Evaluating early lymphocyte-to-monocyte ratio as a predictive biomarker for delirium in older adult patients with sepsis: insights from a retrospective cohort analysis.

Background: This study aims to explore the value of the Lymphocyte-to-Monocyte Ratio (LMR) in predicting delirium among older adult patients with sepsis. Methods: Retrospective data were obtained from the MIMIC-IV database in accordance with the STROBE guidelines. Patients aged 65 and above, meeting the Sepsis 3.0 criteria, were selected for this study. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU). Demographic information, comorbid conditions, severity of illness scores, vital sign measurements, and laboratory test results were meticulously extracted. The prognostic utility of the Lymphocyte-to-Monocyte Ratio (LMR) in predicting delirium was assessed through logistic regression models, which were carefully adjusted for potential confounding factors. Results: In the studied cohort of 32,971 sepsis patients, 2,327 were identified as meeting the inclusion criteria. The incidence of delirium within this subgroup was observed to be 55%. A univariate analysis revealed a statistically significant inverse correlation between the Lymphocyte-to-Monocyte Ratio (LMR) and the risk of delirium (p < 0.001). Subsequent multivariate analysis, which accounted for comorbidities and illness severity scores, substantiated the role of LMR as a significant predictive marker. An optimized model, achieving the lowest Akaike Information Criterion (AIC), incorporated 17 variables and continued to demonstrate LMR as a significant prognostic factor (p < 0.01). Analysis of the Receiver Operating Characteristic (ROC) curve indicated a significant enhancement in the Area Under the Curve (AUC) upon the inclusion of LMR (p = 0.035). Conclusion: The Lymphocyte-to-Monocyte Ratio (LMR) serves as a significant, independent prognostic indicator for the occurrence of delirium in older adult patients with sepsis. Integrating LMR into existing predictive models markedly improves the identification of patients at elevated risk, thereby informing and potentially guiding early intervention strategies.

Allogenic Umbilical Cord-Derived Mesenchymal Stromal Cells Sustain Long-Term Therapeutic Efficacy Compared With Low-Dose Interleukin-2 in Systemic Lupus Erythematosus.

OBJECTIVES: Mesenchymal stromal cells (MSCs) and low-dose interleukin-2 (IL-2) both have demonstrated efficacy in treating systemic lupus erythematosus (SLE). The aim of this study is to conduct a head-to-head comparison between the 2 treatments and provide insights for clinical applications. METHODS: Lupus-prone mice were treated with umbilical cord-derived MSCs (UC-MSCs), IL-2, or a combination of UC-MSCs and IL-2, respectively. The lupus-like symptoms, renal pathology, and T-cell response were assessed 1 or 4 weeks later. Modulation of IL-2 production by MSCs on immune cells was investigated by the coculture assay. Disease activity and serum IL-2 of SLE patients were determined before and after receiving UC-MSCs. RESULTS: Both UC-MSCs and IL-2 improved lupus symptoms in lupus-prone mice 1 week after treatment, while the effects of UC-MSCs lasted up to 4 weeks. Moreover, the UC-MSC-treated group showed better renal pathology improvement. Importantly, UC-MSCs combined with IL-2 did not provide better efficacy than UC-MSCs alone. Consistent with this, UC-MSCs alone and UC-MSCs + IL-2 resulted in similar levels of serum IL-2 and frequencies of Tregs. Neutralization of IL-2 partly reduced the promotion of Tregs by UC-MSCs, suggesting that IL-2 was involved in the upregulation of Tregs by UC-MSCs. Lastly, an increase in serum IL-2 positively correlated with the reduction of disease activity of SLE patients by UC-MSCs. CONCLUSION: Both the single injection of UC-MSCs and repeated IL-2 administration exerted comparable efficacy in alleviating SLE manifestations, but UC-MSCs provided sustained alleviation and showed better improvement in renal pathology.

[Value of interleukin-6 and CD4+ T-lymphocytopenia in assessing the severity and prognosis of coronavirus disease 2019].

OBJECTIVE: To evaluate the role of interleukin-6 (IL-6) and CD4+ T-lymphocytopenia in assessing the severity and prognosis of coronavirus disease 2019 (COVID-19). METHODS: A prospective observational study was conducted. Forty-five patients with COVID-19 admitted to Henan Provincial People's Hospital from January 13 to March 13, 2020 were enrolled and divided into normal group (13 cases), severe group (20 cases), critically severe group (12 cases) according to the severity of the disease. A total of 15 healthy subjects receiving physical examinations during the same period were collected as the healthy control group. Clinical data were collected to compare the clinical characteristics, general test results, IL-6 and CD4+ T-lymphocytopenia levels of patients in different disease severity groups and healthy control group. The receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of each indicator for the severity of COVID-19. Multivariate Cox regression analysis was used to analyze the risk factors affecting the prognosis of COVID-19 patients, and Kaplan-Meier survival curve analysis was performed. RESULTS: The age of the critically severe group was significantly higher than that of the severe and normal groups (years old: 66.91±17.01 vs. 59.35±18.07, 40.23±12.61, both P < 0.05), and the negative conversion time of the 2019 novel coronavirus (2019-nCoV) was significantly longer than that of the severe and normal groups (days: 19.00±10.66 vs. 18.00±7.18, 9.31±3.49, both P < 0.05). With the increase of the severity of disease, white blood cell count (WBC), C-reactive protein (CRP), calcitonin (PCT), total bilirubin (TBil), troponin I (TnI), IL-6, D-dimer and other indicators were significantly increased, while lymphocyte count (LYM), platelet count (PLT), CD4+, CD8+, oxygenation index (PaO2/FiO2) were significantly decreased (all P < 0.01). ROC curve showed that PaO2/FiO2, IL-6 and CD4+ had certain predictive value for disease severity of COVID-19, the area under the ROC curve (AUC) of them were 0.903, 0.871, 0.689, and the 95% confidence interval (95%CI) were 0.806-0.949, 0.769-0.974, 0.542-0.853; the best cut-off values were 196.00 mmHg (1 mmHg = 0.133 kPa), 6.02 ng/L, 355 cells/µL, respectively; the sensitivity were 73.3%, 99.3%, 73.3%, and the specificity were 96.6%, 62.1%, 65.5%, respectively. Multivariate Cox regression analysis showed that age, PaO2/FiO2, high IL-6 and low CD4+ (IL-6 ≥ 6.02 ng/L and CD4+ < 355 cells/µL) were independent risk factors affecting the prognosis of COVID-19 [hazard ratio (HR) was 1.077, 0.053 and 3.490, respectively, all P < 0.05]. Kaplan-Meier survival analysis showed that when both high IL-6 and low CD4+ (IL-6 ≥ 6.02 ng/L and CD4+ < 355 cells/µL) were present, the mean time of adverse prognosis was (20.53±5.71) days; when increased IL-6 and decreased CD4+ were inconsistent, the mean time of adverse prognosis was (53.21±3.16) days. CONCLUSIONS: The levels of IL-6 and CD4+ T-lymphocytopenia are closely related to the severity of COVID-19 disease. When IL-6 ≥ 6.02 ng/L and CD4+ < 355 cells/µL occur simultaneously, the prognosis is poor.

Bidirectional chiral inversion of trantinterol enantiomers after separate doses to rats.

The chiral inversion and pharmacokinetics of two enantiomers of trantinterol, a new ß2 agonist, were studied in rats dosed (+)- or (-)-trantinterol separately. Plasma concentrations of (+)- and (-)-trantinterol were measured by chiral stationary phase liquid chromatography tandem mass spectroscopy (LC-MS/MS). The apparent inversion ratio was calculated as the ratio of AUC0-t of (-)-trantinterol or (+)-trantinterol inverted from their antipodes to the sum of the AUC0-t of (-)- and (+)-trantinterol. Following single intravenous administration, both given enantiomers declined in similar plasma concentrations, suggesting that the two enantiomers have approximately the same disposition kinetics by the route of intravenous administration. However, after single oral administration, plasma concentrations of uninverted (-)-trantinterol at many timepoints were significantly higher than those of uninverted (+)-trantinterol, suggesting that the two enantiomers undergo apparently different absorption or metabolism after oral administration. Significant bidirectional chiral inversion occurred after intravenous and oral administration of (+)- or (-)-trantinterol. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated in vivo. The AUC0-36 of (+)-trantinterol after intravenous and oral dosing of (-)-trantinterol were 16.6 ± 5.2 and 33.3 ± 16%, respectively of those of total [(+) + (-)] trantinterol. The AUC0-36 of (-)-trantinterol after intravenous and oral dosing of (+)-trantinterol were 19.6 ± 8.8 and 37.9 ± 4.5%, respectively, of those of total [(-) + (+)] trantinterol. After intravenous administration of (+)- and (-)-trantinterol the chiral inversion ratios of the two enantiomers were not significantly different and similar results were found for oral administration. The extent of chiral inversion after intravenous administration was apparently lower, indicating that the bidirectional chiral inversion was not only systemic but also presystemic.

[Expression of vitronectin in placental basal plate and its relationship with the pathogenesis of severe preeclampsia].

OBJECTIVE: To investigate the expression of vitronectin (VN) in placental basal plate and its relationship with the pathogenesis of severe preeclampsia. METHODS: From March 2010 to December 2011, 17 patients with early-onset severe preeclampsia who delivered in the Second Hospital of Jilin University were recruited as the early-onset severe preeclampsia group; and 16 women were recruited as the late-onset severe preeclampsia group. Meanwhile, 15 healthy pregnant women who delivered before 34 weeks were defined as the early control group (termination of pregnancy was carried out because of fetal heart malformations), and 15 healthy pregnant women delivered after 34 weeks were defined as the late control group. Immunohistochemistry and semi-quantitative reverse transcription (RT)-PCR were used to investigate the expression of VN protein and mRNA in the placental infarct center and its surrounding tissue of placental basal plate. The levels of serum prothrombin time (PT), part thromboplastin time (APTT) and fibrinogen (FIb) were detected and the international normalized ratio (INR) was calculated. The correlation of abnormal coagulation markers and VN expression levels in the early-onset severe preeclampsia group and the early control group was studied. RESULTS: (1) VN protein was detected in all placental basal plate of the four groups. It was highly expressed in the necrotic tissue of placental infarct center and weakly expressed in the tissue far from the infarcted area. (2) The mean levels of VN protein expression in placental basal plate of the early-onset severe preeclampsia group, the late-onset severe preeclampsia group, the late control group and the early control group were 0.152 ± 0.019, 0.113 ± 0.023, 0.095 ± 0.014 and 0.055 ± 0.010, respectively. And the differences between the groups were statistically significant (P < 0.01). The VN protein expression in placental infarct center, infarct edge, peri-infarct tissue and tissue far from the infarcted area gradually reduced, and the differences were statistically significant (P < 0.01). Compared with the same areas of each group, the differences were not statistically significant (P > 0.05). (3) VN mRNA were detectable in infarct center, infarct edge, per-infarct tissue and tissue far from the infarcted area of placental basal plate. In the early-onset severe preeclampsia group and the early control group, it was statistically higher in infarct center than in tissue far from the infarcted area (P < 0.05). (4) PT of the early-onset severe preeclampsia group was (9.45 ± 0.63) s, significantly shorter than that of the early control group [(9.88 ± 0.17) s, P < 0.05]. While there was no statistically significant difference in APTT, FIB and INR among the four groups (P > 0.05). (5) In the early-onset severe preeclampsia group, VN expression level and PT were significantly negative correlated (r = -0.612, P < 0.05); while in the early control group there was no correlation (r = 0.489, P > 0.05). CONCLUSION: VN was highly expressed in placental basal plate of the early-onset severe preeclampsia group, which caused the imbalance of coagulation and fibrinolysis system and the pathogenesis of severe preeclampsia.

In vivo and in vitro metabolism of a novel ß2-adrenoceptor agonist, trantinterol: metabolites isolation and identification by LC-MS/MS and NMR.

Trantinterol is a novel ß(2)-adrenoceptor agonist used for the treatment of asthma. The aim of this study is to identify the metabolites of trantinterol using liquid chromatography tandem mass spectrometry (LC-MS/MS), to isolate the main metabolites, and confirm their structures by nuclear magnetic resonance (NMR). Urine, feces, bile, and blood samples of rats were obtained and analyzed. Reference standards of six metabolites were achieved with the combination of chemical synthesis, microbial transformation, and the model systems of rats. Moreover, in order to investigate the phase I metabolism of trantinterol in humans and to study the species differences between rats and humans, incubations with liver microsomes were performed. The biotransformation by a microbial model Cunninghamella blakesleana AS 3.970 was also studied. A total of 18 metabolites were identified in vivo and in vitro together, 13 of which were newly detected. Three phase I metabolites were detected in vivo and in vitro as well as in the microbial model, including the arylhydroxylamine (M1), the tert-butyl hydroxylated trantinterol (M2) and the 1-carbonyltrantinterol (M3). Another important pathway in rats is glutathione conjugation and further catabolism and oxidation to form consecutive derivatives (M4 through M10). Other metabolites include glucuronide, glucoside, and sulfate conjugates. The results of in vitro experiments indicate no species difference exists among rats, humans, and C. blakesleana AS 3.970 on the phase I metabolism of trantinterol. Our study provided the most comprehensive picture for trantinterol in vivo and in vitro metabolism to this day, and may predict its metabolism in humans.

Development and validation of UPLC-MS/MS method for determination of domperidone in human plasma and its pharmacokinetic application.

A sensitive, rapid and selective ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed for the determination and pharmacokinetic study of domperidone in human plasma. Diphenhydramine was used as the internal standard. Plasma sample pretreatment involved a one-step liquid-liquid extraction with a mixture of diethyl ether-dichloromethane (3:2, v/v). The analysis was carried out on an Acquity UPLC(TM) BEH C(18) column. The mobile phase consisted of methanol-water containing 10 mmol/L ammonium acetate and 0.5% (v/v) formic acid (60:40, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode via electrospray ionizationsource with positive mode. Each plasma sample was chromatographed within 2.1 min. The standard curves for domperidone were linear (r(2) ≥ 0.99) over the concentration range of 0.030-31.5 ng/mL with a lower limit of quantification of 0.030 ng/mL. The intra- and inter-day precision (relative standard deviation) values were not higher than 13% and accuracy (relative error) was from -7.6 to 1.2% at three quality control levels. The method herein described was superior to previous methods and was successfully applied to the pharmacokinetic study of domperidone in healthy Chinese volunteers after oral administration.

Determination of L-trantinterol in rat plasma by using chiral liquid chromatography-tandem mass spectrometry.

A simple, sensitive, and rapid method for determination of L-trantinterol in rat plasma was developed for the first time by using LC coupled to MS/MS based on chiral stationary phase. A baseline separation of the enantiomers of trantinterol was achieved on a Chirobiotic V column, using a mixture of acetonitrile-methanol-ammonia-acetic acid (80:20:0.01:0.02, v/v/v/v) as the mobile phase. The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via ESI. The calibration curve was linear in concentration range from 0.270 to 108 ng/mL in plasma with the lower limit of quantification of 0.270 ng/mL. The intra- and interday precision (relative standard deviation) values were within 10.9% and the accuracy (relative error) was from 2.6 to 9.2% at all quality control levels. The method has been successfully applied to a study of L-trantinterol pharmacokinetics in rats.

Quantitative determination of lisinopril in human plasma by high performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.

A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to determine lisinopril in human plasma. Sample pretreatment involved a one-step protein precipitation with methanol of 0.1 mL plasma. Analysis was performed on an Inertsil ODS-3 column (2.1 × 50 mm i.d., 3 µm) with mobile phase consisting of methanol-water (containing 0.2% formic acid; 55:45, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode via an electrospray ionization source. Each plasma sample was chromatographed within 2.5 min. The linear calibration curves for lisinopril were obtained in the concentration range of 1.03-206 ng/mL (r(2) ≥ 0.99) with a lower limit of quantification of 1.03 ng/mL. The intra- and inter-day precisions (relative standard deviation) were not higher than 11%, and accuracy (relative error) was within ±6.8%, determined from quality control samples for lisinopril, which corresponded to the guidance of the Food and Drug Administration. The method described herein was fully validated and successfully applied to the pharmacokinetic study of lisinopril tablets in healthy male volunteers after oral administration.

[Epidemiological and clinical analysis of Mycoplasma pneumoniae infection in children with acute respiratory tract infection].

OBJECTIVE: To summarize the epidemiology and clinical characteristics of Mycoplasma pneumoniae (MP) infection in children with acute respiratory tract infection (ARI) in Guangzhou. METHODS: MP was detected using an indirect immunofluorescent method in 2084 children with ARI. The relations between MP infection rate and the gender, age, season, site of infection and wheezing diseases were analyzed. RESULTS: A total of 433 children (20.8%) were positive for MP, including 222 boys (19.8%) and 211 girls (21.9%) without significant difference in the infection rate between the genders (P>0.05). In 0- to 3-year-old group, 106 children were positive for MP (15.0%), while in 3- to 5-year-old group and 5- to 14-year-old group, 163 (25.2%) and 164 (22.5%) were positive, respectively, showing a significant difference in the infection rate between the 3 groups (P<0.05). The MP infection rate was 18.0% in January to March, 25.1% in April to June, 17.7% in July to September, and 20.5% in October to December, showing significant differences between the periods (P<0.05). No significant difference was found in the infection rate between children with acute upper respiratory tract infection (URI) and those with lower respiratory tract infection (LRI) (P>0.05). Among the children with LRI, those having wheezing disease had significantly higher MP positivity rate than those without wheezing. CONCLUSION: MP is a common causative agent for ARI in children. MP infection is not related to gender and infection site, but to age and season. Children over 3 years old are vulnerable to MP infection. MP infection can be associated with wheezing in LRI.