The Associations Between Sleep and Externalizing and Internalizing Problems in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Empirical Findings, Clinical Implications, and Future Research Directions.

Sleep problems are common in youth with attention-deficit/hyperactivity disorder (ADHD). Externalizing and internalizing problems contribute to dysfunction in youth with ADHD and are amplified by disrupted sleep. This objective of this article is to synthesize empirical studies that examined the associations between sleep and internalizing or externalizing problems in individuals with ADHD. The main findings are that sleep problems precede, predict, and significantly contribute to the manifestation of internalizing and externalizing behavior problems among children and adolescents with ADHD. Clinicians should assess sleep and integrate sleep interventions into the management of youth with ADHD.

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice.

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.

The safety concerns regarding immune checkpoint inhibitors in liver cancer patients rising mainly from CHB.

Aim: To analyze the safety of immune checkpoint inhibitors in primary liver cancer patients and to identify the risk factors for immune-related adverse events (irAEs). Methods: The study enrolled 106 patients with primary liver cancer, including 81 with hepatocellular carcinoma and 25 with intrahepatic cholangiocarcinoma. We analyzed the differences between groups in irAE occurrence, including those with and without targeted drugs and those who received interventional therapy. Results: The incidence of irAEs was 39%, with thyroid function, liver function, and skin events being the most common. There was no correlation among irAE incidence and the liver cancer type, stage, or severity; grade of Child-Pugh score; and Barcelona Clinical Liver Cancer classification. However, being overweight was a significant risk factor for irAEs, correlating with high body mass index. The combination of targeted drugs and/or transcatheter arterial chemoembolization therapy did not increase the incidence of irAEs. Conclusion: Being overweight is a potential risk factor for irAEs in primary liver cancer patients. However, there is no correlation between irAE incidence and the liver cancer type, stage, or severity or a combination of targeted drugs or transarterial chemoembolization therapy.

The 20 years transition of clinical characteristics and metabolic risk factors in primary liver cancer patients from China.

Background: The clinical characteristics of primary liver cancer (PLC) patients are changing, maybe due to hepatitis viral vaccination and lifestyle changes, etc. The linkage between these changes and outcomes among these PLCs has not yet been fully elucidated. Methods: It was identified total of 1691 PLC cases diagnosed between 2000 ~ 2020. Cox proportional hazards models were utilized to determine the connections between the clinical presentations and their close risk factor(s) from PLC patients. Results: The average age of PLC patients increased gradually from 52.74 ± 0.5 years in 2000 ~ 2004 to 58.63 ± 0.44 years in 2017 ~ 2020, accompanied by an increased proportion of females from 11.11% to 22.46%, and non-viral hepatitis-related PLC was raised from 1.5% to 22.35%. 840 (49.67%) PLC patients with alpha-fetoprotein (AFP) < 20ng/mL (AFP-negative). The mortality was 285 (16.85%) or 532 (31.46%) PLC patients with alanine transaminase (ALT) between 40 ~ 60 IU/L or ALT > 60 IU/L. The PLC patients with pre-diabetes/diabetes or dyslipidemia also increased from 4.29% or 11.1% in 2000 ~ 2004 to 22.34% or 46.83% in 2017 ~ 2020. The survival period of the PLC patients with normoglycemia or normolipidemic was 2.18 or 3.14 folds longer than those patients with pre-diabetes/diabetes or hyperlipidemia (P<0.05). Conclusions: It was gradually increased that age, the proportion of females, non-viral hepatitis-related causes, AFP-negative, and abnormal glucose/lipids among PLC patients. Proper control of glucose/lipids or ALT may improve the prognosis of PLCs.

A novel model based on qAnti-HBc and conventional biomarkers for identifying significant liver injury among CHB patients with ALT ≤ ULN.

BACKGROUND: Antiviral therapy is not routinely recommended for CHB patients with ALT ≤ ULN (CHB-NALT), based on current international guidelines. However, it is debatable if antiviral treatment should be offered for CHB-NALT patients, because significant liver injury is observed from liver biopsy of some CHB-NALT patients. Quantification of anti-HBc (qAnti-HBc) can predict antiviral response in CHB patients, while its role in CHB-NALT patients remains to be explored. AIM: To determine if it is reliable that the novel non-invasive model based mainly on qAnti-HBc and other conventional biomarkers for providing objective value among CHB-NALT patients with antiviral therapy, in direct comparison with liver biopsy. METHODS: 542 or 110 liver biopsied CHB-NALT patients from 2015 to 2020 or in 2021 were included in training set or validation set. Circulating IL-1ß, IL-2, IL-4, IL-12p70, IL-17, TNF and IFNα were determined in the training set. A non-invasive model was developed based on qAnti-HBc and other conventional biomarkers. RESULTS: Among 423/542 (78%) patients with significant liver injury in the training set, 47% were in grey-zone. Circulating IL-1ß, IL-12p70, IL-17 in the CHB-NALT patients with liver injury was significantly higher than these without liver injury in the training set (p < 0.01). No significant difference of IL-1ß, IL-12p70, IL-17 was observed between CHB-NALT patients with significant liver injury and active CHB with elevated ALT in the training set. There was inverse correlation between liver injury grades and IFNα, IL-4, or IL-2 in these patients (p < 0.05). Serum qAnti-HBc level was significantly higher with CHB-NALT patients with liver injury than these without in the training set (P < 0.01). ALT/ULN, AST, PLT and qAnti-HBc were identified as independent predictors for significant liver injury. Furthermore, our current model demonstrated a good performance in predicting significant liver injury, i.e. AUROCs of 0.95 or 0.86 in training set or validation set. The model cut-off value for anti-viral therapy at ≥1.471. CONCLUSIONS: qAnti-HBc appears to be well correlated with the hepatic damage, in direct comparison with liver biopsy from CHB-NALT patients. The novel model developed seems to be reliable for predicting liver injury in CHB-NALT patients. Such model also provides objective value for decision making of antiviral therapy.

Erratum to: Peginterferon and Entecavir Combination Therapy Improves Outcome of Non-Early Response Hepatitis B e Antigen-Positive Patients.

[This corrects the article DOI: 10.1093/ofid/ofaa462.].

The Associations Between Sleep and Externalizing and Internalizing Problems in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Empirical Findings, Clinical Implications, and Future Research Directions.

Sleep problems are common in youth with attention-deficit/hyperactivity disorder (ADHD). Externalizing and internalizing problems contribute to dysfunction in youth with ADHD and are amplified by disrupted sleep. This objective of this article is to synthesize empirical studies that examined the associations between sleep and internalizing or externalizing problems in individuals with ADHD. The main findings are that sleep problems precede, predict, and significantly contribute to the manifestation of internalizing and externalizing behavior problems among children and adolescents with ADHD. Clinicians should assess sleep and integrate sleep interventions into the management of youth with ADHD.

Sleep Duration Is Associated with Academic Achievement of Adolescent Girls in Mathematics.

PURPOSE: To examine the associations between objective measures of sleep during the school week and academic achievement in mathematics and languages in typically developing adolescent girls. METHODS: Eighty adolescent girls aged 12-17 years (M=14.74, SD=1.3) participated. For five consecutive weeknights, sleep was assessed in the home environment using an actigraph. Academic achievement was assessed using report card grades. RESULTS: Girls who obtained on average less sleep than the recommended amount of 8 to 10 hrs per night had significantly lower grades in mathematics compared to girls who obtained the recommended amount (77.61 vs 86.16, respectively; ηp 2=0.11). Hierarchical regression analyses adjusted for age, pubertal status, and socioeconomic status revealed that longer average sleep time was significantly associated with higher grades in mathematics (B=4.78, 95% CI [2.03,7.53]). No significant associations were found between sleep variables and grades in languages. CONCLUSION: Longer average weekday sleep duration is associated with academic achievement of adolescent girls in mathematics.

Peginterferon and Entecavir Combination Therapy Improves Outcome of Non-Early Response Hepatitis B e Antigen-Positive Patients.

BACKGROUND: The efficacy of nucleot(s)ide analogs (NAs) and pegylated interferon (PegIFN) combination therapy for hepatitis B e antigen-positive (HBeAg+) patients is still controversial. Whether PegIFN and entecavir (ETV) combination therapy could provide a greater benefit for HBeAg+ patients was assessed. METHODS: Treatment-naïve HBeAg+ patients initiated on PegIFN alfa-2a (PegIFNα-2a) for 24 weeks without early response (early response: HBsAg <1500 IU/mL and hepatitis B virus [HBV] DNA <105 copies/mL) were recruited in the current study. Among total of 94 patients, 51 were continued on PegIFNα-2a monotherapy, and 43 were offered PegIFNα-2a and ETV combined therapy. RESULTS: Better outcomes in response to the combined therapy, compared with that of the monotherapy, were demonstrated, including more HBsAg decline and loss and HBV DNA decline and HBeAg clearance. Importantly, the patients with HBsAg levels between 1500 and 20 000 IU/mL initially or between 5000 and 20 000 IU/mL after 24 weeks of PegIFNα-2a benefitted more from the combined therapy, compared with those on monotherapy. CONCLUSIONS: Combined therapy of PegIFNα-2a and ETV is more efficacious for HBeAg+ patients without early response to PegIFN monotherapy, and HBsAg levels are a good predictor of treatment outcomes.

Serum keratin-18 fragments as cell death biomarker in association with disease progression and prognosis in hepatitis B virus-related cirrhosis.

Extensive hepatocyte death leads to hepatic inflammation and contributes to systemic inflammation in decompensated cirrhosis. We aimed to investigate the prognostic value of serum cell death markers in patients with hepatitis B virus (HBV)-related acute decompensation (AD) of cirrhosis with and without acute-on-chronic liver failure (ACLF). We studied two cohorts-cohort 1: 201 outpatients with stable chronic hepatitis B (49 cirrhosis); cohort 2: 232 inpatients with HBV-related cirrhosis admitted for AD. Cell death was determined with serum keratin-18 (K18) for total death and serum caspase-cleaved-K18 (cK18) for apoptosis. Survival analyses were performed using competing risk method. We found that serum K18 and cK18 were significantly (P < 0.001) higher in patients from cohort 2 than those from cohort 1. Among cohort 2, ACLF patients had significantly (P < 0.001) increased K18 and cK18 comparing to those without ACLF. Increased K18 and cK18 were mainly attributed to HBV flare and were associated with liver and coagulation failure. HBV-AD patients without ACLF who admitted with upper tertile of K18 or cK18 were at higher risk of developing ACLF during follow-up. Baseline serum K18 or cK18 was significantly associated with transplant-free 90-day survival independent of leucocytes, HBV DNA, bacterial infection, encephalopathy and severity scores. The combination of cell death biomarkers significantly improved the prognostic value of the currently established prognostic scores. The reduction of cell death level after standard treatment was associated with increased short-term survival. In conclusion, measurements of serum K18 or cK18 in HBV decompensated cirrhosis are a promising tool for predicting ACLF and risk stratification of short-term outcome.

IPS-1 polymorphisms in regulating interferon response in HBV infection.

Single nucleotide polymorphisms (SNP) influence the outcome of antiviral therapy in chronic hepatitis B patients. Interferon ß promoter stimulator 1 polymorphisms (IPS-1) regulate interferon (IFN) mediated viral clearance in hepatitis B virus (HBV) infection. In our study, HepG2 and HepG2.2.15 were transfected with different SNP genotype expression vectors of IPS-1 (wild-type, rs17857295, rs7262903 and rs7269320). The production of IPS-1 and IFN were evaluated in these transfected cells. IPS-1 in the HepG2.2.15 cells transfected with rs17857295 or rs7262903 was 37% or 31% lower than that with wild-type transfection (p < 0.001). IFN-ß in rs17857295 or rs7262903 transfected HepG2.2.15 cells was 5.4 or 3.7 fold higher than that of wild-type transfection (p < 0.0001). IPS-1 in rs7269320 SNP transfected HepG2.2.15 cells was 40% lower than that of wild-type transfection (p < 0.0001); no significantly different IFN-ß was observed between rs7269320 SNP and wild-type transfections. IFN-ß expression was > 2 fold higher in rs17857295 transfected HepG2.2.15 cells than HepG2 cells (p < 0.001). The data suggests that host HBV viral clearance is stronger in IPS-1 rs17857295 or rs7262903 SNP genotype patients than wild-type patients. Relatively weak inducible IFN-ß production in HBV infected patients with IPS-1 rs7269320 SNP or wild-type may contribute to chronic virus infection.

N-myc and STAT interactor correlates with severity and prognosis in acute-on-chronic liver failure of hepatitis B virus.

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is characterized by acute deterioration of chronic liver disease with excessive inflammation. N-myc and STAT interactor (NMI), an inflammation-mediated protein, involves in various inflammatory-related diseases, but the role of NMI in development and prognosis in HBV-ACLF remains to be elucidated. METHODS: Serum NMI from healthy controls (HCs, n = 20), chronic hepatitis B (CHB, n = 50) patients, and HBV-ACLF patients (n = 50) was determined using ELISA. NMI from peripheral blood mononuclear cells and liver was confirmed using quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. RESULTS: Serum NMI was increased 1.9-fold or 2.2-fold from HBV-ACLF patients compared with that from HCs (P < 0.01) or CHB patients (P < 0.01). Consistently, NMI from peripheral blood mononuclear cells was upregulated significantly from HBV-ACLF patients compared with that from HCs and CHB patients at mRNA and protein levels. Hepatic NMI from HBV-ACLF patients was 2.8-fold higher than that from HCs. Serum NMI was correlated with Model for End-stage Liver Disease, Chronic Liver Failure Consortium ACLF score, and ACLF grades. In contrast, serum NMI was significantly decreased in HBV-ACLF ameliorated patients during follow-up, whereas serum NMI was sustained at high levels in non-ameliorated patients. Elevated serum NMI (≥ 198.5 pg/mL) was correlated with poor survival rate of HBV-ACLF patients. Using receiver operating characteristics curves, it was suggested that serum NMI was a potential biomarker in predicting 3-month mortality of HBV-ACLF patients. CONCLUSIONS: Our study highlights the potential role of NMI in assessing the development and prognosis of HBV-ACLF.

Entecavir add-on or switch-to pegylated interferon improves HBsAg clearance in HBe antigen negative chronic hepatitis B patients.

BACKGROUND AND AIMS: Chronic hepatitis B (CHB) patients rarely achieve hepatitis B surface antigen (HBsAg) loss with nucleoside/nucleotide analog therapy. METHODS: In this retrospective study, it was evaluated that the rate of HBsAg loss in the HBe antigen negative (HBeAg-) patients (n=101) treated with entecavir (ETV) for ≥24 weeks followed by switching to (n=22) or adding on (n=26) pegylated interferon (PEG-IFN), and continuing ETV (n=53). RESULTS: HBsAg clearance rate at week 48 was 9% (2/22), 15% (4/26), and 0% (0/53) (P<0.05), in switch-to or add-on, or ETV monotherapy CHB patients, respectively. HBsAg reduction at week 48 was 1.182, 0.6614, or 0.056 log IU/mL, in switch-to, add-on, and ETV patients, respectively (P<0.001). The response rate (HBsAg reduction >1 log IU/mL at week 48) in the switch-to, add-on, and ETV monotherapy CHB patients was 60%, 40%, and 2%, respectively (P<0.001). In the switch-to and add-on patients, HBsAg reduction and clearance were associated with HBsAg titers at week 0 and HBsAg reduction at week 24. Furthermore, HBsAg reduction at week 24 was associated with the response rate at week 48 in the switch-to and add-on patients, showing that the area under the receiver operating characteristic curve was 0.904. Positive predictive value and negative predictive value for response rate was 70% and 100% with cut-off value 0.2 log IU/mL, respectively. CONCLUSION: In summary, we demonstrated that PEG-IFN enhanced HBsAg loss in HBeAg- CHB patients. High HBsAg clearance was achieved in the patients with HBsAg titers at baseline <1,000 IU/mL and HBsAg reduction >0.2 log IU/mL.

Correlation between hepatic human males absent on the first (hMOF) and viral persistence in chronic hepatitis B patients.

BACKGROUND: Chronic hepatitis B (CHB) remains a global health dilemma with high morbidity and mortality. Human males absent on the first (hMOF) (a histone acetyltransferase) is responsible for DNA damage repair, tumorigenesis and cell cycle regulation. Persistence of HBV DNA contributes to cirrhosis and hepatocellular carcinoma (HCC) in CHB patients. Histone acetyltransferase enhances HBV replication, however the precise underlying mechanism of hMOF in HBV replication in CHB patients remains to be explored. This study aims to investigate the correlation between hepatic hMOF and HBV DNA replication in CHB patients, and may provide new insights towards the treatment of CHB patients. METHODS: hMOF in liver biopsy (CHB, n = 33 HBeAg+; n = 20 HBeAg-, and three healthy controls) was determined, using immunohistochemistry, qPCR and Western blot. The correlation between hMOF and HBsAg, as well as, HBeAg were determined. RESULTS: A positive correlation between hMOF and HBV DNA in overall CHB patients was observed. A distinct positive correlation between hMOF and HBsAg and/or HBeAg in HBeAg+ CHB patients was also detected, however not observed between hMOF and HBsAg in HBeAg- CHB patients. No correlation was observed between hMOF and hepatic inflammation severity and fibrotic stage in CHB patients. CONCLUSIONS: Hepatic hMOF might contribute to host HBV clearance in CHB patients and possible pathogenesis.

Genetic variations of NTCP are associated with susceptibility to HBV infection and related hepatocellular carcinoma.

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

Serum soluble ST2 is a promising prognostic biomarker in HBV-related acute-on-chronic liver failure.

BACKGROUND: The IL-33/ST2 axis is involved in the pathogenesis of many diseases such as autoimmune diseases, cancer, and heart failure. However, studies of the IL-33/ST2 pathway in HBV-related acute-on-chronic liver failure (HBV-ACLF) are lacking. The present study aimed to determine the prognostic role of serum IL-33/soluble ST2 (sST2) in HBV-ACLF. METHODS: Serum levels of IL-33 and sST2 in healthy controls (HC, n=18), chronic hepatitis B (CHB, n=27) and HBV-ACLF (n=51) patients at the 1st and 4th week after enrollment were detected using ELISA, and clinical data were collected. The follow-up of HBV-ACLF patients lasted for 6 months at least. RESULTS: There was no significant difference of serum IL-33 level among HC, CHB and HBV-ACLF patients at week 1. However, serum sST2 level differed significantly among the three groups: highest in the HBV-ACLF group, moderate in the CHB group and lowest in the HC group. There was a reverse correlation between serum sST2 level and the survival of HBV-ACLF patients. The level of serum sST2 in HBV-ACLF survivors was significantly declined from week 1 to week 4 following the treatment, whereas that in HBV-ACLF non-survivors remained at a high level during the same period. Furthermore, serum sST2 level was significantly correlated with laboratory parameters and the most updated prognostic scores (CLIF-C OF score, CLIF-C ACLF score and ACLF grades). The receiver operating characteristics curves demonstrated that serum sST2 level was a good diagnostic marker for predicting the 6-month mortality in HBV-ACLF patients, comparable to the most updated prognostic scores. Serum sST2 cut-off points for predicting prognosis in HBV-ACLF patients were 76 ng/mL at week 1 or 53 ng/mL at week 4, respectively. HBV-ACLF patients with serum sST2 level above the cut-off point often had a worse prognosis than those below the cut-off point. CONCLUSION: Serum sST2 may act as a promising biomarker to assess severity and predict prognosis of patients with HBV-ACLF and help for the early identification and optimal treatment of HBV-ACLF patients at high risk of mortality.

Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is an acute deterioration of liver function on chronic liver disease with immune disorder. Th22 cells and IL-22 were correlated with inflammatory and autoimmune diseases. However, Th22 cells and IL-22 in the pathogenesis of HBV-ACLF remains to be elucidated. It was investigated the correlation between Th22 and prognosis in HBV-ACLF. METHODS: Seventy-one HBV-ACLF and 65 chronic hepatitis B patients were recruited. The peripheral frequencies of Th22, Th17 and Th1, or IL-22 and IL-17 were determined, using flow cytometry or ELISA, respectively. It was further analyzed the correlation between Th22 mediated circulating IL-22 and survival rate of HBV-ACLF patients. RESULTS: It was upregulated that the peripheral frequencies of Th22/Th17 cells as well as plasma IL-22 and IL-17 in HBV-ACLF patients, but the frequency of Th1 cells was decreased, compared with health controls. Elevated Th22 cells and IL-22 were correlated with HBV-ACLF disease severity. Elevated plasma IL-22 level (>29.5 pg/ml) was correlated with poor survival rate of HBV-ACLF patients at baseline, using Kaplan-Meier analysis. CONCLUSIONS: Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-ACLF. Th22 cells/IL-22 might be served as biomarkers for evaluating the prognosis of HBV-ACLF.

Serum hepatocyte apoptosis biomarker predicts the presence of significant histological lesion in chronic hepatitis B virus infection.

BACKGROUND: Hepatocyte death, either apoptosis or necrosis, is closely associated with hepatic inflammation and fibrosis. AIMS: To investigate the potential values of hepatocytes death biomarker, M30 (apoptosis) and M65 (total death) in predicting histological lesions in chronic hepatitis B virus (HBV) infection. METHODS: Total 201 treatment-naïve patients were prospectively recruited. Liver biopsies were performed prior to antiviral treatments for treatments starting evaluation. Sera were collected on the day of liver biopsy for biomarker measurements. Sera from 200 age-matched healthy volunteers served as healthy controls (HCs). RESULTS: Significant histological lesions (SHL, i.e. significant inflammation and/or significant fibrosis) were confirmed in 150 (74.63%) patients. There were significantly higher serum M30 and M65 in patients with SHL than those without SHL (p<0.001) or than HCs (p<0.001). Serum M30, but not M65, independently predicted SHL [odds ratio:3.4 (95% CI, 1.8-6.2) per increase of 50U/L, p<0.001] after adjusting other potential confounding factors. A novel model based on M30 provided good diagnostic performance in predicting SHL [AUC, 0.87 (0.81-0.92)]. Cut-off value of >0 to confirm or ≤-0.5 to exclude SHL has ∼12% misclassification rate. CONCLUSION: Hepatocyte apoptosis biomarker, M30 is a promising non-invasive alternative to liver biopsy in chronic HBV infection upon treatment evaluation.

Randomized clinical trial: Nucleos(t)ide analogues improved survival of CHB-related HCC patients via reducing severity and progression of malignancy.

BACKGROUND: The influence of nucleos(t)ide analogues (NAs) to treat Chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored. AIM: To investigate if NAs reduce the severity and progression of CHB-related HCC. RESULTS: Among 532 patients, there were 118 or 414 CHB-related HCC with or without NAs therapy, respectively. BCLC scores, serum level of ALT/AST and HBV DNA were compared. During follow-up, the survival period of CHB-related HCC patients with sustained NAs is significantly longer than that with NAs post-HCC and NAs naïve (p < 0.05). Factors significantly associated with the poor overall survival of CHB-related HCC include BCLC scores (hazard ratio, 1.84 [95% confidence interval, 1.57-2.15], p < 0.001), NAs post-HCC or NAs naïve (1.33 [1.07-1.65], p < 0.01), serum AST ≥ 40 IU/L (1.48 [1.03-2.12], p < 0.05) and HBV DNA ≥ 104 copies/ml (1.36 [1.01-1.83], p < 0.001). METHODS: Outcomes of 532 CHB-related HCC patients with/without NAs were investigated. Overall survival of CHB-related HCC patients, NAs naïve (n = 156), NAs received post-HCC (n = 258) and NAs sustained (n = 118) were determined. CONCLUSIONS: NAs reduced severity of CHB-related HCC patients. Sustained NAs is an important factor associated with the extended survival of CHB-related HCC patients.

Identification of acetyltransferase genes (HAT1 and KAT8) regulating HBV replication by RNAi screening.

BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2.2.15 cells, with KAT8 knockdown reducing both HBsAg and HBeAg more than HAT1 knockdown. Consistent with these observations, HBV replication regulators hepatocyte nuclear factor-4-α (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator- (PPARGC-) 1-α were decreased following knockdown of HAT1 or KAT8. CONCLUSIONS: These data suggest that KAT8 or HAT1 regulate HBV replication and may be potential drug targets of anti-HBV therapy.