Development and validation of a scoring system to predict the mortality of hospitalized patients with SARS-CoV-2 Omicron: a nationwide, multicentre study.

BACKGROUND: The Omicron variant broke out in China at the end of 2022, causing a considerable number of severe cases and even deaths. The study aimed to identify risk factors for death in patients hospitalized with SARS-CoV-2 Omicron infection and to establish a scoring system for predicting mortality. METHODS: 1817 patients were enrolled at eight hospitals in China from December 2022 to May 2023, including 815 patients in the training group and 1002 patients in the validation group. Forty-six clinical and laboratory features were screened using LASSO regression and multivariable logistic regression. RESULTS: In the training set, 730 patients were discharged and 85 patients died. In the validation set, 918 patients were discharged and 84 patients died. LASSO regression identified age, levels of interleukin (IL) -6, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), and D-dimer; neutrophil count, neutrophil-to-lymphocyte ratio (NLR) as associated with mortality. Multivariable logistic regression analysis showed that older age, IL-6, BUN, LDH and D-dimer were significant independent risk factors. Based on these variables, a scoring system was developed with a sensitivity of 83.6% and a specificity of 83.5% in the training group, and a sensitivity of 79.8% and a sensitivity of 83.0% in the validation group. CONCLUSIONS: A scoring system based on age, IL-6, BUN, LDH and D-dime can help clinicians identify patients with poor prognosis early.

Elevated CD169 expressing monocyte/macrophage promotes systemic inflammation and disease progression in cirrhosis.

Systemic inflammation is related to disease progression and prognosis in patients with advanced cirrhosis. However, the mechanisms underlying the initiation of inflammation are still not fully understood. The role of CD169+ monocyte/macrophage in cirrhotic systemic inflammation was undetected. Flow cytometry analysis was used to detect the percentage and phenotypes of CD169+ monocytes as well as their proinflammatory function in patient-derived cirrhotic tissue and blood. Transcriptome differences between CD169+ and CD169- monocytes were also compared. Additionally, a mouse model with specific depletion of CD169+ monocytes/macrophages was utilized to define their role in liver injury and fibrosis. We observed increased CD169 expression in monocytes from cirrhotic patients, which was correlated with inflammatory cytokine production and disease progression. CD169+ monocytes simultaneously highly expressed M1- and M2-like markers and presented immune-activated profiles. We also proved that CD169+ monocytes robustly prevented neutrophil apoptosis. Depletion of CD169+ monocytes/macrophages significantly inhibited inflammation and liver necrosis in acute liver injury, but the spontaneous fibrin resolution after repeated liver injury was impaired. Our results indicate that CD169 defines a subset of inflammation-associated monocyte that correlates with disease development in patients with cirrhosis. This provides a possible therapeutic target for alleviating inflammation and improving survival in cirrhosis.

Oral VV116 versus placebo in patients with mild-to-moderate COVID-19 in China: a multicentre, double-blind, phase 3, randomised controlled study.

BACKGROUND: Spread of SARS-CoV-2 led to a global pandemic, and there remains unmet medical needs in the treatment of Omicron infections. VV116, an oral antiviral agent that has potent activity against SARS-CoV-2, was compared with a placebo in this phase 3 study to investigate its efficacy and safety in patients with mild-to-moderate COVID-19. METHODS: This multicentre, double-blind, phase 3, randomised controlled study enrolled adults in hospitals for infectious diseases and tertiary general hospitals in China. Eligible patients were randomly assigned in a 1:1 ratio using permuted block randomisation to receive oral VV116 (0·6 g every 12 h on day 1 and 0·3 g every 12 h on days 2-5) or oral placebo (on the same schedule as VV116) for 5 days. Randomisation stratification factors included SARS-CoV-2 vaccination status and the presence of high-risk factors for progression to severe COVID-19. Inclusion criteria were a positive SARS-CoV-2 test, an initial onset of COVID-19 symptoms 3 days or less before the first study dose, and a score of 2 or more for any target COVID-19-related symptoms in the 24 h before the first dose. Patients who had severe or critical COVID-19 or who had taken any antiviral drugs were excluded from the study. The primary endpoint was the time to clinical symptom resolution for 2 consecutive days. Efficacy analyses were performed on a modified intention-to-treat population, comprising all patients who received at least one dose of VV116 or placebo, tested positive for SARS-CoV-2 nucleic acid, and did not test positive for influenza virus before the first dose. Safety analyses were done on all participants who received at least one dose of VV116 or placebo. This study was registered with ClinicalTrials.gov, NCT05582629, and has been completed. FINDINGS: A total of 1369 patients were randomly assigned to treatment groups and 1347 received either VV116 (n=674) or placebo (n=673). At the interim analysis, VV116 was superior to placebo in reducing the time to sustained clinical symptom resolution among 1229 patients (hazard ratio [HR] 1·21, 95% CI 1·04-1·40; p=0·0023). At the final analysis, a substantial reduction in time to sustained clinical symptom resolution was observed for VV116 compared with placebo among 1296 patients (HR 1·17, 95% CI 1·04-1·33; p=0·0009), consistent with the interim analysis. The incidence of adverse events was similar between groups (242 [35·9%] of 674 patients vs 283 [42·1%] of 673 patients). INTERPRETATION: Among patients with mild-to-moderate COVID-19, VV116 significantly reduced the time to sustained clinical symptom resolution compared with placebo, with no observed safety concerns. FUNDING: Shanghai Vinnerna Biosciences, Shanghai Science and Technology Commission, and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Plasma human neutrophil peptides as biomarkers of disease severity and mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Human neutrophil peptides (HNP)-1, -2 and -3 are the most abundant proteins in neutrophil azurophilic granules and are rapidly released via neutrophil degranulation upon activation. The aims of our study were to assess the role of HNP1-3 as biomarkers of disease severity in patients with decompensated cirrhosis and their value in predicting short-term mortality. METHODS: In this study, 451 patients with acutely decompensated cirrhosis (AD) were enrolled at the two medical centres. Overall, 281 patients were enrolled as the training cohort from October 2015 to April 2019, and 170 patients were enrolled as the validation cohort from June 2020 to February 2021. Plasma HNP1-3 levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma HNP1-3 increased stepwise with disease severity (compensated cirrhosis: 0.3 (0.2-0.4); AD without acute-on-chronic liver failure (ACLF): 1.9 (1.3-4.8); ACLF-1: 2.3 (1.8-6.1); ACLF-2: 5.6 (2.9-12.3); ACLF-3: 10.3 (5.7-17.2) ng/ml). From the multivariate Cox regression analysis, HNP1-3 emerged as independent predictors of mortality at 30 and 90 days. Similar results were observed in the subgroup analysis. On ROC analysis, plasma HNP1-3 showed better predictive accuracy for 30- and 90-day mortality (area under the receiver operating characteristic (AUROC) of 0.850 and 0.885, respectively) than the neutrophil-to-lymphocyte ratio (NLR) and similar accuracy as end-stage liver disease (MELD: 0.881 and 0.874) and chronic liver failure-sequential organ failure (CLIF-SOFA: 0.887 and 0.878). CONCLUSIONS: Plasma HNP1-3 levels were closely associated with disease severity and might be used to identify patients with AD at high risk of short-term mortality.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults.

INTRODUCTION: Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful "cytokine and chemokine storm" in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). METHODS: Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. RESULTS: The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration-time curve from time zero to 480 h (AUC0-480h), that from time zero to infinity (AUCinf), and peak plasma concentration ©max) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. CONCLUSION: The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. TRIAL REGISTRATION NUMBER: CTR20200429.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

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<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Clinical Risk Score for Invasive Pulmonary Aspergillosis in Patients With Liver Failure: A Retrospective Study in Zhejiang.

Purpose: The mortality of invasive pulmonary aspergillosis (IPA) in patients with liver failure was high. However, the prophylactic treatment in those patients with a high-risk factor in IPA has not been researched. Patients and methods: A multicenter, retrospective study was conducted in patients with liver failure. The study cohort of liver failure was randomly split into a training set for model development and the other served as the testing set for model verification. Multivariate analysis was performed to identify the risk factors of IPA. A weighted risk score for IPA was established. Anti-fungal treatment was prophylactically used in patients with medium and high IPA risk to evaluate the effect. Results: In total, 1,722 patients with liver failure were enrolled. Fifty-seven patients who received prophylactic treatment were excluded from the risk factor system study. About 1,665 patients were randomly split at a ratio of 2:1 into two datasets. Diabetes, glucocorticoids, plasma exchange, and hepatorenal syndrome (HRS) were risk factors in IPA in patients with liver failure, with weighted risk scores of 4, 7, 2, and 3, respectively. In the validation set and test set, the patients with risk scores of ≤ 3 presented low incidences of IPA at 4 and 2.7%. Patients with risk scores of 4-5 had an IPA incidence of 7.6% and 10.1%, and could be considered as a medium-risk group (p < 0.01 vs. the group with scores of ≤ 3), whereas those with risk scores of >5 manifested a significantly higher IPA incidence of 21.2 and 12.7%, who were considered a high-risk group (p < 0.01 vs. the groups with scores of 4-5 and >5, respectively). The IPA risk scores in the training set and the testing set were also analyzed by the ROC with an area under the ROC of 0.7152 and 0.6912. In this study, 57 patients received antifungal prophylaxis; the incidence of IPA was 1.8%, which was significantly lower after prophylactic antifungal therapy (p < 0.001). Conclusions: A weighted risk score for patients with liver failure, complicated with IPA, was established and confirmed in the testing cohort. Voriconazole prophylactic treatment to patients with liver failure with medium and high IPA risk can effectively prevent Aspergillus infection.

Effect of artificial liver blood purification treatment on the survival of critical ill COVID-19 patients.

Our aim was to investigate the effect of artificial liver blood purification treatment on the survival of severe/critical patients with coronavirus disease 2019 (COVID-19). A total of 101 severe and critical patients with coronavirus SARS-CoV-2 infection were enrolled in this open, case-control, multicenter, prospective study. According to the patients' and their families' willingness, they were divided into two groups. One was named the treatment group, in which the patients received artificial liver therapy plus comprehensive treatment (n = 50), while the other was named the control group, in which the patients received only comprehensive treatment (n = 51). Clinical data and laboratory examinations, as well as the 28-day mortality rate, were collected and analyzed. Baseline data comparisons on average age, sex, pre-treatment morbidity, initial symptoms, vital signs, pneumonia severity index score, blood routine examination and biochemistry indices etc. showed no difference between the two groups. Cytokine storm was detected, with a significant increase of serum interleukin-6 (IL-6) level. The serum IL-6 level decreased from 119.94 to 20.49 pg/mL in the treatment group and increased from 40.42 to 50.81 pg/mL in the control group (P < .05), indicating that artificial liver therapy significantly decreased serum IL-6. The median duration of viral nucleic acid persistence was 19 days in the treatment group (ranging from 6 to 67 days) and 17 days in the control group (ranging from 3 to 68 days), no significant difference was observed (P = .36). As of 28-day follow-up,17 patients in the treatment group experienced a median weaning time of 24 days, while 11 patients in the control group experienced a median weaning time of 35 days, with no significant difference between the two groups (P = .33). The 28-day mortality rates were 16% (8/50) in the treatment group and 50.98% (26/51) in the control group, with a significant difference (z = 3.70, P < .001). Cytokine storm is a key factor in the intensification of COVID-19 pneumonia. The artificial liver therapy blocks the cytokine storm by clearing inflammatory mediators, thus preventing severe cases from progressing to critically ill stages and markedly reducing short-term mortality.

Integration of antimicrobial peptides and gold nanorods for bimodal antibacterial applications.

The misuse and abuse of antibiotics have given rise to a severe problem of the drug resistance of bacteria. Solving this problem has been a vitally important task in the modern medical arena. In this work, an antimicrobial peptide (AMP), BF2b, and gold nanorods (AuNRs) were used to develop a specific drug delivery system for killing methicillin-resistant Staphylococcus aureus (MRSA). On the one hand, BF2b has unique anti-bacterial performance and has a lower tendency than traditional antibiotics to engender the drug resistance of bacteria. On the other hand, AuNRs have diverse distinct properties, such as photo-thermal conversion, which can be employed for photo-thermal sterilization. We aimed to integrate the anti-bacterial activity of BF2b and the photo-thermal sterilization of AuNRs to kill drug-resistant bacteria. Fourier-transform infrared spectroscopy, microBCA and zeta potential measurements were utilized to characterize the product, AuNR@PEG/BF2b. Transmittance electron microscopy, UV-vis spectroscopy and photothermal conversion measurement were conducted to verify the stability and photothermal conversion capacity of AuNR@PEG/BF2b. Cell viability and hemolysis assay were carried out to test the biocompatibility of AuNR@PEG/BF2b. Finally, the in vitro and in vivo experiments were performed to demonstrate the excellent bactericidal activity of AuNR@PEG/BF2b.

HIV Infection Does Not Increase 10-Week Mortality of Chinese Cryptococcal Meningitis Patients.

The role of HIV infection in precipitating different clinical features in cryptococcal meningitis (CM) patients remains controversial. One hundred twelve CM patients living with HIV/AIDS (CM+HIV+ patients) and 112 CM patients living without HIV/AIDS (CM+HIV- patients) were enrolled after propensity score matching. Demographic characteristics, symptoms, routine blood tests, and biochemical and cerebrospinal fluid (CSF) profiles were compared between the two groups. Kaplan-Meier analysis and Cox proportional hazards model was used to assess 10-week mortality. CM+HIV+ patients frequently occurred in young (mean age 40.3 ± 10.5) and male (89.3%) populations who also experienced leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, and hypoalbuminemia, less headaches (66.9%), and higher cryptococcemia (23.2%) (all p < .050); they also had higher glucose (2.6 ± 1.1 mmol/L), increased smear positivity (78.8%), and decreased white blood cells [8.0 (2.0-28.0) × 106/L] in initial CSF assay (all p < .050). The 10-week cumulative survival rate was 84.6% for CM+HIV+ patients and 88.5% for CM+HIV- patients (p = .345). Age <35.0 years (hazard ratio (HR) 3.0 (1.0-8.9), p = .046), intracranial pressure (ICP) >250.0 mmH2O (HR: 4.8 (1.1-21.6), p = .041), and treatment lacking amphotericin B [HR: 6.5 (1.9-21.4), p = .003] were independent risk factors for 10-week mortality in CM+HIV+ patients. There are significant clinical differences in CM patients living with or without HIV/AIDS. However, the 10-week survival rate was similar between the two groups. Younger population, high ICP, and treatment lacking amphotericin B were independent risk factors for 10-week mortality of Chinese CM+HIV+ patients.

Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: A Hint for COVID-19 Treatment.

H7N9 viruses quickly spread between mammalian hosts and carry the risk of human-to-human transmission, as shown by the 2013 outbreak. Acute respiratory distress syndrome (ARDS), lung failure, and acute pneumonia are major lung diseases in H7N9 patients. Transplantation of mesenchymal stem cells (MSCs) is a promising choice for treating virus-induced pneumonia, and was used to treat H7N9-induced ARDS in 2013. The transplant of MSCs into patients with H7N9-induced ARDS was conducted at a single center through an open-label clinical trial. Based on the principles of voluntariness and informed consent, 44 patients with H7N9-induced ARDS were included as a control group, while 17 patients with H7N9-induced ARDS acted as an experimental group with allogeneic menstrual-blood-derived MSCs. It was notable that MSC transplantation significantly lowered the mortality of the experimental group, compared with the control group (17.6% died in the experimental group while 54.5% died in the control group). Furthermore, MSC transplantation did not result in harmful effects in the bodies of four of the patients who were part of the five-year follow-up period. Collectively, these results suggest that MSCs significantly improve the survival rate of H7N9-induced ARDS and provide a theoretical basis for the treatment of H7N9-induced ARDS in both preclinical research and clinical studies. Because H7N9 and the coronavirus disease 2019 (COVID-19) share similar complications (e.g., ARDS and lung failure) and corresponding multi-organ dysfunction, MSC-based therapy could be a possible alternative for treating COVID-19.

Plasminogen as a prognostic biomarker for HBV-related acute-on-chronic liver failure.

BACKGROUNDHBV-related acute-on-chronic liver failure (HBV-ACLF) is hallmarked by high short-term mortality rates, calling for accurate prognostic biomarkers for initial risk stratification.METHODSThree tandem mass tag-labeled (TMT-labeled) quantitative proteomic studies were performed on 10 patients with HBV-related acute hepatic decompensation and on 20 patients with HBV-ACLF. Candidate biomarkers were preliminarily verified in a cross-sectional cohort (n = 144) and further confirmed in 2 prospective cohorts (n = 207 and n = 148).RESULTSPlasminogen, a potential prognostic biomarker for HBV-ACLF, was identified by TMT quantitative proteomics and preliminarily verified in the cross-sectional cohort. Further validation with a prospective cohort (n = 207) showed that plasminogen levels at admission were significantly lower (P < 0.001) in HBV-ACLF nonsurvivors than in survivors. The cumulative survival duration of patients with high plasminogen levels was significantly longer (P < 0.001) than that of patients with low plasminogen levels. During hospitalization, plasminogen levels significantly decreased (P = 0.008) in the deterioration group but significantly increased (P < 0.001) in the improvement group. Additionally, plasminogen levels gradually increased in survivors but gradually decreased in nonsurvivors. The P5 score, a prognostic panel incorporating plasminogen levels, hepatic encephalopathy occurrence, age, international normalized ratio (INR), and total bilirubin, was significantly superior to the Child-Pugh, Model for End-stage Liver Disease (MELD), Chronic Liver Failure Consortium ACLF (CLIF-C ACLF), Chinese Group on the Study of Severe Hepatitis B (COSSH), and HINT (a prognostic score based on hepatic encephalopathy occurrence, INR, neutrophil count, and thyroid-stimulating hormone) scores (all P < 0.05). The performances of the plasminogen level and P5 score were validated in a second multicenter, prospective cohort (n = 148).CONCLUSIONSPlasminogen is a promising prognostic biomarker for HBV-ACLF, and sequential plasminogen measurements could profile the clinical course of HBV-ACLF. P5 is a high-performance prognostic score for HBV-ACLF.FUNDINGThe National Key Research and Development Program (2017YFC1200204); the National Natural Science Foundation of China (81400589, 81600497); the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002); the Chinese High-Tech Research and Development Programs (2012AA020204); the National S&T Major Project (2012ZX10002004); and the Zhejiang Provincial Medicine and Health Science and Technology Project (2016147735).

Kaposi's sarcoma manifested as lower gastrointestinal bleeding in a HIV/HBV-co-infected liver cirrhosis patient: A case report.

BACKGROUND: Kaposi's sarcoma (KS) is one of the most common cancers in human immunodeficiency virus (HIV)-positive patients and leads to a high prevalence of morbidity and mortality. It usually appears as cutaneous or mucous lesions. Patients with visceral KS are asymptomatic and clinically silent. As the disease advances, patients may progress from a normal condition to exhibiting severe symptoms. CASE SUMMARY: A 27-year-old man presented with a 2-mo history of fever, bearing-down pain, and rectal bleeding. His hepatitis B virus DNA level was 2.7 ×107 IU/mL. Abdominal computed tomography (CT) indicated liver cirrhosis. Before he was admitted to our hospital, he was diagnosed with HIV infection. His CD4 count was 24 cells/µL. Pelvic cavity CT suggested a thickened rectum wall accompanied by multiple enlarged lymph nodes. The patient was initially treated as having haemorrhoidal varices with bleeding, telbivudine for anti-hepatitis B virus treatment, and antibiotics for anti-infection. After half a month of treatment, the patient felt that his lower lumbus ache and bearing-down pain had not improved, and a colonoscopy was conducted. The result revealed a rectal mass that was histologically confirmed as KS with rectal spindle cells that were positive for cluster of differentiation 117 (CD117), CD34, human herpes virus 8, and CD31. He was administered systemic chemotherapy with 36 mg/d liposomal doxorubicin six times. The patient experienced no sign of lower gastrointestinal bleeding again. CONCLUSION: This case highlights the diagnosis of primary KS with lower gastrointestinal bleeding in HIV-positive patients, which means visceral KS could not be excluded. The gold standard relies on colonoscopy and biopsy findings.

Short-Course Rather Than Low-Dose Amphotericin B May Exert Potential Influence on Mortality in Cryptococcal Meningitis Patients Treated With Amphotericin B Plus Flucytosine Alone or in Combination With Fluconazole.

BACKGROUND: The influence of Amphotericin B (AmB) dose and the addition of fluconazole (Flu) on the AmB + 5-flucytosine (5FC) regimen for cryptococcal meningitis (CM) treatment remain debatable. METHODS: A retrospective study was conducted to compare 44 CM patients treated with AmB + 5FC and 78 CM patients treated with AmB + 5FC + Flu using the propensity score matching method. The effects of AmB dosage, AmB course and Flu addition on the cerebrospinal fluid (CSF) chemical profile recovery, adverse effects, and 90-day mortality were compared between the groups. RESULTS: No differences in adverse effects, the rate of the 14-day CSF chemical profile recovery and 90-day cumulative survival rate (91.2% vs. 87.5%, P = 0.637) were observed between the AmB + 5FC group and the AmB + 5FC + Flu group. However, the incidence rates of hypokalemia (33.9%) and creatinine elevation (7.1%) in patients treated with an AmB dosage of 0.4-0.5 mg/kg/d were less than those (53.0 and 22.7%, respectively) treated with an AmB dosage of 0.6-0.7 mg/kg/d (P = 0.034 and P = 0.018, respectively). The 90-day cumulative survival rate was 70.1% for patients treated with AmB for <14 days and 96.4% for patients treated with AmB for ≥14 days (log-rank P < 0.001). Multivariate Cox proportional hazards models suggested the hazard ratio was 26.8 (95% CI: 3.9-183.2) for patients treated with AmB < 14 days than those treated with AmB ≥ 14 days (P = 0.001). CONCLUSION: Treatment with AmB less than 14 days was associated with a higher 90-day mortality in CM patients. A relative lower dosage but prolonged course of AmB in the +5FC ± Flu regimen led to favorable trends of fewer adverse effects and comparable clinical efficacy.

Activation of the kynurenine pathway is associated with poor outcome in Pneumocystis pneumonia patients infected with HIV: results of 2 months cohort study.

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is a key enzyme in the degradation of tryptophan (Trp) to kynurenine (Kyn). We measured IDO activity as the Kyn to Trp ratio, and investigated whether IDO could be used to assess prognosis of acquired immune deficiency Sydrome (AIDS) patients with pneumocystis pneumonia (PCP). METHODS: The Kyn and Trp concentration were measured by UPLC-MS/MS in plasma samples. A total of 49 AIDS-PCP patients were included in the analysis. Clinical characteristics and Kyn/Trp ratio were compared between survivors and non-survivors. RESULTS: Kyn/Trp ratio was significantly lower after anti-PCP treatment in AIDS patients with PCP (P < 0.0001). Plasma Kyn/Trp ratio was higher in patients with PaO2/FiO2 ≤ 300 mmHg than in those with PaO2/FiO2 > 300 mmHg (P = 0.007). Kyn/Trp ratio, D-dimer and CRP showed much higher AUC for predicting death of AIDS-PCP patients. Kyn/Trp ratio was useful for predicting the mortality of AIDS-PCP due to a significantly higher Kyn/Trp ratio in the non-survivors (P = 0.002). And the high Kyn/Trp ratio group had higher mortality rate than low Kyn/Trp group (32.1% vs. 9.1%, respectively, p = 0.024). CONCLUSION: Activation of the kynurenine pathway is associated with the severity and fatal outcomes of AIDS patients with pneumocystis pneumonia.

Importance of fibrosis 4 index score and mode of anti-fungal treatment to the outcome of Cryptococcal meningitis in hepatitis B virus-infected patients.

BACKGROUND: Hepatitis B virus (HBV) and the associated cirrhosis are risk factors for cryptococcal meningitis (CM). However, the clinical features of co-infection with HBV and CM are unclear. METHODS: Seventy-nine HBV-infected CM patients and 79 HBV-uninfected CM patients were enrolled in a case-control matching study from 476 CM patients. Fibrosis 4 index (FIB4) was used for assessment of HBV-related fibrosis/cirrhosis. Demographic characteristics, symptoms, routine blood tests, liver function and cerebrospinal fluid (CSF) profiles were compared between the two groups. Kaplan-Meier analysis and Cox proportional hazards model were used to assess factors associated with 10-week mortality. RESULTS: Male gender was associated with HBV-infected CM patients (p = .006). CM patients with HBV experienced similar frequencies of symptoms but had lower white blood cell (WBC) (p < .001), platelet (p < .001) and albumin (p = .012), and increased aspartate amino transaminase (AST) (p = .009) and total bilirubin (TBIL) levels (p < .001). Patients with and without HBV infection had similar 10-week cumulative survival rates (85.9 ± 4.2% vs. 78.6 ± 5.4%, p = .569). The hazard ratio was 3.7 times higher for those with FIB4 ≥ 3.25 (p = .020) and 4.5 times higher for those with HBV infection not treated with Amphotericin B + flucytosine ± fluconazole (p = .023). CONCLUSION: HBV-infected CM population experience lower WBC, platelet and albumin, and higher AST and TBIL. Ten-week survival rate was similar between HBV-infected and HBV-uninfected CM patients. CM patients with high FIB4 or not treated with Amphotericin B + flucytosine ± fluconazole are at a higher risk of death.

Unique clinical features of cryptococcal meningitis among Chinese patients without predisposing diseases against patients with predisposing diseases.

The clinical features of cryptococcal meningitis (CM) in patients without predisposing diseases (PD) remain unclear. In sum, 162 of the 167 patients without PD and 162 of the 309 patients with PD were enrolled after propensity score matching. Demographic characteristics, symptoms, blood, and cerebrospinal fluid (CSF) characteristics were compared between the two groups. Kaplan-Meier curves and a Cox proportional hazards model were used to assess the factors associated with 10-week mortality. In total, approximately 35.1% of CM patients were without PD. CM patients without PD had blood profiles of higher white blood cells (WBC) [8.9(6.7-11.0) × 109/l], hemoglobin (128.4 ± 20.9 g/l), platelets [(226.2 ± 64.1) × 109/l], and serum albumin (41.2 ± 5.8 g/l) (all P ≤ .001) and CSF profiles of lower glucose (2.0 ± 1.2 mmol/l), pleocytosis [65.0 (18.0-160.0) × 106/l] and higher total protein [0.9 (0.7-1.4)g/l] (all P < .05). CM patients without PD had lower Cryptococcus culture positivity in CSF (62.5% vs. 74.1%, P = .039) but higher 2-week of CSF culture sterilization rates (69.4% vs. 51.3%, P = .031). The overall 10-week survival rate was 84.7% in patients without PD and 81.1% in patients with PD (Log-rank P = .439). CSF glucose <1.5 mmol/l, CSF fungal burden >20 cells/high power field and treatment lacking amphotericin B had a 3-4 times higher risk of death in patients without PD, whereas serum albumin <35 g/l, CSF glucose < 1.5 mmol/l, and CSF WBC <55 × 106 cell/l were risk factors for patients with PD. CM patients without PD had unique blood and CSF profiles, especially, had lower Cryptococcus culture positivity in CSF, and higher 2-week CSF culture sterilization. Low CSF glucose levels, higher fungal burden, and treatment without amphotericin B were risk factors for 10-week mortality.

The presence of Pneumocystis jirovecii DNA in plasma is associated with a higher mortality rate in patients with AIDS-associated Pneumocystis pneumonia.

To examine the relationship between Pneumocystis jirovecii DNA (PJ-DNA) levels in blood from AIDS-associated Pneumocystis pneumonia (AIDS-PCP) and mortality, and to correlate mitochondrial large subunit rRNA (mtLSUrRNA) gene polymorphism with mortality, we performed a retrospective study including AIDS-PCP patients between 2014 and 2016 from one hospital in China. PJ-DNA in plasma was measured by nested polymerase chain reaction (PCR) of the mtLSUrRNA gene and in positive specimens we further detected the level of PJ-DNA using qPCR. Polymorphisms were observed at two positions (85 and 248) of the mtLSUrRNA gene by sequencing. The PJ-DNA positivity rate for survivors and nonsurvivors was 13.64% (9/66) and 78.57% (11/14) (P ≤ .001), respectively. Using multivariate analysis, we found that lactate dehydrogenase, PaO2, albumin and PJ-positive in blood were independent predictors of death (P = .011; P = .042; P = .01; P ≤ .001, respectively). The PJ-DNA level in the nonsurvivor group (n = 11) was higher than that of the survivor group (n = 9) (54610.3copies/ ml vs. 934.5 copies/ml, P = .006). Nine had genotype 1, and 88.89% (8/9) patients died. Of nine with genotype 3, 11.11% (1/9) died (P = .003). In conclusion, high PJ-DNA level detected by analyzing plasma and mtLSUrRNA genotype 1 are strongly associated with death in AIDS-PCP patients.

A single-center experience of non-bioartificial liver support systems among Chinese patients with liver failure.

INTRODUCTION: Liver failure is one of the most deadly, prevalent, and costly diseases worldwide. Non-bioartificial liver support systems (NBALs) have been shown to be effective in improving the clinical symptoms and laboratory parameters of patients with liver failure. The main aim of this large case series analysis was to investigate the status of NBALs and their effectiveness in improving survival in liver-failure patients. METHODS: In this retrospective study, 460 patients with liver failure who received NBAL treatment in addition to conventional medications were compared with 422 patients who were treated with conventional medications alone. Kaplan-Meier and life table analyses were used to estimate survival rates. RESULTS: Clinical outcomes were improved after NBAL treatment. The 30-day survival rates of subacute liver failure (SALF) patients were 63% among those who received NBALs and 21% among those who did not receive NBALs (p < 0.01). Similarly, the 30-day survival rate of acute-on-chronic liver failure (ACLF) patients who received NBALs was 47%, significantly higher than that of the non-NBAL patients (p < 0.05). The survival rates of ACLF patients with low Model for End-Stage Liver Disease (MELD) scores (MELD ≤ 20) were 64% and 40% among whom received NBALs and those who did not, respectively (p < 0.01). CONCLUSIONS: NBAL treatment is helpful to improve the survival of patients with ALF, SALF or ACLF. ACLF patients with lower MELD scores showed improved outcomes relative to those with higher MELD scores.