The 90-Day Survival Threshold: A Pivotal Determinant of Long-Term Prognosis in HBV-ACLF Patients - Insights from a Prospective Longitudinal Cohort Study.

This work aims to explore the long-term prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). In this prospective study, eligible inpatients with HBV-ACLF are enrolled and followed up from December 2012 to February 2023, for clinical events, laboratory tests at least every 6 months. Overall, the survival rates at 28 days, 90 days, 1 year, 5 years, and 8 years are 64.7%, 48.8%, 46.1%, 43.8%, and 42.2%, respectively. Among the 8-year mortality and liver transplant cases, ACLF survivors (who survived over 90 days) accounted for 7.8% (9/115). Among 101 patients who survived for more than 90 days, 97.9% of patients achieve virologic response at 1 year. For HBeAg-positive patients, the HBeAg seroconversion are 25.5%, 63.6%, and 76.9% at 1, 5, and 8 years, respectively. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, INR, white blood cell count, and albumin levels gradually improve within the first year. Fibrosis biomarkers APRI, FIB-4 and Chitinase-3-like protein 1 (CHI3L1) levels decreases within the first 5 years. The Cox proportional hazards regression reveal that high total bilirubin (HR = 1.008, p = 0.021) is the independent risk factor for 8-year survival of ALCF survivors. The 90-day period following of HBV-ACLF represented a critical juncture for long-term prognosis, revealing favorable outcomes beyond this timeframe.

Unraveling the motion and deformation characteristics of red blood cells in a deterministic lateral displacement device.

Deterministic Lateral Displacement (DLD) device has gained widespread recognition and trusted for filtering blood cells. However, there remains a crucial need to explore the complex interplay between deformable cells and flow within the DLD device to improve its design. This paper presents an approach utilizing a mesoscopic cell-level numerical model based on dissipative particle dynamics to effectively capture this complex phenomenon. To establish the model's credibility, a series of numerical simulations were conducted and the numerical results were validated with nominal experimental data from the literature. These include single cell stretching experiment, comparisons of the morphological characteristics of cells in DLD, and comparison the specific row-shift fraction of DLD required to initiate the zigzag mode. Additionally, we investigate the effect of cell rigidity, which serves as an indicator of cell health, on average flow velocity, trajectory, and asphericity. Moreover, we extend the existing theory of predicting zigzag mode for solid spherical particles to encompass the behavior of red blood cells. To achieve this, we introduce a new concept of effective diameter and demonstrate its applicability in providing highly accurate predictions across a wide range of conditions.

Knockdown of CXCL1 improves ACLF by reducing neutrophil recruitment to attenuate ROS production and hepatocyte apoptosis.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is an acute decompensated syndrome based on chronic liver disease, while neutrophil recruitment is the most critical early step. C-X-C motif chemokine ligand 1 (CXCL1), a cytokine that recruits neutrophils, was significantly upregulated in both ACLF mice and patients with ACLF. This present study aims to explore the role of CXCL1 in the pathogenesis of ACLF. METHODS: We established an ACLF mouse model induced by carbon tetrachloride, lipopolysaccharide, and D-galactosamine, and used adeno-associated virus to achieve overexpression and knockdown of Cxcl1. We employed mass cytometry, flow cytometry, multiplex cytokine and chemokine analysis, Western blot, and reactive oxygen species (ROS) detection in mice blood and liver. ACLF patients (n = 10) and healthy controls (n = 5) were included, and their liver samples were stained using multiplex immunohistochemistry techniques. RESULTS: CXCL1 was significantly elevated in both ACLF mice and patients. CXCL1 recruits neutrophils by binding to the C-X-C motif chemokine receptor 2 on the surface of neutrophils, affects ACLF prognosis by generating ROS and mitochondrial depolarization and modulating caspase3-related apoptotic pathways. We found that the knockdown of CXCL1 attenuated the infiltration of neutrophils in the mouse liver, reduced the expression of inflammatory cytokines, and also significantly downregulated ROS production and caspase3-related hepatocyte apoptosis, thereby ameliorating the liver injury of ACLF. CONCLUSIONS: CXCL1 is a core player in the mobilization of neutrophils in ACLF, and the knockdown of Cxcl1 improves neutrophil infiltration, reduces ROS levels, and reduces hepatocyte apoptosis, thereby attenuating inflammation and liver injury in ACLF. Our results revealed a previously unknown link between CXCL1-induced neutrophil recruitment and ACLF, providing evidencing for potential therapies targeting ACLF.

Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway in vivo and in vitro.

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.

Simulation of a tumor cell flowing through a symmetric bifurcated microvessel.

Microvessel bifurcations serve as the major sites of tumor cell adhesion and further extravasation. In this study, the movement, deformation, and adhesion of a circulating tumor cell flowing in a symmetric microvessel with diverging and converging bifurcations were simulated by dissipative particle dynamics combined with a spring-based network model. Effects of the initial position of the CTC, externally-applied acceleration and the presence of RBCs on the motion of the CTC were investigated. The results demonstrated that the CTC released at the centerline of the parent vessel would attach to the vessel wall when arriving at the apex of diverging bifurcation and slide into the daughter branch determined by its centroid deflection and finally form firm adhesion at relatively lower flow rates. As the external acceleration increases, the increasing shear force enlarges the contact area for the adherent CTC on the one hand and reduces the residence time on the other hand. With the presence of RBCs in the bloodstream, the collision between the adherent tumor cell at the diverging bifurcation and flowing RBCs promotes the firm adhesion of CTC at lower flow rates.

Tripartite motif-containing protein 46 accelerates influenza A H7N9 virus infection by promoting K48-linked ubiquitination of TBK1.

BACKGROUND: Avian influenza A H7N9 emerged in 2013, threatening public health and causing acute respiratory distress syndrome, and even death, in the human population. However, the underlying mechanism by which H7N9 virus causes human infection remains elusive. METHODS: Herein, we infected A549 cells with H7N9 virus for different times and assessed tripartite motif-containing protein 46 (TRIM46) expression. To determine the role of TRIM46 in H7N9 infection, we applied lentivirus-based TRIM46 short hairpin RNA sequences and overexpression plasmids to explore virus replication, and changes in type I interferons and interferon regulatory factor 3 (IRF3) phosphorylation levels in response to silencing and overexpression of TRIM46. Finally, we used Co-immunoprecipitation and ubiquitination assays to examine the mechanism by which TRIM46 mediated the activity of TANK-binding kinase 1 (TBK1). RESULTS: Type I interferons play an important role in defending virus infection. Here, we found that TRIM46 levels were significantly increased during H7N9 virus infection. Furthermore, TRIM46 knockdown inhibited H7N9 virus replication compared to that in the control group, while the production of type I interferons increased. Meanwhile, overexpression of TRIM46 promoted H7N9 virus replication and decrease the production of type I interferons. In addition, the level of phosphorylated IRF3, an important interferon regulatory factor, was increased in TRIM46-silenced cells, but decreased in TRIM46 overexpressing cells. Mechanistically, we observed that TRIM46 could interact with TBK1 to induce its K48-linked ubiquitination, which promoted H7N9 virus infection. CONCLUSION: Our results suggest that TRIM46 negatively regulates the human innate immune response against H7N9 virus infection.

Comprehensive immune cell analysis of human menstrual-blood-derived stem cells therapy to concanavalin A hepatitis.

Autoimmune hepatitis is an autoimmune disease with increasing occurrence worldwide. The most common and convenient mouse model is the concanavalin A (ConA) mouse model. Human menstrual-blood-derived stem cells (MenSCs) have shown great potential as a type of mesenchymal stem cell for treating various diseases. Time-of-flight mass cytometry was performed in phosphate-buffered saline control (NC) group and ConA injection with or without MenSCs treatment groups, and conventional flow cytometry was used for further validation. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and H&E staining depicted that MenSCs treatment could significantly alleviate ConA-induced hepatitis. The t-distributed stochastic neighbor embedding (t-SNE) analysis of nine liver samples displayed favorable cell clustering, and the NC group was significantly different from the other two groups. The proportions of CD69+ T cells, NKT cells, and PD-L1+ macrophages were notably increased by ConA injection, while MenSCs could decrease ConA-induced macrophage percentage and M1 polarization in the liver tissue. The analysis of proinflammatory factors carried out by cytometric bead array demonstrated that tumor necrosis factor alpha (TNF-α), interleukin (IL)-17A, IL-12p70, IL-6, IL-2, IL-1b, and interferon gamma (IFN-γ) were upregulated after ConA injection and then rapidly decreased at 12 h. MenSCs also played an important role in downregulating these cytokines. Here, we described the comprehensive changes in leukocytes in the liver tissue of ConA-induced hepatitis at 12 h after ConA injection and found that MenSCs rescued ConA-induced hepatitis mostly by inhibiting macrophages and M1 polarization in mouse liver.

1,5-Anhydroglucitol Predicts Mortality in Patients with HBV-Related Acute-on-chronic Liver Failure.

Background and Aims: 1,5-Anhydroglucitol (1,5AG) activity has been reported in chronic liver disease. Hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) patients have a high mortality. We aimed to discover the relationship between serum 1,5AG and the prognosis of HBV-ACLF. Methods: Serum 1,5AG levels were determined in 333 patients with HBV-ACLF, 300 without diabetes were allocated to derivation (n=206) and validation cohorts (n=94), and 33 were recruited to evaluate 1,5AG in those with diabetes. Forty patients with chronic hepatitis B, 40 with liver cirrhosis, and 40 healthy people were controls in the validation cohort. Results: In the derivation and validation cohorts, serum 1,5AG levels were significantly lower in nonsurvivors than in survivors. The AUC of 1,5AG for 28-day mortality was 0.811. In patients with diabetes, serum 1,5AG levels were also significantly lower in nonsurvivors than in survivors. In multivariate Cox regression analysis, serum 1,5AG levels were independently associated with 28-day mortality. A novel predictive model (ACTIG) based on 1,5AG, age, TB, cholesterol, and INR was derived to predict mortality. In ACTIG, the AUC for 28-day mortality was 0.914, which was superior to some prognostic score models. ACTIG was also comparable to those prognostic score models in predicting 6-month mortality. In mice with D-galactosamine/lipopolysaccharide-induced liver failure, 1,5AG levels were significantly reduced in serum and significantly increased in urine and liver tissue. Conclusions: Serum 1,5AG levels are a promising predictor of short-term mortality in HBV-ACLF patients. The 1,5AG distribution changed in mice with D-galactosamine/ lipopolysaccharide-induced liver failure.

Gut microbiota in systemic lupus erythematosus: A fuse and a solution.

Gut commensals help shape and mold host immune system and deeply influence human health. The disease spectrum of mankind that gut microbiome may associate with is ever-growing, but the mechanisms are still enigmas. Characterized by loss of self-tolerance and sustained self-attack, systemic lupus erythematosus (SLE) is labeled with chronic inflammation, production of autoantibodies and multisystem injury, which so far are mostly incurable. Gut microbiota and their metabolites, now known as important environmental triggers of local/systemic immune responses, have been proposed to be involved in SLE development and progression probably through the following mechanisms: translocation beyond their niches; molecular mimicry to cross-activate immune response targeting self-antigens; epitope spreading to expand autoantibodies spectrum; and bystander activation to promote systemic inflammation. Gut microbiota which varies between individuals may also influence the metabolism and bio-transformation of disease-modifying anti-rheumatic drugs, thus associated with the efficacy and toxicity of these drugs, adding another explanation for heterogenic therapeutic responses. Modulation of gut microbiota via diet, probiotics/prebiotics, antibiotics/phages, fecal microbiota transplantation, or helminth to restore immune tolerance and homeostasis is expected to be a promising neoadjuvant therapy for SLE. We reviewed the advances in this territory and discussed the application prospect of modulating gut microbiota in controlling SLE.

Immune Enhancement by the Tetra-Peptide Hydrogel as a Promising Adjuvant for an H7N9 Vaccine against Highly Pathogenic H7N9 Virus.

BACKGROUND: Short peptide hydrogel was reported as a possible adjuvant for vaccines. In order to evaluate whether the Tetra-Peptide Hydrogel can be a promising adjuvant for an H7N9 vaccine against the highly pathogenic H7N9 virus, we conducted this study. METHODS: Tetra-Peptide Hydrogels (D and L conformations) were prepared by a self-assembly system using a Naproxen acid modified tetra peptide of GFFY (Npx-GFFY). Mice received two immunizations with the D-Tetra-Peptide Hydrogel adjuvant vaccine, the L-Tetra-Peptide Hydrogel adjuvant vaccine, or the split vaccine. Fourteen days following the second dose, the mice were challenged with the highly pathogenic A/Guangdong/GZ8H002/2017(H7N9) virus. The mice were observed for signs of illness, weight loss, pathological alterations of the lung tissues and immune responses in the following 2 weeks. RESULTS: The D/L-Tetra-Peptide Hydrogels resembled long bars with hinges on each other, with a diameter of ~10 nm. The H7N9 vaccine was observed to adhere to the hydrogel. All the unvaccinated mice were dead by 8 days post infection with H7N9. The mice immunized by the split H7N9 vaccine were protected against infection with H7N9. Mice immunized by D/L-Tetra-Peptide Hydrogel adjuvant vaccines experienced shorter symptomatic periods and their micro-neutralization titers were higher than in the split H7N9 vaccine at 2 weeks post infection. The hemagglutinating inhibition (HI) titer in the L-Tetra-Peptide Hydrogel adjuvant vaccine group was higher than that in the split H7N9 vaccine 1 week and 2 weeks post infection. The HI titer in the D-Tetra-Peptide Hydrogel adjuvant vaccine group was higher than that in the split H7N9 vaccine at 2 weeks post infection. CONCLUSION: The D/L Tetra-Peptide Hydrogels increased the protection of the H7N9 vaccine and could be promising adjuvants for H7N9 vaccines against highly pathogenic H7N9 virus.

Targeted Metabolomics Analysis of Bile Acids in Patients with Idiosyncratic Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is rare but clinically important due to a high rate of mortality. However, specific biomarkers for diagnosing and predicting the severity and prognosis of DILI are lacking. Here, we used targeted metabolomics to identify and quantify specific types of bile acids that can predict the severity of DILI. A total of 161 DILI patients were enrolled in this prospective cohort study, as well as 31 health controls. A targeted metabolomics method was used to identify 24 types of bile acids. DILI patients were divided into mild, moderate, and severe groups according to disease severity. A multivariate analysis was performed to identify characteristic bile acids. Then the patients were divided into severe and non-severe groups, and logistic regression was used to identify bile acids that could predict DILI severity. Among the enrolled DILI patients, 32 were in the mild group, 90 were in the moderate group, and 39 were in the severe group. Orthogonal partial least squares-discriminant analysis (OPLS-DA) modeling clearly discriminated among the different groups. Among the four groups, glycochenodeoxycholate (GCDCA), taurochenodeoxycholate (TCDCA), deoxycholic acid (DCA), Nor Cholic acid (NorCA), glycocholic acid (GCA), and taurocholic acid (TCA) showed significant differences in concentration between at least two groups. NorCA, GCDCA, and TCDCA were all independent risk factors that differentiated severe DILI patients from the other groups. The area under the receiver operating characteristic curve (AUROC) of GCDCA, TCDCA, and NorCA was 0.856, 0.792, and 0.753, respectively. Together, these three bile acids had an AUROC of 0.895 for predicting severe DILI patients. DILI patients with different disease severities have specific bile acid metabolomics. NorCA, GCDTA, and TCDCA were independent risk factors for differentiating severe DILI patients from less-severe patients and have the potential to predict DILI severity.

The viral distribution and pathological characteristics of BALB/c mice infected with highly pathogenic Influenza H7N9 virus.

BACKGROUND: The highly pathogenic Influenza H7N9 virus is believed to cause multiple organ infections. However, there have been few systematic animal experiments demonstrating the virus distribution after H7N9 virus infection. The present study was carried out to investigate the viral distribution and pathological changes in the main organs of mice after experimental infection with highly pathogenic H7N9 virus. METHODS: Infection of mice with A/Guangdong/GZ8H002/2017(H7N9) virus was achieved via nasal inoculation. Mice were killed at 2, 3, and 7 days post infection. The other mice were used to observe their illness status and weight changes. Reverse transcription polymerase chain reaction and viral isolation were used to analyse the characteristics of viral invasion. The pathological changes of the main organs were observed using haematoxylin and eosin staining and immunohistochemistry. RESULTS: The weight of H7N9 virus-infected mice increased slightly in the first two days. However, the weight of the mice decreased sharply in the following days, by up to 20%. All the mice had died by the 8th day post infection and showed multiple organ injury. The emergence of viremia in mice was synchronous with lung infection. On the third day post infection, except in the brain, the virus could be isolated from all organs (lung, heart, kidney, liver, and spleen). On the seventh day post infection, the virus could be detected in all six organs. Brain infection was detected in all mice, and the viral titre in the heart, kidney, and spleen infection was high. CONCLUSION: Acute diffuse lung injury was the initial pathogenesis in highly pathogenic H7N9 virus infection. In addition to lung infection and viremia, the highly pathogenic H7N9 virus could cause multiple organ infection and injury.

Serum CXCL1 Is a Prognostic Factor for Patients With Hepatitis B Virus-Related Acute-On-Chronic Liver Failure.

Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus-related ACLF (HBV-ACLF). Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF. Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009-1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669-0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF. Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.

Corrigendum to "Artificial Liver Support System Improves Short-Term Outcomes of Patients with HBV-Associated Acute-on-Chronic Liver Failure: A Propensity Score Analysis".

[This corrects the article DOI: 10.1155/2019/3757149.].

Progress in hepatitis B virus-related acute-on-chronic liver failure treatment in China: A large, multicenter, retrospective cohort study using a propensity score matching analysis.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality. However, the treatment progression for HBV-ACLF in China in the past decade has not been well characterized. The present study aimed to determine whether the HBV-ACLF treatment has significantly improved during the past decade. METHODS: This study retrospectively compared short-term (28/56 days) survival rates of two different nationwide cohorts (cohort I: 2008-2011 and cohort II: 2012-2015). Eligible HBV-ACLF patients were enrolled retrospectively. Patients in the cohorts I and II were assigned either to the standard medical therapy (SMT) group (cohort I-SMT, cohort II-SMT) or artificial liver support system (ALSS) group (cohort I-ALSS, cohort II-ALSS). Propensity score matching analysis was conducted to eliminate baseline differences, and multivariate logistic regression analysis was used to explore the independent factors for 28-day survival. RESULTS: Short-term (28/56 days) survival rates were significantly higher in the ALSS group than those in the SMT group (P < 0.05) and were higher in the cohort II than those in the cohort I (P < 0.001). After propensity score matching, short-term (28/56 days) survival rates were higher in the cohort II than those in the cohort I for both SMT (60.7% vs. 53.0%, 50.0% vs. 39.8%, P < 0.05) and ALSS (66.1% vs. 56.5%, 53.0% vs. 44.4%, P < 0.05) treatments. The 28-day survival rate was higher in patients treated with nucleos(t)ide analogs than in patients without such treatments (P = 0.046). Multivariate logistic regression analysis revealed that ALSS (OR = 0.962, 95% CI: 0.951-0.973, P = 0.038), nucleos(t)ide analogs (OR = 0.927, 95% CI: 0.871-0.983, P = 0.046), old age (OR = 1.028, 95% CI: 1.015-1.041, P < 0.001), total bilirubin (OR = 1.002, 95% CI: 1.001-1.003, P = 0.004), INR (OR = 1.569, 95% CI: 1.044-2.358, P < 0.001), COSSH-ACLF grade (OR = 2.683, 95% CI: 1.792-4.017, P < 0.001), and albumin (OR = 0.952, 95% CI: 0.924-0.982, P = 0.002) were independent factors for 28-day mortality. CONCLUSIONS: The treatment for patients with HBV-ACLF has improved in the past decade.

Safety and Immunogenicity of a Recombinant Tetanus Vaccine in Healthy Adults in China: A Randomized, Double-Blind, Dose Escalation, Placebo- and Positive-Controlled, Phase 1/2 Trial.

Tetanus is a fatal but vaccine-preventable disease. The currently available tetanus vaccines are tetanus toxoid (TT)-based. Although these vaccines are generally effective, challenges in vaccine development and access remain. A randomized, double-blind, dose escalation, placebo- and positive-controlled, phase 1/2 trial (ChiCTR1800015865) is performed to evaluate the safety and immunogenicity of an alternative recombinant tetanus vaccine based on the Hc domain of tetanus neurotoxin (TeNT-Hc) in healthy adult volunteers. The primary outcome is the safety profile of the recombinant tetanus vaccine, and immunogenicity is the secondary outcome. 150 eligible participants were enrolled and randomly assigned to receive one of the three doses of recombinant tetanus vaccine (TeNT-Hc 10/20/30 µg), TT vaccine, or placebo. The recombinant tetanus vaccine shows a good safety profile. The frequency of any solicited and unsolicited adverse events after each vaccination does not differ across the vaccine and placebo recipients. No serious treatment-related adverse events occur. The recombinant tetanus vaccine shows strong immune responses (seroconversion rates, geometric mean titer, and antigen-specific CD4+/CD8+ T-cell responses), which are roughly comparable to those of the TT vaccine. In conclusion, the findings from this study support that recombinant tetanus vaccine is safe and immunogenic; thereby, it represents a novel vaccine candidate against tetanus.

Numerical study on the adhesion of a circulating tumor cell in a curved microvessel.

The adhesion of a circulating tumor cell (CTC) in a three-dimensional curved microvessel was numerically investigated. Simulations were first performed to characterize the differences in the dynamics and adhesion of a CTC in the straight and curved vessels. After that, a parametric study was performed to investigate the effects of the applied driven force density f (or the flow Reynolds number Re) and the CTC membrane bending modulus Kb on the CTC adhesion. Our simulation results show that the CTC prefers to adhere to the curved vessel as more bonds are formed around the transition region of the curved part due to the increased cell-wall contact by the centrifugal force. The parametric study also indicates that when the flow driven force f (or Re) increases or when the CTC becomes softer (Kb decreases), the bond formation probability increases and the bonds will be formed at more sites of a curved vessel. The increased f (or Re) brings a larger centrifugal force, while the decreased Kb generates more contact areas at the cell-wall interface, both of which are beneficial to the bond formation. In the curved vessel, it is found that the site where bonds are formed the most (hotspot) varies with the applied f and the Kb. For our vessel geometry, when f is small, the hotspot tends to be within the first bend of the vessel, while as f increases or Kb decreases, the hotspot may shift to the second bend of the vessel.

Using advanced oxidation protein products and ischaemia-modified albumin to monitor oxidative stress levels in patients with drug-induced liver injury.

Increased oxidative stress levels play a key role in idiosyncratic drug-induced liver injury (DILI) pathogenesis. To investigated whether advanced oxidation protein products (AOPPs) and ischaemia-modified albumin (IMA) can be used to monitor oxidative stress in DILI patients and to assess disease severity. We performed spectrophotometric assays to assess AOPPs and IMA in 68 DILI patients with severity grade 0-2 (non-severe group), 60 with severity grade 3-5 (severe group), and 38 healthy controls. The results showed that baseline AOPPs and IMA serum levels and AOPPs/albumin and IMA/albumin ratios were significantly higher in DILI patients than in healthy controls. Besides, in comparison to the non-severe group, the severe group showed higher baseline AOPPs and IMA serum levels and AOPPs/albumin and IMA/albumin ratios. AOPPs and IMA serum levels and AOPPs/albumin and IMA/albumin ratios decreased after treatment in both patient groups. Combining the correlation analysis and areas under the receiver operating curve (AUROCs) analysis results, that IMA outperformed to be one is the most reliable marker to assess disease severity of DILI. Our findings indicated that AOPPs and IMA can serve as key biomarkers for monitoring oxidative stress levels in DILI patients and can indicate disease severity. The IMA outperformed to be one of the most reliable oxidative stress biomarkers to assess disease severity of DILI.

Changes of inflammatory cytokines/chemokines during ravidasvir plus ritonavir-boosted danoprevir and ribavirin therapy for patients with genotype 1b hepatitis C infection.

This study investigated the safety and efficacy of ravidasvir (RDV) plus ritonavir-boosted danoprevir (DNVr) and ribavirin (RBV) regimens for treatment-naïve non-cirrhotic patients with hepatitis C virus (HCV) genotype 1b in mainland China. We also gained insight into HCV-host interactions during anti-HCV treatment. 16 patients with HCV and 10 healthy people enrolled the study. Three of 16 patients received 12-weeks' placebo treatment first and served as the placebo controls. All (n = 16) patients received 12-weeks' RDV plus DNVr and RBV treatment. The adverse effects (AEs), viral loads, alanine transaminase, and aspartate aminotransferase were recorded during study. We also performed multianalyte profiling of 48 cytokines/chemokines in 16 patients with HCV and 10 normal controls. Seventy-five percent patients treated with RDV plus DNVr and RBV experienced AEs. No death, treatment-related serious AEs or AEs leading to discontinuation were reported. The serum HCV-RNA levels remained extremely high in 3 placebo controls after treated with placebo. After RDV plus DNVr and RBV treatment, all patients achieved sustained virologic response (SVR) at posttreatment week 12, but 1 patient experienced viral relapse at SVR 24. The cytokine/chemokine expression pattern was markedly altered in patients with HCV as compared with healthy controls. The interferon-inducible protein-10 (IP-10) decreased after anti-HCV treatment, and dramatically increased in one patient with viral relapse. The regimen of RDV and DNVr plus RBV represents a highly safe and effective treatment option for HCV patients in mainland China. The IP-10 has the potential to be an indicator of innate immune viral recognition.