INTRODUCTION:Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS:The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS:In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4-11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION:NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

BACKGROUND:The prevalence of chronic kidney disease (CKD), defined as a glomerular filtration rate (GFR) of <60 mL/min/1.73 m2 for >3 months, is rising in the global population. OBJECTIVE:To assess the global prevalence of CKD in cirrhosis and how it impacts the prognosis of these patients. DESIGN:The Chronic Liver Disease Evolution and Registry for Events and Decompensation consortium prospectively enrolled non-electively admitted cirrhosis patients from 127 sites globally, each with up to 100 patients. Data collected were demographics, comorbid conditions, cirrhosis history, hospital course and patient outcomes. Patients were divided into those with (CKD+) and without CKD (CKD-) and compared. We also compared patients from different World Bank income strata. RESULTS:Of 7040 inpatients enrolled, the global prevalence of CKD was 18.17%, with the highest prevalence observed in high-income countries (HICs), which paralleled their higher prevalence of metabolic syndrome. CKD+ patients had lower median enrolment GFR (32 (21, 44) mL/min/1.73 m2) when compared with CKD- patients (88 (63, 117) mL/min/1.73 m2, p<0.0001), associated with a more complex history of cirrhosis complications, with ascites occurring in 76.5% of CKD+ versus 61.1% of patients with CKD- (p<0.0001). The most common in-hospital complication was the development of AKI (59.4%) in CKD+ versus 27% in CKD- patients (p<0.0001). CKD was associated with higher in-hospital and 30-day postdischarge mortality (both p<0.0001). CONCLUSIONS:The presence of CKD negatively impacts the prognosis of admitted patients with cirrhosis in a global cohort. Meticulous management of ascites and lifestyle changes, especially in HICs, may improve the outcome of these patients.

Tetanus remains an important global public health concern. Currently, the only recommended passive immunization therapy for tetanus prophylaxis is plasma-derived human tetanus immunoglobulin (HTIG), which faces a global supply shortage and can transmit infectious pathogens. Despite not being endorsed by WHO due to safety concerns, equine tetanus antitoxin remains widely used in some countries. We conducted a randomized, double-blind, phase 3 trial to evaluate siltartoxatug—a first-in-class recombinant monoclonal antibody—for tetanus postexposure prophylaxis. Participants ( n = 675) were randomized (2:1) to receive a single intramuscular injection of siltartoxatug 10 mg or HTIG 250 IU. The study met its primary outcome, with siltartoxatug demonstrating superiority to HTIG in the proportion of participants with an increase of anti-tetanus neutralizing antibody titers from baseline (ΔTiter) ≥ 0.01 IU ml − 1 (95.4% versus 53.2%; intergroup difference 42.3% (95% confidence interval, 35.5–49.1; P < 0.0001)). The safety profiles were comparable, with similar incidence of adverse events between the siltartoxatug (38.2%, 168 of 440) and HTIG (33.9%, 75 of 221) groups. These findings highlight siltartoxatug as an effective and safe option for passive immunization against tetanus. ClinicalTrials.gov registration: NCT05664750 .

Background: Infection with hepatitis E virus (HEV) could cause poorer prognosis in patients with chronic hepatitis B (CHB). The study is aimed to better understand mutual influence between hepatitis B virus (HBV) and HEV in clinical course, and provide a revealing insight into susceptibility and immunogenicity of HEV infection in this population.Methods: We retrospectively made comparison between patients with isolated acute hepatitis E (AHE) (n=125) and HBV-HEV co-infection (n=36), and observed changes of liver function and HBV infection status dynamically. Besides, serum samples of 3074 patients with CHB were tested for HEV IgG from 18 clinical centers in China. We also detected HEV IgG in 130 healthy blood donors, 136 patients with acute-on-chronic liver failure, and 111 post-liver transplanted patients in the clinical center of Shanghai as comparison. Furthermore, 188 cases were enrolled to observe annual natural infection rate and protective antibody disappearance of HEV.Findings: The population with underlying CHB were susceptible to HEV infection all the year round, of whom more male and younger patients involved. In the AHE+CHB group, the proportion of liver failure and decompensation was significantly higher than that of the isolated AHE group (p <0.0001). There was also significantly more prolonged INR and reduced platelet (p <0.0001), as well as longer hospital stay (21 days vs 14 days, p <0.05) and higher model for end-stage liver disease score (26.2 vs 22.3, p <0.01) in this group. In the AHE+CHB group, there existed dissociation of bilirubin and aminotransferase within one-week hospitalization (r=-0.662, p <0.0001), and no evident difference of illness severity regardless of HBeAg status and viral load. In population with CHB, the overall HEV seroprevalence in 3074 patients was 31.1%, which increased with age, and higher in male patients and in eastern coastal areas. There was no significant difference of seroprevalence of HEV IgG between patients with chronic HBV infection and healthy people. However, the infection rate of HEV was higher in patients with acute severe liver disease and immunosuppression (p<0.05). The annual natural infection rate of HEV in this population was 8.05% in Guangxi (N=87) and 21.15% in Shanghai (N=52), while the incidence of acute hepatitis E was not recorded. The HEV IgG turned negative in 31.43% to 42.85% of patients with positive baseline during one year.Interpretation: The young-middle aged patients with CHB are at high-risk of HEV infection and prone to severer outcome. Meanwhile, HEV IgG obtained by natural infection can disappear over time. It should be brought to the forefront of public health to prevent HEV infection among this population such as promoting HEV vaccination.Funding: The National Natural Science Foundation of China (81670528, 81672009, and 81871640) and the Shanghai Pujiang Program (17PJD005).Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by the Institutional Ethics Committee for Human Studies at Huashan Hospital, Fudan University (No. KY2016-227).Written informed consent was obtained from all subjects.

There is growing evidence that highlighted the potential effects of CD147 in atherosclerosis, but the potential implication of CD147 in diagnosis and treatment of transient ischemic attack (TIA) and acute cerebral infarction (ACI) is still unclear. In this work, we investigated the serum level of CD147 in patients with TIA and ACI, and CD147 expression in atherosclerotic plaque. The result showed significantly increasing serum level of CD147 in patients with TIA and ACI, and increasing amount of CD147 in vulnerable plaque compared with that in migrating plaque. The serum level of CD147 was correlation with risk of stroke after an episode of TIA. These results together suggest a potential involvement of CD147 in the development and progression of TIA and ACI and CD147 as a potential biomarker for stroke prediction.

BACKGROUND:Hepatitis B virus (HBV) is a major cause of liver infection in human. Because of the lack of an appropriate cell culture system for supporting HBV infection efficiently, the cellular and molecular mechanisms of hepadnavirus infection remain incompletely understood. Duck heptatitis B virus (DHBV) can naturally infect primary duck hepatocytes (PDHs) that provide valuable model systems for studying hepadnavirus infection in vitro. In this report, we explored global changes in cellular protein expression in DHBV infected PDHs by two-dimension gel electrophoresis (2-DE) combined with MALDI-TOF/TOF tandem mass spectrometry (MS/MS).RESULTS:The effects of hepadnavirus infection on hepatocytes were investigated in DHBV infected PDHs by the 2-DE analysis. Proteomic profile of PDHs infected with DHBV were analyzed at 24, 72 and 120 h post-infection by comparing with uninfected PDHs, and 75 differentially expressed protein spots were revealed by 2-DE analysis. Among the selected protein spots, 51 spots were identified corresponding to 42 proteins by MS/MS analysis; most of them were matched to orthologous proteins of Gallus gallus, Anas platyrhynchos or other avian species, including alpha-enolase, lamin A, aconitase 2, cofilin-2 and annexin A2, etc. The down-regulated expression of beta-actin and annexin A2 was confirmed by Western blot analysis, and potential roles of some differentially expressed proteins in the virus-infected cells have been discussed.CONCLUSIONS:Differentially expressed proteins of DHBV infected PDHs revealed by 2-DE, are involved in carbohydrate metabolism, amino acid metabolism, stress responses and cytoskeleton processes etc, providing the insight to understanding of interactions between hepadnavirus and hepatocytes and molecular mechanisms of hepadnavirus pathogenesis.

OBJECTIVES:Programmed death-1 (PD-1) up-regulation impairs virus-specific CD8+ T-cell responses during chronic viral infection. Whether PD-1 expression influences the virus-specific CD8+ T cells in humans with acute viral infection remains largely undefined. This study aims to characterize the PD-1 expression during acute hepatitis B (AHB), and further addresses the association between the PD-1 dynamics and memory T-cell formation during acute HBV infection.METHODS:Peripheral HBV-specific CD8+ T cells from 11 HLA-A2-positive AHB patients were longitudinally quantitatively analyzed, and PD-1, memory markers CCR7, CD45RA and CD127 and activation marker CD38 on HBV-specific CD8+ T cells were measured using flow cytometric assay. Serum ALT, HBsAg, HBsAb and HBV-DNA levels were evaluated for each subject.RESULTS:All 11 AHB patients examined had multiple pentamer-positive CD8+ T-cell responses in their early phase of HBV infection. Specifically, their PD-1 on pentamer-positive CD8+ T-cells was significantly up-regulated at the onset of their disease. Following their disease resolution, the dynamic decrease in PD-1 expression was found to correlate with the phenotypic development of memory CD8+ T cells, indicated by the increases in CCR7, CD45RA and CD127 and decrease in CD38.CONCLUSION:PD-1-mediated negative signaling may be closely associated with memory T-cell formation during acute self-limited hepatitis B.