Efficacy and Safety of Convalescence Plasma Therapy in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Background: The coronavirus disease 2019 (COVID-19) has outbroken into a global pandemic. The death rate for hospital patients varied between 11% and 15%. Although COVID-19 is extremely contagious and has a high fatality rate, the amount of knowledge available in the published literature and public sources is rapidly growing. The efficacy of convalescent plasma (CP) therapy for COVID-19 is controversial. Objective: This meta-analysis was designed to assess the efficacy of CP therapy for COVID-19 through a literature survey. Methods: Until August 30, 2021, a literature search was undertaken in Pubmed, Embase, Web of Science, Cochrane Central Register of Controlling Trials (Central), and China National Knowledge Infrastructure databases. The Risk Ratio (RR) and 95% confidence intervals (CIs) were pooled using a fixed or random effect model in dichotomous data. Mean difference (MD) and 95% confidence intervals (CIs) were pooled using a fixed or random effect model in continuous data. Studies with missing or unsuitable data were presented descriptively in the outcomes. Results: In total, thirteen randomized controlled trials (RCTs) were selected for the present meta-analysis, which included a total of 13232 participants. Our results revealed that the CP group has lower mortality compared to the control group, and there was a statistically significant difference (RR: 0.70, 95% CI: 0.55, 0.89, Z = 2.92, P = 0.004 < 0.01); other secondary outcomes such as the shortness of breath symptom improved significantly in CP group (RR:1.48, 95% CI: 1.13, 1.93, Z = 2.85, P = 0.004 < 0.01), as well as Interleukin-6 (IL-6) (MD: -4.46, 95% CI: -8.28, -0.63, Z = 2.28, P = 0.02 < 0.05) and Ferritin (MD: -447.68, 95% CI: -501.75, -393.6, Z = 16.23, P < 0.00001) are reduced significantly in CP group. However, there was no statistically significant change in the ventilator withdrawal rate, imaging results improvement, or days to hospital discharge. There was also no substantial difference in viral nucleic acid negative conversion rate and neutralizing antibody-positive conversion rate, as well as the incidence of adverse reactions. Conclusions: The safety and potential efficacy of convalescent plasma therapy offer a promising treatment strategy for COVID-19. CP therapy can reduce mortality and improve breath and inflammatory cytokines IL-6 and Ferritin in COVID-19 with no significant increase in adverse reactions. However, it does not affect improving virology indicators. In summary, more high-quality clinical trials are needed to verify the conclusion of the present study.

Establishment of a Stable Acute Drug-Induced Liver Injury Mouse Model by Sodium Cyclamate.

Objective: To establish a stable acute DILI mouse model and explore its possible pathogenesis. Methods: Mice were randomly divided into control, low-dose, middle-dose and high-dose sodium cyclamate groups. Mice in the model group were intraperitoneally injected with corresponding doses of sodium cyclamate, and in the control group intraperitoneally injected with 0.9% normal saline. The toxic effects of sodium cyclamate on liver, heart, kidney were evaluated by biochemical index level and histomorphologically observed. The expression of TNF-α and IL-1ß were measured by immunohistochemistry. Results: 1. The level of ALT in the low-dose and middle-dose groups at 24h, 72h, 120h and 168h were increased, also in the high-dose group at 24h, 72h and 120h. The level of AST in the low-dose group at 72h, 120h, 168h and in the middle-dose group at 168h were increased, also in the middle-dose and high-dose groups at 24h, 72h and 120h. The levels of CK, CK-MB and cTnT in the low-dose and middle-dose groups at 168h were increased, also in the high-dose group at 24h, 72h and 120h. 2. The damage of hepatocytes increased with the increase of sodium cyclamate dosage and treated time. 3. At 120h, the IOD/Area of TNF-α and IL-1ß positive expression increased in the liver tissues with the increase of the dosage. In the heart and kidney tissues, the IOD/Area of TNF-α and IL-1ß positive expression in the high-dose group increased significantly. In the kidney tissues, the IOD/Area of IL-1ß positive expression in the middle-dose group increased significantly. Conclusion: Sodium cyclamate-induced acute DILI mouse model can be established by intraperitoneal injection of 6000 mg/kg/day sodium cyclamate for 5 days successfully. The toxicity of sodium cyclamate to liver showed a dose-response and time-response relationship. Sodium cyclamate induced liver, heart and kidney injury closely related to the inflammatory response mediated by TNF-α and IL-1ß.

miR-3 Encoded by Hepatitis B Virus Downregulates PTEN Protein Expression and Promotes Cell Proliferation.

PURPOSE: Chronic hepatitis B virus (HBV) infection is a key determinant of hepatocellular carcinoma (HCC). However, the mechanism by which HBV contributes to the development of HCC remains to be further explored. HBV-encoded miR-3 (HBV-miR-3) is a newly discovered microRNA that can affect the replication of HBV, but its influence on host genes is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is expressed at low levels in most cancer cells. How HBV-miR-3 acts on PTEN to induce tumorigenesis has not been clarified. MATERIALS AND METHODS: PTEN protein expression was evaluated in HBV-miR-3-transfected cells and HBV-related liver cancer and paracancerous tissues. A luciferase reporter assay was employed to identify the HBV-miR-3 binding site on the 3'-untranslated region (3'-UTR) of PTEN. Cell apoptosis was assessed by flow cytometry. Cell proliferation was evaluated by colony formation assays. Transwell assays were used to detect cancer cell invasion. RESULTS: HBV-miR-3 was identified only in HBV-replicating HCC cells and HBV-infected patients. HBV-miR-3 expression in liver cancer tissues was higher than that in paracancerous tissues, and the corresponding PTEN expression was significantly decreased. Wild-type HBV-miR-3 bound to the 3'-UTR of PTEN and downregulated its protein expression in a dose-dependent manner. Moreover, the inhibition of HBV-miR-3 rescued PTEN protein expression. Furthermore, HBV-miR-3 reduced liver cancer cell apoptosis, enhanced cell invasion, and promoted cell proliferation. CONCLUSION: HBV-miR-3 binds to the 3'-UTR of PTEN mRNA and downregulates PTEN protein expression, thereby reducing cell apoptosis and enhancing cell invasion and proliferation. These results indicate that HBV-miR-3 contributes to the development of HBV-related HCC and may be a therapeutic target for this cancer.

A case presentation for positive SARS-CoV-2 RNA recurrence in a patient with a history of type 2 diabetes that had recovered from severe COVID-19.

Coronavirus disease 2019 (COVID-19) is considered to be spread primarily by people who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss a patient with severe COVID-19 and a history of type 2 diabetes who had a recurrence of positive SARS-CoV-2 ribonucleic acid (RNA) after recovering. The patient was initially discharged after two consecutive negative SARS-CoV-2 RNA tests and partially absorbed bilateral lesions on chest computed tomography (CT). However, at his first follow-up, reverse transcription-polymerase chain reaction (RT-PCR) assay with an oropharyngeal swab sample was positive for SARS-CoV-2. Despite this, he displayed no obvious clinical symptoms and improved chest CT. The patient was prescribed anti-viral medication. Eight consecutive RT-PCR assays on oropharyngeal swab specimens were conducted after he was re-admitted to our hospital. The results tested positive on the 12th, 14th, 19th, 23rd and 26th of March and negative on the 28th of March, and 6th and 12th of April. After his second discharge, he has tested negative for 5 weeks. This case highlights the importance of active surveillance of SARS-CoV-2 RNA during the follow-up period so that an infectivity assessment can be made.

Early hepatitis B viral DNA clearance predicts treatment response at week 96.

AIM: To investigate whether hepatitis viral DNA load at 24 wk of treatment predicts response at 96 wk in patients with chronic hepatitis B. METHODS: A total of 172 hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B patients who received initial treatment at 16 tertiary hospitals in Hunan Province, China were enrolled in this study. All patients received conventional doses of lamivudine and adefovir dipivoxil, telbivudine, entecavir dispersible tablets, or entecavir tablets for 96 wk. Patients who used other antiviral drugs or antitumor and immune regulation therapy were excluded. Patients were stratified into three groups according to their viral DNA load at 24 wk: < 10 IU/mL (group 1), 10-103 IU/mL (group 2), and > 103 IU/mL (group 3). Correlations of 24-wk DNA load with HBeAg negative status and HBeAg seroconversion at 96 wk were analyzed. Receiver operating characteristic curve analysis was used to test the predictive value of the HBV DNA load at 24 wk for long-term response. RESULTS: The rates of conversion to HBeAg negative status and HBeAg seroconversion rates were 53.7% and 51.9%, respectively, in group 1; 35.21% and 32.39% in group 2; and 6.38% and 6.38% in group 3. The receiver operating characteristic curves for the three subgroups revealed that the lowest DNA load (< 10 IU/mL) was better correlated with response at 96 wk than a higher DNA load (10-103 IU/mL). Nested PCR was used for amplifying and sequencing viral DNA in patients with a viral DNA load > 200 IU/mL at 96 wk; resistance mutations involving different loci were present in 26 patients, and three of these patients had a viral DNA load 10-103 IU/mL at 96 wk. CONCLUSION: Hepatitis B viral DNA load at 24 wk of antiviral treatment in patients with chronic hepatitis B is a predictor of the viral load and response rate at 96 wk.

[Polymorphism of hepatitis B virus x gene in hepatocellular carcinoma patients and the biological effects of HBx gene with deletion varations on QSG7701 cells].

OBJECTIVE: To investigate whether there were particular HBx gene mutations associated with hepatocellular carcinoma (HCC) development in patients. METHODS: The HBx genes were examined in 51 paraffin-embedded tumor tissue samples from patients with HCC and 25 serum samples from HBV carriers from southern China by nested polymerase chain reaction (PCR), single-stranded conformational polymorphism analysis, heteroduplex analysis and DNA sequencing. The HBx genes with deletion variations (HBx-d382, HBx-d431) from tumor tissues were cloned and transfected into QSG7701 cells. Then, the biological characteristics of the transfected cells were analyzed in nude mice by MTT assay, soft agar colony formation assay, flow cytometry and xenografting. RESULTS: Deletion mutation and point mutation were found in the HBx genes of HCC tumor tissues, and there were some differences between the HBx gene mutations in genotype B and those in genotype C. More mutations were found in genotype C than those in genotype B (t=-2.522, P < 0.05), but the deletion variations (HBx-d382, HBx-d431) were detected in genotype B HBV from HCC liver tissues. The HBx genes with deletion variations (HBx-d382, HBx-d431) were recombinant with pcDNA3 and transfected into QSG7701 cell lines successfully, which established four permanent transfected QSG7701 cell lines, including pcDNA3/HBx-d382/QSG7701, pcDNA3/HBx-d431/QSG7701, pcDNA3/HBx/QSG7701, and pcDNA3/QSG7701. pcDNA3/HBx-d382/QSG7701 and pcDNA3/HBx-d431/QSG7701 grew faster and had more potential colony formative activity than those of pcDNA3/QSG7701. Moreover, pcDNA3/HBx-d382/QSG7701 and pcDNA3/HBx-431/QSG7701 cells inoculated in nude mice produced tumors more rapidly than those of pcDNA3/HBx/QSG7701, and pcDNA3/QSG7701. The volumes of the tumors in nude mice were also obviously larger in pcDNA3/HBx-d382 and pcDNA3/HBx-d431 groups than those in pcDNA3/HBx/QSG7701 and pcDNA3/QSG7701 groups. CONCLUSION: Our results suggest that HBx gene mutations occur frequently in HCC tissues, and the deletion at nt382-400 of the HBx gene might play a role in carcinogenesis of HCC in southern China.

Polymorphism analyses of hepatitis B virus X gene in hepatocellular carcinoma patients from southern China.

Chronic hepatitis B virus (HBV) infection is one of the major causes of hepatocellular carcinoma (HCC), and the HBV X (HBx) gene plays a critical role in the molecular pathogenesis of HBV-related HCC. We have investigated whether there are particular HBx gene mutations associated with HCC in patients from southern China. The HBx gene was examined in 51 paraffin-embedded tumor tissue samples from patients with HCC and 25 serum samples from the HBV carrier by nested polymerase chain reaction (PCR), single-stranded conformational polymorphism and heteroduplex analysis. The HBx genes with potentially important mutations from tumor tissue samples were cloned, sequenced and aligned with the published HBx gene sequence. HBV genotypes in tumor tissue samples were analyzed by nested PCR. Analyses of HBx gene polymorphism showed that 31.3% of HBx gene fragments in tumor tissue samples had a special pattern. A common deletion at nt 382-400 of the HBx gene accompanied by 29 point mutations was detected in four randomly selected tumor tissue samples with this pattern which caused a frame-shift in the HBx open reading frame with a new stop codon at nt 1818, resulting in an HBx polypeptide chain truncated at the C end in these cases. Among the four randomly selected samples, three were HBV genotype B, and one was not detected by our present assay. In another tumor tissue sample, amplification of the full-length HBx gene yielded a shorter fragment. Sequencing of this fragment revealed a 264 bp deletion between nt 1577 and 1840 of the HBV gene. These results suggest that HBx gene mutation occurs frequently in HCC samples, and the deletion at nt 382-400 of the HBx gene might play a role in carcinogenesis of HCC in southern China.