Yuxi Liu; Chonghua Wan, Email yuxiliu123@126.com; wanchh@hotmail.comObjective: Coronary heart disease (CHD) is a common and frequent disease with a long and incurable course, and the quality of life of patients is severely reduced. This study was to develop and validate a quality of life scale for patients with CHD based on the Chinese context.Methods: The scale QLICD-CHD (V2.0) was developed based on the QLICD-CHD (V1.0), using a programmed decision procedures. Based on the data measuring QoL 3 times before and after treatments from 189 patients with CHD, the psychometric properties of the scale were evaluated with respect to validity, reliability and responsiveness employing correlation analysis, multi-trait scaling analysis, structural equation modeling, t-test and also G-study and D-study of generalizability theory analysis. The SF-36 scale was used as the criterion to evaluate the criterion-related validity. Paired t tests were conducted to evaluate the responsiveness on each domain/facet as well as the total of the scale, with Standardized Response Mean (SRM) being calculated.Results: The QLICD-CHD (V2.0) has been developed with 42 items in 4 domains. The Cronbach’s α of the general module, the specific module and the total scale were 0.91, 0.92 and 0.91 respectively. The overall score and the test-retest reliability coefficients in all domains are higher than 0.60, except for the specific module. Correlation and factor analysis confirmed good construct validity and criterion-related validity. After treatments, the overall score and score of all domains have statistically significant changes (P< 0.01). The SRM of domain-level score ranges from 0.27 to 0.50. Generalizability Theory further confirm the reliability of the scale through more accurate variance component studies.Conclusion: The QLICD-CHD (V2.0) could be used as a useful instrument in assessing QoL for patients with CHD, with good psychometric properties.Keywords: quality of life, classical test theory, standardized response mean, psychometric properties, generalizability theory

Qi Qi,&ast; Jun Yang,&ast; Linhui Yang, Huohuan Tian, Chun Wan, Dan Liu Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Liu; Chun Wan, Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email liudan10965@wchscu.cn; wanchun66@wchscu.cnAbstract: Lemierre syndrome (LS) is a rare and life-threatening condition predominantly caused by Fusobacterium necrophorum. Currently, there are no standardized clinical guidelines for LS management. Here, we describe the case of a 40-year-old male with fever, productive cough, and dyspnea but no sore throat. Diagnostic radiological examinations revealed multiple pulmonary cavitary nodules and an internal jugular vein occlusion. Metagenomic Next-Generation Sequencing (mNGS) of the alveolar lavage fluid identified Fusobacterium necrophorum, thereby confirming the diagnosis of LS. Intriguingly, the patient exhibited a delayed clinical response despite receiving the appropriate antibiotic. After integrating tigecycline into the treatment to address potential co-infecting bacteria, we observed a marked improvement in his clinical symptoms. Subsequent follow-up over 12 weeks post-discharge revealed complete alleviation of symptoms, and a chest CT scan showed marked regression of the lung lesions.Keywords: Lemierre syndrome, Fusobacterium necrophorum, septic thrombophlebitis, antibiotic therapy, anticoagulation

Yulin Chen,1 Yi Zhang,2 Jianjun Wang,3 Xiong Cai,1 Junzhang Chen,1 Xiaobo Min,1 Yunjie Xu,1 Qi Qin,1 Chidan Wan1 1Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Engineering Research Center of Tumor-Targeted Biochemotherapy, Wuhan, 430030, People’s Republic of China; 3Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of ChinaCorrespondence: Qi Qin; Chidan Wan, Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Email qinqi8441@163.com; wcdwhxhgdwk@163.comBackground: Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment.Methods: Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities.Results: Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine.Conclusion: Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine. Keywords: liver cancer, drug-loaded microparticles, tumor immune microenvironment, tumor vaccine

Shuying Rao,1 Chuanzhi Xu,2 Chonghua Wan,1 Zhiwen Huang,3 Xingping Huang,4 Shu Chen1 1Research Center for Quality of Life and Applied Psychology, School of Humanities and Management, Guangdong Medical University, Dongguan, People’s Republic of China; 2Department of Statistics, School of Public Health, Kunming Medical University, Kunming, People’s Republic of China; 3Cardiovascular Department, the Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China; 4Department of Research and Teaching, Dongguan Eighth’ Hospital, Dongguan, People’s Republic of ChinaCorrespondence: Chonghua Wan, Tel/Fax +86-0769-22896255, Email wanchh@hotmail.comPurpose: Coronary heart disease (CHD) is difficult to cure, so more attention should be paid to improving patients’ health-related quality of life (HRQoL). This paper focuses on identifying factors that affect HRQoL.Patients and Methods: Overall, 189 in-patients with coronary heart disease were investigated at the Affiliated Hospital of Guangdong Medical University between 2015 and 2016. The scale Quality of Life Instruments for Chronic Diseases-Coronary heart disease (QLICD-CHD V2.0) was used to evaluate HRQoL and collect demographic information. Medical records were applied to collect patients’ clinical indicators. A simple correlation analysis, Student’s t-test, and a one-way analysis of variance were first performed to filter factors that might associate with HRQoL, and multiple linear regression was applied to finally identify related factors.Results: Findings from multiple linear regression showed that the total score was related to family economy, treatment, indirect bilirubin, and albumin with regression coefficient B=5.209, − 6.615, 0.378, and 0.548, respectively. The physical functions were related to treatment, albumin, globular proteins, chloride, and red blood cell count with B=− 9.031, 1.000, 0.612, 1.320, and 5.161, respectively. The psychological function was in association with family economy, clinical course, serum phosphorus, and percentage of lymphocyte population with B=7.487, 6.411, − 16.458, and 0.090, respectively. The social function was associated with family economy, blood urea nitrogen, serum creatinine, and platelet distribution width with B=7.391, 1.331, − 0.060, and − 0.929, respectively. The special module was in association with treatment, indirect bilirubin, and serum calcium with B=− 7.791, 0.414, and 23.017, respectively.Conclusion: Clinical indicators including albumin, globular proteins, chloride, red blood cell count, serum phosphorus, percentage of lymphocyte population, blood urea nitrogen, serum creatinine, platelet distribution width, indirect bilirubin, and serum calcium, as well as socio-demographic factors including the family economy, clinical course, and treatment, may affect coronary heart disease patients’ HRQoL.Keywords: quality of life, coronary heart disease, socio-demographic factors, clinical indicators, scale

Summary: Background: Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition. Methods: We analysed cross-sectional data from 33,983 adults (≥40 years), recruited between Jan 2, 2003 and Dec 26, 2016, in 41 sites (34 countries) from the Burden of Obstructive Lung Disease (BOLD) study. We estimated the prevalence of chronic cough for each site accounting for sampling design. To identify risk factors, we conducted multivariable logistic regression analysis within each site and then pooled estimates using random-effects meta-analysis. We also calculated the population attributable risk (PAR) associated with each of the identifed risk factors. Findings: The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job. Interpretation: Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors. Funding: Wellcome Trust.

Background Computed tomography (CT)-derived pectoralis muscle area (PMA) measurements are prognostic in people with or at-risk of COPD, but fully automated PMA extraction has yet to be developed. Our objective was to develop and validate a PMA extraction pipeline that can automatically: 1) identify the aortic arch slice; and 2) perform pectoralis segmentation at that slice. Methods CT images from the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study were used for pipeline development. Aorta atlases were used to automatically identify the slice containing the aortic arch by group-based registration. A deep learning model was trained to segment the PMA. The pipeline was evaluated in comparison to manual segmentation. An external dataset was used to evaluate generalisability. Model performance was assessed using the Dice–Sorensen coefficient (DSC) and PMA error. Results In total 90 participants were used for training (age 67.0±9.9 years; forced expiratory volume in 1 s (FEV1) 93±21% predicted; FEV1/forced vital capacity (FVC) 0.69±0.10; 47 men), and 32 for external testing (age 68.6±7.4 years; FEV1 65±17% predicted; FEV1/FVC 0.50±0.09; 16 men). Compared with manual segmentation, the deep learning model achieved a DSC of 0.94±0.02, 0.94±0.01 and 0.90±0.04 on the true aortic arch slice in the train, validation and external test sets, respectively. Automated aortic arch slice detection obtained distance errors of 1.2±1.3 mm and 1.6±1.5 mm on the train and test data, respectively. Fully automated PMA measurements were not different from manual segmentation (p>0.05). PMA measurements were different between people with and without COPD (p=0.01) and correlated with FEV1 % predicted (p

Ran Li,1,2,&ast; Chen Liu,1,2,&ast; Chaoqiong Wan,1,2 Tiantian Liu,1,2 Rongrong Zhang,1,2 Jie Du,1 Xiangyu Wang,1,2 Xiaofeng Jiao,1,2 Ruifang Gao,1,2 Bing Li1 1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, People’s Republic of China; 2Department of Pediatric and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruifang Gao; Bing Li, Email gruifang_26@163.com; libing-1975@163.comPurpose: Oral squamous cell carcinoma (OSCC) is a malignant disease with serious impacts on human health and quality of life worldwide. This disease is traditionally treated through a combination of surgery, radiotherapy, and chemotherapy. However, the efficacy of traditional treatments is hindered by systemic toxicity, limited therapeutic effects, and drug resistance. Fibroblast activation protein (FAP) is a membrane-bound protease. Although FAP has limited expression in normal adult tissues, it is highly expressed in the tumor microenvironment of many solid cancers – a characteristic that makes it an ideal target for anticancer therapy. In this study, we constructed a nano-drug delivery system (NPF@DOX) targeting FAP to increase the therapeutic efficiency of synergistic chemo-photothermal therapy against OSCC.Methods: We utilized PEGylated nano-graphene oxide (NGO) to link doxorubicin (DOX) and fluorescently-labeled, FAP-targeted peptide chains via hydrogen bonding and π–π bonding to enhance the targeting capability of NPF@DOX. The synthesis of NPF@DOX was analyzed using UV–Vis and FT–IR spectroscopy and its morphology using transmission electron microscopy (TEM). Additionally, the drug uptake efficiency in vitro, photo-thermal properties, release performance, and anti-tumor effects of NPF@DOX were evaluated and further demonstrated in vivo.Results: Data derived from FT–IR, UV–Vis, and TEM implied successful construction of the NPF@DOX nano-drug delivery system. Confocal laser scanning microscopy images and in vivo experiments demonstrated the targeting effects of FAP on OSCC. Furthermore, NPF@DOX exhibited a high photothermal conversion efficiency (52.48%) under near-infrared radiation. The thermogenic effect of NPF@DOX simultaneously promoted local release of DOX and apoptosis based on a pH-stimulated effect. Importantly, FAP-targeted NPF@DOX in combination with PTT showed better tumor suppression performance in vivo and in vitro than did either therapy individually.Conclusion: NPF@DOX can precisely target OSCC, and combined treatment with chemical and photothermal therapy can improve the therapeutic outcomes of OSCC. This method serves as an efficient therapeutic strategy for the development of synergistic anti-tumor research.Keywords: fibroblast activation protein, nano-graphene oxide, photothermal therapy, oral squamous cell carcinoma, targeted combination therapy

Abstract Background Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. Methods Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). Results Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77–2.70), chronic cough (OR = 2.56, 95% CI 2.08–3.15), chronic phlegm (OR = 2.29, 95% CI 1.77–4.05), wheeze (OR = 2.87, 95% CI 2.50–3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11–1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. Conclusion Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

Ze-Jun Pei,1– 3,&ast; Chengcheng Li,1,3,&ast; Wenna Dai,4 Zaixiang Lou,3 Xin Sun,1,2 Hongxin Wang,3 Azmat Ali Khan,5 Chunpeng Wan5 1State Key Laboratory of Dairy Biotechnology, Technology Center of Bright Dairy and Food Company Ltd, Shanghai, People’s Republic of China; 2Department of Pharmacy, Wuxi No.2 People’s Hospital, Nanjing Medical University, Wuxi, 214002, People’s Republic of China; 3State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, People’s Republic of China; 4School of Food Science, Wuhu Institute of Technology, Wuhu, 241006, People’s Republic of China; 5Research Center of Tea and Tea Culture, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zaixiang Lou, Email louzaixiang@126.comIntroduction: This study aimed to examine the anti-biofilm activity and mechanism of gallic acid (GA), kaempferol-7-O-glucoside (K7G) and apigenin-7-O-glucoside (A7G) against Staphylococcus aureus and Escherichia coli.Methods: The antibacterial activity of the natural compounds was determined by serial dilution method. The inhibitory activity of natural compounds on biofilms was determined by crystal violet staining method. The effects and mechanisms of natural compounds on bacterial biofilms were analyzed by atomic force microscopy.Results: In our study, compared with GA and K7G, A7G was found to exhibit the strongest anti-biofilm and antibacterial activities. The minimum biofilm inhibitory concentration (MBIC) of A7G against S. aureus and E. coli was 0.20 mg/mL and 0.10 mg/mL, respectively. The inhibition rates of 1/2 MIC of A7G on biofilms of S. aureus and E. coli were 88.9%, and 83.2% respectively. Moreover, atomic force microscope (AFM) images showed the three-dimensional biofilm morphology of S. aureus and E. coli, and the results indicated that A7G was highly effective in biofilm inhibition.Discussion: It was found that the inhibition of A7G on biofilm was achieved through inhibiting on exopolysaccharides (EPS), quorum sensing (QS), and cell surface hydrophobicity (CSH). A7G exerted strong anti-biofilm activities by inhibiting EPS production, QS, and CSH. Hence, A7G, as a natural substance, could be a promising novel antibacterial and anti-biofilm agent for control of biofilm in food industry.Keywords: apigenin-7-O-glucoside, anti-biofilm, exopolysaccharide, quorum sensing, cell surface hydrophobicity, atomic force microscope

Yuchen Li,* Ruxiao Nie,* Xianwei Cao, Chuan Wan Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuan Wan, Department of Dermatology, The First Affiliated Hospital of Nanchang University, Yong Wai Zheng Street 17#, Nanchang, 330006, People’s Republic of China, Tel +86-18070052970, Email chuanwan@ncu.edu.cnAbstract: Eosinophilic pustular folliculitis (EPF) is a rare, chronic, non-infectious inflammatory skin disease. Although the pathogenesis of EPF is unknown, eosinophilic pustular folliculitis may be associated with human immunodeficiency virus (HIV) infection, malignancies or syphilis. Here, we report the first case of EPF associated with syphilis, indicating that syphilis and EPF are correlated with T-helper type 2 immune responses. A 48-year-old man gradually developed erythema and pustules on the face, neck. Physical examination revealed multiple infiltrative red patches and plaques on the face, neck with tiny pustules. Skin biopsy results revealed that the dermal follicular sebaceous gland unit was infiltrated by a large number of neutrophils and eosinophils, forming eosinophilic microabscesses. Therefore, the patient was diagnosed with EPF associated with syphilis and received drug treatment. After the treatment, the pustules markedly decreased, leaving behind pigmentation. Furthermore, the patient is still being followed up.Keywords: eosinophilic pustular folliculitis, secondary syphilis, pathogenesis, T-lymphocyte immune response

Background The 6-min walk test (6MWT) is widely used to assess exercise capacity across chronic health conditions, but is currently not useful to assess symptoms, as the scores do not account for the 6-min walk distance (6MWD). We aimed to 1) develop normative reference equations for breathlessness and leg discomfort intensity expressed as modified Borg (mBorg)/6MWD ratios; and 2) validate the equations in people with COPD. Methods Analysis of people aged ≥40 years who performed two 6MWTs (on a 20-m course) in the Canadian Cohort Obstructive Lung Disease (CanCOLD) study: a healthy cohort (n=291; mean±sd age 67.5±9.4 years; 54% male) with normal 6MWD and lung function, and a COPD cohort (n=156; age 66.2±9.0 years; 56% male; forced expiratory volume in 1 s (FEV1)/forced vital capacity 56.6±8.2%; FEV1 74.4±18.6% pred). The mBorg score was calculated as the Borg 0–10 category ratio intensity rating of breathlessness or leg discomfort recorded at the end of the 6MWT +1 (range 1–11), to avoid zeros and yield ratios proportional to the symptom score and 6MWD−1. Results Using data from the healthy cohort, sex-specific normative reference equations for breathlessness and leg discomfort mBorg/6MWD ratios were developed using multivariable linear regression, accounting for age, and body mass or body mass index. In the COPD cohort, abnormal breathlessness and leg discomfort (mBorg/6MWD>upper limit of normal) showed strong concurrent validity with worse airflow limitation, Medical Research Council breathlessness and COPD Assessment Test scores. Conclusion Normative references for the mBorg/6MWD ratio are presented to assess breathlessness and leg discomfort responses to the 6MWT in COPD.

Background Computed tomography (CT) visual emphysema score is a better predictor of mortality than single quantitative CT emphysema measurements in COPD, but there are numerous CT measurements that reflect COPD-related disease features. The purpose of this study was to determine if linear combinations of quantitative CT measurements by principal component analysis (PCA) have a greater association with forced expiratory volume in 1 s (FEV1) lower limit of normal (LLN) annualised change (ΔFEV1) than visual emphysema score in COPD. Methods In this retrospective, longitudinal study, demographic, spirometry and CT images were acquired. CT visual emphysema score and quantitative analysis were performed; low attenuation area

Hongxuan Wu,&ast; Pingxiu He,&ast; Dong Xie, Jianqiao Wang, Chuan Wan Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chuan Wan, Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China, Tel +86-791-88692799, Email chuanwan@ncu.edu.cnPurpose: The long non-coding RNA (lncRNA) anti-differentiation noncoding RNA (ANCR) is closely related to the occurrence and development of various malignancies. However, its expression and potential role in basal cell carcinoma (BCC) have not been established. In this study, we characterized the effects of ANCR in BCC and its underlying mechanism.Methods: The expression of ANCR in BCC tissues and cells was detected by qRT-PCR. Proliferation, invasion, migration and apoptosis of ANCR overexpressed or knock down TE354.T and A431 cells were examined by CCK8, transwell assay, wound healing assay and flow cytometry analysis, respectively. Western blot was performed to measure the expression of apoptosis-related proteins (BAX, BCL2 and Cleaved-caspase3), epithelial-mesenchymal transformation-related proteins (E-cadherin, N-cadherin, vimentin and β-catenin), and Hedgehog-pathway-related proteins (PTCH, GLI1 and SMO). RNA pull-down assay was used to analyze the relationship between ANCR and PTCH. The effect of ANCR on BCC growth in vivo was analyzed using xenograft model. TUNEL assay was used to determine the cell apoptosis.Results: ANCR and Hedgehog pathway were more highly expressed in BCC tissues than in adjacent normal tissues. ANCR overexpression substantially promoted BCC cell proliferation, invasion, and migration, inhibited apoptosis, and up-regulated BCL2 and decreased the expression of BAX and Cleaved-caspase3 proteins. Additionally, the upregulation of N-cadherin, vimentin, β-catenin, PTCH, GLI1, and SMO expression, and downregulation of E-cadherin expression were observed after ANCR overexpression. Moreover, ANCR knockdown had the opposite effects. An RNA pull-down assay further revealed that ANCR is specifically bound to PTCH. In vivo experiments also showed that ANCR overexpression significantly increased tumor growth and decreased apoptosis, which was reversed by cyclopamine, a specific inhibitor of the Hedgehog signaling pathway.Conclusion: ANCR activates the Hedgehog signaling pathway by binding to PTCH, thereby promoting BCC progression; accordingly, ANCR could be a candidate therapeutic target in BCC.Keywords: anti-differentiation noncoding RNA, basal cell carcinoma, Hedgehog signaling pathway, PTCH, epithelial–mesenchymal transition

Luqi Dai,1,2,&ast; Dan Xu,1,&ast; Chun Wan,1,2 Lian Liu,1 Fuqiang Wen1,2 1Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuqiang Wen; Lian LiuDepartment of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, Guoxuexiang 37 Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86 28 8542 2350Fax +86 28 8558 2944Email wenfuqiang@scu.edu.cn; desertfoxliu@hotmail.comPurpose: WNT/β-catenin signal pathway is a potential hope for lung tissue repair. We investigated the levels of Dickkopf‐1 (DKK1), an endogenous inhibitor of WNT/β-catenin signal pathway, in chronic obstructive pulmonary disease (COPD) patients and airway inflammation.Patients and Methods: Collected the demographic and clinical characteristics of 36 healthy controls, 25 stable COPD patients and 10 acute exacerbation of COPD (AECOPD) patients, then performed pulmonary function and detected serum DKK1 levels. After over-expression of DKK1, detect the levels of DDK1, lipoprotein-related protein 6 (LRP6) and inflammatory factors in bronchial epithelial cells stimulated with cigarette smoke extract (CSE).Results: Serum DKK1 were reduced in stable COPD patients compared to healthy controls (3866.72 ± 775.33 pg/mL vs 5317.61 ± 1317.20 pg/mL, p< 0.0001), but there was no significant difference between stable and acutely exacerbated patients (3866.72 ± 775.33 pg/mL vs 3482.10 ± 841.25 pg/mL, p> 0.05). DKK1 was positively correlated with FEV1 (r = 0.570, p< 0.0001), FEV1/FVC (rho = 0.590, p< 0.0001), FEV1/Pre (r = 0.517, p< 0.0001). Multiple linear regression analysis also suggested that FEV1 levels were higher with increasing DKK1. In vitro, elevated IL-6, IL-8, TNF-α and decreased DKK1, LRP6 were found in Beas-2B cells after CSE treatments, and increased LRP6 and decreased inflammatory factors were found after overexpression of DKK1. Andrographolide restored the CSE-induced decrease in DKK1 and increase in IL-6 and IL-8.Conclusion: DKK1 levels were decreased in COPD patients and positively correlated with lung function, overexpression of DKK1 and andrographolide attenuated airway cell inflammation, both suggesting a potential role in pathophysiology and providing a disease-specific biomarker pattern.Keywords: LRP6, lung function, biomarker, andrographolide

Shuanghong Luo,1,2 Chuncheng Wu,3 Qiuhong Luo,1,2 Mengdong Ran,4 Yin Liu,5 Fei Lei,6 Xin Chen,7 Zheng Yuan,8 Hanmin Liu,1,2 Chaomin Wan1,2 1Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China; 3Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Biostatistics, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 5Research and Development Department, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 6Medical Information Center, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 7Child Health Care Department, Nanxin Community Health Service Center, High-Tech Zone, Chengdu, People’s Republic of China; 8Economics School, Southwestern University of Finance and Economics, Chengdu, People’s Republic of ChinaCorrespondence: Chaomin Wan Tel/Fax +86-28-85503185Email wanchaomin@scu.edu.cnAbstract: As an implementation strategy, the actual functional scope of clinical pathway (CPW) can be mastered is the basis for evaluating and improving CPW management, which is very important for bridging the evidence-to-practice gap. Here, we propose and discuss a design and evaluation model for CPWs through some theoretical lenses that may help the designer master the actual functional scope of CPWs and accumulate and refine effective key management steps of a specific disease. We can thus determine the best-optimized design with the largest net benefit that allows definition of the core management steps for a specific disease.Keywords: implementation science, clinical pathway, evidence-based medicine, health technology assessment, public health economics

Jing An, Ting Yang, Jiajia Dong, Zenglin Liao, Chun Wan, Yongchun Shen, Lei Chen Department of Respiratory and Critical Care Medicine, Division of Pulmonary Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Yongchun Shen; Lei Chen Email Shenshen_yongchun@126.com; lchens@126.comBackground: Chronic obstructive pulmonary disease (COPD) is a heterogeneous chronic inflammatory disease characterized by progressive airflow limitation that causes high morbidity and mortality. MicroRNA, a short-chain noncoding RNA, regulates gene expression at the transcriptional level. microRNA modules with a role in the pathogenesis of COPD may serve as COPD biomarkers.Methods: We downloaded the GSE33336 microarray data set from the Gene Expression Omnibus (GEO) database, the data are derived from 29 lung samples of patients with emphysema undergoing curative resection for lung cancer. We used weighted gene co-expression network analysis (WGCNA) to construct co-expression modules and detect trait-related microRNA modules. We used the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to predict the biological function of the interest modules, and we screened out candidate hub microRNAs based on their module membership (MM) value and top proteins on the results of the protein–protein interaction (PPI) network.Results: Three microRNA modules (royal blue, light yellow and grey60) were highly associated with COPD. Axon guidance, proteoglycans in cancer and mitogen-activated protein kinases (MAPK) signaling pathway were common pathways in these three modules. Keratin18 (KRT18) was the top protein in our study. miR-452, miR-149, miR-133a, miR-181a and miR-421 in hub microRNAs may play a role in COPD.Conclusion: These findings provide evidence for the role of miRNAs in COPD and identify biomarker candidates.Keywords: chronic obstructive pulmonary disease, weighted gene co-expression network analysis, microRNA

Yue Qiu,1,&ast; Daojiong Lin,2,&ast; Yi Xu,3,&ast; Yibing Cheng,4 Fang Wang,5 Qingxiong Zhu,6 Chunhui Zhu,6 Chaomin Wan,7 Yu Zhu,7 Jianning Tong,8 Rui Li,8 Qionghua Zhou,2 Minxia Chen,3 Qingwen Shan,9 Zhiqiang Zhuo,10 Caihong Wang,10 Shiyong Zhao,11 Wen Song,11 Mei Zeng1 1Department of Infectious Diseases, Children’s Hospital of Fudan University, ShangHai, People’s Republic of China; 2Department of Infectious Diseases, Hainan Women and Children’s Medical Center, Haikou, People’s Republic of China; 3Department of Infections Disease, Guangzhou Women and Children’s Medical Center, Guangzhou, People’s Republic of China; 4Department of Emergency, Children’s Hospital Affiliated to Zhengzhou University (Henan Children’s Hospital), Zhengzhou, People’s Republic of China; 5Department of Infections Disease, Children’s Hospital Affiliated to Zhengzhou University (Henan Children’s Hospital), Zhengzhou, People’s Republic of China; 6Department of Infection Diseases, Children’s hospital of Jiangxi Province, Nanchang, People’s Republic of China; 7Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, People’s Republic of China; 8Department of Pediatric, Gastroenterology and Infectious Diseases, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China; 9Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 10Department of Infectious Diseases, Xiamen Children’s Hospital, Xiamen, People’s Republic of China; 11Department of Infectious Diseases, Hangzhou Children’s Hospital, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mei ZengDepartment of Infectious Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, People’s Republic of ChinaTel +86-21-64931132Email zengmeigao@aliyun.comObjective: To assess clinical characteristics, outcomes and antimicrobial resistance of invasive Klebsiella pneumoniae (KP) infections in Chinese pediatric patients in hospital and community settings.Methods: This retrospective study was conducted in the nine tertiary hospitals during 2016– 2018. The 324 pediatric inpatients who had KP isolated from blood and cerebrospinal fluid and had complete medical records reviewed were included. We analyzed the risk factors, outcomes and antimicrobial resistance pattern of KP-infected patients based on comparison between healthcare-associated KP infections (HAI) and community-acquired infections.Results: Of the 324 enrolled patients, 275 (84.9%) were clinically defined as HAI, including 175 (63.6%) neonates and 100 (36.4%) aged > 28 days. The overall prevalence of CRKP was 38.2% (43.4% in HAI verse 8.7% in CAI, P < 0.05). Prematurity (odds ratio (OR): 37.07, 95% CI: 8.29– 165.84), hematologic malignancies (OR: 15.52, 95% CI: 1.89– 127.14) and invasive mechanical ventilation (OR: 13.09, 95% CI: 1.66– 103.56) were independent risk factors for HAI. Patients from rural area (OR: 1.94, 95% CI: 1.12– 3.35), invasive mechanical ventilation (OR: 2.33, 95% CI: 1.25– 4.33), antibiotic therapy prior to admission (OR: 2.33, 95% CI: 1.25– 4.33) and prior hospital stay in the past 30 days (OR: 3.46, 95% CI: 1.87– 6.41) were associated with healthcare-associated CRKP infections. Organ dysfunction was independently correlated with poor outcomes (OR: 2.92, 95% CI: 1.23– 6.95).Conclusion: Pediatric invasive KP infections and high prevalence of CRKP infections largely occurred in healthcare settings in China. The adequate and intensified infection control measures should be focused on high-risk hematologic patients, neonatal patients and intubated patients.Keywords: Klebsiella pneumoniae, healthcare-associated infections, children

Jin Chen,1,* Yan-ni Lv,2,* Xiao-bing Li,1,* Jia-jun Xiong,1,* Hui-ting Liang,1 Liang Xie,3 Chen-yi Wan,1 Yun-qing Chen,1 Han-sen Wang,3 Pan Liu,3 He-qing zheng3 1Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jin ChenDepartment of Neurology, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Road, Nanchang, Jiangxi, 330006, People’s Republic of ChinaEmail jin_chen080706@yeah.netBackground: Post-stroke depression (PSD) is a major complication in stroke survivors, especially in elderly stroke survivors. But there are still no objective methods to diagnose depression in elderly stroke survivors. Thus, this study was conducted to identify potential biomarkers for diagnosing elderly PSD subjects.Methods: Elderly (60 years or older) stroke survivors with depression were assigned into the PSD group, and elderly stroke survivors without depression and elderly healthy controls (HCs) were assigned into the non-depressed group. Urinary metabolite signatures obtained from gas chromatography-mass spectrometry (GC-MS)-based metabolomic platform were collected. Both univariate and multivariate statistical analysis were used to find the differential urinary metabolites between the two groups.Results: The 78 elderly HCs, 122 elderly stroke survivors without depression and 124 elderly PSD subjects were included. A set of 13 differential urinary metabolites responsible for distinguishing PSD subjects from non-depressed subjects were found. The Phenylalanine, tyrosine and tryptophan biosynthesis, Phenylalanine metabolism and Galactose metabolism were found to be significantly changed in elderly PSD subjects. The phenylalanine was significantly negatively correlated with age and depressive symptoms. Meanwhile, a biomarker panel consisting of 3-hydroxyphenylacetic acid, tyrosine, phenylalanine, sucrose, palmitic acid, glyceric acid, azelaic acid and α-aminobutyric acid was identified.Conclusion: These results provided candidate molecules for developing objective methods to diagnose depression in elderly stroke survivors, suggested that taking supplements of phenylalanine might be an effective method to prevent depression in elderly stroke survivors, and would be helpful for future revealing the pathophysiological mechanism of PSD.Keywords: post-stroke depression, metabolomics, biomarker

Shihao Zhang,* Jiansheng Liu,* Taiwen Yuan, Huiyu Liu, Chengwei Wan, Yonghong Le Department of Respiratory and Critical Care Medicine, Ganzhou People’s Hospital, Ganzhou 341000, Jiangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghong LeDepartment of Respiratory and Critical Care Medicine, Ganzhou People’s Hospital, No. 17, Hongqi Avenue, Zhanggong District, Ganzhou 341000, Jiangxi, People’s Republic of ChinaTel/Fax +8613879769189Email Yonghongle3112@163.comBackground: Non-small cell lung cancer (NSCLC) seriously endangers human health. Circular RNAs (circRNAs) regulate diverse types of cancers, including NSCLC. This study investigated the possible mechanism of circ0001313 in NSCLC.Materials and Methods: Circ0001313 expression in NSCLC tissues was measured, and its correlation with clinicopathological features was analyzed. The binding relationships among circ0001313, microRNA (miR)-452 and HMGB3 were tested. The gain and loss of functions were performed to examine NSCLC cell malignant behaviors. After HMGB3 overexpression, ERK/MAPK pathway-related protein levels were detected. Subsequently, the rescue experiment was further performed using an ERK/MAPK pathway inhibitor PD98059.Results: Abnormally elevated circ0001313 and decreased miR-452 in NSCLC cells were observed. Circ0001313 silencing or miR-452 overexpression significantly reduced NSCLC cell proliferation and invasion. Circ0001313 competitively bound to miR-452 to upregulate HMGB3, thus promoting NSCLC cell growth. HMGB3 overexpression activated the ERK/MAPK pathway to contribute to NSCLC development.Conclusion: We highlighted that silencing of circ0001313 blunted the ERK/MAPK pathway via the miR-452/HMGB3 axis, thereby inhibiting NSCLC cell proliferation and invasion.Keywords: non-small cell lung cancer, circular RNA 0001313, microRNA-452, HMGB3, ERK/MAPK pathway, proliferation and invasion

Dongdong Zheng,1,* Caifeng Wan,1,* Hong Yang,2 Li Xu,1 Qi Dong,1 Chengrun Du,3 Jing Du,1 Fenghua Li1 1Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2College of Chemistry and Materials Science, Shanghai Normal University, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Du; Fenghua Li Email beautydujing@163.com; fenghua-li@163.comPurpose: The treatment of breast cancer is often ineffective due to the protection of the tumor microenvironment and the low immunogenicity of tumor cells, leading to a poor therapeutic effect. In this study, we designed a nano-theranostic platform for these obstacles: a photothermal effect mediated by a gold shell could remodel the tumor microenvironment by decreasing cancer-associated fibroblasts (CAFs) and promote the release of doxorubicin (DOX) from nanoparticles. In addition, it could realize photoacoustic (PA)/MRI dual-model imaging for diagnose breast cancer and targeted identification of Her2-positive breast cancer.Methods: Her2-DOX-superparamagnetic iron oxide nanoparticles (SPIOs)@Poly (D, L-lactide-co-glycolide) acid (PLGA)@Au nanoparticles (Her2-DSG NPs) were prepared based on a single emulsion oil-in-water (O/W) solvent evaporation method, gold seed growing method, and carbon diimide method. The size distribution, morphology, PA/MRI imaging, drug loading capacity, and drug release were investigated. Cytotoxicity, antitumor effect, cellular uptake, immunogenic cell death (ICD) effect, and targeted performance on human Her2-positive BT474 cell line were investigated in vitro. BT474/Adr cells were constructed and the antitumor effect of NPs on it was evaluated in vitro. Moreover, chemical-photothermal therapy effect, PA/MRI dual-model imaging, ICD effect induced by NPs, and tumor microenvironment remodeling in human BT474 breast cancer nude mice model were also investigated.Results: Nanoparticles were spherical, uniform in size and covered with a gold shell. NPs had a photothermal effect, and can realize photothermal-controlled drug release in vitro. Chemical-photothermal therapy had a good antitumor effect on BT474/Adr cells and on BT474 cells in vitro. The targeting evaluation in vitro showed that Her2-DSG NPs could actively target and identify Her2-positive tumor cells. The PA/MRI imaging was successfully validated in vitro/vivo. Similarly, NPs could enhance the ICD effect in vitro/vivo, which could activate an immune response. Immunofluorescence results also proved that photothermal effect could decrease CAFs to remodel the tumor microenvironment and enhance the accessibility of NPs to tumor cells. According to the toxicity results, targeted drug delivery combined with photothermal-responsive drug release proved that NPs had good biosafety in vivo. Chemical-photothermal therapy of Her2-targeted NPs has a good antitumor effect in the BT474 nude mice model.Conclusion: Our study showed that chemical-photothermal therapy combined with tumor microenvironment remodeling and immune activation based on the Her2-DSG NPs we developed are very promising for Her2-positive breast cancer.Keywords: tumor microenvironment remodeling, chemoimmunotherapy, photothermal effect, targeted nano-theranostic platform, dual-modal imaging

There is limited understanding of how to identify people at high risk of developing COPD. Our objective was to investigate the association between computed tomography (CT) total airway count (TAC) and incident COPD over 3 years among ever-smokers from the population-based Canadian Cohort Obstructive Lung Disease (CanCOLD) study. CT and spirometry were acquired in ever-smokers at baseline; spirometry was repeated at 3-year follow-up. CT TAC was generated by summing all airway segments in the segmented airway tree (VIDA Diagnostics, Inc.). CT airway wall area, wall thickness for a theoretical airway with 10 mm perimeter (Pi10), and low attenuation areas below −856 HU (LAA856) were also measured. Logistic and mixed effects regression models were constructed to determine the association for CT measurements with development of COPD and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) decline, respectively. Among 316 at-risk participants evaluated at baseline (65±9 years, 40% female, 18±19 pack-years), incident COPD was detected in 56 participants (18%) over a median 3.1±0.6 years of follow-up. Among CT measurements, only TAC was associated with incident COPD (p=0.03), where a 1-sd decrement in TAC increased the odds ratio for incident COPD by a factor of two. In a multivariable linear regression model, reduced TAC was significantly associated with greater longitudinal FEV1/FVC decline (p=0.03), but no other measurements were significant. CT TAC predicts incident COPD in at-risk smokers, indicating that smokers exhibit early structural changes associated with COPD prior to abnormal spirometry.

Studies assessing dyspnoea and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD) have focussed on patients in clinical settings, not the general population. The aim of this analysis was to compare the prevalence and severity of dyspnoea and impaired HRQoL in individuals with and without COPD from the general population, focussing on mild–moderate COPD. Analysis of the 3-year Canadian Cohort Obstructive Lung Disease (CanCOLD) study included four subgroups: mild COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1); moderate COPD (GOLD 2); non-COPD smokers; and non-COPD never-smokers. The primary outcome was dyspnoea (Medical Research Council (MRC) scale), and the secondary outcome was HRQoL (COPD Assessment Test (CAT) score; Saint George's Respiratory Questionnaire (SGRQ) score). Subgroups were analysed by sex, physician-diagnosed COPD status and exacerbations. 1443 participants (mild COPD (n=397); moderate COPD (n=262(; smokers (n=449) and never-smokers (n=335)) were studied. People with mild COPD were more likely to report more severe dyspnoea (MRC 2 versus 1) than those without COPD (OR (95% CI) 1.42 (1.05–1.91)), and non-COPD never-smokers (OR (95%CI) 1.64 (1.07–2.52)). Among people with mild COPD, more severe dyspnoea was reported in women versus men (MRC2 versus 1; OR (95% CI) 3.70 (2.23–6.14)); people with, versus without, physician-diagnosed COPD (MRC2 versus 1; OR (95% CI) 3.27 (1.71–6.23)), and people with versus without recent exacerbations (MRC2 versus 1; ≥2 versus 0 exacerbations: OR (95% CI) 3.62 (1.02–12.86); MRC ≥3 versus 1; 1 versus 0 exacerbation: OR (95% CI): 9.24 (2.01–42.42)). Similar between-group differences were obtained for CAT and SGRQ scores. Careful assessment of dyspnoea and HRQoL could help identify individuals for earlier diagnosis and treatment.

A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.

Abstract It is recommended that screening for COPD be restricted to symptomatic individuals, but supporting evidence is lacking. We determined the performance of wheeze, cough, phlegm, and dyspnea in discriminating COPD versus non-COPD in a population-based sample of 1332 adults. Area Under the Receiver Operating Curves (AUC) indicated that symptoms had modest performance whether assessed individually (AUCs 0.55–0.62), or in combination (AUC for number of symptoms as the predictor 0.64). AUC improved with the inclusion of multiple other factors (AUC 0.71). Restricting screening to symptomatic individuals is unlikely to substantially improve the yield of general population screening for undiagnosed COPD.

Weifeng Huang,1 Liangliang Yao,2 Xiao He,1 Lei Wang,1 Mingxi Li,3 Youxin Yang,3 Chunpeng Wan3–5 1Department of Microbiology and Immunology, Medical College, China Three Gorge University, Yichang, Hubei 443002, China; 2Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, China; 3College of Agronomy, Jiangxi Agricultural University, Nanchang 330045, China; 4Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits & Vegetables, Nanchang 330045, China; 5Collaborative Innovation Center of Post-Harvest Key Technology and Quality Safety of Fruits and Vegetables, Jiangxi Agricultural University, Nanchang 330045, China Background: To investigate hypoglycemic activity and elucidate the active composition of the fruit blueberry (Vaccinium corymbosum). Methods: Methanol extracts of blueberry (MEB) were separated using a D101 macroporous resin column to yield quinic acid derivative (Fr.1)- and flavonoid (Fr.2)-rich fractions. The effects of the blueberry extracts on mRNA expression of GLUT-2 (glucose transporter type 2) and PPARγ (peroxisome proliferator-activated receptor-γ), as well as on the activities of PPRE (peroxisome proliferator response element) and NF-κB were analyzed in LO2 normal liver cells. Real-time PCR was used to detect the expression of GLUT-2, PPARγ, TNF-α, IL-1β, and IL-6 mRNA. The PPRE and NF-κB activities were detected by a luciferase reporter assay. Western blotting was used to detect the levels of PPARγ, GLUT-2, and p65. The active compositions were isolated using various chromatography columns, and were analyzed by NMR. Results: mRNA and protein expression of GLUT-2 and PPARγ were significantly increased upon treatment with 400 μg/mL extracts of blueberry (P

Hao Wang,1,* Caishuang Pang,2,* Ni Zeng,1 Chun Wan,1 Yongchun Shen,1 Fuqiang Wen1 1Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, China; 2Chongqing Cancer Institute & Hospital & Cancer Center, Chongqing, China *These authors contributed equally to this work Background: The gene polymorphism of interleukin-6 (IL-6) has been shown to be implicated in tuberculosis susceptibility in many studies, but with conflicting results. This study aimed to provide more accurate estimation of the relationship between IL-6 gene polymorphism and tuberculosis risk through a meta-analysis Method: A literature search was performed in PubMed, EMBASE, and other databases. Data were retrieved, and pooled odds ratio (OR) with 95% CI were calculated. Statistical analyses were performed by using STATA 12.0. Results: Twelve publications with 2635 cases and 3049 controls were included. The pooled analysis demonstrated significant evidence of association between IL-6 (-174G/C) and low risk of tuberculosis in dominant model (CC+GC vs GG: OR =0.693, 95% CI 0.581–0.826, p

Yechang Shao,1,2 Honglei Yin,3 Chengsong Wan4 1School of Public Health, Southern Medical University, 2Department of Internal Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 3Department of Psychiatry, Nanfang Hospital, 4Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China Objective: The aim of this study was to estimate the prevalence of Type D personality and assess the relationship between this personality type and self-efficacy/social support in Chinese patients with type 2 diabetes mellitus (T2DM).Patients and methods: From January 1, 2014, to July 31, 2014, 532 consecutive patients with T2DM were recruited from two hospitals in Guangzhou, China. The participants completed questionnaires containing questions about sociodemographic characteristics, Type D personality, self-efficacy, and social support scales, and their medical records were reviewed for additional data.Results: Of the 532 patients, 18.2% had Type D personality. Patients with this personality type reported significantly lower levels of self-efficacy (P

BACKGROUND:Patients with chronic obstructive pulmonary disease (COPD) are more likely to be readmitted than patients with other chronic medical conditions, yet knowledge regarding such readmissions is limited. We aimed to determine factors associated with readmission within 30 days of a COPD hospitalization or death with an emphasis on examining aspects of socioeconomic status and specific comorbidities. METHODS:A population-based cohort study was conducted using health administrative data from Ontario, Canada. All hospitalizations for COPD between 2004 and 2014 were considered. The primary exposures were socioeconomic status as measured by residential instability (an ecologic variable), and comorbidities such as cardiovascular disease and cancer. Other domains of socioeconomic status were considered as secondary exposures. Logistic regression with generalized estimating equations was used to examine the effect of exposures, adjusting for other patient factors, on 30-day readmission or death. RESULTS:There were 126,013 patients contributing to 252,756 index COPD hospitalizations from 168 Ontario hospitals. Of these hospitalizations, 19.4% resulted in a readmission and 2.8% resulted in death within 30 days. After adjusting for other factors, readmissions or death were modestly more likely among people with the highest residential instability compared to the lowest (OR 1.05, 95% CI 1.01-1.09). Comorbidities such as cardiovascular disease and cancer, as well as other aspects of low socioeconomic status also increased readmission or death risk. INTERPRETATION:Socioeconomic status, measured in various ways, and many comorbidities predict 30-day readmission or death in patients hospitalized for COPD. Strategies that address these factors may help reduce readmissions and death.

Yanqiu Wu,1,2,* Yongchun Shen,1,2,* Junlong Zhang,3 Chun Wan,1,2 Tao Wang,1,2 Dan Xu,1,2 Ting Yang,1,2 Fuqiang Wen1,21Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, 2Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, 3Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workBackground: Chronic obstructive pulmonary disease (COPD) is associated with abnormal systemic inflammation, and apoptosis is one of the pathogenic mechanisms of COPD. Several studies have suggested that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors were not only involved in diseases associated with apoptosis but also in inflammatory diseases. However, limited data about the possible relationship between COPD and TRAIL/TRAIL-receptors are available.Objective: To evaluate the potential relationship between TRAIL/TRAIL-receptors and COPD.Methods: Serum levels of TRAIL, decoy receptor 5 (DR5), C-reactive protein, and tumor necrosis factor-α were analyzed using multiplex enzyme-linked immunosorbent assay kits. Then, serum levels of TRAIL and DR5 in 57 COPD patients with 35 healthy controls were compared and correlated with lung function and systemic inflammation.Results: Mean levels of serum TRAIL and DR5 were significantly higher in COPD patients than those in controls (50.17±17.70 versus 42.09±15.49 pg/mL, P=0.029; 48.15±22.88 versus 38.94±10.95 pg/mL, P=0.032, respectively). Serum levels of TRAIL and DR5 correlated inversely with forced expiratory volume in 1 second % predicted, an index of lung function in COPD (r=-0.354, P=0.007 for TRAIL; r=-0.394, P=0.002 for DR5) in all participants (r=-0.291, P=0.005 for TRAIL; r=-0.315, P=0.002 for DR5), while DR5 correlated positively with C-reactive protein (r=0.240, P=0.021 for total subjects) and TRAIL correlated positively with tumor necrosis factor-α (r=0.371, P=0.005 for COPD; r=0.349, P=0.001 for total subjects).Conclusion: Our results suggested that circulating TRAIL and DR5 increased in COPD patients and were associated with lung function and systemic inflammation in COPD. Future studies are needed to verify whether and how TRAIL and its receptors play roles in COPD.Keywords: chronic obstructive pulmonary disease, tumor necrosis factor-related apoptosis-inducing ligand, decoy receptor 5, apoptosis, inflammation

Ye Wang,1,# Yongchun Shen,1,# Qiunan Zuo,2 Li Zhao,3 Chun Wan,1 Panwen Tian,1 Lei Chen,1 Fuqiang Wen11Department of Respiratory Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, People’s Republic of China; 2Department of Geriatrics, Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 3Department of Respiratory Medicine, Guizhou People’s Hospital, Guizhou, People’s Republic of China#These authors contributed equally to this work and share joint first authorshipBackground: Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD.Methods: Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD.Results: Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge.Conclusion: We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.Keywords: ghrelin, appetite, pulmonary disease, chronic obstructive, malnutrition, comorbidities

Cong Zhang,1 Fan Peng,1 Wei Liu,1 Jiangling Wan,1 Chunxi Wan,1 Huibi Xu,1,2 Christopher Waikei Lam,2 Xiangliang Yang1,2 1National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 2State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, People's Republic of China Abstract: After oral administration in rodents, triptolide (TP), a diterpenoid triepoxide compound, active as anti-inflammatory, immunosuppressive, anti-fertility, anti-cystogenesis, and anticancer agent, is rapidly absorbed into the blood circulation (from 5.0 to 19.5 minutes after dosing, depending on the rodent species) followed by a short elimination half-life (from about 20 minutes to less than 1 hour). Such significant and rapid fluctuations of TP in plasma likely contribute to its toxicity, which is characterized by injury to hepatic, renal, digestive, reproductive, and hematological systems. With the aim of prolonging drug release and improving its safety, TP-loaded nanostructured lipid carriers (TP-NLCs), composed of Compritol® 888 ATO (solid lipid) and Capryol™ 90 (liquid lipid), were developed using a microemulsion technique. The formulated TP-NLCs were also characterized and in vitro release was evaluated using the dialysis bag diffusion technique. In addition, the pharmacokinetics and toxicology profiles of TP-NLCs were compared to free TP and TP-loaded solid lipid nanoparticles (TP-SLNs; containing Compritol 888 ATO only). Results demonstrate that TP-NLCs had mean particle size of 231.8 nm, increased drug encapsulation with a 71.6% efficiency, and stable drug incorporation for over 1-month. TP-NLCs manifested a better in vitro sustained-release pattern compared to TP-SLNs. Furthermore, TP-NLCs prolonged mean residence time (MRT)0–t (P

BACKGROUND:Thoracic computed tomography (CT) scans are widely performed in clinical practice, often leading to detection of airway or parenchymal abnormalities in asymptomatic or minimally symptomatic individuals. However, clinical relevance of CT abnormalities is uncertain in the general population. METHODS:We evaluated data from 1361 participants aged ≥40 years from a Canadian prospective cohort comprising 408 healthy never-smokers, 502 healthy ever-smokers, and 451 individuals with spirometric evidence of chronic obstructive pulmonary disease (COPD) who had thoracic CT scans. CT images of subjects were visually scored for respiratory bronchiolitis(RB), emphysema(E), bronchial-wall thickening(BWT), expiratory air-trapping(AT), and bronchiectasis(B). Multivariable logistic regression models were used to assess associations of CT features with respiratory symptoms, dyspnea, health status as determined by COPD assessment test, and risk of clinically significant exacerbations during 12 months follow-up. RESULTS:About 11% of life-time never-smokers demonstrated emphysema on CT scans. Prevalence increased to 30% among smokers with normal lung function and 36%, 50%, and 57% among individuals with mild, moderate or severe/very severe COPD, respectively. Presence of emphysema on CT was associated with chronic cough (OR,2.11; 95%CI,1.4-3.18); chronic phlegm production (OR,1.87; 95% CI,1.27-2.76); wheeze (OR,1.61; 95% CI,1.05-2.48); dyspnoea (OR,2.90; 95% CI,1.41-5.98); CAT score≥10(OR,2.17; 95%CI,1.42-3.30) and risk of ≥2 exacerbations over 12 months (OR,2.17; 95% CI, 1.42-3.0). CONCLUSIONS:Burden of thoracic CT abnormalities is high among Canadians ≥40 years of age, including never-smokers and smokers with normal lung function. Detection of emphysema on CT scans is associated with pulmonary symptoms and increased risk of exacerbations, independent of smoking or lung function.

Xiao-Ming Zhu1, Yi-Xiang J Wang1, Ken Cham-Fai Leung2,3, Siu-Fung Lee2, Feng Zhao1, Da-Wei Wang2, Josie MY Lai4, Chao Wan4, Christopher HK Cheng4, Anil T Ahuja11Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR; 2Institute of Molecular Functional Materials and Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR; 3Institute of Creativity and Department of Chemistry, The Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR; 4School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong KongPurpose: To compare the cellular uptake efficiency and cytotoxicity of aminosilane (SiO2-NH2)-coated superparamagnetic iron oxide (SPIO@SiO2-NH2) nanoparticles with three other types of SPIO nanoparticles coated with SiO2 (SPIO@SiO2), dextran (SPIO@dextran), or bare SPIO in mammalian cell lines.Materials and methods: Four types of monodispersed SPIO nanoparticles with a SPIO core size of 7 nm and an overall size in a range of 7–15 nm were synthesized. The mammalian cell lines of MCF-7, MDA-MB-231, HT-29, RAW264.7, L929, HepG2, PC-3, U-87 MG, and mouse mesenchymal stem cells (MSCs) were incubated with four types of SPIO nanoparticles for 24 hours in the serum-free culture medium Dulbecco’s modified Eagle’s medium (DMEM) with 4.5 µg/mL iron concentration. The cellular uptake efficiencies of SPIO nanoparticles were compared by Prussian blue staining and intracellular iron quantification. In vitro magnetic resonance imaging of MSC pellets after SPIO labeling was performed at 3 T. The effect of each SPIO nanoparticle on the cell viability of RAW 264.7 (mouse monocyte/macrophage) cells was also evaluated.Results: Transmission electron microscopy demonstrated surface coating with SiO2-NH2, SiO2, and dextran prevented SPIO nanoparticle aggregation in DMEM culture medium. MCF-7, MDA-MB-231, and HT-29 cells failed to show notable iron uptake. For all the remaining six cell lines, Prussian blue staining and intracellular iron quantification demonstrated that SPIO@SiO2-NH2 nanoparticles had the highest cellular uptake efficiency. SPIO@SiO2-NH2, bare SPIO, and SPIO@dextran nanoparticles did not affect RAW 264.7 cell viability up to 200 µg Fe/mL, while SPIO@SiO2 reduced RAW 264.7 cell viability from 10 to 200 µg Fe/mL in a dose-dependent manner.Conclusion: Cellular uptake efficiency of SPIO nanoparticles depends on both the cell type and SPIO surface characteristics. Aminosilane surface coating enhanced the cellular uptake efficiency without inducing cytotoxicity in a number of cell lines.Keywords: magnetic nanoparticles, SPIO, iron oxide, surface coating, cellular uptake

BACKGROUND: A better understanding of health care costs associated with asthma would enable the estimation of the economic burden of this increasingly common disease.

Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p

The relationship between patient-reported symptoms and objective measures of lung function is poorly understood.To determine the association between responsiveness to bronchodilator and respiratory symptoms in random population samples.4669 people aged 40 years and older from 8 sites in Canada completed interviewer-administered respiratory questionnaires and performed spirometry before and after administration of 200 ug of inhaled salbutamol. The effect of anthropometric variables, smoking exposure and doctor-diagnosed asthma (DDA) on bronchodilator responsiveness in forced expiratory volume in 1 second (FEV1) and in forced vital capacity (FVC) were evaluated. Multiple logistic regression was used to test for association between quintiles of increasing changes in FEV1 and in FVC after bronchodilator and several respiratory symptoms.Determinants of bronchodilator change in FEV1 and FVC included age, DDA, smoking, respiratory drug use and female gender [p

The present supplement summarizes the proceedings of the symposium “Implementing practice guidelines: A workshop on guidelines dissemination and implementation with a focus on asthma and COPD”, which took place in Quebec City, Quebec, from April 14 to 16, 2005. This international symposium was a joint initiative of the Laval University Office of Continuing Medical Education (Bureau de la Formation Médicale Continue), the Canadian Thoracic Society and the Canadian Network for Asthma Care, and was supported by many other organizations and by industrial partners. The objectives of this meeting were to examine the optimal implementation of practice guidelines, review current initiatives for the implementation of asthma and chronic obstructive pulmonary disease (COPD) guidelines in Canada and in the rest of the world, and develop an optimal strategy for future guideline implementation. An impressive group of scientists, physicians and other health care providers, as well as policy makers and representatives of patients’ associations, the pharmaceutical industry, research and health networks, and communications specialists, conveyed their perspectives on how to achieve these goals.