Objective To standardize the management of clinical trials in our hospital,reduce the incidence of protocol deviations,and provide a reference for improving the quality of clinical trials.Methods The healthcare failure mode and effect analysis(HFMEA)method was used to determine the potential failure modes of the current protocol deviation.The frequency,severity and detectability of failure modes were quantified and evaluated.The risk priority number(RPN)was calculated and the corresponding improvement measures were proposed.The RPN values before and after the implementation of HFMEA were statistically analyzed to evaluate the improvement effect.Results After the implementation of HFMEA activities,the RPN values of 14 potential failure modes decreased significantly(P<0.05);The risk level of 12 potential failure modes decreased.The HFMEA team members'ability in finding and solving problems,communication and cooperation were significantly improved.Conclusions The implementation of HFMEA activities contributes to the management of protocol deviation in clinical trials,can effectively reduce the occurrence of protocol deviation,and provides experience for improving the quality of drug clinical trials.

Background::A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI.Methods::In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints.Results::From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a –15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: –3.4%; 95% confidence interval [CI]: –11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: –0.5%; 95% CI: –5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. Conclusion::rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI.Trial registration::www.ClinicalTrials.gov (No. NCT02835534).

Objective:To study the effect of duodenal papillary morphology on selective biliary cannulation (SBC).Methods:Data of 912 patients with biliopancreatic diseases treated with endoscopic retrograde cholangiopancreatography (ERCP) at the Department of Gastroenterology, Affiliated Hospital of Northwest Minzu University from January 2018 to January 2020 were retrospectively analyzed. Duodenal papillary morphology of patients was classified into 4 types by using Haraldsson's endoscopic classification. The success rate of SBC, the pre-incision rate, the difficult intubation rate and the incidence of post-ERCP pancreatitis (PEP) of different papillary types were analyzed.Results:A total of 912 patients were enrolled in this study, and 86.95% (793/912) duodenal papilla conformed to one type of the classification, of which 77.18% (612/793) were regular type (type Ⅰ), 10.21% (81/793) small nipple type (type Ⅱ), 8.58% (68/793) protruding or drooping type (type Ⅲ), and 4.04% (32/793) wrinkled or ridged type (type Ⅳ). The success rates of SBC in four types of duodenal papilla were 98.86% (605/612), 90.12% (73/81), 88.24% (60/68) and 96.60% (28/32) respectively. The success rate of SBC of type Ⅰ was higher than those of type Ⅱ-Ⅳ (all P<0.008) and there was no significant difference between those of type Ⅱ and type Ⅲ ( P> 0.008). The pre-incision rate in the four types of duodenal papilla were 7.84% (48/612), 32.10% (26/81), 50.00% (34/68) and 25.00% (8/32) respectively. The pre-incision rate of type Ⅰ was lower than those of type Ⅱ-Ⅳ (all P<0.008), and there was no significant difference between those of type Ⅱ and type Ⅲ ( P>0.008). The difficult intubation rate in the four types of duodenal papilla were 12.42% (76/612), 39.51% (32/81), 58.82% (40/68) and 28.12% (9/32) respectively .The difficult intubation rate of type Ⅰ was lower than those of type Ⅱ and type Ⅲ (both P<0.001), and that of type Ⅲ was higher than that of type Ⅳ ( P=0.004) . There was no significant difference between those of type Ⅰ and type Ⅳ or type Ⅱ and type Ⅲ (both P>0.008). The incidences of PEP of the four types were 2.61% (16/612), 12.35% (10/81), 5.88% (4/68) and 6.25% (2/32) respectively. The incidences of PEP of type Ⅱ was higher than that of type Ⅰ ( P<0.001) , and there was no significant difference between those of type Ⅰ and type Ⅳ or type Ⅱ and type Ⅲ (both P>0.008). Conclusion:SBC is affected by duodenal papilla morphology, easiest for type Ⅰ and hard for type Ⅱ and Ⅲ. Attention should be paid to risk of PEP in SBC of type Ⅱ.

OBJECTIVE: To analyze the cause and pregnancy outcome for non-reportable cell-free DNA (cfDNA) results during non-invasive prenatal testing (NIPT). METHODS: cfDNA was extracted from maternal plasma from 5898 singleton pregnancies at 12 to 22 gestational weeks and underwent NIPT with strict quality control standards. For those with sub-standard results, redraw or invasive prenatal procedures were recommended. RESULTS: Among the 5898 cases, 32 have failed for the initial NIPT, including 17 cases with substandard cffDNA%, 10 cases with data fluctuation after twice library constructing and sequencing, and 5 cases with unidentifiable sex chromosome abnormalities. For these 32 cases, 2 directly underwent amniocentesis, and karyotyping analysis showed both were normal. Six of the 30 redrawn cases finally turned out to be nonreportable. The final nonreportable rate was therefore 0.1% (8/5898). Of the redrawn cases, 1 trisomy 21, 1 trisomy 18 and 1 trisomy 13 high risk-cases were identified, which were all confirmed to be false positive. Among the 6 nonreportable cases, 2 women underwent invasive prenatal testing, and 1 was found to have a normal fetal karyotype, while another was found to have an abnormal karyotype of mos45,X[32]/46,XY[18]. The other 4 nonreportable cases who did not accept invasive prenatal testing have all reported normal child development at follow-up. CONCLUSION The main reason for nonreportable NIPT results was low cffDNA%. The high success rate of the redrawn cases has effectively increased the overall NIPT success rate and reduced the number of the cases necessitating invasive prenatal diagnosis. The initially nonreportable women may consider retesting after careful counseling with informed consent.
Aneuploidy ; Child ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Noninvasive Prenatal Testing ; Pregnancy ; Prenatal Diagnosis ; Trisomy ; Trisomy 18 Syndrome/genetics*

Objective:To investigate the characteristics of subtype diversity and transmission on HIV-1 among 12 to 30 years old student MSM in Zhejiang province.Methods:A total of 290 newly diagnosed HIV infected student MSM were selected as the research objects for molecular studies on HIV, in Zhejiang province during 2013 to 2015. Data on epidemiology and plasma samples of these people were collected. HIV-1 nucleotide sequences of pol gene regions were amplified using the RT-PCR/nested PCR method and sequenced. Phylogenetic analysis was performed to determine the HIV-1 genotypes. Characteristics of transmission mode among these cases were also analyzed. Results:A total of 290 cases, 50.3 % were diagnosed in Hangzhou and 81.0 % had college or above degrees. 178 sequences including 10 subtypes, were obtained, with the main subtypes as CRF01_AE (49.4 %, 88/178) and CRF07_BC (39.3 %, 70/178). A total of 18 molecular transmission clusters were formed (42 cases, cluster size from 2 to 4), with the proportions of clusters as 23.6 % (42/178). 61.9 % (26/42) of student MSM with their schools located in the same district within the transmission clusters. Their sexual partners would include both student MSM and non-student MSM. The proportion of clusters among middle school students was 38.2 % (13/34), higher than that of college students (20.1 %, 29/144) ( χ2=4.996, P<0.05). Conclusions:The HIV-1 subtypes of student MSM in Zhejiang province appeared diversity, which indicated with the diversity of sources of infection. The geographical distribution of cluster cases is relatively centralized. In order to effectively control the spread of AIDS, more attention should be paid to the sexual partners involved and to specific programs on intervention.

Objective To investigate the significance of whole mount sections after radical prostatectomy in the diagnosis of prostate cancer.Methods The data of 210 patients with radical prostatectomy in the Department of Urology of Northern Jiangsu People's Hospital from April 2018 to July 2015 were collected,of which 150 cases (control group) were examined with routine tissue section examination and 60 cases (study group) were examined with whole mount sections.The age of the study group and the control group were (69.0 ± 5.0) years and (70.0 ± 7.0) years respectively,and PSA was (18.8 ± 2.5) ng/ml and (19.3 ± 2.1) ng/ml respectively.The BMI of the study group was (23.0 ± 1.2) kg/m2,and the control group was (22.8 ± 0.6) kg/m2.The preoperative Gleason score of the study group and the control group were 7.9 ±0.9 and 7.7 ± 1.6 respectively.There were 137 patients (91.3％) with clinical stage cT1-T2 and 13 patients with cT3(8.7％) in control group.In the study group,there were 51 cases (85.0％) with clinical stage cT1-T2,and 9 cases with cT3 (15.0％).There was no significant difference between the two groups (P ＞ 0.05) in term of the patients' demographics.The postoperative Gleason score,positive surgical margin,seminal vesicle invasion lymph node metastasis and pathological stage were compared between the two groups.Results The median prostate volume of the study group was 45.2 (18.3-121.5) ml,and 47.1 (2 1.3-124.2) ml in the control group.The operation time of the study group was 138.2 (119.5-234.1) mins,and 133.5 (116.8-228.2) mins in the control group.In the control group,there were 8 cases(5.3％) with seminal vesicle invasion,and 8 cases (5.3％) with lymph node metastasis.The pathological stages were pT2-T3 in 145 cases(96.7％),and pT4 in 5 cases (3.3％) in control group.The postoperative Gleason score was 8.0 ± 0.9 in control group.In the study group,17 patients (28.3％) with seminal vesicle invasion were pathologically indicated,and there were 6 patients (10.0％) with lymph node metastasis.The pathological stages were pT2-T3 of 57 cases(95.0％),and pT4 of 3 cases (5.0％),postoperative Gleason score was 7.7 ± 1.0 in study group.There was no statistically significant difference in seminal vesicle invasion,lymph node metastasis,pathological stage and postoperative Gleason score between the two groups (P ＞ 0.05).There were 23 patients (15.3％) with positive margins in the control group,and 28 patients(46.7％) in the study group,which showed significant difference (P ＜0.01).For small lesions,there were 7 cases (4.7％) and 22 cases (36.7％) in the control group and the study group,respectively,which showed significant difference (P ＜ 0.01).There were 17 cases (28.3％) of increased Gleason score in the study group,while 31 cases (20.7％) in the control group,with no statistical difference (P =0.232).Conclusions The whole mount section technique can effectively improve the positive surgical margin and the small lesions detection rate in the pathological evaluation of radical prostatectomy,and provide a precise pathological diagnosis for the postoperative treatment and follow-up of the patients.

Objective To understand the characteristics of distribution on HIV-1 subtypes and the transmission clusters in Yiwu in Zhejiang province.Methods A cross-sectional study of molecular epidemiology was carried out on newly reported H1V/AIDS cases in Yiwu.RNA was extracted from 168 plasma samples,followed by RT-PCR and nest-PCR for pol gene amplification,sequencing,phylogenetic tree construction used for analyzing the subtypes and transmission clusters.Mutations on drug resistance was analyzed by CPR 6.0 online tool.Results Subjects were mainly males (86.3％,145/168),with average age as (39.1 ± 13.4) years old and most of them were migrants (66.7％,112/168).The major routes of transmission included homosexual (51.2％,86/168) and heterosexual (48.8％,82/168) contacts.The rate of success for sequence acquisition was 89.9％ (151/168).The dominant subtypes showed as CRF01_AE (74,49.0％) and CRF07_BC (64,42.4％),followed by CRF08_BC (5,3.3％),CRF55_01B (3,2.0％),each case of subtype B,CRF45_cpx,CRF59_01B,CRF85_BC and URF (B/C).CRF45_cpx and CRF85_BC were discovered the first time in Zhejiang province.Twenty-six transmission clusters involving 65 cases were found,with the total clustered rate as 43.0％ (65/151),in which the CRF01_AE clustered rate appeared as 54.1％ (40/74),higher than that of CRF07_BC (21/64,32.8％).The average size of cluster was 2.5 cases/cluster,with average size of cluster in CRF01_AE patients infected through heterosexual transmission as the largest (3.5 cases/cluster).The prevalence of transmitted drug resistance was 4.6％ (7/151).Seven cases with surveillance drug resistant mutations (SDRM) were found,including 5 cases of M46L (3.3％),and one case of F77L or Y181C.Conclusion HIV genetic diversity and a variety of transmission clusters had been noticed in this study area (Yiwu).Programs on monitoring the subtypes and transmission clusters should be continued and strengthened.

Objective To investigate the protective effects of carboxymethylated chitosan (CMCS) on nitric oxide (NO) induced apoptosis in rat chondrocytes, and the probable roles and mechanisms of PI3K/Akt signaling pathway in these process.Methods Rat knee articular cartilage was used as the source of chondrocytes, the cells were identified by immunohistochemical staining against collagen type Ⅱ, odium nitroprusside (SNP, 3 mmol/L) was used to establish the apoptotic models of chondrocytes.Cells were divided into four groups: the control group, the SNP-induced group, the SNP+CMCS treated group, the SNP+CMCS+PI3K inhibitor Wortmannin treated group.Cell proliferation were assessed by cell proliferation assay kit (CCK-8), the apoptotic rate of chondrocytes was determined by FCM with Annexin V-FITC/PI double staining, the expression levels of MMP-13 and TIMP-1 mRNA were detected by real-time polymerase chain reaction (PCR) analysis, the expression of Akt and p-Akt protein levels was detected by Western blotting analysis.One-way analysis of variance (ANOVA) statistical analysis was used to calculate the data.Results Three mmol/L SNP can inhibit proliferation (0.221±0.023), and the proliferation was reduced by 70％ compared with the control group (0.736±0.032, F=8.203, P=0.021);and the induced apoptosis in cultured chondrocytes could be observed.The apoptotic rate was (68.8±5.2)％.Increased MMP-3 and decreased TIMP-1 mRNA expression were observed in SNP-induced cells.After adding CMCS to SNP-induced chondrocytes, the proliferation was increased while apoptotic rate was decreased, the apoptotic rate decreased to (14.7±2.3)％.CMCS could promote the activation of p-Akt in SNP-induced chondrocytes and restore SNP-induced MMP-13 and TIMP-1 mRNA expression.Conclusion CMCS could protect apoptosis in SNP induced chon-drocvtes via activation of PI3K/Akt pathwav.

Objective To observe the effect of intra-articular injection of CM-chitosan on nuclear factor κB (NF-κB) activation and nitric synthase expression in rat osteoarthritis cartilage,and to explore the mechanism of inhibition of joint destruction.Methods Thirty-six SD rats were randomly divided into three groups:A,B,C,12 in each group.Group A was the sham group,group B,C rats had the medial collateral ligaments cut off and part of medial meniscus were removed to establish osteoarthristis model.Group C rats were injected with 3％ carboxymethyl chitosan intra-articularly 0.15 mg/kg 5 weeks later,and then repeated injection every 1 week.Animals were sacrificed 11 weeks after surgery.The gross changes of cartilage and the expression of NF-κB (P65) were compared by immunohistochemistry,the protein expression of I-κB and P65 in nucleus were detected by Western-bloting.Inducible nitric oxide synthase (iNOS) mRNA and protein expres-sion were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and western blot.The general score of cartilage was analyzed by H test,the rest data was analyzed by one-way ANOVA.Results The cartilage degeneration scores pf group C (intra-articular injection of CM-chitosan group) were significantly less than those of group B.The protein expression of NF-κB of the articular cartilage in group C (106±7)was significantly lower than group B (147±8),the I-κB degradation was inhibited significantly in group C,and the expression of iNOS mRNA and iNOS protein were reduced in OA art~icular cartilage of arthritis rat chondrocytes,therefore,it had protective effect on articular cartilage.Conclusion CMC may inhibit NF-κB signaling pathway by inhibiting the degradation of I-κB in cartilage,which reduces iNOS mRNA and protein expression in rat osteoarthritis cartilage,thereby protects rat osteoarthritis cartilage cells.

Objective To investigate the efffect of carboxy-methyl-chitosan (CM-chitosan) on NF-kB activation and iNOS expression in IL-1β-induced rat chondrocytes, and the mechanism is explored. The statistical treatment was ANOVA. Methods The chondrocytes derived from knee joint of rats were cultured in vitro. 10 ng/ml IL-1β with or without CM-chitosan of varied concentrations (100, 200, 300 μg/ml) was added into the culture medium. Inducible NO synthase (iNOS) was examined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The expression of NF-κBn and NFκBc as well as I-κB were examined by Western blotting. Results CM-chitosan could significantly decrease iNOS expression of IL-1β-induced chondrocytes. Degradation of I-κB and NF-κB nuclear translocation were reversed by carbox-ymethyl-chitosan. Conclusion The study has demonstrated that CM-chitosan can inhibit the synthesis of inflammatory mediators in rat chondrocytes when stimulated with IL-1β through a NF-κB-dependent mechanism.