The effects of antioxidant supplementation on short-term mortality in sepsis patients.

Background: The occurrence and development of sepsis are related to the excessive production of oxygen free radicals and the weakened natural clearance mechanism. Further dependable evidence is required to clarify the effectiveness of antioxidant therapy, especially its impact on short-term mortality. Objectives: The purpose of this systematic review and meta-analysis was to evaluate the effect of common antioxidant therapy on short-term mortality in patients with sepsis. Methods: According to PRISMA guidelines, a systematic literature search on antioxidants in adults sepsis patients was performed on PubMed/Medline, Embase, and the Cochrane Library from the establishment of the database to November 2023. Antioxidant supplements can be a single-drug or multi-drug combination: HAT (hydrocortisone, ascorbic acid, and thiamine), ascorbic acid, thiamine, N-acetylcysteine and selenium. The primary outcome was the effect of antioxidant treatment on short-term mortality, which included 28-day mortality, in-hospital mortality, intensive care unit mortality, and 30-day mortality. Subgroup analyses of short-term mortality were used to reduce statistical heterogeneity and publication bias. Results: Sixty studies of 130,986 sepsis patients fulfilled the predefined criteria and were quantified and meta-analyzed. Antioxidant therapy reduces the risk of short-term death in sepsis patients by multivariate meta-analysis of current data, including a reduction of in-hospital mortality (OR = 0.81, 95% CI 0.67 to 0.99; P = 0.040) and 28-day mortality (OR = 0.81, 95% CI 0.69 to 0.95]; P = 0.008). Particularly in subgroup analyses, ascorbic acid treatment can reduce in-hospital mortality (OR = 0.66, 95% CI 0.90 to 0.98; P = 0.006) and 28-day mortality (OR = 0.43, 95% CI 0.24 to 0.75; P = 0.003). However, the meta-analysis of RCTs found that antioxidant therapy drugs, especially ascorbic acid, did substantially reduce short-term mortality(OR = 0.78, 95% CI 0.62 to 0.98; P = 0.030; OR = 0.57, 95% CI 0.36 to 0.91; P = 0.020). Conclusions: According to current data of RCTs, antioxidant therapy, especially ascorbic acid, has a trend of improving short-term mortality in patients with sepsis, but the evidence remains to be further demonstrated.

Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/ß-catenin pathway.

Background: Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods: A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results: DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/ß-catenin pathway. Conclusions: Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Risk model for predicting mortality in patients with necrotizing soft tissue infections in the intensive care unit.

BACKGROUND: The goal of this study is to look into the factors that lead to death in patients with necrotizing soft tissue infections（NSTIs） in the intensive care unit and create a mortality risk model. METHODS: The clinical data of 106 patients with necrotizing soft tissue infections admitted to intensive care unit(ICU) of the First Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2021 were retrospectively analyzed. Univariate analysis and multivariate analysis were performed to evaluate the risk factors impacting patient mortality. The regression coefficient in binary logistic regression analysis was converted into the item score in the model, and then the model score of each patient was calculated. Finally, an ROC curve was constructed to evaluate the efficiency of the model for predicting mortality. Thirteen patients with NSTIs admitted to ICU between January 2022 and November 2022 were used to validate the model. RESULTS: The death group had 44 patients, while the survival group had 62 patients. The overall mortality was 41.5%. Binary logistic regression analysis showed that risk factors for mortality were age≥ 60 years(OR:4.419; 95%CI:1.093-17.862; P = 0.037), creatinine ≥ 132µmol/L(OR:11.166; 95%CI:2.234-55.816; P = 0.003), creatine kinase ≥ 1104 U/L(OR:4.019; 95%CI:1.134-14.250; P = 0.031), prothrombin time ≥ 24.4 s(OR:11.589; 95%CI:2.510-53.506; P = 0.002), and invasive mechanical ventilation (OR:17.404; 95%CI:4.586-66.052; P＜0.000). The AUC of the model for predicting mortality was 0.940 (95% CI:0.894-0.986). When the cut-off value for the model was 4 points, the sensitivity was 95.5% and the specificity was 83.9%. CONCLUSION: The death risk model in this study for NSTIs patients in the intensive care unit shows high sensitivity and specificity. Patients with a score of ≥ 4 points have a higher risk of mortality.

SUPPLEMENTATION WITH NICOTINAMIDE RIBOSIDE ATTENUATES T CELL EXHAUSTION AND IMPROVES SURVIVAL IN SEPSIS.

ABSTRACT: T cell exhaustion is the main cause of sepsis-induced immunosuppression and is associated with the poor prognosis. Nicotinamide adenine dinucleotide (NAD + ) is well known for its anti-aging effect, but its role in sepsis-induced T cell exhaustion remains to be elucidated. In the present study, using a classic septic animal model, we found that the levels of NAD + and its downstream molecule, which is sirtuins 1 (SIRT1), in T cells in sepsis were decreased. Supplementation with nicotinamide ribose (NR), the precursor of NAD + , right after cecal ligation and puncture significantly increased the levels of NAD + and SIRT1. Supplementation with NR alleviated the depletion of mononuclear cells and T lymphocytes in spleen in sepsis and increased the levels of CD3 + CD4 + and CD3 + CD8 + T cells. Interestingly, both Th1 and Th2 cells were expanded after NR treatment, but the balance of Th1/Th2 was partly restored. Nicotinamide ribose also inhibited the regulatory T cells expansion and programmed cell death 1 expression in CD4 + T cells in sepsis. In addition, the bacteria load, organ damage (lung, heart, liver, and kidney), and the mortality of septic mice were reduced after NR supplementation. In summary, these results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion, which is associated with NAD + /SIRT1 pathway.

Mutual promotion of mitochondrial fission and oxidative stress contributes to mitochondrial-DNA-mediated inflammation and epithelial-mesenchymal transition in paraquat-induced pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is one of the main causes of death in patients with paraquat (PQ) poisoning. This study aimed to evaluate the relationship between mitochondrial fission and oxidative stress in PQ-induced epithelial-mesenchymal transition (EMT) and PF. METHODS: C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) staining. Mitochondrial morphology was detected by MitoTracker® Deep Red FM or transmission electron microscopy (TEM). Western blotting and immunofluorescence were used to determine the expression of protein. The migration ability of the cells was detected by the cell scratch test. Mitochondrial DNA (mtDNA) levels were assessed by real-time polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to detect cytokine levels. Superoxide dismutase (SOD) activity and the levels of glutathione (GSH) and malondialdehyde (MDA) were detected by chemichromatometry. RESULTS: PQ exposure caused EMT and PF in vivo and in vitro. PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1 (Drp1), which were accompanied by oxidative stress. Inhibiting mitochondrial fission using mitochondrial division inhibitor-1 (Mdivi-1), a selective inhibitor of Drp1, attenuated PQ-induced EMT and oxidative damage. Treatment with N-acetyl-L-cysteine (NAC), an antioxidant, reduced Drp1 expression, attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF. Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release, the expression of Toll-like receptor 9 (TLR9) and phosphorylation (P)-NF-κB p65 as well as cytokines (interleukin 6 [IL-6], interleukin-1ß [IL-1ß], and tumor necrosis factor-α [TNF-α]) production. CONCLUSION: Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF, which is associated with the mtDNA/TLR9/NF-κB pathway.

Theoretical Study of the Catalytic Mechanism of the Cu-Only Superoxide Dismutase.

The catalytic mechanisms for the wild-type and the mutated Cu-only superoxide dismutase were studied using the hybrid density functional B3LYP and a quantum chemical cluster approach. Optimal protonation states of the active site were examined for each stage of the catalytic cycle. For both the reductive and the oxidative half-reactions, the arrival of the substrate O2•- was found to be accompanied by a charge-compensating H+ with exergonicities of -15.4 kcal·mol and -4.7 kcal·mol, respectively. The second-sphere Glu-110 and first-sphere His-93 were suggested to be the transient protonation site for the reductive and the oxidative half-reactions, respectively, which collaborates with the hydrogen bonding water chain to position the substrate near the redox-active copper center. For the reductive half-reaction, the rate-limiting step was found to be the inner-sphere electron transfer from the partially coordinated O2•- to CuII with a barrier of 8.1 kcal·mol. The formed O2 is released from the active site with an exergonicity of -14.9 kcal·mol. For the oxidative half-reaction, the inner-sphere electron transfer from CuI to the partially coordinated O2•- was found to be accompanied by the proton transfer from the protonated His-93 and barrierless. The rate-limiting step was found to be the second proton transfer from the protonated Glu-110 to HO2- with a barrier of 7.3 kcal·mol. The barriers are reasonably consistent with experimental activities, and a proton-transfer rate-limiting step in the oxidative half-reaction could explain the experimentally observed pH-dependence. For the E110Q CuSOD, Asp-113 was suggested to be likely to serve as the transient protonation site in the reductive half-reaction. The rate-limiting barriers were found to be 8.0 and 8.6 kcal·mol, respectively, which could explain the slightly lower performance of E110X mutants. The results were found to be stable, with respect to the percentage of exact exchange in B3LYP.

Unique gene duplications and conserved microsynteny potentially associated with resistance to wood decay in the Lauraceae.

Wood decay resistance (WDR) is marking the value of wood utilization. Many trees of the Lauraceae have exceptional WDR, as evidenced by their use in ancient royal palace buildings in China. However, the genetics of WDR remain elusive. Here, through comparative genomics, we revealed the unique characteristics related to the high WDR in Lauraceae trees. We present a 1.27-Gb chromosome-level assembly for Lindera megaphylla (Lauraceae). Comparative genomics integrating major groups of angiosperm revealed Lauraceae species have extensively shared gene microsynteny associated with the biosynthesis of specialized metabolites such as isoquinoline alkaloids, flavonoid, lignins and terpenoid, which play significant roles in WDR. In Lauraceae genomes, tandem and proximal duplications (TD/PD) significantly expanded the coding space of key enzymes of biosynthesis pathways related to WDR, which may enhance the decay resistance of wood by increasing the accumulation of these compounds. Among Lauraceae species, genes of WDR-related biosynthesis pathways showed remarkable expansion by TD/PD and conveyed unique and conserved motifs in their promoter and protein sequences, suggesting conserved gene collinearity, gene expansion and gene regulation supporting the high WDR. Our study thus reveals genomic profiles related to biochemical transitions among major plant groups and the genomic basis of WDR in the Lauraceae.

[Identification of Nitrate Source of Surface Water in a Typical Peri-urban Watershed in the Tableland of the Loess Plateau, China].

With the rapid development of industry and agriculture, nitrate pollution in surface water has become one of the serious environmental problems in the Loess Plateau region. In this study, Yanwachuan watershed, a typical suburban watershed in the gully region of a loess plateau, was selected as the research area. Using hydrochemical data and nitrogen and oxygen bistable isotopes, combined with the SIAR model, the contribution rates of different pollution sources of nitrate in surface water in the dry season and wet season were quantitatively identified, and the main reasons for seasonal differences in different pollution sources were clarified. The results showed that inorganic nitrogen mainly existed in the form of NO3--N and NO2--N, and the average concentration of NO3--N and NO2--N in the wet season was higher than that in the dry season, whereas NH4+-N showed the opposite characteristics. Nitrification was the main process of nitrate transformation in the surface water of the basin. In the wet season, the main sources of nitrate were manure and sewage, whereas in the dry season, manure, sewage, and soil N leaching were the dominant sources, followed by ammonium fertilizer. The contribution proportion of different pollution sources to nitrate in surface water of the watershed showed significant seasonal differences. The sewage had the highest contribution, accounting for 31.40% and 65.66% in the dry season and rainy season, respectively, and the contribution of sewage to NO3- in the wet season was much higher than that in the dry season. The increase in residential water consumption in summer led to a large amount of sewage discharge into the watershed.

FCGR2C: An emerging immune gene for predicting sepsis outcome.

Background: Sepsis is a life-threatening disease associated with immunosuppression. Immunosuppression could ultimately increase sepsis mortality. This study aimed to identify the prognostic biomarkers related to immunity in sepsis. Methods: Public datasets of sepsis downloaded from the Gene Expression Omnibus (GEO) database were divided into the discovery cohort and the first validation cohort. We used R software to screen differentially expressed genes (DEGs) and analyzed DEGs' functional enrichment in the discovery dataset. Immune-related genes (IRGs) were filtered from the GeneCards website. A Lasso regression model was used to screen candidate prognostic genes from the intersection of DEGs and IRGs. Then, the candidate prognostic genes with significant differences were identified as prognostic genes in the first validation cohort. We further validated the expression of the prognostic genes in the second validation cohort of 81 septic patients recruited from our hospital. In addition, we used four immune infiltration methods (MCP-counter, ssGSEA, ImmuCellAI, and CIBERSORT) to analyze immune cell composition in sepsis. We also explored the correlation between the prognostic biomarker and immune cells. Results: First, 140 genes were identified as prognostic-related immune genes from the intersection of DEGs and IRGs. We screened 18 candidate prognostic genes in the discovery cohort with the lasso regression model. Second, in the first validation cohort, we identified 4 genes (CFHR2, FCGR2C, GFI1, and TICAM1) as prognostic immune genes. Subsequently, we found that FCGR2C was the only gene differentially expressed between survivors and non-survivors in 81 septic patients. In the discovery and first validation cohorts, the AUC values of FCGR2C were 0.73 and 0.67, respectively. FCGR2C (AUC=0.84) had more value than SOFA (AUC=0.80) and APACHE II (AUC=0.69) in evaluating the prognosis of septic patients in our recruitment cohort. Moreover, FCGR2C may be closely related to many immune cells and functions, such as B cells, NK cells, neutrophils, cytolytic activity, and inflammatory promotion. Finally, enrichment analysis showed that FCGR2C was enriched in the phagosome signaling pathway. Conclusion: FCGR2C could be an immune biomarker associated with prognosis, which may be a new direction of immunotherapy to reduce sepsis mortality.

Successful treatment of metastatic vulvar malignant melanoma with toripalimab: A rare case report and review of the literature.

RATIONALE: Vulvar melanoma is a rare and aggressive tumor with a high risk of local recurrence and distant metastasis. The prognosis is poor with a 5-year overall survival rate of only 46.6%. Management of vulvar melanoma remains a clinical challenge. Recent evidences have shown that immune checkpoint inhibitors are effective in the treatment of vulvar melanoma. PATIENT CONCERNS AND DIAGNOSES: A 63-year-old woman with vulvar malignant melanoma suffered inguinal lymph node metastasis after vulvectomy and chemotherapy. She underwent inguinal lymph node dissection and inguinal radiotherapy. The tumor progressed again and she received immunotherapy. INTERVENTIONS: The tumor progressed again, and she was admitted to our hospital and received toripalimab combined with apatinib and abraxane. OUTCOMES: After 6 cycles of immunotherapy, the efficacy achieved partial remission. And with toripalimab as maintenance therapy, the patient achieved durable antitumor efficacy and good safety. LESSONS: In this rare case, the patient with metastatic vulvar malignant melanoma had durable antitumor efficacy and good safety when receiving toripalimab.

Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.

BACKGROUND: Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. AIMS: To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. METHODS: This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. RESULTS: Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. CONCLUSION: This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).

Vesicle transport related protein Synaptotagmin-1 mediates paraquat transport to antagonize paraquat toxicity.

In this study, A549/PQ cells with moderate resistance to paraquat (PQ) were obtained by treating A549 cells with PQ, their growth rate was slowed down, the accumulation concentration of PQ and the levels of growth inhibition, injury and early apoptosis induced by PQ were significantly lower than those of parental A549 cells. Microarray screening and RT-qPCR detection found that Synaptotagmin-1 (SYT1) expression in drug-resistant cells was significantly increased, and PQ further enhanced its expression. After inhibiting SYT1 expression in A549/PQ cells, cell viability, intracellular PQ concentration and the expression of Bcl-2, SNAP25 and RAB26 were significantly reduced, while the mortality, early apoptosis rate and Bax expression were significantly increased. In vivo experiments also further showed that PQ promoted the expression of SYT1, SNAP25 and RAB26 in PQ-poisoned mice; when inhibiting SYT1 expression, PQ concentration in lung tissues was significantly increased, and the levels of lung injury and apoptosis were also significantly enhanced, while the expression of SNAP25 and RAB26 was significantly reduced. This indicates that PQ poisoning leads to compensatory up-regulation of vesicle transport related proteins such as SYT1 in vivo, thereby promoting PQ transmembrane transport, and then reducing the pulmonary accumulation of PQ and PQ-caused lung injury.

CD71+ Erythroid Cell Expansion in Adult Sepsis: Potential Causes and Role in Prognosis and Nosocomial Infection Prediction.

BACKGROUND: Immune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71+ erythroid cells had unappreciated immunosuppressive functions. This study aimed to investigate the values of CD71+ erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored. METHODS: In total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71+ cells, CD71+CD235a+ cells, and CD45+ CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis. RESULTS: The percentage of CD71+ cells, CECs, and CD45+ CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71+ cells, CECs, and CD45+ CECs were associated with NI development, while CD71+ cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71+ cells, CECs, and CD45+ CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45+ CECs. CONCLUSIONS: CECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis. TRIAL REGISTRATION: ChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645.

Predictive values of serum 8-hydroxydeoxyguanosine on disease progression and prognosis of patients with sepsis / 中华烧伤杂志

Objective: To investigate the values of serum 8-hydroxydeoxyguanosine (8-OHdG) in predicting disease progression and prognosis of patients with sepsis. Methods: The prospective observational research methods were used. A total of 124 patients with sepsis who met the inclusion criteria were admitted to the Department of Emergency of the First Affiliated Hospital of Wenzhou Medical University from April 2015 to July 2016, including 79 males and 45 females, aged (62±15) years. The sepsis-related organ failure assessment (SOFA) scores of all patients on admission and on the second day of admission and their difference (ΔSOFA) were calculated. The patients were divided into non-progression group with ΔSOFA score <2 (n=101) and progression group with ΔSOFA score ≥2 (n=23), and according to the survival during hospitalization, the patients were divided into survival group (n=85) and death group (n=39). Data of patients between non-progression group and progression group, survival group and death group were compared, including the gender, age, days in emergency intensive care unit (ICU), smoking, hypertension, diabetes mellitus, serum white blood cell count, serum C-reactive protein, and serum procalcitonin on admission, and serum 8-OHdG within 24 h of admission. The multivariate logistic regression analysis was used to screen the independent risk factors of disease progression and death during hospitalization in 124 patients with sepsis, the receiver's operating characteristic (ROC) curves were drawn according to the independent risk factors, and the area under the curve (AUC), the best threshold, and the sensitivity and specificity under the best threshold were calculated. The patients were divided into high 8-OHdG group (n=35) and low 8-OHdG group (n=89) according to the best threshold in ROC curve of death during hospitalization. The data including the gender, age, SOFA score on admission, SOFA score on the second day of admission, and ΔSOFA score of patients in the two groups were compared. The survival rates of patients within 90 d of admission in the two groups were compared by the Kaplan-Meier method. Data were statistically analyzed with independent sample t test, Mann-Whitney U test, chi-square test, and Log-rank test. Results: The gender, age, days in emergency ICU, smoking, complicated with hypertension, complicated with diabetes mellitus, serum white blood cell count, serum C-reactive protein, and serum procalcitonin on admission of patients in non-progression group and progression group were similar (P>0.05). The serum 8-OHdG within 24 h of admission of patients in progression group was significantly higher than that in non-progression group (Z=-2.31, P<0.05). Multivariate logistic regression analysis showed that the serum 8-OHdG within 24 h of admission was the independent risk factor for disease progression of 124 patients with sepsis (odds ratio=1.06, with 95% confidence interval of 1.01-1.11, P<0.05). The AUC under the ROC curve of serum 8-OHdG within 24 h of admission to predict disease progression of 124 patients with sepsis was 0.65 (with 95% confidence interval of 0.52-0.79, P<0.05), the optimal threshold was 32.88 ng/mL, and the sensitivity and specificity under the optimal threshold was 52.2% and 79.2%, respectively. The gender, age, days in emergency ICU, smoking, complicated with hypertension, complicated with diabetes mellitus, and serum white blood cell count, serum C-reactive protein, and serum procalcitonin on admission of patients in survival group and death group were similar (P>0.05). The serum 8-OHdG within 24 h of admission of patients in death group was significantly higher than that in survival group (Z=-2.37, P<0.05). Multivariate logistic regression analysis showed that the serum 8-OHdG within 24 h of admission was the independent risk factor for death of 124 patients with sepsis (odd ratio=1.04, with 95% confidence interval of 1.00-1.09, P<0.05). The AUC under the ROC curve of serum 8-OHdG within 24 h of admission to predict death of patients during hospitalization was 0.63 (with 95% confidence interval of 0.52-0.75, P<0.05), the optimal threshold was 32.43 ng/mL, the sensitivity and specificity under the optimal threshold was 51.3% and 84.7%, respectively. The gender and age of patients in high 8-OHdG group and low 8-OHdG group were similar (P>0.05). The SOFA score on admission, SOFA score on the second day of admission, and ΔSOFA score of patients in high 8-OHdG group were significantly higher than those in low 8-OHdG group (with Z values of -2.49, -3.01, and -2.64, respectively, P<0.05 or P<0.01). The survival rate within 90 d of admission of patients in low 8-OHdG group was significantly higher than that in high 8-OHdG group (χ2=14.57, P<0.01). Conclusions: Serum 8-OHdG level is an independent risk factor for disease progression and death in sepsis patients with limited ability for predicting disease progression and prognosis of sepsis of patients. The patients with higher serum 8-OHdG level have higher death risk within 90 d of admission.

Severe immune-related hyperthermia followed by immune-related pneumonitis with PD-1 inhibitor (sintilimab) in small cell lung cancer: A case report.

Immune checkpoint inhibitors (ICIs) have achieved prominent efficacy in the treatment of numerous cancers, which is the most significant breakthrough in cancer therapy in recent years. However, ICIs are associated with a series of immune-related adverse events (irAEs). Pneumonitis is an uncommon but potentially fatal irAE. In the case reported here, a patient with advanced small cell lung cancer (SCLC) had rapid progression of disease following chemotherapy and received ICIs. The patient experienced severe immune-related hyperthermia followed by immune-related pneumonitis. Fortunately, a good clinical response was achieved after the patient received corticosteroids and tocilizumab.

Arterial oxygen pressure targets in critically ill patients: Analysis of a large ICU database.

BACKGROUND: Providing supplemental oxygen is common in the management of critically ill patients, yet the optimal oxygen regimen remains unclear. OBJECTIVES: To explore the optimal range of PaO2 in critically ill patients. METHODS: This is a retrospective study conducted in the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients with a least 48 h of oxygen therapy were included. Nonlinear regression was used to analyze the association between PaO2 and mortality. We derived an optimal range of PaO2 and evaluated the association between the proportion of PaO2 measurements within this range and mortality. RESULTS: In total, 8401 patients were included in the study. A J-shaped relationship was observed between median PaO2 and hospital mortality. Compared with the reference group of 100-120 mmHg, patients with values of 80-100 mmHg and 120-140 mmHg had higher hospital mortality (adjusted odds ratio [aOR], 1.23; 95% CI, 1.05-1.43 and 1.29; 95%CI, 1.08-1.54, respectively). Similarly, mortality rates were significantly higher for PaO2 <80 mmHg and ≥140 mmHg (aOR, 1.97; 95%CI, 1.58-2.45 and 1.42; 95%CI, 1.19-1.69, respectively). Patients spent a greater proportion of time within 100-120 mmHg tended to have a lower mortality rate. CONCLUSION: Among critically ill patients, the relationship between median PaO2 and hospital mortality was J-shaped. The lowest rates of mortality was observed in those with PaO2 levels within 100 to 120 mmHg.

Natural alkaloid 8-oxo-epiberberine inhibited TGF-ß1-triggred epithelial-mesenchymal transition by interfering Smad3.

Epithelial-mesenchymal transition (EMT), the transition of epithelial cells into mesenchymal cells, plays important roles in the metastasis of solid tumors. 8-Oxo-epiberberine (OPB) is a natural alkaloid extracted from the roots of Coptis chinensis Franch. In this study, The effect and the underlying mechanism of OPB on EMT in a TGF-ß1-induced model and the inhibitory effect of OPB on lung metastasis were investigated. TGF-ß1-stimulated lung cancer cells were co-treated with OPB, the morphological changes were examined. The protein expression of EMT biomarkers E-cadherin and N-cadherin was determined by Western blotting and immunofluorescence. The transcription activity of smad2/3 promoter was analyzed by a luciferase reporter assay. The effect of OPB on cell migration, invasion, and adhesion was detected by wound-healing, adhesion, and transwell assays. The in vivo anti-metastatic effect of OPB was evaluated using a 4 T1 cell xenograft mouse model. Results showed that OPB significantly reversed TGF-ß1-triggered morphological changes, expression of EMT biomarkers, and migration, adhesion, and invasion. Furthermore, OPB suppressed TGF-ß1-induced Smad2/3 activation, Smad3 phosphorylation and nuclear translocation, and interaction of Smad3 with Smad4. Besides, OPB dramatically decreased the metastatic nodules in the lung without affecting the growth of primary tumors. In conclusion, OPB inhibited TGF-ß1-induced EMT possibly by interfering with Smad3. OPB might have therapeutic potentials for the treatment of metastatic cancers.

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Understanding the changes of runoff, sediment transport, and hydrodynamic parameters of slopes under the influence of landscape patch coverage and connectivity is of great significance for revealing the hydrodynamic mechanism and hydrological connectivity of slope soil erosion process. In this study, the changes of runoff, sediment transport and hydrodynamic parameters of downhill surface in different coverage levels (0%, 20%, 40%, 60%, 90%) and different connectivity modes (vertical path, horizonal path, S-shaped path, random patches) of shrublands were analyzed by field artificial simulated rainfall test. The results showed that, with the increases of shrub cove-rage, runoff yield and sediment yield decreased exponentially. When the coverage increased to more than 60%, the capacity of shrubs to reduce runoff and sediment became stable. With the increases of shrub coverage, flow velocity, flow depth, Reynolds number, Froude number, stream power, and flow shear resistance significantly decreased, while Manning's roughness coefficient and Darcy-Weisbach resistance coefficient increased significantly. When shrub coverage increased to more than 60%, there was no significant difference in the eigenvalues of hydraulic parameters. The runoff rate under the four connectivity modes followed the order of vertical path > S-shaped path > horizonal path > random patches. The sediment rate was the largest in the vertical path, followed by the S-shaped path, and the horizonal path was not significantly different from the random patches. The path with poor connectivity (horizonal path, random patches) exhibited stronger resistance of hydraulic transmission and poor hydraulic sedimentation capacity than the well-connected path (vertical path, S-shaped path). Our results could provide important theoretical basis for soil erosion control on the Loess Plateau and high-quality development of the Yellow River basin.

Association between furosemide administration and outcomes in critically ill patients with acute kidney injury.

BACKGROUND: Although current guidelines for AKI suggested against the use of furosemide in AKI management, the effect of furosemide on outcomes in real-world clinical settings remains uncertain. The aim of the present study was to investigate the association between furosemide administration and outcomes in critically ill patients with AKI using real-world data. METHODS: Critically ill patients with AKI were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score (PS) matched analysis was used to match patients receiving furosemide to those without diuretics treatment. Linear regression, logistic regression model, and Cox proportional hazards model were used to assess the associations between furosemide and length of stay, recovery of renal function, and in-hospital and 90-day mortality, respectively. RESULTS: A total of 14,154 AKI patients were included in the data analysis. After PS matching, 4427 pairs of patients were matched between the patients who received furosemide and those without diuretics treatment. Furosemide was associated with reduced in-hospital mortality [hazard ratio (HR) 0.67; 95% CI 0.61-0.74; P < 0.001] and 90-day mortality [HR 0.69; 95% CI 0.64-0.75; P < 0.001], and it was also associated with the recovery of renal function [HR 1.44; 95% CI 1.31-1.57; P < 0.001] in over-all AKI patients. Nevertheless, results illustrated that furosemide was not associated with reduced in-hospital mortality in patients with AKI stage 0-1 defined by UO criteria, AKI stage 2-3 according to SCr criteria, and in those with acute-on-chronic (A-on-C) renal injury. CONCLUSIONS: Furosemide administration was associated with improved short-term survival and recovery of renal function in critically ill patients with AKI. Furosemide was especially effective in patients with AKI UO stage 2-3 degree. However, it was not effective in those with AKI SCr stage 2-3 and chronic kidney disease. The results need to be verified in randomized controlled trials.