Telomere-to-telomere and haplotype-resolved genome of the kiwifruit Actinidia eriantha.

Actinidia eriantha is a characteristic fruit tree featuring with great potential for its abundant vitamin C and strong disease resistance. It has been used in a wide range of breeding programs and functional genomics studies. Previously published genome assemblies of A. eriantha are quite fragmented and not highly contiguous. Using multiple sequencing strategies, we get the haplotype-resolved and gap-free genomes of an elite breeding line "Midao 31" (MD), termed MDHAPA and MDHAPB. The new assemblies anchored to 29 pseudochromosome pairs with a length of 619.3 Mb and 611.7 Mb, as well as resolved 27 and 28 gap-close chromosomes in a telomere-to-telomere (T2T) manner. Based on the haplotype-resolved genome, we found that most alleles experienced purifying selection and coordinately expressed. Owing to the high continuity of assemblies, we defined the centromeric regions of A. eriantha, and identified the major repeating monomer, which is designated as Ae-CEN153. This resource lays a solid foundation for further functional genomics study and horticultural traits improvement in kiwifruit.

Inhibition of HBV replication by EVA1A via enhancing cellular degradation of HBV components and its potential therapeutic application.

Hepatitis B virus (HBV) DNA is much higher during HBeAg-positive chronic HBV infection (EP-CBI) than during HBeAg-negative chronic HBV infection (EN-CBI), although the necroinflammation in liver is minimal and the adaptive immune response is similar in both phases. We previously reported that mRNA levels of EVA1A were higher in EN-CBI patients. In this study, we aimed to investigate whether EVA1A inhibits HBV gene expression and examine the underlying mechanisms. The available cell models for HBV replication and model HBV mice were used to investigate how EVA1A regulates HBV replication and the antiviral activity based on gene therapy. The signaling pathway was determined through RNA sequencing analysis. The results demonstrated that EVA1A can inhibit HBV gene expression in vitro and in vivo. In particular, EVA1A overexpression resulted in accelerated HBV RNA degradation and activation of the PI3K-Akt-mTOR pathway, two processes that directly and indirectly inhibiting HBV gene expression. EVA1A is a promising candidate for treating chronic hepatitis B (CHB). In conclusion, EVA1A is a new host restriction factor that regulates the HBV life cycle via a nonimmune process.

Insights into COVID-19-associated critical illness: a narrative review.

Background and Objective: Since the outbreak of the 2019 novel coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS) and sepsis resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have surged in intensive care units around the world. The heterogeneity of ARDS and sepsis has long been observed, and multiple subphenotypes and endotypes correlated with different outcomes and treatment response have been identified in the search for treatable traits. Despite their similarity to typical ARDS and sepsis, COVID-19-associated ARDS and sepsis harbor distinct features, raising the question as to whether they could be considered as subphenotypes or endotypes of the historical syndromes and, accordingly, benefit from specific therapeutic strategies. This review aimed to summarize and discuss the current knowledge of COVID-19-associated critical illness and the intrinsic subphenotypes or endotypes. Methods: Literature on the pathogenesis of COVID-19 and the subphenotyping of COVID-19-associated critical illness was derived from the PubMed database and reviewed. Key Content and Findings: Accumulating evidence, varying from clinical observation to basic research, has contributed to revealing the fundamental pathophysiological features of severe COVID-19 and has advanced our knowledge of the disease. COVID-19-associated ARDS and sepsis exhibit some distinctive features compared to the classic syndromes, including remarkable vascular abnormality and coagulopathy, and distinct respiratory mechanics and immune response. Some conventional subphenotypes derived from classic ARDS and sepsis have been validated in COVID-19, while novel subphenotypes and endotypes have also been identified in patients with this disease, who experience variable clinical outcomes and treatment responses. Conclusions: Subphenotyping of COVID-19-associated ARDS and sepsis can provide new insights into the development and management of these illnesses.

Noninvasive Cuffless Blood Pressure Estimation With Dendritic Neural Regression.

Blood pressure (BP) is one of the most important indicators of health. BP that is too high or too low causes varying degrees of diseases, such as renal impairment, cerebrovascular incidents, and cardiovascular diseases. Since traditional cuff-based BP measurement techniques have the drawbacks of patient discomfort and the impossibility of continuous BP monitoring, noninvasive cuffless continuous BP measurement has become a popular topic. The common noninvasive approach uses machine-learning (ML) algorithms to estimate BP by using the features extracted from simultaneous photoplethysmogram (PPG) and electrocardiogram (ECG) signals, such as the pulse transit time and pulse wave velocity. This study investigates the BP estimation performance of the novel dendritic neural regression (DNR) method proposed by us. Unlike conventional neural networks, DNR utilizes the multiplication operator as the excitation function in each dendritic branch, inspired by biological neuron phenomena, and can effectively capture nonlinear relationships between distinct input features. In addition, AMSGrad is used as the optimization algorithm to further enhance the dendritic neural model's performance. The experimental results show that by being fed a combination of the raw features extracted from the ECG and PPG signals and the components of the BP mathematical models, DNR can increase the accuracy of systolic BP, diastolic BP, and mean arterial pressure estimation significantly, which are superior to the state-of-the-art ML techniques. According to the British Hypertension Society protocol, DNR achieves a grade of A for the long-term BP estimation. Considering its architectural simplicity and powerful performance, the proposed method can be regarded as a reliable tool for estimating long-term continuous BP in a noninvasive cuffless way.

Two-year follow-up of a young male with possible acute hemorrhagic leukoencephalitis: A case report.

RATIONALE: Acute hemorrhagic leukoencephalitis (AHLE) is a rare but fetal fulminant demyelinating disease of unknown etiology. It is commonly regarded as a severe variant of acute demyelinating encephalomyelitis (ADEM). Its rapid clinical deterioration and high mortality appeal to clinicians to attach importance to early diagnosis. Immunosuppressive therapy is the main management to attenuate the autoimmune process, but with varied response and prognosis. PATIENT CONCERNS: A young male presented with moderate fever, headache and seizures after extraction of impacted teeth, and then deteriorated rapidly to deep coma. Initial magnetic resonance imaging (MRI) revealed multiple plaque-like lesions in bilateral cerebra, right thalamus and pontobulbar region with massive edematous swelling and multifocal small hemorrhagic foci. Inflammatory parameters in the peripheral blood were only mild higher with a pleocytosis in CSF. DIAGNOSIS: His clinical presentation, laboratory evaluation and radiological features were consistent with a suspected diagnosis of AHLE. INTERVENTIONS: He underwent pulse corticosteroids initially but failed to respond to it. However, his consciousness improved obviously when he was treated with multiple courses of intravenous injection of immunoglobulin (IVIG) combined with mycophenolate mofetil (MMF). OUTCOMES: The patient regained consciousness gradually on day 180 and was in minimally conscious state (MCS) during the two-year follow-up. LESSONS: AHLE presents distinctly from classical ADEM, and the situation may pose a diagnostic challenge. Clinicians should be vigilant in recognizing AHLE because of its rapid clinical deterioration and high mortality. We highlight the critical role of multimodal MRI, particularly susceptibility-weighted imaging (SWI) in the diagnosis of AHLE if cerebral biopsies are unavailable. Multiple courses of IVIG with MMF may be effective when early single pulse of corticosteroids fails. Individual who survives the initial insult may carry relatively good prognosis.

Intrahepatic transcriptomics reveals gene signatures in chronic hepatitis B patients responded to interferon therapy.

Chronic hepatitis B virus (HBV) infection remains a substantial public health burden worldwide. Alpha-interferon (IFNα) is one of the two currently approved therapies for chronic hepatitis B (CHB), to explore the mechanisms underlying IFNα treatment response, we investigated baseline and 24-week on-treatment intrahepatic gene expression profiles in 21 CHB patients by mRNA-seq. The data analyses demonstrated that PegIFNα treatment significantly induced antiviral responses. Responders who achieved HBV DNA loss and HBeAg or HBsAg seroconversion displayed higher fold change and larger number of up-regulated interferon-stimulated genes (ISGs). Interestingly, lower expression levels of certain ISGs were observed in responders in their baseline biopsy samples. In HBeAg+ patients, non-responders had relative higher baseline HBeAg levels than responders. More importantly, HBeAg- patients showed higher HBsAg loss rate than HBeAg+ patients. Although a greater fold change of ISGs was observed in HBeAg- patients than HBeAg+ patients, upregulation of ISGs in HBeAg+ responders exceeded HBeAg- responders. Notably, PegIFNα treatment increased monocyte and mast cell infiltration, but decreased CD8 T cell and M1 macrophage infiltration in both responders and non-responders, while B cell infiltration was increased only in responders. Moreover, co-expression analysis identified ribosomal proteins as critical players in antiviral response. The data also indicate that IFNα may influence the production of viral antigens associated with endoplasmic reticulum. Collectively, the intrahepatic transcriptome analyses in this study enriched our understanding of IFN-mediated antiviral effects in CHB patients and provided novel insights into the development of potential strategies to improve IFNα therapy.

Prone positioning improves ventilation-perfusion matching assessed by electrical impedance tomography in patients with ARDS: a prospective physiological study.

BACKGROUND: The physiological effects of prone ventilation in ARDS patients have been discussed for a long time but have not been fully elucidated. Electrical impedance tomography (EIT) has emerged as a tool for bedside monitoring of pulmonary ventilation and perfusion, allowing the opportunity to obtain data. This study aimed to investigate the effect of prone positioning (PP) on ventilation-perfusion matching by contrast-enhanced EIT in patients with ARDS. DESIGN: Monocenter prospective physiologic study. SETTING: University medical ICU. PATIENTS: Ten mechanically ventilated ARDS patients who underwent PP. INTERVENTIONS: We performed EIT evaluation at the initiation of PP, 3 h after PP initiation and the end of PP during the first PP session. MEASUREMENTS AND MAIN RESULTS: The regional distribution of ventilation and perfusion was analyzed based on EIT images and compared to the clinical variables regarding respiratory and hemodynamic status. Prolonged prone ventilation improved oxygenation in the ARDS patients. Based on EIT measurements, the distribution of ventilation was homogenized and dorsal lung ventilation was significantly improved by PP administration, while the effect of PP on lung perfusion was relatively mild, with increased dorsal lung perfusion observed. The ventilation-perfusion matched region was found to increase and correlate with the increased PaO2/FiO2 by PP, which was attributed mainly to reduced shunt in the lung. CONCLUSIONS: Prolonged prone ventilation increased dorsal ventilation and perfusion, which resulted in improved ventilation-perfusion matching and oxygenation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04725227. Registered on 25 January 2021.

Transmission trend of the COVID-19 pandemic predicted by dendritic neural regression.

In 2020, a novel coronavirus disease became a global problem. The disease was called COVID-19, as the first patient was diagnosed in December 2019. The disease spread around the world quickly due to its powerful viral ability. To date, the spread of COVID-19 has been relatively mild in China due to timely control measures. However, in other countries, the pandemic remains severe, and COVID-19 protection and control policies are urgently needed, which has motivated this research. Since the outbreak of the pandemic, many researchers have hoped to identify the mechanism of COVID-19 transmission and predict its spread by using machine learning (ML) methods to supply meaningful reference information to decision-makers in various countries. Since the historical data of COVID-19 is time series data, most researchers have adopted recurrent neural networks (RNNs), which can capture time information, for this problem. However, even with a state-of-the-art RNN, it is still difficult to perfectly capture the temporal information and nonlinear characteristics from the historical data of COVID-19. Therefore, in this study, we develop a novel dendritic neural regression (DNR) method to improve prediction performance. In the DNR, the multiplication operator is used to capture the nonlinear relationships between input feature signals in the dendrite layer. Considering the complex and large landscape of DNR's weight space, a new scale-free state-of-matter search (SFSMS) algorithm is proposed to optimize the DNR, which combines the state-of-matter search algorithm with a scale-free local search. The SFSMS achieves a better global search ability and thus can effectively reduce the possibility of falling into local minima. In addition, according to Takens's theorem, phase space reconstruction techniques are used to discover the information hidden in the high-dimensional space of COVID-19 data, which further improves the precision of prediction. The experimental results suggest that the proposed method is more competitive in solving this problem than other prevailing methods.

RNA Helicase DDX17 Inhibits Hepatitis B Virus Replication by Blocking Viral Pregenomic RNA Encapsidation.

DDX17 is a member of the DEAD-box helicase family proteins involved in cellular RNA folding, splicing, and translation. It has been reported that DDX17 serves as a cofactor of host zinc finger antiviral protein (ZAP)-mediated retroviral RNA degradation and exerts direct antiviral function against Raft Valley fever virus through binding to specific stem-loop structures of viral RNA. Intriguingly, we have previously shown that ZAP inhibits hepatitis B virus (HBV) replication through promoting viral RNA decay, and the ZAP-responsive element (ZRE) of HBV pregenomic RNA (pgRNA) contains a stem-loop structure, specifically epsilon, which serves as the packaging signal for pgRNA encapsidation. In this study, we demonstrated that the endogenous DDX17 is constitutively expressed in human hepatocyte-derived cells but dispensable for ZAP-mediated HBV RNA degradation. However, DDX17 was found to inhibit HBV replication primarily by reducing the level of cytoplasmic encapsidated pgRNA in a helicase-dependent manner. Immunofluorescence assay revealed that DDX17 could gain access to cytoplasm from nucleus in the presence of HBV RNA. In addition, RNA immunoprecipitation and electrophoretic mobility shift assays demonstrated that the enzymatically active DDX17 competes with HBV polymerase to bind to pgRNA at the 5' epsilon motif. In summary, our study suggests that DDX17 serves as an intrinsic host restriction factor against HBV through interfering with pgRNA encapsidation. IMPORTANCE Hepatitis B virus (HBV) chronic infection, a long-studied but yet incurable disease, remains a major public health concern worldwide. Given that HBV replication cycle highly depends on host factors, deepening our understanding of the host-virus interaction is thus of great significance in the journey of finding a cure. In eukaryotic cells, RNA helicases of the DEAD box family are highly conserved enzymes involved in diverse processes of cellular RNA metabolism. Emerging data have shown that DDX17, a typical member of the DEAD box family, functions as an antiviral factor through interacting with viral RNA. In this study, we, for the first time, demonstrate that DDX17 inhibits HBV through blocking the formation of viral replication complex, which not only broadens the antiviral spectrum of DDX17 but also provides new insight into the molecular mechanism of DDX17-mediated virus-host interaction.

Viral quasispecies quantitative analysis: a novel approach for appraising the immune tolerant phase of chronic hepatitis B virus infection.

Few non-invasive models were established for precisely identifying the immune tolerant (IT) phase from chronic hepatitis B (CHB). This study aimed to develop a novel approach that combined next-generation sequencing (NGS) and machine learning algorithms using our recently published viral quasispecies (QS) analysis package. 290 HBeAg positive patients from whom liver biopsies were taken were enrolled and divided into a training group (n = 148) and a validation group (n = 142). HBV DNA was extracted and QS sequences were obtained by NGS. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) based on viral operational taxonomic units (OTUs) were performed to explore the correlations among QS and clinical phenotypes. Three machine learning algorithms, including K-nearest neighbour, support vector machine, and random forest algorithm, were used to construct diagnostic models for IT phase classification. Based on histopathology, 90 IT patients and 200 CHB patients were diagnosed. HBsAg titres for IT patients were higher than those of CHB patients (p < 0.001). HCA and PCA analysis grouped IT and CHB patients into two distinct clusters. The relative abundance of viral OTUs differed mainly within the BCP/precore/core region and was significantly correlated with liver inflammation and fibrosis. For the IT phase classification, all machine-learning models showed higher AUC values compared to models based on HBsAg, APRI, and FIB-4. The relative abundance of viral OTUs reflects the severity of liver inflammation and fibrosis. The novel QS quantitative analysis approach could be used to diagnose IT patients more precisely and reduce the need for liver biopsy.

Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.

BACKGROUND & AIMS: HBV remains a global threat to human health. It remains incompletely understood how HBV self-restricts in the host during most adult infections. Thus, we performed multi-omics analyses to systematically interrogate HBV-host interactions and the life cycle of HBV. METHODS: RNA-sequencing and ribosome profiling were conducted with cell-based models for HBV replication and gene expression. The novel translational events or products hereby detected were then characterized, and functionally assessed in both cell and mouse models. Moreover, quasi-species analyses of HBV subpopulations were conducted with patients at immune tolerance or activation phases, using next- or third-generation sequencing. RESULTS: We identified EnhI-SL (Enhancer I-stem loop) as a new cis element in the HBV genome; mutations disrupting EnhI-SL were found to elevate viral polymerase expression. Furthermore, while re-discovering HpZ/P', a previously under-explored isoform of HBV polymerase, we also identified HBxZ, a novel short isoform of HBX. Having confirmed their existence, we functionally characterized them as potent suppressors of HBV gene expression and genome replication. Mechanistically, HpZ/P' was found to repress HBV gene expression partially by interacting with, and sequestering SUPV3L1. Activation of the host immune system seemed to reduce the abundance of HBV mutants deficient in HpZ/P' or with disruptions in EnhI-SL. Finally, SRSF2, a host RNA spliceosome protein that is downregulated by HBV, was found to promote the splicing of viral pre-genomic RNA and HpZ/P' biogenesis. CONCLUSION: This study has identified multiple self-restricting HBV-host interactions. In particular, SRSF2-HpZ/P' appeared to constitute another negative feedback mechanism in the HBV life cycle. Targeting host splicing machinery might thus represent a strategy to intervene in HBV-host interactions. LAY SUMMARY: There remain many unknowns about the natural history of HBV infection in adults. Herein, we identified new HBV-host mechanisms which could be responsible for self-restricting infections. Targeting these mechanisms could be a promising strategy for the treatment of HBV infections.

A Stepwise Evaluation of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure to Optimize the Indication for Urgent Liver Transplantation.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a dynamic but reversible disease. AIM: We aimed to clarify whether the change in Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) grade in HBV-ACLF patients can be used to predict prognosis, and to explore the appropriate conditions for performing urgent liver transplantation. METHODS: We assessed the COSSH-ACLF grades of HBV-ACLF patients at different time points from June 2013 to May 2019 at Huashan Hospital in Shanghai, China, and analyzed the relationship between the change in grade and patient prognosis. RESULTS: A total of 207 HBV-ACLF patients were enrolled, of which 79 underwent urgent liver transplantation. Their COSSH-ACLF grades were calculated at diagnosis, 3-7 days after diagnosis, and on the final day. Most of the final ACLF grades were consistent with their corresponding grades at days 3-7 after diagnosis (62.5%), while only 44.5% were in accordance with the initial grades at diagnosis. In patients who had a poor prognosis (initial ACLF-3 and ACLF-2 or -3 at days 3-7), the 28-day survival rate was 93.3% in those who underwent transplantation and 6.8% in those who did not (P < 0.0001). However, in patients who had a good prognosis (ACLF-0 or ACLF-1 at days 3-7), the 28-day survival rate was 100% in transplanted patients and 91.5% in non-transplanted patients (P = 0.236). CONCLUSIONS: Reevaluation of the COSSH-ACLF grade 3-7 days after diagnosis could potentially show an indication for urgent liver transplantation.

Hepatitis B Virus Precore Protein p22 Inhibits Alpha Interferon Signaling by Blocking STAT Nuclear Translocation.

Antagonism of host immune defenses against hepatitis B virus (HBV) infection by the viral proteins is speculated to cause HBV persistence and the development of chronic hepatitis. The circulating hepatitis B e antigen (HBeAg, p17) is known to manipulate host immune responses to assist in the establishment of persistent viral infection, and HBeAg-positive (HBeAg+) patients respond less effectively to IFN-α therapy than do HBeAg-negative (HBeAg-) patients in clinical practice. However, the function(s) of the intracellular form of HBeAg, previously reported as the precore protein intermediate (p22) without the N-terminal signal peptide, remains elusive. Here, we report that the cytosolic p22 protein, but not the secreted HBeAg, significantly reduces interferon-stimulated response element (ISRE) activity and the expression of interferon-stimulated genes (ISGs) upon alpha interferon (IFN-α) stimulation in cell cultures. In line with this, HBeAg+ patients exhibit weaker induction of ISGs in their livers than do HBeAg- patients upon IFN-α therapy. Mechanistically, while p22 does not alter the total STAT1 or pSTAT1 levels in cells treated with IFN-α, it blocks the nuclear translocation of pSTAT1 by interacting with the nuclear transport factor karyopherin α1 through its C-terminal arginine-rich domain. In summary, our study suggests that HBV precore protein, specifically the p22 form, impedes JAK-STAT signaling to help the virus evade the host innate immune response and, thus, causes resistance to IFN therapy.IMPORTANCE Chronic hepatitis B virus (HBV) infection continues to be a major global health concern, and patients who fail to mount an efficient immune response to clear the virus will develop a life-long chronic infection that can progress to chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma. There is no definite cure for chronic hepatitis B, and alpha interferon (IFN-α) is the only available immunomodulatory drug, to which only a minority of chronic patients are responsive, with hepatitis B e antigen (HBeAg)-negative patients responding better than HBeAg-positive patients. We herein report that the intracellular HBeAg, also known as precore or p22, inhibits the antiviral signaling of IFN-α, which sheds light on the enigmatic function of precore protein in shaping HBV chronicity and provides a perspective toward areas that need to be further studied to make the current therapy better until a cure is achieved.

Host Gene SEL1L Involved in Endoplasmic Reticulum-Associated Degradation Pathway Could Inhibit Hepatitis B Virus at RNA, DNA, and Protein Levels.

Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. Recent studies have found that host factors can suppress HBV replication. HBV envelope proteins are reported to be degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway. As a component of the ERAD pathway, suppressor of lin-12-like 1 (SEL1L) was earlier found to be upregulated in the inactive carrier phase of chronic HBV infection relative to that in the immune tolerant phase. However, the role of SEL1L in regulating HBV replication remains largely unknown. In this study, we found the levels of HBV RNA, DNA, and core and envelope proteins to be significantly downregulated by SEL1L overexpression and upregulated by SEL1L silencing in Huh7 cells transiently transfected with an overlength HBV genome. Similar upregulation was observed in HepG2.2.15 cells as well. SEL1L co-localized with HBV surface antigen (HBsAg), which changed its staining pattern. Treatment with an inhibitor of ERAD pathway remarkably increased intracellular S protein. Surprisingly, silencing SEL1L to block the ERAD pathway activated an alternative ER quality control (ERQC)-autophagy pathway, which might account for the increased HBV RNAs and core protein. Together, our results demonstrate that SEL1L is a host restriction factor that exerts anti-HBV effect through ERAD and alternative ERQC-autophagy pathway.

Exonuclease I and III improve the detection efficacy of hepatitis B virus covalently closed circular DNA.

BACKGROUND: Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is an important biomarker of hepatitis B virus infection. However, the current methods are not specific and sensitive. The present study aimed to develop a specific and sensitive assay method for the quantification of HBV cccDNA. METHODS: Exonuclease I (Exo I) & Exonuclease III (Exo III) and specific primer probes are used in real-time PCR. The virus particles isolated from peripheral blood mononuclear cells were used as negative control and HBV1.3 recombinant plasmid 3.2 kb circular DNA fragment was used as positive control. The methods of cccDNA detection were evaluated in cell lines, plasmid, animal model, patient serum and liver biopsies. RESULTS: A linear range of 101-107 copies/assay using specific primers for HBV cccDNA was established. HBV cccDNA were only detected in cell lines, animal model and liver tissue. It cannot be detected in serum samples. Intrahepatic HBV cccDNA level had good correlation with intrahepatic total HBV DNA level (r = 0.765, P < 0.001). CONCLUSIONS: The real-time quantitative PCR is an effective and feasible method for sensitive and specific detection of low copy number of cccDNA. The novel detection method is fast, provides high sensitivity and specificity and can be used in clinical practice.

Baseline serum miR-125b levels predict virologic response to nucleos(t)ide analogue treatment in patients with HBeAg-positive chronic hepatitis B.

The aim of the present study was to investigate the predictive value of baseline serum microRNA (miRNA)-125b for nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A total of 66 patients with Be antigen (HBeAg)-positive CHB received NAs therapy for 144 weeks. Serum miRNA-125b levels were measured at the baseline, while hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg) and alanine aminotransferase (ALT) levels were measured throughout treatment. Stepwise logistic regression analysis was performed to identify predictors of treatment response. The results indicated that baseline serum miR-125b (OR=4.377; P=0.006), HBsAg (OR=0.120; P=0.010), ALT >5× upper limit of normal (ULN; OR=11.726; P=0.018) and undetectable HBV DNA at week 24 (OR=7.828; P=0.021) were independent predictors of complete response (CR) at 144 weeks (CR is defined as HBV DNA <500 IU/ml and HBeAg seroconversion). The baseline serum miRNA-125b combined with baseline HBsAg level yielded an area under the receiver-operating curve of 0.852 in discriminating CR and non-CR at 144 week. The combination of baseline miRNA-125b ≥1.7 and ALT >5× ULN had a positive predictive value 80% for CR at 144 weeks. The combination of baseline miRNA-125b ≥1.7 and HbsAg ≤4.4 (log10 IU/ml) had a negative predictive value of CR at 144 weeks of 100%. Together, these results suggest that baseline miRNA-125b is a reliable predictor of HBeAg seroconversion following NAs treatment. The present study may be used as a basis for the use of baseline miRNA-125b to optimize treatment prior to NAs therapy.

Validation and comparison of seventeen noninvasive models for evaluating liver fibrosis in Chinese hepatitis B patients.

BACKGROUND & AIMS: To avoid liver biopsy, many noninvasive models comprised of serum markers for liver fibrosis assessment have been developed. Given that most of them were developed in hepatitis C cohorts and few of them have been validated in Chinese hepatitis B patients, we aim to conduct this validation and compare their diagnostic accuracies in such a population. METHODS: A total of 937 HBV-infected patients who underwent liver biopsy were included in this single-centre retrospective study. The diagnostic accuracies of the 17 noninvasive models were assessed by areas under the receiver-operating characteristic curves (AUROCs), using histologically evaluated fibrotic stages of the biopsy specimens as standards. To compare efficiencies of the models, a grading system based on AUROC levels was developed. RESULTS: For discriminating significant fibrosis in all patients, the best three noninvasive models were King's score (AUROC = 0.756), Virahep-C model (AUROC = 0.756) and GPR (AUROC = 0.744); and for diagnosing cirrhosis, Lok index (AUROC = 0.832), FI (AUROC = 0.820) and FIB-4 (AUROC = 0.818) got the first three places. AUROCs in HBeAg-positive group were generally higher than those in HBeAg-negative group. In addition, based on the grading system, Virahep-C and GPR outstood others in evaluating liver fibrosis in all patients. CONCLUSIONS: In Chinese HBV-infected patients, Virahep-C models and GPR had high accuracies in diagnosing liver fibrosis and cirrhosis, while the most discussed models like APRI and FIB-4 did not outstand. Assessment should take into account the HBeAg sero-status, since these noninvasive models were more appropriate for HBeAg-positive patients than HBeAg-negative ones.