Low Hepatitis B Core-Related Antigen Levels Correlate Higher Spontaneous Seroclearance of Hepatitis B Surface Antigen in Chronic Hepatitis B Patients With High Hepatitis B Surface Antigen Levels.

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) indicates functional cure for hepatitis B virus (HBV) infection. Low HBsAg levels can predict HBsAg seroclearance over time. However, little is known about the association between hepatitis B core-related antigen (HBcrAg) levels and spontaneous seroclearance of HBsAg. METHODS: We conducted a retrospective cohort study including 2614 treatment-naïve patients with chronic HBV infection who received long-term follow-up at the National Taiwan University Hospital. The primary end point was spontaneous HBsAg seroclearance. We aimed to explore whether HBcrAg levels could predict HBsAg seroclearance, especially for patients with HBsAg levels >1000 IU/mL. RESULTS: There were 465 patients who cleared HBsAg with 32,414.72 person-years of follow-up, with a mean clearance rate of 1.43% per year. We found that lower HBcrAg levels at baseline were associated with an increased likelihood of HBsAg seroclearance (log rank P < .001). When restricting the study population to 1539 patients with HBsAg levels >1000 IU/mL, only HBcrAg <10,000 U/mL (vs ≥100,000 U/mL) served as an independent viral predictor for HBsAg seroclearance, with adjusted hazard ratio of 1.95 (95% CI, 1.16-3.27). In contrast to the late decline of HBsAg levels (5-9 years before HBsAg seroclearance), HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. This finding was confirmed by the different annual HBsAg seroclearance rates in the first and second decades of follow-up (0.97% vs 3.75%; P < .001) in patients achieving undetectable HBcrAg levels. CONCLUSIONS: Lower serum HBcrAg levels were associated with increased probability of HBsAg seroclearance over time. In patients with HBsAg levels >1000 IU/mL, clearing HBcrAg may serve as an early biomarker for HBsAg seroclearance.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

Nur77 Serves as a Potential Prognostic Biomarker That Correlates with Immune Infiltration and May Act as a Good Target for Prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is the most frequent malignancy, and is the second leading cause of death due to cancer in men. Thus, new prognostic biomarkers and drug targets for PRAD are urgently needed. As we know, nuclear receptor Nur77 is important in cancer development and changes in the tumor microenvironment; whereas, the function of Nur77 in PRAD remains to be elucidated. The TCGA database was used to explore the Nur77 expression and its role in the prognosis of PRAD. It was shown that Nur77 was down regulated in PRAD, and low Nur77 expression was correlated with advanced clinical pathologic characteristics (high grade, histological type, age) and poor prognosis. Furthermore, key genes screening was examined by univariate Cox analysis and Kaplan-Meier survival. Additionally, Nur77 was closely related to immune infiltration and some anti-tumor immune functions. The differentially expressed genes (DEGs) were presented by protein-protein interaction (PPI) network analysis. Therefore, the expression level of Nur77 might help predict the survival of PRAD cases, which presents a new insight and a new target for the treatment of PRAD. In vitro experiments verified that natural product malayoside targeting Nur77 exhibited significant therapeutic effects on PRAD and largely induced cell apoptosis by up-regulating the expression of Nur77 and its mitochondrial localization. Taken together, Nur77 is a prognostic biomarker for patients with PRAD, which may refresh the profound understanding of PRAD individualized treatment.

Hepatitis B Core-Related Antigen Stratifies the Risk of Liver Cancer in HBeAg-Negative Patients With Indeterminate Phase.

INTRODUCTION: Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg). METHODS: Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development. RESULTS: According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts. DISCUSSION: Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management.

Protective Effect of Calcitriol on Organ Damage Induced by 5-Fluorouracil Treatment.

Chemotherapy is a major therapeutic strategy for patients with cancer. Owing to the severe inflammatory response of chemotherapy, patients experience extreme discomfort during treatment, and this may interrupt treatment completion. The vitamin D3 has a role in anti-inflammation, but no study has explored whether vitamin D3 has beneficial effects on patients undergoing chemotherapy. In this study, we investigated the effect of calcitriol (Vit-D) on inflammatory responses during 5-fluorouracil (5-FU) treatment. Rats were divided into five groups and treated with 1:1 dilution of 5-FU with equal amount of 0.9% saline, 1:3 dilution of 5-FU with 0.9% saline threefold dilution, 5-FU, Vit-D, or 5-FU + Vit-D. A single dose of 15 mg/kg of 5-FU was intravenously administered for 4 h, and the blood biochemical substances and inflammatory cytokines were assessed after the intervention. The 5-FU group had higher AST, ALT, LDH, and CPK levels than those in the 5-FU + Vit-D group. The 5-FU + Vit-D group had a lower TNF-α value than the 5-FU. The IL-6 levels in the 5-FU + Vit-D group were also significantly lower than those in 5-FU. Calcitriol administration during 5-FU therapy can alleviate the production of inflammatory cytokines and liver damage.

HEV superinfection accelerates disease progression in patients with chronic HBV infection and increases mortality in those with cirrhosis.

BACKGROUND & AIMS: Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC). METHODS: Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion. RESULTS: In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p <0.001). CONCLUSIONS: In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis. LAY SUMMARY: The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B.

High Level of Hepatitis B Core-Related Antigen Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection of Intermediate Viral Load.

BACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC). Serum levels of HB core-related antigen (HBcrAg) have been associated with active replication of HBV. We investigated whether HBcrAg levels are associated with development of HCC, especially in patients who do not require antiviral treatment. METHODS: We collected data from 2666 adults positive for hepatitis B surface antigen (HBsAg), infected with HBV genotypes B or C, and without liver cirrhosis, who had long-term follow-up at the National Taiwan University Hospital from 1985 through 2000. None of the patients received antiviral treatment during the follow-up. Baseline levels of HBV DNA, HBsAg, and HBcrAg were determined retrospectively and participants were followed for a mean of 15.95 years. The primary end point was an association between serum level of HBcrAg and HCC development. RESULTS: HCC developed in 209 patients in the cohort (incidence rate, 4.91 cases/1000 person-years). We found a positive association between baseline level of HBcrAg and HCC development; HBcrAg level was an independent risk factor in multivariable analysis. In the subgroup of hepatitis B e antigen-negative patients with HBV DNA levels from 2000 to 19,999 IU/mL (intermediate viral load [IVL]) and normal levels of alanine aminotransferase, HBcrAg levels of 10 KU/mL or more identified patients at increased risk of HCC (hazard ratio, 6.29; confidence interval, 2.27-17.48). Patients with an IVL and a high level of HBcrAg had a risk for HCC that did not differ significantly from that of patients with a high viral load (≥20,000 IU/mL). Patients with an IVL but a low level of HBcrAg had a low risk of HCC, with an annual incidence rate of 0.10% (95% confidence interval, 0.04%-0.24%). CONCLUSIONS: In a long-term follow-up study of 2666 patients with chronic HBV infection (genotypes B or C), level of HBcrAg is an independent risk factor of HCC. Moreover, HBcrAg level of 10 KU/mL identifies patients with an IVL who are at high risk for HCC.

Profile and value of FIB-4 in patients with dual chronic hepatitis C and B.

BACKGROUND AND AIMS: Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk of developing adverse outcomes. Coinfection with both viruses may further increase the risk. Currently, little is known about the role of fibrosis-4 (FIB-4) index, a simple liver fibrosis stage biomarker, in predicting the clinical outcomes. METHODS: We retrospectively enrolled 152 non-cirrhotic patients with dual chronic HCV and HBV infection: 56 patients received pegylated interferon/ribavirin therapy, while 96 patients remained untreated. The association between the FIB-4 index and the incidence of liver cirrhosis and hepatocellular carcinoma (HCC) was explored. RESULTS: After a 9.88-year follow-up, the incidence of hepatitis B surface antigen seroclearance was 4.97 (95% confidence interval: 3.13-7.89) per 100 person-years in the treated group and was 1.77 (1.10-2.85) in the untreated group. Of the treated group, only three and six patients developed HCC and liver cirrhosis, respectively, while 17 and 23 patients developed HCC and liver cirrhosis, respectively, in untreated group. Baseline FIB-4 index correlated with the development of liver cirrhosis in multivariable analysis of all subjects. High baseline FIB-4 index (per 1 point increase) in the treated groups was associated with a higher risk of developing liver cirrhosis (P = 0.001) and HCC (P = 0.038) in univariable analysis. FIB-4 index decreased only in the treated group who achieved sustained virological response (n = 34, FIB-4 index decreasing from 1.84 to 1.55). CONCLUSIONS: In Taiwanese patients coinfected with HCV and HBV, FIB-4 index helps identify patients at risk of developing adverse events, even in patients receiving pegylated interferon/ribavirin therapy.

Fibrosis-4 Index Helps Identify HBV Carriers With the Lowest Risk of Hepatocellular Carcinoma.

OBJECTIVES: Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk. METHODS: A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication. RESULTS: A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index >1.29 in the treatment-naive cohort. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level <2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index <1.29, ALT level <40 U/l, and HBsAg level <1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index <1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment. CONCLUSIONS: In non-cirrhotic patients with chronic HBV infection, FIB-4 index <1.29 complements the existing clinical profile to define patients with the lowest HCC risk.

Impact of occult hepatitis B on the clinical outcomes of patients with chronic hepatitis C virus infection: A 10-year follow-up.

BACKGROUND/PURPOSE: Occult hepatitis B infection (OHB) is not rare in countries that are endemic for hepatitis B virus (HBV) and in patients with chronic hepatitis C virus (HCV) infection. Notably, OHB has been shown to play a role in the progression of liver diseases, including the development of hepatocellular carcinoma (HCC); however, the data is inconsistent. We aim to clarify the contribution of concurrent OHB to the progression of liver diseases in a long-term cohort of patients with HCV infection and to investigate the value of total anti-hepatitis B core (anti-HBc) antibody as a surrogate OHB biomarker. METHODS: We included 250 chronic anti-HCV-positive patients who had resolved HBV infection (anti-HBc positive and hepatitis B surface antigen negative). OHB was then detected using a sensitive commercial assay for serum HBV DNA with a low limit of detection of 6 IU/mL. Clinical outcomes, including the development of liver cirrhosis, HCC, and all-cause deaths, were compared between OHB-positive and OHB-negative patients. RESULTS: At baseline, only 183 (73.20%) patients had positive HCV ribonucleic acid, and 56 (30.60%) of these 183 patients with active HCV infection had OHB. The presence of OHB did not correlate with any adverse clinical outcome in multivariate analyses. In addition, chronic hepatitis C patients with OHB did not have a higher level of serum total anti-HBc. CONCLUSION: OHB infection may not contribute to the development of adverse liver outcomes in patients with chronic HCV.

Vitamin D3 Reduces Tissue Damage and Oxidative Stress Caused by Exhaustive Exercise.

Exhaustive exercise results in inflammation and oxidative stress, which can damage tissue. Previous studies have shown that vitamin D has both anti-inflammatory and antiperoxidative activity. Therefore, we aimed to test if vitamin D could reduce the damage caused by exhaustive exercise. Rats were randomized to one of four groups: control, vitamin D, exercise, and vitamin D+exercise. Exercised rats received an intravenous injection of vitamin D (1 ng/mL) or normal saline after exhaustive exercise. Blood pressure, heart rate, and blood samples were collected for biochemical testing. Histological examination and immunohistochemical (IHC) analyses were performed on lungs and kidneys after the animals were sacrificed. In comparison to the exercise group, blood markers of skeletal muscle damage, creatine kinase and lactate dehydrogenase, were significantly (P < 0.05) lower in the vitamin D+exercise group. The exercise group also had more severe tissue injury scores in the lungs (average of 2.4 ± 0.71) and kidneys (average of 3.3 ± 0.6) than the vitamin D-treated exercise group did (1.08 ± 0.57 and 1.16 ± 0.55). IHC staining showed that vitamin D reduced the oxidative product 4-Hydroxynonenal in exercised animals from 20.6% to 13.8% in the lungs and from 29.4% to 16.7% in the kidneys. In summary, postexercise intravenous injection of vitamin D can reduce the peroxidation induced by exhaustive exercise and ameliorate tissue damage, particularly in the kidneys and lungs.

Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers.

BACKGROUND AND OBJECTIVE: Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis. METHODS: 251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages. RESULTS: In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67). CONCLUSIONS: A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.

Hepatitis B surface antigen level complements viral load in predicting viral reactivation in spontaneous HBeAg seroconverters.

BACKGROUND AND AIMS: The level of hepatitis B surface antigen (HBsAg) has been shown to complement hepatitis B virus (HBV)-DNA level in predicting disease progression in hepatitis B e antigen (HBeAg)-negative patients, especially those with low viral loads. Whether this finding could be seen in spontaneous HBeAg seroconverters remains unclear. METHODS: A retrospective cohort of 390 Taiwanese spontaneous HBeAg seroconverters with a mean follow-up period of 7.4 years was enrolled. The relationships between HBV-DNA/HBsAg levels and HBeAg-negative hepatitis/active viral replication (HBV-DNA level ≥ 2000 IU/mL) were investigated. RESULTS: In the overall cohort, serum HBV-DNA level served as a better predictor for HBeAg-negative hepatitis compared with HBsAg level. However, in those with HBV-DNA level < 2000 IU/mL, a higher HBsAg level was associated with a higher risk of HBeAg-negative hepatitis (P = 0.015). Multivariate analysis showed the hazard ratio of HBsAg level ≥ 1000 IU/mL versus < 1000 IU/mL was 4.1 (95% confidence interval: 1.3-13.6). When using the end-point of active viral replication, HBsAg ≥ 1000 IU/mL remained as an independent risk factor, with a hazard ratio of 2.5 (95% confidence interval: 1.1-5.9). CONCLUSIONS: In spontaneous HBeAg seroconverters with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL is associated with increased risks of HBeAg-negative hepatitis and active viral replication. Combining HBV-DNA < 2000 IU/mL and HBsAg level < 1000 IU/mL may be used to define minimal viral activity.

Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen-negative carriers by combining viral biomarkers.

BACKGROUND: The serum hepatitis B virus (HBV) surface antigen (HBsAg) level can predict hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients with an HBV DNA level of <2000 IU/mL. However, little is known regarding how well the combination of both viral biomarkers stratifies HCC risk. METHODS: A total of 2165 Taiwanese HBeAg-negative noncirrhotic patients were followed for 14.9 years. The predictive power of the HBsAg level for HCC was analyzed for different viral load ranges. RESULTS: In patients with HBV DNA levels of 2000-19 999 IU/mL (intermediate viral load), a positive correlation between HBsAg level and HCC development was identified after adjustment for other risk factors (P = .002). In contrast, no association was found between HBsAg level and HCC in patients with higher viral loads. HBsAg level was subsequently included to stratify HCC risk in patients with low and intermediate viral loads. Receiver operating characteristic curve analysis showed that combining HBV DNA and HBsAg level better predicts 10-year HCC development as compared to using HBV DNA level alone in the overall cohort (P = .028). CONCLUSIONS: Serum HBsAg level helps stratify HCC risk in patients with intermediate viral loads. Combining HBV DNA and HBsAg levels better predicts HCC risk.

A narrative review of deep learning in thyroid imaging: current progress and future prospects.

Background and Objective: Deep learning (DL) has contributed substantially to the evolution of image analysis by unlocking increased data and computational power. These DL algorithms have further facilitated the growing trend of implementing precision medicine, particularly in areas of diagnosis and therapy. Thyroid imaging, as a routine means to screening for thyroid diseases on large-scale populations, is a massive data source for the development of DL models. Thyroid disease is a global health problem and involves structural and functional changes. The objective of this study was to evaluate the general rules and future directions of DL networks in thyroid medical image analysis through a review of original articles published between 2018 and 2023. Methods: We searched for English-language articles published between April 2018 and September 2023 in the databases of PubMed, Web of Science, and Google Scholar. The keywords used in the search included artificial intelligence or DL, thyroid diseases, and thyroid nodule or thyroid carcinoma. Key Content and Findings: The computer vision tasks of DL in thyroid imaging included classification, segmentation, and detection. The current applications of DL in clinical workflow were found to mainly include management of thyroid nodules/carcinoma, risk evaluation of thyroid cancer metastasis, and discrimination of functional thyroid diseases. Conclusions: DL is expected to enhance the quality of thyroid images and provide greater precision in the assessment of thyroid images. Specifically, DL can increase the diagnostic accuracy of thyroid diseases and better inform clinical decision-making.

HBcrAg-based risk score performs better than the HBV DNA-based scores for HCC prediction in grey zone patients who are HBeAg-negative.

Background & Aims: Risk scores have been designed to predict the development of hepatocellular carcinoma (HCC) in treatment-naive patients with chronic hepatitis B (CHB). However, little is known about their predictive accuracy in HBeAg-negative patients in the grey zone (GZ). We aimed to develop a HBcrAg-based HCC risk score and explore whether it outperforms other risk scores in GZ patients. Methods: Two retrospective cohorts of HBeAg-negative patients with American Association for the Study of Liver Diseases-defined GZ were established for derivation and validation (Taiwanese, N = 911; Japanese, N = 806). All of them were non-cirrhotic at baseline and remained treatment-naive during the follow-up. The primary endpoint was HCC development. Results: In a median follow-up period of 15.5 years, 85 patients developed HCC in the derivation cohort. We found that age, sex, alanine aminotransferase, platelet count, and HBcrAg, but not HBV DNA levels, were independent predictors and a 20-point GZ-HCC score was developed accordingly. The 10-year and 15-year area under the ROC curve (AUROC) ranged from 0.83 to 0.86, which outperformed the HBV DNA-based HCC risk scores, including REACH-B and GAG-HCC scores (AUROC ranging from 0.66 to 0.74). The better performance was also validated in EASL- and Asian Pacific Association for the Study of the Liver-defined GZ patients. These findings remained consistent in the validation cohort. Finally, the low-risk and high-risk GZ patients (stratified by a score of 8) had an HCC risk close to inactive CHB and immune-active CHB patients, respectively, in both cohorts. Conclusions: The HBcrAg-based GZ-HCC score predicts HCC better than other HBV DNA-based risk scores in GZ patients who are HBeAg-negative patients, which may help optimise their clinical management. Impact and implications: We have developed a risk score based on HBcrAg, which has shown better predictive ability for HCC compared with other risk scores based on HBV DNA. Using a score of 8, GZ patients can be classified into low- and high-risk groups, which can guide follow up and early treatment, respectively. This validated risk score is a valuable tool for optimising the management of GZ patients who are HBeAg-negative.

Comparative Genomics Revealed Fluoroquinolone Resistance Determinants and OmpF Deletion in Carbapenem-Resistant Escherichia coli.

Escherichia coli (E. coli) is a major causative organism of complicated urinary tract infections, bloodstream infections, and pneumonia. With the widespread use of antimicrobial agents, the prevalence of carbapenem resistance in E. coli has been increasing with limited therapeutic options. Fluoroquinolone remains a choice in carbapenem-resistant E. coli (CREc) that were once susceptible to the drug. Despite robust studies on the fluoroquinolone-resistant mechanisms of E. coli, few studies focused specifically on the group of CREc. In this study, we used comparative genomics to identify the fluoroquinolone-resistant mechanisms of CREc and detected gyrA D87N mutation in all the fluoroquinolone-resistant and CREc. Moreover, to investigate the mechanism underlying non-carbapenemase-producing carbapenem-resistant E. coli, we targeted the complete genome sequences for in-depth analysis and found a deletion in OmpF (DEL264-269) that might contribute to carbapenem resistance, which has not been reported before. Further studies focusing on the impact of these mutations on the expression levels are warranted. We further investigate the MLST, serotype, fimH type, phylogroup, and clinical characteristics of the CREc. Combination analysis of clinical and genomic characteristics suggests the polyclonal and highly diverse nature of the CREc in Taiwan. This study provides an insight into the molecular epidemiology of CREc in Taiwan.

Corrigendum: Comparative genomics revealed fluoroquinolone resistance determinants and OmpF deletion in carbapenem-resistant Escherichia coli.

[This corrects the article DOI: 10.3389/fmicb.2022.886428.].

Metagenomic Sequencing and Histology on a Chronic Wound Identified Epstein-Barr Virus-Associated Lymphoma.

Accurate diagnosis of chronic, non-healing wounds is challenging and time-consuming because it can be caused by a variety of etiologies. This brief report presents an unusual case of a chronic wound lasting for 10 months investigated by deep metagenomic sequencing. Epstein-Barr virus (EBV) was identified in the wound and subsequently validated by in situ hybridization. Histopathologic examination eventually revealed that the non-healing wound was due to an EBV-associated NK/T cell lymphoma. By identifying mutations across the viral genome, the virus was classified as Type I EBV and clustered with others of geographic proximity. Our results suggest that metagenomic shotgun sequencing can not only rapidly and accurately identify the presence of underlying pathogens but also provide strain-level resolution for the surveillance of viral epidemiology.