BACKGROUND:Hepatotoxicity is a serious adverse effect associated with tigecycline therapy and may necessitate discontinuation of treatment. Optimal dosing strategies and predictive indicators are urgently needed to improve safety. OBJECTIVES:This study aims to identify risk factors associated with tigecycline-induced hepatotoxicity and to determine a serum concentration threshold that can serve as a predictive indicator for this adverse event. METHODS:This retrospective and single-centre study included patients with severe infections who received tigecycline therapy. Clinical data and serum concentration parameters were extracted from the electronic medical records of these patients. Patients were classified into hepatotoxicity group and normal group to identify the risk factors associated with tigecycline-induced hepatotoxicity. Logistic regression analysis and receiver operating characteristic curve analysis were used to determine the risk factors related to tigecycline-induced hepatotoxicity and to establish a serum-concentration-threshold prediction of this adverse effect. RESULTS:A total of 151 patients were enrolled in this study, of whom 35.10% developed hepatotoxicity. Multivariate regression analysis revealed that trough concentration (Cmin), peak concentration (Cmax), concentration at 6 h post-dose (C6h), 24-h area under the concentration-time curve (AUC0-24), and concomitant use of voriconazole or statins were all significantly associated with an increased risk of hepatotoxicity (P < 0.05). Furthermore, Cmin and C6h were identified as the optimal predictors of tigecycline-induced hepatotoxicity in ICU patients, with optimal cut-off values of 0.535 and 0.690 mg/L, respectively. CONCLUSIONS:Tigecycline exposure is significantly associated with tigecycline-induced hepatotoxicity. Therefore, we recommend closely monitoring plasma tigecycline concentrations in patients to ensure both therapeutic efficacy and patient safety.

Indobufen is a new generation of antiplatelet agents and has been shown to have antithrombotic effects in animal models. However, its therapeutic potential and mechanisms against cerebral ischemia/reperfusion (I/R) injury remain unclear. In this study, we evaluated the in vivo neuroprotective effects of indobufen through both pretreatment and posttreatment regimens in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). In vitro, human umbilical vein endothelial cells (HUVECs) subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were employed to investigate the relationship between indobufen and the pyroptosis-associated NF-u03BAB/Caspase-1/GSDMD pathway. The pharmacodynamic tests revealed that indobufen ameliorated I/R injury by decreasing the level of thromboxane B2 (TXB2), infarct size, brain edema and neurological impairment in rats and rescuing cell pyroptosis in HUVECs. The underlying mechanisms were probably related to pyroptosis suppression by regulating the NF-u03BAB/Caspase-1/GSDMD pathway. Overall, these studies indicate that indobufen exerts protective and therapeutic effects against I/R injury by pyroptosis suppression via downregulating NF-u03BAB/Caspase-1/GSDMD pathway.

Non-valvular atrial fibrillation (NVAF) is a major stroke risk factor, and edoxaban is commonly used for thromboprophylaxis. However, marked interindividual variability in plasma edoxaban exposure may raise bleeding or thromboembolism risk. This study aimed to determine plasma edoxaban concentrations and identify clinical and demographic factors associated with its variable exposure in NVAF patients. This observational study enrolled 103 adult patients with NVAF receiving standard edoxaban therapy at Zhongda Hospital, Southeast University, from December 2024 to December 2025. Trough edoxaban concentrations were measured by validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Dose-normalized concentration (C/dose) was calculated to adjust for dosage differences. Pearson correlation analysis was performed to assess the associations between C/dose and age, body mass index (BMI), and creatinine clearance (CrCl). Of 103 patients, 70 (68.0

ABSTRACT This systematic review and network meta‐analysis compared the urate‐lowering and antihypertensive effects of seven angiotensin receptor blockers used as monotherapy in adults with hypertension and elevated serum urate or hyperuricaemia. Randomised controlled trials comparing one angiotensin receptor blocker with placebo or another angiotensin receptor blocker were searched in eight databases from inception to 17 April 2025. Risk of bias was assessed using RoB 2. Pairwise meta‐analysis and frequentist network meta‐analysis with multivariate random‐effects models were performed. Treatment effects were expressed as mean differences with 95% confidence intervals, and rankings were estimated using surface under the cumulative ranking curve. Consistency was assessed using design‐by‐treatment interaction, loop‐specific and node‐splitting approaches; exploratory meta‐regression examined heterogeneity. Fifty‐five randomised controlled trials involving 4559 participants were included. In the full‐network primary analysis, allisartan and losartan generally ranked among the leading treatments for serum urate reduction, whereas valsartan ranked lowest. Allisartan also showed favourable systolic and diastolic blood pressure effects. Significant inconsistency was mainly concentrated in the losartan–valsartan–allisartan loop, and removing the direct valsartan–allisartan comparison shifted estimates towards a larger apparent allisartan benefit. Meta‐regression suggested that baseline serum urate and baseline systolic blood pressure were associated with serum urate treatment effects, but explained limited heterogeneity. Evidence for eprosartan and candesartan was sparse, with low or very low certainty for several comparisons. Allisartan and losartan may be favourable options when both urate reduction and blood pressure control are considered, but rankings should not be viewed as definitive superiority. PROSPERO: CRD420251007246.

BACKGROUND:Most antidepressants with similar pharmacological characteristics exhibit comparable therapeutic efficacy but differ in side effects. Therefore, we used a retrospective design to compare biochemical changes induced by six antidepressants and identify differences among them. METHODS:Case records from 1706 hospitalized patients with major depressive disorder (MDD) receiving antidepressant monotherapy were divided into six groups based on the specific antidepressants used: paroxetine, sertraline, fluoxetine, escitalopram, venlafaxine, and duloxetine. Electrolytes, hepatic and renal functions, body weight, and glycolipid metabolism were assessed at baseline and 2 weeks post-antidepressant initiation. Paired analysis was used for comparing the changes prior to and after administration within each group, and analysis of covariance was used for evaluating the distinctions among the six groups. RESULTS:After 2 weeks of treatment, significant decreases in serum sodium and chloride levels were observed with venlafaxine, duloxetine, and fluoxetine, while potassium, phosphorus, and carbon dioxide concentrations tended to increase across all six antidepressants. In terms of hepatic indicators, these antidepressants significantly elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (GGT) levels, with duloxetine showing the most pronounced changes from baseline, while decreasing total and direct bilirubin. Sertraline effectively reduced uric acid, although changes in renal indicators were mild with other antidepressants. Notably, these antidepressants were associated with an unfavorable lipid profile, particularly elevated triglycerides and cholesterol, but they lowered blood glucose during the acute phase. LIMITATION:Residual confounding may indirectly influence the retrospective outcomes. CONCLUSION:Early biochemical changes can distinguish differences among antidepressants and guide individualized medication.

The complexity of critically ill patients leads to high pharmacokinetic (PK) variability and an increased risk of drug resistance. For this special patient group, antimicrobial treatment regimens require individualized strategies, as traditional treatment models may have certain limitations in clinical practice. Machine learning (ML) has emerged as a novel tool for processing multidimensional clinical data. It could identify complex patterns to enhance diagnostic accuracy, treatment optimization, and drug behavior predictions across diverse populations. Based on the underlying power of ML, this review highlights its application in three critical domains: (1) predictive modeling of antimicrobial resistance (AMR) patterns to optimize the empirical antibiotic selection and mitigate resistance development; (2) data-driven forecasting of drug exposure to guide personalized dose adjustments; and (3) identify patients who potentially require antibiotic de-escalation therapy and optimize antimicrobial drug use while ensuring therapeutic efficacy. Furthermore, this paper suggests that ML algorithms could be combined with population pharmacokinetic (PopPK) models to construct an analytical framework with superior predictive performance and maintain interpretability. This method could provide a more accurate quantitative analysis of the dose-exposure-response relationship of antimicrobial drugs in critically ill patients. Despite these advances, challenges persist in data quality, clinical validation, and ethical regulation. Future research might prioritize prospective clinical trials to bridge the gap between theoretical models and bedside applications.

Antifungal resistance is the leading cause of antifungal treatment failure in invasive candidiasis. Metabolic rewiring could become a new insight to account for antifungal resistance as to find innovative clinical therapies. Here, we show that dynamic surface-enhanced Raman spectroscopy is a promising tool to identify the metabolic differences between fluconazole-resistant and fluconazole-sensitive Candida albicans through the signatures of biochemical components and complemented with machine learning algorithms and two-dimensional correlation spectroscopy, an underlying resistance mechanism, that is, the change of purine metabolites induced the resistance of Candida albicans has been clarified yet never reported anywhere. We hope the integrated methodology introduced in this work could be beneficial for the interpretation of cellular regulation, propelling the development of targeted antifungal therapies and diagnostic tools for more efficient management of severe antifungal resistance.

Sintilimab, a fully human immunoglobulin G4 monoclonal antibody targeting the programmed cell death receptor 1 (PD-1) pathway, has emerged as significant in cancer immunotherapy, demonstrating promising antitumor effects in various malignancies. The present review summarizes the current clinical data, highlighting the role of sintilimab in treating various types of cancer, including non-small cell lung cancer, liver cancer, gastric cancer and neuroendocrine tumors. The review also explores the mechanism of action of sintilimab, its structural and pharmacokinetic properties and its safety profile, which includes a comprehensive analysis of immune-related adverse events. Notably, the high binding affinity of sintilimab to PD-1 and its fully humanized nature contribute to its potent immunotherapeutic effects and favorable safety profile. Clinical trials have shown that sintilimab, either used as a monotherapy or in combination with chemotherapeutic agents, can significantly extend progression-free and overall survival in patients with advanced cancers. Furthermore, the economic implications and accessibility of sintilimab, particularly in resource-limited settings, are discussed. The current review reports on the innovative potential of sintilimab in shaping future cancer treatment strategies and emphasizes the need for personalized therapy based on individual patient biomarkers. The study reveals that sintilimab is not only a viable alternative to existing PD-1 inhibitors, but also a promising candidate for further research and development in immuno-oncology.

Type 1 diabetes (T1D) is a significant health challenge for children. Assessing the epidemiological patterns and health inequalities associated with T1D at the global, regional, and national levels, along with future projections, is essential for informing equitable public health policies. Based on the Global Burden of Disease (GBD) 2021 database, this study examined trends in the incidence, prevalence, disability-adjusted life years (DALYs), and mortality of T1D in children aged 0–14 years. Attribution decomposition analysis was used to explore the main drivers of the changes in the T1D burden, including the effects of population growth, epidemiological changes, and fertility rates. Regression models and concentration curves were employed to evaluate health inequality among countries and regions with different sociodemographic index (SDI) levels, and predictive models were used to estimate future trends of T1D over the next 30 years. From 1990 to 2021, the global incidence and prevalence of T1D increased significantly, by 32.04

Objectives Hypofibrinogenaemia is a serious adverse reaction associated with tigecycline (TGC) therapy and may lead to the discontinuation of the treatment. This study aimed to explore the relevant factors of TGC-induced hypofibrinogenaemia and determine the thresholds of serum concentration as a predictive indicator of TGC-induced hypofibrinogenaemia. Methods A retrospective single-centre study was conducted on patients with severe infection who were treated with TGC. Clinical data and serum concentration parameters were extracted from the electronic medical records of these patients. Patients were divided into the hypofibrinogenaemia group (< 2.0 g/L) and the normal fibrinogen group (>= 2.0 g/L) in order to evaluate risk factors associated with TGC-induced hypofibrinogenaemia. Logistic regression analysis and receiver operating characteristic curves were utilized to identify the risk factors associated with TGC-induced hypofibrinogenaemia and to establish plasma concentration thresholds as predictive indicators. Results A total of 114 patients were enrolled in this study, with 59.6% experiencing hypofibrinogenaemia. The multivariate regression analysis indicated that baseline fibrinogen level, trough concentration (C-min), peak concentration (C-max), the concentration at 6 h after the dosing (C-6h) and the area under the concentration-time curve over a 24-h period (AUC(0-24)) were significantly associated with hypofibrinogenaemia (P < 0.05). Furthermore, it was found that AUC(0-24) is the optimal predictor of TGC-induced hypofibrinogenaemia. The optimal cut-off for the AUC(0-24) of TGC in ICU patients was determined to be 17.03 mg h/L. Conclusions TGC exposure is highly predictive of TGC-induced hypofibrinogenaemia. We recommend closely monitoring plasma concentrations of TGC in patients to ensure patient efficacy and safety.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) activity in depression is a topic of debate, and the underlying mechanisms remain largely unclear. Here, we elucidate how hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviours, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons using behavioural analyses, microdialysis coupled with mass spectrometry and electrophysiological recordings. Moreover, 5-HT2CR modulated the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction by influencing intracellular Ca2+ release, as determined by fibre photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON with the specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP abolished 5-HT2CR inhibition-induced depressive-like behaviours, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviours in the presence of a 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviours and highlight hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioural consequences of 5-HT2CR inhibition.

Introduction: Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory. Aims: This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing. Methods: Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n = 38), medium-concentration (MC, n = 27), and high-concentration (HC, n = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range. Results: The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations. Conclusion: Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients.

Interferon-induced tetrapeptide repeat (IFIT) family proteins are an important component of the antiviral immune response. There are four known members of the human IFIT family, namely IFIT1, IFIT2, IFIT3 and IFIT5. More and more evidence shows that IFIT family members are involved in a variety of pathophysiological processes in vivo, regulate the homeostasis and differentiation of a variety of cells including immune cells, and are closely related to a variety of autoimmune diseases, which is expected to become a new therapeutic target. This review reviews the biological roles of different IFIT proteins in various autoimmune diseases, and highlights the potential use of these molecules as biomarkers and prognostic factors in autoimmune diseases, with a view to providing ideas for exploring the diagnosis and treatment of autoimmune diseases.

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.

As a new means of oncology treatment, immune checkpoint inhibitors (ICIs) can improve survival rates in patients with resistant or refractory tumors. However, there are obvious inter-individual differences in the unsatisfactory response rate, drug resistance rate and the occurrence of immune-related adverse events (irAE). These questions have sparked interest in researchers looking for a way to screen sensitive populations and predict efficacy and safety. Therapeutic drug monitoring (TDM) is a way to ensure the safety and effectiveness of medication by measuring the concentration of drugs in body fluids and adjusting the medication regimen. It has the potential to be an adjunctive means of predicting the safety and efficacy of ICIs treatment. In this review, the author outlined the pharmacokinetic (PK) characteristics of ICIs in patients. The feasibility and limitations of TDM of ICIs were discussed by summarizing the relationships between the pharmacokinetic parameters and the efficacy, toxicity and biomarkers.

CONTEXT:Patients with membranous nephropathy (MN) are recognized as individuals with high risk of thrombosis. However, prophylactic anticoagulant therapy in this population is still a controversial topic for a lack of high-quality evidence. Subject of Review: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases was published in Kidney International in October 2021, and it was updated on the topic of prophylactic anticoagulant therapy in patients with MN. Differing from the previous main concern about the risk of venous thromboembolism (VTE) in MN, it paid attention to the risk of arterial thromboembolism (ATE) as well. Additionally, the risk of ATE was considered to be associated with hypoalbuminemia. A tool for evaluating the risk of bleeding in patients with MN was proposed in the KDIGO 2021 guideline, and individuals with low risk of bleeding as well as high risk of VTE were suggested to use warfarin or low-molecular-weight heparin (LMWH) combined with aspirin, as an alternative regimen for warfarin. Second Opinion: Our analysis shows that no consensuses have been reached on whether the prevention of ATE is necessary for patients with MN or whether the risk of ATE is associated with hypoalbuminemia. The proposed tool is not the only choice of tools for bleeding assessment, and the HAS-BLED risk score might be a better choice from the perspective of general applicability and availability. Furthermore, in our opinion, the suggestion for prophylaxis regimen of LMWH combined with aspirin showed a lack of consideration and might be inappropriate to some degree. In summary, there are still many controversies in the field of prophylactic anticoagulation for MN; as a consequence, more high-quality studies are required to provide guidance.

The gut microbiome is closely shaped by host genetic and dietary factors to regulate metabolic health and disease. However, the signaling mechanisms underlying such interactions have been largely unclear. Here we identify G protein-coupled receptor 35 (Gpr35) as a regulator of gut microbial ecology and the susceptibility to obesity and hepatic steatosis in mice. Both global and intestinal epithelia specific ablation of Gpr35 aggravated high-fat diet (HFD)-induced metabolic disturbance and hepatic steatosis in mice. Gpr35 deficiency induced a remarkable loss of goblet cells and an extensive remodeling of the gut microbiome, featuring enrichment of the Bacteroides and Ruminococcus genera. Antibiotics treatment and co-housing alleviated the metabolic disturbance markers in Gpr35 deficient mice. Spatiotemporal profiling and mono-colonization screening revealed that Ruminococcus gnavus synergized with HFD to promote hepatic steatosis possibly via tryptophan and phenylalanine pathway metabolites. Our results provide mechanistic insights into a genetic-diet-microbe interplay that dictates susceptibility to metabolic disorder.

Meropenem, a carbapenem antibiotic, has been used for empirical and definitive therapy of severe infections for many years. Therapeutic drug monitoring (TDM) plays an indispensable role in the individualization of mer-openem particularly in the preterm neonates, a population in which adjusting proper dosages has always been one of the most challenging tasks for their growth changes. In this report, a simple and accurate method for the quantitative analysis of meropenem in dried blood spot (DBS) samples by LC-MS/MS was developed. The traditional DBS drawbacks were conquered in this study by combining microfluidic-based volumetric sampling, shorten drying procedure, and sensitive detection. Moreover, the on-card stability of meropenem was improved obviously. The DBS-based method validation included hematocrit (Hct) effect, selectivity, carry-over, linearity, accuracy, precision, matrix effect, recovery and stability (high temperature and humidity). The calibration linear range of meropenem was 0.3-100 mu g/mL. The acceptance criteria of accuracy (relative error < 4.53 %) and precision (coefficient of variation < 8.63 %) were met in all levels of quality control samples. The DBS samples was stable at 40 degrees C for 12 h, room temperature for 1 day, 4 degrees C for 7 days,-20 degrees C for 14 days and-40 degrees C for 30 days, respectively. A good correlation was observed between DBS concentration and plasma concentration of meropenem. There was 93.4 % of the samples between estimated plasma concentration and plasma concen-tration within 20 % of the mean of concentration, and no significant Hct effect was observed on the quantifi-cation. It has been successfully applied to samples derived from preterm neonates with severe infections. The supported data indicated that the DBS-based method using microfluidic-based volumetric sampling could be an alternative strategy to carry on TDM of meropenem in preterm neonates, with satisfactory performance and logistics advantages.

目的 调研分析我国《β-内酰胺类抗菌药物皮肤试验指导原则(2021年版)》颁布后医疗机构执行情况,为推进该类药物皮试规范管理提供参考.方法 设计问卷开展调查并运用Excel汇总整理,SPSS 26.0统计分析.调研覆盖我国18个省(自治区、直辖市)共计143家医疗机构.问卷内容涵盖医院基本信息、院内皮试管理相关规定、β-内酰胺类药物皮肤试验方法等共计42个问题.结果 共收到有效反馈问卷143份.调研显示大部分医疗机构已根据《指导原则》规范院内β-内酰胺类药物皮肤试验流程,在不同发文部门更新率、是否选择皮试、皮试液来源及浓度、判读标准等方面有显著性差异.结论 各医疗机构对于《指导原则》执行情况良好,但仍存在固有观念及流程难以转变,实际操作缺乏统一管理标准等问题.我国皮试相关权威资料应统一修订管理,各级医疗机构皮试规定有待进一步规范化与精细化,流程制定需药学专业人员参与.