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HBV-related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure with high mortality. Artificial liver support system (ALSS) is an important mean to reduce the mortality of HBV-ACLF but lacking index to assess its effectiveness. The cytokines are closely related to the prognosis of HBV-ACLF patients with ALSS treatment, however, which is not fully understood.One hundred forty-two patients with HBV-ACLF and 25 healthy donors were enrolled. The cytokine profile of peripheral blood was determined in the patients before and after ALSS treatment, and their relationship with effectiveness of ALSS treatment in HBV-ACLF was analyzed.Serum IL-28A levels were markedly lower in ALSS-effective patients than those in non-effective patients pre-ALSS treatment. Similarly, serum IL-6 was significantly lower in ALSS-effective patients. Furthermore, for patients with effective treatment, serum IL-28A levels were positively related with IL-6 levels post-ALSS (r = 0.2413, p = 0.0383). The ROC curve analysis showed that serum levels of IL-28A (AUC = 0.6959 when alone or 0.8795 when combined with total bilirubin, platelet count and INR, both p 0.0001) and IL-6 (AUC = 0.6704, p = 0.0005) were useful indices for separating effective from non-effective ALSS treatment of HBV-ACLF patients. Multivariate logistic regression analysis demonstrated that lower level of IL-28A was independently associated with higher effective rate of ALSS treatments.Lower level of IL-28A is a predictive biomarker for ALSS in effective treatment of HBV-ACLF patients and IL-28A may be potential target for the treatment of HBV-ACLF.

ObjectiveHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.MethodsFour hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).ResultsThe functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.ConclusionsThis study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

Objective. An artificial liver support system (ALSS) is an effective therapy for patients with severe liver injury. A vasovagal reaction (VVR) is a common complication in various treatment settings but has not been reported previously in ALSS. Methods. This study retrospectively evaluated patients who suffered an ALSS-related VRR between January 2018 and June 2019. We collected data from VVR episodes including onset time, duration, changes in heart rate (HR) and blood pressure (BP), and drug treatment. Results. Among 637 patients who underwent ALSS treatment, 18 were included in the study. The incidence of VVR was approximately 2.82%. These patients were characterized by a rapid decrease in BP or HR with associated symptoms such as chest distress, nausea, and vomiting. The majority of patients (78%) suffered a VVR during their first ALSS treatment. Sixteen patients (89%) had associated symptoms after treatment began. Sixteen patients (89%) received human albumin or Ringer’s solution. Atropine was used in 11 patients (61%). The symptoms were relieved within 20 min in 15 patients and over 20 min in 3 patients. Conclusions. A VVR is a rare complication in patients with severe liver injury undergoing ALSS treatment. Low BP and HR are the main characteristics of a VVR.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with rapid progression. This study aimed to develop and validate a prognostic score to predict the onset of ACLF in hepatitis B virus (HBV) etiology.The prospective clinical data of 1373 patients with acute deterioration of HBV-related chronic liver disease were used to identify clinical characteristics and develop a prognostic score for the onset of ACLF.Of the patients assessed using the Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF criteria, 903 patients with non-ACLF at admission (1 received transplantation at 5 days) were stratified: 71 with progression to ACLF and 831 without progression to ACLF at 7 days. Four predictors (total bilirubin, international normalized ratio, alanine aminotransferase, and ferritin) were associated significantly with ACLF onset at 7 days. The COSSH-onset-ACLF score was constituted as follows: (0.101 × ln [alanine aminotransferase] + 0.819 × ln [total bilirubin] + 2.820 × ln [international normalized ratio] + 0.016 × ln [ferritin]). The C-indexes of the new score for 7-/14-/28-day onset (0.928/0.925/0.913) were significantly higher than those of 5 other scores (Chronic Liver Failure Consortium ACLF development score/Model for End-stage Liver Disease score/Model for End-stage Liver Disease sodium score/COSSH-ACLF score/Chronic liver failure Consortium ACLF score; all P.001). The improvement in predictive errors, time-dependent receiver operating characteristic, probability density function evaluation, and calibration curves of the new score showed the highest predictive value for ACLF onset at 7/14/28 days. Risk stratification of the new score showed 2 strata with high and low risk (≥6.3/6.3) of ACLF onset. The external validation group further confirmed the earlier results.A new prognostic score based on 4 predictors can accurately predict the 7-/14-/28-day onset of ACLF in patients with acute deterioration of HBV-related chronic liver disease and might be used to guide clinical management.

Hepatitis B virus (HBV) is the main causative viral agent for liver diseases in China. In liver injury, exosomes may impede the interaction with chromatin in the target cell and transmit inflammatory, apoptosis, or regeneration signals through RNAs. Therefore, we attempted to determine the potential functions of exosomal RNAs using bioinformatics technology. We performed RNA sequencing analysis in exosomes derived from clinical specimens of healthy control (HC) individuals and patients with chronic hepatitis B (CHB) and acute-on-chronic liver failure caused by HBV (HBV-ACLF). This analysis resulted in the identification of different types and proportions of RNAs in exosomes from the HC individuals and patients. Exosomes from the CHB and HBV-ACLF patients showed distinct upregulation and downregulation patterns of differentially expressed genes compared with those from the HC subjects. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analysis further confirmed different patterns of biological functions and signalling pathways in CHB and HBV-ACLF. Then we chose two upregulated RNAs both in CHB and HBV-ACLF for further qPCR validation. It confirmed the significantly different expression levels in CHB and HBV-ACLF compared with HC. Our findings indicate selective packaging of the RNA cargo into exosomes under different HBV attacks; these may represent potential targets for the diagnosis and treatment of HBV-caused liver injury.

Since the December 2019 outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, the infection has spread locally and globally resulting in a pandemic. As the numbers of confirmed diagnoses and deaths continue to rise, COVID-19 has become the focus of international public health. COVID-19 is highly contagious, and there is no effective treatment yet. New treatment strategies are urgently needed to improve the treatment success rate of severe and critically ill patients. Increasing evidence has shown that a cytokine storm plays an important role in the progression of COVID-19. The artificial-liver blood-purification system (ALS) is expected to improve the outcome of the cytokine storm. In the present study, the levels of cytokines were detected in 12 COVID-19 patients pre- and post-ALS with promising results. The present study shows promising evidence that ALS can block the cytokine storm, rapidly remove the inflammatory mediators, and hopefully, suppress the progression of the disease, thereby providing a new strategy for the clinical treatment of COVID-19.

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is more prevalent among males than females and has a high rate of short-term mortality, and low serum testosterone has been prevalent in critical illness such as acute respiratory failure and cirrhosis, we investigated the association between testosterone level and severity of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) in males remains unknown.MethodsThis single-center observational study involved patients with HBV-ACLF planned to undergo treatment with an artificial liver support system. Morning blood samples were collected and androgen levels analyzed by chemi-bioluminescent immunoassay. Time to death or liver transplantation within 90 days comprised the primary composite outcome. We assessed the relationships between androgen levels, stage (early, middle, or late, categorized according to clinical manifestation), severity scores, and clinical outcomes of HBV-ACLF.ResultsAmong 160 male subjects, 32 had early stage HBV-ACLF, 61 middle stage, and 67 end stage. Serum levels of total testosterone (TT), free testosterone index (FTI), dehydroepiandrosterone sulfate and cortisol were significantly lower among subjects than chronic hepatitis B patients and healthy controls, while androstenedione was higher. Low TT, SHBG, FTI and high androstenedione were associated with increased stage (of HBV-ACLF, ascites, and hepatic encephalopathy) and severity scores (Model for End-stage Liver Disease and Chinese Group on the Study of Severe Hepatitis B-ACLF scores). Low TT (

Tetanus is a fatal but vaccine‐preventable disease. The currently available tetanus vaccines are tetanus toxoid (TT)‐based. Although these vaccines are generally effective, challenges in vaccine development and access remain. A randomized, double‐blind, dose escalation, placebo‐ and positive‐controlled, phase 1/2 trial (ChiCTR1800015865) is performed to evaluate the safety and immunogenicity of an alternative recombinant tetanus vaccine based on the Hc domain of tetanus neurotoxin (TeNT‐Hc) in healthy adult volunteers. The primary outcome is the safety profile of the recombinant tetanus vaccine, and immunogenicity is the secondary outcome. 150 eligible participants were enrolled and randomly assigned to receive one of the three doses of recombinant tetanus vaccine (TeNT‐Hc 10/20/30 µg), TT vaccine, or placebo. The recombinant tetanus vaccine shows a good safety profile. The frequency of any solicited and unsolicited adverse events after each vaccination does not differ across the vaccine and placebo recipients. No serious treatment‐related adverse events occur. The recombinant tetanus vaccine shows strong immune responses (seroconversion rates, geometric mean titer, and antigen‐specific CD4+/CD8+ T‐cell responses), which are roughly comparable to those of the TT vaccine. In conclusion, the findings from this study support that recombinant tetanus vaccine is safe and immunogenic; thereby, it represents a novel vaccine candidate against tetanus., This study is the first randomized, phase 1/2 trial comparing dose escalation recombinant tetanus vaccine (TeNT‐Hc) with TT vaccine and placebo in healthy adults. All three doses of recombinant tetanus vaccine show a good safety profile, and strong immune responses, which are roughly comparable with TT vaccine. Thus, recombinant tetanus vaccine might be a novel vaccine candidate against tetanus.

Highlights • The artificial liver could reduce the cytokine levels in COVID-19 patients. • The artificial liver could decrease the level of inflammation-related indicators in COVID-19 patients. • The artificial liver could promote the absorption of pulmonary lesions in COVID-19 patients., Objective To explore the application value of artificial liver support system in the clinical treatment of coronavirus disease 2019 (COVID-19) patients with cytokine storm. Methods Six cases of severe or critically severe COVID-19 patients treated in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 22 to February 4, 2020 were recruited, and all of them received artificial liver support treatment. Statistical analysis was carried out on the change of cytokines (TNF-α, IL-10, IL-6, IFN-γ, IL-2, IL-4), inflammation-related indicators (white blood cell, neutrophil, lymphocyte, C-reactive protein and procalcitonin), immune-related indicators (B lymphocyte percentage, natural killer cell percentage, CD3+CD4+CD8 T cell percentage), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 6 patients before and after treatment, and the proportions of patients with abnormal indicators were analyzed as well. In addition, computed tomography (CT) was used to observe the absorption of pulmonary lesions before and after the artificial liver support treatment. Results The levels of cytokines (IL-6 and IL-10) were effectively reduced in the 6 patients after treatment with the artificial liver support system. Meanwhile, the proportions of patients with abnormal TNF-α, IL-10, IL-6 and IFN-γ were all decreased (p 0.05). CT imaging showed that the artificial liver support treatment contributed to absorption of pulmonary lesions. Conclusions The artificial liver support system had a great clinical effect in the treatment of cytokine storm and inflammation in COVID-19 patients, and it could promote the absorption of infected lesions.

Background: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation (LT) in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients; however, its impact on patient survival remains unknown. This study aimed to assess the effects of ALSS on survival in patients with HBV-ACLF. Methods: The clinical data of HBV-ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment. The main endpoints were cumulative survival rates at days 21, 28 and 90. A case-control matched analysis was used to reduce bias between the ALSS and SMT groups. A propensity score matching (PSM) and inverse probability treatment weighting (IPTW) analysis were performed to confirm the survival effect of ALSS. Findings: In the entire cohort, the cumulative survival rates at days 21, 28 and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P

Summary Background Predictors of quantitative evaluation of hepatic steatosis and liver fat content (LFC) using clinical and laboratory variables available in the general practice in the obese children are poorly identified. Objective To build predictive models of hepatic steatosis and LFC in obese children based on biochemical parameters and anthropometry. Methods Hepatic steatosis and LFC were determined using proton magnetic resonance spectroscopy in 171 obese children aged 5.5–18.0 years. Routine clinical and laboratory parameters were also measured in all subjects. Group analysis, univariable correlation analysis, and multivariate logistic and linear regression analysis were used to develop a liver fat score to identify hepatic steatosis and a liver fat equation to predict LFC in each subject. Results The predictive model of hepatic steatosis in our participants based on waist circumference and alanine aminotransferase had an area under the receiver operating characteristic curve of 0.959 (95% confidence interval: 0.927–0.990). The optimal cut-off value of 0.525 for determining hepatic steatosis had sensitivity of 93% and specificity of 90%. A liver fat equation was also developed based on the same parameters of hepatic steatosis liver fat score, which would be used to calculate the LFC in each individual. Conclusions The liver fat score and liver fat equation, consisting of routinely available variables, may help paediatricians to accurately determine hepatic steatosis and LFC in clinical practice, but external validation is needed before it can be employed for this purpose.

Microcystin-RR (MCRR), a very widespread toxic microcystin in China, has previously been proved to induce sensitive apoptosis in Carassius auratus lymphocytes in vitro. This study focused on the role of intracellular Ca(2+), mitochondrial membrane potential, reactive oxygen species, and intracellular ATP in the mechanism of MCRR-induced apoptotic toxicity to fish lymphocytes. Compared with controls, administration of MCRR (10 nmol L(-1)) caused a massive calcium influx resulting in elevation of reactive oxygen species (ROS), rapid disruption of mitochondrial membrane potential (DeltaPsim), and depletion of ATP. This study provided a possible mechanism for the cytotoxicity of microcystins to fish lymphocytes.

Microcystin-LR (MCLR), the most toxic microcystin up to date, could induce apoptosis in many kinds of fish and mammalian cells. For the fish immunotoxicity, it was found that MCLR could induce apoptosis in Carassius auratus lymphocytes in vitro. So this study focused on the role of intracellular Ca(2+), mitochondrial membrane potential, reactive oxygen species (ROS), and intracellular ATP in response to the mechanisms of MCLR-induced apoptosis in fish lymphocytes. MCLR (10 nM) administration resulted in a massive elevation in ROS, intracellular Ca(2+), decreased ATP, and rapid mitochondrial membrane potential (DeltaPsi(m)) disruption. When compared to controls, both a fourfold significant (P < 0.001) elevation in O(2) (-) in 1.5 h and an approximately twofold increase in Ca(2+) in 0.5 h were observed. After 6 h of treatment, an approximately 30% decrease for DeltaPsi(m) but about 75% decline for ATP were found. Together, the results demonstrated that MCLR-induced apoptosis was associated with a massive calcium influx, resulting in O(2) (-) elevation, DeltaPsi(m) disruption, and ATP depletion. This study provided a possible cytotoxic mechanism of fish lymphocytes caused by MCLR.