Rice husk hydrochar prepared by hydrochloric acid assisted hydrothermal carbonization for levofloxacin removal in bioretention columns.

Hydrochars are promising adsorbents in pollutant removal for water treatment. Herein, hydrochloric acid (HCl) co-hydrothermally treated hydrochars were prepared from rice husk biomass at 180 °C via a one-step hydrothermal method. Adsorption behaviors of levofloxacin (LVX) on hydrochars were evaluated. The specific surface area and pore volume of the hydrochar synthesized in 5 mol/L HCl (5H-HC) were almost 17 and 8 times of untreated hydrochar, respectively. The 5H-HC sample exhibited the highest LVX adsorption capability at room temperature (107 mg/g). Thermodynamic experimental results revealed that adsorption was a spontaneous endothermic process. Yan model provided the best description of the breakthrough behavior of LVX in bioretention column, indicating that the adsorption on the samples involved several rate-limiting factors including diffusion and mass transfer. The results show that facile HCl co-hydrothermal carbonization of waste biomass can produce novel hydrochars with high LVX adsorption ability.

Integrated HBV DNA and cccDNA maintain transcriptional activity in intrahepatic HBsAg-positive patients with functional cure following PEG-IFN-based therapy.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroclearance marks regression of hepatitis B virus (HBV) infection. However, more than one-fifth of patients with functional cure following pegylated interferon-based therapy may experience HBsAg seroreversion. The mechanisms causing the HBV relapse remain unclear. AIM: To investigate the level and origin of HBV transcripts in patients with functional cure and their role in predicting relapse. METHODS: Liver tissue obtained from patients with functional cure, as well as uncured and treatment-naïve HBeAg-negative patients with chronic hepatitis B (CHB) were analysed for intrahepatic HBV markers. HBV capture and RNA sequencing were used to detect HBV integration and chimeric transcripts. RESULTS: Covalently closed circular DNA (cccDNA) levels and the proportion of HBsAg-positive hepatocytes in functionally cured patients were significantly lower than those in uncured and treatment-naïve HBeAg-negative patients. Integrated HBV DNA and chimeric transcripts declined in functionally cured patients compared to uncured patients. HBsAg-positive hepatocytes present in 25.5% of functionally cured patients, while intrahepatic HBV RNA remained in 72.2%. The levels of intrahepatic HBV RNA, integrated HBV DNA, and chimeric transcripts were higher in functionally cured patients with intrahepatic HBsAg than in those without. The residual intrahepatic HBsAg in functionally cured patients was mainly derived from transcriptionally active integrated HBV DNA; meanwhile, trace transcriptional activity of cccDNA could also remain. Two out of four functionally cured patients with intrahepatic HBsAg and trace active cccDNA experienced HBV relapse. CONCLUSION: Integrated HBV DNA and cccDNA maintain transcriptional activity and maybe involved in HBsAg seroreversion in intrahepatic HBsAg-positive patients with functional cure and linked to virological relapse.

Double Plasma Molecular Adsorption System with Sequential Low-dose Plasma Exchange in Patients with Hepatitis B Virus-related Acute-on-chronic Liver Failure: A Prospective Study.

Background and Aims: To investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-dose plasma exchange (LPE) in treating early hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Methods: Clinical data of patients with HBV-ACLF were prospectively collected, including patients in a DPMAS with sequential LPE (DPMAS+LPE) group and those in a standard medical treatment (SMT) group. The primary endpoint was death or liver transplantation (LT) at 12 weeks of follow-up. Propensity-score matching was performed to control the effects of confounding factors on prognosis between the two groups. Results: After 2 weeks, total bilirubin, alanine aminotransferase, blood urea nitrogen levels, and Chinese Group on the Study of Severe Hepatitis B score, were significantly lower in the DPMAS+LPE group than those in the SMT group (p<0.05). After 4 weeks, laboratory parameters of the two groups were similar. The cumulative survival rate of the DPMAS+LPE group was significantly higher than that of the SMT group at 4 weeks (97.9% vs. 85.4%, p=0.027), but not at 12 weeks (85.4% vs. 83.3%, p=0.687). Cytokine levels were significantly lower in 12-week survival group than in the death-or-LT group (p<0.05). Functional enrichment analysis showed that downregulated cytokines were mainly involved in positive regulation of proliferation and activation of lymphocytes and monocytes, regulation of immune effect response, regulation of endotoxin response, and glial cell proliferation. Conclusion: DPMAS+LPE significantly improved the 4-week cumulative survival rate, and ameliorated the inflammatory response in patients. DPMAS+LPE may be a promising modality for patients with early HBV-ACLF.

A harsh environment resistant robust Co(OH)2@stearic acid nanocellulose-based membrane for oil-water separation and wastewater purification.

Traditional membranes are inefficient in treating highly toxic organic pollutants and oily wastewater in harsh environments, which is difficult to meet the growing demand for green development. Herein, the Co(OH)2@stearic acid nanocellulose-based membrane was prepared by depositing Co(OH)2 on the nanocellulose-based membrane (NBM) through chemical soaking method, which enables efficient oil/water mixtures separation and degradation of pollutants by photocatalysis in harsh environments. The Co(OH)2@stearic acid nanocellulose-based membrane (Co(OH)2@stearic acid NBM) shows good photocatalytic degradation performance for methylene blue pollutants in harsh environment, and has significant degradation rate (93.66%). At the same time, the Co(OH)2@stearic acid NBM with superhydrophobicity and superoleophilicity also exhibits respectable oil/water mixtures separation performance (n-Hexane, dimethyl carbonate, chloroform and toluene) under harsh environment (strong acid/strong alkali), which has an excellent oil-water mixtures separation flux of 87 L·m-2·h-1 (n-Hexane/water) and oil-water mixture separation efficiency of over 93% (n-Hexane/water). In addition, this robust Co(OH)2@stearic acid NBM shows good self-cleaning and recycling performance. Even though seven oil-water separation tests have been carried out under harsh environment, it can still maintain respectable oil-water mixture separation rate and flux. The multifunctional membrane has excellent resistance to harsh environments, oil-water separation and pollutant degradation can be performed even in harsh environments, which provides a convenient way to treat sewage under harsh conditions efficiently and has great potential in practical application.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma.

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Adsorption and photodegradation of reactive red 120 with nickel-iron-layered double hydroxide/biochar composites.

Layered double hydroxide (LDH) materials were widely applied for adsorption and photodegradation of pollutants for wastewater treatment. New efficient LDH materials with adsorption and photodegradation abilities will be promising candidates for pollutants removal. Hence, a series of NiFe-LDH/biochar (NiFe/BC) were fabricated by the coprecipitation method for synergistic adsorption and photodegradation anionic dyes of reactive red 120 (RR120). The removal experiment showed that the addition of an appropriate amount of biochar into NiFe-LDH enhanced the adsorption capacity and its photocatalytic ability. The optimized NiFe/BC2 composite can remove 88.5 % of RR120 under visible light by adsorption and photocatalysis, which was much better than NiFe-LDH (63.3 %) and biochar (2.6 %). The photodegradation kinetic constant of the NiFe/BC2 composite was 3.1 and 104.8 times that of NiFe-LDH and BC. In addition, active species capture experiments and electron spin resonance (ESR) tests revealed the removal mechanisms of NiFe/BC composites for RR120 removal. This work affords a feasible strategy for preparing LDH-based photocatalyst with excellent adsorption and photocatalytic performance for wastewater treatment.

Human liver tissue transcriptomics revealed immunometabolic disturbances and related biomarkers in hepatitis B virus-related acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a major cause of liver-related death worldwide, but its key pathological features remain incompletely defined. This study aimed to reveal the molecular basis of hepatitis B virus-related ACLF (HBV-ACLF) by transcriptome sequencing of human liver tissue. A total of 18 human liver tissues from patients with different stages of HBV-related disease were collected for RNA sequencing, and liver tissues from patients and mouse models with ACLF were used for subsequent validation. Specifically, 6,853 differentially expressed genes (DEGs) and 5,038 differentially expressed transcripts were identified in patients with ACLF compared to patients with chronic hepatitis B (CHB) and normal controls (NCs). Investigation of functional by KEGG pathway enrichment analysis revealed prominent immune and metabolic dysregulation at the ACLF stage. We found that the key genes FGF19, ADCY8 and KRT17, which are related to immunometabolic disturbances, were significantly upregulated in the progression of ACLF. The three key genes were validated in human and mouse samples, indicating their prognostic and therapeutic potential in ACLF. In summary, our work reveals that immunometabolic disorder is involved in HBV-ACLF pathogenesis and indicates that FGF19, ADCY8 and KRT17 may be sensitive biomarkers for HBV-related ACLF.

Virological Changes of Chronic Hepatitis B Patients with Minimally Elevated Levels of Alanine Aminotransferase: A Meta-Analysis and Systematic Review.

Background: Chronic hepatitis B (CHB) patients with normal or minimally increased levels of alanine aminotransferase (ALT) are still at the risk of hepatocellular carcinoma, cirrhotic events, and mortality. However, there is a debate over the initiation of antiviral treatment for these patients. This systematic review and mate-analysis aimed to explore this problem. Methods: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were systematically searched for retrieving relevant studies with risk ratios (RRs) or risk differences (RDs) for virological changes between antivirus-treated and no antivirus-treated CHB patients with ALT levels less than two-fold of the upper limit of normal. Retrieved data ranged from January 1990 to October 2020. Results: Of 6783 abstracts screened, 9 studies met the criteria for inclusion in the systematic review and had a low risk of bias. Among studies that were involved in the meta-analyses, it was found that the rates of HBsAg loss (RR = 12.22, 95% confidence interval (CI): 4.28-34.95, P < 0.001), HBsAg seroconversion (RR = 19.90, 95% CI: 2.75-144.09, P=0.003), and undetectable HBV DNA (RR = 11.89, 95% CI: 2.44-57.89, P=0.002) were both higher in the antiviral treatment group compared with placebo or no treatment group. Subgroup analysis suggested that patients who received interferon (IFN)-based therapy were more inclined to achieve HBsAg loss (P=0.010), HBsAg seroconversion (P=0.020), and HBeAg loss (P=0.002). Conclusion: From a sizable population, it was revealed that CHB patients with normal or minimally increased levels of ALT could benefit from the antiviral therapy, especially those who received IFN-based treatment.

Role of hepatitis B surface antibody in seroreversion of hepatitis B surface antigen in patients achieving hepatitis B surface antigen loss with pegylated interferon-based therapy.

It is unclear whether hepatitis B surface antibody (HBsAb) confers clinical benefits after HBsAg seroclearance, especially in hepatitis B surface antigen (HBsAg) seroreversion and maintenance of HBsAb. We evaluated this in patients (n = 222) with HBsAg loss following treatment with pegylated interferon (PEG-IFN)-based therapy who completed a 48-week follow-up period. Serum hepatitis B virus (HBV) markers and biochemical indicators were evaluated every 3 months. The primary endpoint was HBsAg seroreversion. Factors associated with HBsAg seroreversion were also investigated. HBsAb ≥100 mIU/ml resulted in a lower HBsAg seroreversion rate than an HBsAb-negative status (5.5% vs. 29.5%, p < .001); however, the seroreversion rate was not significantly different between patients with HBsAb 10-100 mIU/ml and those in the HBsAb-negative group. Patients with HBsAb ≥100 mIU/ml had a lower HBsAb loss rate than those with HBsAb 10-100 mIU/ml (7.3% vs. 21.7%, p = .005). The final HBsAg seroreversion and HBV DNA relapse rates were 13.5% and 1.8%, respectively. HBsAb ≥100 mIU/ml at the off-treatment time (odds ratio [OR] 0.110, 95% confidence interval [CI]: 0.034-0.353, p < .001) and treatment time to attain HBsAg loss >28 weeks (OR 2.508, 95% CI: 1.068-5.890, p = .035) were predictors of HBsAg seroreversion. Consolidation therapy for 12-24 weeks resulted in higher HBsAb titres than consolidation therapy for ≤12 weeks in HBsAb-negative patients at the off-treatment time (p < .001). HBsAg seroconversion with HBsAb ≥100 mIU/ml decreases HBsAg seroreversion and provides an efficient maintenance rate of HBsAb. HBsAg seroconversion with high HBsAb titres may be clinically beneficial for chronic hepatitis B treated with PEG-IFN-based therapy.

Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a severe disease with high mortality and global incidence. However, the interaction between the gut microbiome and combined immunotherapy for HCC is yet unclear. In this prospective clinical study, patients with unresectable HCC who had not received systemic treatment previously were recruited. Fecal and serum samples were collected at the baseline point and before each subsequent administration as specified. Between 20 October 2019 and 2 February 2021, 61 patients were screened for eligibility, of whom 35 patients were finally included in this study. Alpha diversity of fecal samples from patients who responded to immunotherapy was higher than that of nonresponders at baseline. However, the prominent alpha-diversity between responders and nonresponders became similar as early as week 6 after treatment. The beta diversity of intergroup did not show significant difference at the ninth week after treatment. Alpha-d-Glucose was the only serum metabolite that differed between the responders and nonresponders after 3 months. Responder-enriched Ruminococcus showed a positive correlation with serum galactaric acid, while Klebsiella was positively associated with 3-methylindole and lenticin (all P < .01). The machine learning classifier based on serum metabolites were more able to discriminate HCC patients who potentially benefited from immunotherapy at baseline (AUC 0.793, 95% CI: 0.632-0.954) than the classifier of gut microbiome. In conclusion, gut microbiome biomarkers are associated with the response to anti-PD-1 based immunotherapy in HCC patients. Classifiers based on gut microbiota and serum metabolites are feasible.

Prognostic value of decline in model for end-stage liver disease score and hepatic encephalopathy in hepatitis B-related acute-on-chronic liver failure patients treated with plasma exchange.

OBJECTIVE: To investigate the prognostic value of Model for End-Stage Liver Disease (MELD) score and Hepatic Encephalopathy (HE) for short-term prognosis of Hepatitis B virus-related Acute-on-Chronic Liver Failure (HBV-ACLF) patients treated with plasma exchange (PE). METHODS: A total of 108 patients with HBV-ACLF treated with PE were retrospectively enrolled between January 2014 to December 2020. Based on survival at 28 days, patients were divided into survival (N = 87) and death groups (N = 21). Clinical data and laboratory indicators were analyzed. RESULTS: Compared with the survival group, the death group was associated with higher ACLF grade and incidence of HE. The levels of total bilirubin, prothrombin time, creatinine, blood urea nitrogen, MELD score, and Chinese Group on the Study of Severe Hepatitis B-ACLF II (COSSH II) score were significantly higher in the death group than in the survival group (p < .05). Grade 1 ACLF and the MELD score after PE treatment at one week were independent risk factors for 28-day liver transplantation-free mortality (OR = 0.062, 95%CI: 0.005-0.768; OR = 1.328, 95%CI: 1.153-1.531). A MELD score at one week of at least 25.5 was associated with a poor short-term prognosis. Of note, HE was a strong independent risk factor for a decline in MELD score at one week. (OR = 11.815, 95%CI: 3.187-43.796, p < 0.001). CONCLUSION: We found patients with HE at admission and MELD score of at least 25.5 at one week after PE treatment had a poor short-term prognosis and should prompt preparation for liver transplantation. Trial Registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565). Registered 13 May 2020.

Long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure: a retrospective study.

BACKGROUND: The long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is not well characterised. We assessed long-term outcomes and the associated risk factors of HBV-ACLF patients in southern China. METHODS: We retrospectively analysed clinical data, adverse events, and clinical endpoint events of HBV-ACLF patients treated at our department between January 2014 and December 2018. RESULTS: A total of 616 (52.3%) patients with cirrhosis and 561 (47.7%) patients without cirrhosis were included. In 973 (83%) patients, the disease was associated only with HBV, while 204 (17%) patients had two or more aetiological factors. The proportion of patients receiving antiviral treatment for HBV was low (20.3%). Further analyses indicated that patients without cirrhosis had a significantly lower 90-day liver transplantation-free mortality and higher 5-year survival rate than those with cirrhosis (59.5% vs. 27.6%; 62% vs. 36%; P < 0.05). Remarkably, self-withdrawal of nucleos(t)ide analog (NA) was an independent risk factor for short-term prognosis. Age, cirrhosis at admission, and platelet level were closely related to long-term prognosis of HBV-ACLF patients. CONCLUSION: The proportion of HBV-ACLF patients receiving antiviral treatment is very low in south China. Cirrhosis at admission has a significant effect on both short-term and long-term prognosis. No significant improvement in the short-term prognosis of HBV-ACLF patients was observed compared with previous studies. More comprehensive access to antiviral treatment and long-term surveillance of HBV patients are key imperatives to reduce the incidence of HBV-ACLF and improve the prognosis. Trial Registration The trial was registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565) on May 13, 2020: https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S0009OZY&selectaction=Edit&uid=U00036P1&ts=2&cx=27seqt.

Increased serum LOXL2 concentration in pelvic inflammatory disease with pelvic adhesion.

BACKGROUND: Lysyl oxidase-like 2 (LOXL2) belongs to a family of the LOX secretory enzyme, which involves the cross-linkage of extracellular matrix (ECM) proteins. Here, we aimed to analyze the correlation between serum LOXL2 and pelvic adhesion in chronic pelvic inflammatory disease (PID). METHODS: A total of 143 patients with PID and 130 healthy controls were included in this study. The serum levels of LOXL2 were measured using enzyme-linked immunosorbent assay (ELISA) kits. The patients were divided into non-adhesion group (102 cases) and adhesion group (41 cases). RESULTS: It was found that the serum level of LOXL2 expression was elevated in PID patients compared with healthy controls, and was elevated in PID patients with pelvic adhesion compared to patients without adhesion. In all PID patients, serum LOXL2 level was positively correlated with matrix metalloproteinases-9 (MMP-9), transforming growth factor-ß (TGF-ß1), whole blood viscosity (WBV) at low shear rate (LSR), WBV at high shear rate (HSR), and hematocrit (HcT). Multivariate logistic regression analysis showed that serum LOXL2 level was an independent risk factor for pelvic adhesion in PID patients (OR = 1.058; 95% CI = 1.030-1.086, P < 0.001). CONCLUSIONS: Serum LOXL2 level not only predicts the presence of PID, but serum LOXL2 concentration is also associated with the presence of pelvic adhesions.

Ball-milled bismuth oxybromide/biochar composites with enhanced removal of reactive red owing to the synergy between adsorption and photodegradation.

In this paper, bismuth oxybromide (BiOBr)/biochar composites were synthesized by a facile ball milling method for synergistic adsorption and photodegradation of Reactive red 120 (RR120). The characterizations show that ball milling changed the degree of crystallization, increased the surface area, and promoted the charge transfer ability of biochar. The 70% BiOBr/BC composite showed the best removal efficiency for RR120 removal with or without light illumination, which proves its enhanced removal ability by adsorption and photodegradation. The biochar is served as a support of BiOBr for preventing its aggregation and a transporter of charges for promoting the separation of photo-induced carriers in composites. BiOBr can release the adsorption sites on the surface of composites by degradation, which facilitated the RR120 removal and regenerated the photocatalyst for reusing. The strong interactions between BiOBr and biochar in composites resulted from ball milling were beneficial for the charge transfer and synergistic removal of adsorption and degradation. Findings of this work indicate that ball milling method is an effective method to prepare highly efficient biochar-based composites for RR120 removal through synergistic adsorption and photodegradation.

Mean arterial pressure drop is an independent risk factor of hepatorenal syndrome in patients with HBV-ACLF.

BACKGROUND/AIMS: In patients with acute-on-chronic liver failure (ACLF), type 1 hepatorenal syndrome (HRS) is a critical organ failure complication that resulted in rapid mortality. There are no efficient parameters to predict HRS in hepatitis B virus (HBV)-related ACLF. To assess HBV-ACLF risk factors and evaluate the association between mean arterial pressures (MAP), HRS and survival in patients with HBV-ACLF. METHODS: A total of 420 ACLF patients were screened from June 2015 to June 2016, and 57 HBV-ACLF patients were included in the study. Clinical data and MAP measurements of these patients were collected. Multivariate analyses, Cox proportional hazards regression and receiver operator characteristic (ROC) curves were used to analyze. RESULTS: In a 30-day study period, 43 (75.44%) patients survived. Patients in the HRS group were older and had higher Model for End-Stage Liver Disease (MELD) scores than patients in the non-HRS group. A MAP drop of ≥9.5 mmHg was an independent predictor of HRS with a sensitivity and specificity of 92.86 and 69.77%, respectively. The baseline MELD score was also an independent risk factor of HRS. MAP drop (OR, 1.582; P = 0.000), prothrombin time, HRS, MELD and FIB were independent prognostic factors for 30-day mortality. The area under the ROC curve of MAP drop was 0.808 (P = 0.001). CONCLUSION: A decrease in MAP was a valuable predictor of HRS in patients with HBV-related ACLF. MAP drop ≥9.5 mmHg may be useful for predicting patient prognosis and exploring new treatment measures in patients with HBV-related ACLF.

A multifunctional and environmentally safe superhydrophobic membrane with superior oil/water separation, photocatalytic degradation and anti-biofouling performance.

Wastewater is typically complicated with spilled oil, water soluble toxic dyes and microorganisms, making it hard to be processed and causing a significant threat to the environmental safety and human health. In this paper, we demonstrate a simple solution immersion method to obtain a multifunctional cellulose-based membrane (CBM) that possesses both superhydrophobicity with a water contact angle of 163° and superior functionalities including self-cleaning, oil-water separation, anti-biofouling, and photocatalytic degradation capabilities. The achievement of separation efficiency (96%), comparatively high flux (141 L·m-2·h-1) and recyclable (7 times) oil/water separation performance is attributed to the robust superhydrophobicity enabled by the synergy of metal oxide (i.e., CuO) nanostructure coating and stearic acid (SA) modification. The superhydrophobic CBM also preferentially adsorbs organic dyes in aqueous solution, e.g., methylene blue (MB), promoting their efficient decomposition (about 70.3% of MB decomposed in 3 h) with high recyclability under UV irradiation. Most remarkably, the CBM exhibits superior anti-biofouling capability and persistently resists the algae adhesion in long duration (over 20 days), as a result of the self-cleaning ability as well as the antimicrobial property of CuO nanoparticles. Our finding here paves the way to use simple, cost-effective, environmentally safe, and reliable method to fabricate multifunctional materials for wastewater treatment in complex environments.

Cost-effectiveness analysis of first-line treatment for chronic hepatitis B in China.

OBJECTIVES: Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. METHODS: A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. RESULTS: Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). CONCLUSIONS: Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.

NLRX1 can counteract innate immune response induced by an external stimulus favoring HBV infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells.

INTRODUCTION: This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action. METHODS: A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-ß, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways. RESULTS: NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-ß, and IL-6. CONCLUSIONS: NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.

Serum from Acute-on-chronic Liver Failure Patients May Affect Mesenchymal Stem Cells Transplantation by Impairing the Immunosuppressive Function of Cells.

BACKGROUND AND AIMS: The safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of acute-on-chronic liver failure (ACLF) have been validated. However, the impact of the pathological ACLF microenvironment on MSCs is less well understood. This study was designed to explore the changes in the functional properties of MSCs exposed to ACLF serum. METHODS: MSCs were cultured in the presence of 10%, 30% and 50% serum concentrations from ACLF patients and healthy volunteers. Then, the cell morphology, phenotype, apoptosis and proliferation of MSCs were evaluated, including the immunosuppressive effects. Subsequently, mRNA sequencing analysis was used to identify the molecules and pathways involved in MSC functional changes in the context of ACLF. RESULTS: In the presence of ACLF serum, MSC morphology significantly changed but phenotype did not. Besides, MSC proliferation activity was weakened, while the apoptosis rate was lightly increased. Most importantly, the immunosuppressive function of MSCs was enhanced in a low-concentration serum environment but transformed into a proinflammatory response in a high-concentration serum environment. RNA sequencing indicated that 10% serum concentration from ACLF patients mediated the PI3K-Akt pathway to enhance the anti-inflammatory effect of MSCs, while the 50% serum concentration from ACLF patients promoted the conversion of MSCs into a proinflammatory function by affecting the cell cycle. CONCLUSIONS: The 50% ACLF serum concentration is more similar to the environment in the human body, which means that direct peripheral blood intravenous infusion of MSCs may reduce the effect of transplantation. Combining treatments of plasma exchange to reduce harmful substances in serum may promote MSCs to exert a stronger anti-inflammatory effect.