Carvedilol Plus NUC for Patients With HBV-Compensated Cirrhosis Under Virological Suppression: A Randomized Open-Label Trial.

INTRODUCTION: Portal hypertension progression can be relieved after controlling the etiology of liver cirrhosis. Whether beta-blockers could additionally enhance the effects during treatment, particularly for small esophageal varices (EV), was unclear. This study aims to assess the efficacy of add-on carvedilol to delay EV progression during anti-hepatitis B virus (HBV) treatment in HBV-related cirrhosis. METHODS: This randomized controlled trial enrolled patients with virologically suppressed HBV-compensated cirrhosis and small/medium EV. The participants were randomly assigned to receive nucleos(t)ide analog (NUC) or carvedilol 12.5 mg plus NUC (1:1 allocation ratio). The primary end point was the progression rate of EV at 2 years of follow-up. RESULTS: A total of 238 patients (small EV, 77.3%) were randomized into 119 NUC and 119 carvedilol plus NUC (carvedilol [CARV] combination group). Among them, 205 patients (86.1%) completed paired endoscopies. EV progression rate was 15.5% (16/103) in the NUC group and 12.7% (13/102) in the CARV combination group (relative risk = 0.79, 95% confidence interval 0.36-1.75, P = 0.567). Subgroup analysis on medium EV showed the CARV combination group had a more favorable effect in promoting EV regression (43.5% vs 13.1%, P = 0.022) than NUC alone, but not in small cases ( P = 0.534). The incidence of liver-related events (decompensation, hepatocellular carcinoma, or death/liver transplantation) within 2 years was similar between the 2 groups (11.2% vs 10.4%, P = 0.881). DISCUSSION: The overall results did not show statistically significant differences between the added carvedilol strategy and NUC monotherapy in preventing EV progression in patients with virologically suppressed HBV-compensated cirrhosis. However, the carvedilol-added approach might offer improved outcomes specifically for patients with medium EV (NCT03736265).

Optimal allocation of agricultural water and land resources integrated with virtual water trade: A perspective on spatial virtual water coordination.

Agricultural production consumes the majority of global freshwater resources. The worsening water scarcity has imposed significant stress on agricultural production when regions seek food self-sufficiency. To seek optimal allocation of spatial agricultural water and land resources in each water function zone of the objective region, a multi-objective optimization model was developed to tackle the trade-offs between the water-saving objective and the economic benefit objective considering virtual water trade (VWT). The cultivated area of each crop in each water function zone was taken into account as the decision variable, while a set of strong constraints were used to restrict land resources and water availability. Then, a decomposition-simplex method aggregation algorithm (DSMA) was proposed to solve this nonlinear, bounding-constrained, and multi-objective optimization model. Based on the quantitative analysis of the spatial blue and green virtual water in each agricultural product, the proposed methodology was applied to a real-world, provincial-scale region in China (i.e., Jiangsu Province). The optimized results provided 18 Pareto solutions to reallocate the land resources in the 21 IV-level water function zones of Jiangsu Province, considering four major rainy-season crops and two dry-season crops. Compared to the actual scenario, the superior scheme increased by 7.95% (5.6 × 109 RMB) for economic trade and decreased by 1.77% (2.0 × 109 m3) for agricultural water consumption. It was mainly because the potential of spatial blue and green virtual water in Jiangsu was fully exploited by improving spatial land resource allocation. The food security of Jiangsu could be guaranteed by achieving self-sufficiency in the superior scheme, and the total VWT in the optimal scheme was 2.2 times more than the actual scenario. The results provided a systematic decision-support methodology from the perspective of spatial virtual water coordination, yet, the methodology is widely applicable.

ATOH8 promotes HBV immune tolerance by inhibiting the pyroptotic pathway in hepatocytes.

The mechanism of hepatitis B virus (HBV) immune tolerance remains unclear. Our previous studies showed that ATOH8 plays an important role in the liver tumor immune microenvironment; however, the specific immune regulatory mechanism requires further studies. Studies have shown that the hepatitis C virus (HCV) can cause hepatocyte pyroptosis; however, the relationship between HBV and pyroptosis is contested. Therefore, this study aimed to determine whether ATOH8 interfered with HBV activity through pyroptosis to further study the mechanism of ATOH8 on immune regulation and enrich our understanding of HBV­induced invasion. The expression levels of pyroptosis­related molecules (GSDMD and Caspase­1) in liver cancer tissues and peripheral blood mononuclear cells (PBMCs) of patients with HBV were assessed using qPCR and western blotting. HepG2.2.15 and Huh7 cells were used to overexpress ATOH8 using a recombinant lentiviral vector. The HBV DNA expression levels in HepG2.2.15 cells were detected using absolute quantitative (q)PCR, and the hepatitis B surface antigen expression levels in the HepG2.2.15 cell culture supernatant were measured using ELISA. The expression of pyroptosis­related molecules in Huh7 and HepG2.2.15 cells was detected using western blotting and qPCR. Additionally, the expression levels of inflammatory factors including TNF­α, INF­α, IL­18, and IL­1ß were detected using qPCR and ELISA. The liver cancer tissues and PBMCs of patients with HBV showed higher expressions of pyroptosis­related molecules than those of normal samples. ATOH8­overexpressed HepG2.2.15 cells had higher HBV expression levels but lower levels of pyroptosis­related molecules, such as GSDMD and Caspase­1, than those in the control group. Similarly, the expression levels of pyroptosis­related molecules in Huh7 cells overexpressing ATOH8 were lower than that in Huh7­GFP cells. Further detection of the expression of INF­α and TNF­α in HepG2.2.15 cells overexpressing ATOH8 showed that ATOH8 overexpression increased the expression of these inflammatory factors, including those associated with pyroptosis (IL­18 and IL­1ß). In conclusion, ATOH8 promoted HBV immune escape by inhibiting hepatocyte pyroptosis.

Development and validation of a machine learning-based model for varices screening in compensated cirrhosis (CHESS2001): an international multicenter study.

BACKGROUND AND AIMS: The prevalence of high-risk varices (HRV) is low among compensated cirrhotic patients undergoing EGD. Our study aimed to identify a novel machine learning (ML)-based model, named ML EGD, for ruling out HRV and avoiding unnecessary EGDs in patients with compensated cirrhosis. METHODS: An international cohort from 17 institutions from China, Singapore, and India were enrolled (CHESS2001). The variables with the top 3 importance scores (liver stiffness, platelet count, and total bilirubin) were selected by the Shapley additive explanation and input into a light gradient-boosting machine algorithm to develop ML EGD for identification of HRV. Furthermore, we built a web-based calculator for ML EGD, which is free with open access (http://www.pan-chess.cn/calculator/MLEGD_score). Unnecessary EGDs that were not performed and the rates of missed HRV were used to assess the efficacy and safety for varices screening. RESULTS: Of 2794 enrolled patients, 1283 patients formed a real-world cohort from 1 university hospital in China used to develop and internally validate the performance of ML EGD for varices screening. They were randomly assigned into the training (n = 1154) and validation (n = 129) cohorts with a ratio of 9:1. In the training cohort, ML EGD spared 607 (52.6%) unnecessary EGDs with a missed HRV rate of 3.6%. In the validation cohort, ML EGD spared 75 (58.1%) EGDs with a missed HRV rate of 1.4%. To externally test the performance of ML EGD, 966 patients from 14 university hospitals in China (test cohort 1) and 545 from 2 hospitals in Singapore and India (test cohort 2) comprised the 2 test cohorts. In test cohort 1, ML EGD spared 506 (52.4%) EGDs with a missed HRV rate of 2.8%. In test cohort 2, ML EGD spared 224 (41.1%) EGDs with a missed HRV rate of 3.1%. When compared with the Baveno VI criteria, ML EGD spared more screening EGDs in all cohorts (training cohort, 52.6% vs 29.4%; validation cohort, 58.1% vs 44.2%; test cohort 1, 52.4% vs 26.5%; test cohort 2, 41.1% vs 21.1%, respectively; P < .001). CONCLUSIONS: We identified a novel model based on liver stiffness, platelet count, and total bilirubin, named ML EGD, as a free web-based calculator. ML EGD could efficiently help rule out HRV and avoid unnecessary EGDs in patients with compensated cirrhosis. (Clinical trial registration number: NCT04307264.).

Elucidating nitrifying performance, nitrite accumulation and microbial community in a three-stage plug flow moving bed biofilm reactor (PF - MBBR).

A three-stage plug flow moving bed biofilm reactor (PF - MBBR, consisting of three identical chambers of N1, N2 and N3) was proposed for nitrifier enrichment using synthetic wastewater. During the stable operation, the average NH4+-N effluent was 0.67 mg/L and NH4+-N removal was as high as 97.19% with the nitrite accumulation ratio (NAR) of 54.23%, although the biofilm thickness and biomass both presented downward trends from N1 (296 µm, 2280 mg/L), N2 (248 µm, 1850 mg/L) to N3 (198 µm, 1545 mg/L). Particularly, the comparative results of three stages revealed that N2 showed the optimum NH4+-N removal (77.27%) and NAR (75.21%) in the continuous-flow, while NAR of N3 unexpectedly maintained a high level of 65.83% in the batch test, suggesting that ammonia oxidizing bacteria (AOB) accounted for absolute advantage over nitrite oxidizing bacteria (NOB). High-throughput sequencing initially verified different distribution of bacterial community structure, where N2 was far away from N1 and N3 with the lowest community richness and community diversity (operational taxonomic units (OTUs): 454(N2)<527(N3)<621(N1)). Proteobacteria (77.60%-83.09%), Bacteroidetes (1.66%-3.66%), Acidobacteria (2.28%-4.67%), and Planctomycetes (1.19%-6.63%) were the major phyla. At the genus level, AOB (mainly Nitrosomonas) accounted for 5.08% (N1), 20.74% (N2) and 14.24% (N3) while NOB (mainly Nitrospira) increased from 0.14% (N1), 7.06% (N2) to 4.91% (N3) with the total percentages of 5.22%, 27.80% and 19.15%. Finally, the application feasibility of MBBR optimization linked with nitrite (NO2--N) accumulation for deep-level nutrient removal was discussed.

Clinical features of sporadic hepatitis E virus infection in pregnant women in Shanghai, China.

OBJECTIVES: Hepatitis E virus (HEV) infection causes high mortality in pregnant women of developing regions during large outbreaks. The aim of this study was to investigate the clinical features of HEV-infected pregnant women in Shanghai, China where the epidemiology of HEV has shifted from large outbreaks to the sporadic form. METHODS: Clinical data of 516 pregnant and nonpregnant child-bearing age women diagnosed with HEV infection during 2009-2020 was collected at the Shanghai Public Health Clinical center. Patients' data were analysed for clinical features and laboratory parameters accordingly. RESULTS: Most of the hospitalized HEV-infected pregnant women (85.23%, 127/149) showed no obvious clinical symptoms and the disease outcome was generally benign with no liver failure or maternal mortality observed in the patients. By comparison, fewer (37.21%, 32/86) of the HEV-infected nonpregnant women were asymptomatic, and five cases (5.81%, 5/86) of liver failure were observed among them. The levels of serum alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBiL), direct bilirubin (DBiL) and total bile acids (TBA) were significantly higher (P < 0.05) in nonpregnant women than those of the pregnant women. We found 42.99% (46/107) births had adverse foetal/neonatal outcome. Mothers who presented with adverse foetal/neonatal outcome showed higher (P < 0.05) serum TBiL, DBiL and TBA levels than those without. CONCLUSION: We found that the clinical features of sporadic HEV infection in pregnant women in Shanghai, China are generally mild and no maternal mortality occurred. However foetal/neonatal adverse outcomes including preterm births and stillbirths were observed in HEV-infected pregnant women.

Health-related quality of life improves after entecavir treatment in patients with compensated HBV cirrhosis.

BACKGROUND AND AIM: Antiviral therapy is effective in decreasing disease progression in HBV cirrhosis. However, the long-term effect of antiviral therapy on health-related quality of life (HRQoL) in patients with compensated HBV cirrhosis is unknown. METHODS: The patients with compensated HBV cirrhosis enrolled in a randomized controlled trial of entecavir-based therapy were recruited in the present study, if they had HRQoL score at 5-year follow-up or who developed liver-related events (LRE) during follow-up were included. HRQoL was measured with 36-Item Short-Form Health Survey (SF-36) and EuroQol-5D (EQ-5D) at baseline and yearly during follow-up. LRE was defined as the development of decompensation, HCC, or death. RESULTS: A total of 161 patients were included in the present study, with a median age of 48.0 (41.0, 53.0) years, 77.6% being male and 37.2% being HBeAg-positive. During 5 years, 45 patients developed LRE. All eight dimensions of SF-36 were significantly improved after 5 years of antiviral therapy (all p < 0.001), with all dimensions improved more than five points except for physical functioning. Proportion of patients reporting no problems in all five dimensions in EQ-5D increased from 57.8 to 72.0%; visual analogue scale (VAS) and utility index (UI) increased significantly (VAS 79.8 ± 16.4 to 84.4 ± 13.2, UI 0.91 ± 0.13 to 0.95 ± 0.10, both p < 0.001). HRQoL improved or kept stable in the majority of patients who had LRE during follow-up, even stratified by Baveno VI criteria for clinically significant portal hypertension. CONCLUSION: After 5 years of ETV treatment, HRQoL significantly improved in patients with compensated HBV cirrhosis. (NCT01943617, NCT02849132).

Transcription factor specificity protein 1-mediated Serine/threonine kinase 39 upregulation promotes the proliferation, migration, invasion and epithelial-mesenchymal transition of hepatocellular carcinoma cells by activating the transforming growth factor-ß1 /Smad2/3 pathway.

Bioinformatics analysis showed that Serine/threonine kinase 39 (STK39), which was testified to play an important role in human cancers, may be a hub gene in diagnosing hepatocellular carcinoma (HCC). This study aimed to explore whether STK39 could be regulated by specificity protein 1 (SP1) to affect HCC cells malignant processes. Firstly, STK39 expression in tissues of HCC patients and several cell lines was analyzed. After STK39 silencing, cell proliferation was evaluated by methyl thiazolyl tetrazolium and colony formation assay. Tunel staining was used to detect cell apoptosis. Then, the abilities of cell migration and invasion were determined with wound healing and transwell assays. The expression of epithelial-mesenchymal transition (EMT)-related proteins and transforming growth factor-ß1 (TGF-ß1)/Smad2/3 pathway proteins was tested by western blot analysis. Thereafter, cells were overexpressed with SP1 under the circumstance of STK39 knockdown, and then the above cellular processes were under observation. Results revealed that the increased expression of STK39, which was found in both HHC patients and HCC cell lines, exhibited poor HCC prognosis. STK39 silencing inhibited Hep3b cell proliferation, migration, invasion, EMT and TGF-ß1/Smad2/3 expression but promoted cell apoptosis. Additionally, SP1 could bind to the STK39 promoter and facilitate STK39 expression. Further studies revealed that the effects of STK39 silencing on Hep3b cells were blocked by SP1 overexpression. In conclusion, SP1-mediated STK39 up-regulation leads to the increased proliferation, migration, invasion and EMT of HCC cells via activating TGF-ß1/Smad2/3 pathway. Therapies that target SP1 to knockdown STK39 expression may contribute to the inhibition of HCC progression.

Case report: histopathology and molecular pathology analysis on enteric tissue of a COVID-19 patient.

AIMS: Patients with COVID-19 can also have enteric symptoms. Here we analyzed the histopathology of intestinal detachment tissue from a patient with COVID-19. METHODS: The enteric tissue was examined by hematoxylin & eosin stain, PAS (Periodic acid-Schiff) staining, Gram staining, Ziehl-Neelsen stain and Grocott's Methenamine Silver (GMS) Stain. The distribution of CD3, CD4, CK20 and CD68, cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) antigen were determined by immunohistochemistry. In situ hybridization (ISH) of SARS-CoV-2 and Epstein-Barr virus-encoded small RNA (EBER) were also performed. RESULTS: We observed mucosal epithelium shedding, intestinal mucosal erosion, focal inflammatory necrosis with hemorrhage, massive neutrophil infiltration, macrophage proliferation accompanied by minor lymphocyte infiltration. Fungal spores and gram positive cocci but not mycobacteria tuberculosis were identified. Immunohistochemistry staining showed abundant CD68+ macrophages but few lymphocytes infiltration. HSV, CMV and EBV were negative. ISH of SARS-CoV-2 RNA showed positive signal which mostly overlapped with CD68 positivity. CONCLUSIONS: The in situ detection of SARS-CoV-2 RNA in intestinal macrophages implicates a possible route for gastrointestinal infection. Further study is needed to further characterize the susceptibility of enteric cells to SARS-CoV-2 infection.

Prediction of liver-related events in patients with compensated HBV-induced cirrhosis receiving antiviral therapy.

BACKGROUND AND AIMS: Many models have been developed to predict liver-related events (LRE) in chronic hepatitis B, few focused on compensated HBV-induced cirrhosis. We aimed to describe the incidence of LRE and to determine independent risk predictors of LRE in compensated HBV-induced cirrhosis patients receiving antiviral therapy using routinely available parameters. METHODS: Prospective cohorts of treatment-naïve adults with compensated HBV-induced cirrhosis were enrolled. Patients were treated with entecavir (ETV) or ETV + thymosin-alpha1 (Thy-α1) or lamivudine (LAM) + adefovir (ADV). Data were collected at baseline and every 6 months. LRE was defined as development of decompensation, HCC or death. RESULTS: Totally 937 patients were included, 608 patients treated with ETV, 252 with ETV + Thy-α1, and 77 with LAM + ADV. After a median follow-up of 4.5 years, 88 patients developed LRE including 48 with HCC. The cumulative incidence of LRE at year 1, 3, and 5 was 2.1%, 7.0%, and 12.7%, respectively, and was similar for three treatment groups. All models using variables at month 6 or 12 had better fit than models using baseline values. The best model for prediction of LRE used PLT, GGT, and AFP at month 6 [AUC: 0.762 (0.678-0.814)], for hepatic decompensation-PLT, LSM and GGT at month 12 (AUC: 0.834 (0.675-0.919)), and for HCC-AFP and GGT at month 6 [AUC 0.763 (0.691-0.828)]. All models had negative predictive values of 94.0-98.8%. CONCLUSION: Models using on-treatment variables are more accurate than models using baseline variables in predicting LRE in patient with compensated HBV-induced cirrhosis receiving antiviral therapy. ClincialTrials.gov number NCT01943617, NCT01720238, NCT03366571, NCT02849132.

Screening varices in patients with HBV-related cirrhosis on antiviral therapy: Platelet alone or together with LSM.

BACKGROUND & AIMS: Non-invasive assessment criteria to rule out high-risk varices (HRV) in compensated hepatitis B virus (HBV) cirrhosis on antiviral therapy remains unclear. METHODS: HBV-related compensated cirrhotic patients who underwent screening endoscopy during antiviral therapy were enrolled and randomly divided into the derivation and validation sets. HRV were defined as medium to large varices or small varices with red signs. Univariate and multivariate logistic analysis were used to determine the parameters associated with HRV. RESULTS: A total of 436 HBV-related compensated cirrhotic patients screened for varices were enrolled, the median duration of antiviral therapy was 4 years (IQR: 2.5-5.5 years). In the derivation set (N = 290, 17.2% with HRV), only platelet (PLT) count (OR = 0.972, 95% CI 0.961-0.984, P < .05) was independently associated with HRV, whereas liver stiffness measurement was not associated with the presence of HRV. With a PLT count cut-off value of 105 × 109 /L, unnecessary endoscopies could be spared in 56.9% patients, with a 3.6%. risk of missing HRV. In the validation cohort (N = 146, 16.4% with HRV), the proportion of patients that could safely spare endoscopies (61.0%) identified by this PLT count cut-off value was higher than that obtained by using Baveno VI criteria (34.9%), with an acceptable risk of missing HRV (3.4%). CONCLUSION: Compared with the 'Baveno VI criteria or beyond' criteria, PLT count higher than 105 × 109 /L could safely spare more screening endoscopies without increasing the risk of missing HRV in patients with HBV-related compensated cirrhosis on antiviral therapy.

ATOH8 overexpression inhibits the tumor progression and monocyte chemotaxis in hepatocellular carcinoma.

OBJECTIVE: ATOH8 is reported to be associated with the progression of many tumors; however, there are remaining controversies. The aim of this study is to explore the role of ATOH8 in hepatocellular carcinoma (HCC) and its effect on monocyte chemotaxis. METHODS: Bioinformatics analysis was performed based on the LIHC data in GEPIA and LinkedOmic. Fresh human liver cancer and adjacent nontumor tissue specimens were collected at the Shanghai Public Health Clinical Center. qRT-PCR was performed to determine the transcript level, and western blot analysis and ELISA were used to detect protein expression. CCK8, colony formation, wound-healing, Transwell migration and invasion assays were performed to examine cell proliferation, migration and invasion. An HCC xenograft mouse model was used to determine oncogenicity in vivo. Cell apoptosis and related markers were detected by flow cytometry. Additionally, chemotaxis was assessed by the Transwell migration assay. RESULTS: ATOH8 expression is downregulated in HCC tissue and hepatoma cell lines. High expression of ATOH8 predicts a favorable prognosis. Overexpression of ATOH8 in liver cancer cells inhibits proliferation, migration and invasion in vitro, and tumor progression in nude mice. Knockdown of ATOH8 promotes proliferation of Huh7 and EMT-related proteins. Overexpression of ATOH8 increases chemosensitivity to 5-FU, which is probably caused by inhibiting the phosphorylation of AKT (Ser473). Furthermore, overexpression of ATOH8 in Huh7 reduced MCP1 to inhibit chemotactic THP-1, and promoted antitumor inflammatory cytokine (TNF-α and IFN-γ) secretion in monocytes. CONCLUSION: In addition to the intrinsic oncosuppressive function of ATOH8 in the liver, ATOH8 may modulate the microenvironment to create an immune activation state. This may partly be attributed to ATOH8 inhibition of the monocyte recruitment via suppressing MCP1 expression so as to promote antitumor inflammatory cytokine secretion in monocytes.

The effects of renin-angiotensin system inhibitors (RASI) in coronavirus disease (COVID-19) with hypertension: A retrospective, single-center trial.

INTRODUCTION AND OBJECTIVE: A recent outbreak of coronavirus disease 2019 (COVID-19) occurs in the worldwide. Angiotensin-converting enzyme 2 (ACE2) can mediate coronavirus entry into host cells. Therefore, renin-angiotensin system inhibitors (RASI) were suspected of contributing to the increase of coronavirus infection. We aimed to analyze the effects of RASI in COVID-19 patients with hypertension. PATIENTS AND METHOD: In this retrospective, single-center study, 27 COVID-19 patients with hypertension, who were admitted to the Shanghai Public Health Clinical Center from January 25, 2020 to January 31, 2020, were analyzed for clinical features, laboratory parameters, medications and the length of stay. All the patients were given antiviral and antihypertension treatment, of which 14 patients were treated with RASI and 13 patients without RASI. RESULTS: Comparing the two groups, we did not found statistically significant differences in clinical symptoms and laboratory tests. Furthermore, cough was not aggravated. CONCLUSIONS: Through the analysis of this small sample, RASI could be deemed safe and effective to control high blood pressure of COVID-19 patients. Further analysis with a larger sampling size is required to explore the underlying mechanisms.

INTRODUCCIÓN Y OBJETIVO: Un reciente brote de la enfermedad coronavirus 2019 (COVID-19) se produce en todo el mundo. La enzima convertidora de angiotensina 2 (ACE2) puede mediar la entrada del coronavirus en las células huésped. Por lo tanto, se sospechaba que los inhibidores del sistema renina-angiotensina (SRA) contribuían al aumento de la infección por coronavirus. Nos propusimos analizar los efectos de los SRA en los pacientes COVID-19 con hipertensión. PACIENTES Y MÉTODO: En este estudio retrospectivo, de un solo centro, se analizaron 27 pacientes de COVID-19 con hipertensión, que fueron admitidos en el Centro Clínico de Salud Pública de Shangai desde el 25 de enero de 2020 hasta el 31 de enero de 2020, para determinar las características clínicas, los parámetros de laboratorio, los medicamentos y la duración de la estancia. A todos los pacientes se les administró un tratamiento antiviral y antihipertensivo, de los cuales 14 pacientes fueron tratados con SRA y 13 sin SRA. RESULTADOS: Comparando los dos grupos, no encontramos diferencias estadísticamente significativas en los síntomas clínicos y las pruebas de laboratorio. Además, la tos no se agravó. CONCLUSIONES: A través del análisis de esta pequeña muestra, el SRA podría considerarse seguro y eficaz para controlar la presión arterial alta de los pacientes con COVID-19. Es necesario realizar más análisis con una muestra de mayor tamaño para explorar los mecanismos subyacentes.

The effects of renin-angiotensin system inhibitors (RASI) in coronavirus disease (COVID-19) with hypertension: A retrospective, single-center trial.

INTRODUCTION AND OBJECTIVE: A recent outbreak of coronavirus disease 2019 (COVID-19) occurs in the worldwide. Angiotensin-converting enzyme 2 (ACE2) can mediate coronavirus entry into host cells. Therefore, renin-angiotensin system inhibitors (RASI) were suspected of contributing to the increase of coronavirus infection. We aimed to analyze the effects of RASI in COVID-19 patients with hypertension. PATIENTS AND METHOD: In this retrospective, single-center study, 27 COVID-19 patients with hypertension, who were admitted to the Shanghai Public Health Clinical Center from January 25, 2020 to January 31, 2020, were analyzed for clinical features, laboratory parameters, medications and the length of stay. All the patients were given antiviral and antihypertension treatment, of which 14 patients were treated with RASI and 13 patients without RASI. RESULTS: Comparing the two groups, we did not found statistically significant differences in clinical symptoms and laboratory tests. Furthermore, cough was not aggravated. CONCLUSIONS: Through the analysis of this small sample, RASI could be deemed safe and effective to control high blood pressure of COVID-19 patients. Further analysis with a larger sampling size is required to explore the underlying mechanisms.

Clinical characteristics in patients with SARS-CoV-2/HBV co-infection.

COVID-19 has become a global pandemic and garnered international attention. Although the clinical features of COVID-19-related liver injury have been investigated, there have been no reports and studies on the clinical characteristics of COVID-19 patients co-infected with hepatitis B virus (HBV). This study aimed to evaluate whether SARS-CoV-2/HBV co-infection could influence liver function and the disease outcome. All 326 confirmed COVID-19 cases in Shanghai Public Health Clinical Center (The COVID-19 designated hospital in Shanghai, China) from 20 January 2020 to 24 February 2020 were enrolled and followed up until February 29 in this study. The clinical, laboratory data and the length of stay were collected and analysed retrospectively. 20 patients with HBV co-infection (6.1%) and 306 patients (93.9%) without HBV infection showed no differences in the level of liver function parameters. However, compared with HBsAg- patients [145.4 mg/L (103.9-179.2)], HBsAg + patients had a lower level of prealbumin [(102.3 mg/L (76.22-160.2), P = .0367]. There were also no significant differences for the discharge rate and the length of stay between two groups. Taken together, we found no evidence that SARS-CoV-2/HBV co-infection could aggravate liver injury or extend duration of hospitalization.

MicroRNA-499 Suppresses the Growth of Hepatocellular Carcinoma by Downregulating Astrocyte Elevated Gene-1.

The aim of this study is to investigate the role of microRNA-499 (miR-499) in hepatocellular carcinoma tumor growth and the underlying molecular mechanisms. The expression of miR-499 was significantly decreased in hepatocellular carcinoma tissues compared with that in adjacent normal tissues. Furthermore, miR-499 overexpression in HEPG2 cell was related to the tumor growth in nude mice xenograft models. Likewise, miR-499 mimic or inhibitor decreased or accelerated cell proliferation, respectively. Mechanistically, miR-499 directly targeted the 3'- untranslated region of astrocyte elevated gene-1 and downregulate astrocyte elevated gene-1 expression. Restoration of astrocyte elevated gene-1 expression in hepatocellular carcinoma cells reversed the inhibitory effect of miR-499 on cell growth. In addition, astrocyte elevated gene-1 and miR-499 expression were inversely correlated in human and mice hepatocellular carcinoma tissues. Our study identified miR-499 as a tumor-suppressive miR in hepatocellular carcinoma, thus providing a candidate therapeutic target for the future diagnosis or treatment of hepatocellular carcinoma.

Entecavir add-on Peg-interferon therapy plays a positive role in reversing hepatic fibrosis in treatment-naïve chronic hepatitis B patients: a prospective and randomized controlled trial.

BACKGROUND: The efficacy of entecavir (ETV) add-on peg-interferon therapy compared with ETV monotherapy in treatment-naïve hepatitis B virus (HBV) patients remains controversial. We investigated whether adding peg-interferon to ongoing ETV treatment leads to a better curative effect or not. METHODS: All patients have been recruited between August 2013 and January 2015 from the Shanghai Public Health Clinical Center and Zhongshan Hospital (China). Eligible HBV patients (n = 144) were randomly divided (1:1) to receive either ETV monotherapy (n = 70) or peg-interferon add-on therapy from week 26 to 52 (n = 74). Patients were followed-up for at least 2 years. Indexes including hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) seroconversion rate, sustained virologic response, transient elastography value, and histological scores were evaluated every 3 months until the end of the study. The rate of patients with HBsAg loss was defined as the primary endpoint criteria. RESULTS: At week 26, no patient achieved HBsAg seroconversion in either group. At week 52, one patient in the monotherapy group was HBsAg-negative but there was none in the combination therapy group. The monotherapy group showed significantly better liver function recovery results than the combination therapy group. At week 78, one patient in the combination group had HBsAg seroconverted. At week 104, only three patients in the combination therapy group were HBsAg-negative compared with one patient in monotherapy. The mean alanine aminotransferase and aspartate aminotransferase levels and transient elastography values decreased significantly compared with baseline. Both groups showed a favorable decrease in alpha-fetoprotein (monotherapy: 4.5 [2.8, 7.1] vs. 2.2 [1.8, 3.1] ng/mL, P < 0.001; combination therapy: 5.7 [3.0, 18.8] vs. 3.2 [2.0, 4.3] ng/mL, P < 0.001) and an improved result of liver biopsy examination scores. The combination group showed a better improvement in histology compared with the monotherapy group (mean transient elastography value 6.6 [4.9, 9.8] vs. 7.8 [5.4, 11.1] kPa, P = 0.028). But there was no significant difference in HBsAg conversion rate (1.8% [1/56] vs. 4.1% [3/73], P = 0.809) and HBeAg conversion rate (12.5% [7/56] vs. 11.0% [8/73], P = 0.787), as well as HBV-DNA, sustained virologic response (93.2% vs. 98.5%, P = 0.150) between the two groups. CONCLUSIONS: Both therapies supported liver function recovery and histology improvement. Combination therapy did not show better anti-viral efficacy in HBsAg or HBeAg seroconversion compared with monotherapy. However, combination therapy played a more positive role in reversing hepatic fibrosis compared with monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02849132; https://clinicaltrials.gov/ct2/show/NCT02849132.

Clinical Features of COVID-19-Related Liver Functional Abnormality.

BACKGROUND & AIMS: Some patients with SARS-CoV-2 infection have abnormal liver function. We aimed to clarify the features of COVID-19-related liver damage to provide references for clinical treatment. METHODS: We performed a retrospective, single-center study of 148 consecutive patients with confirmed COVID-19 (73 female, 75 male; mean age, 50 years) at the Shanghai Public Health Clinical Center from January 20 through January 31, 2020. Patient outcomes were followed until February 19, 2020. Patients were analyzed for clinical features, laboratory parameters (including liver function tests), medications, and length of hospital stay. Abnormal liver function was defined as increased levels of alanine and aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, and total bilirubin. RESULTS: Fifty-five patients (37.2%) had abnormal liver function at hospital admission; 14.5% of these patients had high fever (14.5%), compared with 4.3% of patients with normal liver function (P = .027). Patients with abnormal liver function were more likely to be male, and had higher levels of procalcitonin and C-reactive protein. There was no statistical difference between groups in medications taken before hospitalization; a significantly higher proportion of patients with abnormal liver function (57.8%) had received lopinavir/ritonavir after admission compared to patients with normal liver function (31.3%). Patients with abnormal liver function had longer mean hospital stays (15.09 ± 4.79 days) than patients with normal liver function (12.76 ± 4.14 days) (P = .021). CONCLUSIONS: More than one third of patients admitted to the hospital with SARS-CoV-2 infection have abnormal liver function, and this is associated with longer hospital stay. A significantly higher proportion of patients with abnormal liver function had received lopinavir/ritonavir after admission; these drugs should be given with caution.