Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.

Exonuclease I and III improve the detection efficacy of hepatitis B virus covalently closed circular DNA.

BACKGROUND: Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is an important biomarker of hepatitis B virus infection. However, the current methods are not specific and sensitive. The present study aimed to develop a specific and sensitive assay method for the quantification of HBV cccDNA. METHODS: Exonuclease I (Exo I) & Exonuclease III (Exo III) and specific primer probes are used in real-time PCR. The virus particles isolated from peripheral blood mononuclear cells were used as negative control and HBV1.3 recombinant plasmid 3.2 kb circular DNA fragment was used as positive control. The methods of cccDNA detection were evaluated in cell lines, plasmid, animal model, patient serum and liver biopsies. RESULTS: A linear range of 101-107 copies/assay using specific primers for HBV cccDNA was established. HBV cccDNA were only detected in cell lines, animal model and liver tissue. It cannot be detected in serum samples. Intrahepatic HBV cccDNA level had good correlation with intrahepatic total HBV DNA level (r = 0.765, P < 0.001). CONCLUSIONS: The real-time quantitative PCR is an effective and feasible method for sensitive and specific detection of low copy number of cccDNA. The novel detection method is fast, provides high sensitivity and specificity and can be used in clinical practice.

Dibromidobis{1-[4-(pyridin-4-yl)phen-yl]ethanone-κN}mercury(II).

In the title compound, [HgBr(2)(C(13)H(11)NO)(2)], the Hg(II) atom adopts a four-coordinated HgN(2)Br(2) geometry, formed by two pyridine N atoms from two ligands and two bromide anions. The complex is located on a twofold axis. The coordination geometry is close to forming a see-saw (SS-4) polyhedron, the symmetry-related organic ligands being almost perpendicular; the dihedral angles between the two pyridine rings and between the two benzene rings are 85.5 (4) and 87.7 (4)°, respectively. Within the organic ligand, the pyridine ring is nearly coplanar with the benzene ring [dihedral angle = 13.1 (8)°]. In the crystal, the mol-ecular complexes are connected through weak inter-molecular C-H⋯Br contacts.

Efficacy and safety of moxibustion for benign prostatic hyperplasia: A protocol of systematic review and meta-analysis.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate gland that is common in older men. The clinical manifestations of BPH are frequent urination, urgency, incomplete dribbling of urine, and urinary retention. Moxibustion, as a convenient, safe and effective method, has been widely applied in the clinical treatment of BPH. The study aim to assess the efficacy and safety of moxibustion for BPH. METHODS: The following electronic databases will be searched regardless of language and publication status: Pubmed, MEDLINE, EMBASE, China Biomedical Database, China National Knowledge Infrastructure, VIP Database, and Wanfang Database, to select studies that meet the requirements. The study will consist of a prospective randomised controlled clinical trials (RCTs) of moxibustion in the treatment of BPH, language of publication does not have barrier of blinding or restrictions, adverse events will be assessed and reported for safety assessment. Two reviewers will independently conduct and screen all included studies and the meta-analysis will be performed with RevMan V5.3. RESULTS: The study will provide a high-quality convincing assessment of efficacy and safety of moxibustion for BPH. CONCLUSION: The conclusion of this study will provide the latest evidence for judging whether moxibustion is effective and safe in the treatment of BPH. TRIAL REGISTRATION NUMBER: INPLASY2021120021.

[Relationship between Early Treatment Response and Prognosis in Children with Acute Lymphoblastic Leukemia].

OBJECTIVE: To analyze the relationship between the early treatment response and the pregnosis in children with acute lymphoblastic leukemia(ALL). METHODS: Two hundred and Seventy-eight ALL children diagnosed and treated in Hainan general hospital from March 2013 to March 2017 were collected. All ALL children received therapy with CCLg-ALL-2008 regimen. The 3 year event-free survival (EFS) rate of ALL children in different groups was analyzed in terms of 4 indexes including sensitivity response to prednison at day 8 (D8-SRP), bone marrow remission at day 15 (D15-BMR) and at day 33 (D33-BMR), and minimal residual disease at day 33 (D33-BMR), and minimal residual disease at day 33(D33-MRD). These 4 indexes and other indexes possibly affecting the prognosis of ALL children were enrolled in Cox regression model for analysis of independent factors affecting the prognosis of ALL children. RESULTS: The D8-SRP test showed that among 269 ALL children, 240(89.22%) cases displayed prednisone poor response (PPR); the 3-year EFS rate in predrisone good response(PGR) group was significantly higher than that in PPR group(P<0.05). The D15-BMR detection showed that among 262 ALL children, the bone marrow remission(BMR) as M1 was observed in 230 cases (87.79%), M2 in 20 cases (7.63%) and M3 in 9 cases (4.58%); the 3-year EFS rate showed as follows:M1 group >M2 group >M3 group(P<0.05). The D33-BMR detection showed that among 257 ALL children, the BMR as M1 was observed in 227 cases (88.33%), M2 in 21 cses(8.17%) and M3 in 9 caes (3.51%); the 3-year EFS rate in 3 groups showed as follows: M1 group >M2 group >M3 group(P<0.05). The D33-MRD detection showed that among 185 ALL children, MRD<10-10 was found in 128 cases (69.19%), MRD≥10-4-10-2 in 43 cases (23.24%), MRD ≥10-2 in 14 cases (7.57%); the 3-year EFS rate in 3 groups showed as follows: MRD <10-4 group > MRD≥ 10-4-10-2 group>MRD≥10-2 group. The Cox regression analysis showed that PPR in D8-SRP test, M2 and M3 in D15 and D33 BMR detection, and MRD≥10-2 in D33 MRD detection as well as T-ALL typing were independent risk factors affecting the prognosis of ALL children. CONCLUSION: The early treatment response can predict the prognosis of ALL children, which is an independent prognostic factor for ALL children.

Diagnostic value of serum hepatitis B virus RNA levels on liver significant inflammation of chronic hepatitis B patients with normal or mildly elevated alanine transaminase levels / 中华传染病杂志

Objective:To investigate the relationship and diagnostic value of serum hepatitis B virus(HBV) RNA on liver significant inflammation in chronic hepatitis B (CHB)patients with normal or mildly elevated alanine transaminase (ALT) levels.Methods:A total of 211 treatment-naive CHB patients with ALT<two times of the upper limit of normal in Shanghai Public Health Clinical Center, Fudan University between January 2016 and June 2019 were retrospectively studied.All of them received liver biopsy. Serum HBV RNA levels were quantified by quantitative reverse transcription polymerase chain reaction. Statistical analyses were performed with t test, Mann-Whitney U test, chi-square test and logistic regression analysis. Results:In 83 hepatitis B e antigen (HBeAg)-positive patients, the serum HBV RNA levels decreased with the increasing severity of liver inflammation ((6.208±1.363) lg copies/mL vs (4.654±0.962) lg copies/mL, t=6.035, P<0.01). In 138 HBeAg-negative patients, the serum HBV RNA levels increased with the increasing severity of liver inflammation ((3.101±0.720) lg copies/mL vs (3.965±0.782) lg copies/mL, t=-5.892, P<0.01). Logistic regression analysis showed that serum HBV RNA level was an independent predictor for significant liver inflammation (odds ratio ( OR)=0.168, P=0.003) in HBeAg-positive patients. Area under receiver operator characteristic curve (AUROC) was 0.82 (95% confidence interval ( CI) 0.73-0.91) of HBV RNA and 0.56(95% CI 0.44-0.69) of ALT for the diagnosis of significant liver inflammation. The difference was statistically significant ( z=2.975, P=0.003). Serum HBV RNA ( OR=4.960, P<0.01), γ-glutamyl transpeptidase ( OR=1.021, P=0.019) and blood platelet (PLT) ( OR=0.987, P=0.008) were independent predictors for significant liver inflammation in HBeAg-negative patients. The AUROC of HBV RNA and ALT was 0.78(95% CI 0.69-0.87) and 0.65(95% CI 0.55-0.75), respectively. The AUROC of combination diagnostic model consisting of HBV RNA, γ-glutamyl transpeptidase and blood platelet was 0.86(95% CI 0.79-0.93) for the diagnosis of significant liver inflammation. Conclusions:The serum HBV RNA levels are significantly different among the different phases of liver inflammation in treatment-naive CHB patients with normal or mildly elevated ALT levels. Inflammation-related serum HBV RNA and combination diagnostic model are expected to be the novel non-invasive diagnostic biomarkers for significant liver inflammation and of great benefit for determining the time for clinical medication of treatment-naive CHB patients.

Aberrant DNA methylation of P16, MGMT, hMLH1 and hMSH2 genes in combination with the MTHFR C677T genetic polymorphism in gastric cancer.

Associations of P16, MGMT, hMLH1 and hMLH2 with gastric cancer and their relation with MTHFR status in gastric patients who were confirmed with pathological diagnosis were assessed. Aberrant DNA methylation of P16, MGMT, hMLH1 and hMLH2 and polymorphisms of MTHFR C677T were assayed. The proportional DNA hypermethylation in P16, MGMT, hMLH1 and hMLH2 in cancer tissues was significantly higher than in remote normal-appearing tissues. DNA hypermethylation of P16 and MGMT was correlated with the T and N stages. Individuals with homozygotes (TT) of MTHFR C677T had significant risk of hypermethylation of MGMT in cancer tissues [OR (95% CI)= 3.47(1.41-7.93)]. However, we did not find association between polymorphism in MTHFR C677T and risk of hypermethylation in P16, MGMT, hMLH1 and hMLH2 genes either in cancer or remote normal-appearing tissues. Aberrant hypermethylation of P16, MGMT, hMLH1 and hMLH2 could be predictive of gastric cancer.

Relationship between Early Treatment Response and Prognosis in Children with Acute Lymphoblastic Leukemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the relationship between the early treatment response and the pregnosis in children with acute lymphoblastic leukemia(ALL).</p><p><b>METHODS</b>Two hundred and Seventy-eight ALL children diagnosed and treated in Hainan general hospital from March 2013 to March 2017 were collected. All ALL children received therapy with CCLg-ALL-2008 regimen. The 3 year event-free survival (EFS) rate of ALL children in different groups was analyzed in terms of 4 indexes including sensitivity response to prednison at day 8 (D8-SRP), bone marrow remission at day 15 (D15-BMR) and at day 33 (D33-BMR), and minimal residual disease at day 33 (D33-BMR), and minimal residual disease at day 33(D33-MRD). These 4 indexes and other indexes possibly affecting the prognosis of ALL children were enrolled in Cox regression model for analysis of independent factors affecting the prognosis of ALL children.</p><p><b>RESULTS</b>The D8-SRP test showed that among 269 ALL children, 240(89.22%) cases displayed prednisone poor response (PPR); the 3-year EFS rate in predrisone good response(PGR) group was significantly higher than that in PPR group(P<0.05). The D15-BMR detection showed that among 262 ALL children, the bone marrow remission(BMR) as M1 was observed in 230 cases (87.79%), M2 in 20 cases (7.63%) and M3 in 9 cases (4.58%); the 3-year EFS rate showed as follows:M1 group >M2 group >M3 group(P<0.05). The D33-BMR detection showed that among 257 ALL children, the BMR as M1 was observed in 227 cases (88.33%), M2 in 21 cses(8.17%) and M3 in 9 caes (3.51%); the 3-year EFS rate in 3 groups showed as follows: M1 group >M2 group >M3 group(P<0.05). The D33-MRD detection showed that among 185 ALL children, MRD<10 was found in 128 cases (69.19%), MRD≥10-10 in 43 cases (23.24%), MRD ≥10 in 14 cases (7.57%); the 3-year EFS rate in 3 groups showed as follows: MRD <10 group > MRD≥ 10-10 group>MRD≥10 group. The Cox regression analysis showed that PPR in D8-SRP test, M2 and M3 in D15 and D33 BMR detection, and MRD≥10 in D33 MRD detection as well as T-ALL typing were independent risk factors affecting the prognosis of ALL children.</p><p><b>CONCLUSION</b>The early treatment response can predict the prognosis of ALL children, which is an independent prognostic factor for ALL children.</p>

Growth factors promote the therapeutical effects of autologous bone marrow mesenchymal stem cell transplantation on acute myocardial infarction / 中国组织工程研究

BACKGROUND:The growth factor is a potent mobilization agent for stem cels, which can increase adhesion and proliferation of injected cels, induce stem cels to migrate to the infarct zone, proliferate, differentiate, as wel as participate in myocardiac repair. OBJECTIVE: To investigate the effect of hepatocyte growth factor (HGF) and insulin-like growth factor (IGF) on transplantation of bone marrow mesenchymal stem cels (BMSCs) after acute myocardial infarction. METHODS: Primary rabbit BMSCs were culturedin vitro and labeled by red fluorescence dye CM-Dil for transplantation. After the mid third of left anterior descending was ligated, model rabbits were grouped into four groups: control group, BMSCs group, HGF+IGF group, and HGF+IGF+BMSCs group (n=6 in each group). Different interventional agents were injected into the myocardium at four sites within the ischemic region. Masson trichrome staining was performed to determine viable myocardium, and immunofluorescence staining was used to identify BMSCs differentiation. The cardiac function was assessed with Doppler echocardiography. RESULTS AND CONCLUSION:Four weeks after treatment, CM-Dil/cTNT+ cels significantly increased in the HGF+IGF+BMSCs group, compared with BMSCs group. Consequently, viable myocardial tissues significantly increased, left ventricular ejection fraction was significantly improved, and left ventricular end-diatolic volume significantly decreased in the HGF+IGF+BMSCs group, relative to the other three groups. Combination of HGF and IGF that promotes differentiation of transplanted autologous BMSCs into cardiomyocytes, thus increasing viable myocardium, improving left ventricular function, and inhibiting left ventricular remodeling, may be a new method for the celltreatment of acute myocardial infarction.

[Treatment of proximal tibial multi-segment comminuted fractures with closed reduction and less invasive stabilization systems].

OBJECTIVE: To explore the clinical effects of closed reduction and less invasive stablization system for the treatment of proximal tibial multi-segment comminuted fractures, and to discuss the influence of LISS on reduction and bone union. METHODS: From 2003.7 to 2007.12, 19 patients with proximal tibial multi-segment comminuted fractures were treated with closed reduction and LISS fixation. Fourteen patients were male, 5 patients were female, ranging in age from 21 to 49 years, with an average of 39.2 years. Fifteen patients were injured with direct violence, 4 indirect violence. The reasons of the injuries were vehicle crashes for 14 cases and falling from high places for 3 cases and falling to the ground for 2 cases. All the patients were followed up postoperatively. Callus formation and bony union were recorded by X-ray. RESULTS: All the patients were followed up for a period averaged 12.2 months (ranged 8 to 21 months). No failure of fixation and nonunion. No deformation of plates and screws occurred in patients,no superficial wound infection. According to the criteria of Merchan, 14 patients got an excellent result, 3 good, and 2 poor. CONCLUSION: Closed reduction and less invasive stabilization systems can provide rigid internal fixation for proximal tibial multi-segment comminuted fractures. The LISS provides stable fixation, a high rate of union, and a low rate of infection for proximal tibial multi-segment comminuted fractures.

Clinical characteristics of 638 patients infected with hepatitis C virus by post blood transfusion,in Shanghai / 中华流行病学杂志

Objective To investigate me clinical-epidemiologic characteristics of patients with hepatitis C virus(HCV)infection by post blood transfusion.Methods Polymerase chain reaction (PCR)and enzynle linked immunosorbent assay(ELISA)were used to detect HCV RNA and anti.HCV,respectively.Analysis was performed on patients'age distribution,cause of primary diseases,years ofexposure,ingredient and amount of transfusion,incubation period,disorder on liver function and changes on abdominal ultrasound image,etc.Results HCV RNA levels were higher than 3.0log10 copy/ml in 90.8%infected patients、with a median as 6.10 log10 copy/ml.19.2%of the patients showed viral load 3.0 to 4.0 iog10 copy/ml,and 66.1%of them showed 5.0 to 6.0 log10 copy/ml.Only 14.7%of the infected persons had HCV RNA levels higher than 7.0 log10 copy/ml.Eighty-one point five percent(44/54)of the infected persons were confirmed as HCV RNA positive by HCV RNA qualitative analysis with HCV genotype as primarily type 1.99.8%(636/637)of the pmients were detected as anti-HCV positive by serological test.The sensitivity of serological test was higher than both quantitative and qualitative HCV RNA assays(P=0.000,P=0.000,respectively).HCV infection post blood transfusion was more seen in common people at 40 to 60 years old Most cases(85.7%)had their first exposure during 1990 to 1994.More than 10% of the cases had primary diseases aS obstetrics,orthopedics or gastrointestinal tract hemorrhage.79.9%of the patients received whole blood product transfusion.The mean interval between transfusion and clinical diagnosis was 8.5±5.5 years.90.1%of the infected patients had liver function damage,while most of them showed elevated alanine aminotransferase(ALT)no more than 5 upper limits of normal(ULN).wheteas Serum total bilirubin(TBIL).ALT and aspartate aminotransferase(AST)≥5×ULN level were showing more clinicaI manifestations(P=0.000.P=0.001,P=0.009,respectively).Abdominal ultrasound among 8.9%of the infected persons showed changes in cirrhosis,and most of them werc older than 50years of age.Conclusion Most of the post transfusion HCV infected cases happened in adulthood,and were mainly exposed during 1990 to 1994.Infected pmients usually had their liver function damaged with elevated ALT no more than 5×ULN and with medium HCV RNA levels.HCV genotype was mainly for type 1.Patients who weTe ofolder age showed higher incidence ofcirrhosis.If a patients'infection period Was longer than 5 years,he/she would show higher incidence of cirrhosis.

Treatment of proximal tibial multi-segment comminuted fractures with closed reduction and less invasive stabilization systems / 中国骨伤

<p><b>OBJECTIVE</b>To explore the clinical effects of closed reduction and less invasive stablization system for the treatment of proximal tibial multi-segment comminuted fractures, and to discuss the influence of LISS on reduction and bone union.</p><p><b>METHODS</b>From 2003.7 to 2007.12, 19 patients with proximal tibial multi-segment comminuted fractures were treated with closed reduction and LISS fixation. Fourteen patients were male, 5 patients were female, ranging in age from 21 to 49 years, with an average of 39.2 years. Fifteen patients were injured with direct violence, 4 indirect violence. The reasons of the injuries were vehicle crashes for 14 cases and falling from high places for 3 cases and falling to the ground for 2 cases. All the patients were followed up postoperatively. Callus formation and bony union were recorded by X-ray.</p><p><b>RESULTS</b>All the patients were followed up for a period averaged 12.2 months (ranged 8 to 21 months). No failure of fixation and nonunion. No deformation of plates and screws occurred in patients,no superficial wound infection. According to the criteria of Merchan, 14 patients got an excellent result, 3 good, and 2 poor.</p><p><b>CONCLUSION</b>Closed reduction and less invasive stabilization systems can provide rigid internal fixation for proximal tibial multi-segment comminuted fractures. The LISS provides stable fixation, a high rate of union, and a low rate of infection for proximal tibial multi-segment comminuted fractures.</p>

Preliminary evaluation of magnetic resonance fresh blood imaging for diagnosis of Budd-Chiari syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Budd-Chiari syndrome (BCS) is a rare disease with portal hypertension caused by the blockage of the hepatic vein and/or the inferior vena cava (IVC). Angiography is the "golden standard" for diagnosis, but it is an invasive examination. To assess the diagnostic value of a fresh blood imaging (FBI) relative to BCS, we used a magnetic resonance angiography (MRA) with an FBI sequence for a preoperative evaluation of the BCS patients in this study.</p><p><b>METHODS</b>Fifty patients who were suspected of having BCS after they had been checked by a B-ultrasound were studied. 2D and 3D FBI were performed on a 1.5T superconductive MR scanner. Original images were rebuilt using a maximal intensity projection (MIP) method on the console. Two doctors reviewed all images before they learned of the angiography results. We then compared the diagnoses obtained from the FBI and angiography results to evaluate the diagnostic value of the FBI.</p><p><b>RESULTS</b>Forty-one patients were diagnosed as BCS and 9 as non-BCS based on an angiography. The FBI correctly diagnosed 38 patients, incorrectly diagnosed 1 patient, and missed diagnosis in 3 patients. Thus, the diagnostic sensitivity of the FBI is 93% (38/41), the specificity is 89% (8/9) and the accuracy is 92% (46/50). The FBI images of the 13 membranous stenoses of the IVC showed a sudden stenosis of the post-liver segment of the IVC. The Images of the 5 patients with a membranous obstruction of the IVC showed IVC thickening and an absence of blood signals in the post-hepatic segment of the IVC. The images of the 4 patients with the segmental thrombosis of the IVC showed abnormal and intermittent signals in the IVC. The images of the 6 patients with a simple hepatic vein obstruction showed obstructive hepatic veins. The images of the 6 patients with the stenosis of both the IVC and the hepatic veins showed the stenosis of the IVC, the thickening of the hepatic veins and the formation of a compensatory circulation within the liver. Lastly, the images of the 7 patients showed a combination of the IVC thrombosis with stenosis or with the obstruction of one or two hepatic veins.</p><p><b>CONCLUSIONS</b>An FBI can show a membranous stenosis, and an obstruction and thrombosis of the IVC. In addition, it can also demonstrate the thickening of the flexural hepatic vein and the development of intra-hepatic compensatory branches with slow blood flow. Thus, it can guide the puncturing and opening of the hepatic vein involved in an interventional therapy for BCS patients.</p>