ObjectiveTo investigate the changing trends of the incidence rate， prevalence rate， mortality rate， and disability-adjusted life years （DALYs） of benign hepatobiliary and pancreatic diseases among people aged 15 — 39 years in China in 1990 — 2021. MethodsThe data of 2021 Global Burden of Disease Study were downloaded to obtain the epidemiological data of liver fibrosis/chronic liver disease， benign gallbladder/biliary tract diseases， and pancreatitis among people aged 15 — 39 years in China， and estimated annual percentage change （EAPC） was calculated to assess the changing trends of incidence， prevalence， mortality， and DALY rates. The Bayesian age-period-cohort model was used to predict the incidence and mortality rates from 2022 to 2030. ResultsIn 2021， there were 10 448 778 new cases of benign hepatobiliary and pancreatic diseases among the individuals aged 15 — 39 years in China， which was increased by 3.8% compared with the data in 1990， while the numbers of prevalent cases， deaths， and DALYs were reduced by 20.4%， 59.6%， and 50.2%， respectively. In 2021， the age-standardized incidence rates of liver fibrosis/chronic liver disease， benign gallbladder/biliary tract diseases， and pancreatitis were 1 104.40/100 000， 1 045.05/100 000， and 16.64/100 000， respectively； the age-standardized prevalence rates were 20 592.37/100 000， 2 364.85/100 000， and 9.43/100 000， respectively； the age-standardized mortality rates were 1.61/100 000， 0.04/100 000， and 0.18/100 000， respectively. From 1990 to 2021， there was a tendency of increase in the age-standardized incidence rate of liver fibrosis/chronic liver disease （EAPC=0.43， 95% confidence interval ［CI］： 0.23 — 0.63）， and there was also a tendency of increase in the age-standardized incidence and prevalence rates of benign gallbladder/biliary tract diseases （incidence rate： EAPC=1.07， 95%CI： 0.91 — 1.24； prevalence rate： EAPC=0.75， 95%CI： 0.59 — 0.89）， while there was a tendency of reduction in the age-standardized mortality rate of all three disease categories. Predictions for 2022 — 2030 indicated a potential reduction in the incidence rate of benign gallbladder/biliary tract diseases and an increase in the incidence rate of pancreatitis. ConclusionThere has been an overall upward trend in the incidence rate of liver fibrosis/chronic liver disease and gallbladder/biliary tract diseases over the past three decades， and it is needed to pay attention to the disease burden of benign hepatobiliary diseases among the people aged 15 — 39 years in China.

Objective To exploring the mechanism of Jinshui Chenfei formula(JCF)in ameliorating silica(SiO2)-induced silicosis fibrosis based on endogenous metabolite changes.Methods A total of 32 SPF male Sprague-Dawley(SD)rats were divided into normal control group,model group,JCF group(9.72 g·kg-1·d-1),and Tetrandrine group(27 mg·kg-1·d-1)according to random number table method.The experimental silicosis model was established by intratracheal injection with SiO2 suspension(250 mg/kg)on day 1.From week 5-8,silicosis rats were treated with tetrandrine or JCF.On the end of week 8,the changes of pulmonary function index,including forced vital capacity(FVC),tidal volume(TV)and lung dynamic compliance(Cydn)were detected.The pathological changes of lung tissue were analyzed by hematoxyline-osin(HE)staining and Masson staining,the severity of focal alveolitis and fibrosis was also evaluated using the Szapiel scale and the Ashcroft scale,the positive staining of collagen Ⅰ(COL Ⅰ)and COL Ⅲ was detected using immunohistochemistry;the protein expression of transforming growth factor-β1(TGF-β1),fibronectin(FN),andα-smooth muscle actin(α-SMA)were measured by Western blotting.The rat serum samples were further screened for differential metabolites using ultra performance liquid chromatographytandem quadrupole time of flight mass spectrometr(UPLC-Q-TOF-MS)and pathway analysis was performed based on MetaboAnalyst 5.0.Results Compared with those in the normal control group,pathological changes such as alveolar structure destruction,the fibrous nodules encapsulated SiO2 particles were increased in lung tissues of rats in model group,alveolitis score and pulmonary fibrosis score were significantly higher(alveolitis score:2.62±0.27 vs.0.20±0.15,pulmonary fibrosis score:5.42±0.66 vs.0.50±0.84,both P<0.01);pulmonary function index including Cydn,FVC,and TV were significantly decreased[Cdyn(mL/cmH2O):0.26±0.03 vs.0.33±0.03,FVC(mL):8.09±0.47 vs.10.99±0.38,TV(mL):1.95±0.19 vs.2.53±0.26,all P<0.01];positive staining of COL Ⅰ,COL Ⅲ and ɑ-SMA,FN,TGF-β1 proteins expression showed higher in lung tissues[positive staining of COL Ⅰ(A value):13.47±1.76 vs.5.77±0.45;positive staining of COL Ⅲ(A value):10.39±0.47 vs.6.19±0.77,FN protein expression(FN/GAPDH):0.33±0.02 vs.0.21±0.07,α-SMA protein expression(α-SMA/GAPDH):1.78±0.16 vs.1.11±0.24,TGF-β1 protein expression(TGF-β1/GAPDH):0.52±0.10 vs.0.11±0.46,all P<0.01].Compared with the model group,the pathological changes of lung tissues were almost restored,alveolitis score and lung fibrosis score were significantly reduced in JCF and Tetrandrine groups(alveolitis score:1.10±0.15,1.33±0.31 vs.2.62±0.27,pulmonary fibrosis score:3.50±0.45,4.33±0.98 vs.5.42±0.66,all P<0.01);the pulmonary function index Cydn,FVC and TV were significantly increased[Cdyn(mL/cmH2O):0.32±0.05,0.31±0.04 vs.0.26±0.03,FVC(mL):9.41±0.85,8.70±0.92 vs.8.09±0.47,TV(mL):2.70±0.19,2.27±0.15 vs.1.95±0.19,all P<0.05];positive staining of COL Ⅰ,COL Ⅲ,and protein expression of FN,ɑ-SMA,and TGF-β1 in lung tissues was significantly decreased[COL Ⅰ(A value):7.09±0.67,8.13±0.64 vs.13.47±1.76,COL Ⅲ(A value):8.19±0.66,8.52±0.22 vs.10.39±0.47,FN protein expression(FN/GAPDH):0.19±0.06,0.24±0.03 vs.0.33±0.02,α-SMA protein expression(α-SMA/GAPDH):0.89±0.41,0.88±0.08 vs.1.78±0.16,TGF-β1 protein expression(TGF-β1/GAPDH):0.04±0.03,0.06±0.01 vs.0.52±0.10,all P<0.05].Metabolomics analysis showed that a total of 10 major differential metabolites were identified between normal control group,model group and JCF group,including arachidonic acid,palmitic acid,indole-3-acetic acid,propionylcarnitine,(S)-4-hydroxymandelonitrile,nalidixic acid,benzocaine,gramine,4-ethylphenol,N-benzylfor mamide.The differential metabolites in silicosis rats reversed by JCF treatment were mainly enriched,including unsaturated fatty acid biosynthesis,arachidonic acid metabolism,tryptophan metabolism,fatty acid elongation,fatty acid degradation and biosynthesis.Conclusion JCF could effectively improve the silicosis fibrosis,which is mainly related to biosynthesis of unsaturated fatty acids biosynthesis,arachidonic acid metabolism,tryptophan metabolism,fatty acid elongation,fatty acid degradation and biosynthesis.

Objective:To investigate the effect of on-demand glucocorticoid strategy on the occurrence and outcome of porcine anti-lymphocyte globulin (p-ALG) -associated serum sickness in aplastic anemia (AA) .Methods:The data of AA patients who received in the Anemia Diagnosis and Treatment Center of Haematology Hospital, CAMS & PUMC from January 2019 to January 2022 were collected. Among them, 35 patients were enrolled in the on-demand group, with the glucocorticoid strategy adjusted based on the occurrence and severity of serum sickness; 105 patients were recruited in the usual group by matching the age and disease diagnosis according to 1∶3 ratio in patients who received a conventional glucocorticoid strategy in the same period. The incidences, clinical manifestations, treatment outcomes of serum sickness, and glucocorticoid dosage between the two groups were analyzed.Results:The incidences of serum sickness in the on-demand group and the usual group were 65.7% and 54.3% ( P=0.237) , respectively. The median onset of serum sickness was the same [12 (9, 13) d vs the 12 (10, 13) d, P=0.552], and clinical symptoms and signs, primarily joint, and/or muscle pain, fever, and rash were similar. Severity grades were both dominated by Grades 1-2 (62.8% vs 51.4%) , with only a few Grade 3 (2.9% vs 2.9%) , and no Grades 4-5. No significant difference in the serum sickness distribution ( P=0.530) . The median duration of serum sickness was the same [5 (3, 7) d vs 5 (3, 6) d, P=0.529], and all patients were completely cured after glucocorticoid therapy. In patients without serum sickness, the average dosage of prophylactic glucocorticoid per patient in the usual group was (469.48 ±193.57) mg (0 in the on-demand group) . When compared to the usual group, the average therapeutic glucocorticoid dosage per patient in the on-demand group was significantly lower [ (125.91±77.70) mg vs (653.90±285.56) mg, P<0.001]. Conclusions:In comparison to the usual glucocorticoid strategy, the on-demand treatment strategy could significantly reduce glucocorticoid dosage without increasing the incidence of serum sickness; in addition, the duration of serum sickness and the incidence of above Grade 2-serum sickness were similar.

Objective:To analyze the diagnostic value of cell-free plasma metagenomic next-generation sequencing (mNGS) pathogen identification for severe aplastic anemia (SAA) bloodstream infection.Methods:From February 2021 to February 2022, mNGS and conventional detection methods (blood culture, etc.) were used to detect 33 samples from 29 consecutive AA patients admitted to the Anemia Diagnosis and Treatment Center of the Hematology Hospital of the Chinese Academy of Medical Sciences to assess the diagnostic consistency of mNGS and conventional detection, as well as the impact on clinical treatment benefits and clinical accuracy.Results:①Among the 33 samples evaluated by mNGS and conventional detection methods, 25 cases (75.76%) carried potential pathogenic microorganisms. A total of 72 pathogenic microorganisms were identified from all cases, of which 65 (90.28%) were detected only by mNGS. ②All 33 cases were evaluated for diagnostic consistency, of which 2 cases (6.06%) were Composite, 18 cases (54.55%) were mNGS only, 2 cases (6.06%) were Conventional method only, 1 case (3.03%) was both common compliances (mNGS/Conventional testing) , and 10 cases (30.3%) were completely non-conforming (None) . ③All 33 cases were evaluated for clinical treatment benefit. Among them, 8 cases (24.24%) received Initiation of targeted treatment, 1 case (3.03%) received Treatment de-escalation, 13 cases (39.39%) received Confirmation, and the remaining 11 cases (33.33%) received No clinical benefit. ④ The sensitivity of 80.77%, specificity of 70.00%, positive predictive value of 63.64%, negative predictive value of 84.85%, positive likelihood ratio of 2.692, and negative likelihood ratio of 0.275 distinguished mNGS from conventional detection methods (21/12 vs 5/28, P<0.001) . Conclusion:mNGS can not only contribute to accurately diagnosing bloodstream infection in patients with aplastic anemia, but can also help to guide accurate anti-infection treatment, and the clinical accuracy is high.

Objective:Short-term efficacy and safety of afatrombopag conversion therapy in patients with aplastic anemia (AA) who were previously ineffectively treated with intense immunosuppressive therapy (IST) combined with TPO receptor Agonist (TPO-RA) or who were unable to tolerate the side effects of TPO-RA.Methods:Analysis of patients with severe aplastic anemia (SAA) treated in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 2021 to December 2021 who received IST combined with TPO-RA (eltrombopag/hatrombopag) for at least 6 months, but was ineffective for at least 3 months or patients who cannot continue to use TPO-RA due to side effects, and switched from TPO-RA to avatrombopag (APAG) , and treated for at least 6 months. This study analyzed its short-term efficacy and evaluated its safety.Results:The median age was 54 (14-68) years old among the 16 patients with AA (8 male and eight female) . A total of ten patients (refractory group) who did not respond to IST combined with TPO-RA were converted to APAG median therapy for 6 (6-10) months. Only seven patients (70% ) obtained trilineage HR [four cases of complete treatment response (CTR) , one case of good treatment response (GPR) , and two cases of partial treatment response (PR) ], all of which began to take effect at 3 months of APAG treatment. There were six patients with TPO-RA intolerance, and APAG was treated for 6 (2 to 8) months. About four patients (67% ) received HR (three GPR cases and one PR case) , of which two patients received PR at 3 months and four patients received HR at 6 months of APAG treatment. No APAG-related grade 2 or more adverse events occurred during the APAG therapy, no thrombotic events occurred, no fibrologic tissue hyperplasia was found in the bone marrow pathology reexamination at 6 months of treatment, and none of the patients discontinued the drug due to adverse events.Conclusion:APAG may be a better switching treatment option for patients with AA who are refractory or are intolerant to TPO-RA.

Objective:To evaluate the efficacy and safety of iron supplement in patients who have paroxysmal nocturnal hemoglobinuria (PNH) with iron deficiency.Methods:We performed analyses on the clinical data of 48 patients who accepted oral and/or intravenous iron treatment. Forty-eight consecutive PNH patients with iron deficiency who visited our hospital between November 2011 and August 2018 were enrolled in the study.Results:Total 30 patients received oral iron; 18 patients received intravenous iron supplements, including 6 who did not respond to oral iron. The median PNH clone size was 90.2% (38.5%-99.9%) in the granulocytes and 69.7% (27.6%-98.1%) in the red blood cells. The response rate was 56% (20/36) in patients who received oral iron, and the hemoglobin concentration increased 21 (10-52) g/L compared to that at baseline. Sixteen out of eighteen (89%) patients responded to intravenous iron; 6 patients who did not respond to oral iron received intravenous iron, and the hemoglobin level of 5 patients increased. Patients exhibited increased LDH levels and deepen urine after iron supplementation; however, no severe adverse events, such as thrombosis and iron-related adverse effects, were noted.Conclusion:Iron treatment is safe and effective in increasing the hemoglobin level in PNH patients with iron deficiency; those who did not respond to oral iron could benefit from intravenous iron supplement.

Objective:This study aims to evaluate the efficacy and safety of secondary immunosuppressive therapy (IST) in refractory or relapsed severe aplastic anemia.Methods:The hematologic response and safety of 23 patients with refractory or relapsed SAA treated with secondary IST (including ATG/ALG + cyclosporine or HD-CTX) in our hospital were retrospectively analyzed.Results:A total of 23 patients were involved, including 11 males and 12 females, with a median age of 21 (11-62) years. In the refractory group, the interval of IST was 7 (6-12) months. In the relapsed group, on the other hand, the interval between two courses of IST was 39 (14-51) months. At 6 months after IST, the overall response rate was 69.5% (16/23) ; 60% (6/10) of the refractory group vs 77% (10/13) of the relapsed group; 64% (7/11) of the ATG/ALG group vs 75% (9/12) of the HD-CTX group. Among the patients who got the hematologic response, two patients relapsed again, all of them from the relapse group. After the third IST, they got the response again. Conclusion:The second IST is safe and effective for refractory and relapsed SAA patients; the early serologic reaction should be paid attention to when using the same ATG/ALG, and the risk can be reduced by changing the type of ATG/ALG or other IST programs. The third IST can still obtain the treatment response for the second relapse patients.

Objective:To evaluate the safety and efficacy of eltrombopag combined with immunosuppressive therapy in patients with aplastic anemia (AA) in China.Methods:We investigated and analyzed the clinical data of AA patients from 14 hematological treatment centers who were treated with oral eltrombopag for at least 3 mon.Results:We enrolled 56 AA patients, including 19 treatment-na?ve patients and 37 IST-refractory patients. The median administration period for eltrombopag was 7 (3-31) months, and the median maximum stable dosage was 75 mg/d (50-150 mg/d) . The 3-month hematological response (HR) rate was 60%, and the complete response (CR) rate was 30% in 10 SAA patients who were treated with first-line eltrombopag and standard IST (ATG+CsA) . Eight of 9 eltrombopag and CsA ± androgen first-line treated SAA patients responded (8/9, 89%) and 4 (44%) gave CR. The overall HR and CR rates were 79% and 52.6%, respectively, among these 19 patients by the end of the follow-up period. Of the 19 AA patients who were refractory to CsA ± androgen, 11 achieved HR (57.9%) at 3 mon, and the best HR rate was 44% in standard IST (ATG+CsA) refractory 18 patients after eltrombopag treatment. Fifty-one percent of the patients experienced mild or moderate adverse events, and gastrointestinal discomfort was the most common adverse effect reported by the study subjects.Conclusion:Adding Eltrombopag in first-line IST can accelerate the acquisition and improve the quality of hematological responses in AA patients. AA with relatively more residual hematopoietic cells may be well treated with eltrombopag and non-ATG IST. Eltrombopag can be used as salvage therapy for CsA±androgen refractory patients. Eltrombopag was generally safe and well tolerated by AA patients in China.

OBJECTIVETo study the effect of chrysin in inducing apoptosis of human hepatic carcinoma cells and explore the possible mechanism.

METHODSHuman hepatic carcinoma SMMC-7721 cells treated with DMSO or chrysin at different concentrations (5-200 μg/mL) were examined for changes in the cell proliferation using CCK-8 assay. The morphological changes of SMMC-7721 cells were observed in response to treatment with 5, 10, or 20 μg/mL chrysin, and the changes in the cell nuclei were observed using DAPI nuclear staining. Annexin Ⅴ-FITC/PI flow cytometry was used to determine the cell apoptosis rate. The changes in the apoptosis-related proteins (PARP and caspase-3) and MAPKs signal pathway were detected with Western blotting.

RESULTSChrysin treatment obviously suppressed the proliferation of SMMC-7721 cells in a dose-dependent manner below the concentration of 60 μg/mL. Chrysin (20 μg/mL) also caused significantly increased cell apoptosis and significant cleavage of PARP and caspase-3. Chrysin significantly activated MAPKs signaling pathway in a time-and dose-dependent manner, with the peak activation level occurring at 15 min. Pretreatment of the cells with specific inhibitors of the MAPKs pathway obviously inhibited the effect of chrysin in inducing cell apoptosis.

CONCLUSIONSChrysin inhibits the proliferation and promotes apoptosis of SMMC-7721 cells by regulating the activation of MAPKs signaling.

Objective: To evaluate the impact of the targeted next-generation sequencing (NGS) assay for difficult congenital anemias. Methods: Blood Disease Hospital Anemia Panel 2014 (BDHAP-2014) including 217 known genes of congenital anemias was developed. NGS and parental verification were performed for patients who were suspected diagnosed with congenital anaemia from August 2014 to July 2017. Results: A total of 46 patients were enrolled in this study, the clinical suspection were 11 cases Fanconi anemia (FA), 8 cases congenital dyserythropoietic anemia (CDA), 6 cases congenital sideroblast anemia (CSA), 12 cases congenital hemolytic anemia (CHA), 1 case dyskeratosis congenital (DC), 4 cases iron-refractory iron deficiency anemia and 4 cases unexplained cytopenia (Uc), respectively. 28 (60.9%) of 46 patients became confirmed cases after targeted NGS, corresponding to 44 mutations of which 33 were new. 26(56.5%) patients with results of the assay matching to clinical suspection, including FA (5/11, 45.5%), CSA (6/6, 100.0%), CDA (3/8, 37.5%) and CHA (12/12, 100.0%). 2 (4.3%) cases not matching to clinical suspection, including dyskeratosis congenital (DC) was made in 1(2.2%) patients with suspected FA and familial hemophagocytic lymphohistiocytosis (FHL) was made in 1(2.2%) patients with suspected unexplained cytopenia (Uc). In 12 CHA patients, the hemolytic type was further clarified by the NGS. The remaining 18 cases were not clearly diagnosed. Conclusion Targeted NGS assay is of major impact on congenital anemias. The assay should be used routinely in congenital anemias.