Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Ascorbate uptake enables tubular mitophagy to prevent septic AKI by PINK1-PARK2 axis.

Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCFFbxw7α cascade. Ascorbate restriction, or knockout of SVCT-1 and -2, the circumstance reminiscent to blockade of ascorbate uptake, endows tubular cells more vulnerable to the LPS-inducible apoptosis, whereas exogenous administration of ascorbate overrides the ruin execution, for which the PINK1-PARK2, rather than BNIP3-NIX axis is required. Ascorbate increases, while SVCT-1 and -2 knockout or ascorbate restriction dampens tubular mitophagy upon LPS stimuli. Treatment of endotoxemic mice with high-dose ascorbate confers mitophagy and substantial protection against mortality and septic acute kidney injury (AKI). Our work provides a rationale for clinical management of septic AKI with high doses of ascorbate.

[The influence of serum magnesium level on the prognosis of critically ill patients].

OBJECTIVE: To investigate the incidence of hypomagnesemia and the effect of serum magnesium levels on the prognosis of critically ill patients in intensive care unit (ICU). METHODS: A single-center prospective observation was conducted. The adult patients admitted to ICU of Zhejiang Provincial People's Hospital from January 2012 to January 2014 were enrolled, and they were expected to stay in hospital for more than 48 hours. All the patients who had been diagnosed with hypomagnesemia before ICU admission, or those who had received magnesium supplement therapy were excluded. All patients were monitored for serum magnesium levels within 24 hours after ICU admission, and they were divided into three groups: normomagnesemic group (serum magnesium levels 0.7-1.2 mmol/L), hypomagnesemic group (serum magnesium levels < 0.7 mmol/L), and hypermagnesemic group (serum magnesium levels > 1.2 mmol/L). Various parameters were recorded for every patient, including general information, disease composition, laboratory indexes, duration of mechanical ventilation, ICU stay days and final outcome. The acute physiology and chronic health evaluation II (APACHEII) score and sequential organ failure assessment (SOFA) score during the first 24 hours after ICU admission were calculated. The risk factors for the death in critically ill patients were postulated by logistic regression analysis. RESULTS: A total of 374 critically ill patients were enrolled, with 242 patients (64.71%) in normomagnesemic group, 102 (27.27%) in hypomagnesemic group, and 30 (8.02%) in hypermagnesemic group. As to the disease composition, although the patients in normomagnesemic group and hypomagnesemic group were mainly consisted of patients with nervous system diseases (33.06%, 31.37%) or pneumonia (25.62%, 25.49%), the proportion of patients with major abdominal and thoracic surgery (15.69% vs. 5.78%, χ (2) = 8.837, P = 0.003) or severe sepsis (7.84% vs. 1.65%, χ (2) = 9.935, P = 0.007) was significantly greater in the hypomagnesemic group compared with that of normomagnesemic group, and most hypermagnesemic patients were complicated by renal dysfunction in different degrees. Compared with the normomagnesemic group, the hypomagnesemic group was found to have higher SOFA scores (6.86±3.12 vs. 5.46±2.75, t = -2.930, P = 0.004), longer stay in ICU (days: 15.98±13.29 vs. 12.43±7.14, t = -2.318, P = 0.034) and higher mortality [54.90% (56/102) vs. 33.88% (82/242), χ (2) = 6.587, P = 0.010], but no statistically significant differences were found in gender composition, age, levels of other electrolytes (natrium, potassium, calcium, phosphorus), and APACHEII score. As shown by the result of the logistic regression analysis, APACHEII score [odds ratio (OR) = 1.129, 95% confidence interval (95%CI) = 1.064-1.197, P = 0.000] and serum magnesium level (OR = 2.163, 95%CI = 1.015-4.610, P = 0.046) were independent risk factors for death in critically ill patients. CONCLUSIONS: Serum magnesium levels are closely related to mortality rate in patients in ICU, so more attention should be paid to the occurrence of hypomagnesemia in critically ill patients.

Ammonia-oxidizing bacteria and archaea in wastewater treatment plant sludge and nearby coastal sediment in an industrial area in China.

Under the increasing pressure of human activities, Hangzhou Bay has become one of the most seriously polluted waters along China's coast. Considering the excessive inorganic nitrogen detected in the bay, in this study, the impact of an effluent from a coastal industrial park on ammonia-oxidizing microorganisms (AOMs) of the receiving area was interpreted for the first time by molecular technologies. Revealed by real-time PCR, the ratio of archaeal amoA/bacterial amoA ranged from 5.68 × 10(-6) to 4.79 × 10(-5) in the activated sludge from two wastewater treatment plants (WWTPs) and 0.54-3.44 in the sediments from the effluent receiving coastal area. Analyzed by clone and pyrosequencing libraries, genus Nitrosomonas was the predominant ammonia-oxidizing bacteria (AOB), but no ammonia-oxidizing archaea (AOA) was abundant enough for sequencing in the activated sludge from the WWTPs; genus Nitrosomonas and Nitrosopumilus were the dominant AOB and AOA, respectively, in the coastal sediments. The different abundance of AOA but similar structure of AOB between the WWTPs and nearby coastal area probably indicated an anthropogenic impact on the microbial ecology in Hangzhou Bay.

[Effects of nitrogen application rates and straw returning on nutrient balance and grain yield of late sowing wheat in rice-wheat rotation].

Field experiments were conducted to study the effects of nitrogen application rates and straw returning on grain yield, nutrient accumulation, nutrient release from straw and nutrient balance in late sowing wheat. The results showed that straw returning together with appropriate application of nitrogen fertilizer improved the grain yield. Dry matter, nitrogen, phosphorus and potassium accumulation increased significantly as the nitrogen application rate increased. At the same nitrogen application rate (270 kg N · hm(-2)), the dry matter, phosphorus and potassium accumulation of the treatment with straw returning were higher than that without straw returning, but the nitrogen accumulation was lower. Higher-rate nitrogen application promoted straw decomposition and nutrient release, and decreased the proportion of the nutrient released from straw after jointing. The dry matter, phosphorus and potassium release from straw showed a reverse 'N' type change with the wheat growing, while nitrogen release showed a 'V' type change. The nutrient surplus increased significantly with the nitrogen application rate. At the nitrogen application rate for the highest grain yield, nitrogen and potassium were surplus significantly, and phosphorus input could keep balance. It could be concluded that as to late sowing wheat with straw returning, applying nitrogen at 257 kg · hm(-2) and reducing potassium fertilizer application could improve grain yield and reduce nutrients loss.

Ventricular hypertrophy abrogates intralipid-induced cardioprotection by alteration of reperfusion injury salvage kinase/glycogen synthase kinase 3ß signal.

Recent studies have demonstrated that intralipid (ILP) conferred myocardial protection against ischemia-reperfusion (IR) injury through activation of reperfusion injury salvage kinase (RISK) pathway. As RISK signal has been shown to be impaired in hypertrophied myocardium, we investigated whether ILP-induced cardiac protection was maintained in hypertrophied rat hearts. Transverse aortic constriction was performed on male Sprague-Dawley rats to induce left ventricular hypertrophy, then sham-operated or hypertrophied rat hearts were isolated and perfused retrogradely by the Langendorff for 30 min (equilibration) followed by 40 min of ischemia and then 120 min of reperfusion. The isolated hearts received 15-min episode of 1% ILP separated by 15 min of washout or three episodes of 5-min ischemia followed by 5-min reperfusion before ischemia. The hemodynamics, infarct size, apoptosis, phosphorylated protein kinase B (p-Akt), phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2), phosphorylated glycogen synthase kinase 3ß (GSK3ß), Bcl-2, phosphorylated Bad, and Bax were determined. We found that ILP significantly improved left ventricular hemodynamics and reduced infarct size and the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells in the sham-operated rat hearts exposed to IR. However, such myocardial infarct-sparing effect of ILP was completely blocked by phosphatidylinositol-3-kinase inhibitor wortmannin, but only partially by mitogen-activated protein kinase kinase inhibitor PD98059 in sham-operated hearts. Intralipd upregulated the phosphorylation of Akt, extracellular regulated protein kinase 1/2 (ERK1/2), and their downstream target of GSK3ß and antiapoptotic Bcl-2 expression in healthy rat hearts. Nonetheless, ILP failed to improve left ventricular hemodynamics and reduced infarct size and apoptosis and increase the phosphorylated Akt, ERK1/2, GSK3ß, and antiapoptotic Bcl-2 in hypertrophied myocardium. In contrast, ischemic preconditioning increased the phosphorylation of Akt, ERK1/2 and GSK3ß, improved heart pump function, and reduced myocardial necrosis in sham-operated hearts, a phenomenon partially attenuated by ventricular hypertrophy. Interestingly, GSK inhibitor SB216763 conferred cardioprotection against IR injury in sham-operated hearts, but failed to exert cardioprotection in hypertrophied myocardium. Our results indicated that ventricular hypertrophy abrogated ILP-induced cardioprotection against IR injury by alteration of RISK/GSK3ß signal.