Comparative efficacy of vancomycin in treating ST5 and ST764 methicillin-resistant Staphylococcus aureus infections in adult patients.

IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to multiple drugs and can cause serious infections. In recent years, one of the most widespread strains of MRSA worldwide has been the clonal complex 5 (CC5) type. Sequence type 5 (ST5) and ST764 are two prevalent CC5 strains. Although ST5 and ST764 are genotypically identical, ST764 is classified as a hybrid variant of ST5 with characteristics of community-associated MRSA (CA-MRSA). In contrast to ST5, ST764 lacks the tst and sec genes but carries the staphylococcal enterotoxin B (seb) gene. Vancomycin is commonly used as the first-line treatment for MRSA infections. However, it is currently unclear whether the genetic differences between the ST5 and ST764 strains have any impact on the efficacy of vancomycin in treating MRSA infections. We conducted a prospective observational study comparing the efficacy of vancomycin against ST5-MRSA and ST764-MRSA in five hospitals in China. There were significant differences in bacteriological efficacy between the two groups, with virulence genes, such as the tst gene, being a risk factor for bacterial persistence (adjusted odds ratio, 4.509; 95% confidence interval, 1.216 to 16.724; P = 0.024). In the future, it may be necessary to consider personalized vancomycin treatment strategies based on the genetic characteristics of MRSA isolates.

Chinese expert consensus on interventional diagnosis and management of acquired digestive-respiratory tract fistulas (second edition).

Acquired digestive-respiratory tract fistulas occur with abnormal communication between the respiratory tract and digestive tract caused by a variety of benign or malignant diseases, leading to the alimentary canal contents in the respiratory tract. Although various departments have been actively exploring advanced fistula closure techniques, including surgical methods and multimodal therapy, some of which have gotten good clinical effects, there are few large-scale evidence-based medical data to guide clinical diagnosis and treatment. The guidelines update the etiology, classification, pathogenesis, diagnosis, and management of acquired digestive-respiratory tract fistulas. It has been proved that the implantation of the respiratory and digestive stent is the most important and best treatment for acquired digestive-respiratory tract fistulas. The guidelines conduct an in-depth review of the current evidence and introduce in detail the selection of stents, implantation methods, postoperative management and efficacy evaluation.

Analysis of Cognition, Protection, Psychological, and Job-search Intentions Among Medical and Nonmedical College Students During COVID-19 Epidemic.

Context: Since December 2019, medical practitioners discovered a novel coronavirus causing an acute respiratory-tract infection in some hospitals in Wuhan, Hubei Province. COVID-19 has spread globally, making it an epidemic worldwide at present. Understanding the mental-health responses of college students to COVID-19 can help a school staff to better guide students seeking education. Objective: The study aimed to explore the differences between nonmedical and medical college students during the COVID-19 epidemic in their cognitive interest about the disease, preventive behaviors, psychological effects, and job-search intentions, hoping to provide more targeted measures for virus-coping education for college students. Design: The research team conducted a cross-sectional study, using an anonymous online questionnaire. Setting: The study took place at Shanghai, China. Participants: Participants were 1648 college students studying different specialties in various provinces of China, 485 nonmedical students and 1163 medical students. Outcome Measures: The survey's questions covered the respondents': (1) general demographic characteristics, (2) cognitive interest and knowledge about COVID-19 and its infectiousness as well as efforts at active learning about infectious diseases and viruses, (3) awareness of precautionary behaviors against COVID-19, (4) effects on mental health, and (5) effects on job-search intentions. The research team used descriptive statistics and Chi-square tests to analyze the survey data. Results: Among nonmedical students: (1) 297 participants (61.2%) were interested in learning about COVID-19, (2) 321 participants (66.2%) took the initiative to learn about the virus, (3) 301 participants (62.1%) took the initiative to learn about infectious disease, and (4) 151 participants (31.1%) watched medical-themed movies or TV series about COVID-19. Among medical students, the corresponding proportions were 772 participants (66.4%), 855 participants (73.5%), 791 participants (68.1%), and 791 participants (68.1%), respectively. Among nonmedical students, 223 participants (46.0%) had N95 masks available, 429 participants (88.5%) had disinfectant supplies available, 271 participants (55.9%) wore goggles in public places, 75 participants (15.5%) chose public transportation, and 77 participants (15.9%) were exposed to public places in the week prior to the survey. Among medical students, the corresponding proportions were 470 participants (40.4%), 935 participants (80.4%), 575 participants (49.4%), 243 participants (20.9%), and 297 participants (25.5%), respectively. Furthermore, COVID-19 had a stronger effect on medical students' psychology and job-search ambitions. Conclusions: The news about COVID-19 piqued the interest of medical students. Nonmedical students had stronger protective behavior than medical students. The COVID-19 outbreak had a significant influence on medical students' lives, studies, and moods. In addition, COVID-19 had a greater impact on the job-search intentions of medical students.

Comprehensive Analysis of Circular RNA Expression Profiles in Gefitinib-Resistant Lung Adenocarcinoma Patients.

Introduction: Gefitinib is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) widely used in lung adenocarcinoma (LUAD) patients harboring sensitive EGFR mutations. Although it has a good initial efficacy, acquired resistance to gefitinib is eventually inevitable. Studies have shown that circular RNA (circRNA) is involved in the development of acquired resistance to different anti-cancer drugs, but the comprehensive analysis of its expression profile and functions on acquired gefitinib resistance remains poor. Methods: To explore the aberrant circRNAs expression profiles, we collected peripheral plasma samples from 4 gefitinib-sensitive and 4 gefitinib-resistant patients for performing microarray analysis. Candidates of differentially expressed circRNAs were used and analyzed by bioinformatics modalities including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and a constructed circRNA-microRNA RNA network. The differential expression of selected circRNAs was verified by quantitative real-time PCR (qRT-PCR). Results: A total of 2571 circRNAs with significantly different expression between the groups were identified by microarray analysis. GO, KEGG, and pathway enrichment analyses reveal that these differentially expressed circRNAs (DECs) were complicated in many biological pathways that may be related to EGFR-TKI resistance such as ABC transporter and PI3K-Akt pathways. A circRNA-microRNA network was constructed by 10 circRNAs potentially involved in EGFR-TKI resistance togethering with their corresponding microRNAs (miRNAs). Consistent with the results of microarray assay, hsa_circ_0030591 and hsa_circ_0040348 were validated to be upregulated in gefitinib-resistant patients by qRT-PCR. Conclusions: Our study provides valuable data on circRNAs expression profiles detected in liquid biopsy for LUAD patients with acquired gefitinib resistance, and we validate that upregulations of hsa_circ_0030591 and hsa_circ_0040348 may play key roles in EGFR-TKI resistance and thus serving as candidates for biomarker.

Analysis of sputum microbial metagenome in COPD based on exacerbation frequency and lung function: a case control study.

BACKGROUND: The role of the sputum microbiome in chronic obstructive pulmonary disease (COPD) progression remains elusive. As the advent of the new culture-independent microbial sequencing technique makes it possible to disclose the complex microbiome community of the respiratory tract. The aim of this study was to use metagenomic next-generation sequencing (mNGS) to confirm whether there are differences in sputum microbiome of COPD between different exacerbation frequencies and lung function. METHODS: Thirty-nine COPD patients were divided into a frequent exacerbators (FE) group (n = 20) and a non-frequent exacerbators (NFE) (n = 19) group according to their exacerbation history, or a mild group (FEV1/pre ≥ 50%, n = 20) and a severe group (FEV1/pre < 50%, n = 19) according to the lung function. Sputum was collected during their stable phase, followed by DNA extraction, untargeted metagenomic next-generation sequencing (mNGS) and bioinformatic analysis. RESULTS: mNGS identified 3355 bacteria, 71 viruses and 22 fungi at the specie level. It was found that Shannon index and Simpson index in FE group was lower than that in NFE group (p = 0.005, 0.008, respectively) but similar between mild and severe groups. Out of top 10 bacteria taxa, Veillonella, Fusobacterium and Prevotella jejuni had a higher abundance in NFE group, Rothia had a higher abundance in mild group. Linear discriminant analysis revealed that many bacterial taxa were more abundant in NFE group, and they mostly belonged to Actinobacteria, Bacteroidetes and Fusobacteria phyla. Frequency of exacerbations was also found to be negatively correlated with alpha diversity (with Shannon index, r = - 0.423, p = 0.009; with Simpson index, r = - 0.482, p = 0.002). No significant correlation was observed between alpha diversity and FEV1/pre. CONCLUSIONS: Microbiome diversity in FE group was lower than that in NFE group. There was a significant difference in microbiome taxa abundance between FE and NFE groups, or mild and severe groups. These findings demonstrated that sputum microbiome community dysbiosis was associated with different exacerbation frequencies and lung function in stable COPD.

Sequence Type 5 (ST5) as a Possible Predictor of Bacterial Persistence in Adult Patients with Methicillin-Resistant Staphylococcus aureus Pneumonia Treated with Vancomycin.

Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.

Translation and validation of the Chinese version of Patient-completed Asthma Knowledge Questionnaire and its implementation in patient education.

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 (χ2/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.

Revealing consensus gene pathways associated with respiratory functions and disrupted by PM2.5 nitrate exposure at bulk tissue and single cell resolution.

BACKGROUND: Nitrate is a major pollutant component in ambient PM2.5. It is known that chronic exposure to PM2.5 NO3- damages respiratory functions. We aim to explore the underlying toxicological mechanism at single cell resolution. METHODS: We systematically conducted exposure experiments on forty C57BL/6 mice, assessed respiratory functions, and profiled lung transcriptome. . Afterward, we estimated the cell type compositions from RNA-seq data using deconvolution analysis. The genes and pathways associated with respiratory function and dysregulated by to PM2.5 NO3- exposure were characterized at bulk-tissue and single-cell resolution. RESULTS: PM2.5 NO3- exposure did not significantly modify the cell type composition in lung, but profoundly altered the gene expression within each cell type. At ambient concentration (22 µg/m3), exposure significantly (FDR<10%) altered 95 genes' expression. Among the genes associated with respiratory functions, a large fraction (74.6-91.7%) were significantly perturbed by PM2.5 NO3- exposure. For example, among the 764 genes associated with peak expiratory flow (PEF), 608 (79.6%) were affected by exposure (p = 1.92e-345). Pathways known to play role in lung disease pathogenesis, including circadian rhythms, sphingolipid metabolism, immune response and lysosome, were found significantly associated with respiratory functions and disrupted by PM2.5 NO3- exposure. CONCLUSIONS: This study extended our knowledge of PM2.5 NO3- exposure's effect to the levels of lung gene expression, pathways, lung cell type composition and cell specific transcriptome. At single cell resolution, we provided insights in toxicological mechanism of PM2.5 NO3- exposure and subsequent pulmonary disease risks.

Chronic Exposure to PM2.5 Nitrate, Sulfate, and Ammonium Causes Respiratory System Impairments in Mice.

Water-soluble inorganic (WSI) ions are major components of ambient air PM2.5 (particulate matter of diameter ≤2.5 µm); however, their potential health effects are understudied. On C57BL/6 mice, we quantified the effect of three major PM2.5 WSIs (NO3-, SO42-, and NH4+) on respiratory systems. Exposure scenarios include different WSI types, concentrations, animal development stages (young vs adult), and sex. The exposure effects were comprehensively assessed, with special focus on the respiratory function and tissue/cell level changes. Chronic PM2.5 NO3- exposure produced significant respiratory function decline, mainly presented as airflow obstruction. The decline was more profound in young mice than in adult mice. In young mice, exposure to 22 µg/m3 PM2.5 NO3- reduced FEV0.05 (forced expiratory volume in 0.05 s) by 11.3% (p = 9.6 × 10-3) and increased pulmonary neutrophil infiltration by 7.9% (p = 7.1 × 10-3). Causality tests identified that neutrophil infiltration was involved in the biological mechanism underlying PM2.5 NO3- toxicity. In contrast, the effects of PM2.5 SO42- were considerably weaker than NO3-. PM2.5 NO3- exposure was 3.4 times more potent than PM2.5 SO42- in causing reduction of the peak expiratory flow. PM2.5 NH4+ exposure had no statistically significant effects on the respiratory function. In summary, this study provided strong evidence on the adverse impacts of PM2.5 WSIs, where the impacts were most profound in young mice exposed to PM2.5 NO3-. If confirmed in humans, toxicity of PM2.5 WSI will have broad implications in environment health and policy making.

Assessing risk factors for SARS-CoV-2 infection in patients presenting with symptoms in Shanghai, China: a multicentre, observational cohort study.

Background: The outbreak of COVID-19 has led to international concern. We aimed to establish an effective screening strategy in Shanghai, China, to aid early identification of patients with COVID-19. Methods: We did a multicentre, observational cohort study in fever clinics of 25 hospitals in 16 districts of Shanghai. All patients visiting the clinics within the study period were included. A strategy for COVID-19 screening was presented and then suspected cases were monitored and analysed until they were confirmed as cases or excluded. Logistic regression was used to determine the risk factors of COVID-19. Findings: We enrolled patients visiting fever clinics from Jan 17 to Feb 16, 2020. Among 53 617 patients visiting fever clinics, 1004 (1·9%) were considered as suspected cases, with 188 (0·4% of all patients, 18·7% of suspected cases) eventually diagnosed as confirmed cases. 154 patients with missing data were excluded from the analysis. Exposure history (odds ratio [OR] 4·16, 95% CI 2·74-6·33; p<0·0001), fatigue (OR 1·56, 1·01-2·41; p=0·043), white blood cell count less than 4 × 109 per L (OR 2·44, 1·28-4·64; p=0·0066), lymphocyte count less than 0·8 × 109 per L (OR 1·82, 1·00-3·31; p=0·049), ground glass opacity (OR 1·95, 1·32-2·89; p=0·0009), and having both lungs affected (OR 1·54, 1·04-2·28; p=0·032) were independent risk factors for confirmed COVID-19. Interpretation: The screening strategy was effective for confirming or excluding COVID-19 during the spread of this contagious disease. Relevant independent risk factors identified in this study might be helpful for early recognition of the disease. Funding: National Natural Science Foundation of China.

Comparative Analysis of Early-Stage Clinical Features Between COVID-19 and Influenza A H1N1 Virus Pneumonia.

Introduction: Influenza virus pneumonia and COVID-19 are two different types of respiratory viral pneumonia but with very similar clinical manifestations. The aim of the present study was to help clinicians gain a better understanding about differences between Influenza virus pneumonia and COVID-19 by comparative analysis of the early-stage clinical features. Methods: Clinical data of patients with confirmed diagnosis of COVID-19 and influenza A pneumonia identified in our hospital were collected and analyzed retrospectively to identify the clinical features that could differentiate between the two types of viral pneumonia. Results: The two types of viral pneumonia mainly affected adults, especially people over 50 years, with no gender difference between them. Fever, cough, sputum and muscle soreness were the most common symptoms of COVID-19. Some patients with COVID-19 may also exhibit digestive tract symptoms. Elevation of C-reactive protein (CRP) was a more common phenomenon in patients with COVID-19 than that in patients with influenza A H1N1 virus pneumonia. In addition, eosinophil count was decreased and the monocyte percentage was increased in COVID-19 patients. The grid-form shadow was a typical presentation of COVID-19 on the lung CT image, and the disease usually progressed quickly within a week. Conclusion: Influenza pneumonia and COVID-19 are two different types of respiratory viral pneumonia with very similar clinical manifestations. The percentage of monocytes is increased and the eosinophil count is decreased in COVID-19. Glass-ground density exudation shadow located peripherally is the typical sign of COVID-19 on the lung CT image, and the shadow often with grid-form sign. These features may not be typically observed in patients with influenza pneumonia. Chest CT scan combined with nucleic acid detection is an effective and accurate method for diagnosing COVID-19. Blood routine test has a limited diagnostic value in differentiating the two forms of pneumonia.

Adenylyl cyclase­associated protein 1­targeted nanoparticles as a novel strategy for the treatment of metastatic non­small cell lung cancer.

Non­small cell lung cancer (NSCLC) is one of the most fatal cancers worldwide. Adenylyl cyclase­associated protein 1 (CAP1) belongs to a family of cyclase­associated proteins that are involved in the development of cancerous tumors. A previous study by our group confirmed the association between CAP1, lung cancer and the metastasis of cancer cells. In the present study, poly(lactic­polyglycolic acid; PLGA)/CAP1­small interfering (si)RNA nanoparticles were prepared and delivered into A549 cells. The performance of PLGA/siCAP1­siRNA nanoparticles for siRNA delivery was measured based on the results of migration assay and animal experiments. The multifunctional nanoparticles were determined to be capable of inhibiting CAP1 expression, which reduced NSCLC metastasis in vitro and in vivo. Therefore, the findings of the current study highlighted the potential use of PLGA/siCAP1­siRNA nanoparticles for the treatment of NSCLC metastasis.

Evaluation of efficacy and nephrotoxicity during vancomycin therapy: A retrospective study in China.

The aim of the present study was to investigate the predictive value of vancomycin serum concentrations regarding its efficacy and nephrotoxicity in a Chinese population and to determine a relatively safe optimal target concentration during vancomycin therapy. A total of 65 patients that received vancomycin between March 2013 and March 2018 at Shanghai 10th People's Hospital (Shanghai, China) were enrolled and their vancomycin trough and peak concentrations were monitored. Factor analysis was performed in order to exclude interaction between variables. Univariate and multivariate analyses were used to identify predictors of drug efficacy and nephrotoxicity. Receiver operating characteristic curve analysis was performed to determine the thresholds of the vancomycin trough and peak concentrations for optimal efficacy and acceptable nephrotoxicity, respectively. Among the 65 cases, treatment was deemed to be effective for 43 patients and ineffective for 22 patients. Furthermore, 20 patients fulfilled the criteria for nephrotoxicity. A total of 15 continuous variables loaded the first five factors by factor analysis (which converts large numbers of highly inter-correlated variables into a small number of comprehensive indicators that reflect a dimensionality reduction) and the factors were as follows: Inflammation, renal function, liver function, vancomycin trough and peak concentrations, and nutritional status. Univariate and multivariate analyses identified the trough concentration and peak concentration as independent variables associated with efficacy and nephrotoxicity of vancomycin, and the nutritional status was a risk factor associated with efficacy. Regarding efficacy, the critical values for the trough concentration and peak concentration were determined to be 9.02 mg/l (95.3% sensitivity and 68.2% specificity) and 23.62 mg/l (83.7% sensitivity and 59.1% specificity), respectively. The thresholds of vancomycin trough and peak concentrations for the development of nephrotoxicity were 16.08 mg/l (80.0% sensitivity and 84.4% specificity) and 30.42 mg/l (75.0% sensitivity and 73.3% specificity), respectively. In conclusion, during vancomycin therapy, the trough and peak concentrations are associated with efficacy and nephrotoxicity. Furthermore, a trough concentration between 9.02 and 16.08 mg/l and a peak concentration of 23.62-30.42 mg/l were determined to be relatively safe (the clinical trial registry no. ChiCTR-OPC-16007920).

A Prospective Multicenter Clinical Observational Study on Vancomycin Efficiency and Safety With Therapeutic Drug Monitoring.

Background: Vancomycin is a first-line antibiotic used for the treatment of severe gram-positive bacterial infections. Clinical guidelines recommend that the vancomycin trough concentration be 10-15 mg/L for regular infections and 15-20 mg/L for severe infections. We investigated whether increasing the vancomycin concentration would result in better clinical outcomes with sustainable adverse effects (AEs) in the Chinese population. Methods: A prospective, open, multicenter clinical observational study was performed in patients with gram-positive bacterial infections from 13 teaching hospitals. Patients received vancomycin therapeutic drug monitoring. Clinical, microbiological, and laboratory data were collected. Results: In total, 510 patients were enrolled, and 470 were evaluable, of whom 370 were adults and 100 were children; 35.53% had methicillin-resistant Staphylococcus aureus infections (vancomycin 50% minimum inhibitory concentration [MIC50] = 1, 90% minimum inhibitory concentration [MIC90] = 1), and 23.19% had Enterococcus species infections (vancomycin MIC50 = 1, MIC90 = 2). The average trough concentration was 10.54 ± 8.08 mg/L in adults and 6.74 ± 8.93 mg/L in children. The infection was eradicated in 86.22% of adults and 96% of children. Thirty-six vancomycin-related nephrotoxicity cases were reported in the enrolled population. No severe AEs or deaths were related to vancomycin therapy. Logistic regression analysis showed that trough concentration had no relationship with clinical outcomes (adults P = .75, children P = .68) but was correlated with adult nephrotoxicity (P < .0001). Vancomycin trough concentration had an applicable cut point at 13 mg/L. Conclusions: Our study shows that vancomycin trough concentration has no statistical correlation with clinical outcomes, and is an indicator of nephrotoxicity in the observed population. We found no evidence that increasing vancomycin trough concentration to 15-20 mg/L can benefit Chinese patients with complicated infections. Clinical Trials Registration: ChiCTR-OPC-16007920.

Model-based Evaluation of the Clinical and Microbiological Efficacy of Vancomycin: A Prospective Study of Chinese Adult In-house Patients.

Background: Our aims in this prospective study were to evaluate the correlations between pharmacokinetic/pharmacodynamic (PK/PD) indices and the clinical/microbiological efficacy of vancomycin and to identify an appropriate PK/PD target in the Chinese population to guide vancomycin treatment in the clinic. Methods: Adult patients from 11 hospitals in China with gram-positive infections who received vancomycin therapy for ≥5 days and who were under therapeutic drug monitoring (TDM) were enrolled in this study. A 1-compartment population PK model was established and validated. The correlations between PK/PD indices (Cmin, Cmax, 0-24 hour area under the curve (AUC0-24), and AUC0-24/minimum inhibitory concentration (MIC) and clinical outcomes (clinical efficacy and bacterial eradication) were evaluated. Results: In total, 402 adult Chinese patients were enrolled. Among them, 380 patients were evaluable for PK analysis, and 334 were evaluable for PK/PD analysis. In the final population PK model, creatinine clearance (CLCR) was the significant covariate on CL (typical value, 3.87 L/hour; between-subject variability (BSV), 12.5%), and age was the significant covariate on volume of distribution (V) (typical value, 45.1 L; BSV, 24.8%). The univariate analysis showed that Cmax, AUC0-24, and AUC0-24/MIC were significantly different or marginally significantly different (P values were 0.009, 0.0385, and 0.0509, respectively) between microbiological outcome groups with coagulase-negative Staphylococcus infections. However, there were no significant differences (P > .05) in the above PK parameters by multivariate logistic regression analysis, indicating there was no independently associated factor. Conclusions: No significant correlations were identified between PK/PD indices and the clinical or microbiological efficacy of vancomycin in Chinese patients. The necessity of vancomycin TDM based on trough concentration and the current treatment target of AUC0-24/MIC ≥400 need to be further evaluated and confirmed in additional prospective studies.

CDK5 Functions as a Tumor Promoter in Human Lung Cancer.

Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, plays an important role in the nervous system. Recent studies have shown that CDK5 is also associated with tumors. However, few studies have been done to investigate the mechanism underlying the connection between CDK5 and cancers. To explore the role of CDK5 in cancers by using an extensive bioinformatics data mining process. We mined the transcriptional, survival, functions and structure of CDK5 gene through databases and in vitro experiments. We found that higher CDK5 expression levels in most cancer cell lines while lower expression in liver and brain cancer cell lines. High expression of CDK5 was associated with shorter overall survival (OS) in lung cancer. In addition, high expression level of CDK5 promoted lung cancer cells proliferation and metastasis. Inhibited CDK5 decreases CAP1 phosphorylation. CDK5 may prove to be a valid target of anticancer therapies.

Chinese expert consensus on diagnosis and management of acquired respiratory-digestive tract fistulas.

Acquired respiratory-digestive tract fistulas occur with abnormal communication between the airways and digestive tract, causing the interflow of gas and liquid. Despite advances in surgical methods and the development of multimodal therapy in recent years, patients with acquired respiratory-digestive tract fistulas continue to exhibit unfavorable clinical outcomes. Therefore, in order to guide clinical practice in China, the Respiratory and Cancer Intervention Alliance of the Beijing Health Promotion Association organized a group of experienced experts in the field to develop this consensus document. Based on a study of clinical application and expert experience in the diagnosis and management of acquired respiratory-digestive tract fistulas at home and abroad, an Expert Consensus was developed. The panelists recruited comprised experts in pulmonology, oncology, thoracic surgery, interventional radiology, and gastroenterology. PubMed, Chinese Biology Abstract, Chinese Academic Journal, and Wanfang databases were used to identify relevant articles. The guidelines address etiology, classification, pathogenesis, diagnosis and management of acquired respiratory-digestive tract fistulas. The statements on treatment focus on the indications for different procedures, technical aspects, and preprocedural, post-procedural and complication management. The proposed guidelines for the diagnosis and management of acquired respiratory-digestive tract fistulas are the first to be published by Chinese experts. These guidelines provide an in-depth review of the current evidence and standard of diagnosis and management.

Evaluation of the predictive value of red blood cell distribution width for onset of cerebral infarction in the patients with obstructive sleep apnea hypopnea syndrome.

Red blood cell distribution width (RDW) is a risk factor for the complications caused by obstructive sleep apnea hypopnea syndrome (OSAHS). This study was aimed to evaluate the predictive value of RDW for the occurrence of cerebral infarction in patients with OSAHS.We conducted a prospective study of 129 consecutive patients who were admitted to the Sleep Laboratory of in the Tenth People's Hospital of Shanghai (China) with complaints of snoring, apnea, or daytime sleepiness. All patients underwent polysomnography between June 2011 and May 2012. In total, 90 patients met the study criteria and were included in the study; there are 71 men and 19 women.RDW correlated positively with the apnea hypopnea index (AHI) (P = .00, r = 0.76). Logistic regression analysis showed correlations between each variation and cerebral infarction, high blood pressure (odds ratio [OR] = 4.72, P = .220), diabetes (OR = 2.67, P = .490), hyperlipidemia (OR = 7.42, P = .190), RDW (OR = 58.24, P = .020), and AHI (OR = 243.92, P = .001). RDW ≥ 15% showed a higher predictive value for the occurrence of cerebral infarction in patients with OSAHS (area under curve 0.837; sensitivity 0.919; specificity 0.755), with positive and negative predictive values of 0.697 and 0.938, respectively.RDW correlates positively with AHI. RDW values ≥15% are predictive for the occurrence of cerebral infarction in patients with OSAHS.

Systematic analysis of gene expression alterations and clinical outcomes of adenylate cyclase-associated protein in cancer.

Adenylate Cyclase-associated protein (CAP) is an evolutionarily conserved protein that regulates actin dynamics. Our previous study indicates that CAP1 is overexpressed in NSCLC tissues and correlated with poor clinical outcomes, but CAP1 in HeLa cells actually inhibited migration and invasion, the role of CAP was discrepancy in different cancer types. The present study aims to determine whether CAP can serve as a prognostic marker in human cancers. The CAP expression was assessed using Oncomine database to determine the gene alteration during carcinogenesis, the copy number alteration, or mutations of CAP using cBioPortal, International Cancer Genome Consortium, and Tumorscape database investigated, and the association between CAP expression and the survival of cancer patient using Kaplan-Meier plotter and PrognoScan database evaluated. Therefore, the functional correlation between CAP expression and cancer phenotypes can be established; wherein CAP might serve as a diagnostic marker or therapeutic target for certain types of cancers.

The mechanisms and significance of up-regulation of RhoB expression by hypoxia and glucocorticoid in rat lung and A549 cells.

Small guanosine triphosphate (GTP)-binding protein RhoB is an important stress sensor and contributes to the regulation of cytoskeletal organization, cell proliferation and survival. However, whether RhoB is involved in the hypoxic response and action of glucocorticoid (GC) is largely unknown. In this study, we investigated the effects of hypoxia or/and GC on the expression and activition of RhoB in the lung of rats and human A549 lung carcinoma cells, and further studied its mechanism and significance. We found that hypoxia and dexamethasone (Dex), a synethic GC, not only significantly increased the expression and activation of RhoB independently but also coregulated the expresion of RhoB in vitro and in vivo. Up-regulation of RhoB by hypoxia was in part through stabilizing the RhoB mRNA and protein. Inhibiting hypoxia-activated hypoxia-inducible transcription factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) with their specific inhibitors significantly decreased hypoxia-induced RhoB expression, indicating that HIF-1α, JNK and ERK are involved in the up-regulation of RhoB in hypoxia. Furthermore, we found that knockdown of RhoB expression by RhoB siRNA not only significantly reduced hypoxia-enhanced cell migration and cell survival in hypoxia but also increased the sensitivity of cell to paclitaxel (PTX), a chemotherapeutic agent, and reduced Dex-enhanced resistance to PTX-chemotherapy in A549 cells. Taken together, the novel data revealed that hypoxia and Dex increased the expression and activation of RhoB, which is important for hypoxic adaptation and hypoxia-accelerated progression of lung cancer cells. RhoB also enhanced the resistance of cell to PTX-chemotherapy and mediated the pro-survival effect of Dex.