OBJECTIVE To provide direction and reference for the adjustment of the discount rate （DR） in China’s pharmacoeconomic guidelines. METHODS Search was conducted on the official websites of the International Society for Pharmacoeconomics and Outcomes Research， health technology assessment agencies in various countries/regions， as well as relevant websites of other upper-middle-income or high-income countries/regions. The recommended DR， adjustment trends， and setting rationales in pharmacoeconomic evaluation guidelines across different countries/regions were then summarized and compared. Based on theoretical derivation and literature analysis， the effects of different DR on the incremental cost-effectiveness ratio （ICER） were examined. RESULTS & CONCLUSIONS Among the 40 included guidelines， the base-case DR ranged from 1.5% to 5%， with 5% being the most common value； the range for sensitivity analysis was 0 to 12%. Thirty-six countries/regions applied the same DR to both costs and health outcomes， while in the Netherlands， Belgium， Poland and Czech Republic， DR for costs was higher than for health outcomes. In recent years， Korea， France and Ireland had lowered their DR in response to economic changes， whereas the Netherlands and Czech Republic had raised their DR for cost. The setting of the DR was primarily based on the public project investment interest rate or referred to recommendations from internationally authoritative institutions and other relevant guidelines. The direction and magnitude of the impact of different DR on the ICER largely depended on the distribution of costs and health outcomes between the intervention and reference measure. The setting and adjustment of DR were closely associated with the economic environment. Based on international experience, the DR in China can be lowered by 0.5% to 1.5%， and localized empirical research can be conducted using internationally common estimation methods.

AIM:To explore the synergistic sensitization effect of human umbilical cord mesenchymal stem cell culture supernatant(hUMSC-CM)combined with temozolomide(TMZ)on various glioma cell lines,and to elucidate the underlying mechanisms.METHODS:The hUMSC-CM was harvested using two different serum deprivation tech-niques at 24 and 48 h,and was converted into freeze-dried powder,which was then given to rat malignant glioma cell line RG-2,human astrocytoma cell line U251 and human glioblastoma cell line LN-428 at 5 concentrations(0,1,3,6 and 9 g/L).The effectiveness and sensitivity of hUMSC-CM for inhibiting growth of glioma cells at 24,48 and 72 h were as-sessed using CCK-8 assay.Hematoxylin-eosin(HE)staining combined with CCK-8 assay was employed to evaluate the chemotherapy sensitivity of glioma cells after 48 h of treatment with TMZ at 6 concentrations(0,25,50,100,200 and 400 μmol/L).Two concentrations(3 and 9 g/L)of hUMSC-CM and 3 concentrations(50,100 and 200 μmol/L)of TMZ were chosen for concurrent treatment of glioma cells to assess the proliferation and pathological alterations.TUNEL staining was utilized to detect apoptosis.Flow cytometry was utilized to analyze cell cycle modifications.The expression alterations of apoptosis-inducing proteins,cleaved caspase-3,cleaved caspase-8 and cleaved PARP1,as well as autophagy-inducing proteins beclin-1 and LC3,were examined using Western blot to investigate the synergistic sensitization mechanism of hUMSC-CM combined with TMZ in vitro.RESULTS:The susceptibility of glioma cell lines to hUMSC-CM and TMZ varied,with RG-2 showing the highest sensitivity,followed by U251,and then LN-428.The inhibitory effect of hUMSC-CM(3 and 9 g/L)and TMZ(50,100 and 200 μmol/L)combined treatment on glioma cells was significantly greater than that that of single-agent treatments(P＜0.05),demonstrating a dose-and concentration-dependent enhancement.Notably,the combination of 9 g/L hUMSC-CM(C9)with 50 μmol/L TMZ(T50)effectively suppressed glioma cell growth.CCK-8 as-say indicated a significant reduction of cell viability in C9+T50 group compared with either C9 or T50 alone(P＜0.05).HE staining and TUNEL staining revealed pronounced morphological changes and significant apoptotic features in glioma cells treated with C9+T50.Flow cytometric analysis confirmed that C9+T50 induced cell cycle arrest in glioma cells.Fur-thermore,compared with control group,the levels of cleaved caspase-3,cleaved caspase-8,cleaved PARP1,beclin-1,and LC3-Ⅱ/LC3-Ⅰ were significantly elevated in the C9+T50-treated glioma cells(P＜0.01).CONCLUSION:(1)The concomitant administration of hUMSC-CM and TMZ exerts a broad inhibitory effect on glioma cells,with a synergistic sen-sitization observed across different cell lines.(2)The enhancement of glioma cell sensitivity to TMZ by hUMSC-CM may be attributed to the modulation of caspase-8/caspase-3/PARP1 signaling pathway and the induction of both apoptosis and autophagy in glioma cells.

Objective To investigate the relationship between disease courses and severity and monocyte subsets distribution and surface CD31 intensity in patients of hemorrhagic fever with renal syndrome (HFRS). Methods Peripheral blood samples from 29 HFRS patients and 13 normal controls were collected. The dynamic changes of classical monocyte subsets (CD14⁺⁺CD16^-), intermediated monocyte subsets (CD14⁺⁺CD16⁺) and non-classical monocyte subsets (CD14⁺CD16⁺⁺) and the mean fluorescent intensity (MFI) of CD31 on monocyte subsets were detected by multiple-immunofluorescent staining and flow cytometry. Results In acute phase of HFRS, the ratio of classical monocyte subsets to total monocytes was dramatically decreased compared to convalescent phase and normal control. It was still much lower in convalescent phase compared to normal controls. The ratio of classical monocyte subsets to total monocytes were decreased in HFRS patients compared to that in normal control, whereas there was no difference between severe/critical groups and mild/moderate groups. On the contrary, the ratio of intermediate monocyte subsets to total monocytes in acute phase of HFRS was significantly increased compared to convalescent phase and normal control. The ratio of intermediate monocyte subsets to total monocytes were increased in HFRS patients compared to that in normal control, whereas no difference was found between severe/critical groups and mild/moderate groups. Phases or severity groups had no difference in ratio of non-classical monocyte subsets to total monocytes. Additionally, the ratio of classical monocyte subsets had a tendency to decline and that of intermediate monocyte subsets showed an increase both to total monocytes between the acute and convalescent phases in 11 HFRS patients with paired-samples. Moreover, in acute phase of HFRS, the mean fluorescent intensity (MFI) of CD31 on three monocyte subsets all decreased, specifically classical monocyte subsets showed the highest MFI of CD31 while the normal control reported the highest MFI of CD31 in non-classical monocyte subsets. In convalescent phase, the MFI of CD31 on classical and intermediated monocyte subsets were both lower than that of normal control, while MFI of CD31 was still significantly lower than normal control on non-classical monocyte subsets. Finally, MFI of CD31 on classical and intermediated monocyte subsets in severe/critical group were both lower than those in mild/moderate group, showing no statistical difference in MFI of CD31 on non-classical monocyte subset across groups of different disease severity. Conclusion The ratio of classical and intermediated monocyte subsets to total monocytes are correlated with the course of HFRS, and so are the surface intensity of CD31 on these monocyte subsets with the disease course and severity. The surface intensity of CD31 on non-classical monocyte subsets, however, is correlated only with the course of the disease. Together, the underlying mechanisms for the observed changes in monocyte subsets in HFRS patients should be further investigated.
Humans ; Monocytes ; Lipopolysaccharide Receptors ; Hemorrhagic Fever with Renal Syndrome ; Receptors, IgG ; Disease Progression

The concept of "ntigen"is a relative one. The narrow concept of it condenses the process of activation of adaptive immune response and re-recognition of the same antigen, revealing the protective mechanism of vaccines with great significance for research and development of vaccines. However, the narrow concept involves adaptive immune system members: B cells, T cells and their effector products, which is difficult for beginners to understand the inherent meaning. Meanwhile, antigen classification fully summarizes the immune response process, so a variety of classification approach increases the difficulty in learning. Our teaching team analyzes the difficulties of this chapter in depth, and we implements the strategy that takes antibody structure and function as the breakthrough point and simplified adaptive immune response process as the core in teaching. A mind map that includes the main contents of this chapter is made during the process, which promotes the effectiveness of classroom teaching greatly.
Learning ; Vaccines ; Antibodies

Objective:To investigate the application of the decision-oriented context-input-process-product (CIPP) model combined with integrated teaching in standardized training of medical oncology.Methods:A total of 98 standardized training residents who participated in standardized training in Department of Oncology, Jiangsu Cancer Hospital, were enrolled as subjects, and they were divided into control group and observation group using a simple random number table, with 49 residents in each group. The residents in the control group received routine teaching, and those in the observation group received CIPP model combined with integrated teaching. The two groups were compared in terms of department examination score and assessment of subjective learning effect, and the observation group was assessed in terms of critical thinking ability before and after training. SPSS 22.0 was used for the t-test. Results:Compared with the control group, the observation group had significant increases in theoretical examination score ( t=2.95, P=0.004), practical operation score ( t=17.04, P<0.001), and total score ( t=3.55, P=0.001). After training, the observation group had significant increases in the scores of each dimension of critical thinking ability and the total score of critical thinking ability ( t=2.89, 3.55, 3.37, 3.20, 3.13, 2.67, 3.06, 3.13; P=0.005, 0.001, 0.001, 0.002, 0.002, 0.009, 0.003, 0.002). The observation group had significantly higher assessment scores of subjective learning effect than the control group ( t=3.46, 3.56, 2.83, 2.85, 2.57, 3.07; P=0.001, 0.001, 0.006, 0.005, 0.012, 0.003). Conclusion:The CIPP model combined with integrated teaching can improve the department examination score and critical thinking ability of standardized training residents in medical oncology, with good assessment results of subjective learning effect.

Objective:To investigate the role of modification level of lysine trimethylation at position 27 of histone 3 (H3K27me3) on expression of anti-apoptotic protein B lymphocyte tumor-2 gene (BCL2) during arsenic-induced hepatocyte apoptosis.Methods:Rat liver BRL-3A cells were cultured in vitro. According to the arsenic treatment factor, the experiment was divided into two parts, in the first part arsenic was not added, the experiment was divided into normal, transfection reagent, negative transfection, H3K27me3 specific demethylase (JMJD3) small interfering RNA (siRNA) transfection and H3K27me3 methyltransferase (EZH2) siRNA transfection groups. In the second part arsenic was added, the experiment was divided into control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups. When arsenic was not added, the corresponding siRNA and transfection reagent was used to transfect cells at a ratio of 100 pmol : 7.5 μl for 6 h [the normal group was treated with phosphate buffer solution (PBS) of the same volume as transfection reagent], then the medium was changed and the cells were incubated for a total of 48 h. After 24 h of treatment with the above transfection and culture method in arsenic added group, a final concentration of 30 μmol/L sodium arsenite (NaAsO 2) was added and the cells were incubated for 24 h (the control group was treated with PBS with the same volume of NaAsO 2 for 24 h). Real-time cell analysis (RTCA) was used to measure the proliferation of BRL-3A cells in arsenic added group. Apoptosis of BRL-3A cells was analyzed by flow cytometry in arsenic added group. Western blotting was used to detect JMJD3, EZH2, H3K27me3 and BCL2 in no-arsenic and arsenic-added BRL-3A cells. The modification levels of H3K27me3 in BCL2 gene promoter regions were detected by chromatin immunoprecipitation of the cells exposed to arsenic. Results:There were statistically significant differences of the proliferation rates [control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups: (100.00 ± 10.43)%, (12.19 ± 3.37)%, (31.86 ± 1.95)%, (24.58 ± 3.64)%, (11.53 ± 1.11)%] and the apoptosis rates [(1.15 ± 0.04)%, (13.06 ± 1.33)%, (17.39 ± 0.22)%, (23.90 ± 1.66)%, (15.07 ± 0.88)%] between groups ( F = 146.50, 194.30, P < 0.001), correspondingly. The protein expression level of H3K27me3 in JMJD3siRNA transfection group was higher than that of normal, transfection reagent and negative transfection groups, while EZH2siRNA transfection group had an opposite result ( P < 0.05). The protein expression level of BCL2 in JMJD3siRNA transfection group was lower than that of normal, transfection reagent and negative transfection groups, while EZH2siRNA transfection group had an opposite result ( P < 0.05). The protein expression levels of H3K27me3 and BCL2 were not statistically significant differences between normal, transfection reagent and negative transfection groups ( P > 0.05). The protein expression levels of JMJD3, EZH2, H3K27me3 and BCL2 among control, arsenic treatment, arsenic + negative transfection, arsenic + JMJD3siRNA transfection and arsenic + EZH2siRNA transfection groups were compared, and the differences were statistically significant ( F = 26.56, 7.82, 9.81, 31.19, P < 0.05). Compared with control group, the protein expression levels of JMJD3 and EZH2 in arsenic treatment group were significantly reduced ( P < 0.05), and the protein expression level of H3K27me3 was higher ( P < 0.05), meanwhile the protein expression level of BCL2 was lower ( P < 0.05). Compared with arsenic + negative transfection group, the protein expression level of JMJD3 was significantly reduced in arsenic + JMJD3siRNA group, and the protein expression level of EZH2 was significantly reduced in arsenic + EZH2siRNA group ( P < 0.05). In addition, arsenic + JMJD3siRNA increased the level of H3K27me3 modification while reducing the protein expression of BCL2, while arsenic + EZH2siRNA had an opposite result ( P < 0.05). Compared with control group, the enrichment levels of H3K27me3 in BCL2 gene promoter regions (CHIP1 and CHIP2) in arsenic treatment group were significantly higher ( P < 0.05). Conclusion:Arsenic may inhibit the expression of BCL2 by increasing the enrichment level of H3K27me3 in the promoter regions of BCL2 gene, and promoting hepatocyte apoptosis.

OBJECTIVE: To analyze the clinical features and genetic basis for a Chinese pedigree affected with familial adenomatous polyposis (FAP). METHODS: Clinical information of the patient was collected. Genomic DNA was extracted from peripheral blood sample of the patient and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 33-year-old female, was found to have multiple adenomatous polyps in the intestine. WES revealed that she has harbored a heterozygous variant of the APC gene, namely c.1922dupA (p.N641fs*10), which was unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic. CONCLUSION The c.1922dupA (p.N641fs*10) variant of the APC gene probably underlay the FAP in this pedigree. Above finding has enabled genetic counseling for this family.
Female ; Humans ; Adult ; Pedigree ; Adenomatous Polyposis Coli Protein/genetics* ; Germ-Line Mutation ; Adenomatous Polyposis Coli/genetics* ; China ; Mutation

To investigate the effects of different fluid resuscitation on renal function and glycocalyx in septic shock rats. The septic shock SD rats (induced by lipopolysaccharide) were randomly divided into control group, normal saline resuscitation group, Lactate Ringer′s solution resuscitation group and succinyl gelatin resuscitation group ( n=6 each). The mean arterial pressure, heart rate, serum creatinine (Scr), urea nitrogen (BUN), renal blood flow, renal tissue pathology, serum interleukin-6, tumor necrosis factor α and glycocalyx were measured at baseline, the development of septic shock, 0 hour and 8 hours after resuscitation. When shock was established, the renal blood flow significantly decreased ( P<0.05) and recovered to normal at 0 hour and 8 hours after resuscitation. Compared with normal saline group and succinyl gelatin group, the levels of Scr, BUN and glycocalyx components (heparan sulfate, syndecan-1) were significant lower in Lactate Ringer′s solution group ( P<0.05). The pathology of kidney tissue suggested that the microscopic ischemic damage with Lactate Ringer′s solution were minor than the other two groups. Compared with normal saline and succinyl gelatin, Lactate Ringer′s solution can reduce the damage of renal function and glycocalyx in septic shock rats.

Objective To investigate the timing and scheme of surgical treatment for the concomitant ureteropelvic junction obstruction(UPJO) and congenital abnormalities of the kidney.Methods The clinical data of 155 patients with concomitant UPJO and congenital abnormalities of the kidney from January 2006 to January 2016 was retrospectively analyzed.There were 107 males and 48 females,who aged 6 months to 16 years and 6 months.The average time was 5 years and 9 months old when they received operation.There were 8 cases less than 1 year old.There were 93 cases of UPJO on the left side,54 cases on the right side,and 8 cases on both sides.There were 33 cases with duplication of kidney,19 cases with solitary kidney,and 6 cases with renal dysplasia,6 cases with renal ectopia,12 cases with polycystic kidney disease,and 41 cases with dysplasia;2 cases with renal malrotation.There were 100 cases with symptoms such as fever,abdominal pain,vomiting.5 cases had received Anderson-Hynes pyeloplasty in other hospitals,2 cases received nephrectomy with symptoms did not relieve.4 cases were treated with nephrostomy in other hospital.Children with the repeated clinical symptoms,or renal function decreased significantly,or hydronephrosis progressive to the anteroposterior diameter of more than 30 mm received surgical treatment.Results There were 140 cases received Anderson-Hynes pyeloplasty,and 8 cases received nephrectomy with 5 cases were UPJO side and 3 cases were only abnormalities of the kidney without UPJO.All patients received IVP or ultrasonography postoperative 3-6 months,which showed hydronephrosis improved or no obvious change,and 4 cases were improved obviously.The IVP results showed that 5 patients with renal dysplasia together with UPJO had the renal function improved.There were 128 cases followed up for 12 to 106 months,with an average of 64.5 months.All patients had no clinical symptoms.83 cases were reexamined by IVP or ultrasonography,and hydronephrosis was getting better or no change.Conclusions The patients with concomitant UPJO and congenital abnormalities of the kidney don't need surgery in advance.The best choice for those patients is Anderson-Hynes pyeloplasty.The indication of nephrectomy should be considered carefully.

Posterior urethral valves(PUV) is the most common cause of lower tract obstruction in boys.With the understanding of the prognostic factors of PUV in depth,PUVs can have a profound effect on the function of bladder and upper urinary tract though valves are completely resected.The treatments of PUV include prenatal intervention,the antenatal vesicoamniotic shunt and fetal cystoscopy can be considered in selected patients with oligohydramnios.But the role of antenatal intervention is unclear.The gold standard for postnatal treatment of PUV is valve ablation.Vesicostomy is reserved primarily for the children with PUV whose urethra cannot accommodate an endoscope, as well as have severe urinary tract infections.Circumcision should be encouraged as a prophylactic measure for children with PUV who should have high rate of urinary tract infection.Vesicoureteral reflux is very common in PUV patients, and life-long monitoring of these patients is mandatory, as bladder dysfunction and valve bladder may be found during follow-up.These factors contribute toward the devolution of a bladder into dysfunction status are high voiding pressures and increased residual urine.Medication and clean intermittent catheterization are two main interventions, for the children who difficult to treat, an appendicovesicostomy utilizing the Mitrofanoff principle presents an useful option.Renal transplantation is an alternative for patients with PUV who progress to end-stage renal disease.Bladder dysfunction plays an important role in the development of PUV and urodynamic examination can be used to assess the function of the bladder to achieve timely and effective intervention.