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Background: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined. Methods: De novo purine synthesis in proliferative VSMCs was evaluated by liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of ATIC-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesions. Results: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis. Conclusions: These results reveal that de novo purine synthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases.

Emerging evidence suggests that elevated concentrations of triglyceride-rich lipoprotein remnants (TRLs) derived from hepatic and intestinal sources contribute to the risk of atherosclerotic cardiovascular events. Natural selection studies support a causal role for elevated concentrations of remnant cholesterol and the pathways contributing to perturbations in metabolic pathways regulating TRLs with an increased risk of atherosclerotic cardiovascular disease events. New therapies targeting select catalytic pathways in TRL metabolism reduce atherosclerosis in experimental models, and concentrations of TRLs in patients with a vast range of triglyceride levels. Clinical trials with inhibitors of angiopoietin-like 3 protein and apolipoprotein C-III will be required to provide further guidance on the potential contribution of these emerging therapies in the paradigm of cardiovascular risk management in patients with elevated remnant cholesterol.

Background: Coronary allograft vasculopathy (CAV) is a devastating sequela of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. Methods: We assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle–specific Tet2 knockout mice; and in vitro studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNγ (interferon γ), a cytokine elaborated by T cells that drives CAV progression. Results: In the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. Conclusions: TET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.

Myocardial injury resulting from sepsis is the leading cause of death worldwide. Micro RNA miR-122-5p is involved in various physiological and pathological processes and is highly expressed in the heart of septic rats. However, its function in sepsis-caused myocardial injury remains elusive. Herein, a rat model of septic myocardial injury was established by intraperitoneal injection of lipopolysaccharide (LPS), and cardiomyocyte H9c2 was exposed to LPS to induce sepsis-related inflammatory injury in vitro. Inhibition of miR-122-5p suppressed LPS-triggered myocardial injury evidenced by decreased heart weight index (HWI), reduced inflammatory cell infiltration and cell rupture, and reduced cardiac marker enzymes cTnI and LDH. MiR-122-5p inhibition inhibited ROS production and enhanced the activities of antioxidant enzymes CAT, SOD and GSH-px in LPS-treated rats and H9c2 cells. MiR-122-5p inhibition reduced the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β, and inhibited cell apoptosis along with decreased cleaved-caspase 3 induced by LPS. Moreover, increased GIT1 expression was found following miR-122-5p inhibition. We further verified GIT1 as a target of miR-122-5p, and silencing GIT1 partially reversed the benefits of miR-122-5p loss in LPS-injured H9c2 cells. The HO-1 and NQO-1 expression and Nrf-2 activation were enhanced by miR-122-5p inhibition, which was reversed by GIT1 depletion, indicating the involvement of Nrf-2/HO-1 signaling in regulating miR-122-5p/GIT1-mediated cardioprotection. Taken together, our data suggest that inhibition of miR-122-5p may mitigate sepsis-triggered myocardial injury through inhibiting inflammation, oxidative stress and apoptosis via targeting GIT1, which provides a possible therapeutic target for sepsis., GRAPHICAL ABSTRACT

Introduction: Statin use after heart transplant (HT) has been shown to reduce rates of CAV and improve morbidity and mortality regardless of lipid profile. However, drug-drug interactions (DDIs) between statins and immunosuppressive therapies limit their use, particularly at higher doses. Recently, non-statin lipid modifying therapies have also been used in the HT population, despite a lack of outcome trials. Objective: We sought to examine current trends in lipid profiles and lipid-lowering therapy use in the HT population. Methods: We performed a retrospective chart review of 198 HT recipients (average age 53.6 years, 139 males, 59 females) transplanted between 4/8/2016 and 3/24/2020 at a single center. Of those patients, 82 underwent HT for ischemic cardiomyopathy (ICM), and 116 underwent HT for nonischemic cardiomyopathy (NICM). Lipid panels and medications were collected pre-transplant, immediately post-transplant, and 1-year post-transplant. Most recent values were also collected. At each point the 2018 lipid guidelines were used to determine the recommended intensity of statin each patient should ideally be on if they were not transplant patients. Results: Median cholesterol, triglyceride, HDL, and LDL values were reasonably well-controlled post HT. Despite high overall rates of statin use, our data suggest that most HT recipients are on lower than guideline-recommended statin doses due to DDI, particularly in the ICM group. The proportion of patients on non-statin lipid modifying therapies increased over time. Conclusions: There is emerging evidence that non-statin therapies added to statins can further reduce atherothrombotic events in non-transplant patients. These therapies may offer options for additional lipid control in transplant recipients whose statin use is limited by DDIs. However, the pathophysiology of CAV and atherosclerosis are different, and outcome trials of non-statin lipid therapies in HT patients are urgently needed.

The lipid aldehyde 4-oxo-2-nonenal (ONE) is a highly reactive protein crosslinker derived from peroxidation of n-6 polyunsaturated fatty acids and generated together with 4-hydroxynonenal (HNE). Lipid peroxidation product-mediated crosslinking of proteins in high-density lipoprotein (HDL) causes HDL dysfunction and contributes to atherogenesis. Although HNE is relatively well-studied, the role of ONE in atherosclerosis and in modifying HDL is unknown. Here, we found that individuals with familial hypercholesterolemia (FH) had significantly higher ONE-ketoamide (lysine) adducts in HDL (54.6 ± 33.8 pmol/mg) than healthy controls (15.3 ± 5.6 pmol/mg). ONE crosslinked apolipoprotein A-I (apoA-I) on HDL at a concentration of > 3 mol ONE per 10 mol apoA-I (0.3 eq), which was 100-fold lower than HNE, but comparable to the potent protein crosslinker isolevuglandin. ONE-modified HDL partially inhibited HDL's ability to protect against lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) gene expression in murine macrophages. At 3 eq, ONE dramatically decreased apoA-I exchange from HDL, from ∼46.5 to ∼18.4% (p < 0.001). Surprisingly, ONE modification of HDL or apoA-I did not alter macrophage cholesterol efflux capacity. LC-MS/MS analysis revealed that Lys-12, Lys-23, Lys-96, and Lys-226 in apoA-I are modified by ONE ketoamide adducts. Compared with other dicarbonyl scavengers, pentylpyridoxamine (PPM) most efficaciously blocked ONE-induced protein crosslinking in HDL and also prevented HDL dysfunction in an in vitro model of inflammation. Our findings show that ONE-HDL adducts cause HDL dysfunction and are elevated in individuals with FH who have severe hypercholesterolemia.

Background Persons with low socioeconomic status and nonwhite persons in the United States have high rates of cardiovascular disease. The use of combination pills (also called “polypills”)...

Septic shock with heart dysfunction is common in intensive care units. However, the mechanism underlying myocardial depression is still unclear. Whether circular RNA (circRNA) or microRNA (miRNA) profiles differ between patients with and without myocardial depression is unknown. We generated a hypodynamic septic shock model induced by lipopolysaccharide (LPS) in adolescent rats. A total of 12 rats were utilized and heart tissue from each was collected. RNA sequencing was performed on left ventricular tissue. We focused on features of circRNAs and miRNAs, predicting their function by bioinformatic analysis and constructing circRNA-associated and miRNA-associated regulatory networks in heart tissue. We detected 851 circRNAs in heart samples, and 11 showed differential expression. A total of 639 annotated miRNAs and 91 novel miRNAs were explored including 78 showing differential expression between the two groups. We then constructed the most comprehensive circRNA-associated and miRNA-associated networks to explore their regulatory relationship in septic heart tissue, and demonstrated that different networks could potentially participate in and regulate the pathological process of sepsis. Furthermore, gene ontology term enrichment indicated miRNAs, and miRNA-mRNA networks could be associated with regulation and metabolic process, or influence cellular functions. The construction of regulator networks could improve the understanding of the basic molecular mechanisms underlying myocardial depression. It will be important for future investigations to ascertain the biological mechanisms present during the development of sepsis-induced myocardial depression to influence approaches to treatment.

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10−4) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

Background Short-term recurrence of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA) polymerase chain reaction (PCR) in discharged coronavirus disease 2019 (COVID-19) patients attracts the public’s concern. This study aimed to determine the clinical and epidemiological results of such patients. Methods This retrospective study was conducted on 32 designated hospitals for COVID-19 patients discharged from January 14 to March 10, 2020. After 28-day followed-up, patients who tested positive again for SARS-CoV-2 RNA and confirmed by reverse-transcriptase polymerase chain reaction were re-admitted to hospital for further treatments. All of the close contacts of patients who tested positive again were asked to self-segregate for 14 days. Data of epidemiology, symptoms, laboratory tests, and treatments were analyzed in those patients, and their close contacts were investigated. Results Of 1282 discharged patients, 189 (14.74%) tested positive again for SARS-CoV-2 RNA during 28-day follow-up. The median time from discharge to the next positive test was 8 days (interquartile range [IQR], 5–13). Patients in the group that tested positive again were younger (34 vs 45 years, P < .001) with a higher proportion of moderate symptoms (95.77% vs 84.35%, P < .001) in the first hospitalization than in the negative group. During the second hospitalization, all patients who tested positive again showed normal peripheral white blood cells and lymphocytes and no new symptoms of COVID-19; 78.31% further improved on chest computed tomography scan compared with the first discharge, yet 25.93% accepted antiviral therapy. The median time of re-positive to negative test was 8 days (IQR, 4–15). None of the close contacts developed COVID-19. Conclusions Our data suggest that the short-term recurrence of positive SARS-CoV-2 RNA in discharged patients is not a relapse of COVID-19, and the risk of onward transmission is very low. This provides important information for managing COVID-19 patients.

Mitochondrial damage is considered one of the main pathogenetic mechanisms in septic cardiomyopathy. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is critical for maintaining energy homeostasis in different organs and in various physiological and pathological states. It is also a key regulator gene in mitochondrial metabolism. In this study, we investigated whether regulation of the PGC-1α gene had protective effects on septic cardiomyopathy. We developed a rat model of septic cardiomyopathy. H9c2 myocardiocytes were treated with lipopolysaccharide (LPS) and PGC-1α expression measured. PGC-1α-overexpressing lentivirus was used to transfect H9c2 cells. ZLN005 was used to activate PGC-1α. The effect of the inhibition of PGC-1α expression on myocardial cell injury and its underlying mechanisms were also explored. Cell viability was measured by CCK-8 assay. Mitochondrial damage was determined by measuring cellular ATP, reactive oxygen species, and the mitochondrial membrane potential. An apoptosis analysis kit was used to measure cellular apoptosis. Mitochondrial DNA was extracted and real-time PCR performed. LC3B, mitochondrial transcription factor A (TFA), P62, Bcl2, and Bax were determined by immunofluorescence. LC3B, TFA, P62, Parkin, PTEN-induced putative kinase 1, and PGC-1α proteins were determined by Western blotting. We found mitochondrial damage and apoptotic cells in the myocardial tissue of rats with septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α expression was decreased in the late phase of septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α activation by ZLN005 and PGC-1α overexpression reduced apoptosis in myocardiocytes after LPS incubation. PGC-1α gene overexpression alleviated LPS-induced cardiomyocyte mitochondrial damage by activating mitochondrial biogenesis and autophagy functions. Our study indicated that mitochondrial damage and apoptosis occurred in septic cardiomyopathy and LPS-treated cardiomyocytes. The low expression level of PGC-1α protein may have contributed to this damage. By activating the expression of PGC-1α, apoptosis was reduced in cardiomyocytes. The underlying mechanism may be that PGC-1α can activate mitochondrial biogenesis and autophagy functions, reducing mitochondrial damage and thereby reducing apoptosis.

Given the success of both targeted and immunotherapies against cancer, there is increasing utility for identifying targeted agents that also promote anti-tumor immunity. EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in non-small cell lung cancer (NSCLC). Effects of EphA2 overexpression in murine NSCLC cells were evaluated in both in vitro cell viability assays and in vivo tumor models. Tumor immune infiltrate was assessed by flow cytometry. Cytokine and chemokine expression was evaluated using NanoString technology and qRT-PCR. Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrate revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T cell activation, particularly in CD8 T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1. Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape. Further studies are needed to determine the molecular mechanisms by which EphA2 affects the recruitment of these cell types and to test the function of these myeloid cells.

An outbreak of novel coronavirus-related pneumonia COVID-19, that was identified in December 2019, has expanded rapidly, with cases now confirmed in more than 211 countries or areas. This constant transmission of a novel coronavirus and its ability to spread from human to human have prompted scientists to develop new approaches for treatment of COVID-19. A recent study has shown that remdesivir and chloroquine effectively inhibit the replication and infection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCov) in vitro. In the United States, one case of COVID-19 was successfully treated with compassionate use of remdesivir in January of 2020. In addition, a clinically proven protease inhibitor, camostat mesylate, has been demonstrated to inhibit Calu-3 infection with SARS-CoV-2 and prevent SARS-2-spike protein (S protein)-mediated entry into primary human lung cells. Here, we systemically discuss the pharmacological therapeutics targeting RNA-dependent RNA polymerase (RdRp), proteinase and S protein for treatment of SARS-CoV-2 infection. This review should shed light on the fundamental rationale behind inhibition of SARS-CoV-2 enzymes RdRp as new therapeutic approaches for management of patients with COVID-19. In addition, we will discuss the viability and challenges in targeting RdRp and proteinase, and application of natural product quinoline and its analog chloroquine for treatment of coronavirus infection. Finally, determining the structural-functional relationships of the S protein of SARS-CoV-2 will provide new insights into inhibition of interactions between S protein and angiotensin-converting enzyme 2 (ACE2) and enable us to develop novel therapeutic approaches for novel coronavirus SARS-CoV-2.

Background: a2A adrenoceptor receptor (a2A-AR) plays an important role in inflammatory response in Kupffer cells in sepsis. Blockage of a2A-AR inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNF-a) production and protects the target organ functions in sepsis animal models; however, its expression and function in microglia have remained obscure. This study aimed to determine whether a2A-AR was expressed in microglia and whether its activation would exacerbate microglial inflammation and sepsis-related neurological dysfunction. Methods: Western blotting and immunofluorescence were used to detect a2A-AR expression in BV-2 microglia. Enzyme-linked immunosorbent assay (ELISA) was used to assess the TNF-a production in the supernatant after LPS induced BV-2 cells were pretreated with a2A-AR agonist BHT933, and/or a2A-AR antagonist BRL44408, and also in the supernatants derived from BV-2 cells treated with BHT933 and/or PKC inhibitor. Signaling pathways including JNK，P38，ERK，IκBa, CREB and PCK were detected by western blotting. a2A-AR gene knock-out (KO) and wild type (WT) mice were prepared by intraperitoneal injection of LPS. Lectin /TNF-a labeled microglia and synaptophysin/NeuN expression in the hippocampus were localized by immunofluorescence. Morris water maze test, Rotating-stick test, Elevated plus maze test and Open-field test were conducted over 4 weeks.Results: a2A-AR was constitutively expressed in BV-2 microglia, which was enhanced by LPS. Pretreatment with BHT933 promoted LPS-induced IκB and JNK phosphorylation, and TNF-a secretion in BV-2 microglia which were abrogated by BRL44408. Activation of a2A-AR by BHT933 also increased PKC phosphorylation in LPS-treated BV-2 microglia. PKC inhibitor significantly reversed the promoting effects of BHT933 on IκB and JNK phosphorylation as well as TNF-a secretion in LPS-treated BV-2 microglia. Furthermore, LPS treatment significantly increased hippocampal microglia activation and TNF-a expression, decreased hippocampal synaptophysin expression, and impaired cognitive and motor functions in WT mice, all of which were markedly reversed by a2A-AR gene knockout. Conclusion: a2A-AR activation promotes LPS-induced IκB and JNK phosphorylation as well as TNF-a production in microglia through the PKC signaling pathway. Knockout of a2A-AR gene significantly improves LPS-induced cognitive and motor impairments in mice, indicating that a2A-AR is a potential therapeutic target for sepsis-associated encephalopathy.

Background: Around the globe, moderate cases account for the largest proportion of all COVID-19 patients, and deteriorated moderate patients contribute the most in mortality. However, published articles failed to address the deterioration details of moderate case, especially on when and how they deteriorated. Methods: All moderate COVID-19 patients hospitalized in Guangdong Province from Jan 14th to Mar 16th, 2020 were included in this multi-centre, retrospective, cohort study, and were divided into deteriorated and non-deteriorated groups according to clinical status. Demography, symptoms, therapy and laboratory characteristics were collected to explore the features of disease deterioration. Findings: Of 1168 moderate patients included, 148 (13%) deteriorated to severe (130 cases) or critical (18 cases) status. Over 20% of the older subgroup (＞50 years old) showed deterioration. The median time for deterioration was 11 days after onset (IQR 9-14). 12.2% severe cases could further develop to critical status after 3 days (IQR 2-6.5) of severe condition. Respiratory dysfunction and hypoxia were the major manifestations as disease deterioration, while 76 cases (52.1%) showed respiratory rate > 30 breaths/min, 119 cases showed (80.4%) SaO2 2.0mmol/L. In view of multiple organs dysfunction, 87.8% of acute respiratory distress syndrome (ARDS), 20.2% of acute kidney injury (AKI), 6.8% of coagulopathy, 4% of acute heart failure (AHF), 3.4% of acute hepatic injury (AHI), and 5.4% of Shock were occurred in deteriorated patients; while the organs injuries occurred in following sequence: ARDS, AKI, AHF, Coagulopathy, AHI and Shock. Interpretation: The deteriorated pattern of moderate COVID-19 patients is characterized as the 11th day from onset (IQR 9-14) being an important time point of disease deterioration with further exacerbate to critical condition in 3 days (IQR 2-6.5); and ARDS followed by AKI being the typical mode of sequential organs damage. Funding Statement: This study is supported by Special Project on Emergency Response to Control of Novel Coronavirus Infection of Guangdong Province (NO. 2020B1111330003) and National Natural Science Foundation of China (NO. 81701875). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Board of Guangdong Health Commission and Guangdong Provincial People’s Hospital (No. GDREC2020028H). Written informed consent was waived in light of the urgent need to collect data.

Background: COVID-19 has already become a global pandemic There are few detailed descriptions of moderate cases and their clinical progression Our aim was to

Background: Recurrence of positive SARS-CoV-2 RNA in discharged COVID-19 patients attracts the public’s concern. It remained unknown whether this phenomenon means relapse of disease or transmissible, which is essential to the management of discharged COVID-19 patients. Methods: A multi-center, retrospective, observational study was conducted on 32 designated hospitals for COVID-19 in Guangdong Province. All COVID-19 discharged patients from January 14 th to March 10 th , 2020 were enrolled in this study, and were followed up for 14 days with testing of SARS-CoV-2 nucleic RNA, observation of clinical symptoms, chest CT scan and laboratory tests. Clinical symptoms and RNA test also were carried out in their close contacts. Findings: Of 1,282 discharged patients enrolled in this study, 155(12.1%)were tested positive of SARS-CoV-2 RNA during 14 days’ follow-up. The median time of recurrence of SARS-CoV-2 RNA was 7 days (IQR4-9). Compared to negative group, the patients from re-positive group were a younger (35yr vs 45yr mean,p

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors effectively lower LDL (low‐density lipoprotein) cholesterol and have been shown to reduce cardiovascular outcomes in high‐risk patients. We used real‐world electronic health record data to characterize use of PCSK9 inhibitors, in addition to standard therapies, according to cardiovascular risk status. Methods and Results Data were obtained from 18 health systems with data marts within the National Patient‐Centered Clinical Research Network (PCORnet) using a common data model. Participating sites identified >17.5 million adults, of whom 3.6 million met study criteria. Patients were categorized into 3 groups: (1) dyslipidemia, (2) untreated LDL ≥130 mg/dL, and (3) coronary artery disease or coronary heart disease. Demographics, comorbidities, estimated 10‐year atherosclerotic cardiovascular disease risk, and lipid‐lowering pharmacotherapies were summarized for each group. Participants’ average age was 62 years, 50% were female, and 11% were black. LDL cholesterol ranged from 85 to 151 mg/dL. Among patients in groups 1 and 3, 54% received standard lipid‐lowering therapies and a PCSK9 inhibitor was prescribed in Conclusions We successfully used electronic health record data from 18 PCORnet data marts to identify >3.6 million patients meeting criteria for 3 patient groups. Approximately half of patients had been prescribed lipid‐lowering medication, but

Prostaglandin (PG) D2 is formed by two distinct PGD synthases (PGDS): lipocalin-type PGDS (L-PGDS), which acts as a PGD2-producing enzyme and as extracellular lipophilic transporter, and hematopoietic PGDS (H-PGDS), a σ glutathione-S-transferase. PGD2 plays an important role in the maintenance of vascular function; however, the relative contribution of L-PGDS– and H-PGDS–dependent formation of PGD2 in this setting is unknown. To gain insight into the function played by these distinct PGDS, we assessed systemic blood pressure (BP) and thrombogenesis in L-Pgds and H-Pgds knockout (KO) mice. Deletion of L-Pgds depresses urinary PGD2 metabolite (PGDM) by ∼35%, whereas deletion of H-Pgds does so by ∼90%. Deletion of L-Pgds, but not H-Pgds, elevates BP and accelerates the thrombogenic occlusive response to a photochemical injury to the carotid artery. HQL-79, a H-PGDS inhibitor, further depresses PGDM in L-Pgds KO mice, but has no effect on BP or on the thrombogenic response. Gene expression profiling reveals that pathways relevant to vascular function are dysregulated in the aorta of L-Pgds KOs. These results indicate that the functional impact of L-Pgds deletion on vascular homeostasis may result from an autocrine effect of L-PGDS–dependent PGD2 on the vasculature and/or the L-PGDS function as lipophilic carrier protein.

Background and Purpose Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti-inflammatory and cardio-protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury. Experimental Approach Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical- and ferric chloride-induced carotid artery thrombosis were employed to evaluate platelet function. Key Results FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX-1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury-induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co-administration of FO and aspirin decreased the expression of pro-inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro-resolution lipid mediator-Resolvin E1, was significantly elevated in plasma in FO/aspirin-treated mice. Conclusions and Implications Co-administration of FO and low-dose aspirin may act synergistically to protect against thrombosis and injury-induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease. Linked Articles This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.

There is growing evidence suggesting that high-density lipoprotein (HDL) function is more important than the HDL cholesterol (HDL-C) levels. HDL particles are highly heterogeneous and their function may also differ among different patient populations. There are two populations that are recognized tohave significant residual cardiovascular risk despite intensive statin therapy: atherogenic dyslipidaemia and diabetes mellitus. Atherogenic dyslipidemia and diabetes have significant homology with regards to lipid profiles. However, systemic epidemiological studies that describes the overlapping profiles between atherogenic dyslipidemia and diabetes is lacking. The function and types of HDL in these two populations needs to be carefully elucidated. HDL has many functions includingreverse cholesterol transport, anti-oxidant activity and anti-inflammatory activity. HDL may also exert “antiplatelet effects”but the mechanism is unclear.We assessed the prevalence of atherogenic dyslipidemia in diabetes mellitus using data from the National Health and Nutrition Examination Survery (NHANES) and data from Yale New Haven Health (YNHH). We found that atherogenic dyslipidemia and diabetes mellitushave overlapping lipid profiles but are clearly two distinct conditions. In our preliminary studies, we found that HDL inhibits platelet aggregation and activation. Very interestingly, we found HDL can induce mitochondria dependent platelet apoptosis. The antiplatelet effect of HDL, as observed by others in the past, may arise fromapoptotic platelets that do not aggregate, and thus the inhibition of platelet aggregation. Whether HDL subtypes from atherogenic dyslipidemia and diabetes patient have differential effects on platelet apoptosis are currently being investigated.

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

Aims Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. Methods and results Eight-week-old male apolipoprotein E knockout ( ApoE −/−) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n −3 long chain fatty acids (LC n −3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. Conclusion Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n −3 FA.

Summary Background Prostaglandin (PG) D2 is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma. Objectives Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD2, monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE2, thromboxane A2 and PGI2, also measured as major urinary metabolites. Methods Eighteen subjects with asthma participated in a cross-over study where celecoxib 200 mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV1 and airway inflammation as fraction of exhaled nitric oxide (FENO). Results Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV1 or FENO. Conclusion and Clinical Relevance Biosynthesis of PGD2 was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE2. The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics. Cite this as: K. Daham, W.- L. Song, J. A. Lawson, M. Kupczyk, A. Gulich, S.-E. Dahlen, G. A. FitzGerald and B. Dahlen, Clinical & Experimental Allergy, 2011 (41) 36–45.

The total and stereospecific synthesis of d(4)-5-epi-8,12-iso-iPF(3alpha)-VI 55 and d(4)-8,12-iso-iPF(3alpha)-VI 64, EPA-derived all-syn-isoprostanes (iPs), has been accomplished. Because of issues related to volatility and yield with some of the primary deuterated synthons an improved synthesis is presented. These two deuterated analogs were used to discover and quantify the presence of the corresponding endogenous isoprostanes in human urine. These assays may serve as a valuable index of oxidative stress in population with omega-3 fatty acid enriched diets containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and may also be useful as an index of the severity of inflammatory diseases such as atherosclerosis and Alzheimer's disease.

The stereospecific synthesis of two all-syn-EPA-derived isoprostanes (iPs), 5-epi-8,12-iso-iPF(3alpha)-VI 17 and 8,12-iso-iPF(3alpha)-VI 18, has been accomplished. These two synthetic probes have been used to discover and identify their presence in human urine. The eventual quantitative measurement of these two iPs may be a valuable index of oxidative stress in people with eicosapentaenoic acid- (EPA) and docosahexaenoic acid- (DHA) enriched phospholipids.

Prostaglandins (PGs), particularly PGE2 and prostacyclin (PGI2), are potent mediators of pain and inflammation. Both atherosclerosis and aortic aneurysm exhibit the hallmarks of inflammation. However, randomized trials of inhibitors of PG synthesis--nonsteroidal anti-inflammatory drugs--reveal that they predispose to cardiovascular risk. This appears to be consequent to inhibition of PGI2 and PGE2 formed by cyclooxygenase-2 (COX-2). Inhibitors of microsomal PGE synthase-1 (mPGES-1) are being developed for relief of pain and interest has focused on their potential impact on the cardiovascular system. Deletion of mPGES-1 retards atherogenesis and limits aortic aneurysm formation in hyperlipidaemic mice. However, it does not predispose to thrombogenesis and has a limited impact on blood pressure compared to inhibition of COX-2. This occurs despite the potential of the suppressed PGE2 in affording cardioprotection via its EP2 and EP4 receptors. However, deletion of mPGES-1 permits rediversion of the PGH2 substrate to other PG synthases and augmented formation of PGI2 and PGD2 mitigates this effect. However, increased PGI2 may also attenuate relief of pain. Pain relief seems likely to be a nuanced indication for mPGES-1 inhibitors, but they have therapeutic potential in syndromes of cardiovascular inflammation, cancer and perhaps in neurodegenerative disease. However, as the products of substrate rediversion vary according to cell type, these drugs may have contrasting impact amongst individuals at varied stages of disease evolution.

Background— Microsomal prostaglandin (PG) E 2 synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH 2 into PGE 2 . Deletion of mPGES-1 modulates experimentally evoked pain and inflammation and retards atherogenesis. The role of mPGES-1 in abdominal aortic aneurysm is unknown. Methods and Results— The impact of mPGES-1 deletion on formation of angiotensin II–induced abdominal aortic aneurysm was studied in mice lacking low-density lipoprotein receptor (LDLR −/− ). Male mice deficient in both mPGES-1 and LDLR (mPGES-1 −/− LDLR −/− ) and littermate LDLR −/− mice were initiated on a high-fat diet at 6 months of age, followed 1 week later by continuous infusion of angiotensin II (1 μg/kg per minute) for an additional 4 weeks. Angiotensin II infusion upregulated aortic expression of cyclooxygenase-2 and mPGES-1, increased aortic macrophage recruitment and vascular nitrotyrosine staining (which reflects local oxidative stress), and augmented urinary excretion of the isoprostane 8,12- iso -iPF 2α -VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence (87.5% versus 27.3%; P =0.02) and the severity of abdominal aortic aneurysm and depressed the aortic and systemic indices of oxidative stress. Deletion of mPGES-1 also depressed urinary PGE-M, whereas it augmented excretion of PGD 2 and PGI 2 metabolites, reflecting rediversion of the accumulated PGH 2 substrate in the double knockouts. Conclusions— Deletion of mPGES-1 protects against abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice, coincident with a reduction in oxidative stress. The potential efficacy of selective inhibition of mPGES-1 in preventing or retarding aneurysm formation warrants further investigation.

Isoeicosanoids are free radical-catalyzed isomers of the enzymatic products of arachidonic acid. They are formed in situ in cell membranes, are cleaved, circulate, and are excreted in urine. Isomers of prostaglandin F(2alpha), the F(2)-isoprostanes, have emerged as sensitive indices of lipid peroxidation in vivo. Analogous compounds formed from docosahexaenoic acid (DHA) are termed neuroprostanes and are more abundant than isoprostanes (iPs) in brain. Isofurans are another class of isoeicosanoids characterized by a substituted tetrahydrofuran ring. They are preferentially formed, relative to iPs, under conditions of elevated oxygen tension. Here, we report the discovery of neurofurans (nFs), the analogous family of compounds formed from DHA. Formation of nFs is characterized by mass spectrometry and confirmed by oxidation of DHA in vitro and following CCl(4) administration in liver in vivo. It is demonstrated that the levels of nFs are elevated in the brain cortex of a mouse model of Alzheimer disease and are depressed in mouse brain cortex by deletion of p47(phox), an essential component of the phagocyte NADPH oxidase. Measurement of the nFs may ultimately prove useful in diagnosis, timing, and selection of dose in the treatment and chemoprevention of neurodegenerative disease.

The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.

To study the risk factors for the development of acute respiratory distress syndrome (ARDS) in children with measles.The clinical data of 55 children with measles were retrospectively studied. Of the 55 children, 11 were complicated by ARDS. The risk factors for the development of ARDS were investigated by univariate analysis and multivariate non-conditional logistic regression analysis.The univariate analysis showed that there were significant differences in the oxygen inhalation mode (nasal catheter/mask), the rate of sepsis, blood C-reactive protein (CRP) levels and lymphocyte counts at admission between the ARDS and non-ARDS groups (P0.05). The presence of sepsis and higher blood CRP levels were identified as the major risk factors for the development of ARDS by the multivariate logistic regression analysis (OR=116.444, 1.050 respectively; P0.05).The children with measles who have sepsis and higher blood CRP levels are at risk of ARDS.

Background Healthcare-acquired Pseudomonas aeruginosa (P. aeruginosa) infections in the Pediatric Intensive Care Unit (PICU), which have a high incidence, increase treatment costs and mortality, and seriously threaten the safety of critically ill children. It is essential to seek convenient and effective methods to control and prevent healthcare-acquired infections (HAIs). This research was conducted to study the effect of infection control nurses on the occurrence of P. aeruginosa HAIs and multi-drug resistance (MDR) strains in PICU. Methods The clinical data was divided into two groups, with the age ranging from 1 month to 14 years. One group of the critically ill patients(N = 3,722) was admitted to PICU from 2007 to 2010, without the management of infection control nurses. The other group of the critically ill patients (N = 3,943) was admitted to PICU from 2011 to 2013, with the management of infection control nurses. Compare the mortality, morbidity and the incidence of acquired P. aeruginosa infections to evaluate the effect of infection control nurses. Results After implementation of the post of infection control nurses, the patient's overall mortality fell from 4.81% to 3.73%. Among the patients with endotracheal intubation more than 48 hours, the incidence of endotracheal intubation-related pneumonia decreased from 44.6% to 34.32%. The mortality of patients with endotracheal intubation decreased from 16.96% to 10.17%, and the morbidity of HAIs with P. aeruginosa decreased from 1.89% to 1.07%. The mutual different rate (MDR) dropped from 67.95% to 44.23%. There were remarkable differences in these rates between the two groups (p

Suppression of prostacyclin (PGI 2 ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2–derived PGI 2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI 2 receptor (IP) or suppression of PGI 2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A 2 and the isoprostane, 8, 12 – iso iPF 2α -VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA 2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2–derived PGI 2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.

To investigate the factors that influence the short-term (6 months) prognosis in children with acute liver failure.The clinical information of 53 children with acute liver failure treated between June 2008 and September 2013 was retrospectively analyzed. The patients were divided into survival group (n=21) and death group (n=32) according to their outcomes. The liver function parameters and incidence of complications were compared between the two groups, and multivariate logistic regression analysis was used to identify major factors affecting the short-term prognosis in these patients.There were significant differences between the death and survival groups in the indices of international normalized ratio (INR), blood ammonia and serum albumin (Alb), and complications such as hepatic encephalopathy, gastrointestinal hemorrhage, and multiple organ failure (P0.05). Multivariate logistic regression analysis demonstrated that serum Alb, INR, and hepatic encephalopathy were the major factors affecting the short-term prognosis of acute liver failure (OR=0.616, 75.493 and 1210.727 respectively; P0.05).INR, hepatic encephalopathy and serum Alb are the major factors that influence the short-term prognosis in children with acute liver failure.