IntroductionDrug-drug interactions (DDIs) are an important issue in medication safety and a potential cause of adverse drug events in the pre- and early post-hematopoietic stem cell transplantation (HSCT). This study introduced a physiologically based pharmacokinetic (PBPK) modeling platform to evaluate complex DDIs in these critical stages and to optimize dosing for personalized treatment.MethodsPBPK models were developed using a bottom-up with middle-out approach and executed with PK-Sim® software. Model validation required that predicted PK values fall within a twofold range of observed data. Then, the validated model was used to simulate alternative dosing regimens to achieve target therapeutic levels.ResultsPBPK models were developed and evaluated for 13 drugs commonly used in HSCT, including cyclosporine, tacrolimus, sirolimus, busulfan, phenytoin, voriconazole, posaconazole, itraconazole, fluconazole, letermovir, fosaprepitant, aprepitant, and omeprazole. Simulation results indicated marked DDIs in the pre- and early post-HSCT phases, particularly involving cyclosporine and phenytoin. Several drugs notably increased cyclosporine concentrations, while phenytoin substantially reduced the exposure to other medications.ConclusionThis PBPK modeling platform provides a robust tool for identifying and mitigating DDIs in the pre- and early post-HSCT phases. By enabling the optimization of treatment regimens, this model serves as a valuable tool for improving drug safety and therapeutic outcomes for patients with HSCT.

Although polymyxins are a suboptimal option for difficult-to-treat resistant infections, they are still preferred as the first-line treatment, especially in low- and middle-income countries. This study assesses the efficacy of ceftazidime-avibactam (CAZ-AVI) following polymyxin B failure in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. We retrospectively reviewed cases of infections caused by CRKP in adults who received CAZ-AVI as salvage therapy. Clinical features and outcomes were described, and a logistic regression model was used to assess the risk factors associated with in-hospital crude mortality. One hundred and six patients were included in this study. The median age was 56 years. The most common infectious sites were lung. The patients received CAZ-AVI as salvage therapy for a median duration of 9 days following initial treatment with polymyxin B (median, 12.5 days). Also, 91 (85.8%) patients received CAZ-AVI combination therapy, and 34 (32.1%) patients received CAZ-AVI in combination with polymyxin B. The rate of in-hospital crude mortality was 25.5% (27/106), with the highest rate observed in patients treated with regimens containing polymyxin B (41.2%; 14/34). Therapeutic response was observed in 81 (76.4%) patients, with microbiological eradication achieved in 77.1% (74/96) of cases. Multivariable analysis identified that the length of intensive care unit stays, the sequential organ failure assessment (SOFA) score at CAZ-AVI withdrawal, and regimens containing polymyxin B were independently associated with in-hospital mortality, whereas the duration of CAZ-AVI treatment was independently associated with survival. CAZ-AVI salvage therapy demonstrated improved survival outcomes in patients who experienced failure with polymyxin B therapy.IMPORTANCEFor patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, published experience with salvage therapy is limited after the failure of polymyxin-based initial therapy. Here, we found that ceftazidime-avibactam salvage therapy for patients with CRKP infections offers benefit in mortality.

Interleukin-33 (IL-33) is a pleiotropic cytokine of the IL-1 family that plays a key role in innate and adaptive immune responses and contributes to tissue homeostasis. Its role in adipose tissue function has been extensively studied, as adipose tissue serves as an important mediator of metabolic dysfunction. In adipose tissue, IL-33 is primarily produced by stromal cells. Its production is regulated by factors, such as androgens, aging, sympathetic innervation, and various inflammatory stimuli that affect the proliferation and differentiation of IL-33-producing stromal cells. Many studies have elucidated the mechanisms by which IL-33 interacts with the immune system components, local nerve fibers, and adipocytes to influence energy balance, with important consequences in obesity, cold-induced thermogenesis, and aging-related metabolic dysfunction. Here, we detail our current understanding of the molecular events that regulate the production of IL-33 within adipose tissue and discuss its role in regulating adipose function.

Obesity is characterized by chronic low-grade inflammation and is strongly associated with multiple immunological diseases, including cancer and inflammatory diseases. Recent animal studies revealed that obesity-induced immunological changes worsen immune-driven diseases and cause resistance to immunotherapy. Here, we discuss the role of obesity in the immunopathology and treatment responses of cancers, respiratory and allergic diseases, and IL-17-mediated inflammatory diseases. We summarize the unique features of the inflammatory state of these diseases, which are orchestrated by obesity. In particular, obesity alters the immune landscape in cancers with a reprogrammed metabolic profile of tumor-infiltrating immune cells. Obesity exacerbates airway inflammation by dysregulating multiple immune-cell subsets. Obesity also dysregulates Th17, IL-17-producing mucosal-associated invariant T (MAIT), and γδ T cells, which contribute to IL-17-mediated inflammatory response in multiple sclerosis, inflammatory bowel disease, psoriasis, atopic dermatitis, and rheumatoid arthritis. By identifying the effects of obesity on immunological diseases, new strategies could be devised to target immune dysregulation caused by obesity.

Background: The incidence of carbapenem-resistant organism (CRO) infections is increasing in children. However, pediatric-specific treatment strategies present unique challenges. Ceftazidime/avibactam is a f3-lactam/f3-lactamase inhibitor combination, showing adequate efficiency against CRO isolates. However, clinical data on the efficacy of ceftazidime/avibactam in children are still lacking.Methods: This was a retrospective study of children (aged <18 years) infected with confirmed or suspected carbapenem-resistant pathogens and treated with ceftazidime-avibactam at the First Affiliated Hospital of Zhengzhou University between 2020 and 2022. Results: We identified 38 children aged 14 (5.0-16.3) years; 20 (52.6%) had hematologic malignancies. 25 children with confirmed CRO infections were administered ceftazidime-avibactam as targeted therapy. The median treatment was 10 (6.0-16.5) days. Among them, 24 had infections caused by carbapenem-resistant Enterobacterales (CRE) (18 carbapenem-resistant Klebsiella pneumoniae and six carbapenem-resistant Escherichia coli species) and one with carbapenem-resistant Pseudomonas aeruginosa strains. The source of infection was the bloodstream in 60.0% of the cases (15/25). The clinical response rate was 84.0% (21/25), and 30-day mortality rate was 20% (5/25). 13 children were administered ceftazidime-avibactam as empiric therapy for suspected infections. The median treatment was 8 (6.0-13.0) days. No deaths occurred and clinical response was achieved in 12 of the 13 patients (92.3%) who empirically treated with ceftazidime-avibactam.Conclusion: Ceftazidime-avibactam is important for improving survival, and clinical response in children with infections caused by CRO.

Background and Aims:We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. Methods:IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. Results:Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. Conclusions:IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

<p>Supplementary Table1.Characteristic of antibodies used in the flow cytometry evaluation.Supplementary Table2.Primer sequence and product size for PCR amplification.Supplementary Table3.Clinical and baseline clinical characteristics of OC patients with diabetes</p>

<p>Supplementary Fig.1.Increased MDSCs levels in peripheral blood and tumor from OC patients.Supplementary Fig.2.Characterization of phenotype and immunosuppressive activity of MDSCs in OC patients.Supplementary Fig.3.Phenotypic analysis of MDSCs following metformin treatment.</p>

Pancreatic β-cell dysfunction plays a vital role in the development of diabetes. IL-33 exerts anti-diabetic effects via its anti-inflammatory properties and has been demonstrated to increase insulin secretion in animal models. However, IL-33, as a pleiotropic cytokine, may also exert a deleterious effect on β-cells, which has not been rigorously studied. In the present study, we found that IL-33 promoted cell survival and insulin secretion in MIN6 (a mouse pancreatic β-cell line) cells under diabetogenic conditions. IL-33 increased the expression of its receptor ST2 and the transcription factor PPARγ, whereas PPARγ inhibition impaired IL-33-mediated β-cell survival and insulin release. IL-33 did not repress the expression of pro-inflammatory mediators, including Tf, Icam1, Cxcl10, and Il1b, whereas it significantly reduced the expression of Ccl2. IL-33 decreased TNF-α secretion and increased IL-10 secretion; these effects were completely reversed by PPARγ inhibition. IL-33 increased glucose uptake and expression of Glut2. It upregulated the expression of glycolytic enzyme genes, namely, Pkm2, Hk2, Gpi1, and Tpi, and downregulated the expression of Gck, Ldha, and Mct4. However, it did not alter hexokinase activity. Moreover, IL-33 increased the number and activity of mitochondria, accompanied by increased ATP production and reduced accumulation of ROS. IL-33 upregulated the expression of PGC-1α and cytochrome c, and mitochondrial fission- and fusion-associated genes, including Mfn1, Mfn2, and Dnm1l. IL-33-mediated mitochondrial homeostasis was partially reversed by PPARγ inhibition. Altogether, IL-33 protects β-cell survival and insulin secretion that could be partially driven via PPARγ, which regulates glucose uptake and promotes mitochondrial function and anti-inflammatory responses.

OBJECTIVES:Carbapenem-resistant Klebsiella pneumoniae (CRKP) is increasingly being identified in children, but data on the clinical outcomes in this population are limited. This study aimed to characterise the risk factors for 30-day mortality with CRKP bloodstream infection (BSI) in children. METHODS:A retrospective study was performed from January 2018 to December 2021 at the First Affiliated Hospital of Zhengzhou University. Patients aged < 18 years and with CRKP BSI were included. Multivariable Cox and logistic regression were performed to determine risk factors for death and the development of septic shock following CRKP infection, respectively. RESULTS:This study identified 33 neonates aged 0-4 weeks and 37 older children. The 30-day mortality rate was 39.4% in neonates and 43.2% in older children. In the neonatal population, a higher Pitt bacteremia score (HR 1.694; 95% CI 1.313-2.186; P < 0.001) was an independent risk factor for 30-day mortality. In the non-neonatal population, higher platelet count (HR 0.990; 95% CI 0.982-0.998; P = 0.010), the use of carbapenems (HR 0.212; 95% CI 0.064-0.702; P = 0.011) and appropriately targeted antimicrobial treatment (HR 0.327; 95% CI 0.111-0.969; P = 0.044) were associated with decreased 30-day mortality. Monocyte count < 0.1 × 109 cells/L (OR 3.615; 95% CI 1.165-11.444; P = 0.026) and a higher Pitt bacteremia score (OR 1.330; 95% CI 1.048-1.688; P = 0.019) were identified as risk factors for the development of septic shock. CONCLUSIONS:Carbapenem-resistant Klebsiella pneumoniae BSI was associated with high mortality in children. Appropriate antimicrobial treatment is important to improve survival, but more work is needed to assess the efficacy of specific treatment regimens in children.

Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.

目的 系统评价口服Janus激酶(JAK)抑制剂治疗斑秃的有效性和安全性,为临床用药提供循证参考.方法 计算机检索PubMed、Embase、Web of Science、the Cochrane Library、中国知网、万方数据库和中国生物医学文献服务系统,收集口服JAK抑制剂(试验组)对比安慰剂(对照组)治疗斑秃的随机对照试验(RCT),检索时限均为建库至2022年3月29日.由2位评价者独立筛选文献、提取资料并评价纳入研究的质量后,采用RevMan 5.4软件进行Meta分析和发表偏倚分析.结果 共纳入5项RCT,合计2170例患者,试验组1619例、对照组551例.Meta分析结果显示,与对照组比较,试验组患者第24周[RR=6.10,95％CI(3.86,9.63),P<0.00001]和第36周[RR=6.59,95％CI(4.16,10.43),P<0.00001]脱发严重程度评分工具(SALT)评分≤20分的患者比例均更高;第24周医院焦虑抑郁量表-焦虑(HADS-A)评分[RR=0.35,95％CI(0.07,0.64),P=0.02]和医院焦虑抑郁量表-抑郁(HADS-D)评分[RR=0.50,95％CI(0.22,0.77),P=0.0004]的降低值更大,第36周HADS-A评分[RR=0.55,95％CI(0.21,0.89),P=0.001]和HADS-D评分[RR=0.50,95％CI(0.16,0.84),P=0.004]的降低值亦更大.试验组患者痤疮[RR=4.07,95％CI(1.83,9.08),P=0.0006]和低密度脂蛋白升高[RR=1.66,95％CI(1.21,2.28),P=0.002]的发生率均更高(P<0.05),而两组患者尿道感染、上呼吸道感染、头疼、鼻咽炎、磷酸肌酶升高的发生率比较差异均无统计学意义(P>0.05).发表偏倚分析结果显示,本研究存在发表偏倚的可能性较小.结论 口服JAK抑制剂可显著促进斑秃患者的毛发再生长并改善其焦虑抑郁情况,痤疮和低密度脂蛋白升高为其主要不良事件.

目的 系统评价博纳吐单抗治疗急性淋巴细胞白血病(ALL)的有效性与安全性,为其临床应用提供循证参考.方法 计算机检索PubMed、Embase、Web of Science、Cochrane图书馆、中国知网、万方数据和中国生物医学文献服务系统,收集博纳吐单抗(试验组)对比传统化疗方案(对照组)治疗ALL的随机对照试验(RCT)和队列研究,检索时限均为建库起至2022年2月3日.筛选文献、提取资料后,采用Cochrane系统评价员手册5.1.0推荐的偏倚风险评估工具评价RCT的质量,采用纽卡斯尔-渥太华量表(NOS)评价队列研究的质量,采用RevMan 5.4软件进行Meta分析;采用证据推荐分级的评估、制订与评价(GRADE)系统对结局指标的证据质量进行评价;采用倒漏斗图进行发表偏倚分析.结果 共纳入8项研究,其中3项RCT、5项队列研究,共计2841例患者.Meta分析结果显示,试验组患者随访1年以上的总生存率[RR=1.30,95％CI(1.14,1.48),P<0.0001]、无复发生存率[RR=1.78,95％CI(1.50,2.12),P<0.00001]、完全缓解率[RR=1.42,95％CI(1.11,1.82),P=0.006]、震颤发生率[RR=16.98,95％CI(2.17,133.12),P=0.007]、细胞因子释放综合征发生率[RR=14.11,95％CI(3.43,58.01),P=0.0002]均显著高于对照组,两组患者头痛发生率比较差异无统计学意义[RR=1.31,95％CI(0.66,2.59),P=0.44].试验组患者≥3级不良事件、感染、口腔炎、血小板减少症、发热性嗜中性粒细胞减少症、厌食、便秘、腹泻、腹痛、低血钾的发生率均显著低于对照组(P<0.05),咳嗽、红疹、低丙球蛋白血症、发热的发生率均显著高于对照组(P<0.05);两组患者的总不良事件、脓毒血症、贫血、白细胞降低、嗜中性白细胞减少症、淋巴细胞减少、恶心、呕吐、高血糖、低血压、高血压、转氨酶升高、鼻衄的发生率比较差异均无统计学意义(P>0.05).按研究类型不同进行亚组分析的结果显示,无论是RCT还是队列研究,试验组患者随访1年以上的总生存率、无复发生存率、完全缓解率(队列研究除外)均显著高于对照组(P<0.05).GRADE评价结果显示,本研究纳入的指标证据总体质量为低级.发表偏倚分析结果显示,本研究存在发表偏倚的可能性较小.结论 博纳吐单抗治疗ALL的疗效较好,感染和消化系统不良事件的发生率较低,但震颤、咳嗽、红疹、发热、低丙球蛋白血症和细胞因子释放综合征的发生率较高.本研究纳入的指标证据质量普遍偏低.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are increasingly identified in solid organ transplant recipients (SOTRs), but data on the clinical outcomes and risk factors for death following such infections remain limited. Here, we reported CRKP infection was associated with 38.3% of overall 30-day mortality in SOTRs. Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are associated with significant morbidity and mortality. Among solid organ transplant recipients (SOTRs), clinical outcomes and risk factors for death following such infections remain not well documented. A single-center retrospective study was performed. All SOTRs with a CRKP infection at the First Affiliated Hospital of Zhengzhou University between 1 January 2018 and 31 December 2021 were included. Multivariable Cox regression was performed to determine risk factors for death following CRKP infection. We identified 94 SOTRs with CRKP infection, with a median age of 50 years old. CRKP infections resulted in 38.3% of overall 30-day mortality. On multivariable analysis, independent risk factors for death following CRKP infection included older age (hazard ratio [HR], 1.044; 95% confidence interval [CI], 1.007 to 1.083; P = 0.02), allograft failure (HR, 3.962; 95% CI, 1.628 to 9.644; P = 0.002), and septic shock (HR, 8.512; 95% CI, 3.294 to 21.998; P < 0.001). Receiving appropriate targeted therapy was associated with a reduced hazard of death (HR, 0.245; 95% CI, 0.111 to 0.543; P = 0.001). Our study characterized the clinical features and mortality in SOTRs with CRKP infection. The protective effects of appropriate targeted therapy highlight the importance of assessing how antibiotic choices affect the clinical outcomes among SOTRs.IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are increasingly identified in solid organ transplant recipients (SOTRs), but data on the clinical outcomes and risk factors for death following such infections remain limited. Here, we reported CRKP infection was associated with 38.3% of overall 30-day mortality in SOTRs. Independent risk factors for death after CRKP infection included older age, allograft failure, and septic shock. Appropriate targeted therapy was important for alleviating the impact of CRKP infections on these SOTRs.

目的 采用AGREEⅡ工具评价服用二甲双胍的2型糖尿病患者行碘造影剂检查的指南推荐意见质量,为医生的临床决策提供参考.方法 计算机检索PubMed、EMbase、The Cochrane Library、中国生物医学文献数据库(CBM)、中国知网、万方数据库以及指南相关数据库网站,查找有关2型糖尿病患者使用二甲双胍进行碘造影剂检查的推荐意见的临床指南,检索时限从建库至2021年11月28日.由2位研究者独立筛选文献、提取资料,4位研究者采用AGREEⅡ工具评价指南质量.结果 共纳入7部指南.评价结果显示,皇家澳大利亚和新西兰放射医师学院的指南总得分最高;6个领域中,得分最高的是领域四(清晰性),最低的是领域五(应用性).纳入指南对服用二甲双胍的2型糖尿病患者进行碘造影剂检查的推荐意见不一致:对于肾小球滤过率(eGFR)>60 mL?min?(1.73 m2)-1的患者,有6部指南明确提出检查前后无需停药,仅中国指南要求停用二甲双胍;对eGFR在30～60 mL?min?(1.73 m2)-1的患者,指南推荐意见存在较大分歧;对eGFR<30 mL?min?(1.73 m2)-1的患者,仅3部指南给出推荐意见.结论 目前服用二甲双胍的糖尿病患者进行碘造影剂检查的停药时机的推荐意见存在分歧,而且部分指南的质量有待提高.建议指南制定者应该遵循指南制定和更新的方法学,同时加强对指南各领域,尤其是应用性领域的描述.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is associated with high mortality and has become a major public problem threatening patients. This study aimed to explore risk factors for death in patients with Klebsiella pneumoniae (KP) and identify risk factors for CRKP infection. Methods: The study retrospectively analyzed clinical characteristics and microbiological data from patients infected with KP from January 2019 to October 2021 to identify risk factors and mortality, using multivariate logistic regression analysis and Cox regression analysis. Results: A total of 214 KP inpatients were enrolled in our study. The in-hospital mortality rate was significantly higher in patients infected with CRKP (13/68, 19.12%) than carbapenem-susceptible KP (CSKP) (2/146, 1.37%) and the difference was statistically significant (P= 0.03). Multivariate Cox regression analysis showed CRKP isolation (HR 12.26, 95% CI 2.43-61.68, P = 0.002), lower TP (HR 10.50, 95% CI 1.33-82.76, P = 0.03), antibiotic days of therapy >15 (HR 0.08, 95% CI 0.01-0.56, P= 0.01) and length of stay (LOS) (HR 0.03, 95% CI 0.002-0.61, P= 0.02) were independent risk factors for death from KP. Additionally, intensive care unit (ICU) stay (OR 21.69, 95% CI 4.50-118.76, P< 0.001) and previous carbapenem exposure (OR 5.26, 95% CI 1.38-21.19, P= 0.02) are independent risk factors for CRKP. Conclusion: Our findings showed that patients infected with CRKP have a higher in-hospital mortality rate. Identifying the independent risk factors for CRKP infection may contribute to the management of CRKP and reduce the mortality of KP patients.

Interleukin-33 (IL-33) is a pleiotropic cytokine linked to various immune cells in the innate and adaptive immune systems. Recent studies of the effects of IL-33 on immune cells are beginning to reveal its regulatory mechanisms at the levels of cellular metabolism and epigenetic modifications. In response to IL-33 stimulation, these programs are intertwined with transcriptional programs, ultimately determining the fate of immune cells. Understanding these specific molecular events will help to explain the complex role of IL-33 in immune cells, thereby guiding the development of new strategies for immune intervention. Here, we highlight recent findings that reveal how IL-33, acting as an intracellular nuclear factor or an extracellular cytokine, alters metabolic checkpoints and cellular metabolism, which coordinately contribute to cell growth and function. We also discuss recent studies supporting the role of IL-33 in epigenetic alterations and speculate about the mechanisms underlying this relationship.

Background Evidence supports therapeutic drug monitoring of polymyxin B, but clinical data for establishing an area under the concentration–time curve across 24 h at steady state (AUC ss,24 h ) threshold are still limited. This study aimed to examine exposure–response/toxicity relationship for polymyxin B to establish an AUC ss,24 h threshold in a real-world cohort of patients. Methods Using a validated Bayesian approach to estimate AUC ss,24 h from two samples, AUC ss,24 h threshold that impacted the risk of polymyxin B-related nephrotoxicity and clinical response were derived by classification and regression tree (CART) analysis and validated by Cox regression analysis and logical regression analysis. Results A total of 393 patients were included; acute kidney injury (AKI) was 29.0%, clinical response was 63.4%, and 30-day all-cause mortality was 35.4%. AUC ss,24 h thresholds for AKI of > 99.4 mg h/L and clinical response of > 45.7 mg h/L were derived by CART analysis. Cox and logical regression analyses showed that AUC ss,24 h of > 100 mg h/L was a significant predictor of AKI (HR 16.29, 95% CI 8.16–30.25, P < 0.001) and AUC ss,24 h of ≥ 50 mg h/L (OR 4.39, 95% CI 2.56–7.47, P < 0.001) was independently associated with clinical response. However, these exposures were not associated with mortality. In addition, the correlation between trough concentration (1.2–2.8 mg/L) with outcomes was similar to AUC ss,24 h . Conclusions For critically ill patients, AUC ss,24 h threshold of 50–100 mg h/L was associated with decreased nephrotoxicity while assuring clinical efficacy. Therapeutic drug monitoring is recommended for individualizing polymyxin B dosing.

Forkhead box protein 3 (Foxp3(+))-expressing regulatory T (Treg) cells are a unique CD4(+)T cell subset that suppresses excessive immune responses. The epigenetic plasticity and metabolic traits of Treg cells are crucial for the acquisition of their phenotypic and functional characteristics. Therefore, alterations to the epigenetics and metabolism affect Treg cell development and function. Recent evidence reveals that altering the metabolic pathways and generation of metabolites can regulate the epigenetics of Treg cells. Specifically, some intermediates of cell metabolism can directly act as substrates or cofactors of epigenetic-modifying enzymes. Here, we describe the metabolic and epigenetic features during Treg cell development, and discuss how metabolites can contribute to epigenetic alterations of Treg cells, which affects Treg cell activation, differentiation, and function.