Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.

Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.

Risk factors for preeclampsia in patients with chronic kidney disease primarily focused on stage 1 CKD. Are referred and registered patients alike?

Limited research exists on identifying risk factors for preeclampsia (PE) in the chronic kidney disease (CKD) population, especially across different patient sources. This study aimed to address this gap by analyzing clinical data from CKD pregnant women admitted to Peking University Third Hospital from January 2012 to December 2022. Logistic regression analysis identified independent risk factors for PE in the CKD population and assessed variations among patients from different sources. Additionally, a predictive model for PE was established using data from the registered group. The study included 524 CKD patients. Hypertension, proteinuria, fibrinogen >4 g/L, serum albumin ≤30 g/L, and uric acid >260 µmol/L were independent risk factors for PE in the overall CKD population. Subgroup analysis revealed that hypertension, serum albumin ≤30 g/L, and uric acid >260 µmol/L were independent risk factors in the referred group, while hypertension, uric acid >260 µmol/L, and fibrinogen >4 g/L were independent risk factors in the registered group. The prediction model based on registered group risk factors showed good predictive efficiency, with the area under the curve of 0.774 in the training set and 0.714 in the validation set. In conclusion, this study revealed that hypertension and elevated uric acid are independent risk factors for PE in CKD patients regardless of patient source, while serum albumin and fibrinogen levels are associated with PE risk in specific patient subgroups. Our predictive model enables clinicians to quickly identify the risk of PE in CKD patients, and early intervention treatment to improve pregnancy outcomes.

[Research Progress on Influence of Centrifugal Blood Pump on Blood Injury].

Centrifugal blood pumps drive blood flow by regulating blood flow rate, and have been widely used in clinical applications, including extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass (CPB), and extracorporeal circulation carbon dioxide removal (ECCO2R). However, because different structures and different forms of centrifugal pumps have different requirements for blood extracorporeal circulation in clinical application scenarios, blood pumps face different application conditions in clinical use. In this study, the effects of different structures of centrifugal pumps and different working conditions on blood damage are summarized for reference by relevant institutions and R&D personnel.

[Clinical characteristics of pregnancy complicated with inflammatory bowel disease].

OBJECTIVE: To analyze the clinical characteristics of patients with inflammatory bowel diseases (IBD) in pre-pregnancy, pregancy and loctation. METHODS: The clinical data of pregnancy complicated with IBD in Department of Obstetrics and Gynecology of Peking University Third Hospital and deli-very from September 2011 to June 2022 were collected. The clinical characteristics of the patients were analyzed retrospectively. According to the state of diseases during pre-pregnancy, pregnancy and lactation, the patients were divided into active and remission group, and the two groups were compared interms of pre-pregnancy counseling, nutritional status, pregnancy and delivery complications, gestational week, mode of delivery, and neonatal outcome. RESULTS: A total of 33 pregnant women with IBD were included in this study, of which 7 delivered a second child, for a total of 40 deliveries, with 36 natural pregnancies (90.0%) and 4 assisted reproductions (10.0%). Among the 40 cases, 21 cases (52.5%) were sustained in remission in pre-pregnancy, pregnancy and lactation, and 19 cases (47.5%) in disease activity, of which 8 cases (42.1%) were due to self-withdrawal of drugs or failure to take medicine regularly. Compared with the activity group, the disease remission group had a higher rate of pre-pregnancy counseling (57.1% vs. 15.8%, P=0.010), and higher levels of hemoglobin [(112.67±8.53) g/L vs. (102.84±5.23) g/L, P < 0.001], serum total protein [(66.58±6.34) g/L vs. (60.83±6.25) g/L, P=0.006], serum albumin [36.4 (35.1, 38.3) g/L vs. 34.3 (31.1, 35.6) g/L, P=0.006], serum calcium [(2.25±0.10) µmol/L vs. (2.13±0.15) µmol/L, P=0.004], but a lower incidence of gestational hypertensive disorders (0 vs. 31.6%, P=0.007). In 40 deliveries, there were 27 cases of vaginal delivery (67.5%), 13 cases of cesarean section (32.5%). The analysis of neonatal outcomes showed 38 full-term deliveries and 2 preterm deliveries; 1 case of macrosomia, 1 case of small-for-gestational-age, 1 case of low birth weight and 3 cases of birth defects. There were 10 newborns admitted to neonatal intensive care unit, including 4 cases of neonatal infections and 2 cases of neonatal jaundice. CONCLUSION: Pre-pregnancy counseling and evaluation of IBD patients are very important, and good pregnancy outcomes can be obtained through careful management during pregnancy in the most of the patients.

Simultaneous Determination of Ibrutinib, Dihydroxydiol Ibrutinib, and Zanubrutinib in Human Plasma by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry.

BACKGROUND: Ibrutinib and zanubrutinib are Bruton tyrosine kinase inhibitors used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Dihydroxydiol ibrutinib (DHI) is an active metabolite of the drug. A liquid chromatography-tandem mass spectrometry method was developed to detect ibrutinib, DHI, and zanubrutinib in human plasma. METHODS: The method involved a protein precipitation step, followed by chromatographic separation using a gradient of 10 mM ammonium acetate (containing 0.1% formic acid)-acetonitrile. Ibrutinib-d5 was used as an internal standard. Analytes were separated within 6.5 minutes. The optimized multiple reaction monitoring transitions of m/z 441.1 → 304.2, 475.2 → 304.2, 472.2 → 455.2, and 446.2 → 309.2 were selected to inspect ibrutinib, DHI, zanubrutinib, and the internal standards in positive ion mode. RESULTS: The validated curve ranges included 0.200-800, 0.500-500, and 1.00-1000 ng/mL for ibrutinib, DHI, and zanubrutinib, respectively. The precisions of the lower limit of quantification of samples were below 15.5%, the precisions of the other level samples were below 11.4%, and the accuracies were between -8.6% and 8.4%. The matrix effect and extraction recovery of all compounds ranged between 97.6%-109.0% and 93.9%-105.2%, respectively. The selectivity, accuracy, precision, matrix effect, and extraction recovery results were acceptable according to international method validation guidelines. CONCLUSIONS: A simple and rapid method was developed and validated in this study. This method was used to analyze plasma concentrations of ibrutinib and zanubrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or diffuse large B-cell lymphoma. The selected patients were aged between 44 and 74 years.

Biomechanical Effects of Mechanical Stress on Cells Involved in Fracture Healing.

Fracture healing is a complex staged repair process in which the mechanical environment plays a key role. Bone tissue is very sensitive to mechanical stress stimuli, and the literature suggests that appropriate stress can promote fracture healing by altering cellular function. However, fracture healing is a coupled process involving multiple cell types that balance and limit each other to ensure proper fracture healing. The main cells that function during different stages of fracture healing are different, and the types and molecular mechanisms of stress required are also different. Most previous studies have used a single mechanical stimulus on individual mechanosensitive cells, and there is no relatively uniform standard for the size and frequency of the mechanical stress. Analyzing the mechanisms underlying the effects of mechanical stimulation on the metabolic regulation of signaling pathways in cells such as in bone marrow mesenchymal stem cells (BMSCs), osteoblasts, chondrocytes, and osteoclasts is currently a challenging research hotspot. Grasping how stress affects the function of different cells at the molecular biology level can contribute to the refined management of fracture healing. Therefore, in this review, we summarize the relevant literature and describe the effects of mechanical stress on cells associated with fracture healing, and their possible signaling pathways, for the treatment of fractures and the further development of regenerative medicine.

The Amino Acid Transporter PtCAT7 and Ammonium Nutrition Enhance the Uptake of Thiamethoxam in Citrus Rootstock Seedlings.

Thiamethoxam (THX), when applied to the soil, can be taken up by citrus roots and subsequently transported to the leaves, providing effective protection of plants against the Asian citrus psyllid (Diaphorina citri Kuwayama). In this study, the field experiments showed that the coapplication of THX and nitrogen fertilizer (AN) did not affect THX uptake in six-year-old citrus plants. However, their coapplication promoted THX uptake in three-year-old Potassium trifoliate rootstocks and relieved the inhibition of AN at a higher level on plant growth characteristics, including biomass and growth of root and stem. RNA-seq analysis found that THX induced upregulation of a cationic amino acid transporter (PtCAT7) in citrus leaves. PtCAT7 facilitated THX uptake in the yeast strain to inhibit its growth, and the PtCAT7 protein was localized on the plasma membrane. Our results demonstrate that THX and N fertilizer can be coapplied and PtCAT7 may be involved in THX uptake in citrus.

Synergistic Effect of Co3(HPO4)2(OH)2 Cocatalyst and Al2O3 Passivation Layer on BiVO4 Photoanode for Enhanced Photoelectrochemical Water Oxidation.

Bismuth vanadate (BVO) is regarded as an exceptional photoanode material for photoelectrochemical (PEC) water splitting, but it is restricted by the severe photocorrosion and slow water oxidation kinetics. Herein, a synergistic strategy combined with a Co3(HPO4)2(OH)2 (CoPH) cocatalyst and an Al2O3 (ALO) passivation layer was proposed for enhanced PEC performance. The CoPH/ALO/BVO photoanode exhibits an impressive photocurrent density of 4.9 mA cm-2 at 1.23 VRHE and an applied bias photon-to-current efficiency (ABPE) of 1.47% at 0.76 VRHE. This outstanding PEC performance can be ascribed to the suppressed surface charge recombination, facilitated interfacial charge transfer, and accelerated water oxidation kinetics with the introduction of the CoPH cocatalyst and ALO passivation layer. This work provides a novel and synergistic approach to design an efficient and stable photoanode for PEC applications by combining an oxygen evolution cocatalyst and a passivation layer.

Transcriptome and biochemical analyses reveal phenolic compounds-mediated flavor differences in loquat (Eriobotrya japonica Lindl.) cultivars Chunhua No.1 and Dawuxing.

The novel loquat cultivar 'Chunhua No.1' (CH1) is a promising commercial cultivar. However, CH1 has texture characteristics different from those of common loquat, and its formation mechanism remains unclear. Here, we first identified the phenolic compounds of CH1 and its parent ('Dawuxing', DWX) and the effect on texture formation. The special presence of stone cells explained the flavor differences in CH1. Chlorogenic acid, neochlorogenic acid, and coniferyl alcohol were the main phenolic compounds in loquat, and the high content of coniferyl alcohol was a potential factor for the rough texture of CH1. Transcriptome reveals that phenylpropanoid metabolism was activated during CH1 fruit texture formation. Kyoto Encyclopedia of Genes and Genomes (KEGG) identified 51 structural genes involved in phenylpropanoid biosynthesis, and Weighted Gene Co-expression Network Analysis (WGCNA) identified four structural genes and 88 transcription factors. These findings provide new insights into the phenolic metabolism and flavor formation of loquat fruit.

A comparative assessment of time-consuming and laborious diatom analysis：Brief experimentation with suggestion of automatic identification.

Diatom testing is considered a useful method for providing supportive evidence for the diagnosis of drowning in forensic pathology. However, various factors remain controversial for recognizing diatoms, such as being time-consuming and laborious and influencing the consistency of the results. Given the absence of precise and well-defined studies on this subject, this study aimed to determine the relationship between the ability to identify diatoms and researchers with different technical backgrounds. A total of 55 samples from 18 cases, including water, lungs, liver, and kidneys, were treated using the microwave digestion-vacuum filtration-automated scanning electron microscopy (MD-VF-Auto SEM), which was used to compare diatom analyses among three groups of well-trained forensic pathologists (FPs), trained junior employees (JEs), and new trainees (TEs). In addition to achieving similar accuracy of positive findings from drowning cases, counting efficiency was evaluated based on taxonomy records and counting time after viewing more than 5500 diatom images. In contrast to the higher counting efficiency of the JE group than that of the TE group, we observed a statistically significant difference (p < 0.05) in the diatom classification between these two groups. Based on our experiments, an efficient analysis for automatically identifying and classifying diatoms is urgently required.

Comparison of Bone-setting Robots and Conventional Reduction in the Treatment of Intertrochanteric Fracture: A Retrospective Study.

OBJECTIVE: Intertrochanteric fracture of the femur is a common fracture in older people. Due to the poor systemic condition and prognosis of elderly patients, it is prone to more complications. We introduce the bone-setting concept in the design of the robots, which are used for intertrochanteric fracture of the femur reduction. The purpose of this study is to compare the effect of bone-setting robots and conventional reduction in the treatment of intertrochanteric fracture of the femur (IFF). METHODS: From June 2021 to January 2023, 60 patients with IFF who were treated surgically were assigned to bone-setting robots group and conventional reduction methods group in this retrospective study. The reduction time, operation time, total time, intraoperative blood loss, incision length, fluoroscopy time, and the follow-up time were reviewed. The visual analogue scale (VAS) and Harris scores were used for functional assessment. For continuous variables, independent t-tests were applied; for categorical data, the chi-square test was applied. The significance level as p < 0.05. RESULTS: Among the 60 patients with IFF, 31 were assigned to the bone-setting robots group, and 29 were assigned to the conventional reduction methods group. Both groups with a similar baseline in the number, gender, age, and classification (p > 0.05). The reduction time, operation time, total time, intraoperative blood loss, and fluoroscopy time were less than those in the bone-setting robots reduction group compared to the conventional reduction group. In the bone-setting robots reduction group, the preoperative VAS score was 6.2 ± 1.3, the Harris score was 35.3 ± 3.1, 1 week after surgery VAS score was 3.3 ± 1.2, the Harris score was 57.3 ± 3.7, and at the last follow-up VAS score was 2.4 ± 0.8, and the Harris score was 88.7 ± 3.4. While in the conventional reduction group, the preoperative VAS score was 6.3 ± 1.3, the Harris score was 35.9 ± 2.9, 1 week after surgery VAS score was 4.8 ± 1.4, the Harris score was 46.8 ± 2.8, and at the last follow-up VAS score was 2.6 ± 0.8, and the Harris score was 87.3 ± 3.3. There were no significant differences between the two groups at the preoperative and 6-month postoperative follow-ups in VAS score and Harris score (p > 0.05, p > 0.05, respectively). But the difference was statistically significant at the one-week postoperative follow-up in VAS and Harris scores (p < 0.001). CONCLUSION: The bone-setting robots can better protect the "fracture environment" and have the advantages of being precise, minimally invasive, simple, short time, low radiation, and rapid fracture recovery. The clinical effect of closed repair of IFF is ideal.

Immune-regulatory properties of endovascular extravillous trophoblast cells in human placenta.

INTRODUCTION: Uterine spiral artery remodeling is the prerequisite for ensuring adequate blood supply to the maternal-fetal interface during human pregnancy. One crucial cellular event in this process involves the extensive replacement of the spiral artery endothelial cells by endovascular extravillous trophoblasts (enEVTs), a subtype of extravillous trophoblasts (EVTs). However, our understanding of the properties of enEVTs remains limited. METHODS: Human enEVTs in decidual tissues during early pregnancy was purified using flow sorting by specific makers, NCAM1 and HLA-G. The high-throughput RNA sequencing analysis as well as the cytokine antibody array experiments were carried out to analyze for cell properties. Gene ontology (GO) enrichment, kyoto encyclopedia of genes and genomes (KEGG) enrichment, and gene set enrichment analysis (GSEA) were performed on differentially expressed genes of enEVTs. Immunofluorescent assays were used to verify the analysis results. RESULTS: Both enEVTs and interstitial EVTs (iEVTs) exhibited gene expression patterns typifying EVT characteristics. Intriguingly, enEVTs displayed gene expression associated with immune responses, particularly reminiscent of M2 macrophage characteristics. The active secretion of multiple cytokines and chemokines by enEVTs provided partial validation for their expression pattern of immune-regulatory genes. DISCUSSION: Our study reveals the immune-regulatory properties of human enEVTs and provides new insights into their functions and mechanisms involved in spiral artery remodeling.

Transcriptomics reveals a core transcriptional network of K-type cytoplasmic male sterility microspore abortion in wheat (Triticum aestivum L.).

BACKGROUND: Cytoplasmic male sterility (CMS) plays a crucial role in hybrid production. K-type CMS, a cytoplasmic male sterile line of wheat with the cytoplasms of Aegilops kotschyi, is widely used due to its excellent characteristics of agronomic performance, easy maintenance and easy restoration. However, the mechanism of its pollen abortion is not yet clear. RESULTS: In this study, wheat K-type CMS MS(KOTS)-90-110 (MS line) and it's fertile near-isogenic line MR (KOTS)-90-110 (MR line) were investigated. Cytological analysis indicated that the anthers of MS line microspore nucleus failed to divide normally into two sperm nucleus and lacked starch in mature pollen grains, and the key abortive period was the uninucleate stage to dinuclear stage. Then, we compared the transcriptome of MS line and MR line anthers at these two stages. 11,360 and 5182 differentially expressed genes (DEGs) were identified between the MS and MR lines in the early uninucleate and binucleate stages, respectively. Based on GO enrichment and KEGG pathways analysis, it was evident that significant transcriptomic differences were "plant hormone signal transduction", "MAPK signaling pathway" and "spliceosome". We identified 17 and 10 DEGs associated with the IAA and ABA signal transduction pathways, respectively. DEGs related to IAA signal transduction pathway were downregulated in the early uninucleate stage of MS line. The expression level of DEGs related to ABA pathway was significantly upregulated in MS line at the binucleate stage compared to MR line. The determination of plant hormone content and qRT-PCR further confirmed that hormone imbalance in MS lines. Meanwhile, 1 and 2 DEGs involved in ABA and Ethylene metabolism were also identified in the MAPK cascade pathway, respectively; the significant up regulation of spliceosome related genes in MS line may be another important factor leading to pollen abortion. CONCLUSIONS: We proposed a transcriptome-mediated pollen abortion network for K-type CMS in wheat. The main idea is hormone imbalance may be the primary factor, MAPK cascade pathway and alternative splicing (AS) may also play important regulatory roles in this process. These findings provided intriguing insights for the molecular mechanism of microspore abortion in K-type CMS, and also give useful clues to identify the crucial genes of CMS in wheat.

Reaching the cyclosporine a level target slowly in four weeks correlates with better prognosis for Chinese patients after allogeneic haematopoietic cell transplantation.

OBJECTIVES: This study investigated the impact of early cyclosporin A (CsA) initiation (day -5) on the risk of acute graft versus host disease (aGvHD) after allogeneic haematopoietic cell transplantation (allo-HSCT). METHODS: Sixty-seven leukaemia patients who underwent allo-HSCT were investigated. The correlation between the CsA level in the first four weeks and the following indices was examined: GvHD, cumulative incidence (CI) of GvHD, CI of relapse at month 18, and non-relapse mortality (NRM) at month 18. RESULTS: A significant association between aGvHD and CsA level in the fourth week after allo-HSCT was observed, with the incidence of aGvHD in the fourth week in the lower level group being higher than that in the higher level group (p = 0.044). The CI of aGvHD was 30.1% and 9.8% at day +90 and 42.3% and 17.1% at day +180 in the lower level and higher level groups, respectively. CONCLUSION: For Chinese patients, early introduction and reaching the target CsA concentration within four weeks after allo-HSCT have a positive effect on preventing GvHD, especially in the fourth week after HSCT. Compared to the Western population, the target CsA concentration is lower and the time required to reach the target (within 4 weeks) is longer in the Chinese population (274.75 ng/mL).

Comparison of two novel methods for counting wheat ears in the field with terrestrial LiDAR.

BACKGROUND: The metrics for assessing the yield of crops in the field include the number of ears per unit area, the grain number per ear, and the thousand-grain weight. Typically, the ear number per unit area contributes the most to the yield. However, calculation of the ear number tends to rely on traditional manual counting, which is inefficient, labour intensive, inaccurate, and lacking in objectivity. In this study, two novel extraction algorithms for the estimation of the wheat ear number were developed based on the use of terrestrial laser scanning (TLS) in conjunction with the density-based spatial clustering (DBSC) algorithm based on the normal and the voxel-based regional growth (VBRG) algorithm. The DBSC involves two steps: (1) segmentation of the point clouds using differences in the normal vectors and (2) clustering of the segmented point clouds using a density clustering algorithm to calculate the ear number. The VBRG involves three steps: (1) voxelization of the point clouds, (2) construction of the topological relationships between the voxels as a connected region using the k-dimensional tree, and (3) detection of the wheat ears in the connected areas using a regional growth algorithm. RESULTS: The results demonstrated that DBSC and VBRG were promising in estimating the number of ears for different cultivars, planting densities, N fertilization rates, and growth stages of wheat (RMSE = 76 ~ 114 ears/m2, rRMSE = 18.62 ~ 27.96%, r = 0.76 ~ 0.84). Comparing the performance of the two algorithms, the overall accuracy of the DBSC (RMSE = 76 ears/m2, rRMSE = 18.62%, r = 0.84) was better than that of the VBRG (RMSE = 114 ears/m2, rRMSE = 27.96%, r = 0.76). It was found that with the DBSC, the calculation in points as units permitted more detailed information to be retained, and this method was more suitable for estimation of the wheat ear number in the field. CONCLUSIONS: The algorithms adopted in this study provide new approaches for non-destructive measurement and efficient acquisition of the ear number in the assessment of the wheat yield phenotype.

A Physiologically Based Pharmacokinetic Approach to Recommend an Individual Dose of Tacrolimus in Adult Heart Transplant Recipients.

Tacrolimus is the principal immunosuppressive drug which is administered after heart transplantation. Managing tacrolimus therapy is challenging due to a narrow therapeutic index and wide pharmacokinetic (PK) variability. We aimed to establish a physiologically based pharmacokinetic (PBPK) model of tacrolimus in adult heart transplant recipients to optimize dose regimens in clinical practice. A 15-compartment full-PBPK model (Simbiology® Simulator, version 5.8.2) was developed using clinical observations from 115 heart transplant recipients. This study detected 20 genotypes associated with tacrolimus metabolism. CYP3A5*3 (rs776746), CYP3A4*18B (rs2242480), and IL-10 G-1082A (rs1800896) were identified as significant genetic covariates in tacrolimus pharmacokinetics. The PBPK model was evaluated using goodness-of-fit (GOF) and external evaluation. The predicted peak blood concentration (Cmax) and area under the drug concentration-time curve (AUC) were all within a two-fold value of the observations (fold error of 0.68-1.22 for Cmax and 0.72-1.16 for AUC). The patients with the CYP3A5*3/*3 genotype had a 1.60-fold increase in predicted AUC compared to the patients with the CYP3A5*1 allele, and the ratio of the AUC with voriconazole to alone was 5.80 when using the PBPK model. Based on the simulation results, the tacrolimus dosing regimen after heart transplantation was optimized. This is the first PBPK model used to predict the PK of tacrolimus in adult heart transplant recipients, and it can serve as a starting point for research on immunosuppressive drug therapy in heart transplant patients.

Association of IL-17 and IL-27 polymorphisms with susceptibility to recurrent pregnancy loss and pre-eclampsia: A systematic review and meta-analysis.

OBJECTIVE: Recurrent pregnancy loss (RPL) and pre-eclampsia (PE) are immune-related pregnancy complications that have been linked to CD4+ T cells and their cytokines, which can be influenced by genetic polymorphisms. This meta-analysis aimed to investigate the relationship between interleukin (IL)-17 and -27 polymorphisms and the susceptibility to RPL and PE. METHODS: All eligible case-control studies published up to February 2023 were identified by searching PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar. The risk of recurrent pregnancy loss and PE associated with the IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were estimated for each study. RESULTS: The meta-analysis incorporated a total of 13 studies. The overall analysis indicated that IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with immune-related pregnancy complications, including RPL and PE. However, when the analysis was stratified by disease type, the IL-17 rs2275913 polymorphism was found to be associated with an increased risk of RPL (recessive model AA/GA + GG: OR = 1.68, 95% confidence interval [CI]: 1.13-2.49, p = .01). CONCLUSIONS: The IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with RPL and PE, whereas the IL-17 rs2275913 polymorphism was associated with the susceptibility to recurrent miscarriage.

LC-MS/MS methods for determination of venetoclax in human plasma and cerebrospinal fluid.

We developed and validated sensitive MS/MS methods for the determination of venetoclax, an oral selective B-cell lymphoma-2 inhibitor, in human plasma and cerebrospinal fluid (CSF). Acetonitrile was used as protein precipitant. The mobile phase was 10 mM ammonium formate consisting of 0.1% formic acid and acetonitrile (40:60, v/v). The analytes were separated on an ACQUITY UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) in 5 min. An API 4000 mass spectrometer was selected to quantify venetoclax and internal standard using m/z 868.3 → 636.3 and 876.3 → 644.3 under multiple response monitoring mode. In plasma, the calibration curve exhibited good linearity ranging from 20.0 to 5000 ng/mL, whereas in the CSF, the linear range was 0.500-100 ng/mL. The matrix effect of venetoclax and internal standard (venetoclax-d8) was not obvious in both plasma and CSF. The inter- and intra-run accuracy was within ±11.9%, and the inter- and intra-run precision was below 13.6%. Both methods had no carryover, and the recovery was close to 100%. The validated methods were employed to quantify the concentrations of venetoclax in the plasma and CSF of patients diagnosed with chronic lymphocytic leukemia or acute myelogenous leukemia.

Preparation and activity of sodium carboxymethyl cellulose (CMC-Na) and Metarhizium rileyi ZHKUMR1 composite membrane.

Improving the adhesion capability of Metarhizium rileyi ZHKUMR1 on leaves enabled by the combination with Carboxymethyl Cellulose (CMCNa) materials is feasible to improve the utilization rate of Metarhizium rileyi. Herein, the CMC-Na-ZHKUMR1 membrane was prepared by simply mixing Carboxymethyl Cellulose (CMCNa) with Metarhizium rileyi. Through compatibility test, it was found that the inhibition rates of spore germination and mycelial growth of ZHKUMR1 were only 1.51 % and 3.13 % when the concentration of Carboxymethyl Cellulose (CMCNa) was 0.5 %. By adding 2 % of Carboxymethyl Cellulose (CMCNa) under UV irradiation for 30 min, the protective rate of spore germination of ZHKUMR1 was up to ~12.44 %, where the wettability on corn leaves was achieved and the retention of ZHKUMR1 spores on corn leaves was increased. After indoor activity determination, it was found that after 3 min of simulated rain washing, the lethal rate of corn leaves pretreated with CMC-Na-ZHKUMR1 on the 2nd instar larvae of Spodoptera frugiperda was 46.67 %, which was much higher than that of ZHKUMR1 spore suspension alone. This work clearly showed that Carboxymethyl Cellulose (CMCNa) effectively improved the field application effect of Metarhizium rileyi ZHKUMR1, and this strategy provided guidance for improving the field efficacy of Metarhizium rileyi ZHKUMR1.