Erdheim-Chester disease (ECD) is an uncommon non-Langerhans cell histiocytosis that affects multiple body systems and can present clinically in a myriad of ways. We report the case of a 29-year-old man presented with ...Erdheim-Chester disease (ECD) is an uncommon non-Langerhans cell histiocytosis that affects multiple body systems and can present clinically in a myriad of ways. We report the case of a 29-year-old man presented with fever and diffuse bone pain. Physical examination showed bilateral and symmetrical long bone pain, especially the knees. Radiographs showed multiple mixed bone lesions with sclerotic and lytic areas of the femora, tibiae, and fibula. Biopsy of the tibial area displayed foamy lipid-laden histiocytes, confirming the diagnosis of ECD.展开更多
Environmental exposure to pesticides is widespread and commonly occurs in mixtures,and pregnant women are particularly concerned.Trimethylamine N-oxide(TMAO),a dietary-derived catabolite linked to cardiometabolic dise...Environmental exposure to pesticides is widespread and commonly occurs in mixtures,and pregnant women are particularly concerned.Trimethylamine N-oxide(TMAO),a dietary-derived catabolite linked to cardiometabolic disease,may be influenced by pesticide exposure.However,limited knowledge exists regarding the associations,and studies have primarily been restricted to single pesticides.To address this gap,we examined the associations of pesticide exposure with urinary TMA,TMAO,and TMAO-to-TMA ratio among 1067 pregnant women residing in a rural area.Latent class analysis(LCA)was applied to identify distinct patterns of pesticide exposure based on urinary metabolite concentrations.Multiple linear regression(MLR)models and Bayesian kernel machine regression(BKMR)models were employed to estimate the effects of single pesticides,exposure patterns,and combined exposure.Four distinct pesticide exposure patterns were identified.Higher concentrations of pesticide metabolites were found to be associated with increased urinary TMAO levels(β:0.043 to 0.254,p<0.05).In the MLR models for individual pesticides and exposure patterns,carbofuran phenol(CFP),pentachlorophenol(PCP),and 2-phenylphenol(OPP)exhibited positive associations with urinary TMA concentrations,while pyrethroid pesticide metabolites were correlated with the up-regulation of the TMAO-to-TMA ratio.Significant positive associations of pesticide mixtures with TMA,TMAO,and TMAO-to-TMA ratio were observed in the BKMR model,primarily driven by PCP and trans-DCCA.Our findings provided a perspective to reveal that the mechanisms and contributions to TMAO alterations may vary among different pesticides in mixture exposure.展开更多
Granulocyte-macrophage colony-stimulating factor （GM-CSF） is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses ...Granulocyte-macrophage colony-stimulating factor （GM-CSF） is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells （DCs） could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus （HBV） therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine （rHBVvac） in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic （HBsAg-Tg） animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-y production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8＋ T cells from immunized animals, antigen-specific CD8＋ T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients.展开更多
Background and Aims:Ravidasvir(RDV)is a new generation pangenotypic hepatitis C virus(HCV)NS5A inhibitor,with high barrier to baseline resistance-associated species.This is the first phase 2/3 study conducted in China...Background and Aims:Ravidasvir(RDV)is a new generation pangenotypic hepatitis C virus(HCV)NS5A inhibitor,with high barrier to baseline resistance-associated species.This is the first phase 2/3 study conducted in China's Mainland confirming the efficacy and safety of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks in treatment-naive noncirrhotic patients with genotype 1 infection in a large population.Methods:In this multicenter,randomized,doubleblinded,placebo-controlled phase 2/3 trial(NCT03362814),we enrolled 424 treatment-nafve,noncirrhotic adult HCV genotype 1 patients.All patients were randomized at 3∶1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day(body weight<75/≥75 kg)(n=318)or placebo(n=106)for 12 weeks.The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment,and the safety was evaluated and compared between treatment and placebo groups.Results:The overall rate of sustained virological response at 12 weeks after treatment is 99%(306/309,95%,CI:97%-100%)under per protocol set analysis.All patients harboring baseline NS5A resistance-associated species in the treatment group(76/76,per protocol set)achieved sustained virological response at 12 weeks after treatment.No treatment-related serious adverse events were reported.Laboratory abnormalities showed mild or moderate severity(grade 1 and grade 2)in liver function tests.Conclusions:In treatment-na(i)ve,noncirrhotic HCV Chinese patients infected with HCV genotype 1,all-oral regimen of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks was highly efficacious,safe,and well tolerated.展开更多
Background and Aims:A functional cure,or hepatitis B virus(HBV)surface antigen(HBsAg)loss,is difficult to achieve in patients with hepatitis B virus e antigen(HBeAg)-positive chronic hepatitis B.The HBV vaccine and gr...Background and Aims:A functional cure,or hepatitis B virus(HBV)surface antigen(HBsAg)loss,is difficult to achieve in patients with hepatitis B virus e antigen(HBeAg)-positive chronic hepatitis B.The HBV vaccine and granulocyte-macrophage colony-stimulating factor(GM-CSF)have been reported to help reduce HBsAg levels and promote HBsAg loss.In this prospective randomized trial,we evaluated HBsAg loss in patients receiving pegylated interferon α2b(PEGIFN-α2b)and tenofovir disoproxil fumarate(TDF),with and without GM-CSF and HBV vaccination.Methods:A total of 287 patients with HBeAg positive chronic hepati-tis B and seroconversion after nucleot(s)ide analog treat-ment were assigned randomly to three treatment groups for 48 weeks,TDF alone(control),PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine.The prima-ry endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.Resu/ts:The cumulative HBsAg loss rates in the control,PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine groups at week 48 were 0.0%,28.3%,and 41.1%,respec-tively.The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%,21.7%,and 33.9%,respec-tively.Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss(p=0.017)and seroconversion(p=0.030).Con-clusions:In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment,immunomodulatory/antiviral treatment regimens effective-ly improved HBsAg loss,and the regimen including GM-CSF and HBV vaccination was most effective.展开更多
Dear Editor,With an estimated 240 million chronically infected people worldwide,hepatitis B virus(HBV)infection is a major public health problem(Schweitzer et al.,2015).Despite more than 30 years of in tense research,...Dear Editor,With an estimated 240 million chronically infected people worldwide,hepatitis B virus(HBV)infection is a major public health problem(Schweitzer et al.,2015).Despite more than 30 years of in tense research,many aspects of the HBV life cycle still remain unknown.展开更多
In this paper, microstructure and mechanical properties of welding metals in 610 MPa high strength low alloy （HSLA） were studied after high-heat-input welding. Both the base material and the weld joint proved excell...In this paper, microstructure and mechanical properties of welding metals in 610 MPa high strength low alloy （HSLA） were studied after high-heat-input welding. Both the base material and the weld joint proved excellent strength and toughness by vibratory electrogas arc （VEGA） welding under 90 to 100 kJ/cm heatinput. The heat-affected zone （HAZ） was comprised of fine-grain zone （FGZ） and coarse-grain zone （CGZ）, which characterizes fine granular structure and lathing-bainite substructure, It has found that large quantity of dispersed TiN and M23E6 precipitates restrain structure growing in HAZ and strengthen the weldment together with dislocations in the welded joint.展开更多
Background and aims:Tenofovir disoproxil fumarate(TDF)is the first-line therapy for chronic hepatitis B.This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatiti...Background and aims:Tenofovir disoproxil fumarate(TDF)is the first-line therapy for chronic hepatitis B.This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis from China.Methods:Patients were assessed for incidence of newly diagnosed hepatocellular carcinoma(HCC)and disease progression,liver stiffness measurement(LSM),virological suppression(serum hepatitis B virus DNA<20 IU/mL),alanine aminotransferase normalization,hepatitis B e antigen(HBeAg)loss and seroconversion,histological liver fibrosis score,and safety at Week 144.Results:Overall,197 patients were enrolled.At Week 144,the incidence of newly diagnosed HCC was observed in 2.1%patients,and the incidence of disease progression was observed in 3.6%patients.The mean(standard deviation)change in LSM from baseline was5.1(5.85)kPa.Serum hepatitis B virus DNA<20 IU/mL was observed in 94.1%patients,alanine aminotransferase normalization in 33.5%patients,HBeAg loss in 35.6%patients,and HBeAg seroconversion in 14.4%patients.Among patients with stage F3 or F4 fibrosis at baseline by LSM,38.3%patients regressed to stage F0/1,and 22.0%of patients regressed to stage F2 at Week 144.Overall,67.7%patients experienced≥1 adverse events,13.8%patients experienced TDF-related adverse events,and 16.4%patients experienced serious(none were TDF-related).Conclusions:At Week 144 of TDF treatment,low incidence of HCC and disease progression were reported.Virological suppression was observed in 94.1%patients,which was associated with fibrosis regression.No new safety events were identified.展开更多
文摘Erdheim-Chester disease (ECD) is an uncommon non-Langerhans cell histiocytosis that affects multiple body systems and can present clinically in a myriad of ways. We report the case of a 29-year-old man presented with fever and diffuse bone pain. Physical examination showed bilateral and symmetrical long bone pain, especially the knees. Radiographs showed multiple mixed bone lesions with sclerotic and lytic areas of the femora, tibiae, and fibula. Biopsy of the tibial area displayed foamy lipid-laden histiocytes, confirming the diagnosis of ECD.
文摘Environmental exposure to pesticides is widespread and commonly occurs in mixtures,and pregnant women are particularly concerned.Trimethylamine N-oxide(TMAO),a dietary-derived catabolite linked to cardiometabolic disease,may be influenced by pesticide exposure.However,limited knowledge exists regarding the associations,and studies have primarily been restricted to single pesticides.To address this gap,we examined the associations of pesticide exposure with urinary TMA,TMAO,and TMAO-to-TMA ratio among 1067 pregnant women residing in a rural area.Latent class analysis(LCA)was applied to identify distinct patterns of pesticide exposure based on urinary metabolite concentrations.Multiple linear regression(MLR)models and Bayesian kernel machine regression(BKMR)models were employed to estimate the effects of single pesticides,exposure patterns,and combined exposure.Four distinct pesticide exposure patterns were identified.Higher concentrations of pesticide metabolites were found to be associated with increased urinary TMAO levels(β:0.043 to 0.254,p<0.05).In the MLR models for individual pesticides and exposure patterns,carbofuran phenol(CFP),pentachlorophenol(PCP),and 2-phenylphenol(OPP)exhibited positive associations with urinary TMA concentrations,while pyrethroid pesticide metabolites were correlated with the up-regulation of the TMAO-to-TMA ratio.Significant positive associations of pesticide mixtures with TMA,TMAO,and TMAO-to-TMA ratio were observed in the BKMR model,primarily driven by PCP and trans-DCCA.Our findings provided a perspective to reveal that the mechanisms and contributions to TMAO alterations may vary among different pesticides in mixture exposure.
文摘Granulocyte-macrophage colony-stimulating factor （GM-CSF） is known to be a potential vaccine adjuvant despite contradictory results from animal and human studies. The discrepancies may be due to the different doses and regimens of GM-CSF that were used, given that either mature or immature dendritic cells （DCs） could be induced under different conditions. To test the hypothesis that GM-CSF can be used as a novel adjuvant for a hepatitis B virus （HBV） therapeutic vaccine, we administered GM-CSF once per day for three days prior to vaccination with recombinant HBV vaccine （rHBVvac） in mice. We observed greater DC maturation in these pre-treated animals at day 3 as compared to day 1 or day 2 of daily GM-CSF administration. This strategy was further investigated for its ability to break the immune tolerance established in hepatitis B surface antigen-transgenic （HBsAg-Tg） animals. We found that the levels of induced anti-HBsAg antibodies were significantly higher in animals following three days of GM-CSF pre-treatment before rHBV vaccination after the third immunization. In addition to the increase in anti-HBsAg antibody levels, cell-mediated anti-HBsAg responses, including delayed-type hypersensitivity, T-cell proliferation, interferon-y production, and cytotoxic T lymphocytes, were dramatically enhanced in the three-day GM-CSF pre-treated group. After adoptive transfers of CD8＋ T cells from immunized animals, antigen-specific CD8＋ T cells were observed in the livers of recipient HBsAg-Tg animals. Moreover, the three-day pre-treatments with GM-CSF prior to rHBVvac vaccination could significantly eliminate HBsAg-positive hepatocytes, suggesting beneficial therapeutic effects. Therefore, this protocol utilizing GM-CSF as an adjuvant in combination with the rHBVvac vaccine has the potential to become a novel immunotherapy for chronic hepatitis B patients.
基金Ascletis BioScience Co.,Ltd.provided financial support for this study
文摘Background and Aims:Ravidasvir(RDV)is a new generation pangenotypic hepatitis C virus(HCV)NS5A inhibitor,with high barrier to baseline resistance-associated species.This is the first phase 2/3 study conducted in China's Mainland confirming the efficacy and safety of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks in treatment-naive noncirrhotic patients with genotype 1 infection in a large population.Methods:In this multicenter,randomized,doubleblinded,placebo-controlled phase 2/3 trial(NCT03362814),we enrolled 424 treatment-nafve,noncirrhotic adult HCV genotype 1 patients.All patients were randomized at 3∶1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day(body weight<75/≥75 kg)(n=318)or placebo(n=106)for 12 weeks.The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment,and the safety was evaluated and compared between treatment and placebo groups.Results:The overall rate of sustained virological response at 12 weeks after treatment is 99%(306/309,95%,CI:97%-100%)under per protocol set analysis.All patients harboring baseline NS5A resistance-associated species in the treatment group(76/76,per protocol set)achieved sustained virological response at 12 weeks after treatment.No treatment-related serious adverse events were reported.Laboratory abnormalities showed mild or moderate severity(grade 1 and grade 2)in liver function tests.Conclusions:In treatment-na(i)ve,noncirrhotic HCV Chinese patients infected with HCV genotype 1,all-oral regimen of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks was highly efficacious,safe,and well tolerated.
基金Ministry of science and technology of China(2017ZX10202202)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-045)National Key R&D Program of China(2022YFC2304500).
文摘Background and Aims:A functional cure,or hepatitis B virus(HBV)surface antigen(HBsAg)loss,is difficult to achieve in patients with hepatitis B virus e antigen(HBeAg)-positive chronic hepatitis B.The HBV vaccine and granulocyte-macrophage colony-stimulating factor(GM-CSF)have been reported to help reduce HBsAg levels and promote HBsAg loss.In this prospective randomized trial,we evaluated HBsAg loss in patients receiving pegylated interferon α2b(PEGIFN-α2b)and tenofovir disoproxil fumarate(TDF),with and without GM-CSF and HBV vaccination.Methods:A total of 287 patients with HBeAg positive chronic hepati-tis B and seroconversion after nucleot(s)ide analog treat-ment were assigned randomly to three treatment groups for 48 weeks,TDF alone(control),PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine.The prima-ry endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks.Resu/ts:The cumulative HBsAg loss rates in the control,PEGIFN-α2b+TDF,and PEGIFN-α2b+TDF+GM-CSF+HBV vaccine groups at week 48 were 0.0%,28.3%,and 41.1%,respec-tively.The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%,21.7%,and 33.9%,respec-tively.Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss(p=0.017)and seroconversion(p=0.030).Con-clusions:In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment,immunomodulatory/antiviral treatment regimens effective-ly improved HBsAg loss,and the regimen including GM-CSF and HBV vaccination was most effective.
文摘Dear Editor,With an estimated 240 million chronically infected people worldwide,hepatitis B virus(HBV)infection is a major public health problem(Schweitzer et al.,2015).Despite more than 30 years of in tense research,many aspects of the HBV life cycle still remain unknown.
文摘In this paper, microstructure and mechanical properties of welding metals in 610 MPa high strength low alloy （HSLA） were studied after high-heat-input welding. Both the base material and the weld joint proved excellent strength and toughness by vibratory electrogas arc （VEGA） welding under 90 to 100 kJ/cm heatinput. The heat-affected zone （HAZ） was comprised of fine-grain zone （FGZ） and coarse-grain zone （CGZ）, which characterizes fine granular structure and lathing-bainite substructure, It has found that large quantity of dispersed TiN and M23E6 precipitates restrain structure growing in HAZ and strengthen the weldment together with dislocations in the welded joint.
基金supported by GlaxoSmithKline(China)R&D Company Limited.
文摘Background and aims:Tenofovir disoproxil fumarate(TDF)is the first-line therapy for chronic hepatitis B.This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis from China.Methods:Patients were assessed for incidence of newly diagnosed hepatocellular carcinoma(HCC)and disease progression,liver stiffness measurement(LSM),virological suppression(serum hepatitis B virus DNA<20 IU/mL),alanine aminotransferase normalization,hepatitis B e antigen(HBeAg)loss and seroconversion,histological liver fibrosis score,and safety at Week 144.Results:Overall,197 patients were enrolled.At Week 144,the incidence of newly diagnosed HCC was observed in 2.1%patients,and the incidence of disease progression was observed in 3.6%patients.The mean(standard deviation)change in LSM from baseline was5.1(5.85)kPa.Serum hepatitis B virus DNA<20 IU/mL was observed in 94.1%patients,alanine aminotransferase normalization in 33.5%patients,HBeAg loss in 35.6%patients,and HBeAg seroconversion in 14.4%patients.Among patients with stage F3 or F4 fibrosis at baseline by LSM,38.3%patients regressed to stage F0/1,and 22.0%of patients regressed to stage F2 at Week 144.Overall,67.7%patients experienced≥1 adverse events,13.8%patients experienced TDF-related adverse events,and 16.4%patients experienced serious(none were TDF-related).Conclusions:At Week 144 of TDF treatment,low incidence of HCC and disease progression were reported.Virological suppression was observed in 94.1%patients,which was associated with fibrosis regression.No new safety events were identified.
