Dynamic changes in the real-time glomerular filtration rate and kidney injury markers in different acute kidney injury models.

In this study, we dynamically monitored the glomerular filtration rate and other assessment of renal function and markers of injury in various mice models of acute kidney injury. Male C57BL/6 mice were utilized to establish acute kidney injury models of sepsis, ischemia reperfusion, cisplatin, folic acid, aristolochic acid and antibiotic. In addition to the real time glomerular filtration rate, renal LCN-2 and HAVCR-1 mRNA expression levels, and serum creatinine, urea nitrogen and cystatin c levels were also used to evaluate renal function. In addition, the protein levels of LCN-2 and HAVCR-1 in renal, serum and urine were measured. Our results demonstrated that the changes in biomarkers always lagged the real time glomerular filtration rate during the progression and recovery of renal injury. Cystatin-c can reflect renal injury earlier than other markers, but it remains higher in the recovery stage. Perhaps the glomerular filtration rate does not reflect the greater injury caused by vancomycin plus piperacillin.

Gut microbiota composition and changes in patients with sepsis: potential markers for predicting survival.

BACKGROUND: Sepsis can cause immune dysregulation and multiple organ failure in patients and eventually lead to death. The gut microbiota has demonstrated its precise therapeutic potential in the treatment of various diseases. This study aimed to discuss the structural changes of the gut microbiota in patients with sepsis and to analyze the differences in the gut microbiota of patients with different prognoses. METHODS: We conducted a multicenter study in which rectal swab specimens were collected on the first and third days of sepsis diagnosis. A total of 70 specimens were collected, and gut microbiota information was obtained by 16S rRNA analysis. RESULTS: The relative abundance of Enterococcus decreased in rectal swab specimens during the first three days of diagnosis in patients with sepsis, while the relative abundance of inflammation-associated Bacillus species such as Escherichia coli, Enterobacteriaceae, and Bacteroidetes increased. By comparing the differences in the flora of the survival group and the death group, we found that the abundance of Veillonella and Ruminococcus in the death group showed an increasing trend (p < 0.05), while the abundance of Prevotella_6 and Prevotella_sp_S4_BM14 was increased in surviving patients (p < 0.05). CONCLUSIONS: The Firmicutes/Bacteroidetes ratio, reflecting overall gut microbial composition, was significantly lower on day three of sepsis diagnosis. Changes in the abundance of specific gut microbiota may serve as prognostic markers in patients with sepsis.

Effect of early serum phosphate disorder on in-hospital and 28-day mortality in sepsis patients: a retrospective study based on MIMIC-IV database.

BACKGROUND: This study aims to assess the influence of early serum phosphate fluctuation on the short-term prognosis of sepsis patients. METHODS: This retrospective study used the Medical Information Mart for Intensive Care IV database to analyze serum phosphate levels in sepsis patients within 3 days of ICU admission. According to the absolute value of delta serum phosphate (the maximum value minus the minimum value of serum phosphorus measured within three days), the patients were divided into four groups, 0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl. Meanwhile, the direction of delta serum phosphate was compared. With the serum phosphate change group of 0-1.3 mg/dl as the reference group, the relationship between delta serum phosphate and in-hospital mortality and 28-day mortality was analyzed by multivariate Logistics regression analysis. RESULTS: The study involved 1375 sepsis patients. Serum phosphate changes (0-1.3, 1.4-2.0, 2.1-3.1, and ≥ 3.2 mg/dl) correlated with in-hospital and 28-day mortality variations (p = 0.005, p = 0.008). Much higher serum phosphate fluctuation elevated in-hospital and 28-day mortality. Compared to the 0-1.3 mg/dl change group, adjusted odds ratios (OR) in other groups for in-hospital mortality were 1.25 (0.86-1.81), 1.28 (0.88-1.86), and 1.63 (1.10-2.43), and for 28-day mortality were 1.21 (0.86-1.72), 1.10 (0.77-1.57), and 1.49 (1.03-2.19). Under the trend of increasing serum phosphate, the ORs of in-hospital mortality and 28-day mortality in ≥ 3.2 mg/dl group were 2.52 and 2.01, respectively. CONCLUSION: In conclude, the delta serum phosphate ≥ 3.2 mg/dl was associated with in-hospital mortality and 28-day mortality in patients with sepsis.

Effects of carrimycin on biomarkers of inflammation and immune function in tumor patients with sepsis: A multicenter double-blind randomized controlled trial.

Carrimycin is a potential immune-regulating agent for sepsis in patients with tumors. In this study, we investigated its effects on inflammation and immune function in tumor patients with sepsis. In total, 120 participants were randomized to receive either carrimycin treatment (400 mg/day) (n = 62) or placebo (n = 58) for 7 days. The primary outcomes were immune-related indicators. Subsequently, patients were stratified into two subgroups (CD4 < 38.25% and CD8 < 25.195%). Ninety-nine participants were analyzed: 47 and 52 in the carrimycin and placebo groups, respectively. HLA-DR levels were rapidly increased in the carrimycin group; however, the placebo group initially experienced a decline in HLA-DR level at 1 day after administration. In the subgroup with CD4 < 38.25%, the carrimycin group exhibited significantly higher HLA-DR levels than the placebo group (2.270, P = 0.023) 1 day after administration and the degree of increase in HLA-DR in the carrimycin group was higher than that in the placebo group (2.057, P = 0.040). In the CD8 < 25.195% subgroup, the carrimycin group demonstrated significantly higher levels of CD8+ T cells than the placebo group at 3 (2.300,P = 0.027) and 5 (2.106, P = 0.035) days after administration. Carrimycin intervention led to significant reductions in the SOFA, APACHE II, PCT, and CRP levels. No adverse events were observed. In tumor patients with sepsis, particularly in those experiencing immunological suppression, carrimycin effectively regulates immune responses by increasing HLA-DR and CD8+ T cell levels and plays an anti-infective role, reducing disease severity. (Chictr.org.cn, ID Number: ChiCTR2000032339).

Gut microbiota disruption during sepsis and the influence of innate metabolites on sepsis prognosis.

Sepsis causes high mortality in intensive care units. Although there have been many studies on the gut microbiota in patients with sepsis, the impact of sepsis on the gut microbiota has not been directly determined because the treatment of sepsis also affects the gut microbiota. Therefore, we designed this animal experiment to explore gut microbiota alterations during sepsis. Mice were divided into two groups, mice that survived less than 3 days and mice that survived more than 3 days. Fecal samples collected on the day of cecal ligation and puncture (CLP), as well as on the 3rd and 7th days after CLP, were subjected to microbial community analysis and nontargeted metabolomics analysis. The results showed significantly lower bacterial diversity in fecal samples after CLP. At the genus level, the fecal samples obtained on the 3rd and 7th days after CLP exhibited significantly increased relative abundances of Bacteroides, Helicobacter, etc., and significantly decreased relative abundances of Alloprevotella, Prevotella, etc. Innate metabolite levels were significantly different in mice that survived less than 3 days and mice that survived more than 3 days. In conclusion, CLP-induced sepsis in mice changes the structure of the gut microbiome, and innate metabolites affect the prognosis of septic mice.

Early gut microbiological changes and metabolomic changes in patients with sepsis: a preliminary study.

The gut microbiota is closely related to the development of sepsis. The aim of this study was to explore changes in the gut microbiota and gut metabolism, as well as potential relationships between the gut microbiota and environmental factors in the early stages of sepsis. Fecal samples were collected from 10 septic patients on the first and third days following diagnosis in this study. The results showed that in the early stages of sepsis, the gut microbiota is dominated by microorganisms that are tightly associated with inflammation, such as Escherichia-Shigella, Enterococcus, Enterobacteriaceae, and Streptococcus. On sepsis day 3 compared to day 1, there was a significant decrease in Lactobacillus and Bacteroides and a significant increase in Enterobacteriaceae, Streptococcus, and Parabacteroides. Culturomica_massiliensis, Prevotella_7 spp., Prevotellaceae, and Pediococcus showed significant differences in abundance on sepsis day 1, but not on sepsis day 3. Additionally, 2-keto-isovaleric acid 1 and 4-hydroxy-6-methyl-2-pyrone metabolites significantly increased on sepsis day 3 compared to day 1. Prevotella_7 spp. was positively correlated with phosphate and negatively correlated with 2-keto-isovaleric acid 1 and 3-hydroxypropionic acid 1, while Prevotella_9 spp. was positively correlated with sequential organ failure assessment score, procalcitonin and intensive care unit stay time. In conclusion, the gut microbiota and metabolites are altered during sepsis, with some beneficial microorganisms decreasing and some pathogenic microorganisms increasing. Furthermore, Prevotellaceae members may play different roles in the intestinal tract, with Prevotella_7 spp. potentially possessing beneficial health properties and Prevotella_9 spp. potentially playing a promoting role in sepsis.

The accuracy of artificial intelligence in predicting COVID-19 patient mortality: a systematic review and meta-analysis.

BACKGROUND: The purpose of this paper was to systematically evaluate the application value of artificial intelligence in predicting mortality among COVID-19 patients. METHODS: The PubMed, Embase, Web of Science, CNKI, Wanfang, China Biomedical Literature, and VIP databases were systematically searched from inception to October 2022 to identify studies that evaluated the predictive effects of artificial intelligence on mortality among COVID-19 patients. The retrieved literature was screened according to the inclusion and exclusion criteria. The quality of the included studies was assessed using the QUADAS-2 tools. Statistical analysis of the included studies was performed using Review Manager 5.3, Stata 16.0, and Meta-DiSc 1.4 statistical software. This meta-analysis was registered in PROSPERO (CRD42022315158). FINDINGS: Of 2193 studies, 23 studies involving a total of 25 AI models met the inclusion criteria. Among them, 18 studies explicitly mentioned training and test sets, and 5 studies did not explicitly mention grouping. In the training set, the pooled sensitivity was 0.93 [0.87, 0.96], the pooled specificity was 0.94 [0.87, 0.97], and the area under the ROC curve was 0.98 [0.96, 0.99]. In the validation set, the pooled sensitivity was 0.84 [0.78, 0.88], the pooled specificity was 0.89 [0.85, 0.92], and the area under the ROC curve was 0.93 [1.00, 0.00]. In the subgroup analysis, the areas under the summary receiver operating characteristic (SROC) curves of the artificial intelligence models KNN, SVM, ANN, RF and XGBoost were 0.98, 0.98, 0.94, 0.92, and 0.91, respectively. The Deeks funnel plot indicated that there was no significant publication bias in this study (P > 0.05). INTERPRETATION: Artificial intelligence models have high accuracy in predicting mortality among COVID-19 patients and have high prognostic value. Among them, the KNN, SVM, ANN, RF, XGBoost, and other models have the highest levels of accuracy.

Chinese critical care certified course in intensive care unit: a nationwide-based analysis.

BACKGROUND: A training program for intensive care unit (ICU) physicians entitled "Chinese Critical Care Certified Course" (5 C) started in China in 2009, intending to improve the quality of intensive care provision. This study aimed to explore the associations between the 5 C certification of physicians and the quality of intensive care provision in China. METHODS: This nationwide analysis collected data regarding 5 C-certified physicians between 2009 and 2019. Fifteen ICU quality control indicators (three structural, four procedural, and eight outcome-based) were collected from the Chinese National Report on the Services, Quality, and Safety in Medical Care System. Provinces were stratified into three groups based on the cumulative number of 5 C certified physicians per million population. RESULTS: A total of 20,985 (80.41%) physicians from 3,425 public hospitals in 30 Chinese provinces were 5 C certified. The deep vein thrombosis (DVT) prophylaxis rate in the high 5 C physician-number provinces was significantly higher than in the intermediate 5 C physician-number provinces (67.6% vs. 55.1%, p = 0.043), while ventilator-associated pneumonia (VAP) rate in the low 5 C physician-number provinces was significantly higher than in the high 5 C physician-number provinces (14.9% vs. 8.9%, p = 0.031). CONCLUSIONS: The higher number of 5 C-certified physicians per million population seemed to be associated with higher DVT prophylaxis rates and lower VAP rates in China, suggesting that the 5 C program might have a beneficial impact on the quality of intensive care provision.

Efficacy and Safety of SARS-CoV-2 Neutralizing Antibody JS016 in Hospitalized Chinese Patients with COVID-19: a Phase 2/3, Multicenter, Randomized, Open-Label, Controlled Trial.

Recombinant human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibody JS016 showed neutralizing and therapeutic effects in preclinical studies. The clinical efficacy and safety of the therapy needed to be evaluated. In this phase 2/3, multicenter, randomized, open-label, controlled trial, hospitalized patients with moderate or severe coronavirus disease 2019 (COVID-19) were randomly assigned in a 1:1 ratio to receive standard care or standard care plus a single intravenous infusion of JS016. The primary outcome was a six-level ordinal scale of clinical status on day 28 since randomization. Secondary outcomes include adverse events, 28-day mortality, ventilator-free days within 28 days, length of hospital stay, and negative conversion rate of SARS-CoV-2 nucleic acid on day 14. A total of 199 patients were randomized, and 197 (99 in the JS016 group and 98 in the control group) were analyzed. Most patients, 95 (96%) in the JS016 group and 97 (99%) in the control group were in the best category on day 28 since randomization. The odds ratio of being in a better clinical status was 0.31 (95% confidence interval [CI], 0.03 to 3.19; P = 0.33). Few adverse events occurred in both groups (3% in the JS016 group and 1% in the control group, respectively; P = 0.34). SARS-CoV-2 neutralizing antibody JS016 did not show clinical efficacy among hospitalized Chinese patients with moderate to severe COVID-19 disease. Further studies are needed to assess the efficacy of the neutralizing antibody to prevent disease deterioration and its benefits among groups of patients specified by disease course and severity. (This study has been registered at ClinicalTrials.gov under identifier NCT04931238.).

circ-Katnal1 Enhances Inflammatory Pyroptosis in Sepsis-Induced Liver Injury through the miR-31-5p/GSDMD Axis.

Background: Sepsis is a systemic inflammatory response that can elicit organ dysfunction as well as circulatory diseases in serious cases. When inflammatory responses are especially dysregulated, severe complications can arise, including sepsis-induced liver injury. Various microRNAs along with circular (circ) RNAs are involved in inflammatory responses; nevertheless, their functions in regulating sepsis-induced liver injury remain unknown. The cecal ligation and puncture (CLP) procedure can induce liver injury as well as polymicrobial sepsis. Methods: In this study, CLP was used to induce liver injury as well as polymicrobial sepsis. Then, liver function, inflammatory cytokine expression, and hepatic histopathology were evaluated. High-throughput sequencing was employed to investigate the abnormal hepatic circRNA expression after CLP. Raw264.7 cells were utilized to simulation an in vitro sepsis inflammation model with LPS induce. The relative mRNA as well as protein levels of TNF-α, IL-1ß, and IL-6 was explored by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. We explored functional connections among circRNAs, miR-31-5p, and gasdermin D (GSDMD) using dual-luciferase reporter assays. Western blot was employed to test GSDMD, caspase-1, and NLRP3 expression in mice and cell models. Results: Our results showed that CLP-induced sepsis promoted liver injury via increasing inflammatory pyroptosis. The abnormal expression of circ-Katnal1 played an important role in CLP-induced sepsis. Downregulating circ-Katnal1 suppressed LPS-induced inflammatory pyroptosis in Raw264.7 cells. Bioinformatics and luciferase reporter results confirmed that miR-31-5p and GSDMD were downstream targets of circ-Katnal1. Inhibiting miR-31-5p or upregulating GSDMD reversed the protective effects of silencing circ-Katnal1. Conclusion: Taken together, circ-Katnal1 enhanced inflammatory pyroptosis in sepsis-induced liver injury through the miR-31-5p/GSDMD axis.

Identification of distinct clinical phenotypes of acute respiratory distress syndrome with differential responses to treatment.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, and the identification of homogeneous subgroups and phenotypes is the first step toward precision critical care. We aimed to explore whether ARDS phenotypes can be identified using clinical data, are reproducible and are associated with clinical outcomes and treatment response. METHODS: This study is based on a retrospective analysis of data from the telehealth intensive care unit (eICU) collaborative research database and three ARDS randomized controlled trials (RCTs) (ALVEOLI, FACTT and SAILS trials). We derived phenotypes in the eICU by cluster analysis based on clinical data and compared the clinical characteristics and outcomes of each phenotype. The reproducibility of the derived phenotypes was tested using the data from three RCTs, and treatment effects were evaluated. RESULTS: Three clinical phenotypes were identified in the training cohort of 3875 ARDS patients. Of the three phenotypes identified, phenotype I (n = 1565; 40%) was associated with fewer laboratory abnormalities, less organ dysfunction and the lowest in-hospital mortality rate (8%). Phenotype II (n = 1232; 32%) was correlated with more inflammation and shock and had a higher mortality rate (18%). Phenotype III (n = 1078; 28%) was strongly correlated with renal dysfunction and acidosis and had the highest mortality rate (22%). These results were validated using the data from the validation cohort (n = 3670) and three RCTs (n = 2289) and had reproducibility. Patients with these ARDS phenotypes had different treatment responses to randomized interventions. Specifically, in the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on ventilator-free days differed by phenotype (p = 0.001); in the FACTT cohort, there was a significant interaction between phenotype and fluid-management strategy for 60-day mortality (p = 0.01). The fluid-conservative strategy was associated with improved mortality in phenotype II but had the opposite effect in phenotype III. CONCLUSION: Three clinical phenotypes of ARDS were identified and had different clinical characteristics and outcomes. The analysis shows evidence of a phenotype-specific treatment benefit in the ALVEOLI and FACTT trials. These findings may improve the identification of distinct subsets of ARDS patients for exploration in future RCTs.

Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation.

Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5'-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.

Pharmacokinetics and Pharmacodynamics of Linezolid in Patients With Sepsis Receiving Continuous Venovenous Hemofiltration and Extended Daily Hemofiltration.

BACKGROUND: This prospective study compared pharmacokinetics (PK) and pharmacodynamics (PD) of linezolid in patients with sepsis receiving continuous venovenous hemofiltration (CVVH) with patients receiving extended daily hemofiltration (EDH). METHODS: Patients with sepsis treated with linezolid and CVVH or EDH were included. Serial blood samples were collected and linezolid concentrations measured. PKs were analyzed using Pmetrics. Monte Carlo simulations were used to evaluate PD target achievement. RESULTS: From 20 patients, 320 blood samples were collected for PK and PD analysis. PK profiles of linezolid were best described by a 2-compartment model. PK parameters were not significantly different between EDH and CVVH groups and were associated with body weight, renal replacement therapy (RRT) duration, and sequential organ failure assessment score. Monte Carlo simulations showed poor fractional target attainment for a minimum inhibitory concentration (MIC) of 2 mg/L with standard 600 mg intravenous administration every 12 hours. CONCLUSIONS: Patients with sepsis receiving RRT exhibited variability in PK/PD parameters for linezolid. PK parameters were not significantly different between CVVH- and EDH-treated patients. Higher probability of target attainment would be achievable at a MIC of 2 mg/L in EDH patients. Higher linezolid doses should be considered for patients on RRT to achieve adequate blood levels.

The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey.

OBJECTIVES: We performed a national cross-sectional survey to determine the epidemiologic characteristics of patients with sepsis in ICU in China. DESIGN: A cross-section survey study. SETTING: Forty-four hospitals in mainland China from December 1, 2015, to January 31, 2016. PATIENTS: All septic patients diagnosed according sepsis-1 criteria admitted to participating ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We recorded demographic, physiologic, and microbiological data with follow-up for 90 days or death, if sooner. The frequency of sepsis and 90-day mortality rate were computed, and the relationship with gross domestic product determined. Multivariate logistic regression analysis was used to determine risk factors for 90-day mortality in patients with sepsis. Two-thousand three-hundred twenty-two patients with sepsis were included in the analysis, of whom 786 patients (33.9%) had hospital-acquired sepsis. The most common infection site was the lung (68.2%), followed by abdomen (26.6%) and bloodstream (7.8%). The frequency of sepsis in the ICU was 20.6 cases per 100 ICU admissions (95% CI, 15.8-25.4) with a 90-day mortality of 35.5%. The proportion of sepsis, severe sepsis, and septic shock were 3.10%, 43.6%, and 53.3% with a 90-day mortality of 2.78%, 17.69%, and 51.94%, respectively. Older age, low body weight, higher Sequential Organ Failure Assessment score, the number of systemic inflammatory response syndrome criteria, comorbid with heart failure, hematologic cancer, immunosuppression, higher level of lactate, infection site (pneumonia and bloodstream) were associated with 90-day mortality. CONCLUSIONS: Sepsis affects a fifth of patients admitted to ICUs in mainland China with a 90-day mortality rate of 35.5%. Our findings indicate that a large burden of sepsis, and we need to focus on sepsis as a quality improvement target in China given the high mortality. In addition, further studies are needed to delineate the epidemiology of sepsis outside the ICU.

Acute right ventricular dysfunction in severe COVID-19 pneumonia.

To investigate the right heart function in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome (ARDS), a retrospective analysis of 49 COVID-19 patients with ARDS was performed. Patients were divided into severe group and critically-severe group according to the severity of illness. Age-matched healthy volunteers were recruited as a control group. The cardiac cavity diameters, tricuspid annular plane systolic excursion (TAPSE), tricuspid valve regurgitation pressure gradient biggest (TRPG), pulmonary arterial systolic pressure (PASP), maximum inferior vena cava diameter (IVCmax) and minimum diameter (IVCmin), and inferior vena cava collapse index (ICV-CI) were measured using echocardiography. We found that the TAPSE was significantly decreased in pneumonia patients compared to healthy subjects (P < 0.0001), and it was significantly lower in critically-severe patients (P = 0.0068). The TAPSE was less than 17 mm in three (8.6%) severe and five (35.7%) critically-severe patients. In addition, the TAPSE was significantly decreased in severe ARDS patients than in mild ARDS patients. The IVCmax and IVCmin were significantly increased in critically-severe patients compared to healthy subjects and severe patients (P < 0.01), whereas the ICV-CI was significantly decreased (P < 0.05). COVID-19 patients had significantly larger right atrium and ventricle than healthy controls (P < 0.01). The left ventricular ejection fraction (LVEF) in critically-severe patients was significantly lower than that in severe patients and healthy controls (P < 0.05). Right ventricular function was impaired in critically-severe COVID-19 patients. The assessment and protection of the right heart function in COVID-19 patients should be strengthened.

Analysis of tizoxanide, active metabolite of nitazoxanide, in rat brain tissue and plasma by UHPLC-MS/MS.

Tizoxanide, the active metabolite of nitazoxanide, has recently been reported as an effective agent for the treatment of glioma. As there had been no report about the analysis of tizoxanide in brain tissue, we established extraction and UHPLC-MS/MS methods to quantify tizoxanide in rat brain and plasma to evaluate the brain-to-plasma ratio of tizoxanide. The biological samples were mainly prepared by acetonitrile and the separation was performed on a Waters XBridge® BEH C18 column. The mobile phase was composed of water mixed with 10 mm ammonium formate (pH 3.0) and acetonitrile according a gradient volume. Tizoxanide and topiramate (internal standard) were monitored utilizing negative electron spray ionization in multiple reaction monitoring mode. The methods were validated to be precise and accurate within the dynamic range of 5-1000 ng/mL and 0.2-50 ng/g for plasma and brain tissue samples, respectively. The lower limit of quantitation of the method was 0.2 ng/g, which was far more sensitive than all existing methods to quantify tizoxanide in biological samples. Application performed on rats exhibited that the brain-to-plasma ratio of tizoxanide ranged from 3.16 to 26.86% in 1 h after administration of 10 mg/kg nitazoxanide.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial.

OBJECTIVES: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. DESIGN: Prospective, randomized, controlled study. SETTING: Thirty-three hospitals in China. PATIENTS: A total of 710 adults 18-75 years old with severe community-acquired pneumonia. INTERVENTIONS: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9-21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4-15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). CONCLUSIONS: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

Influence of AS3MT polymorphisms on arsenic metabolism and liver injury in APL patients treated with arsenic trioxide.

Arsenic-induced side effects limit its application in the treatment of acute promyelocytic leukemia (APL). We recently demonstrated that AS3MT 14215 (rs3740390) genotypes were associated with urinary arsenic metabolites and hematological and biochemical values. To further decipher the role of AS3MT genotypes on arsenic metabolism and toxicity, AS3MT 27215 (rs11191446), 35587 (rs11191453), 35991 (rs10748835), and their interactive effects were examined in fifty APL patients treated with arsenic trioxide (As2O3) for the first time. Urinary arsenic metabolites and methylation capacity indexes were evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), primary methylation index (PMI, MMA/iAs), secondary methylation index (SMI, DMA/MMA), and total methylation index (TMI, [MMA+DMA]/iAs). Results showed 27215 (rs11191446) genotypes had no statistical significance in arsenic metabolism, as only 5 (10%) patients were the non-wild-type genotypes. 35587 (rs11191453) genotypes were significantly associated with MMA%, DMA%, and SMI. 35991 (rs10748835) genotypes were significantly associated with iAs%, DMA%, PMI, TMI, and the level of ALT and AST. Patients with both 35587 (rs11191453) TT and 35991 (rs10748835) AG+GG genotypes were significantly associated with DMA% and SMI. In addition, patients with both 35991 (rs10748835) AA and 35587 (rs11191453) TC+CC genotypes had the highest DMA%, SMI, and TMI, but the lowest iAs%, ALT and AST level, indicating that additive effects exist on arsenic metabolism and liver function. Our data promotes the realization that AS3MT 35587 (rs11191453), 35991 (rs10748835), especially their joint genotypes 35991 (rs10748835) AA / 35587 (rs11191453) TC+CC, is a novel predictive biomarker for the therapeutic efficacy of As2O3 in the treatment of APL.

Release of volatile organic compounds (VOCs) from colorectal cancer cell line LS174T.

Colorectal cancer (CRC) is the third most common cancer worldwide. To date, no non-invasive and specific biomarkers have been identified for the diagnosis of CRC. The analysis of volatile organic compounds (VOCs) is attracting increasing attention and provides the possibility of a non-invasive diagnosis. Solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) have been used to analyze the VOCs released from the headspace gas of LS174T (Dukes' type B colorectal adenocarcinoma) cells, arsenic trioxide (ATO)-treated LS174T cells and the blood from tumor-bearing mice. The data were processed using principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA), which showed that the levels of decanal, 2,4-dimethyl- heptane, and twelve other metabolites were significantly greater in the headspace gas of the LS174T cells and blood of tumor-bearing mice. Additionally, in vivo experiments indicated that formic acid, ethenyl ester and p-trimethylsilyloxyphenyl-(trimethylsilyloxy)trimethylsilylacrylate were consumed during tumor growth. In conclusion, VOCs such as 1-methoxy-hexane and 2,4-dimethyl-heptane could be useful diagnostic markers for CRC. Further research should focus on the potential metabolic pathways associated with these profiles.

Effects of immunotherapy on mortality in neonates with suspected or proven sepsis: a systematic review and network meta-analysis.

BACKGROUND: To investigate the efficacies of different immunotherapies in neonates with suspected or proven sepsis. METHODS: We searched the Cochrane Library, EMBASE, MEDLINE, EBSCOhost, and Web of Science for studies published before May 2019 that investigated different immunotherapies in neonates with suspected or proven sepsis. Comparisons were among immunotherapies and between immunotherapy and placebo. The review was registered in the PROSPERO CRD database. RESULTS: All-cause mortality was not significantly different between patients who received the immunoglobulin (IgG), IgM-enriched immunoglobulin (IgGAM), granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) immunotherapies and those who received placebo. The RRs of the immunotherapies were 0.80 (95% CI: 0.57 to 1.1), 0.45 (95% CI: 0.17 to 1.0), 0.93 (95% CI: 0.64 to 1.2) and 0.67 (95% CI: 0.39 to 1.1), respectively. Compared with placebo, none of the interventions showed statistically significant differences in the duration of hospital stay. The MDs of the immunotherapies were - 2.7 (95% CI: - 8.4 to 3.5), - 0.18 (95% CI: - 7.3 to 7.7), - 1.7 (95% CI: - 7.3 to 3.9) and - 7.2 (95% CI: - 28 to 13), respectively. CONCLUSIONS: No significant differences in all-cause mortality or the duration of hospital stay were found in neonates with suspected or proven sepsis treated with the four types of immunotherapies and those treated with placebo.