Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acutely decompensated cirrhosis

BACKGROUND AND AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in cirrhosis patients with acute decompensation (AD), focusing on NHVs and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 cirrhosis patients with AD in study cohort. Ten healthy volunteers and 20, 39, and 81 patients with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation in a validation cohort (n = 58) were performed and exploratory treatment instituted. RESULTS: In study cohort, 188 microorganisms were detected in 74.4% (96/129) patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). Patients with AD had an NHV signature, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure (ACLF), and 90-day mortality. The NHV signature in ACLF patients was similar to patients with sepsis and hematological malignancies. The treatable NHV, CMV was detected in 24.1% (14/58) patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, 9 were further validated by DNA RT-PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in exploratory manner with clinical resolutions. CONCLUSIONS: The results of this study suggests that NHVs may have a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated in the routine management of AD patients. IMPACT AND IMPLICATIONS: ●Cirrhosis patients with acute decompensation have a non-hepatotropic virus (NHV) signature, which is similar to that in sepsis and hematological malignancies patients. ●The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. ●The treatable NHV, CMV reactivation may be involved in the clinical outcomes of decompensated cirrhosis. ●Routine screening for NHVs, especially CMV, may be useful for the management of patients with acutely decompensated cirrhosis

Different Effects of Total Bilirubin on 90-Day Mortality in Hospitalized Patients With Cirrhosis and Advanced Fibrosis: A Quantitative Analysis

Introduction: Total bilirubin (TB) is a major prognosis predictor representing liver failure in patients with acute on chronic liver failure (ACLF). However, the cutoff value of TB for liver failure and whether the same cutoff could be applied in both cirrhotic and non-cirrhotic patients remain controversial. There is a need to obtain the quantitative correlation between TB and short-term mortality via evidence-based methods, which is critical in establishing solid ACLF diagnostic criteria.Methods: Patients hospitalized with cirrhosis or advanced fibrosis (FIB-4 > 1.45) were studied. TB and other variables were measured at baseline. The primary outcome was 90-day transplantation-free mortality. Multi-variable Cox proportional hazard model was used to present the independent risk of mortality due to TB. Generalized additive model and second derivate (acceleration) were used to plot the “TB-mortality correlation curves.” The mathematical (maximum acceleration) and clinical (adjusted 28-day transplantation-free mortality rate reaching 15%) TB cutoffs for liver failure were both calculated.Results: Among the 3,532 included patients, the number of patients with cirrhosis and advanced fibrosis were 2,592 and 940, respectively, of which cumulative 90-day mortality were 16.6% (430/2592) and 7.4% (70/940), respectively. Any increase of TB was found the independent risk factor of mortality in cirrhotic patients, while only TB >12 mg/dL independently increased the risk of mortality in patients with advanced fibrosis. In cirrhotic patients, the mathematical TB cutoff for liver failure is 14.2 mg/dL, with 23.3% (605/2592) patients exceeding it, corresponding to 13.3 and 25.0% adjusted 28- and 90-day mortality rate, respectively. The clinical TB cutoff for is 18.1 mg/dL, with 18.2% (471/2592) patients exceeding it. In patients with advanced fibrosis, the mathematical TB cutoff is 12.1 mg/dL, 33.1% (311/940) patients exceeding it, corresponding to 2.9 and 8.0% adjusted 28- and 90-day mortality rate, respectively; the clinical TB cutoff was 36.0 mg/dL, 1.3% (12/940) patients above it.Conclusion: This study clearly demonstrated the significantly different impact of TB on 90-day mortality in patients with cirrhosis and advanced fibrosis, proving that liver failure can be determined by TB alone in cirrhosis but not in advanced fibrosis. The proposed TB cutoffs for liver failure provides solid support for the establishment of ACLF diagnostic criteria

PPARα Targeting GDF11 Inhibits Vascular Endothelial Cell Senescence in an Atherosclerosis Model

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Using molecular biology and cell biology approaches to detect senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11). GDF11 levels declined with age in several organs including the myocardium, bone, central nervous system, liver, and spleen in mice and participated in the regulation of aging. Our results showed that PPARα inhibited vascular endothelial cell senescence and apoptosis and promoted vascular endothelial cell proliferation and angiogenesis by increasing GDF11 production. Taken together, these results demonstrated that PPARα inhibited vascular endothelial cell aging by promoting the expression of the aging-related protein GDF11, thereby delaying the occurrence of AS

Identification of Urban Ecological Security Pattern Based on Ecosystem Services Supply–Demand

The construction of ecological security pattern (ESP) is an effective way to ensure regional ecological security. Although the method of constructing the regional ESP based on ecosystem services (ESs) has been widely recognized and applied, the spatial characteristics of ESs supply–demand mismatch has not been well included into ESP construction. We constructed a regional ESP framework connecting demand sources and ecological sources from the perspective of ESs supply–demand mismatch. Taking the Wuhan urban agglomeration (WUA), findings indicated distinct spatial aggregations of ecological sources and demand sources due to the supply–demand mismatch of ESs. Ecological sources (12,406.29 km2 or 21.42%) were primarily located in the south and north of WUA, while demand sources (1,191.26 km2 or 2.07%) were concentrated mainly in the central. Two types of corridors jointly ensured regional ecological security. A total of 86 supply–supply corridors in the north ensured the supply ability of ESs by connecting ecological sources, while 35 supply–demand corridors in the south alleviated the supply–demand mismatch of ESs. The targeted implementation of ecological governance based on the corridor types provides a new approach to coordinate the mismatch of ESs supply–demand and enhance ecological security. However, 63.38 km2 of pinch points, recognized as high-flow areas within the corridors, primarily comprised fragmented landscapes, and barriers covering 99.67 km2 obstructed corridor flow, notably surrounding the demand sources. These regions should be prioritized for ecological conservation. Overall, this research framework provides a reliable scientific basis for configuring spatial landscape patterns and developing ecological strategies in urban agglomerations

Laser diagnostics and chemical kinetic analysis of PAHs and soot in co-flow partially premixed flames using diesel surrogate and oxygenated additives of n-butanol and DMF

Effects of oxygenated fuels on soot reduction strongly depend on the base fuel. Interesting candidates from oxygenated fuels in this respect include both n-butanol and 2,5-dimethylfuran (DMF), because they have already been used in diesel engines recently. However, information is rather limited on n-butanol and DMF added into a diesel fuel surrogate in fundamental flames to investigate the mechanism of soot reduction. In the current work, both n-butanol and DMF was successively added into diesel surrogate (80% n-heptane and 20% toluene in volume, named as T20) in co-flow partially premixed flames. The effects of different oxygenated structures on polycyclic aromatic hydrocarbons (PAHs) and soot were investigated at the same oxygen weight fractions of 4% and the same volume fractions of 20%. The diagnostics on PAHs, soot volume fractions and soot sizes were conducted by using both laser-induced fluorescence (LIF) and two-color laser-induced incandescence (2C-LII). A combined detailed kinetic model (n-heptane/toluene/butanols/DMF/PAHs) has been obtained in order to clarify the chemical effects of the different oxygenated fuels on PAHs formation. Results show that the reduced toluene content due to the addition of oxygenated fuels is the dominant factor for the reduction of soot, as compared with the base fuel of T20. The oxygenated structure of n-butanol has a higher ability to reduce PAHs and soot as compared with the addition of DMF. This is due to the fact that the consumption of DMF leads to much formation of C5H5 which enhances the formation of PAHs and subsequent soot. However, the formation of PAHs can be inhibited remarkably as blending n-butanol because only small hydrocarbons like C2H2 and C3H3 etc. are formed. The formation rate of A4 is more similar to that of soot in comparison with the smaller ring aromatics. For the size of soot particles, the distribution range is shrunk from 19–70 nm for T20 to 20–40 nm for the addition of oxygenated fuels. As compared to the effects of oxygenated structures, DMF20 presents a little wider distribution on soot sizes than that of B16.8. Some larger soot particles are detected in DMF20 flame but cannot be found in B20 flame