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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.

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.

Immune checkpoint inhibitors (ICIs) are mAbs against cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 receptor (PD-1) and programmed death-ligand 1 (PD-L1), which the inhibitory pathways that leads to T cell inactivation. Here, we report a case of ICI-induced immune-mediated hepatotoxicity with liver biopsy. A 63-year-old man with brain metastasis from lung adenocarcinoma was treated with three times of g knife treatment, following by a combination of chemotherapy [carboplatin and (550 mg) + pemetrexed (1000 mg)] plus bevacizumab (anti-VEGF monoclonal antibody) (600 mg D1) and camrelizumab (anti-PD-1 mAb) (200 mg D1). Around 21 days later, abnormal liver function was detected. He received a diagnosis of ICI-induced liver injury after liver biopsy. The liver function of this patient was recovered, following methylprednisolone treatment. Such data offers useful information for clinicians to deal with cancer patients for ICI treatment, suggesting that liver function must be closely monitored.

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.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.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-1β, 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.Among 423/542 (78%) patients with significant liver injury in the training set, 47% were in grey-zone. Circulating IL-1β, 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-1β, 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.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.

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.

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 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.

Lei Yan,1,* Chuanwu Zhu,2,* Jing Li,3,* Liwen Chen,1 Yezhou Ding,1 Zhujun Cao,1 Kehui Liu,1,4 Lanyi Lin,1 Weiliang Tang,1 Qing Xie,1 Yumin Xu,1 Shisan Bao,5 Hui Wang1 1Department of Infectious Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 2Department of Infectious Diseases, The Fifth People’s Hospital of Suzhou, Jiangsu 215007, China; 3Department of Infectious Diseases, Huai-An Fourth People’s Hospital, Jiangsu 223002, China; 4Department of Infectious Diseases, Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai 201801, China; 5Discipline of Pathology, School of Medical Sciences and Bosch Institute, Charles Perkin Centre, University of Sydney, Sydney, NSW, Australia *These authors contributed equally to this work 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) (P1 log IU/mL at week 48) in the switch-to, add-on, and ETV monotherapy CHB patients was 60%, 40%, and 2%, respectively (P0.2 log IU/mL. Keywords: chronic hepatitis B, HBsAg, PEG-IFN, entecavir, switch-to, add-on

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. Electronic supplementary material The online version of this article (10.1186/s13578-018-0215-5) contains supplementary material, which is available to authorized users.

// Peng Wang 1, 2, * , Ruidong Mo 1, 2, * , Rongtao Lai 1, 2, * , Yumin Xu 1, 2 , Jie Lu 2 , Gangde Zhao 1, 2 , Yuhan Liu 1, 2 , Zhujun Cao 1, 2 , Xiaolin Wang 1, 2 , Ziqiang Li 1, 2 , Lanyi Lin 1 , Huijuan Zhou 1 , Wei Cai 1 , Hui Wang 1 , Shisan Bao 1, 3 , Xiaogang Xiang 1, 2 and Qing Xie 1, 2 1 Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 3 Discipline of Pathology, School of Medical Sciences and Bosch Institute, The University of Sydney, New South Wales 2006, Australia * These authors have contributed equally to this work Correspondence to: Qing Xie, email: xieqingrjh@163.com Xiaogang Xiang, email: shine-xxg@163.com Keywords: Na + taurocholate cotransporting polypeptide; association study; HBV; HCC; meta-analysis Received: July 19, 2017 Accepted: September 21, 2017 Published: October 31, 2017 ABSTRACT 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

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.

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 up-regulated 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 to health controls (HCs). 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.

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

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.

// Yun Wang 1, * , Xiaogang Xiang 1, * , Liwen Chen 1 , Zhujun Cao 1 , Rebecca Bao 2 , Huijuan Zhou 1 , Weiliang Tang 1 , Jie Lu 1 , Lanyi Lin 1 , Qing Xie 1 , Shisan Bao 3 , Hui Wang 1 1 Department of Infectious Diseases and Hepatology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Discipline of Anatomy and Histology F13, The University of Sydney, New South Wales, Australia 3 Discipline of Pathology, School of Medical Sciences and Bosch Institute, The University of Sydney, New South Wales, Australia * These authors contributed equally to this work Correspondence to: Hui Wang, email: wanghuirj@163.com Shisan Bao, email: bob.bao@sydney.edu.au Keywords: nucleos(t)ide analogues, survival, chronic hepatitis B, hepatocellular carcinoma Received: April 21, 2016 Accepted: June 06, 2016 Published: June 18, 2016 ABSTRACT 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 naive ( 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 naive (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 ≥ 10 4 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 naive ( 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.

Introduction Healthy sleep promotes cognitive functioning and is associated with better academic performance, whereas insufficient, poor, and inconsistent sleep schedules are associated with poor school performance. Several studies have identified gender differences in the timing, duration, and quality of sleep in adolescence, with adolescent girls having poorer sleep compared to adolescent boys, yet research shows that girls outperform boys academically. This could be because sleep might not affect all subjects similarly and previous studies regarding sleep and academic performance combined both genders. The goal of the present study was to determine which aspects of academic performance are specifically associated with short or poor sleep in typically developing adolescents girls. Methods 80 adolescent girls aged 12-17 years participated in the study. Sleep was assessed in the home environment for five consecutive weeknights using actigraphy. Academic performance was assessed using report card grades. Results 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. No significant associations were found between sleep variables and grades in other subjects. Conclusion Longer average weekday sleep duration is associated with better mathematics grades in typically developing adolescent girls. Support NSERC grant to Reut Gruber

Additional file 1. Correlation between serum HBV DNA level, and HBsAg status and severity of inflammation and stage of fibrosis of liver.

Background & Aims: Extensive hepatocyte death leads to hepatic inflammation contributing to systemic inflammation and acute-on-chronic liver failure (ACLF) in alcoholc cirrhosis. We aimed to investigate hepatocyte death in relation to disease progression in cirrhosis with HBV infection. Methods: Cohort 1: 201 outpatients with stable chronic hepatitis B receving liver biopsy (152 non-cirrhotic and 49 cirrhotic). Cohort 2: 327 inpatients admitted for acute decompensation (AD) of cirrhosis. Cell death was determined with serum Keratin-18(K18) for total death and serum caspase-cleaved-K18(cK18) for apoptosis. Survival analyse was performed using competing risk method. Results: Serum K18 and cK18 were significantly (p

Background and Aim Antiviral therapy is important in advanced liver fibrosis/cirrhosis with chronic hepatitis B (AdLF-CHB) patients, but complete regression of cirrhosis remains to be the challenge. We aimed to investigate whether up to 10 years lamivudine treatment achieves liver fibrosis/cirrhosis regression in AdLF-CHB patients. Methods Improvement of hepatic fibrosis/cirrhosis, virological response and disease progression were evaluated in 28 AdLF-CHB patients with up to 10 years lamivudine treatment. Liver biopsy was performed in all of the 28 patients at baseline, but only 19 patients had second biopsy at year 10. Results There were 24 hepatitis B e antigen (HBeAg)-positive and 4 HBeAg-negative patients within the original 28 AdLF-CHB patients. At the end of 10 years lamivudine treatment, 20 of the 24 HBeAg-positive patients had HBeAg loss. HBeAg seroconversion was detected in 10 of these 20 HBeAg loss patients. HBsAg loss was observed in 4 of the original 28 patients. Among these four HBsAg loss patients, three had HBsAg seroconversion. All patients achieved hepatitis B virus DNA (HBV DNA) undetectable. Histopathology was evaluated between paired original and final liver biopsies among 19 patients as follows: 4/19 achieved complete liver fibrosis/cirrhosis regression; 9/19 improved in Ishak fibrosis score; whereas 6/19 showed no fibrosis improvement. About 75% patients achieved inflammatory/fibrotic improvement. No significant disease progression was observed in 24/28 patients. Furthermore, no significant difference in histopathology improvement, cirrhosis regression, disease progression between non-resistance and rescue for resistance was observed. Conclusion Long-term lamivudine therapy achieves regression of fibrosis/cirrhosis and improvement of histological and disease progression in AdLF-CHB patients.

BACKGROUND: Considerable research points to the importance of sleep for academic success. Short and inconsistent sleep are common in adolescents. Many adolescents present high intraindividual variability (IIV), the day-to-day variability in an individual’s sleep duration, timing, and efficiency, even within school nights. To date, only a paucity of studies has examined the associations between sleep IIV and averages with school grades in adolescents. However, these studies used subjective measures of sleep and showed mixed results. OBJECTIVES: The goal of this study was to determine the extent to which averages and IIV in sleep duration, timing, and efficiency were associated with academic performance in adolescents using objective sleep measures. It was hypothesized that longer average sleep duration, higher sleep continuity, and smaller IIV would be associated with better grades. DESIGN/METHODS: The sample consisted of 119 participants: 36 boys and 83 girls aged 12–18 years (SD = 1.35 years). Nighttime sleep was measured for five school nights using actigraphy paired with sleep logs. Academic performance was measured using report card grades. RESULTS: The associations between sleep and academic performance were examined using hierarchical regression analyses adjusted for potential confounds of puberty status, gender, and socioeconomic status. IIV of the sleep measures sleep duration, timing, and efficiency were calculated using individual standard deviations. The average duration of time spent asleep and the number of immobile minutes, indicating higher sleep continuity, measured by actigraphy were found to be associated with better grades in Mathematics and in French. IIV in sleep duration, timing, and efficiency were not significantly associated with report card grades. CONCLUSION: Longer average time asleep and immobile sleep time were associated with higher Math and French grades, suggesting that sleep quality and duration both contribute to students’ performance in core school subjects. Weekday IIV in sleep measures were not associated with academic performance in adolescent students. Pediatricians and other health professionals can contribute to improving youth academic success by helping them to maintain or achieve healthy sleep.

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.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.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.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.

Hepatocyte death, either apoptosis or necrosis, is closely associated with hepatic inflammation and fibrosis.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.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).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 (p0.001) or than HCs (p0.001). Serum M30, but not M65, independently predicted SHL [odds ratio:3.4 (95% CI, 1.8-6.2) per increase of 50U/L, p0.001] 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 of0 to confirm or ≤-0.5 to exclude SHL has ∼12% misclassification rate.Hepatocyte apoptosis biomarker, M30 is a promising non-invasive alternative to liver biopsy in chronic HBV infection upon treatment evaluation.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13578-015-0059-1) contains supplementary material, which is available to authorized users.

Investigations on survival of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) are sparse and urgently needed. The current study aimed to evaluate the prognostic value of circulating cell death biomarkers (M30-anigen, M65-antigen and HMGB1) for HBV ACLF. In this prospective study (2/2013–8/2014), 94 patients including 54 HBV-ACLF and 40 chronic hepatitis B (CHB) patients were recruited. 40 healthy controls (HC) were also recruited. HBV-ACLF were followed up for 3 months for short-term mortality. All three biomarkers were significantly elevated in HBV-ACLF compared with CHB or HC. M30- and M65-antigens could significantly discriminate between non-survivors and survivors in HBV-ACLF. However, HMGB1 showed no prognostic value. By Cox regression analysis, M30- and M65-antigens and MELD were identified as independent predictors for short-term mortality. A novel prognostic model, MELD-CD (MELD-cell death) was established based on the multivariate results. The adjusted Harrell’s C-index of MELD-CD was 0.86 (P P P P P

To investigate the changes in circulating plasmacytoid dendritic cells (pDCs) in patients with chronic hepatitis B (CHB) during the course of treatment with pegylated-interferon alfa-2s (peg-IFNa-2a) and to determine the correlations with therapeutic response.Forty-one patients with CHB who were receiving peg-IFNa-2a antiviral treatment for 48 weeks were enrolled in the study.Expression of the Toll-like receptor 9 (TLR9) on and frequency and functionality of the pDCs were analyzed at treatment weeks 0, 2, 12, 24, 36 and 48.All patients exhibited an initially rapid decrease in the numbers of circulating pDCs and showed CpG-induced endogenous IFNa production within the first 2 weeks of treatment.Subsequently, all responders displayed a continuous increase in pDC numbers as well as functionality, both of which peaked around week 12 of treatment; in addition, these treatment responses were accompanied by significantly increased levels of type 1 T helper cytokines (P less than 0.05), which did not occur in the non-responders.pDCs are involved in the initial therapeutic immune response stimulated by peg-IFNa-2a treatment.Recovery of blood pDC number and functionality may represent a predictor of favorable response to peg-IFNa-2a antiviral treatment in patients with CHB.

Acute liver failure (ALF) still has an unacceptable high mortality rate, despite substantial improvements with multidisciplinary care. The precise underlying mechanism of ALF remains to be explored. It has been reported that microRNAs (miRNAs) are novel regulators in a number of liver diseases, but the role of miRNAs in the development of ALF is not fully understood. An ALF murine model was generated by ip injection of d-GalN/LPS, which was confirmed with histopathology and biochemistry. The hepatic miRNA expression profile in ALF was determined by microarray and verified by qRT-PCR. The functions and signal pathways of the targeted genes of these deregulated miRNAs were predicted, using bioinformatics analysis. The possible underlying mechanism was investigated by exploring the relationship between miRNA modification and hepatocyte apoptosis. There were a total of 95 significantly changed miRNAs in ALF compared to mock-treated (P < 0.01). Among these 95 miRNAs, 20 were up-regulated and 26 were down-regulated at both 5 and 7 h time points. Bioinformatics analysis predicted that some of these 46 miRNAs were involved in apoptosis. Among the up-regulated miRNAs involved in apoptosis, miR-15b and miR-16 showed the highest enrichment and targeted the common anti-apoptotic gene, BCL2. Our in vitro data demonstrated that miR-15b and/or miR-16 regulated BCL2 at the protein level. Inhibition of miR-15b and/or miR-16 reduced hepatic apoptosis and TNF production. These data suggest that miR-15b and miR-16 regulate TNF mediated hepatic apoptosis via BCL2 during ALF, and may shed light on the development of a therapeutic strategy for treatment of ALF.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for viral persistence. This study aimed to investigate the serum surrogate markers for cccDNA and to evaluate the intrahepatic viral events associated with disease activity in HBeAg-negative chronic hepatitis B patients. Thirty-three treatment-naive patients with a negative HBeAg who had a liver biopsy were studied. Active disease was defined as a serum alanine aminotransferase >40 IU/L and a serum HBV DNA >10,000 copies/ml. This study showed significant correlation between serum HBV DNA and both log cccDNA (r = 0.41, P = 0.018) and log total intrahepatic HBV DNA (r = 0.71, P < 0.0001). No significant correlation was observed between serum HBsAg and log cccDNA (P = 0.15) or log total intrahepatic HBV DNA (P = 0.97). Fourteen and 19 patients had inactive and active disease, respectively. The median log cccDNA and log total intrahepatic HBV DNA (copies/10(6) cells) were significantly higher in patients with active disease compared with those with inactive disease (4.11 vs. 3.53, P = 0.03 and 5.46 vs. 4.64, P < 0.001, respectively). The HBV replicative efficiency, defined as the ratio of serum HBV DNA to cccDNA, was approximately 20% higher in patients with active disease. No significant difference was observed in the HBsAg levels and the ratio of serum HBsAg to cccDNA between the two groups. In conclusion, serum HBV DNA, but not HBsAg, reflects the amount of cccDNA and the replication efficiency of HBV in patients with HBeAg-negative chronic hepatitis B.

Hepatitis C virus (HCV) infection is still a major global health issue despite decades of research. The liver-specific microRNA-122 (miR-122) can stimulate HCV replication/translation in vitro, indicating that miR-122 contributes to pathogenesis of HCV. However, it remains controversial whether interferon (IFN) inhibits HCV via modulating miR-122 expression. The underlying mechanism of ribavirin (RBV) in enhancing IFN treatment for HCV patients has yet to be explored. We investigated the relationship between miR-122 expression and anti-HCV activity of IFN beta in combination with RBV in vitro, due to difficulty accessing an HCV animal model. Upregulation of ISG54 mRNA or cytostatic effect was detected in Huh7 and HCV replicon cell lines in response to IFN beta or RBV stimulation, respectively. It was found that IFN beta and/or RBV suppressed miR-122 expression marginally, with a synergetic anti-HCV effect between IFN beta and RBV. Marginal modification of other miRNAs was also observed in these cell lines, using miRNA array following IFN beta and RBV treatment. Taken together, our data suggest that miRNAs are not crucial in anti-HCV action, following IFN beta and/or RBV stimulation in vitro.

The renin angiotensin system (RAS) plays a major role in liver fibrosis. A novel homologue of angiotensin converting enzyme, ACE2, was identified as a negative regulator of RAS as it degrades Ang II to Ang1-7. We investigated in vivo the expression of ACE2 in liver fibrosis. We evaluated the relationship between biochemical variables and liver tissue expression of ACE2, the correlation between a histological assessment of liver fibrosis and liver tissue expression of ACE2. Male SD rats were randomly divided into a CCL4 group which received injections of CCL4 and the control group which received injections of olive oil. Liver pathology was examined by HE and Sirius red staining, and real-time PCR was performed to determine the gene expression levels of ACE2 and ACE. Real-time PCR analysis revealed that ACE2 mRNA was higher at the two-, four-, and six-week time points, respectively (p0.01). Similarly, hepatic ACE mRNA was significantly increased after CCL4 injection. There was a significant correlation between ACE and ACE2 gene expression (r=0.750, P0.001). ACE2 gene expression strongly correlated with ALT (r=0.669, P0.0001) and AST levels (r=0.815, P0.0001). There was a significant correlation between circulating ACE2 and histological scores of liver fibrosis. ACE2 and ACE gene expression correlated with the ISHAK score (r=0.850, P0.001; r=0.806, P0.001). There was a significant relationship between ACE2 gene expression and the degree of liver fibrosis. ACE2 plays a crucial role in liver fibrogenesis.

Hepatitis B virus (HBV) infection leads to the development of liver inflammation, causing morbidity and mortality. Multiple factors influence HBV progression, including genetic factors. Toll-like receptor (TLR)9 plays a key role in innate immunity, and mutations in the genes encoding this receptor have been associated with liver damage progression. Our study aimed to investigate one-tag single nucleotide polymorphisms (rs187084) representing the majority of common variations in TLR9 in a population-based study of Chinese patients. A total of 209 Chinese patients with HBV infection (130 with chronic hepatitis and 79 with liver cirrhosis) and 193 healthy individuals were studied. Our results showed that the frequencies of the C/C genotype and C allele were statistically higher in patients with HBV-related liver cirrhosis than in the healthy controls (26.6 vs. 15.5%; OR=1.97, 95% CI 1.05-3.71, χ2=4.483, P=0.034/43.1 vs. 37.8%; OR=1.49, 95% CI 1.02-2.16, χ2=4.323, P=0.038). No significant differences in the frequencies of alleles or genotypes were found between patients with chronic hepatitis B and the control subjects. In conclusion, this study is the first to show that small effects within TLR9 contribute towards the development of HBV, supporting the hypothesis that little is currently known regarding the contribution of genetic factors to HBV.

Chronic hepatitis B virus (HBV) infection is a complex interaction between replicating noncytopathic virus and dysregulatory host antiviral immunity. Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immunity via secreting type I interferons. Toll-like receptor (TLR) 9 is involved in major pattern recognition receptors expressed in pDCs. The frequency of pDCs and TLR9 expression in peripheral blood mononuclear cells (PBMC) was determined, using flow cytometry. IFN-alpha production by PBMC was evaluated in vitro in the presence of cytidine phosphate guanosine (CpG) with/without pDCs. The correlation between TLR9, pDCs frequency and viral load was also evaluated. TLR9 expression in pDCs in chronic HBV patients was significantly ( approximately 50%) reduced, supported by approximately 70% reduction of TLR9 mRNA, in comparison to healthy controls, correlating with the impairment of IFN-alpha production in vitro. Furthermore, pDCs frequency in these patients was substantially reduced ( approximately 30%), inversely correlating with serum ALT levels and HBV viral load. HBsAg and HBcAg were detected by immunohistochemistry in pDCs in chronic HBV patients. We conclude that HBV infection results in reduced frequency of circulating pDCs and their functional impairment via inhibiting the expression of TLR9. These data may provide useful information in both basic research and clinical treatment of chronic HBV infection.