Development of novel prognostic models based on dynamic changes in risk factors for hepatitis B associated acute-on-chronic liver failure:a 10-year retrospective study.

Background/Aims: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality, and early prediction is critical to reduce the deaths of ACLF patients. To date, however, the prognostic accuracy of current models for ACLF is unsatisfactory, particularly, in patients with hepatitis B virus (HBV) infection. This study aims to develop novel prognostic models based on the dynamic changes in variables to predict the short-term mortality of HBV-associated ACLF (HBV-ACLF). Methods: A retrospective cohort study was conducted, with the population comprised in whom ACLF was confirmed.319 patients were enrolled and their clinical data were collected on Days 1 and 7 following hospital admission. Univariate and multivariate analyses were performed to identify risk factors for 28 and 90-day mortality. The dynamic alterations in the risk factors were further analyzed, and Days 1 and 7 prognostic models were constructed. Receiver operating characteristic (ROC) analysis were used to identify and compared the predictors of prognosis among our model. Results: Univariate and multivariate analyses revealed significant risk factors at Days 1 and 7, which when combined with the clinically important parameters, were used to establish the Days 1 and 7 prognostic models. For 28-day mortality, the predictive accuracy of the Day 1 prognostic model was significantly higher than that of the albumin-bilirubin (ALBI) model. For 90-day mortality, the predictive accuracy of the Days 1 and 7 prognostic models was significantly higher than that of the Model of End-Stage Liver Disease (MELD), MELD-sodium (MELD-Na), and ALBI prognostic models. Conclusions: The prognostic models established in this study were superior to the existing prognostic scoring systems to accurately predict short-term mortality, and therefore, could be potential novel prognostic tools for HBV-ACLF.

Safety and efficacy of lentinan nasal drops in patients infected with the variant of COVID-19: a randomized, placebo-controlled trial.

Objective: Lentinan has antiviral, anti-tumor, immunomodulatory, stimulating interferon production, and other pharmacological effects. Previous animal experiments have shown that lentinan nasal drops can assist [Corona Virus Disease 2019) COVID-19] vaccine to induce high levels of neutralizing antibodies and can effectively resist the invasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to evaluate the safety and efficacy of lentinan nasal drops in patients infected with Omicron (SARS-CoV-2 variant) through a dose-escalation study and a placebo-controlled trial. Methods: A randomized, placebo-controlled trial. The study was divided into two phases: Phase I: a dose escalation trial in which 24 COVID-19 patients were enrolled, that is, 12 in the escalation dose group (50, 75, and 100 µg/day) and 12 in the standard treatment group. The aim was to evaluate the safety and tolerance of lentinan nasal drops. The second stage was a placebo-controlled study. The optimal dose group of the first stage was used as the therapeutic dose, and the sample size was expanded to verify the anti-COVID-19 efficacy of lentinan nasal drops. Results: In the dose-increasing study, lentinan nasal drops showed good safety, and no serious adverse reactions occurred. The virus shedding time of the 100 µg dose group was significantly shorter than that in the control group (7.75 ± 1.71 VS 13.41 ± 3.8 days) (p = 0.01), and the 100 µg/day lentinan nasal drops were tolerated well. The results of the placebo-controlled study showed that compared with that in the placebo group, the time for COVID-19 antigen to turn negative was significantly shorter in the 100 µg lentinan nasal drop group (p = 0.0298), but no significant difference was observed in symptom improvement between the two groups. In the placebo-controlled study, two patients experienced mild nasal discomfort with nasal drops, but the symptoms relieved themselves. Conclusion: Lentinan nasal drops are tolerated well and can shorten the time of virus clearance.

Efficacy and safety of molnupiravir in patients with Omicron variant vaccine breakthrough COVID-19 infection: a randomized, controlled trial.

Introduction: Randomized, controlled trials of molnupiravir in real-world use during the Omicron wave are scarce. The frequency of hospitalization and death is low, so further research is needed to confirm the virological efficacy of molnupiravir. Methods: A single-center, randomized, controlled clinical trial was conducted, and 111 hospitalized coronavirus disease 2019 (COVID-19) patients were randomly assigned at a ratio of 1:1. Fifty-three patients in the molnupiravir group were administered 800 mg of molnupiravir twice daily for 5 days in addition to the standard therapy, and 58 patients in the control group only received the standard therapy in accordance with local guidelines. The antiviral effect and adverse events were evaluated during the follow-up. Results: The median viral clearance time in the molnupiravir group was significantly shorter than that in the control group (p = 0.003). Furthermore, patients who started molnupiravir therapy within 3 days had significantly shorter viral clearance time than the controls (p = 0.003). In the vaccinated subgroup, molnupiravir therapy was also associated with a shorter viral clearance time (p = 0.003). A total of three adverse events, which were minor, were reported in the molnupiravir group. One of the patients had mild liver function abnormalities, and all of them were resolved without intervention. However, the remission time was similar between the two tested groups. Conclusion: Molnupiravir exhibited good viral replication inhibitor efficacy in patients with Omicron variant vaccine breakthrough COVID-19 infection. Clinical Trial Registration: [https://www.chictr.org.cn/], identifier [ChiCTR2200059796].

Disease Progression of Hospitalized Elderly Patients with Omicron BA.2 Treated with Molnupiravir.

INTRODUCTION: The efficacy of molnupiravir (MLN) on Omicron sublineages is limited. We investigated the effectiveness of MLN in older adults diagnosed with Omicron BA.2. METHODS: Data of elderly COVID-19 patients (over 60 years) admitted to Chinghai Hospital (Shanghai, China) from 26 March to 31 May 2022 were reviewed. Study outcomes were a composite of undetectable viral load (VL) and disease progression [all-cause mortality, initiation of oxygen supply through high-flow device or invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission] and their individual outcomes. RESULTS: A total of 42 elderly patients were enrolled: 26 of them received MLN, 17 (40.5%) were males, the median age was 84 years, and 12 were fully vaccinated (31.0%). Among these elderly COVID-19 patients, five (11.90%) experienced obvious dyspnea or were transferred to ICU [three MLN users (11.5%) versus two non-MLN users (12.5%)]. Compared with no MLN use, MLN use was associated with rapid undetectable VL. At day 10, MLN users achieved significantly greater undetectable VL than non-MLN users. Adjusted analysis showed that elderly patients who received MLN were 7.584 times more likely to achieve undetectable VL at day 10 than non-MLN users. Overall, elderly patients experienced a median hospital stay of 13 days. Compared with patients receiving standard care (SC), the median hospital stay of MLN users was reduced by 2.5 days. CONCLUSION: Early initiation of MLN in elderly COVID-19 was associated with fast undetectable VL and short hospital stay.

Preparation of Galactosyl Nanoparticles and Their Targeting Efficiency to Hepatocellular Carcinoma.

Liver diseases seriously endanger people's physical health, especially liver cancer, and its morbidity and mortality have increased year by year. The reason why liver cancer is difficult to cure is that in addition to the low lethality of cancer drugs to cancer cells, another important factor is that the drugs do not have liver targeting, and there is no way to efficiently deliver anti-cancer drugs to the liver lesions. Hepatocytes can specifically recognize galactose, therefore the galactosyl liver-targeted drug carrier can deliver the drug to the liver in a targeted manner, so that the drug can be directed to the liver, reduce the dose and times of drug administration, reduce toxic side effects, and reduce the adverse reactions of patients, which is of great significance for the treatment of liver cancer. In this thesis, paclitaxel long-circulating nano-liposomes targeting liver cancer constructed with galactose as raw materials can improve the pharmacokinetics and tissue distribution of traditional formulations of paclitaxel, and enhance the safety and tumor suppressive effect of paclitaxel in vivo.

Clinical prediction for outcomes of patients with acute-on-chronic liver failure associated with HBV infection: A new model establishment.

OBJECTIVE: The acute-on-chronic liver failure associated with hepatitis B virus (HBV-ACLF) was a type of clinical syndrome with rapid deterioration of liver function. It was characterized by short-term elevated bilirubin, ascites, prolonged clotting time, hepatic encephalopathy, organ failures, and high short-term mortality. It was important to predict and evaluate the disease early. This study intended to comprehensively analyze the prognostic factors of patients with ACLF associated with HBV DNA infection through clinical manifestations and laboratory tests, and to establish a corresponding prediction and evaluation model for further clinical guidance. METHODS: A total of 220 patients were first diagnosed with HBV-ACLF and admitted to and treated at the Department of Infectious Diseases of the First Affiliated Changhai Hospital of the Second Military Medical University from 2009 to 2018. These patients' records were collected and divided into two groups: (1) 120 patients who were improved and discharged were classified as good prognosis group and (2) 100 patients who died or underwent liver transplantation were classified as poor prognosis group. By analyzing baseline characteristics and clinical indicators of the two groups, the main potential factors affecting prognosis were identified and the corresponding prognostic evaluation model was established. This model's advantages and disadvantages were compared with classic prognostic scoring systems. RESULTS: The proportion of ascites and the proportion of hepatic encephalopathy of poor prognosis group were significantly higher than those of good prognosis group. The total bilirubin, creatinine, white blood cell count, and NEU (%) levels of poor prognosis group were significantly higher than those of good prognosis group, and the international normalized ratio, albumin (ALB), alanine aminotransferase, Na, Cl, RBC, and PLT levels of poor prognosis group were significantly lower than those of good prognosis group. A new prediction model LR(p) = 1/(1 + e -Z ) was established, where z = 10.0127 + 0.3687 × NEUT (%) - 0.0082 × PLT + 1.8157 × hepatic encephalopathy. The area under receiver operating characteristic (ROC) curve was 0.89, specificity was 80.83%, and sensitivity was 81%. The newly established prognostic model was compared with other three scoring systems including model for end-stage liver disease (MELD), MELD-Na, and ALBI scores. The results showed that the specificity, sensitivity, and area under the ROC curve of the newly established model were significantly higher than the other three scoring systems. CONCLUSION: Hepatic encephalopathy, NEU (%), and PLT levels were independent risk factors for predicting the prognosis of HBV-ACLF. The new prediction model LR(p) had better prediction accuracy than the other three scoring models of MELD, MELD-Na, and ALBI and could more accurately assess the prognosis of HBV-ACLF, but in the later stage, it was still necessary to expand the sample size for verification.

Hepatocellular carcinoma with worsened hypoglycemia after transarterial chemoembolization: a case report and systematic review.

Non-islet cell tumor hypoglycemia (NICTH) is an extremely uncommon and serious complication of hepatocellular carcinoma (HCC). Here, we reported a case of a 47-year-old male patient with moderate to poorly differentiated HCC complicated by hypoglycemia that worsened after transarterial chemoembolization (TACE). The patient was admitted into The First Affiliated Hospital of Naval Medical University due to fatigue, nausea, dizziness and passage of tea colored urine. He was diagnosed with NICTH induced by HCC according to CT scanning and laboratory tests. TACE was used as the primary therapy but the hypoglycemia worsened afterward. Then the patient received a liver transplantation as a possible radical cure and hypoglycemia was resolved. We systematically review the management of hypoglycemia caused by HCC and the results show that patients undergoing treatment that mainly alleviate tumor burdens obtained a significantly higher response rate than patients undergoing therapies mainly regulating biologic functions (50.0% vs 27.3%). Cytoreductive surgery, TACE and radiotherapy which aimed to alleviate tumor burdens are effective therapies have great potential, but the risk of hypoglycemic deterioration requires particular attention when using these treatments, especially with TACE.

Changes in circulating Foxp3(+) regulatory T cells and interleukin-17-producing T helper cells during HBV-related acute-on-chronic liver failure.

AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression. METHODS: We measured the expression of seven Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 18 ACHBLF, 18 chronic hepatitis B (CHB) disease controls and 10 healthy controls (HCs) by real-time quantitative PCR and enzyme linked immunosorbent assay. Peripheral Th17 and Treg cell frequencies were analyzed by flow cytometry. RESULTS: From the onset of ACHBLF, patients presented with a conductive Th17 differentiation cytokine environment accompanied by high Th17 frequency and high serum IL-17 levels, which were sustained throughout the disease course. The Treg-related cytokine IL-2 and Foxp3 were also up-regulated from disease onset, and Foxp3 gene expression showed a gradually increasing trend during ACHBLF. The circular phenotype of Treg and Th17 cells showed changes from the onset of ACHGLF. At disease onset, Th17 frequency increased significantly compared with both CHB and HCs, but Treg cell frequency decreased significantly compared with CHB. During the ACHBLF event, Th17 frequency remained higher compared with HCs, but decreased sharply from the peak point to the recovery point; Treg cell frequency increased gradually during the ACHBLF event. Treg and Th17 cell counts correlated with ACHBLF development; in all patients, serum IL-17 levels significantly correlated with patient serum ALT levels. In survivors, Th17 frequency at the onset point and the Treg to Th17 ratio at the peak point correlated with the patient's model for end stage liver disease (MELD) plus sodium (MELD-Na) score. The Treg to Th17 ratio and the Th17 frequency at onset were significant predictors of patient survival. Low Treg/Th17 cell ratios at the onset predicted poor survival. Survivors exhibited an initial decrease in the circulating Treg/Th17 ratio from the onset to the peak time, and subsequently displayed a continuous increase. CONCLUSION: Treg and Th17 cells showed changes in genes, protein levels and T cell phenotypes during ACHBLF events. An increased Treg/Th17 ratio was associated with the survival of ACHBLF patients.

Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B.

AIM: To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy. METHODS: Fifty-two hepatitis B envelope antigen (HBeAg) positive CHB patients were enrolled and divided equally into two groups. One group received telbivudine (LDT, 600 mg/d), and the other group received lamivudine (LAM, 100 mg/d). Clinical, virological and immunological parameters were assessed at the baseline and at 4, 12, 24, 36 and 48 wk. RESULTS: Both groups achieved significant hepatitis B virus (HBV) replication inhibition and alanine aminotransferase normalization at 48 wk. At the baseline, compared to healthy controls, CHB patients had a lower circulating CD8 T cell frequency (29.44% ± 11.55% vs 37.17% ± 7.30%, P = 0.03) and higher frequencies of programmed death 1 positive CD8 T cells (PD-1+ CD8 T) (16.48% ± 10.82% vs 7.02% ± 3.62%, P = 0.0001) and CD4+ CD25+ FoxP3+ T regulatory cells (Tregs) (23.64% ± 9.38% vs 13.60% ± 6.06%, P = 0.001). On therapy, at the beginning 24 wk with the levels of hepatitis B virus deoxyribonucleic acid (HBV DNA) and HBeAg declining, the frequencies of PD-1+ CD8 T cells and Treg cells gradually and significantly declined at 12 and 24 wk in both therapy groups. At treatment week 4, patients treated with LDT had a lower frequency of PD-1+ CD8 T cells compared to patients treated with LAM (10.08% ± 6.83% vs 20.51% ± 20.96%, P = 0.02). The frequency of PD-1+ CD8 T cells in all of the CHB patients was significantly correlated with both the HBV DNA level (r = 0.45, P = 0.01) and HBeAg level (r = 0.47, P = 0.01) at treatment week 24, but the frequency of Treg cells was only significantly correlated with the HBeAg level (r = 0.44,P = 0.02). Furthermore, the ability of CD8 T cells to secrete pro-inflammatory cytokines was partially restored after 24 wk of therapy. CONCLUSION: NA-mediated HBV suppression could down-regulate the production of negative regulators of host immunity during the first 24 wk of therapy and could partially restore the ability of CD8 T cells to secrete pro-inflammatory cytokines. This immune modulating response may be correlated with the levels of both HBV DNA and HBeAg.