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.

Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a pivotal role in regulating glycolipid metabolism;nevertheless,its obesity-combatting potency remains unclear.In this study,a substantial reduction was observed in serum PPP1R3G levels in high-body mass index(BMI)and high-fat diet(HFD)-exposed mice,establishing a positive correlation between PPP1R3G and non-12α-hydroxylated(non-12-OH)BA content.Additionally,hepatocyte-specific overexpression of Ppp1r3g(PPP1R3G HOE)mitigated HFD-induced obesity as evidenced by reduced weight,fat mass,and an improved serum lipid profile;hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology.PPP1R3G HOE considerably impacted systemic BA homeostasis,which notably increased the non-12-OH BAs ratio,particularly lithocholic acid(LCA).16S ribosomal DNA(16S rDNA)sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population,and elevating the relative abundance of Blautia,which exhibited a positive correlation with serum LCA levels.A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent.Mechanistically,PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase(CYP7A1)and sterol-12α-hydroxylase(CYP8B1),and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled BA receptor 5(TGR5)expression under HFD conditions.Furthermore,LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels.These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis,which may serve as potential ther-apeutic targets for obesity-related disorders.

OBJECTIVE To investigate the current situation of the review and comment on inpatient medical orders in Beijing municipal hospitals， and to put forward countermeasures and suggestions for further improving related work. METHODS A questionnaire survey was conducted to investigate the current situation of the review and comment on inpatient medical orders in 22 Beijing municipal hospitals. The statistical analysis was conducted for the survey results. RESULTS A total of 22 questionnaires were distributed， with recovery effective rate of 100%. The 22 hospitals carried out inpatient medical order comment， but their proportion varied among hospitals （0.88%-98.54%）； medical order comment mainly focused on antibiotics， proton pump inhibitors， anesthetic drugs/class Ⅰ psychotropic drugs， auxiliary drugs and other categories； 205 pharmacists participated in the comment of inpatient medical orders， most of whom hold intermediate or higher professional titles （89.27%）； 21 hospitals conducted inpatient medical order comment and feedback the results to relevant departments/responsible persons， but the intervention situation was not the same. Eighteen hospitals had carried out the review of inpatient medical orders； reviewed drug category was roughly the same as the category involved in the medical order comment； review content involved the suitability of administration routes， dosage， etc. The review was conducted mainly through the cooperation of audit software and pharmacists. CONCLUSIONS The comment and review of inpatient medical orders in Beijing municipal hospitals carried out in an orderly manner， and preliminary results have been achieved； at the same time， it is necessary to further increase the ability of participating pharmacists， improve audit standards， optimize pre-audit （No.ZYLX201805） software， and promote rational drug use among hospitalized patients through doctor-pharmacist collaboration.

Objective:To study the incidence, clinical features and genetic mutation profiles of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) using screening strategy.Methods:From September 2015 to September 2020, neonates in Xuzhou area were prospectively screened for genetic metabolic diseases using tandem mass spectrometry. Suspected infants were further confirmed using urinary organic acid test and SLC25A13 gene mutation analysis. The clinical manifestations, biochemical and gene mutation results, treatment and prognosis of the confirmed cases were analyzed.Results:A total of 468,494 live-birth newborns were screened with 112 cases suspected and 95 cases received urinary organic acid test and SLC25A13 gene mutation analysis. 13 cases of NICCD were diagnosed with a prevalence of 1/36,038. Most confirmed cases presented with delayed disappearance of neonatal jaundice, feeding difficulties and poor weight gain. Biochemical changes included increased bile acid, abnormal liver enzymes, increased alpha-fetoprotein, hypoglycemia, decreased hemoglobin, abnormal coagulation function and increased blood ammonia. Tandem mass spectrometry showed increased citrulline, methionine, arginine, tyrosine and phenylalanine, and in some cases with slightly increased acylcarnitine. Urine organic acid analysis mainly showed increased 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvate. All confirmed cases received genetic mutation tests and a total of 13 mutation loci were detected, including c.852_855delTATG, c.511dupG, c.1638_1660dup, IVS16ins3kb, c.1078C>T, c. 615+5G>A, c.742G>A, c.44G>A, c.1311+1G>A, c.1399C>T, c.889G>T, c.1177+1G>A, c.1841+3_1841+4del, among which, c.852_855delTATG was the most common one. A total of 5 novel mutation loci were discovered in this study with c.1841+3_1841+4del, c.511dupG and c.889G>T predicted as pathogenic variants. Special formula of lactose-free and fortified medium-chain triglyceride (MCT) were used in confirmed cases and most of the symptoms were relieved within 1 year and abnormal indicators significantly improved.Conclusions:The prevalence of NICCD in Xuzhou was 1/36,038. c.852_855delTATG mutation is the most frequent one. Five novel mutation loci are discovered, expanding the SLC25A13 gene mutation spectrum. Most infants with NICCD have a good prognosis, requiring early diagnosis, treatment and life-long follow-up.

Objective:To evaluate the safety and effectiveness of the accurate puncture during sacral neuromodulation (SNM) guided with 3D printing navigation template based on reconstruction techniques using fusing sacral CT and MRI images.Methods:Totally 42 patients operated with SNM were selected in Renji Hospital, School of Medicine, Shanghai Jiaotong University from July 2016 to August 2017. The patients were randomly divided into control group ( n=22) and experimental group ( n=20) using random number table. The conventional cross-positioning technique under X-ray was used for puncture during SNM in the control group. While in the experimental group, the sacral CT and MRI images were fused for reconstruction and design of the navigation template, printed by 3D technique for the puncture in SNM. The times of punctures, the average time for puncture operation, the time of intraoperative testing of the stimulator device, the minimum onset voltage of the stimulator, the X-ray radiation dose, postoperative curative effect (rate of secondary transformation) and the incidence rate of complications were compared between the two methods using independent-simple t test or χ 2 test. Results:Compared to control group, fewer times of punctures, shorter time needed for puncture operation, shorter time of intraoperative testing of the stimulator, smaller radiation dose and minimum effective voltage were found in the experimental group ( P<0.05). There were 15 and 16 patients who completed the secondary transformation in the control group and experimental group, and there was no significant difference between the two groups (χ2=0.757, P=0.384). There were 3 cases of complications in the control group, including 2 cases of infection and 1 case of bleeding, while no complications in the experimental group. Conclusions:CT and MRI images fusion reconstruction-guided 3D printing navigation template can help perform accurate and safe punctures in SNM. Compared to conventional puncture positioned under X-ray, it can effectively improve the puncture efficiency, and reduce the radiation dose in the operation.

Objective: To estimate the levels of free carnitine and acylcarnitine in neonates, and summarize the incidence and clinical characteristics of carnitine absorption deficiency in Xuzhou. Methods: Between November 2015 and December 2017, 216 903 newborns were recruited with carnitine absorption deficiency screened via tandem mass spectrometry in Xuzhou.They were divided into different groups according to gestational age, birth body weight, blood collecting time and season, in which the group with gestational age <37 weeks was selected as the premature delivery group, and the group with gestational age 37-41^{+ 6} weeks as the normal gestational age group for gestational age analysis, while the group with the birth body mass <2 500 g was selected as low birth body mass group and the group with the birth body mass of 2 500-3 999 g as normal birth body mass group for body mass analysis.SPSS 16.0 software was used for data analysis to clarify the influence of the above factors on the detection of carnitine indexes by tandem mass spectrometry.DNA sequencing was performed to confirm the diagnosis and analyze the relevant pathogenic genotypes in children with positive screening, and these confirmed individuals were followed up. Results: There was no statistical difference in the levels of C3, C8 and C102 between preterm infants and normal body mass infants in the gestational age group(all P>0.05), but other carnitine levels had statistically significant differences(all P<0.05). The difference of C102 level between the different birth weight groups was not statistically significant(P>0.05), but that of other carnitine levels were statistically significant(all P<0.05). There was no significant difference in the level of C182 between different blood collection time(P>0.05). The levels of free carnitine and acylcarnitine between the different season groups had statistically significant differences(all P<0.05). Primary carnitine deficiency was diagnosed in 10 cases, including 7 cases of maternal carnitine absorption deficiency.The incidence in Xuzhou was approximately 121 690.The pathogenic genotype showed a specific regional distribution characteristic in Xuzhou, in which pathogenic mutation type c. 1400C >G was the most common one. Conclusions Some factors play a role in neonatal screening for carnitine absorption deficiency by tandem mass spectrometry including gestational age, birth body weight, blood collecting time and season.Pathogenic genes present a regional characteristic in Xuzhou and maternal carnitine absorption deficiency with a higher rate, the clinical attention should be paid to screening for maternal carnitine absorption deficiency.

Objective To investigate the clinical features and SLC22A5 gene mutation types in patients with primary carnitine deficiency(PCD).Methods The free carnitine(CO) and acylcarnitine levels in the blood of 210 908 neonates from newborn screening program and 576 children with suspected clinical inherited metabolic diseases were measured by using liquid chromatography tandem mass spectrometry method during September 2015 to December 2017,after that the SLC22A5 gene mutations were analyzed in the children with low CO level and the diagnosis was made.The clinical characteristics,laboratory findings,genotypes,treatment and prognosis were retrospectively analyzed in patients.Paired sample t test was used to compare the biochemical indexes of patients before and after the treatments.Results Ten children were diagnosed with PCD(9 cases from newborn screening program,1 case from clinical patients),and 7 children were diagnosed with maternal carnitine deficiency.After treatment with oral Levocarnitine,the free carnitine and acylcarnitine of the patients returned to the normal levels.The clinical symptoms disappeared in 1 patient out of clinical patients,and the other 16 patients from newborn screening program were asymptomatic and showed normal growth and development.Seventeen patients got genetic analysis,and 10 types of mutations were found,including c.1400C ＞ G,c.1462C ＞ T,c.797C ＞ T,c.95A ＞ G,c.92C ＞ T,c.1093A ＞ C,c.761G ＞ A,c.865C ＞ T,c.428C ＞ T,c.1195C ＞ T,among which two of them (c.1093A ＞ C and c.92C ＞ T) were novel mutations.The most common mutation of SLC22A5 gene was c.1400C ＞ G.Conclusions Liquid chromatography tandem mass spectrometry technology is sufficient to screen newborns and maternal carnitine deficiency,and the c.1400C ＞ G mutation is found at the highest frequency in Xuzhou area.If patients receive early treatment,they may have a good prognosis.

Objective To investigate the effect of Bortezomib on renal tubular epithelialmesenchymal transition (EMT),and to determine whether Smad ubiquitin regulatory factor 2 (Smurf2) expression induced by tumor necrosis factor-α (TNF-α) can be reversed by Bortezomib in human renal tubular epithelial cells (HK-2).Methods The HK-2 cells were divided into control group (cultured with fetal bovine serum),TNF-α group (cultured with TNF-α),Bortezomib group (cultured with Bortezomib) and experimental group (treated with Bortezomib and TNF-α together).Each group of cells was observed under an inverted microscope,and then the cells of each group were collected.RT-PCR and Western blotting were performed to detect the expression levels of fibronectin (FN),Smurf2,E-cadherin and α-smooth muscle actin (α-SMA).Results As compared with the TNF-α-treated group,the morphology of HK-2 cells was still cobblestone-like after intervention with bortezomib;however,the cellular morphology did not change significantly in the bortezomib-treated group as compared with the control group.As compared with the control group,the expression of FN mRNA and protein in the TNF-α group was significantly increased (P＜0.05).As compared with the TNF-α group,bortezomib inhibited the expression of FN induced by TNF-α (P＜0.05) There was no significant difference in the expression of FN between bortezomib-treated group and control group (P ＞0.05).As compared with the control group,E cadherin was significantly decreased in HK-2 cellsafter treatment with TNF-α,and α-SMA was significantly increased (P＜0.05).As compared with TNFα group,co-stimulation with bortezomib reversed the expression of E cadherin and α-SMA induced by TNF-α (P ＜ 0.05),but the expression of E-cadherin and α-SMA did not change significantly in the bortezomib-treated group as compared with the control group (P ＞ 0.05).As compared with the control group,TNF-α could increase the expression of Smurf2 mRNA and protein (P＜0.05),and bortezomib could inhibit the increase in Smurf2 induced by TNFα (P＜0.05).As compared with the control group,the expression of Smurf2 did not change significantly in the bortezomib-treated group (P＞0.05).Conclusion Bortezomib can antagonize the expression of Smurf2 and EMT induced by TNF-α in HK-2 cells.

Objective To explore the role and mechanism of tumor necrosis factor-α (TNF-α) in the formation of chronic transplant renal interstitial fibrosis and to study Smurf2 expression change and role played in this process.Methods We collected 26 cases of normal renal tissues and 26 cases of renal allograft specimens from chronic allograft dysfunction patients to observe the degree of renal interstitial fibrosis by Hematoxylin and eosin (HE) staining and Masson staining.Immunohistochemical staining was applied to detect the expression and distribution of E-cadherin,α-smooth muscle actin (α-SMA) and TNF-α,Smad ubiquitination regulatory factor 2 (Smurf2).Furthermore,The HK2 cells were divided into five groups depending on different concentrations of TNF-α (0,10,20,50,and 100 ng/mL).After 48 h,we collected the cells to analyze the expression changes of Smurf2,E-cad,α-SMA by Western blotting.Results As compared with normal group,the degree of renal interstitial fibrosis in CAD group was aggravated according to the results of HE and Masson staining (P＜0.01).Immunohistochemical staining results showed that the positive expression of E-cadherin was reduced,and that of α-SMA,TNF-α and Smurf2 increased greatly in CAD group as compared with normal group (P＜0.01).The results of Western blotting also revealed that after treatment with different concentrations of TNF-α for 48 h,the expression of E-cadherin was downregulated,and that of α-SMA and smurf2 was up-regulated in HK2 cells (P＜0.05).Conclusion TNF-α may promote the formation of allograft renal interstitial fibrosis via transdifferentiation of human tubular epithelial cells to mesenchymal cells by up-regulating the expression of Smurf2.

Objective:To evaluate whether urological patients at nutritional risk are at higher risk for complications after radical cystectomy than those not at nutritional risk .Methods:We performed a retro-spective observational study in the consecutive patients undergoing radical cystectomy between 2010 and 2013 .A total of 147 patients were enrolled in this study .The nutritional risk score was assessed preoper-atively by a specialized study nurse .The patients with NRS ( nutritional risk screening ,NRS2002) scores≥3 were considered to have nutritional deficiency .Postoperative complications were defined using the standardized Clavien-Dindo classification .Univariate and multivariate analyses were performed to identify the predictors of complications.Results:The patients aged ≥70 years(50.57%) were more prone to nutritional risk than those aged <70 years (31.67%, P=0.023).Of the 63 patients at nutritional risk, 39 (61.90%) presented with at least 1 complication compared with 29 of the 84 controls (34.52%, P=0 .001 ) .The patients at nutritional risk were at threefold risk for complications on binary Logistic analysis (OR=3.128,95%CI 1.538-6.361,P=0.002).The length of hospital stay of the patients at higher nutritional risk was longer than that of those without nutritional risk [(12.9 ±5.7) d vs.(10.4 ± 4.3) d, P=0.003].Conclusion:The patients aged ≥70 years are at higher nutritional risk than that of those aged <70 years .Patients at nutritional risk are more prone to complications after radical cystectomy .