Objective:To investigate the therapeutic effects of the copper chelator ammonium tetrathiomolybdate (TTM) on rheumatoid arthritis (RA) in a mouse model.Methods:Twenty-four male dilution brown non-Agoutia/1 mice were randomly divided into 4 groups: a blank control group (Ctrl group, n=6), a collagen-induced arthritis (CIA) + phosphate buffer saline (PBS) treatment group (PBS group, n=6), a CIA+TTM treatment group (TTM group, n=6), and a CIA+Elesclomol treatment group (Eles group, n=6). Eles, a copper ion carrier, served as a control for administration of TTM, a copper ion chelator. One week after treatment, the swelling of mouse paw was observed, and the clinical scoring of the arthritis in mice was evaluated once a week. Paw mechanical pain detection was performed and photographs were taken to observe the severity of paw swelling before the mice were sacrificed. Catwalk gait analysis system was used to evaluate the gait changes in mice. HE and saffron O solid green staining were used to evaluate pathomorphologic changes in the mice knee joints and paws. Immunostaining techniques were used to detect the protein expression of MMP3, CD31, and VEGF in the mice paws. Luminex technology was used to detect alterations in the serum inflammatory factors. Results:Compared with the Ctrl group, in the PBS and Eles groups, the joints were red, swollen and deformed; the arthritis clinical scores were significantly higher; the bone destruction, synovial hyperplasia and inflammatory cell infiltration and pathological changes in the joint tissues were obvious; the expression levels of inflammatory factors, such as serum MCP-1, IL-1 β, IL-9, and IFN- γ, were significantly higher while the expression level of IL-10 was significantly lower. Simultaneously, the expression of CD31 and VEGF factors was significantly enhanced. Compared with the PBS group, in the TTM group, the joint swelling and deformation were significantly improved, the arthritis clinical score was reduced, and the joint bone destruction, inflammatory cell infiltration and synovial hyperplasia were alleviated, and the levels of serum MCP-1, IL-1 β, IL-9 and IFN- γ were significantly decreased while the level of anti-inflammatory factor IL-10 was increased. There was no significant difference in the expression of MMP-3, CD31 or VEGF factors between the CTRL group and the TTM group. Conclusion:TTM can block synovial inflammation, angiogenesis, and bone destruction multiple times by simultaneously targeting multiple inflammatory factors, VEGF factors, and bone destruction mediators, thereby alleviating the pathological damage to the joint tissues induced by CIA in RA mice.

Objective:To investigate the therapeutic effects of the copper chelator ammonium tetrathiomolybdate (TTM) on rheumatoid arthritis (RA) in a mouse model.Methods:Twenty-four male dilution brown non-Agoutia/1 mice were randomly divided into 4 groups: a blank control group (Ctrl group, n=6), a collagen-induced arthritis (CIA) + phosphate buffer saline (PBS) treatment group (PBS group, n=6), a CIA+TTM treatment group (TTM group, n=6), and a CIA+Elesclomol treatment group (Eles group, n=6). Eles, a copper ion carrier, served as a control for administration of TTM, a copper ion chelator. One week after treatment, the swelling of mouse paw was observed, and the clinical scoring of the arthritis in mice was evaluated once a week. Paw mechanical pain detection was performed and photographs were taken to observe the severity of paw swelling before the mice were sacrificed. Catwalk gait analysis system was used to evaluate the gait changes in mice. HE and saffron O solid green staining were used to evaluate pathomorphologic changes in the mice knee joints and paws. Immunostaining techniques were used to detect the protein expression of MMP3, CD31, and VEGF in the mice paws. Luminex technology was used to detect alterations in the serum inflammatory factors. Results:Compared with the Ctrl group, in the PBS and Eles groups, the joints were red, swollen and deformed; the arthritis clinical scores were significantly higher; the bone destruction, synovial hyperplasia and inflammatory cell infiltration and pathological changes in the joint tissues were obvious; the expression levels of inflammatory factors, such as serum MCP-1, IL-1 β, IL-9, and IFN- γ, were significantly higher while the expression level of IL-10 was significantly lower. Simultaneously, the expression of CD31 and VEGF factors was significantly enhanced. Compared with the PBS group, in the TTM group, the joint swelling and deformation were significantly improved, the arthritis clinical score was reduced, and the joint bone destruction, inflammatory cell infiltration and synovial hyperplasia were alleviated, and the levels of serum MCP-1, IL-1 β, IL-9 and IFN- γ were significantly decreased while the level of anti-inflammatory factor IL-10 was increased. There was no significant difference in the expression of MMP-3, CD31 or VEGF factors between the CTRL group and the TTM group. Conclusion:TTM can block synovial inflammation, angiogenesis, and bone destruction multiple times by simultaneously targeting multiple inflammatory factors, VEGF factors, and bone destruction mediators, thereby alleviating the pathological damage to the joint tissues induced by CIA in RA mice.

Background/Aims: Metabolic syndrome is common in patients with acute pancreatitis and its components have been reported to be associated with infectious complications. In this post hoc analysis, we aimed to evaluate whether metabolic abnormalities impact the effect of immuneenhancing thymosin alpha-1 (Tα1) therapy in acute necrotizing pancreatitis (ANP) patients. Methods: All data were obtained from the database for a multicenter randomized clinical trial that evaluated the efficacy of Tα1 in ANP patients. Patients who discontinued the Tα1 treatment prematurely were excluded. The primary outcome was 90-day infected pancreatic necrosis (IPN) after randomization. Three post hoc subgroups were defined based on the presence of hyperglycemia, hypertriglyceridemia, or both at the time of randomization. In each subgroup, the correlation between Tα1 and 90-day IPN was assessed using the Cox proportional-hazards regression model. Multivariable propensity-score methods were used to control potential bias. Results: Overall, 502 participants were included in this post hoc analysis (248 received Tα1 treatment and 254 received matching placebo treatment). Among them, 271 (54.0%) had hyperglycemia, 371 (73.9%) had hypertriglyceridemia and 229 (45.6%) had both. Tα1 therapy was associated with reduced incidence of IPN among patients with hyperglycemia (18.8% vs 29.7%: hazard ratio, 0.80; 95% confidence interval, 0.37 to 0.97; p=0.03), but not in the other subgroups. Additional multivariate regression models using three propensity-score methods yielded similar results. Conclusions Among ANP patients with hyperglycemia, immune-enhancing Tα1 treatment was associated with a reduced risk of IPN (ClinicalTrials.gov, Registry number: NCT02473406).

Objective:To investigate the urine output threshold of acute kidney injury in patients with acute pancreatitis(AP) and to guide early fluid therapy.Methods:The clinical data of AP patients from Medical Information Mart for Intensive Care Ⅳ (MIMIC-Ⅳ) were collected. The 24-h urine output rate [24-h urine output·kg-1·24-h-1, 24-UR mL/ (kg·h) ] and 48-h urine output rate [48-h urine output·kg-1·48-h-1, 48-UR mL/ (kg·h) ] were calculated, and according to the occurrence of acute kidney injury within 7 days (7-AKI), AP patients were divided into the 7-AKI group and non-7-AKI group. The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of 24-UR and 48-UR on 7-AKI in AP patients. 24-UR and 48-UR were grouped according to the optimal cut-off value obtained from the ROC curve. Logistic regression was used to analyze the risk factors of 7-AKI, and Kaplan-Meier (KM) survival curve was drawn to analyze the effect of 24-UR and 48-UR on in-hospital mortality of AP patients.Results:A total of 713 AP patients were included, ROC curve analysis showed that the area under the ROC curve (AUC) of 24-UR in predicting 7-AKI in AP patients was 0.76. Based on the maximum Youden index, the cut-off value of 24-UR was 0.795 mL/ (kg·h) , and the AUC of 48-UR was 0.78 and the cut-off value of 48-UR was 0.975 mL/ (kg·h) . Logistic regression analysis showed that 24-UR≤0.795 mL/ (kg·h) was an independent risk factor for 7-AKI compared with 24-UR>0.795 mL/ (kg·h) ( OR: 4.22, 95% CI:1.50-11.85, P=0.006). Similarly, compared with 48-UR>0.975 mL/ (kg·h) , 48-UR0.975 mL/ (kg·h) was an independent risk factor for 7-AKI ( OR: 3.75, 95% CI: 1.45-9.72, P=0.007). The KM survival curve showed that the cumulative in-hospital survival rate in the high 24-UR group was higher than that in the low 24-UR group. Conclusions:24-UR can be used to guide early fluid therapy in AP patients.

Objective:To investigate the blood pressure change in patients with acute ischemic stroke (AIS) and hypertension treated with cinepazide maleate injection.Methods:This was a subgroup analysis of post-marketing clinical confirmation study of cinepazide maleate injection for acute ischemic stroke: a randomized, double-blinded, multicenter, placebo-parallel controlled trial, which conducted in China from August 2016 to February 2019. Eligible patients fulfilled the inclusive criteria of acute anterior circulation ischemic stroke with National Institutes of Health Stroke Scale (NIHSS) scores of 7-25. The primary endpoints were mean blood pressure of AIS patients treated with cinepazide maleate or control, which were assessed during the treatment period (14 days), and the proportion of the patients with normal blood pressure was analyzed after the treatment period. Furthermore, a subgroup analysis was performed to investigate a possible effect of the history of hypertension on outcomes.Results:This analysis included 809 patients with hypertension. There was no significant difference in patients blood pressure and the proportion of patients with normal blood pressure (60.5% vs. 59.0%, P>0.05) between cinepazide maleate group and control group. Conclusion:Administration of cinepazide maleate injection does not affect the management of clinical blood pressure in patients with AIS.

Objective:To evaluate the effect of invasive arterial blood pressure (IBP) monitoring on the prognosis of patients with sepsis.Methods:Patients with sepsis from the MIMIC-Ⅳ database were collected and divided into IBP and non-invasive blood pressure monitoring (NIBP) groups according to whether IBP monitoring was performed. Baseline variables that were considered clinically relevant or showed a univariate relationship with the outcome were entered into a multivariate logistic regression model as covariates.Propensity score matching(PSM) and inverse probability of treatment weighing(IPTW) were used to adjust confounders to ensure the robustness of findings.Subgroup analysis were conducted to evaluate the effect of differences in IBP onset and duration on outcome.Results:The 28-day mortality is lower in IBP group compared with NIBP group( OR=0.54, 95% CI 0.46-0.62, P<0.001), the conclusion maintain robust after PSM and IPTW.Then we conducted a series of logistic regression regarding to different initial IBP time(<24 h,24 h-48 h,>48 h) and the initial IBP time within 24 h showed the same results compared to primary outcoms( OR=0.42, 95% CI: 0.36-0.49, P<0.001). IBP duration varied (≤1day, ≤2days, ≤3days, ≤4days, >4days) all showed a statistically significant association with decreased 28-day mortality in the IBP group. Conclusions:IBP is associated with decreased 28-day mortality in patients with sepsis, and the optimal time of IBP is within 24 hours.

Antimicrobial resistance is a serious problem for anti-infective treatment. Molecular technology can quickly, sensitively and accurately detect the mechanism of drug resistance of bacteria, improving the efficacy of anti-infection treatment and the level of infection control. The construction of quality assurance system is a guarantee for the effective application of molecular diagnostic technology in the detection of bacterial resistance. However, due to the complex mechanism of drug resistance, coupled with genetic mutations and other factors, there are problems such as false negatives, false positives, and inconsistency between mechanisms and phenotypes, there are certain restrictions on the application of molecular detection technology. With the development of molecular technology and deepening of people′s understanding of the drug resistance mechanism, the application of molecular diagnostic technology in the detection of bacterial resistance will be more widespread.

Objective To investigate the antimicrobial resistance profile of the clinical isolates collected from selected hospitals across China. Methods Twenty-nine general hospitals and five children's hospitals were involved in this program. Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems. Results were interpreted according to CLSI 2017 breakpoints. Results A total of 190 610 clinical isolates were collected from January to December 2017, of which gram negative organisms accounted for 70.8％ (134 951/190 610) and gram positive cocci 29.2％ (55 649/190 610). The prevalence of methicillin-resistant strains was 35.3％ in S. aureus (MRSA) and 80.3％ in coagulase negative Staphylococcus (MRCNS) on average. MR strains showed much higher resistance rates to most of the other antimicrobial agents than MS strains. However, 91.6％ of MRSA strains were still susceptible to trimethoprim-sulfamethoxazole, while 86.2％ of MRCNS strains were susceptible to rifampin. No staphylococcal strains were found resistant to vancomycin. E. faecalis strains showed much lower resistance rates to most of the drugs tested (except chloramphenicol) than E. faecium. Vancomycin-resistant Enterococcus (VRE) was identified in both E. faecalis and E. faecium. The identified VRE strains were mainly vanA, vanB or vanM type based on phenotype or genotype. The proportion of PSSP or PRSP strains in the non-meningitis S.pneumoniae strains isolated from children decreased but the proportion of PISP strains increased when compared to the data of 2016. Enterobacteriaceae strains were still highly susceptible to carbapenems. Overall, less than 10％ of these strains (excluding Klebsiella spp.) were resistant to carbapenems. The prevalence of imipenem-resistant K. pneumoniae increased from 3.0％ in 2005 to 20.9％ in 2017, and meropenem-resistant K. pneumoniae increased from 2.9％ in 2005 to 24.0％ in 2017, more than 8-fold increase. About 66.7％ and 69.3％ of Acinetobacter (A. baumannii accounts for 91.5％) strains were resistant to imipenem and meropenem, respectively. Compared with the data of year 2016, P. aeruginosa strains showed decreasing resistance rate to carbapenems. Conclusions Bacterial resistance is still on the rise. It is necessary to strengthen hospital infection control and stewardship of antimicrobial agents. The communication between laboratorians and clinicians should be further improved in addition to surveillance of bacterial resistance.

Objective To evaluate the changing pattern of antibiotic resistance inKlebsiella strains isolated from the patients in 19 hospitals across China based on the data from CHINET Antimicrobial Resistance Surveillance Program during the period from 2005 through 2014.Methods Kirby-Bauer disk diffusion and automated susceptibility testing methods were used to test the susceptibility ofKlebsiella isolates to the commonly used antibiotics. The results were interpreted according to the criteria of the Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing (CLSI-2014).Results A total of 61 406Klebsiella strains were identified between 2005 and 2014, includingK. pneumoniae (56 281 strains), K. oxytoca(4 779),Klebsiella pneumoniae subsp.Ozaenae (300) and otherKlebsiella species (46). Most (89.0%, 54 664/61 406) of theKlebsiella strains were isolated from inpatients, and 60.0% (36 835/61 406) were from respiratory tract speciems. About 16.7% (10 248/61 406) of the strains were isolated from pediatric patients aged 0-17 years and 83.3% (51 158/61 406) from adult patients. The prevalence ofKlebsiella spp. increased with time from 10.1% in 2005 to 14.3% in 2014. Based on the surveillance data during the 10-year period, we found a marked increase of resistance to imipenem (2.9% to 10.5%) and meropenem (2.8% to 13.4%) inKlebsiella spp. The prevalence of ESBLs-producing isolates inK. pneumoniae andK. oxytoca decreased from 39.0% in 2005 to 30.1% in 2014. The resistance to amikacin, ceftazidime, ciprolfoxacin, pipracillin-tazobactam and cefoperazone-sulbactam was on decline. The resistance rate to cefotaxime remained high about 49.5%. Carbapenem resistantance was identiifed in 5 796 (9.4%) of the isolates, including 5 492 strains ofK. pneumoniae and 280 strains ofK. oxytoca. Overall, 4 740 (7.8%) strains were identiifed as extensively-drug resistant (XDR), including 4 520 strains ofK. pneumoniae and 202 strains ofK. oxytoca. The carbapenem-resistant strains showed high (>60%) resistance rate to majority of the antimicrobial agents tested, but relatively low resistance to tigecycline (16.8%), amikacin (54.4%), and trimethoprim-sulfamethoxazole (55.5%).Conclusions During the 10-year period from 2005 through 2014, carbapenem resistance amongKlebsiella isolates has increased dramatically in the hospitals across China. The level of resistance to other antibiotics remains stable.

Objective To investigate the susceptibility and resistance of clinical isolates collected from hospitals in several regions of China . Methods Fourteen general hospitals and two children ’ s hospitals were involved in this program . Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated Systems .Results were analyzed according to CLSI 2013 breakpoints .Results A total of 84 572 clinical isolates were collected from January to December 2013 ,of which gram negative organisms and gram positive cocci accounted for 73 .0% and 27 .0%respectively .Methicillin-resistant strains in S .aureus (MRSA) and coagulase negative Staphylococcus (MRCNS) accounted for an average of 45 .2% and 73 .5% respectively .The resistance rates of methicillin-resistant strains to β-lactams and other antimicrobial agents were much higher than those of methicillin-susceptible strains .However ,92 .2% of MRSA strains were still susceptible to trimethoprim-sulfamethoxazole while 87 .4% of MRCNS strains were susceptible to rifampin . No staphylococcal strains were found resistant to vancomycin ,teicoplanin or linezolid .In Enterococcus spp .,the resistance rates of E . f aecalis strains to most tested drugs (except chloramphenicol) were much lower than those of E . f aecium .Some strains of both species were resistant to vancomycin .Vancomycin-resistant strains of E . f aecalis and E . f aecium were mainly VanA type based on their phenotype .Regarding non-meningitis S . pneumoniae strains ,the prevalence of penicillin-susceptible S . pneumoniae and penicillin-intermediate S . pneumoniae strains isolated from both adults and children were lower than those isolated in 2012 ,but the prevalence of penicillin-resistant S .pneumoniae strains increased .The prevalence of ESBLs producing strains was 54 .0% in E .coli ,31 .8% in Klebsiella spp .(K .pneumoniae and K .oxytoca) and 16 .5% in Proteus mirabilis isolates on average . ESBLs-producing Enterobacteriaceae strains were more resistant than non-ESBLs-producing strains in terms of antibiotic resistance rates .The strains of Enterobacteriaceae were still highly susceptible to carbapenems .Overall less than 7 .0% of these strains were resistant to carbapenems .About 62 .8% and 59 .4% of Acinetobacter spp .(A .baumannii accounts for 89 .2% ) strains were resistant to imipenem and meropenem ,respectively .Compared with the data of year 2012 , extensively-drug resistant strains in K . pneumoniae and A . baumannii decreased .Conclusions The antibiotic resistance of clinical bacterial isolates is growing in 2013 .The disseminated multi-drug or pan-drug resistant strains in a special region poses a serious threat to clinical practice and implies the importance of strengthening infection control .