Establishment and validation of a risk prediction model incorporating concentrations of linezolid and its metabolite PNU142300 for linezolid-induced thrombocytopenia.

BACKGROUND: Linezolid-induced thrombocytopenia is the main factor restricting the clinical application of linezolid. OBJECTIVES: To investigate the relationship between PNU-14230 concentration and linezolid-induced thrombocytopenia and further develop and validate a risk model for predicting linezolid-induced thrombocytopenia. METHODS: A regression model was constructed to predict the occurrence of linezolid-induced thrombocytopenia, and further externally validated. The predictive performance was evaluated by receiver operating characteristic curve and Hosmer-Lemeshow test. Linezolid Cmin and PNU-142300 concentrations were compared for different kidney function groups. The Kaplan-Meier method was used to estimate the difference in cumulative incidence of linezolid-induced thrombocytopenia among different kidney function patients. RESULTS: In the derivation (n = 221) and validation (n = 158) cohorts, 28.5% and 24.1% of critically ill patients developed linezolid-induced thrombocytopenia. Logistic regression analysis indicated that the independent risk factors were linezolid Cmin, PNU-142300 concentration, baseline platelet count, renal insufficiency (RI) and continuous venovenous haemofiltration (CVVH). The AUC for the risk model was 0.901, and the model was good (P = 0.633). The model also showed good discrimination (AUC 0.870) and calibration (P = 0.282) in the external validation cohort. Compared with normal kidney function patients, patients with RI and CVVH had higher linezolid Cmin and PNU-142300 concentrations (P < 0.001) and higher cumulative incidence of linezolid-induced thrombocytopenia (P < 0.001). CONCLUSIONS: PNU142300 concentration, as well as linezolid Cmin, might identify patients at risk of linezolid-induced thrombocytopenia. The risk prediction model had good predictive performance for linezolid-induced thrombocytopenia development. Concentrations of linezolid and PNU-142300 accumulated in patients with RI and CVVH.

High PD-L1 level of advanced hepatic lymphoepithelioma-like carcinoma response favorably to lenvatinib plus toripalimab.

Lymphoepithelioma-like carcinoma (LELC) is an uncommon subtype of primary liver cancer with predominant lymphocyte infiltration and a relatively favorable outcome. However, no standard treatment for advanced hepatic LELC has been established. Here, we give a first report of a 60-year-old man with advanced hepatic LELC who had a high expression of PD-L1 in tumor cells and a high level of tumor-infiltrating leukocytes (TILs) in the tumor microenvironment (TME). After receiving six cycles of multiple receptor tyrosine kinase inhibitor (rTKI) with lenvatinib plus PD-1 inhibitor toripalimab treatment, the patient achieved persistent partial response (PR). Our report indicates that advanced hepatic LELC with high expression of PD-L1 may benefit from the combination of rTKI and PD-L1/PD-1 blockade. Therefore, this potential strategy should be considered when treating those rare liver cancers.

Continuous infusion versus intermittent infusion of vancomycin in critically ill patients undergoing continuous venovenous hemofiltration: a prospective interventional study.

BACKGROUND: A prospective interventional study comparing outcomes in critically ill patients receiving intermittent infusion (II) or continuous infusion (CI) of vancomycin during continuous venovenous hemofiltration (CVVH) is lacking. The objective of this study was to compare the pharmacokinetic/pharmacodynamics (PK/PD) target attainment, therapeutic efficacy and safety among critically ill patients who received CI or II of vancomycin in a prospective interventional trial and to explore the correlations of effluent flow rate (EFR) with PK/PD indices. METHODS: This prospective interventional study was conducted in two independent intensive care units (ICUs) from February 2021 to January 2022. Patients in one ICU were assigned to receive CI (intervention group) of vancomycin, whereas patients in the other ICU were assigned to receive II regimen (control group). The primary outcome was to compare the PK/PD target attainment, including target concentration and target area under the curve over 24 h to minimum inhibitory concentration (AUC24/MIC). RESULTS: Overall target attainment of PK/PD indices was higher with CI compared with II, irrespective of target concentration (78.7% vs. 40.5%; P < 0.05) or AUC24/MIC (53.2% vs. 28.6%; P < 0.05). There were no significant differences in clinical success (72.2% vs. 50.0%; P = 0.183) and microbiological success (83.3% vs. 75.0%, P = 0.681) between the patients treated with CI or II of vancomycin. Adverse reactions occurred at similar rates (0.0% vs. 4.4%; P = 0.462), and mortality between the two modalities was also not significant different (21.7% vs. 17.9%; P = 0.728). Correlation analysis showed a weak to moderately inverse correlation of EFR with observed concentration (r = - 0.3921, P = 0.01) and AUC24/MIC (r = - 0.3811, P = 0.013) in the II group, whereas the correlation between EFR and observed concentration (r = - 0.5711, P < 0.001) or AUC24/MIC (r = - 0.5458, P < 0.001) in the CI group was stronger. CONCLUSION: As compared to II, CI of vancomycin in critically ill patients undergoing CVVH was associated with improved attainment of PK/PD indices. Furthermore, the inverse correlation of PK/PD indices with EFR was stronger among patients treated with CI of vancomycin. Trial registration The trial was registered in the Chinese clinical trial registration center (21/01/2021-No. ChiCTR2100042393).

Elevated levels of preß1-high-density lipoprotein are associated with cholesterol ester transfer protein, the presence and severity of coronary artery disease.

BACKGROUND: Preß1-high-density lipoprotein (preß1-HDL), plays an important role in reverse cholesterol transport and exhibits potent risk for coronary artery disease (CAD). However, the association of plasma preß1-HDL and cholesterol ester transfer protein (CETP) levels in CAD patients and the relationship of preß1-HDL with extent of CAD are debatable. METHODS: Preß1-HDL and CETP levels were measured by enzymed-linked immunosorbent assay (ELISAs) in 88 acute coronary syndromes (ACS), 79 stable coronary artery disease (SCAD) patients and 85 control subjects. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. RESULTS: The preß1-HDL and CETP levels in ACS patients were significantly higher than those in SCAD patients and both of them were higher than controls'. Preß1-HDL levels were positively associated with CETP (R = 0.348, P = 0.000), the diameter of stenosis (R = 0.253, P = 0.005), the number of vessel disease (R = 0.274, P = 0.002) and Gensini score (R = 0.227, P = 0.009) in CAD patients. Stepwise multiple linear regression analyses showed that CETP was one of the determinants of preß1-HDL levels. Logistic regression analysis revealed that elevated preß1-HDL and CETP were potential risk factors for both ACS and SCAD. CONCLUSION: The elevated preß1-HDL levels may change with CETP concentrations in CAD patients and were related to the presence and severity of CAD.

Differentially expressed microRNAs in kidney biopsies from various subtypes of nephrotic children.

BACKGROUND: Our previous study showed a set of increased miRNAs in serum or urine from nephrotic syndrome children. In this study, we investigated the renal expression of these miRNAs in nephrotic children and explored their role in pathogenesis and as potential indicators to differentiate subtypes of kidney diseases. METHODS: We enrolled 52 children with six different subtypes of nephropathy, and 8 normal kidney tissues were used as controls. RT-qPCR was used to quantify the expression of miR-191, miR-151-3p, miR-150, miR-30a-5p and miR-19b in renal tissues. RESULTS: miR-191 and miR-151-3p exhibited significantly higher and lower intrarenal expression in all six subtypes of kidney diseases compared to controls. miR-19b was upregulated in three subtypes, and miR-30a-5p and miR-150 were downregulated in two and four subtypes, respectively. The intrarenal expression of miR-150 was significantly different between minimal change disease (MCD) and some other subtypes. The renal levels of these miRNAs correlated significantly with some renal functions and immune parameters. Bioinformatics showed that some target genes of these miRNAs were associated with immune and renal pathological changes. CONCLUSIONS: These five miRNAs may be involved in the pathogenesis of nephropathy in children. miR-150 is a potential typing indictor to differentiate MCD from other nephropathy subtypes.

A nomogram incorporating linezolid and metabolite concentrations for predicting linezolid induced thrombocytopenia in patients with renal impairment.

A nomogram to estimate the risk of linezolid-induced thrombocytopenia in patients with renal impairment is not available. The aim of the study is to develop a nomogram for predicting linezolid-induced thrombocytopenia in patients with renal impairment and to investigate the incremental value of PNU-142300 concentration beyond clinical factors and linezolid trough concentration (Cmin) for risk prediction. Logistic regression was used to identify independent risk factors for linezolid-induced thrombocytopenia in patients with renal impairment and nomograms were established. The performance of the nomograms was assessed in terms of area under the receiver operating characteristic curve (AUROC), net reclassification improvement (NRI), integrated discrimination improvement (IDI) , decision curve analysis (DCA) and calibration. Internal validation and external validation of the nomograms were also performed. Four nomograms were created: nomogram A including total bilirubin, creatinine clearance and concomitant mannitol use; nomogram B containing linezolid Cmin additionally; nomogram C containing total bilirubin, concomitant mannitol use, linezolid Cmin, and PNU142300 concentration; nomogram D including total bilirubin, concomitant mannitol use, and PNU142300 concentration. Nomogram C improved the prediction performance than nomogram A (AUROC 0.881 vs. 0.749; NRI 0.290; IDI 0.226) and nomogram B (AUROC 0.881 vs. 0.812; NRI 0.152; IDI 0.130) in the training cohort. DCA analysis showed that nomogram C yielded a greater net benefit. Compared with nomogram A and nomogram B, nomogram C also showed superior discriminatory efficacy, good calibration and clinical usefulness in the external validation cohort. The nomogram containing PNU-142300 concentration and linezolid Cmin had better predictive capability than that containing linezolid Cmin for predicting linezolid-induced thrombocytopenia in patients with renal impairment.

Adjuvant chemoradiotherapy vs chemotherapy for resectable biliary tract cancer: a propensity score matching analysis based on the SEER database.

BACKGROUND: Although the role of adjuvant chemotherapy (CT) for resectable biliary tract cancer (BTC) is gradually recognized, the benefit of adjuvant chemoradiotherapy (CRT) is still controversial. Our study is designed to compare the prognosis of CRT versus CT in BCT patients. METHODS: Clinicopathologic characteristics of patients with operable gallbladder cancer (GBCA), intrahepatic bile duct cancer (IHBDC), or extrahepatic bile duct cancer (EHBDC) were obtained from the Surveillance, Epidemiology and End Results (SEER) database (2004-2015). Univariate and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Selection bias were reduced by propensity-score matching (PSM). Kaplan-Meier analysis was used to estimate the survival time. RESULTS: Within 922 patients, 53.9% received adjuvant CRT, and 46.1% received adjuvant CT. Multivariate analysis showed age, primary tumor site, T stage, N stage, tumor size, number of removed lymph nodes, and treatment were independent risk factors for OS. Similar improvement of CRT on survival was identified by PSM in the matched cohort compared with CT (28.0 months vs. 25.0 months, p = 0.033), particularly in GBCA cohort (25.0 months vs. 19.0 months, p = 0.003). Subgroup analysis indicated CRT improved outcomes of patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases. CONCLUSION: Adjuvant CRT correlated with improved survival in patients with resected BTC compared with adjuvant CT, particularly in GBCAs. In addition, patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases may receive more benefits from adjuvant CRT.

Dose optimisation of linezolid in critically ill patients based on a population pharmacokinetic model: A two-centre prospective interventional study.

OBJECTIVES: This study evaluated the intervention effect of clinical pharmacist-mediated optimisation of a linezolid regimen using a population pharmacokinetic (PPK) model. METHODS: Patients treated with linezolid in two medical centres from January 2020 to June 2021 were retrospectively included in the control group; those treated from July 2021 to June 2022 were prospectively enrolled in the intervention group. Clinical pharmacists optimised the dosage regimen according to a published linezolid PPK model in the intervention group. An interrupted times series approach was used to analyse the data. The incidence of linezolid-induced thrombocytopenia (LIT), target attainment of pharmacokinetic/pharmacodynamic parameters and other adverse drug reactions (ADRs) were compared between the two groups. RESULTS: In total, 77 and 103 patients were enrolled in the control and intervention groups, respectively. The intervention group had a lower incidence of LIT and other ADRs than the control group (10.7% vs. 23.4%, P = 0.002; 1.0% vs. 7.8%, P = 0.027). The intervention group exhibited a considerably lower trough concentration (Cmin) and area under the concentration-time curve/MIC ratio (AUC24/MIC) (P = 0.001 and P < 0.001). Cmin and AUC24/MIC rates within the target range were substantially higher in the intervention group (49.6% vs. 20.0%, adjusted P < 0.05; 48.1% vs. 25.6%, adjusted P < 0.05). CONCLUSION: Interventions by clinical pharmacists reduced the incidence of LIT and other ADRs. Implementation of model-informed precision dosing (MIPD) for linezolid markedly increased the Cmin and AUC24/MIC rates within the target range. We recommend MIPD-guided linezolid dose reduction for patients with renal impairment.

A Regression Model to Predict Linezolid Induced Thrombocytopenia in Neonatal Sepsis Patients: A Ten-Year Retrospective Cohort Study.

Background: Linezolid-induced thrombocytopenia (LIT) is the main factor limiting the clinical application of linezolid (LZD). The incidence and risk factors of LIT in neonatal patients were possibly different from other populations based on pathophysiological characteristics. The purpose of this study was to establish a regression model for predicting LIT in neonatal sepsis patients. Methods: We retrospectively included 518 patients and divided them into the LIT group and the non-LIT group. A logistic regression analysis was used to analyze the factors related to LIT, and a regression model was established. A receiver operating characteristic (ROC) curve was drawn to evaluate the model's predictive value. We prospectively collected 39 patients' data to validate the model and evaluate the effect of LZD pharmacokinetics on LIT. Results: Among the 518 patients, 103 patients (19.9%) developed LIT. The Kaplan-Meier plot revealed that the overall median time from the initiation of LZD treatment to the onset of LIT in preterm infants was much shorter when compared with term infants [10 (6, 12) vs. 13 (9.75, 16.5), p = 0.004]. Multiple logistic regression analysis indicated that the independent risk factors of LIT were lower weight at medication, younger gestational ages, late-onset sepsis, necrotizing enterocolitis, mechanical ventilation, longer durations of LZD treatment, and lower baseline of platelet level. We established the above seven-variable prediction regression model and calculated the predictive probability. The ROC curve showed that the predicted probability of combined body weight, gestational age, duration of LZD treatment, and baseline of platelet had better sensitivity (84.4%), specificity (74.2%), and maximum AUC (AUC = 0.873). LIT occurred in 9 out of 39 patients (23.1%), and the accuracies of positive and negative predictions of LIT were 88.9 and 76.7%, respectively. Compared with the non-LIT patients, the LIT patients had higher trough concentration [11.49 (6.86, 15.13) vs. 5.51 (2.80, 11.61) mg/L; p = 0.028] but lower apparent volume of distribution (Vd) [0.778 (0.687, 1.421) vs. 1.322 (1.099, 1.610) L; p = 0.010]. Conclusion: The incidence of LIT was high in neonatal sepsis patients, especially in preterm infants. LIT occurred earlier in preterm infants than in term infants. The regression model of seven variables had a high predictive value for predicting LIT. LIT was correlated with higher trough concentration and lower Vd.

Dose Optimization of Teicoplanin for Critically Ill Patients With Renal Dysfunction and Continuous Renal Replacement Therapy: Experience From a Prospective Interventional Study.

Background: Due to the lack of updated information on teicoplanin (TEI) for continuous renal replacement therapy (CRRT), no exact dosage regimen has been recommended. The aim of this study was to optimize the dosage regimen of TEI in renal dysfunction patients with or without CRRT, evaluate the influence factors of the eradication of Gram-positive bacteria, and evaluate the effect of CRRT on the clearance of TEI. Methods: Patients with renal dysfunction receiving TEI treatment in the ICU were prospectively recruited and divided into CRRT and non-CRRT groups. Logistic regression analysis was used to screen the factors affecting the eradication of Gram-positive bacteria. The filtrate concentration of the CRRT group was measured at the time of TEI Cmin, and the filtration coefficient of TEI was calculated to evaluate the effect of CRRT on the clearance of TEI. Results: A total of 106 patients were included, 40 cases in the CRRT group and 66 cases in the non-CRRT group. After giving high-loading doses of TEI, 75.8 and 70% of TEI Cmin in the non-CRRT and CRRT groups reached the range of 10-30 mg/L before the 3rd dose, respectively. The risk of G+ bacteria being uneradicated was higher while the APACHEⅡscore was higher than 22.5. The albumin level before the start of TEI administration and before the 6th-8th dose was lower than 32.8 g/L and 29.3 g/L, respectively, and Cmin before the 3rd dose and 6th-8th dose was lower than 13.2 mg/L and 17.1 mg/L, respectively, with the duration of TEI therapy shorter than 10.5 days. The correlation coefficient (r) was 0.6490 between Cmin before the 3rd dose and the albumin level (p < 0.001). The filtration coefficient of TEI was 10.7 ± 2.4% at Cmin and 11.1 ± 2.5% at Cmax. The GFR had no correlation with the filtration coefficient (r = -0.06204; r = -0.08059). The clearance of TEI in CRRT patients was negatively correlated with the albumin level (r = -0.6305, p = 0.0013). Conclusion: The early stage of the albumin level can significantly affect the initial Cmin and clinical efficacy of TEI, and also had effect on the clearance of TEI by CRRT. The filtration coefficient of TEI was stable, even with a higher ultrafiltration rate.

Genome-wide DNA methylome alterations in acute coronary syndrome.

Acute coronary syndrome (ACS) is a common disease with high mortality and morbidity rates. The methylation status of blood DNA may serve as a potential early diagnosis and prevention biomarker for numerous diseases. The present study was designed to explore novel genome-wide aberrant DNA methylation patterns associated with ACS. The Infinium HumanMethylation450 assay was used to examine genome-wide DNA methylation profiles in 3 pairs of ACS and control group samples. Epigenome-wide DNA methylation, genomic distribution, Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The results were confirmed using methylation-specific polymerase chain reaction (MSP) and Sequenom MassARRAY analyses in ACS, stable coronary artery disease (SCAD) and control samples. A total of 11,342 differentially methylated (DM) 5'-C-phosphate-G-3' (CpG) sites were identified, including 8,865 hypomethylated and 2,477 hypermethylated CpG sites in the ACS group compared with the control samples. They varied in frequency across genomic compartments, but were particularly notable in gene bodies and shores. The results of GO term and KEGG pathway enrichment analyses revealed that the methylated genes were associated with certain biological processes and pathways. Despite the considerable variability in methylation data, the candidate selected possessed significant methylation alteration in mothers against decapentaplegic homolog 3 (SMAD3) transcription start site 155 (Chr1:67356838-Chr1:67356942). MSP analysis from 81 ACS samples, 74 SCAD samples and 53 healthy samples, and Sequenom MassARRAY analysis, confirmed that differential CpG methylation of SMAD3 was significantly corrected with the reference results of the HumanMethylation450 array. The data identified an ACS-specific DNA methylation profile with a large number of novel DM CpG sites, some of which may serve as candidate markers for the early diagnosis of ACS.

Elevated beta2-glycoprotein I-low-density lipoprotein levels are associated with the presence of diabetic microvascular complications.

AIMS: To investigate serum beta2-glycoprotein I-low-density lipoprotein (ß2-GPI-LDL) and oxidized low-density lipoprotein (ox-LDL) levels in type 2 diabetes mellitus (T2DM) patients, and to further evaluate the associations of ß2-GPI-LDL with ox-LDL in vivo and with the presence of diabetic microvascular complications. METHODS: We determined ß2-GPI-LDL, ox-LDL and small dense low density lipoprotein cholesterol (sdLDL-C) levels in 236 T2DM patients with or without microvascular complications and 75 controls. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. RESULTS: Compared with controls, ß2-GPI-LDL and ox-LDL levels were significantly elevated in both groups of T2DM patients and those with microvascular complications exhibited the more significant increase than those without complications. Serum ß2-GPI-LDL levels were positively correlated with ox-LDL as well as sdLDL-C levels in T2DM patients. Multiple linear regression analyses showed that ox-LDL was one of the independent determinants of ß2-GPI-LDL levels. Logistic regression analyses indicated that elevated ß2-GPI-LDL and ox-LDL levels had significant predictive values for diabetic microvascular complications. CONCLUSIONS: Elevated serum ß2-GPI-LDL levels may be a serological hallmark of enhanced LDL oxidation in vivo and closely associated with the presence of diabetic microvascular complications.

Glycerol extracting dealcoholization for the biodiesel separation process.

By means of utilizing sunflower oil and Jatropha oil as raw oil respectively, the biodiesel transesterification production and the multi-stage extracting separation were carried out experimentally. Results indicate that dealcoholized crude glycerol can be utilized as the extracting agent to achieve effective separation of methanol from the methyl ester phase, and the glycerol content in the dealcoholized methyl esters is as low as 0.02 wt.%. For the biodiesel separation process utilizing glycerol extracting dealcoholization, its technical and equipment information were acquired through the rigorous process simulation in contrast to the traditional biodiesel distillation separation process, and results show that its energy consumption decrease about 35% in contrast to that of the distillation separation process. The glycerol extracting dealcoholization has sufficient feasibility and superiority for the biodiesel separation process.