Risk of immune system and skin and subcutaneous tissue related adverse events associated with oxaliplatin combined with immune checkpoint inhibitors: a pharmacovigilance study.

Background: Few studies have analysed oxaliplatin-induced adverse events (ADEs) in the immune system and skin and subcutaneous tissues through pharmacovigilance. We used this approach to analyse the risk of such ADEs when oxaliplatin combined with immune checkpoint inhibitors (ICIs). Methods: We evaluated the association between oxaliplatin and ADEs in the immune system and skin and subcutaneous tissues using the reporting odd ratio (ROR) for mining the ADE report signals in the FDA Adverse Event Reporting System database. Risk factors were analyzed using a binary logistic regression analysis using the sex and age of the patients. Results: There were 40,474 reports of oxaliplatin as primary suspect drug or second suspect drug. The signal intensities of ADEs such as type II hypersensitivity, type I hypersensitivity, type III immune complex-mediated reaction, anaphylactoid shock and cytokine release syndrome were high in PTs classified by SOC as immune system disorders; in the PTs classified as skin and subcutaneous tissue disorders by SOC, the signal intensities of ADEs such as skin toxicity, skin reaction, rash maculo-papular and skin fissures were higher. In the risk assessment between the two groups, rash showed an increased risk in the oxaliplatin-ICI group, with an OR of 1.96. Nivolumab in combination with oxaliplatin had an OR of 2.196 and an adjusted OR of 2.231. Combined with pembrolizumab, OR was 2.762 and the adjusted OR was 2.678. Conclusion: Type II hypersensitivity shows a stronger pharmacovigilance signal. Oxaliplatin in combination with nivolumab or pembrolizumab has been shown to increase the risk of rash.

Uncertainty reduction for precipitation prediction in North America.

Large differences in projected future annual precipitation increases in North America exists across 27 CMIP6 models under four emission scenarios. These differences partly arise from weak representations of land-atmosphere interactions. Here we demonstrate an emergent constraint relationship between annual growth rates of future precipitation and growth rates of historical temperature. The original CMIP6 projections show 0.49% (SSP126), 0.98% (SSP245), 1.45% (SSP370) and 1.92% (SSP585) increases in precipitation per decade. Combining observed warming trends, the constrained results show that the best estimates of future precipitation increases are more likely to reach 0.40-0.48%, 0.83-0.93%, 1.29-1.45% and 1.70-1.87% respectively, implying an overestimated future precipitation increases across North America. The constrained results also are narrow the corresponding uncertainties (standard deviations) by 13.8-31.1%. The overestimated precipitation growth rates also reveal an overvalued annual growth rates in temperature (6.0-13.2% or 0.12-0.37°C) and in total evaporation (4.8-14.5%) by the original models' predictions. These findings highlight the important role of temperature for accurate climate predictions, which is important as temperature from current climate models' simulations often still have systematic errors.

Tf2O-Mediated P(O)-N Bond Formation of Either P(O)-OH or P(O)-H Reagents with Multitype Amines.

We have developed a Tf2O-mediated approach for the direct amination of either P(O)-OH or P(O)-H reagents with a variety of aliphatic or aromatic amines. Without the requirement of precious metals and toxic reagents, this protocol provides an alternative route to various phosphinamides and phosphoramides. The reaction proceeds under simple and mild conditions and can be effectively scaled up with similar efficiency.

A randomized clinical trial for meal bolus decision using learning-based control in adults with type 2 diabetes.

BACKGROUND: We proposed an artificial-pancreas-like algorithm (AP-A) which could automatically determine the pre-prandial insulin dose based on intermittently scanned continuous glucose monitoring (isCGM) data trajectories in multiple dose injection (MDI) therapy. We aim to determine whether pre-prandial insulin dose adjustments guided by the AP-A is as effective and safe as physician decisions. METHODS: We performed a randomized, single-blind, clinical trial at a tertiary, referral hospital in Beijing, China. Type 2 diabetes participants were eligible if they were aged  18 years, with a glycated hemoglobin of 8.0% or higher. Eligible participants were randomly assigned (1:1) to the AP-A arm supervised by physician and the conventional physician treatment arm. The primary objective was to compare percentage time spent with sensor glucose level in 3.9-10.0 mmol/L (TIR) between the two study arms. Safety was assessed by the percentage time spent with sensor glucose level below 3.0 mmol/L (TBR). RESULTS: 140 participants were screened, of whom 119 were randomly assigned to AP-A arm (n = 59) or physician arm (n = 60). The TIR achieved by the AP-A arm was statistically non-inferior compared with the control arm (72.4% (63.3-82.1) vs. 71.2% (54.9-81.4)), with a median difference of 1.33% (95% CI, -6.00 to 10.94, non-inferiority margin -7.5%). TBR was also statistically non-inferior between the AP-A and control arms (0.0% (0.0-0.0) vs. 0.0% (0.0-0.0), respectively; median difference (95% CI, 0.00% (0.00 to 0.00), non-inferiority margin 2.0%). CONCLUSIONS: The AP-A supported physician titration of pre-prandial insulin dosage offers non-inferior glycemic control compared with optimal physician care in type 2 diabetes.

Preserved C-peptide is common and associated with higher time in range in Chinese type 1 diabetes.

Objective: The aim of this study is to determine the residual C-peptide level and to explore the clinical significance of preserved C-peptide secretion in glycemic control in Chinese individuals with type 1 diabetes (T1D). Research design and methods: A total of 534 participants with T1D were enrolled and divided into two groups, low-C-peptide group (fasting C-peptide ≤10 pmol/L) and preserved-C-peptide group (fasting C-peptide >10 pmol/L), and clinical factors were compared between the two groups. In 174 participants who were followed, factors associated with C-peptide loss were also identified by Cox regression. In addition, glucose metrics derived from intermittently scanned continuous glucose monitoring were compared between individuals with low C-peptide and those with preserved C-peptide in 178 participants. Results: The lack of preserved C-peptide was associated with longer diabetes duration, glutamic acid decarboxylase autoantibody, and higher daily insulin doses, after adjustment {OR, 1.10 [interquartile range (IQR), 1.06-1.14]; OR, 0.46 (IQR, 0.27-0.77); OR, 1.04 (IQR, 1.02-1.06)}. In the longitudinal analysis, the percentages of individuals with preserved C-peptide were 71.4%, 56.8%, 71.7%, 62.5%, and 22.2% over 5 years of follow-up. Preserved C-peptide was also associated with higher time in range after adjustment of diabetes duration [62.4 (IQR, 47.3-76.6) vs. 50.3 (IQR, 36.2-63.0) %, adjusted P = 0.003]. Conclusions: Our results indicate that a high proportion of Chinese patients with T1D had preserved C-peptide secretion. Meanwhile, residual C-peptide was associated with favorable glycemic control, suggesting the importance of research on adjunctive therapy to maintain ß-cell function in T1D.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Tf2O/DMSO-mediated dual activation of aryl phosphinate to access various aryl phosphonates.

A metal-free method for the dual activation of aryl phosphinate has been developed; the P-H and P-O bonds are sequentially activated by the Tf2O/DMSO system. Without the requirement of metals and unstable P-reagents, this one-pot procedure provides a convenient and practical access to a variety of aryl phosphonates. A mechanism involving twice generation of electrophilic P-species and two SN-processes is proposed on the basis of the control experiments.

Proteomic and Phenotypic Studies of Mycoplasma pneumoniae Revealed Macrolide-Resistant Mutation (A2063G) Associated Changes in Protein Composition and Pathogenicity of Type I Strains.

Mycoplasma pneumoniae (MP) is an important respiratory pathogen, the prevalence of macrolide-resistant MP (mainly containing A2063G mutation in 23S rRNA) increased in recent years. Epidemiological studies suggest a higher prevalence of type I resistant (IR) strains than corresponding sensitive (IS/IIS) strains, but not type II resistant (IIR) strains. Here, we aimed to analyze the factors underlying the altered prevalence of IR strains. First, proteomic analyses exhibit the protein compositions were type specific, while more differential proteins were detected between IS and IR (227) than IIS and IIR strains (81). mRNA level detection suggested posttranscriptional regulation of these differential proteins. Differential protein-related phenotypic changes were also detected: (i) P1 abundance was different between genotypes (I < II, IR < IS), the adhesion of MPs showed accordance to P1 abundance within IS and IIS strains; (ii) type I, especially IR, strains had a higher proliferation rate, which is potentially associated with differential proteins participating in glycolysis and one carbon pool metabolisms; (iii) A549 cells infected with IR strains had lower activity of caspase-3 and higher levels IL-8, but the differences were not significant between groups (P > 0.05). Correlations of P1 abundance to caspase-3 activity and proliferation rate to the level of IL-8 were obtained. These results suggest changes in protein composition influenced the pathogenicity of MP, especially in IR strains, which may impact the prevalence of MP strains of different genotypes. IMPORTANCE The prevalence of macrolide-resistant MPs increased the difficulty in treatment of MP infections and posed potential threats to children's health. Epidemiological studies showed a high prevalence of IR-resistant strains (mainly A2063G in 23S rRNA) in these years. However, the trigger mechanisms for this phenomenon are not clear. In this paper, proteomic and phenotypic studies suggest that IR strains have reduced levels of multiple adhesion proteins and increased proliferation rate, which may lead to higher transmission rate of IR strains in the population. This suggests that we should pay attention to the prevalence of IR strains.

Rapid and Accurate Detection of SARS-CoV-2 Using an iPad-Controlled, High-Throughput, Portable, and Multiplex Hive-Chip Platform (HiCube).

Rapid and accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the most effective measures to control the coronavirus disease 2019 (COVID-19) pandemic. However, there is still lack of an ideal detection platform capable of high sample throughput, portability, and multiplicity. Herein, by combining Hive-Chip (capillary microarray) and reverse transcriptional loop-mediated isothermal amplification (RT-LAMP), we developed an iPad-controlled, high-throughput (48 samples at one run), portable (smaller than a backpack), multiplex (monitoring 8 gene fragments in one reaction), and real-time detection platform for SARS-CoV-2 detection. This platform is composed of a portable Hive-Chip device (HiCube; 32.7 × 29.7 × 20 cm, 5 kg), custom-designed software, and optimized Hive-Chips. RT-LAMP primers targeting seven SARS-CoV-2 genes (S, E, M, N, ORF1ab, ORF3a, and ORF7a) and one positive control (human RNase P) were designed and prefixed in the Hive-Chip. On-chip RT-LAMP showed that the limit of detection (LOD) of SARS-CoV-2 synthetic RNAs is 1 copy/µL, and there is no cross-reaction among different target genes. The platform was validated by 100 clinical samples of SARS-CoV-2, and the results were highly consistent with those of the traditional real-time PCR assay. In addition, on-chip detection of 6 other respiratory pathogens showed no cross-reactivity. Overall, our platform has great potential for fast, accurate, and on-site detection of SARS-CoV-2.

A dual-attention based coupling network for diabetes classification with heterogeneous data.

Diabetes Mellitus (DM) is a group of metabolic disorders characterized by hyperglycaemia in the absence of treatment. Classification of DM is essential as it corresponds to the respective diagnosis and treatment. In this paper, we propose a new coupling network with hierarchical dual-attention that utilizes heterogeneous data, including Flash Glucose Monitoring (FGM) data and biomarkers in electronic medical records. The long short-term memory-based FGM sub-network extracts the time-dependent features of dynamic FGM sequences, while the biomarkers sub-network learns the features of static biomarkers. The convolutional block attention module (CBAM) for dispersing the feature weights of the spatial and channel dimensions is implemented into the FGM sub-network to endure the variability of FGM and allows us to extract high-level discriminative features more accurately. To better adjust the importance weights of the characteristics of the two sub-networks, self-attention is introduced to integrate the characteristics of heterogeneous data. Based on the dataset provided by Peking University People's Hospital, the proposed method is evaluated through factorial experiments of multi-source heterogeneous data, ablation studies of various attention strategies, time consumption evaluation and quantitative evaluation. The benchmark tests reveal the proposed network achieves a type 1 and 2 diabetes classification accuracy of 95.835% and the comprehensive performance metrics, including Matthews correlation coefficient, F1-score and G-mean, are 91.333%, 94.939% and 94.937% respectively. In the factorial experiments, the proposed method reaches the maximum area under the receiver operating characteristic curve of 0.9428, which indicates the effectiveness of the coupling between the nominated sub-networks. The coupling network with a dual-attention strategy performs better than the one without or only with a single-attention strategy in the ablation study as well. In addition, the model is also tested on another data set, and the accuracy of the test reaches 94.286%, reflecting that the model is robust when it is transferred to untrained diabetes data. The experimental results show that the proposed method is feasible in the classification of diabetes types. The code is available at https://github.com/bitDalei/Diabetes-Classification-with-Heterogeneous-Data.

Modification of Vancomycin Dosing in Cardiac Surgery With Cardiopulmonary Bypass.

This study aims to assess the risk factors for insufficient vancomycin concentrations for its prophylactic use in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and to modify the dosing regimen to achieve appropriate plasma concentrations. A total of 27 patients with vancomycin dosing of 1 to 1.5 g based on a weight cutoff of 67 kg were included, of which only 13 (48.15%) had vancomycin plasma concentration >15 mg/L at surgical closure. Risk factors of vancomycin concentration <15 mg/L at surgical-site closure were confirmed by multivariate logistic regression analysis, which showed that CPB duration was an independent predictor. Patients with CPB duration >4 hours had significantly lower vancomycin concentrations and lower proportion in achieving target vancomycin concentration at the end of CPB and surgical closure. For patients with CPB >4 hours, the modified dosing regimen that a second dose of 0.5 to 0.75 g added at 4 hours since the onset of CPB improved the target achievement of vancomycin concentration at surgical closure. Taken together, CPB duration >4 hours was the risk factor for insufficient vancomycin concentration at surgical closure, while our modified dosing could improve the vancomycin concentrations for its prophylactic use in patients undergoing cardiac surgery with CPB.

Linezolid and the risk of QT interval prolongation: A pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.

AIMS: Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation. METHODS: Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated. RESULTS: A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6-30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI = 7.1-28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI = 1.3-7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI = 0.8-4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1-488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI = 3.4-5.3) and 1.2 (95% CI = 0.8-1.6), respectively. CONCLUSION: The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD.

Pilot genome-wide association study of antibody response to inactivated SARS-CoV-2 vaccines.

Vaccines are a key weapon against the COVID-19 pandemic caused by SARS-CoV-2. However, there are inter-individual differences in immune response to SARS-CoV-2 vaccines and genetic contributions to these differences have barely been investigated. Here, we performed genome-wide association study (GWAS) of antibody levels in 168 inactivated SARS-CoV-2 vaccine recipients. A total of 177 SNPs, corresponding to 41 independent loci, were identified to be associated with IgG, total antibodies or neutral antibodies. Specifically, the rs4543780, the intronic variant of FAM89A gene, was associated with total antibodies level and was annotated as a potential regulatory variant affecting gene expression of FAM89A, a biomarker differentiating bacterial from viral infections in febrile children. These findings might advance our knowledge of the molecular mechanisms driving immunity to SARS-CoV-2 vaccine.

Pyrazinamide Resistance and pncA Mutation Profiles in Multidrug Resistant Mycobacterium Tuberculosis.

Purpose: Pyrazinamide (PZA) is a critical component of standardized chemotherapy for tuberculosis (TB) and is recommended for the treatment of multidrug-resistant (MDR) TB. We aimed to characterize mutations in pncA of M. tuberculosis and evaluate their diagnostic accuracy for PZA susceptibility in China. We also combined genotypic methods with phenotypic susceptibility testing and pyrazinamidase (PZAse) activity to confirm PZA-resistant M. tuberculosis isolates. Results: An evaluation of 82 MDR M. tuberculosis strains revealed that 28.0% (23/82) were phenotypically resistant to 100 mg/L PZA and 15.9% (13/82) showed resistance to 300 mg/L PZA. Mutations in pncA were detected at 33 unique sites, and the majority were point mutations. No evident mutation hotspots or mutations affecting multiple amino acids were found, but the association between pncA mutations and PZA resistance was significant under 100 and 300 mg/L. The sensitivity of pncA mutation detection for predicting PZA susceptibility was 82.6% (19/23), and the specificity was 61.0% (36/59), based on 100 mg/L PZA, whereas the sensitivity was 84.6% (11/13) and the specificity was 55.1% (38/69), based on 300 mg/L PZA. All mutations identified in the highly PZA-resistant (300 mg/L) strains had an 80% loss relative to PZAse activity. No evident PZAse activity loss was observed in one synonymous mutation strain and the loss exceed 60% in all other strains. Conclusion: The association between pncA mutation and PZA resistance was significant. Relatively, the molecular method have shown better reliability than the phenotypic method for the detection of PZA resistance. This provides a theoretical basis for the clinical diagnosis of drug-resistant TB.

Preserved C-peptide secretion is associated with higher time in range (TIR) on intermittently scanned continuous glucose monitoring in Chinese adults with type 1 diabetes.

Objective: To explore the relationship between C-peptide secretion and time in range (TIR) in adult patients with type 1 diabetes. Methods: From December 2018 to December 2020, 76 type 1 diabetes participants were enrolled from the Department of Endocrinology and Metabolism of Peking University People's Hospital. All participants wore intermittently scanned continuous glucose monitoring (isCGM), and insulin dosage was adjusted according to standardized clinical procedures. Subjects were divided into low C-peptide group (<10 pmol/L) and preserved C-peptide group (10-200 pmol/L) based on fasting serum C-peptide levels. Differences of TIR, metrics related to glucose variability and hypoglycemic events were compared. Results: A total of 94,846 isCGM values obtained from 39 male and 37 female participants were analyzed. Individuals with preserved C-peptide secretion had shorter diabetes duration (2.0 (0.5, 10.0) vs 10.0 (3.0, 18.3) years, P = 0.002). TIR was higher in the individuals with preserved C-peptide than those with decreased C-peptide (67.1% (54.2, 75.8) vs 45.5% (33.9, 56.1), P < 0.001), and time above range was significantly lower in those with preserved C-peptide (28.0% (15.6, 42.4) vs 49.4% (39.1, 64.2), P < 0.001). Preserved C-peptide was associated with lower glucose variability, as defined by s.d. (3.0 mmol/L (2.6, 3.4) vs 3.8 mmol/L (3.2, 4.3), P < 0.001) and interquartile range (4.3 mmol/L (3.1, 4.8) vs 5.3 mmol/L (4.5, 6.3), P < 0.001). Metrics related to hypoglycemia were not different between the two groups. Conclusion: Preserved C-peptide secretion was associated with higher TIR and lower glucose variability in Chinese type 1 diabetes adults.

Cell damage and neutrophils promote the infection of Mycoplasma pneumoniae and inflammatory response.

Mycoplasma pneumoniae (MP) is an important respiratory pathogen of human. The infection of MP can cause direct damage and immune damage in lung, resulting in Mycoplasma pneumoniae pneumonia (MPP). In this study, we aim to investigate the pathogenesis of MPP by detecting the proliferation of MP under conditions of cell damages and neutrophils in vitro. Firstly, we found the supplements of intracellular fluid, protein and RNA derived from intracellular fluid of A549 cells contribute to the survival of MP, thereby promoting the infection of MP. Cell damage can also significantly contribute to the survival of MP without supplements. At the same time, the additions of supplements contribute to apoptosis and the expression of IL-8 and IL-1ß. Further, we found live neutrophils show bactericidal activity to MP, and the phagocytosis of MP promotes apoptosis of neutrophils. When co-incubated with MP and A549 cells, the proliferation of MP in the high neutrophils proportion groups were accelerated with functional decline of neutrophils, and the level of extracellular IL-1ß showed a time and dose dependent manner to neutrophils. These results suggest that the release of intracellular nutrients by damaged cells and functional decline of neutrophils can promote the infection of MP and play roles in the activation of inflammatory response. Therefore, lung damage and infiltration of neutrophils would be important factors affecting the development of MPP.

Outpatient Randomized Crossover Comparison of Zone Model Predictive Control Automated Insulin Delivery with Weekly Data Driven Adaptation Versus Sensor-Augmented Pump: Results from the International Diabetes Closed-Loop Trial 4.

Background: Automated insulin delivery (AID) systems have proven effective in increasing time-in-range during both clinical trials and real-world use. Further improvements in outcomes for single-hormone (insulin only) AID may be limited by suboptimal insulin delivery settings. Methods: Adults (≥18 years of age) with type 1 diabetes were randomized to either sensor-augmented pump (SAP) (inclusive of predictive low-glucose suspend) or adaptive zone model predictive control AID for 13 weeks, then crossed over to the other arm. Each week, the AID insulin delivery settings were sequentially and automatically updated by an adaptation system running on the study phone. Primary outcome was sensor glucose time-in-range 70-180 mg/dL, with noninferiority in percent time below 54 mg/dL as a hierarchical outcome. Results: Thirty-five participants completed the trial (mean age 39 ± 16 years, HbA1c at enrollment 6.9% ± 1.0%). Mean time-in-range 70-180 mg/dL was 66% with SAP versus 69% with AID (mean adjusted difference +2% [95% confidence interval: -1% to +6%], P = 0.22). Median time <70 mg/dL improved from 3.0% with SAP to 1.6% with AID (-1.5% [-2.4% to -0.5%], P = 0.002). The adaptation system decreased initial basal rates by a median of 4% (-8%, 16%) and increased initial carbohydrate ratios by a median of 45% (32%, 59%) after 13 weeks. Conclusions: Automated adaptation of insulin delivery settings with AID use did not significantly improve time-in-range in this very well-controlled population. Additional study and further refinement of the adaptation system are needed, especially in populations with differing degrees of baseline glycemic control, who may show larger benefits from adaptation.

Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients.

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency. Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model. Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25-21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan-Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30-60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min. Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.