Biliary fibrosis (BF) is the result of pathological repair of bile tract injury, characterized by thickening and sclerosis of the bile duct wall and progressive stricture of the lumen, which may ultimately lead to serious adverse outcomes such as biliary obstruction, biliary cirrhosis, liver failure, and hepatobiliary malignancies. Current research describes BF as a pathological feature of certain bile tract diseases, lacking a systematic summary of its etiology, pathophysiology, molecular mechanisms, and treatment. BF is a common but easily neglected disease state in biliary system, which may promote the development and progression of hepatobiliary diseases through abnormal repair mechanism after pathological biliary tract injury. Based on the latest research progress from both domestic and international perspectives, the authors review the concept, clinical manifestation, etiology, pathogenesis, and therapeutic strategies of BF to provide a reference for clinical physicians.

Objective:To establish a derivative gas chromatography method for quantitative determination of hydra-zine hydrate in afatinib maleate.Methods:Acetone-glacial acetic acid solution and DB-225 capillary column(0.25 mm×30 m × 0.25 μm)and FID was used to separate andquantitative decermine hydrazine hydrate.Results:Excellent linearity showed within the range of 1.258-50.34 μg·mL-1(r＞0.999),detection limit was 0.001％,and the recovery rate was 91.7％-107.2％.Conclusion:The method shows low testing cost,satisfac-tory repeatability,simplicity and convenience,and is valid in derivative separation and analysis of hydrazine hydrate in afatinib maleate.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Background: There is an urgent need to find reliable and rapid bovine tuberculosis (bTB) diagnostics in response to the rising prevalence of bTB worldwide. Toll-like receptor 2 (TLR2) recognizes components of bTB and initiates antigen-presenting cells to mediate humoral immunity. Evaluating the affinity of antigens with TLR2 can form the basis of a new method for the diagnosis of bTB based on humoral immunity. Objectives: To develop a reliable and rapid strategy to improve diagnostic tools for bTB. Methods: In this study, we expressed and purified the sixteen bTB-specific recombinant proteins in Escherichia coli. The two antigenic proteins, MPT70 and MPT83, which were most valuable for serological diagnosis of bTB were screened. Molecular docking technology was used to analyze the affinity of MPT70, MPT83, dominant epitope peptide of MPT70 (M1), and dominant epitope peptide MPT83 (M2) with TLR2, combined with the detection results of enzyme-linked immunosorbent assay to evaluate the molecular docking effect. Results: The results showed that interaction surface Cα-atom root mean square deviation of proteins (M1, M2, MPT70, MPT83)-TLR2 protein are less than 2.5 A, showing a high affinity.It is verified by clinical serum samples that MPT70, MPT83, MPT70-MPT83 showed good diagnostic potential for the detection of anti-bTB IgG and M1, M2 can replace the whole protein as the detection antigen. Conclusions Molecular docking to evaluate the affinity of bTB protein and TLR2 combined with ELISA provides new insights for the diagnosis of bTB.

Objective:To compare the efficacy and safety of Tonghua Dongbao′s insulin aspart injection (Rishulin) and NovoRapid (Novo Nordisk) in the treatment of diabetes.Methods:A 26-week, randomized, open-label, parallel-group, positive control drug and non-inferiority trial was conducted in 23 centers in China. A total of 563 diabetes with poor blood glucose control treated with insulin for at least 3 months before were included. The subjects were randomized(stratified block random method) into those receiving Rishulin or NovoRapid at a ratio of 3∶1. Both groups were combined with basal insulin (Lantus). The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to the end of 24 weeks of treatment.Results:For full analysis set, after 24 weeks of treatment, HbA1c level of Ruishulin group decreased from (8.66±1.28)% to (7.77±1.09)% ( P<0.001), and that of NovoRapid group decreased from (8.47±1.28) % to (7.65±0.97) % ( P<0.001). Treatment difference in HbA1c (NovoRapid group-Ruishulin group) was -0.061% (95% CI -0.320-0.199). HbA1c<7.0% target reacing rates were 24.26% and 21.21% ( P=0.456), and HbA1c<6.5% target reacing rates were 9.65% and 6.82% ( P=0.310) in Ruishulin group and NovoRapid group, repectively. The standard 2 hours postprandial blood glucose (2hPG) in Ruishulin group decreased from (16.23±5.22) mmol/L to (12.65±4.57) mmol/L ( P<0.001), and 2hPG in NovoRapid group decreased from (16.13±5.37) mmol/L to (11.91)±4.21) mmol/L ( P<0.001). The fingertips blood glucose at 7-point of both groups exhibited varying degrees of reduction compared with those at baseline, repectively. Positive ratios of specific antibodies were 31.68% in Ruishulin group and 36.36% in NovoRapid group ( P=0.320). Ratios of negative to positive were 7.43% and 10.61% ( P=0.360), and ratios of positive to negative were 10.40% and 7.58% ( P=0.360) in Ruishulin group and NovoRapid group, respectively. The incidence of hypoglycemia was 60.05% and 55.40% ( P=0.371), and the incidence of adverse events was 76.60% and 77.70% ( P=0.818) in Ruishulin group and NovoRapid group, respectively. Conclusions:Rishulin is not inferior to NovoRapid, and has shown good efficacy and safety. It can be an ideal choice for clinicians in patients with poor blood glucose control with insulin.

Liver injury caused by acetaminophen (AP) overdose is a leading public health problem. Although AP-induced liver injury is well recognized as the formation of N-acetyl-p-benzoquinone (NAPQI), a toxic metabolite of AP, resulting in cell damage, emerging evidence indicates that AP-induced liver injury is also associated with gut microbiota. However, the gut microbiota-involved mechanism remains largely unknown. In our study, we found that vancomycin (Vac) pretreatment (100 mg/kg, twice a day for 4 days) attenuated AP-induced liver injury, altered the composition of gut microbiota, and changed serum metabolic profile. Moreover, we identified Vac pretreatment elevated cecum and serum 2-hydroxybutyric acid (2-HB), which ameliorated AP-induced cell damage and liver injury in mice by reducing AP bioavailability and elevating GSH levels. Our current results revealed the novel role of 2-HB in protecting AP-induced liver injury and add new evidence for gut microbiota in affecting AP toxicity.

Objective:To investigate the value of ultrasound elastography combined with serum urokinase plasminogen activator (uPA) in differential diagnosis of benign and malignant thyroid nodules.Methods:From May 2018 to May 2019, 150 patients with thyroid nodules (160 nodules) were selected, 69 patients with benign nodules (76 benign nodules) and 81 patients with malignant nodules (84 malignant nodules) were diagnosed by postoperative pathology. In the same period, 40 healthy people underwent health examination were selected as the control group. All preoperative patients were subjected to ultrasound elastography. The results of pathological examination were diagnosed as "gold standard"; the characteristics of ultrasound elastography were observed and scored, and compared with the results of pathological examination. The level of serum uPA was measured by enzyme-linked immunosorbent assay (ELISA), the sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were compared among single real-time ultrasound elastography, serum uPA and combined diagnosis.Results:Among the 150 patients (160 nodules), for ultrasound elastography, the sensitivity was 97.37% (74/76), the specificity was 85.71% (72/84), the accuracy was 91.25% (146/160), and the Kappa value was 0.726. The ratio of 0 to 2 points in malignant group was significantly lower than that in the benign group, the ratio of 3 to 4 points was significantly higher than that in the benign group ( P < 0.05). Compared with the control group, the levels of serum uPA in the benign group and the malignant group increased significantly ( P < 0.05). Compared with the benign group, serum uPA level in the malignant group increased significantly ( P < 0.05). The AUC of combined diagnosis was 0.869, 95% confidence interval ( CI): 0.789 - 0.949, and the best cut-off point for the combined diagnosis was uPA = 982.16 mU/L, at this time, the diagnostic sensitivity was 0.646, and the diagnostic specificity was 0.575. The AUC of ultrasound elastography was 0.814, 95% CI: 0.721 - 0.907, and the AUC of combined diagnosis was higher than that of ultrasound elastography. Conclusion:The clinical value of ultrasound elastography combined with serum uPA in differentiating benign and malignant thyroid nodules is higher than that of ultrasound elastography.

Objective:To analyze the diagnosis of renal injury caused by chronic arsenism by color Doppler ultrasound and the observation of renal hemodynamics.Methods:From January 2018 to April 2019, 74 patients with occupational chronic arsenism admitted to Binzhou People's Hospital were selected and divided into two groups according to whether the patients were complicated with renal injury or not, 26 patients in renal injury group and 48 patients in non-renal injury group. The renal function indexes [serum creatinine (SCr), blood urea nitrogen (BUN), urine and blood β2-microglobulin (β2-MG)] were measured and the renal hemodynamics [peak blood flow velocity during systole (Vmax), minimum blood flow velocity during diastole (Vmin), resistance index (RI)] of the two groups were analyzed by color Doppler ultrasound, and the correlation between renal function indexes and renal hemodynamics was analyzed.Results:The levels of SCr, BUN, urine β2-MG and blood β2-MG in renal injury group were significantly higher than those in non-renal injury group [(136.28 ± 21.05) vs (108.42 ± 26.49) μmol/L, (8.03 ± 1.04) vs (5.36 ± 0.97) mmol/L, (157.48 ± 25.63) vs (127.42 ± 18.95) μg/L, (3.97 ± 1.12) vs (2.35 ± 0.84) mg/L, t = 4.625, 11.022, 5.740, 7.028, P < 0.05]. The Vmax and Vmin of the main renal artery and interlobular artery in renal injury group were significantly lower than those in non-renal injury group [cm/s: (50.34 ± 13.42) vs (75.32 ± 16.52), (18.13 ± 5.21) vs (29.83 ± 7.05), (12.31 ± 3.82) vs (17.22 ± 5.07), (4.08 ± 1.15) vs (6.03 ± 1.93), t = 6.833, 7.084, 4.657, 4.775, P < 0.05], and the RI of the main renal artery and interlobular artery in renal injury group was significantly higher than that in non-renal injury group [(0.71 ± 0.06) vs (0.62 ± 0.08), (0.68 ± 0.10) vs (0.56 ± 0.08), t = 5.017, 5.634, P <0.05]. Vmax and Vmin of the main renal artery and interlobular artery were negatively correlated with SCr, BUN, urine β2-MG and blood β2-MG ( P < 0.05). RI of the main renal artery and interlobular artery were positively correlated with SCr, BUN, urine β2-MG and blood β2-MG ( P < 0.05). Conclusions:Color Doppler ultrasound can effectively reflect the status of renal injury in chronic arsenism patients. The renal blood flow perfusion in renal injury patients is decreased, and the blood flow resistance is increased, which is closely related to the degree of renal injury and deserves clinical attention.

Objective: To evaluate the post-marketing safety profiles of the inactivated enterovirus type 71 (EV-A71) vaccine (Vero cell) after routine inoculation. Methods: Eleven cities of Zhejiang Province, Fengtai district of Beijing, Qinnan district, two counties as Pingle and Pingguo of Guangxi Zhuang Autonomous Region, and Dongtai city of Jiangsu Province were selected as the field sites. A total of 45 239 subjects were enrolled in this study from children who seeked the vaccination of EV-A71 vaccine during the period from July, 2016 to June, 2018. Different sampling method were adopted in different sites. All vaccinated children were invited to participate in the study in Fengtai and Dongtai, however, systematic sampling method were adopted in other sites. Active surveillance was conducted and information about adverse reactions (ARs) occurred in 30 min, 3 d and 30 d following each dose of EV-A71 immunization was collected by field observation, phone-call or face-to-face interview. The incidence of ARs in different types, symptoms and grades were described. Results: In total, there were 45 239 children who received 71 243 doses EV-A71 vaccine. The overall incidence of ARs was 1.079% (769 doses), with the highest incidence of 1.182% (177/14 973) in 5-11 month group and the lowest incidence of 0.849% (18/2 119) in ≥ 36 month group among different age groups. There was a higher incidence in solicited ARs, which was 1.047% (746 doses). The incidences of grade 1 and grade 2 ARs were also higher, which were 0.404% (288 doses) and 0.554% (395 doses), respectively. No grade 4 ARs occurred. The doses of the first and the second vaccination was 40 736 and 30 507, respectively, and the incidences of ARs were 1.281% (522 doses) and 0.810% (247 doses). Also, the incidences of ARs were 0.091% (37 doses) and 0.043% (13 doses) in local, and 1.168% (476 doses) and 0.760% (232 doses) in system. The symptoms of ARs after the two doses of vaccination were basically the same. Redness at the injection site was the most common local ARs after each dose vaccination, with doses of 24 and 11, while fever was the most common systemic ARs, with doses of 362 and 190. Moreover, ARs mainly occurred in 30 min to 3 d after each dose vaccination, with incidence of 1.016% (414 doses) and 0.698% (213 doses) in the first and second dose, respectively. Conclusion The ARs had a low incidence after vaccination in children and most were mild or moderate. EV-A71 vaccine with good safety is suitable for inoculation in a large scale.