Distinguishing infectivity in patients with pulmonary tuberculosis using deep learning.

Introduction: This study aimed to develop and assess a deep-learning model based on CT images for distinguishing infectivity in patients with pulmonary tuberculosis (PTB). Methods: We labeled all 925 patients from four centers with weak and strong infectivity based on multiple sputum smears within a month for our deep-learning model named TBINet's training. We compared TBINet's performance in identifying infectious patients to that of the conventional 3D ResNet model. For model explainability, we used gradient-weighted class activation mapping (Grad-CAM) technology to identify the site of lesion activation in the CT images. Results: The TBINet model demonstrated superior performance with an area under the curve (AUC) of 0.819 and 0.753 on the validation and external test sets, respectively, compared to existing deep learning methods. Furthermore, using Grad-CAM, we observed that CT images with higher levels of consolidation, voids, upper lobe involvement, and enlarged lymph nodes were more likely to come from patients with highly infectious forms of PTB. Conclusion: Our study proves the feasibility of using CT images to identify the infectivity of PTB patients based on the deep learning method.

Identification of Crucial Genes and Signaling Pathways in Alectinib-Resistant Lung Adenocarcinoma Using Bioinformatic Analysis.

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has been shown to be effective for patients with ALK-positive non-small cell lung cancer (NSCLC). However, alectinib resistance is a serious problem worldwide. To the best of our knowledge, little information is available on its molecular mechanisms using the Gene Expression Omnibus (GEO) database. In this study, the differentially expressed genes (DEGs) were selected from the gene expression profile GSE73167 between parental and alectinib-resistant human lung adenocarcinoma (LUAD) cell samples. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) annotation enrichment analyses were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). The construction of protein-protein interaction (PPI) network was performed to visualize DEGs. The hub genes were extracted based on the analysis of the PPI network using plug-in cytoHubba of Cytoscape software. The functional roles of the key genes were investigated using Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer (UALCAN), Gene Set Enrichment Analysis (GSEA), and Tumor Immune Estimation Resource (TIMER) analysis. The networks of kinase, miRNA, and transcription-factor targets of SFTPD were explored using LinkedOmics. The drug sensitivity analysis of SFTPD was analyzed using the RNAactDrug database. Results showed a total of 144 DEGs were identified. Five hub genes were extracted, including mucin 5B (MUC5B), surfactant protein D (SFTPD), deleted in malignant brain tumors 1 (DMBT1), surfactant protein A2 (SFTPA2), and trefoil factor 3 (TFF3). The survival analysis using GEPIA displayed that low expression of SFTPD had a significantly negative effect on the prognosis of patients with LUAD. GSEA revealed that low expression of SFTPD was positively correlated with the pathways associated with drug resistance, such as DNA replication, cell cycle, drug metabolism, and DNA damage repair, including mismatch repair (MMR), base excision repair (BER), homologous recombination (HR), and nucleotide excision repair (NER). The SFTPD expression was negatively correlated with the drug sensitivity of alectinib according to RNAactDrug database. The expression of SFTPD was further validated in parental H3122 cells and alectinib-resistant H3122 cells by quantitative reverse transcription PCR (RT-qPCR). In conclusion, our study found that the five hub genes, especially low expression of SFTPD, are closely related to alectinib resistance in patients with LUAD.

Artificial intelligence CT radiomics to predict early recurrence of intrahepatic cholangiocarcinoma: a multicenter study.

OBJECTIVES: In this multicenter study, we sought to develop and validate a preoperative model for predicting early recurrence (ER) risk after curative resection of intrahepatic cholangiocarcinoma (ICC) through artificial intelligence (AI)-based CT radiomics approach. MATERIALS AND METHODS: A total of 311 patients (Derivation: 160; Internal and two external validations: 36, 74 and 61) from 8 medical centers who underwent curative resection were collected retrospectively. In derivation cohort, radiomics and clinical-radiomics models for ER prediction were constructed by LightGBM (a machine learning algorithm). A clinical model was also developed for comparison. Model performance was validated in internal and two external cohorts by ROC. In addition, we investigated the interpretability of the LightGBM model. RESULTS: The combined clinical-radiomics model that included 15 radiomic features and 3 clinical features (CA19-9 > 1000 U/ml, vascular invasion and tumor margin), resulting in the area under the curves (AUCs) of 0.974 (95% CI 0.946-1.000) in the derivation cohort, and 0.871-0.882 (95% CI 0.672-0.962) in the internal and external validation cohorts, respectively, which are higher than the AJCC 8th TNM staging system (AUCs: 0.686-0.717, p all < 0.05). Especially, the sensitivity of this machine learning model could reach 94.6% on average for all the cohorts. CONCLUSIONS: This AI-driven combined radiomics model may provide as a useful tool to preoperatively predict ER and improve therapeutic management of ICC patients.

PPP2R5D promotes hepatitis C virus infection by binding to viral NS5B and enhancing viral RNA replication.

BACKGROUND: Hepatitis C virus (HCV) infection increased the risk of hepatocellular carcinoma. Identification of host factors required for HCV infection will help to unveil the HCV pathogenesis. Adaptive mutations that enable the replication of HCV infectious clones could provide hints that the mutation-carrying viral protein may specifically interact with some cellular factors essential for the HCV life cycle. Previously, we identified D559G mutation in HCV NS5B (RNA dependent RNA polymerase) important for replication of different genotype clones. Here, we searched for the factors that potentially interacted with NS5B and investigated its roles in HCV infection. METHODS: Wild-type-NS5B and D559G-NS5B of HCV genotype 2a clone, J6cc, were ectopically expressed in hepatoma Huh7.5 cells, and NS5B-binding proteins were pulled down and identified by mass spectrometry. The necessity and mode of action of the selected cellular protein for HCV infection were explored by experiments including gene knockout or knockdown, complementation, co-immunoprecipitation (Co-IP), colocalization, virus infection and replication, and enzymatic activity, etc. RESULTS: Mass spectrometry identified a number of cellular proteins, of which protein phosphatase 2 regulatory subunit B'delta (PPP2R5D, the PP2A regulatory B subunit) was one of D559G-NS5B-pulled down proteins and selected for further investigation. Co-IP confirmed that PPP2R5D specifically interacted with HCV NS5B but not HCV Core and NS3 proteins, and D559G slightly enhanced the interaction. NS5B also colocalized with PPP2R5D in the endoplasmic reticulum. Knockdown and knockout of PPP2R5D decreased and abrogated HCV infection in Huh7.5 cells, respectively, while transient and stable expression of PPP2R5D in PPP2R5D-knockout cells restored HCV infection to a level close to that in wild-type Huh7.5 cells. Replicon assay revealed that PPP2R5D promoted HCV replication, but the phosphatase activity and catalytic subunit of PP2A were not affected by NS5B. CONCLUSIONS: PPP2R5D interactes with HCV NS5B and is required for HCV infection in cultured hepatoma cells through facilitating HCV replication.

Novel Role of Long Non-Coding RNA ASAP1-IT1 in Progression of Hepatocellular Carcinoma.

The long non-coding RNA (lncRNA) ASAP1-IT1 has been recently shown to aberrantly increase in ovarian and bladder cancer, while its role in other malignancies remains unexplored. This study was to characterize the expression and assess the potential role of ASAP1-IT1 in hepatocellular carcinoma (HCC). Fifty-four paired HCC and histologically normal tissues were obtained from HCC patients. Human HCC cell lines (HepG2, Huh7, SMMC-7721, and BEL-7402) and a normal liver cell line (LO2) were used for in vitro studies. ASAP1-IT1-specific siRNAs were used to silence ASAP1-IT1 expression, while the pcDNA-ASAP1-IT1 vector was constructed to up-regulate its expression. In situ hybridization and qRT-PCR were performed to characterize subcellular localization and expression of ASAP1-IT1. Cell proliferation and migration assays were conducted to examine the role of ASAP1-IT1 in the progression of HCC. In silico analysis was conducted to predict putative miRNA binding sites, which were validated by luciferase reporter assays. ASAP1-IT1 levels were significantly increased in HCC tissues and cells compared with controls. Notably, higher ASAP1-IT1 levels were significantly associated with poorer prognosis of HCC patients. In situ hybridization analysis revealed that ASAP1-IT1 was mainly localized in the nucleus of hepatoma cells and differentially expressed in trabecular, compact, and pseudoglandular forms of liver cancer. Furthermore, knockdown of ASAP1-IT1 significantly suppressed cell proliferation and migration, while its overexpression significantly promoted cell proliferation and migration of HCC cells. Mechanistically, ASAP1-IT1 might exert its role in HCC progression, at least in part, by directly interacting with miR-221-3p. In conclusion, ASAP1-IT1 is abnormally elevated in HCC, and higher levels are correlated with poorer prognosis. An underlying mechanism has been proposed for ASAP1-IT1-associated promotion of proliferation and migration in HCC cells. These findings have provided evidence supporting the oncogenic role of ASAP1-IT1 in HCC.

Three-Dimensional Computed Tomography Bronchography and Angiography-Guided Thoracoscopic Segmentectomy for Pulmonary Nodules.

BACKGROUND: Three-dimensional computed tomography bronchography and angiography (3D-CTBA) provides detailed imaging information for pulmonary segmentectomy. This study was performed to verify the feasibility of 3D-CTBA-guided thoracoscopic segmentectomy for the treatment of pulmonary nodules. METHODS: A retrospective analysis was performed on all patients who underwent 3D-CTBA-guided uniport thoracoscopic segmentectomies or subsegmentectomies for pulmonary nodules in the period from May 2019 to May 2020. All of the information related to perioperative management and surgical operations was retrieved from the medical records and operating notes for detailed analysis. RESULTS: A total of 104 eligible operations involving the resection of 110 nodules with diameters in the range of 5-20 mm were included. Under 3D-CTBA guidance, the pulmonary nodules were located with an accuracy of 100% (110/110) and the median resection margin was 24.3 mm (17-33 mm). Additionally, the segmental (subsegmental) bronchi, arteries, and veins were identified with accuracy rates of 100% (104/104), 96.2% (100/104), and 94.2% (98/104), respectively. The postoperative complications consisted of 3 cases of pulmonary infection (2.9%), 6 cases of arrhythmia (5.8%), 2 cases of hemoptysis (1.9%), 4 cases of air leak (3.8%), and 2 cases of subcutaneous emphysema (1.9%). No perioperative death occurred. CONCLUSION: 3D-CTBA-guided thoracoscopic segmentectomy is an effective surgical approach for the management of pulmonary nodules.

A Novel Post-Operative ALRI Model Accurately Predicts Clinical Outcomes of Resected Hepatocellular Carcinoma Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading malignant tumors worldwide. Prognosis and long-term survival of HCC remain unsatisfactory, even after radical resection, and many non-invasive predictors have been explored for post-operative patients. Most prognostic prediction models were based on preoperative clinical characteristics and pathological findings. This study aimed to investigate the prognostic value of a newly constructed nomogram, which incorporated post-operative aspartate aminotransferase to lymphocyte ratio index (ALRI). METHODS: A total of 771 HCC patients underwent radical resection from three medical centers were enrolled and grouped into the training cohort (n = 416) and validation cohort (n = 355). Prognostic prediction potential of ALRI was assessed by receiver operating curve (ROC) analysis. The Cox regression model was used to identify independent prognostic factors. Nomograms for overall survival (OS) and disease-free survival (DFS) were constructed and further validated externally. RESULTS: The ROC analysis ranked ALRI as the most effective prediction marker for resected HCC patients, with the cut-off value determined at 22.6. Higher ALRI level positively correlated with larger tumor size, higher tumor node metastasis (TNM) stage, and inversely with lower albumin level and shorter OS and DFS. Nomograms for OS and DFS were capable of discriminating HCC patients into different risk-groups. CONCLUSIONS: Post-operative ALRI was of prediction value for HCC prognosis. This novel nomogram may categorize HCC patients into different risk groups, and offer individualized surveillance reference for post-operative patients.

Preoperative Gadoxetic Acid-Enhanced MRI Based Nomogram Improves Prediction of Early HCC Recurrence After Ablation Therapy.

PURPOSE: This study aimed to identify preoperative gadoxetic acid-enhanced MRI features and establish a nomogram for predicting early recurrence (≤ 2 years) of hepatocellular carcinoma (HCC) after ablation therapy. METHODS: A total of 160 patients who underwent gadoxetic acid-enhanced MRI and ablation HCC therapy from January 2015 to June 2018, were included retrospectively and divided into a training cohort (n = 112) and a validation cohort (n = 48). Independent clinical risk factors and gadoxetic acid-enhanced MRI features associated with early recurrence were identified by univariate and multivariate logistic regression analysis and used for construction of a nomogram. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility. RESULTS: Alpha-fetoprotein (AFP) level, tumor number, arterial peritumoral enhancement, satellite nodule and peritumoral hypointensity at hepatobiliary phases in the training cohort were identified as independent risk factors for early recurrence after ablation. A new nomogram that was constructed with these five features showed an area under the curve (AUC) of 0.843 (95%CI 0.771-0.916) and 0.835 (95%CI 0.713-0.956) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) suggested that the nomogram had good consistency and clinical utility. CONCLUSIONS: A new nomogram that was constructed using four preoperative gadoxetic acid-enhanced MRI features and serum AFP level can predict the risk of early HCC recurrence after ablation therapy with AUC up to 0.843. The strong performance of this nomogram may help hepatologists to categorize patients' recurrent risk to guide selecting treatment options and improve postoperative management.

Effect of Pegylated Interferon Plus Tenofovir Combination on Higher Hepatitis B Surface Antigen Loss in Treatment-naive Patients With Hepatitis B e Antigen -positive Chronic Hepatitis B: A Real-world Experience.

PURPOSE: The loss of serum hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered an ideal clinical outcome but rarely achieved with current standard of care. We evaluated the effectiveness in inducing HBsAg seroclearance in a real-world clinical cohort of Chinese patients with CHB treated with a combination of pegylated interferon (Peg-IFN) with tenofovir disoproxil fumarate (TDF) or monotherapy with each agent. METHODS: A total of 330 patients with CHB were assigned to receive Peg-IFN plus TDF for 48 weeks (Peg-IFN plus TDF group), Peg-IFN alone for 48 weeks (Peg-IFN group), or TDF alone for 144 weeks (TDF group). The primary end point was the percentages of patients who achieved HBsAg seroclearance at week 72. Differences from the baseline characteristics and treatment data were compared using the χ2 test for categorical variables or 1-way ANOVA for continuous variables. A Kaplan-Meier test was performed to compare the HBsAg loss among the 3 groups. Discrimination of responders versus nonresponders was quantified using AUC curves. Optimal cut-offs were selected based on Youden's J statistic defined as J = sensitivity + specificity-1. FINDINGS: At week 72, the Kaplan-Meier cumulative HBsAg loss was 11.5% in the Peg-IFN plus TDF group, 5.7% in the Peg-IFN group, and 0% in the TDF group. The percentage of patients with HBsAg loss was comparable in the Peg-IFN plus TDF and Peg-IFN groups (P = 0.143), but both were significantly higher than that in the TDF group (P = 0.000 and P = 0.010). In addition, a significantly higher percentage of patients in the combination group and Peg-IFN group had serum HBsAg of <100 IU/mL compared with the TDF group (32.7% vs 23.6% vs 9.2%; P < 0.001) but no significant differences in the percentages of patients with HBsAg <1000 IU/mL, the undetectable serum HBV DNA and hepatitis B e antigen seroconversion. Our model predicted serum HBsAg loss at week 72 (AUC = 0.846) if the HBsAg level was reduced by > 1.5 log10 IU/mL from baseline at treatment week 24, an optimal timepoint for prediction of HBsAg loss in this cohort. IMPLICATIONS: A 48-week course of Peg-IFN and TDF combination therapy led to profound reduction in serum HBsAg level, resulting in a significantly higher rate of HBsAg loss compared with TDF monotherapy. Patients with steep HBsAg decline >1.5 log10 IU/mL at week 24 well signaled a higher probability of achieving HBsAg loss at week 72.

Effectiveness and postoperative pain level of single-port versus two-port thoracoscopic lobectomy for lung cancer: a retrospective cohort study.

OBJECTIVES: Single-port thoracoscopic lobectomy is a new therapeutic technique for patients with lung cancer; however, insufficient data are available regarding its clinical outcomes. We therefore compared the clinical outcomes of single-port and two-port thoracoscopic lobectomies for lung cancer. METHODS: We retrospectively analyzed and compared the data of 204 and 368 patients with lung cancer who underwent single-port or two-port thoracoscopic lobectomy, respectively, between October 2014 and October 2017 at our institution. Patients in both groups underwent 1:1 propensity score matching, and 400 patients (200 patients in each group) were included. Perioperative clinical indicators were analyzed, including operation time, lymph node dissection stations and numbers, incidence of postoperative complications, and pain scores at 24 h, 72 h, and 1 week after surgery. RESULTS: No perioperative deaths occurred in either group. The operation time, intraoperative blood loss, chest drainage duration, duration of postoperative hospital stay, lymph node dissection station and number, rate of conversion to open surgery, number of ruptured intraoperative pulmonary vessel, and incidence of postoperative complications were not significantly different between the groups (all P > 0.05). However, analysis of the 24-h (P = 0.005), 72-h (P = 0.011), and 1-week (P = 0.034) visual analog scale score after surgery revealed that the postoperative pain levels were significantly lower in the single-port than in the two-port group. CONCLUSIONS: Single-port and two-port thoracoscopic lobectomies had similar perioperative outcomes, although the postoperative pain was lower after single-port than two-port thoracoscopic lobectomy. Hence, we concluded that single-port thoracoscopic lobectomy is an effective, minimally invasive, and promising surgical procedure.

Evidence that the second human pegivirus (HPgV-2) is primarily a lymphotropic virus and can replicate independent of HCV replication.

The second human pegivirus HPgV-2 is a novel blood-borne virus that is strongly associated with the hepatitis C virus (HCV) infection. However, the molecular evidence for their association as well as the natural history and tissue tropism of HPgV-2 remain to be elucidated. In this longitudinal study, a total of 753 patients including 512 HIV-1 and HCV co-infected patients were enrolled to characterize the natural history of HPgV-2 infection. Peripheral blood mononuclear cells (PBMCs) and liver biopsies were collected to determine the tissue tropism of HPgV-2 using immunohistochemical staining of the HPgV-2 antigen and in situ hybridization of HPgV-2 RNA. We documented both persistent HPgV-2 infection with the presence of HPgV-2 viral RNA and antibodies up to 4.6 years and resolved HPgV-2 infection, accompanied by a simultaneous decline of anti-HPgV-2 antibodies and clearance of HPgV-2 viremia. Furthermore, we observed the clearance of HCV, but not HPgV-2, by treatment with direct-acting antivirals (DAAs). Biochemical tests and pathological analyses did not reveal any indication of hepatic impairment caused by HPgV-2. HPgV-2 RNA and nonstructural antigen were detected in the lymphocytes, but not in the hepatocytes present in the liver biopsy samples. In addition, both positive- and negative-strand HPgV-2 RNAs were detected in PBMCs, especially in B cells. The present study is the first to provide evidence that HPgV-2 is a lymphotropic, but not a hepatotropic virus and that HPgV-2 replication is independent of HCV viremia. These new findings let us gain insights into the evolution and persistent infection of RNA viruses in humans.

[Incidence and characteristics of benign liver space-occupying mass in 17 721 patients with chronic hepatitis B: a color Doppler ultrasound-based case-control study].

OBJECTIVE: To analyze the incidence and risk factors of benign liver space-occupying mass in patients with chronic hepatitis B (CHB) and the ultrasound features that differentiate these masses from small hepatocellular carcinoma. METHODS: We retrospectively analyzed the color Doppler and clinical data of 17 721 patients with CHB treated in the Hepatology Unit of Nanfang Hospital between January, 2016 and December, 2017. The data were compared with those of 21629 healthy control subjects undergoing routine physical examination in the Center of Heath Management of Nanfang Hospital during the same period. RESULTS: Compared with the control subjects, the patients with CHB had significantly higher incidences of hepatic cysts (11.8% vs 8.7%, P < 0.05), hepatic hemangioma (8.2% vs 1.6%, P < 0.05) and hepatic cirrhosis nodules (20.6% vs 2.4%, P < 0.05). The incidences of hepatic cysts and cirrhosis nodules increased with age and was significantly higher in male than in female patients (P < 0.001). The highest incidence of hepatic hemangioma was found in CHB patients aged 30-49 years without a gender difference (P>0.05). Sonographically, the benign liver masses commonly showed homogeneous echo within the lesion with clear boundaries and regular shape. Hepatic hemangioma was distinctively hyperechoic in 83.32% (1579/1895) of the patients, while small hepatocellular carcinoma presented with weaker peripheral and internal blood flow signals with a lower flow velocity in the arteries and a higher flow velocity in the portal vein. Liver cirrhosis nodules mostly showed a mixture of strong and weak echoes (79.60%; 7637/9595) without blood flow signal within or around the nodule; an increased volume of the nodule accompanied by heterogeneous echoes within the nodule indicated an increased probability of malignant lesion. Hepatic cysts often displayed no echo within the lesion, but the echo could be enhanced posteriorly. CONCLUSIONS: The patients with CHB are at a significantly higher risk of developing hepatic cysts, hepatic hemangiomas and hepatic cirrhosis nodules than the control population, and an older age and the male gender are associated with a higher incidence of hepatic cysts or cirrhosis. The differences in the sonographic and hemodynamic features can help to differentiate hepatic benign mass from malignant lesions, and kinetic changes in sonography can be used to monitor potential malignant transformation of the cirrhotic lesions.

[Antiviral and antifibrotic therapies reduce occurrence of hepatocellular carcinoma in patients with chronic hepatitis B and liver fibrosis: a 144-week prospective cohort study].

OBJECTIVE: To compare the efficacy and safety of different antiviral and antifibrotic regimens in patients with chronic hepatitis B (CHB) and hepatic fibrosis and the incidence of hepatocellular carcinoma (HCC) associated with these therapies. METHODS: A total of 840 patients with CHB and concurrent hepatic fibrosis, who received antiviral therapy in Nanfang Hospital between June, 2010 and June, 2018, were enrolled in this follow-up cohort study. The patients were assigned to 3 cohorts matched for gender, age (difference≤5 years), HBeAg status and liver stiffness measurement (LSM) for treatment with one of the 3 antiviral drugs, namely entecavir, tenofovir dipivoxil and adefovir dipivoxil; each cohort was divided into 2 groups, with one of the groups having a combined treatment with Fufang Biejiaruangan tablet. The cumulative negative conversion rate of HBV DNA, normalization rate of ALT, hepatic fibrosis regression and the incidence of HCC were compared among the 3 cohorts and across the 6 groups at 144 weeks. RESULTS: A total of 749 patients were available to follow-up at 144 weeks. Compared with the baseline data, the cumulative negative conversion rate of HBV DNA increased gradually and the abnormal rate of ALT decreased significantly over time during the treatment in all the 6 groups (all P < 0.001). Compared with the any of the antiviral drugs used alone, the combined treatments all resulted in significantly better antifibrotic effects (χETV cohort2=11.345, χTDF cohort2=10.160, χADV cohort2=6.358; all P < 0.05). At 144 weeks, the incidence of HCC were 2.2%, 1.7%, 1.7% and 3.3% in enecavir group, enecavir with Biejiaruangan tablet group, adefovir group, and adefovir with Biejiaruangan tablet group, respectively, showing no significant difference between the two cohorts (4 groups; χ2=6.813, P=0.138). None of the patients in the 2 groups with tenofovir treatment had HCC by the end of the observation. CONCLUSIONS: Antiviral therapy combined with antifibrotic therapy can effectively reverse hepatic fibrosis and reduce the incidence of HCC in patients with CHB; among the 3 antiviral drugs, tenofovir dipivoxil can be a better option for reducing the incidence of HCC in these patients.

Serum­derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K­Akt pathway.

Extra­hepatic manifestations are frequently observed in hepatitis C virus (HCV)­infected patients; however the underlying mechanisms remain largely unknown. In the present study, the human glioblastoma SF268 cell line (the precise origin of the cell type is not clear) was infected with HCV using HCV­positive serum, and viral replication was assessed by immunofluorescence, reverse transcription­polymerase chain reaction (PCR), quantitative PCR and western blotting following infection. HCV core protein and HCV RNA were detected in HCV­positive serum­infected SF268 cells at day 4 post­infection, while no infection was observed in cells exposed to HCV­negative serum. The mean HCV RNA levels at day 4 post­infection were up to 5.00 IU/ml log10; however, HCV RNA and immunostaining for core protein were negative when cultured to day 6 or longer. The data suggest that human glioblastoma SF268 cells were transiently infected with HCV. AKT serine/threonine kinase phosphorylation was also detected in HCV­infected SF268 cells at day 4 post­infection. To the best of our knowledge, this is the first demonstration that a human glioblastoma cell line can be infected with serum­derived HCV. The results provide evidence that HCV infection can occur in cells of the central nervous system. Neurological disorder­associated phosphoinositide 3­kinase­AKT signaling pathway was activated in parallel with HCV infection, suggesting that SF268 may serve as an in vitro model for investigating HCV­nervous system cell interactions.

AFP specificity for HCC surveillance is increased by mitigating liver injury among treated chronic hepatitis B patients with elevated AFP.

OBJECTIVE: The aim of this study was to assess AFP response in chronic hepatitis B (CHB) patients with baseline positive AFP (≥7 ng/mL) who received antiviral therapy thereafter. METHODS: A cohort study was conducted to assess AFP response in CHB patients who had baseline positive AFP and got antiviral therapy. RESULTS: This retrospective study enrolled 302 antiviral-treatment-naïve CHB patients with positive AFP. After a 12-month antiviral treatment, 144 patients normalized AFP during follow-up while the rest remained AFP-positive. There were no significant differences in baseline characteristics and virologic and ALT responses to antiviral therapy between the two groups. During a mean follow-up of 34 ± 6 months, 16 patients (5.3%) in this cohort developed HCC, and 14 (8.9%) of them emerged in the AFP positive group. There was a significant difference (P=0.004) in HCC occurrence between AFP normalized and non-normalized groups after treatment. Univariate and multivariate analyses revealed that cirrhosis (HR=9.983, 95% CI=3.609-27.617, P<0.001), and non-AFP response to antiviral treatment (HR=6.517, 95% CI=1.475-28.784, P=0.013) were two independent factors associated with HCC occurrence. CONCLUSIONS: To our knowledge, this is the first investigator-initiated cohort study to assess the performance of on-treatment AFP in CHB patients with baseline positive AFP. In contrast to the criticism that AFP is neither sensitive nor specific, the current study has provided important evidence that on-antiviral-treatment AFP normalization is a specific protective marker for HCC in patients with HBV-related chronic liver diseases who started antiviral therapy thereafter.

Sofosbuvir-Based Therapies for Patients with Hepatitis C Virus Infection: Real-World Experience in China.

Background and Aims: There is scarcity of data in literature regarding the treatment response to sofosbuvir- (SOF-) based therapies in Chinese patients with chronic Hepatitis C Virus (HCV) infection. The aim of this study was to evaluate the efficacy and safety of SOF-based regimens for chronic hepatitis C (CHC) patients without cirrhosis in a real-world setting in mainland China. Methods: A total of 226 patients receiving SOF plus daclatasvir (DCV), ledipasvir (LDV), or velpatasvir (VEL) were enrolled from December 2014 to June 2017. The primary observation point was the percentage of patients with a sustained virologic response (SVR) at posttreatment week 12 (SVR12), and all adverse events were monitored during treatment and follow-up period. Results: The overall SVR12 rate was 96% (216/226), and individual SVR12 ranged from 93% to 100% in different treatment groups. No significant differences of efficacy were detected between genotypes 1b and 6a (98% for GT 1b versus 100% for GT 6a, P=0.322). Comparing the high success rates in GT 1b and 6a patients, SVR12 was relatively low in GT 3a and 3b patients. A significant difference in efficacy was observed between GT 3 and not GT 3 patients (77% versus 98%, respectively, P<0.001). No significant differences in efficacy were detected among different regimens (93% versus 97% versus 100%, respectively, P=0.153), gender (95% for male versus 96% for female, P=0.655), or baseline HCV RNA lever (96% versus 95%, respectively, P=0.614). Similar SVR rates were also obtained in naïve and previously treated patients (98% versus 93%, respectively, P=0.100). Conclusions: NS5B polymerase inhibitor SOF plus one of the NS5A inhibitors, such as DCV, LDV, or VEL for 12 weeks was associated with high SVR12 rates and well tolerated in HCV-infected patients without cirrhosis. Moreover, patients with DAAs failure should be retreated with more effective regimens like SOF/VEL.

Effects of preventive therapy for latent tuberculosis infection and factors associated with treatment abandonment: a cross-sectional study.

BACKGROUND: Routine data on the use of preventive therapy (PT) for latent tuberculosis infection (LTBI) in students are scarce in high tuberculosis (TB) burden countries. This study aimed to investigate the effects of PT and identify factors related to PT abandonment during the school TB epidemic in Guangzhou, southern China. METHODS: Purified protein derivative (PPD) skin testing was performed on all staff and students in a vocational school in Guangzhou, southern China during December 2014. Subjects (n=362) with a reactive PPD induration ≥15 mm, or with papules, blisters, and a normal chest X-ray image were recommended for PT. The subjects were assigned to a PT group (n=156) and control group (n=206), respectively, on a voluntary basis. Subjects in the PT group received isoniazid (INH) combined with rifampicin (RFP) for 3 consecutive months; after which, the incidence of TB and protective rate of PT for reducing TB were observed during a 2-year follow up period. An improved questionnaire was used to identify factors that influenced treatment abandonment. All data were subjected to univariate and multivariate logistic regression analyses. RESULTS: Two cases in the PT group and 20 cases in the control group developed TB. The protective rate of PT for reducing TB was 86.8%. In the PT group, 69 cases finished PT, with a completion rate of 44.2%, and the incidence rates of adverse events and hepatotoxicity were 12.2% and 1.9%, respectively. Among 362 LTBI cases, a total of 293 cases abandoned PT. Discrimination (OR =7.173, 95% CI, 3.361-15.307), worry about adverse drug reactions (OR =2.752, 95% CI, 1.459-5.192), a low parental education level (OR =2.605, 95% CI, 1.420-4.777), and accepting the opinion of a non-TB specialist (OR =6.017, 95% CI, 3.077-11.765) were identified as high-risk factors for abandoning PT. CONCLUSIONS: A PT regimen consisting of INH combined with RFP for 3 consecutive months is reasonable for use in schools. Discrimination, worry about adverse drug reactions, a low parental education level, and accepting the opinion of a non-TB specialist are all factors that may increase the risk for treatment abandonment among LTBI cases. To overcome psychological obstacles is critical for improving treatment adherence.

Genotype Distribution and Molecular Epidemiology of Hepatitis C Virus in Guangzhou, China: Predominance of Genotype 1b and Increasing Incidence of Genotype 6a.

BACKGROUND/AIMS: Distribution of Hepatitis C virus (HCV) genotypes vary geographically and may associate with the mode of transmission. Little is known about the molecular epidemiology of HCV infection in Guangzhou, China. METHODS: A cross-sectional survey included 561 subjects with chronic HCV infection registered at Nanfang Hospital, Southern Medical University, was performed. All residents were invited for a questionnaire interview to collect information about their personal status and commercial blood donation history. RESULTS: A total of 463 chronic hepatitis C (CHC) patients were finally enrolled. Among the 463 samples, 426 were characterized by partial core-E1 sequences and classified into 7 subtypes: 1b (n=263, 61.7%), 6a (n=86, 20.2%), 2a (n=26, 6.1%), 3b (n=26, 6.1%), 3a (n=22, 5.2%), 6u (n=2, 0.5%), and 4a (n=1, 0.2%). Analysis of genotype-associated risk factors revealed that blood donation and transfusion were strongly associated with subtypes 1b and 2a, while genotype 3b and 6a were more frequent in intravenous drug users. CONCLUSIONS: Phylogeographic analyses demonstrated that the distribution of HCV genotypes in Guangzhou is complex. Interestingly, 6a has become a local endemic in Guangzhou and may be the second source region to disseminate 6a to other provinces.

[Depression and anxiety caused by pegylated interferon treatment in patients with chronic hepatitis B and the therapeutic effects of escitalopram and alprazolam].

OBJECTIVE: To evaluate the incidence of depression and anxiety caused by pegylated interferon α (PegIFN-α) treatment for chronic hepatitis B (CHB) and assess the efficacy of intervention with escitalopram and alprazolam. METHODS: A total of 165 CHB patients receiving PegIFN-α-based treatment for 12 weeks were assessed for moderate to severe depression and anxiety using Patient Health Questionnaire (PHQ-9) and 7-item Generalized Anxiety Disorder Scale (GAD-7)]. The patients identified to have moderate to severe depression and anxiety treated with escitalopram or alprazolam and the psychological condition of the patients was assessed at the 2nd, 4th and 8th weeks of the treatments. RESULTS: In the 165 patients receiving PegIFN-α treatment, 51 patients developed moderate to severe psychiatric symptoms, incuding 37 (22.4%) with depression, 31 (18.8%) with anxiety, and 17 (10.3%) with both. The symptoms of depression and anxiety was both significantly improved by intervention with escitalopram (P=0.000); alprazolam was effective for anxiety (P=0.001) but did not produce obvious effects on depression (P=0.904). Nevertheless, alprazolam had a much better therapeutic effect than escitalopram on anxiety in these patients (t=-3.198, P=0.010). CONCLUSION: Psychological symptoms are common in CHB patients receiving PegIFN-α treatment. The symptoms of depression and anxiety can be ameliorated by intervention with escitalopram and alprazolam, respectively.

A different inhibitor is required for overcoming entecavir resistance: a comparison of four rescue therapies in a retrospective study.

AIMS: Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance. METHODS: A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared. RESULTS: There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2  = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ2  = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log10 IU ml-1 , -2.16 ± 0.81 log10 IU ml-1 , -1.17 ± 1.23 log10 IU ml-1 and -2.49 ± 1.10 log10 IU ml-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence. CONCLUSIONS: TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.