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Background Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). Methods This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18–59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). Findings Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 μg group, 13 [65%] of 20 in the 10 μg group, 17 [85%] of 20 in the 15 μg group, 19 [95%] of 20 in the 20 μg group, 16 [100%] of 16 in the 25 μg group; p

Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients.We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death.The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission.During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).

Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ∼1%-2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post-mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9)-specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission.

Background & Aims Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. Methods Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. Results In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups ( p >0.05). Conclusions Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation.

To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined.Median HBsAg titers were different in each phase of CHB (P0.001): IT (4.85 log10 IU/mL), IC (4.36 log10 IU/mL), ENH (2.95 log10 IU/mL), LR (3.18 log10 IU/mL) and LC (2.69 log10 IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P0.001). No correlation between serum HBsAg level and ALT/AST was observed.The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.

The 2009 pandemic H1N1 (pH1N1) influenza showed that relatively young adults accounted for the highest rates of hospital admission and death. In preparation for pH1N1, the aim of the study is to identify factors associated with the mortality of patients with 2009 pH1N1 infection, especially for young patients without chronic medical conditions.Retrospective observational study of 2151 severe or critical adult cases (≥ 14 years old) admitted to a hospital with pH1N1 influenza from September 1, 2009 to December 31, 2009 from 426 hospitals of 27 Chinese provinces. A confirmed case was a person whose pH1N1 virus infection was verified by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR). Severe and critical cases were defined according to the H1N1 2009 Clinical guidelines (Third Edition, 2009) released by the Ministry of Health of China.Among the 2151 patients, the mean age was 34.0 years. Two hundred and ninty-three (13.6%) died during hospital stay. One thousand four hundred and forty-two patients (67.0%) had no comorbidities and 189 (13.1%) of them died. Pregnancy (OR 8.03), pneumonia (OR 8.91), dyspnea (OR 3.95), central nervous system (CNS) symptom (OR 1.55), higher APACHE (Acute Physiology and Chronic Health Evaluation) II score (OR 1.06), Alanine aminotransferase (ALT) (OR 1.002), and the lactate dehydrogenase (LDH) level (OR 1.001) were independent risk factors for death among adults without chronic medical conditions. Higher APACHE II score (OR 1.08) and age (OR 1.06) were independent risk factors for death among adults with respiratory diseases. A multivariate analysis showed an association between mortality and CNS symptoms (OR 2.66), higher APACHE II score (OR 1.03), ALT (OR 1.006), and LDH level (OR 1.002) in patients with cardiovascular diseases. Dyspnea (OR 11.32) was an independent risk factor for patient death in patients with diabetes mellitus.Clinical knowledge of identified prognostic factors for mortality may aid in the management of adult influenza infection.

Liver cirrhosis is the fatal consequence of chronic hepatitis, making early diagnosis of liver cirrhosis critical. Liver biopsy is still the standard diagnostic method for liver cirrhosis, although its use in a broad population with alcoholism or hepatitis B virus (HBV) infection remains difficult. In this study, we used a metabonomic approach to detect potential biomarkers for early diagnosis of liver cirrhosis.Serum specimens were collected prospectively from normal control subjects (n = 22) and patients with alcoholic cirrhosis (n = 18) or HBV-induced cirrhosis (n = 19). The serum metabonome was analyzed using ultraperformance liquid chromatography (LC)/time-of-flight mass spectrometry (MS) integrated with chemometrics. The acquired LC-MS data were normalized and processed using principal component analysis (PCA) and partial least squares discrimination analysis (PLS-DA).Significant differences in the metabonomics among the three groups were observed. Lysophosphatidyl cholines (LPCs) (LPC C16:0, LPC C18:0, LPC C18:2, LPC C18:3, LPC C20:3, LPC C20:5) were decreased in the serum of patients with hepatic cirrhosis, whereas bile acids (glycocholic acid, glycochenodeoxycholic acid), hypoxanthine, and stearamide were increased in the serum of patients with hepatic cirrhosis. These metabolites are considered "common" biomarkers for hepatic cirrhosis. Oleamide and myristamide were increased in the serum of patients with alcoholic cirrhosis but decreased in those with HBV-induced cirrhosis. These could be specific biomarkers for differential diagnosis between alcohol- and HBV-induced hepatic cirrhosis.There are significant metabonomic differences between alcohol- and HBV-induced liver cirrhosis. Metabonomics is a top-down systems biology tool for conducting research on clinical problems.

Sepsis due to Enterobacter aerogenes (E. aerogenes) is rare after liver transplantation but is also a serious infection that may cause liver abscess. The purpose of this case report is to relate an unusual presentation of liver transplantation to show how successive treatment can be an appropriate option in septic patients after liver transplantation.We report on a patient with liver transplantation who developed sepsis due to extended spectrum beta-lactamases and AmpC-producing E. aerogenes.A 39-year-old man had a biliary fistula and then was found to have multiple liver abscesses through abdominal ultrasound and an abdominal computed tomography scan, and carbapenem-sensitive E. aerogenes infection was confirmed. The patient was not successfully treated with conservative treatment consisting of intravenous carbapenems, percutaneous transhepatic cholangial drainage, and biliary stent placement by endoscopic retrograde cholangiopancreatography, so a second liver transplantation followed. Carbapenem-resistant E. aerogenes was detected in bile and blood after a five-week course of carbapenem therapy. The patient developed septic shock and multiple organ dysfunction syndrome.We first report an unusual case of sepsis caused by E. aerogenes after liver transplantation in China. Carbapenem-resistant E. aerogenes finally leads to uncontrolled sepsis with current antibiotics. We hypothesize that the infection developed as a result of biliary fistula and predisposing immunosuppressive agent therapy. Further research is progressing on the aspect of immunomodulation therapy.

The prognosis of tuberculous meningitis (TBM) is linked to early diagnosis and prescription of adequate treatment.To evaluate the efficacy of the rpoB nested polymerase chain reaction (PCR) and sequencing assay to detect and identify Mycobacterium tuberculosis complex (MTC) strains and strains resistant to rifampicin (RMP) in cerebrospinal fluid specimens (CSF) from patients with highly suspected TBM.Retrospective blinded hospital-based study.rpoB nested PCR and sequencing assay detected MTC in 31/36 CSF specimens from 16 patients with clinically suspected TBM. All of the control CSF specimens from 25 patients with non-TBM showed negative results. One of the 16 patients had a mutation at codon C526G as compared to the rpoB sequences in GenBank. This corresponds to a diagnostic sensitivity of 86% (95%CI 71-95) and a specificity of 100% (95%CI 86-100).Our results suggest that rpoB nested PCR and sequencing assay can detect MTC and simultaneously determine its RMP susceptibility in CSF from patients with highly suspected TBM.

To investigate the prevalence and associated risk factors of bacterial translocation (BT) in patients with cirrhosis after liver transplantation and analyze the effect of BT on bacterial infection after the surgery.Mesenteric lymph nodes (MLN), portal vein blood, and peripheral blood were collected during the liver transplantation for microbiological culture from 78 patients with cirrhosis. And meanwhile, all related clinical data were analyzed to investigate the risk factors of BT and its relationship with post-liver transplantation infections.BT was occurred in 8 of 78 cirrhotic patients (10.3%) and positive-rate of MLN culture was 5/8. Gram-negative aerobic bacillus was the main causative bacterium of BT (5/9), followed by Gram-positive aerobic enterococcus (22.2%, 2/9). Total bilirubin level in patients with BT was significantly higher than that in patients without BT.It suggests that hyperbilirubinemia is the only risk factor for BT, and BT is associated with an increased infectious rate after liver transplantation.

The pathogenesis of severe hepatitis B remains unknown. Reports have indicated that hepatitis B virus (HBV) mutations are important factors in the pathogenesis of this disease. This study was to investigate the genetic heterogeneity of HBV strains from serum samples of patients with fulminant hepatitis B.Full-length HBV genomes from 4 patients with severe hepatitis B were cloned and sequenced to observe mutations in every open reading-frame (ORF). Serum samples of another 25 patients with severe hepatitis B, 30 patients with chronic hepatitis B, and 25 HBV carriers were collected for sequencing and comparison of mutations in preS2, preC and core promoter regions.Of 4 HBV full-length genome sequences, 3 had a G to A mutation at nucleotide A1896 in the preC region and 1 had double mutations of T1762-A1764 in the core promoter region. The 4 sequences showed mutations in the known B or T cell epitopes of the preS2 and C regions. For the other 3 groups, more mutations were seen in the preS2 region in the HBV isolates from the patients with severe hepatitis B than those from the patients with chronic hepatitis B and HBV carriers (P0.01). There was a significant difference of mutations in the T cell epitope region of preS2 between the patients with severe hepatitis B and those with chronic hepatitis B or HBV carriers (P0.01). In the preC and core promoter regions, the mutation frequencies of T1653 and C1753 were 48.0% and 24.0% respectively in the patients with severe hepatitis B, but none of these mutations were observed in the patients with chronic hepatitis B group or HBV carriers (P0.01). The mutation frequency of T1762-A1764 was 76.0% in the patients with severe hepatitis B, 40.0% in the patients with chronic hepatitis B (P0.01), and 16.0% in the HBV carriers (P0.01). There was a significant difference in A1896 mutation between the patients with severe hepatitis B and the patients with chronic hepatitis B (P0.05) or the HBV carriers (P0.05).Our observations suggest that the accumulation and persistence of high frequency mutations or complex mutations may be associated with the development and deterioration of HBV infection.

To study the association between hepatitis B virus (HBV) mutants and the pathogenesis of severe hepatitis B by full-length HBV genome.Serum samples from 10 severe hepatitis B patients were collected in our hospital. Serum HBV DNAs were extracted using DNA mini Kit, and amplified by LA Taq DNA polymerase to yield full-length HBV DNA. PCR products were isolated and cloned into vector pUCm-T, then transfected into DH-5 alpha cells. Positive clones were selected and checked by digestion, and full-length HBV DNAs were sequenced.4 cases were cloned into vector pUCm-T successfully and completed the full-length sequencing. Among them, 3 cases had a G to A mutation at nucleotide 1896 in pre-C region and 1 had a double mutation of T1762-A1764 in the core promoter region. Some amino acid changes occurred within the known CTL, B or T cell epitopes of the PrS2 and C regions.This method could serve to study the relationship between HBV genome and the pathogenesis of severe hepatitis B.

To evaluate the clinical efficacy and study the mechanism of combining plasma exchange and continuous veno-venous hemofiltration in treating patients with chronic severe viral hepatitis B in their mid- and late stages.94 patients suffering from chronic severe viral hepatitis B were divided into three groups. 29 patients were treated with plasma exchange plus continuous veno-venous hemofiltration (group A). 31 patients were treated with plasma exchange alone (group B). 34 patients received routine treatment (group C). The efficacy of treatment and survival rate of the three groups was investigated. Before and after artificial liver support system treatment the levels of cytokine were examined.In group A, hyponatremia improved, the levels of interleukin 8 (IL-8) obviously decreased, the level of IL-10 increased, 5 of the 10 patients in coma regained normal consciousness (50.0%) and their survival rate was 48.3%. In group B, hyponatremia did not change, the level of IL-8 and IL-10 did not change. 2 of 11 patients in coma regained normal consciousness (18.2%) while survival rate was 22.6%. In group C, 1 of 11 patients in coma regained normal consciousness (9.1%) while survival rate was 20.6%.It shows that plasma exchange with continuous veno-venous hemofiltration in treating patients with mid- and late stage chronic severe viral hepatitis B can increase the survival rate. IL-8 can be significantly removed, IL-10 significantly increased. This combined therapy is easy to practice, and should be used as an artificial liver support system.

To evaluate the efficacy of a hybrid artificial liver support system in the treatment of chronic severe hepatitis.The hybrid artificial liver support system (HALSS) consisted of a bioreactor containing more than 5 x 10(9) porcine hepatocytes and plasma exchange device. 15 patients with chronic severe viral hepatitis were treated with the hybrid system.All the patients experienced a reduction in symptoms, such as fatigue, abdominal distention or ascites. After each treatment serum total bilirubin decreased markedly (from 493.5 micromol/L+-139.8 micromol/L to 250.9 micromol/L+-91.3 micromol/L, t=8.695, P0.001), while prothrombin activity increased (from 24.5%+-8.4% to 30.6%+-6.3%, t=3.325, P0.01). There were 11 patients whose progress of hepatocytes necrosis stopped after HALSS treatment, and finally they recovered completely. Four patients died of their worsen conditions. No serious adverse events were noted in the 15 patients.HALSS is a reliable hepatic support device for chronic severe hepatitis.