BACKGROUND:The involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. METHODS:Patient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. RESULT:Based on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype. The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and N-dealkyl quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 < 0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. CONCLUSION:The results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

BACKGROUND:Posaconazole is widely recommended for preventing and treating invasive fungal infections (IFIs) in immunocompromised patients, especially those with prolonged neutropenia. However, the concentration of the oral suspension formulation can be affected by factors such as co-administration with acid-suppressing medications, influencing its efficacy and safety. AIM:This study examined the impact of proton pump inhibitors (PPIs) and other factors on posaconazole concentrations and the concentration-to-dose ratio (C/D) while also evaluating adverse drug reactions in patients with hematologic malignancies. METHOD:We conducted a retrospective analysis of patients who received posaconazole for IFI prophylaxis or treatment, assessing demographic and clinical data, adverse reactions, treatment outcomes, and drug concentration assays. The study focused on the effects of PPIs on Cmin and C/D. RESULTS:Data from 283 posaconazole Cmin measurements in 86 patients were analyzed. The incidence of probable or proven IFIs was 6.4% (5/78). PPI use reduced posaconazole Cmin levels but did not significantly impact prophylactic efficacy. Esomeprazole and rabeprazole were explicitly associated with decreased Cmin. Hepatotoxicity was linked to the co-administration of hepatotoxic drugs, indicating that posaconazole was not the sole contributor. CONCLUSION:Co-administration of esomeprazole or rabeprazole lowers posaconazole plasma concentrations without compromising prophylactic efficacy against IFIs. Nonetheless, caution is advised when combining these drugs in high-risk immunocompromised patients.

BackgroundPosaconazole is a potent antifungal agent widely used to manage invasive fungal infections, especially in immunocompromised individuals. Achieving optimal therapeutic concentrations of posaconazole can be challenging due to interpatient variability, the availability of multiple formulations, and various dosing strategies.MethodsWe conducted a systematic search of PubMed, EMBASE, and the Cochrane Library to identify studies evaluating factors that influence blood concentrations of posaconazole. The primary outcome was the assessment of posaconazole concentrations in relation to various influencing factors, including age, sex, drug interactions, disease state, administered dose, and formulation.ResultsOur analysis included 46 studies involving a total of 8,505 patients. Co-administration of drugs that affect posaconazole metabolism significantly reduced its concentrations. High-fat meals, age, and sex did not have a significant impact on posaconazole oral suspension (POS) concentrations. Diarrhea substantially decreased concentrations of both delayed-release tablets (DRT) and POS. Neither vomiting nor mucositis significantly affected POS concentrations. Acid-suppressing agents, such as H2 receptor antagonists and proton pump inhibitors, notably decreased POS concentrations but had no significant effect on DRT. Comparative studies of different dosage forms revealed significantly higher concentrations with DRT compared to POS.ConclusionDRT maintain more stable concentrations than POS and are not affected by acid-suppressing drugs. Given the significant fluctuations in posaconazole concentrations, patients experiencing diarrhea require close monitoring.Systematic Review RegistrationPROSPERO, Identifier CRD42023428822 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023428822).

Objective This study aimed to present a deep-learning network called contrastive learning-based cycle generative adversarial networks (CLCGAN) to mitigate streak artifacts and correct the CT value in four-dimensional cone beam computed tomography (4D-CBCT) for dose calculation in lung cancer patients. Methods 4D-CBCT and 4D computed tomography (CT) of 20 patients with locally advanced non-small cell lung cancer were used to paired train the deep-learning model. The lung tumors were located in the right upper lobe, right lower lobe, left upper lobe, and left lower lobe, or in the mediastinum. Additionally, five patients to create 4D synthetic computed tomography (sCT) for test. Using the 4D-CT as the ground truth, the quality of the 4D-sCT images was evaluated by quantitative and qualitative assessment methods. The correction of CT values was evaluated holistically and locally. To further validate the accuracy of the dose calculations, we compared the dose distributions and calculations of 4D-CBCT and 4D-sCT with those of 4D-CT. Results The structural similarity index measure (SSIM) and peak signal-to-noise ratio (PSNR) of the 4D-sCT increased from 87% and 22.31 dB to 98% and 29.15 dB, respectively. Compared with cycle consistent generative adversarial networks, CLCGAN enhanced SSIM and PSNR by 1.1% (p < 0.01) and 0.42% (p < 0.01). Furthermore, CLCGAN significantly decreased the absolute mean differences of CT value in lungs, bones, and soft tissues. The dose calculation results revealed a significant improvement in 4D-sCT compared to 4D-CBCT. CLCGAN was the most accurate in dose calculations for left lung (V5Gy), right lung (V5Gy), right lung (V20Gy), PTV (D98%), and spinal cord (D2%), with the relative dose difference were reduced by 6.84%, 3.84%, 1.46%, 0.86%, 3.32% compared to 4D-CBCT. Conclusions Based on the satisfactory results obtained in terms of image quality, CT value measurement, it can be concluded that CLCGAN-based corrected 4D-CBCT can be utilized for dose calculation in lung cancer.

Abstract Objectives Accurate segmentation of the clinical target volume (CTV) of CBCT images can observe the changes of CTV during patients' radiotherapy, and lay a foundation for the subsequent implementation of adaptive radiotherapy (ART). However, segmentation is challenging due to the poor quality of CBCT images and difficulty in obtaining target volumes. An uncertainty estimation- and attention-based semi-supervised model called residual convolutional block attention-uncertainty aware mean teacher (RCBA-UAMT) was proposed to delineate the CTV in cone-beam computed tomography (CBCT) images of breast cancer automatically. Methods A total of 60 patients who undergone radiotherapy after breast-conserving surgery were enrolled in this study, which involved 60 planning CTs and 380 CBCTs. RCBA-UAMT was proposed by integrating residual and attention modules in the backbone network 3D UNet. The attention module can adjust channel and spatial weights of the extracted image features. The proposed design can train the model and segment CBCT images with a small amount of labeled data (5%, 10%, and 20%) and a large amount of unlabeled data. Four types of evaluation metrics, namely, dice similarity coefficient (DSC), Jaccard, average surface distance (ASD), and 95% Hausdorff distance (95HD), are used to assess the model segmentation performance quantitatively. Results The proposed method achieved average DSC, Jaccard, 95HD, and ASD of 82%, 70%, 8.93, and 1.49 mm for CTV delineation on CBCT images of breast cancer, respectively. Compared with the three classical methods of mean teacher, uncertainty-aware mean-teacher and uncertainty rectified pyramid consistency, DSC and Jaccard increased by 7.89–9.33% and 14.75–16.67%, respectively, while 95HD and ASD decreased by 33.16–67.81% and 36.05–75.57%, respectively. The comparative experiment results of the labeled data with different proportions (5%, 10% and 20%) showed significant differences in the DSC, Jaccard, and 95HD evaluation indexes in the labeled data with 5% versus 10% and 5% versus 20%. Moreover, no significant differences were observed in the labeled data with 10% versus 20% among all evaluation indexes. Therefore, we can use only 10% labeled data to achieve the experimental objective. Conclusions Using the proposed RCBA-UAMT, the CTV of breast cancer CBCT images can be delineated reliably with a small amount of labeled data. These delineated images can be used to observe the changes in CTV and lay the foundation for the follow-up implementation of ART.

报道1例轻链型范可尼综合征患者，在常规电解质补充治疗的基础上，病情未缓解。随着新型抗浆细胞药物的应用，给予患者以硼替佐米为基础的化疗方案治疗，患者骨痛基本消失，血清游离轻链正常，获得血液学缓解。

目的 探讨泊沙康唑联用质子泵抑制剂(PPI)对恶性血液病患者血药浓度和侵袭性真菌病(IFD)发生风险的影响.方法选择2020年12月-2021年12月我院血液内科收治的恶性血液病患者40例,按随机数字表法分为对照组(20例)和观察组(20例).对照组患者给予泊沙康唑口服混悬液,观察组患者给予泊沙康唑口服混悬液联合PPI.比较两组患者的IFD发生率,血药浓度达标率,发生IFD预防到突破时间,IFD相关病死率,感染患者治疗情况及两组患者服用泊沙康唑第7、14、21、28 天的血药浓度;记录两组患者用药期间的不良事件发生情况.结果 观察组有2例患者、对照组有9例患者因服用泊沙康唑不足7 d即出院而终止研究.观察组患者的IFD发生率显著高于对照组,血药浓度达标率显著低于对照组(P＜0.05).两组患者发生IFD预防到突破时间、IFD相关病死率、感染患者治疗情况、不良事件发生率比较,差异均无统计学意义(P＞0.05).用药第7 天,观察组患者的泊沙康唑血药浓度显著低于对照组(P＜0.05);用药第14天,两组患者的泊沙康唑血药浓度比较,差异无统计学意义(P＞0.05).结论泊沙康唑联用PPI可降低恶性血液病患者的血药浓度,增加IFD发生风险,临床应尽量避免二者联用或在治疗药物监测指导下联用.

BackgroundStroke is the second leading cause of death and the third leading cause of disability worldwide, with ischemic stroke (IS) being the most prevalent. A substantial number of irreversible brain cell death occur in the short term, leading to impairment or death in IS. Limiting the loss of brain cells is the primary therapy target and a significant clinical issue for IS therapy. Our study aims to establish the gender specificity pattern from immune cell infiltration and four kinds of cell-death perspectives to improve IS diagnosis and therapy.MethodsCombining and standardizing two IS datasets (GSE16561 and GSE22255) from the GEO database, we used the CIBERSORT algorithm to investigate and compare the immune cell infiltration in different groups and genders. Then, ferroptosis-related differently expressed genes (FRDEGs), pyroptosis-related DEGs (PRDEGs), anoikis-related DEGs (ARDEGs), and cuproptosis-related DEGs (CRDEGs) between the IS patient group and the healthy control group were identified in men and women, respectively. Machine learning (ML) was finally used to generate the disease prediction model for cell death-related DEGs (CDRDEGs) and to screen biomarkers related to cell death involved in IS.ResultsSignificant changes were observed in 4 types of immune cells in male IS patients and 10 types in female IS patients compared with healthy controls. In total, 10 FRDEGs, 11 PRDEGs, 3 ARDEGs, and 1 CRDEG were present in male IS patients, while 6 FRDEGs, 16 PRDEGs, 4 ARDEGs, and 1 CRDEG existed in female IS patients. ML techniques indicated that the best diagnostic model for both male and female patients was the support vector machine (SVM) for CDRDEG genes. SVM’s feature importance analysis demonstrated that SLC2A3, MMP9, C5AR1, ACSL1, and NLRP3 were the top five feature-important CDRDEGs in male IS patients. Meanwhile, the PDK4, SCL40A1, FAR1, CD163, and CD96 displayed their overwhelming influence on female IS patients.ConclusionThese findings contribute to a better knowledge of immune cell infiltration and their corresponding molecular mechanisms of cell death and offer distinct clinically relevant biological targets for IS patients of different genders.

多发性骨髓瘤( mutltiple myeloma,MM)为血液系统第二位常见恶性肿瘤,以克隆性浆细胞增殖为主要特点,病灶多局限于骨髓,骨髓瘤细胞一旦累及髓外其他组织和器官,就形成髓外病变( extramedullary disease,EMD) ,其中骨髓瘤细胞突破骨皮质累及周围软组织,形成骨旁髓外病变( EMD-B );另一部分则通过血液播散至髓外软组织和器官,形成骨外髓外病变( EMD-S).EMD在初诊MM的发生率为3％～5％,在疾病进展过程中的发生率为6％～20％,并且与初诊EMD患者相比,疾病进展中出现的EMD往往更具侵袭性[1].本文回顾性分析河北医科大学第三医院2021年2月至2022年4月应用以泊马度胺为基础的方案治疗2例合并EMD 的MM 患者资料,参照中国MM诊治指南进行诊断[2-4].本研究经医院伦理委员会批准.