APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Antiviral immunity of severe fever with thrombocytopenia syndrome: current understanding and implications for clinical treatment.

Dabie Banda virus (DBV), a tick-borne pathogen, was first identified in China in 2009 and causes profound symptoms including fever, leukopenia, thrombocytopenia and multi-organ dysfunction, which is known as severe fever with thrombocytopenia syndrome (SFTS). In the last decade, global incidence and mortality of SFTS increased significantly, especially in East Asia. Though previous studies provide understandings of clinical and immunological characteristics of SFTS development, comprehensive insight of antiviral immunity response is still lacking. Here, we intensively discuss the antiviral immune response after DBV infection by integrating previous ex- and in-vivo studies, including innate and adaptive immune responses, anti-viral immune responses and long-term immune characters. A comprehensive overview of potential immune targets for clinical trials is provided as well. However, development of novel strategies for improving the prognosis of the disease remains on challenge. The current review may shed light on the establishment of immunological interventions for the critical disease SFTS.

The efficacy of antiviral treatment in chronic hepatitis B patients with hepatic steatosis.

Background & aims: With a drastic increase in the number of chronic hepatitis B (CHB) patients with coexisting nonalcoholic fatty liver disease (NAFLD), there is an urgent need to evaluate antiviral treatment effects in this special population. Methods: CHB patients with hepatic steatosis (CHB + HS) were prospectively recruited with followed-up of 3 years. HS and liver fibrosis were assessed by transient elastography. HS was defined as controlled attenuation parameter (CAP) ≥248 dB/m, and fibrosis progression was defined with ≥1-stage fibrosis increment. Multivariate and propensity score matching (PSM) analysis were used to evaluate antiviral therapy effects on fibrosis progression. Results: In total 212 recruited CHB + HS patients (median age 36 years, median ALT 59 U/L), 49.1% (104/212) received antiviral therapy and 50.9% (108/212) did not. Among patients with antiviral therapy, rates of serum HBV DNA undetectable, HBeAg and HBsAg loss, and ALT normalization at year 3 were 88.5%, 31.0%, 8.7% and 70.2%, respectively. Patients with mild-moderate HS didn't differ patients with severe HS regarding biochemical and virological responses. Antiviral therapy was independently associated with a lower risk of fibrosis progression among the entire cohort (odds ratio 0.473, 95% CI 0.245-0.911, P = 0.025). This finding was further verified by PSM analysis. When stratified by the severity of HS, the antiviral therapy benefits in reducing fibrosis progression were mainly seen in patients with mild-moderate HS. Conclusions: Among CHB + HS patients, long-term antiviral treatment effectively inhibits HBV replication and reduces fibrosis progression. Our findings have implications for the optimal management of this population.

Expert consensus on the diagnosis and treatment of end-stage liver disease complicated by infections.

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Disease severity and antiviral response in patients with chronic hepatitis B with non-obese NAFLD.

BACKGROUND: The burden of nonalcoholic fatty liver disease (NAFLD) is growing in patients with chronic hepatitis B (CHB). NAFLD is typically associated with obesity, however, it is increasingly being identified in non-obese patients. This study aimed to investigate disease severity and antiviral response in non-obese patients with CHB with NAFLD (CHB + NAFLD). METHODS: A total of 809 patients with CHB + NAFLD were prospectively recruited and followed up for 3 years. NAFLD was diagnosed by transient elastography and defined as controlled attenuation parameter ≥248 dB/m, in the absence of excessive alcohol intake. Obesity status was defined by the Asian body mass index (BMI) cutoff of 25 kg/m2. Metabolic abnormality was defined by the presence of dyslipidemia, hypertension or diabetes. Fibrosis staging was defined according to the EASL-ALEH guidelines, with fibrosis progression defined as ≥1-stage increment. RESULTS: In the total cohort (median age 40 years, 59.0% antiviral-treated), 33.3% were non-obese. Non-obese patients were less metabolically abnormal than obese patients (60.2% vs 72.0%, P = 0.003). After 3-year follow up, the rate of fibrosis progression was comparable between non-obese and obese patients (17.5% vs 21.9% in the total cohort, P = 0.145; 15.7% vs 14.6% in antiviral-treated cohort with persistent viral suppression, P = 0.795). No significant differences in virological and biochemical responses were observed between non-obese and obese patients (P >0.05 for all). CONCLUSIONS: Approximately one third of CHB + NAFLD patients were non-obese. Non-obese patients, while less metabolically abnormal, had a similar risk for fibrosis progression as obese patients. Obesity status did not impact the efficiency of antiviral therapy.

C-C chemokine receptor 5 is essential for conventional NK cell trafficking and liver injury in a murine hepatitis virus-induced fulminant hepatic failure model.

BACKGROUND: Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. AIM: This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis  virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. RESULTS: By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1ß and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1ß or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. CONCLUSION: The CCR5-MIP-1ß/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Tenofovir alafenamide and tenofovir disoproxil fumarate reduce incidence of hepatocellular carcinoma in patients with chronic hepatitis B.

Background & Aims: Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB. Methods: The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated. Results: Of the 1,632 patients (TAF, n = 1,093; TDF, n = 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 (p <0.001) vs. 0.56 (p = 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 (p <0.001) vs. 0.58 (p = 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively). Conclusions: This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis. Impact and implications: Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB. Clinical trial numbers: NCT01940341; NCT02836249; NCT01940471; NCT02836236.

Fibrinogen-like protein 2 regulates macrophage glycolytic reprogramming by directly targeting PKM2 and exacerbates alcoholic liver injury.

BACKGROUND & AIMS: Switching of the macrophage activation phenotype affects the pathogenesis of alcoholic liver diseases, and metabolic reprogramming can provide the energy demand for macrophage phenotypes shift. However, the molecular mechanism by which immune metabolism regulates the activation of proinflammatory macrophages remains unclear. APPROACH: Expression of Fgl2 was examined in patients with alcoholic hepatitis and healthy controls. Mice were fed with a Lieber-DeCarli diet. Livers from mice were used to observe liver injury and macrophage activation. Fgl2 overexpressing THP-1 cell was used to find interacting partners through immunoprecipitation plus mass spectrometry. Naive bone marrow derived macrophages stimulated with LPS and ethanol were used for cell experiments. RESULTS: Expression of Fgl2 was elevated in macrophages of livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Fgl2 depletion ameliorated ethanol diet-induced hepatic steatosis and oxidative injury as well as the levels of proinflammatory cytokines. Fgl2-/- mice exhibited suppressed M1 polarization and glycolysis pathway activation. Fgl2 interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and facilitated PKM2 nuclear translocation, thus promoting glycolysis in M1 macrophages and the secretion of proinflammatory cytokines. Furthermore, Fgl2 overexpression in THP-1 cells enhances PKM2-dependent glycolysis and inflammation, which could be reversed by activation of enzymatic PKM2 using DASA58. CONCLUSIONS: Taken together, Fgl2 hastens the development of alcoholic liver injury by mediating PKM2 dependent aerobic glycolysis in proinflammatory macrophages. Strategies that inhibiting proinflammatory macrophage activation by silencing Fgl2 might be a potential therapeutic intervention for alcoholic liver injury.

Response characteristics of MAPbBr3 direct conversion X-ray detectors based on measurements and Monte Carlo simulation.

In recent years, higher requirements have been placed on the response characteristics of X-ray detectors in the field of medical diagnostic imaging. Due to this, high sensitivity, high attenuation coefficient and low cost detection materials need to be developed. In this paper, the geometric model of a detector was established by Geant4 code. The absorption efficiency and mass attenuation coefficient of MAPbBr3 crystals were calculated in the energy range of 30 keV to 100 keV. Compared with the mass attenuation coefficient of the NIST database, the deviation was within 1.39%. The signal charge number and detection sensitivity of the X-ray interaction with the MAPbBr3 crystal ware calculated. Compared with the CdTe crystal and α-Se, the MAPbBr3 crystal still had a larger detection sensitivity under a smaller applied electric field, which was approximately 9 times higher than that of α-Se. This result indicated that the detection sensitivity could be greatly improved by using a high atomic number and high charge mobility-lifetime product. Based on the simulation results, the 2 mm thick MAPbBr3 crystal exhibited the highest detection sensitivity at 60 keV X-rays, which was in agreement with the experimental results.

Long-term SARS-CoV-2 neutralizing antibody level prediction using multimodal deep learning: A prospective cohort study on longitudinal data in Wuhan, China.

The ongoing epidemic of SARS-CoV-2 is taking a substantial financial and health toll on people worldwide. Assessing the level and duration of SARS-CoV-2 neutralizing antibody (Nab) would provide key information for government to make sound healthcare policies. Assessed at 3-, 6-, 12-, and 18-month postdischarge, we described the temporal change of IgG levels in 450 individuals with moderate to critical COVID-19 infection. Moreover, a data imputation framework combined with a novel deep learning model was implemented to predict the long-term Nab and IgG levels in these patients. Demographic characteristics, inspection reports, and CT scans during hospitalization were used in this model. Interpretability of the model was further validated with Shapely Additive exPlanation (SHAP) and Gradient-weighted Class Activation Mapping (GradCAM). IgG levels peaked at 3 months and remained stable in 12 months postdischarge, followed by a significant decline in 18 months postdischarge. However, the Nab levels declined from 6 months postdischarge. By training on the cohort of 450 patients, our long-term antibody prediction (LTAP) model could predict long-term IgG levels with relatively high area under the receiver operating characteristic curve (AUC), accuracy, precision, recall, and F1-score, which far exceeds the performance achievable by commonly used models. Several prognostic factors including FDP levels, the percentages of T cells, B cells and natural killer cells, older age, sex, underlying diseases, and so forth, served as important indicators for IgG prediction. Based on these top 15 prognostic factors identified in IgG prediction, a simplified LTAP model for Nab level prediction was established and achieved an AUC of 0.828, which was 8.9% higher than MLP and 6.6% higher than LSTM. The close correlation between IgG and Nab levels making it possible to predict long-term Nab levels based on the factors selected by our LTAP model. Furthermore, our model identified that coagulation disorders and excessive immune response, which indicate disease severity, are closely related to the production of IgG and Nab. This universal model can be used as routine discharge tests to identify virus-infected individuals at risk for recurrent infection and determine the optimal timing of vaccination for general populations.

Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment.

CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

Shared-care models are highly effective and cost-effective for managing chronic hepatitis B in China: reinterpreting the primary care and specialty divide.

Background: We evaluate the impact and cost-effectiveness of shared primary-specialty chronic hepatitis B (CHB) care models in China. Methods: We constructed a decision-tree Markov model to simulate hepatitis B virus (HBV) disease progression in a cohort of 100,000 CHB individuals aged ≥18 years over their lifetime (aged 80). We evaluated the population impacts and cost-effectiveness in three scenarios: (1) status quo; (2) shared-care model with HBV testing and routine CHB follow-ups in primary care and antiviral treatment initiation in specialty care; and (3) shared-care model with HBV testing, treatment initiation and routine CHB follow-up in primary care and treatment for predetermined conditions in specialty care. We evaluated from a healthcare provider's perspective with 3% discounting rate and a willingness-to-pay (WTP) threshold of 1-time China's GDP. Findings: Compared with status quo, scenario 2 would result in an incremental cost of US$5.79-132.43m but a net gain of 328-16,993 quality-adjusted life years (QALYs) and prevention of 39-1935 HBV-related deaths over cohort's lifetime. Scenario 2 was not cost-effective with a WTP of 1-time GDP per capita, but became cost-effective when treatment initiation rate increased to 70%. In contrast, compared with status quo, secnario 3 would save US$144.59-192.93m in investment and achieve a net gain of 23,814-30,476 QALYs and prevention of 3074-3802 HBV-related deaths. Improving HBV antiviral treatment initiation among eligible CHB individuals substantially improved the cost-effectiveness of the shared-care models. Interpretation: Shared-care models with HBV testing, follow up and referring of predetermined conditions to specialty care at an appropriate time, especially antiviral treatment initiation in primary care, are highly effective and cost-effective in China. Funding: National Natural Science Foundation of China.

Novel Prognostic Nomogram to Predict Progression-Free Survival of Patients with Hepatocellular Carcinoma After Transarterial Chemoembolization.

Purpose: A retrospective analysis of hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) to identify risk factors was conducted, and a novel predictive nomogram model was constructed. Patients and Methods: A total of 346 HCC patients who underwent TACE as initial treatment were retrospectively included, of which 208 were randomly allocated to the derivation cohort and 138 were allocated to the validation cohort. Progression-free survival (PFS) was used as the follow-up endpoint according to mRECIST. Kaplan‒Meier analysis and the Cox regression model screened out some indicators associated with short-term prognosis, and R language was further used to construct a nomogram model. The nomogram was compared with the classical BCLC staging system. Results: The independent predictors affecting PFS in HCC patients undergoing TACE included the following: 1. Baseline indicators: age (P=0.013), albumin-bilirubin (ALBI) grade (grade 2 vs grade 1, P=0.029; grade 3 vs grade 1, P<0.001), and portal vein tumour thrombus (PVTT, P<0.001); 2. Indicators at the 1-month follow-up: Neutrophil To Lymphocyte Ratio (NLR, P=0.032) and changes in alpha-fetoprotein (AFP, P<0.05) and des-γ-carboxy prothrombin (DCP, P<0.001); and 3. Cumulative treatment numbers of TACE in 6 months (P=0.007). In the derivation cohort, the calibration curve of the nomogram showed a high consistency between the predicted and actual PFS probability, and the nomogram outperformed the BCLC staging system (P=0.004). This result was also confirmed in the validation cohort (P=0.012). Conclusion: The constructed nomogram was suggested to have good predictive efficacy and could be used as a complementary assessment to predict the survival and prognosis of HCC patients treated with TACE.

FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress.

Introduction: The impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined. Methods: Lipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying. Results: Upon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs. Conclusion: Our findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis.

Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.

Identifying the early predictors of non-response to steroids in patients with flare of autoimmune hepatitis causing acute-on-chronic liver failure.

BACKGROUND AND AIMS: Early identification of non-response to steroids is critical in patients with autoimmune hepatitis (AIH) causing acute-on-chronic liver failure (ACLF). We assessed if this non-response can be accurately identified within first few days of treatment. METHODS: Patients with AIH-ACLF without baseline infection/hepatic encephalopathy were identified from APASL ACLF research consortium (AARC) database. Diagnosis of AIH-ACLF was based mainly on histology. Those treated with steroids were assessed for non-response (defined as death or liver transplant at 90 days for present study). Laboratory parameters, AARC, and model for end-stage liver disease (MELD) scores were assessed at baseline and day 3 to identify early non-response. Utility of dynamic SURFASA score [- 6.80 + 1.92*(D0-INR) + 1.94*(∆%3-INR) + 1.64*(∆%3-bilirubin)] was also evaluated. The performance of early predictors was compared with changes in MELD score at 2 weeks. RESULTS: Fifty-five out of one hundred and sixty-five patients (age-38.2 ± 15.0 years, 67.2% females) with AIH-ACLF [median MELD 24 (IQR: 22-27); median AARC score 7 (6-9)] given oral prednisolone 40 (20-40) mg per day were analyzed. The 90 day transplant-free survival in this cohort was 45.7% with worse outcomes in those with incident infections (56% vs 28.0%, p = 0.03). The AUROC of pre-therapy AARC score [0.842 (95% CI 0.754-0.93)], MELD [0.837 (95% CI 0.733-0.94)] score and SURFASA score [0.795 (95% CI 0.678-0.911)] were as accurate as ∆MELD at 2 weeks [0.770 (95% CI 0.687-0.845), p = 0.526] and better than ∆MELD at 3 days [0.541 (95% CI 0.395, 0.687), p < 0.001] to predict non-response. Combination of AARC score > 6, MELD score > 24 with SURFASA score ≥ - 1.2, could identify non-responders at day 3 (concomitant- 75% vs either - 42%, p < 0.001). CONCLUSION: Baseline AARC score, MELD score, and the dynamic SURFASA score on day 3 can accurately identify early non-response to steroids in AIH-ACLF.

Effect of Anti-HBs on Mortality Among Resolved HBV Infection: a Population-Based Prospective Cohort Study.

INTRODUCTION: Surveillance programs after hepatitis B surface antigen (HBsAg) loss are not yet well established, and the role of hepatitis B surface antibodies (anti-HBs) remains controversial. We aimed to evaluate the risk factors for increased mortality and the association between anti-HBs and all-cause and cause-specific mortality in a representative US (United States) population of patients with resolved HBV (Hepatitis B virus) infections. METHODS: Data were taken from the US National Health and Nutrition Examination Survey (NHANES) 1999-2018. A total of 3455 US adults with resolved HBV infection [defined as hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive] were enrolled in this study. The primary outcome measures were all-cause and cause-specific mortality from baseline until 31 December 2019. RESULTS: During a mean follow-up of 10.3 years, 741 deaths occurred. Age, race, marital status, smoking status, physical activity level, and presence of cirrhosis, diabetes, cardiovascular diseases, chronic obstructive pulmonary diseases, cancer, and anti-HBs were significant factors for increased mortality, and a nomogram tool was developed and validated for the risk stratification of mortality. Compared with participants who were anti-HBs positive, those who were anti-HBs negative had a 23% (hazard ratio 1.23, 95% CI 1.02-1.46) higher risk of all-cause mortality in NHANES 1999-2018. For cause-specific mortality, the fully adjusted hazard ratios of participants who were anti-HBs negative were 0.71 (95% CI 0.48-1.06) for heart disease, 1.44 (95% CI 1.01-2.05) for cancer, and 1.44 (95% CI 1.13-1.83) for other conditions, compared to those of participants who were anti-HBs positive. CONCLUSIONS: Among US adults with resolved HBV infections, anti-HBs-negative status was associated with an increased risk of death from all causes and cancer, implying that the role of anti-HBs in resolved HBV infection should not be ignored. On the public health level, more rigorous surveillance was needed for populations of individuals who were isolated anti-HBc positive.