VISTA deficiency exerts anti-tumor effects in breast cancer through regulating macrophage polarization.

Growing evidence had showed that tumor-associated macrophages (TAMs) have a tumor-promoting M2 phenotype which could drive pathological phenomena. In breast cancer, TAMs are abundantly present and may play an important role in the development of breast cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory checkpoint and immunotherapy target for tumor through regulating immune response. However, its effects on macrophages have not been investigated, which was also the focus of this study. Here, the scRNA-seq data further revealed that VISTA was highly expressed in multiple macrophage subclusters. In vitro experiments showed that the absence of VISTA enhanced the M1 polarization of macrophages, inhibited the M2 polarization of macrophages and the proliferation and phagocytosis of 4 T1 cells induced by M2-CM. VISTA regulated the activation of STAT1 and STAT6 signaling pathways in the process of macrophage polarization. In vivo experiments demonstrated that VISTA deficient mice exhibited reduced tumor growth, possibly due to the increase of M1 macrophages and the decrease of M2 macrophages. In summary, our study is the first to reveal the effect of VISTA on macrophages in breast cancer, which showed that VISTA affects tumor growth by critically regulating the macrophage polarization through the STAT pathway.

Impact of digital inclusive finance on agricultural total factor productivity in Zhejiang Province from the perspective of integrated development of rural industries.

Improving agricultural total factor productivity is crucial for comprehensive rural revitalization and building a strong agricultural nation. Digital inclusive finance amalgamates the benefits of digital technology and inclusive finance, mitigating financial exclusion in agricultural production. It fosters rural revitalization and the modernization of agriculture by bolstering farmers' innovation, entrepreneurship, and agricultural technology advancements. Consequently, it significantly enhances overall agricultural total factor productivity. This study uses panel data from 2011 to 2020 to empirically investigate the impact and mechanism of digital inclusive finance on agricultural total factor productivity in Zhejiang Province, China. The research results show that digital inclusive finance significantly enhances agricultural total factor productivity in Zhejiang Province, which holds true even after a series of robustness tests. Analysis of the mechanism reveals that the integrated development of rural industries plays a crucial mediating role in empowering agricultural total factor productivity through digital inclusive finance. Furthermore, heterogeneity analysis indicates that the positive effect of digital inclusive finance on agricultural total factor productivity is more pronounced in the northeastern region of Zhejiang Province and in areas ranked in the second tier of agricultural development. Therefore, we recommend comprehensively enhancing the development of digital inclusive finance in rural areas, fostering a financial ecosystem that integrates rural industries, promoting the coordinated development of digital inclusive finance in different regions, and comprehensively improving agricultural total factor productivity.

Co-expression of immune checkpoints in glioblastoma revealed by single-nucleus RNA sequencing and spatial transcriptomics.

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system. The pattern of immune checkpoint expression in GBM remains largely unknown. We performed snRNA-Seq and spatial transcriptomic (ST) analyses on untreated GBM samples. 8 major cell types were found in both tumor and adjacent normal tissues, with variations in infiltration grade. Neoplastic cells_6 was identified in malignant cells with high expression of invasion and proliferator-related genes, and analyzed its interactions with microglia, MDM cells and T cells. Significant alterations in ligand-receptor interactions were observed, particularly between Neoplastic cells_6 and microglia, and found prominent expression of VISTA/VSIG3, suggesting a potential mechanism for evading immune system attacks. High expression of TIM-3, VISTA, PSGL-1 and VSIG-3 with similar expression patterns in GBM, may have potential as therapeutic targets. The prognostic value of VISTA expression was cross-validated in 180 glioma patients, and it was observed that patients with high VISTA expression had a poorer prognosis. In addition, multimodal cross analysis integrated SnRNA-seq and ST, revealing complex intracellular communication and mapping the GBM tumor microenvironment. This study reveals novel molecular characteristics of GBM, co-expression of immune checkpoints, and potential therapeutic targets, contributing to improving the understanding and treatment of GBM.

Imatinib and M351-0056 enhance the function of VISTA and ameliorate the development of SLE via IFN-I and noncanonical NF-κB pathway.

V-domain immunoglobulin suppressor of T-cell activation (VISTA), an important negative checkpoint protein, participates in immunoregulation. Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients exhibit high levels of autoantibodies and multi-organ tissue injury, primarily involving the kidney and skin. In wild-type (WT) mice and Vsir-/- mice with pristane-induced lupus-like disease, we found that VISTA deficiency exacerbated the lupus-like disease in mice, possibly through aberrant activation of type I interferon (IFN-I) signaling, CD4+ T cell, and noncanonical nuclear factor-κB (NF-κB) pathway. Surface plasmon resonance results showed that imatinib, an FDA-approved tyrosine kinase inhibitor, may have a high affinity for human VISTA-ECD with a KD value of 0.2009 µM. The biological activities of imatinib and VISTA agonist M351-0056 were studied in monocytes and T cells and in lupus-like disease murine model of chronic graft-versus-host disease (cGVHD) and lupus-prone MRL/lpr mice. VISTA small-molecule agonist reduced the cytokine production of peripheral blood mononuclear cells (PBMCs) and Jurkat cells and inhibited PBMCs proliferation. Moreover, they attenuated the levels of autoantibodies, renal injury, inflammatory cytokines, chemokines, and immune cell expansion in the cGVHD mouse model and MRL/lpr mice. Our findings also demonstrated that VISTA small-molecule agonist ameliorated the development of SLE through improving aberrantly activated IFN-I signaling and noncanonical NF-κB pathway. In conclusion, VISTA has a protective effect on the development and progression of SLE. VISTA agonist M351-0056 and imatinib have been firstly demonstrated to attenuate SLE, suggesting interventions to enhance VISTA function may be effective in treating SLE. VISTA deficiency exacerbates pristane-induced lupus-like disease in mice by promoting activation of the IFN-I and noncanonical NF-κB pathway. Imatinib was screened as a small-molecule VISTA agonist by molecular docking, SPR, and cellular level experiments. VISTA agonists (M351-0056 and imatinib) alleviated lupus-like disease progression in the cGVHD mouse model and MRL/lpr mice by inhibiting activation of IFN-I and noncanonical NF-κB pathway.

Exercise attenuates neuronal degeneration in Parkinson's disease rat model by regulating the level of adenosine 2A receptor.

Parkinson's disease occurs due to loss of dopaminergic neurons, which alters the behavioural changes. The present study evaluates the effect of exercise on neurodegeneration against Parkinson's disease (PD) rat model and postulates its effect on novel molecular pathway. Rotenone was administered at 1 mg/kg s.c. every 48 h for 18 days for the in-duction of PD and exercise was given to rats for a period of 2 weeks after the confirmation of PD. Moreover, PD rats also received CGS 21680 (adenosine A2A receptor agonist, 0.5 mg/kg, i.p.) with exercise for a period of 2 weeks after confirmation of PD. The effect of exercise was assessed for motor and cognitive function in PD rats. The level of inflammatory cytokines and neurotransmitters was estimated in brain tissue of PD rats. Data of investigation reveal that exercise attenuates cognitive and motor function in PD rats, the exercise + CGS 21680 group shows reverse in the behavioural changes compared to exercise-treated PD rats. The level of inflammatory cytokines and neurochemical level ameliorated in the exercise-treated group compared to the PD group of rats, which is reversed in the exercise + CGS 21680 group. In conclusion, exercise protects neurodegeneration in PD rats by reducing aggregation of a-synuclein and activity of adenosine 2A receptor.

Immune-related adverse events associated with nab-paclitaxel/paclitaxel combined with immune checkpoint inhibitors: a systematic review and network meta-analysis.

Objective: The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile. Methods: We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs. Results: There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups. Conclusion: Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.

Anlotinib and fruquintinib co-administrated with warfarin increases the risk of bleeding: Studied from pharmacokinetic and pharmacodynamic perspectives.

BACKGROUND: Recent studies have reported a higher risk of bleeding among patients that are co-administrated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and anticoagulant, which raises our concern about the possible TKIs-warfarin pharmacokinetic and pharmacodynamic interaction that could be life-threatening to tumor patients who take warfarin for preventing deep vein thrombosis (DVT). METHODS: Influences of anlotinib and fruquintinib on the pharmacokinetic and dynamic behavior of warfarin were estimated. Influence on the activity of cytochrome P450 (CYP450) enzymes was detected in vitro through rat liver microsomes. Quantitative analysis of blood concentration in rats was finished by a validated UHPLC-MS/MS method. Furthermore, pharmacodynamic interactions were studied in rats by monitoring prothrombin time (PT) and activated partial thromboplastin time (APTT), while Inferior vena cava (IVC) stenosis-induced DVT model was built to further investigate the antithrombotic effect after co-administration. RESULTS: Anlotinib inhibited the activity of cyp2c6, cyp3a1/2 and cyp1a2 in rat liver microsomes in a dose-dependent manner, meanwhile enhanced the AUC0∼t and AUC0∼∞ of R-warfarin. However, fruquintinib showed no effects on pharmacokinetics of warfarin. Anlotinib and fruquintinib co-administrated with warfarin was found to exert more significant increase on PT and APTT values than that taking warfarin alone. In IVC stenosis-induced DVT model rats, the co-administration groups significantly reduced the length of thrombus compared with the single warfarin group. CONCLUSIONS: Anlotinib and fruquintinib enhanced the anticoagulated and antithrombotic effect of warfarin. The anlotinib-induced interaction may due to the inhibition of the metabolism of warfarin. The mechanism of the pharmacodynamic interaction between fruquintinib and warfarin should be further investigated.

Improving the anti-tumor effect of EGCG in colorectal cancer cells by blocking EGCG-induced YAP activation.

(-)-Epigallocatechin-3-gallate (EGCG) is the primary active ingredient in green tea and has been used for cancer prevention in clinical trials. The anti-tumor effects of EGCG stem from its ability to inhibit the activities of many oncoproteins, such as AKT, VEGFR, STAT3, and mutant p53. However, the clinical efficacy of EGCG is unsatisfactory. How to improve the anti-tumor effects of EGCG is an open question. Here we report that EGCG inhibits the tumor suppressive Hippo signaling pathway and activates downstream YAP in colorectal cancer (CRC) cells. Activation of YAP impedes the anti-tumor effects of EGCG. YAP blockade increases the sensitivity of CRC cells to EGCG treatment.

Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation.

Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml-1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO-) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability.

Single-Cell RNA Sequencing Reveals the Immune Cell Profiling in IMQ Induced Psoriasis-Like Model.

Purpose: Psoriasis is a chronic systemic inflammatory skin disease with a high recurrence rate. The immune response plays an important role in psoriasis. However, the subsets of immune cells involved in inflammation in psoriatic mice have not been fully studied. This study showed the immune environment characteristics of psoriasis in mice. Methods: We used single-cell RNA sequencing (10× Genomics) as an unbiased analytical strategy to investigate the heterogeneity of skin immune cells in imiquimod-induced psoriasis mice systematically. Results: We identified 10 major clusters and their marker genes among 14,439 cells. The proportions of macrophages, NK/T cells, conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) were increased in psoriatic mice. Macrophages were the largest group and were further divided into 7 subgroups, and all macrophage clusters were increased in psoriatic mice. Differentially expressed genes in control versus psoriatic mice skin lesions showed that Fcgr4, Saa3 and Acp5 in macrophages, Acp5, Fcgr4 and Ms4a6d in NK/T cells, Saa3 in cDCs, and Ifitm1 in pDCs were upregulated in psoriasis mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis emphasized the role of oxidative phosphorylation signals and antigen processing and presentation signals in murine psoriasis-like models. Conclusion: Our study reveals the immune environment characteristics of the commonly used IMQ induced psoriasis-like models and provides a systematic insight into the immune response of mice with psoriasis, which is conducive to comparing the similarities and differences between the mouse model and human psoriasis.

Conformational Trimorphism in an Ionic Cocrystal of Hesperetin.

We report the existence of conformational polymorphism in an ionic cocrystal (ICC) of the nutraceutical compound hesperetin (HES) in which its tetraethylammonium (TEA+) salt serves as a coformer. Three polymorphs, HESTEA-α, HESTEA-ß and HESTEA-γ, were characterized by single-crystal X-ray diffraction (SCXRD). Each polymorph was found to be sustained by phenol···phenolate supramolecular heterosynthons that self-assemble with phenol···phenol supramolecular homosynthons into C 3 2(7) H-bonded motifs. Conformational variability in HES moieties and different relative orientations of the H-bonded motifs resulted in distinct crystal packing patterns: HESTEA-α and HESTEA-ß exhibit H-bonded sheets; HESTEA-γ is sustained by bilayers of H-bonded tapes. All three polymorphs were found to be stable upon exposure to humidity under accelerated stability conditions for 2 weeks. Under competitive slurry conditions, HESTEA-α was observed to transform to the ß or γ forms. Solvent selection impacted the relationship between HESTEA-ß (favored in EtOH) and HESTEA-γ (favored in MeOH). A mixture of the ß and γ forms was found to be present following H2O slurry.

Influence of positive and negative affect on self-management among patients with early chronic kidney disease during the COVID-19 pandemic: The mediating and suppressing effect of ego depletion.

Background: Self-management in patients with early chronic kidney disease (CKD) can effectively delay damage to renal function. However, with the continuous spread of COVID-19, patients cannot receive timely treatment, which can lead to different affects, resulting in ego depletion and serious challenges to self-management. This study aimed to investigate the mediating and suppressing roles of ego depletion on the relationship between positive and negative affect and self-management among patients with early CKD during the COVID-19 pandemic in China. Methods: A total of 383 patients with early CKD from three tertiary hospitals were enrolled by convenience sampling in our cross-sectional study from September 2021 to March 2022. Participants completed the Sociodemographic Questionnaire, Positive Affect and Negative Affect Scale, Self-Regulating Fatigue Scale and Chronic Kidney Disease Self-Management Instrument. A structural equation model was conducted to test the mediating and suppressing effects of ego depletion on the relationship between positive and negative affect and self-management. Results: The average score of the participants' self-management was 84.54 (SD: 19.72), and nearly 60% of them were at low and moderate levels. The mediating effect of positive affect on self-management through ego depletion was significant (ß = 0.248, 95% CI: 0.170 to 0.376), accounting for 53.22% of the total effect. The suppressing effect of negative affect on self-management through ego depletion was significant (ß = -0.191, 95% CI: -0.310 to -0.118), and the absolute value of the ratio of the suppressing effect to the direct effect was 66.55%. Conclusions: Ego depletion partially mediated the relationship between positive affect and self-management while suppressing the relationship between negative affect and self-management among patients with early CKD during the COVID-19 pandemic. The reduction of patients' ego depletion must be taken as the intervention target to improve self-management and delay the progression of CKD.

Comparative analysis of sensitivity and specificity of computer-aided cognitive test in screening mild cognitive impairment patients and test of reliability and validity.

OBJECTIVES: To evaluate the reliability and validity of the computer-aided cognitive test (CACT). METHODS: 219 Subjects of Tongji Hospital's Brain Health cohort (115 cases of Mild Cognitive Impairment (MCI) patients and 104 cases of normal controls) were enrolled, of which 24 cases received a retest after 2 weeks. Finally, the reliability and validity of the scale were tested and analyzed. RESULTS: (1) Reliability: (a) the internal consistency reliability of the total score of the scale was 0.645; (b) the retest reliability correlation coefficient of the total score of the scale was 0.900; (c) the Guttman Split-Half coefficient was 0.631; (2) Validity: (a) construct validity analysis showed that the correlation coefficient between each section score was between 0.036 and 0.408, and the correlation coefficient between each section score and the total score was between 0.468 and 0.781; (b) criterion validity analysis showed that the correlation coefficient between the total score of CACT and that of the Mini Mental State Examination (MMSE) was 0.733, and the coefficient between the total score of CACT and that of the basic version of the Montreal Cognitive Assessment (MoCA) was 0.763; (c) the area under the ROC curve of the CACT to distinguish between MCI patients and controls was 0.920, with an optimal diagnostic threshold of 20, a sensitivity of 88.5%, and a specificity of 80.9%. CONCLUSION: The CACT is little influenced by education level. It has good reliability and validity, which can be used for early clinical screening of cognitive dysfunction.

Reference values of normal abdominal aortic areas in Chinese population measured by contrast-enhanced computed tomography.

Objective: To generate reference values of the normal areas of the abdominal aorta at various levels among Chinese people and to explore the factors that may promote the expansion of the abdominal aorta. Methods: The areas of normal abdominal aortas were gauged at various levels based on inner-to-inner measurements in 1,066 Chinese adult patients (>18 years) without the abdominal aortic disease. The areas of subphrenic abdominal, suprarenal abdominal, infrarenal abdominal, and distal abdominal aortas were measured. The demographic and clinical characteristics were collected into a specifically designed electronic database. Multivariable linear regression was used to analyze the potential risk factors promoting the expansion of the abdominal aorta. Results: In males, the median areas of the subphrenic abdominal aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and distal abdominal aorta were 412.1, 308.0, 242.2, and 202.2 mm2, respectively. In females, the median areas of the subphrenic abdominal aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and distal abdominal aorta were 327.7, 243.4, 185.4, and 159.6 mm2, respectively. The areas of the abdominal aorta at different levels were larger in males than in females and increased with age. Multiple linear stepwise regression analysis showed that the subphrenic abdominal aortic area was significantly related to age (ß = 0.544, p < 0.001), sex (ß = 0.359, p < 0.001), and hypertension (ß = 0.107, p < 0.001). Suprarenal abdominal aortic area was related to age (ß = 0.398, p < 0.001), sex (ß = 0.383, p < 0.001), history of smoking (ß = 0.074, p = 0.005), and hypertension (ß = 0.111, p < 0.001). The infrarenal abdominal aortic area was correlated with age (ß = 0.420, p < 0.001), sex (ß = 0.407, p < 0.001), and history of smoking (ß = 0.055, p = 0.036). The distal abdominal aortic area was correlated with age (ß = 0.463, p < 0.001), sex (ß = 0.253, p < 0.001), and hypertension (ß = 0.073, p = 0.013). Conclusion: The abdominal aortic areas at different levels were larger in males than in females. Aging, hypertension, and smoking prompt the expansion of abdominal aorta.

Crystal Engineering of Ionic Cocrystals Sustained by the Phenol-Phenolate Supramolecular Heterosynthon.

Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol-phenolate supramolecular heterosynthon (PhOH···PhO-). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO- supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO- interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO- interaction to be around 3 times stronger than the phenol-phenol hydrogen bond. The PhOH···PhO- supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.

Simultaneous Characterization and Determination of Warfarin and Its Hydroxylation Metabolites in Rat Plasma by Chiral Liquid Chromatography-Tandem Mass Spectrometry.

Warfarin is extensively used for venous thromboembolism and other coagulopathies. In clinical settings, warfarin is administered as a mixture of S- and R-warfarin, and both enantiomers are metabolized by multiple cytochrome P450 enzymes into many hydroxylation metabolites. Due to the high degree of structural similarity of hydroxylation metabolites, their profile possesses significant challenges. The previous methods generally suffer from lacking baseline resolution and/or involving complex analysis processes. To overcome this limitation, a sensitive and specific chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously identify warfarin and hydroxywarfarins enantiomers. Chromatographic separation was achieved on a HYPERSIL CHIRAL-OT column. The mass spectrometric detection was carried out in negative ion MRM mode with electrospray ionization source. The optimized method exhibited satisfactory within-run and between-run accuracy and precision with lower limit of quantification (LLOQ) of 10.0 ng/mL and 1.0 ng/mL for warfarin and 7-, 10(R)-OH-warfarin enantiomers, respectively. Linear responses of warfarin enantiomers and 7-, and 10(R)-OH-warfarin enantiomers in rat plasma were observed over the range of 10.0-8000 ng/mL, and 1.00-800 ng/mL, respectively. The analytes were shown to be stable in various experimental conditions in rat plasma. Protein precipitation was used in sample preparation without a matrix effect. This method was successfully applied to pharmacokinetic study for quantitating the concentrations of S/R-warfarin, S/R-7-OH-warfarin, and S/R-10(R)-OH-warfarin and relatively quantitating 3'-, 4-, 6-, and 8-OH warfarin enantiomers in rat plasma.

Network structure of family function and self-management in patients with early chronic kidney disease amid the COVID-19 pandemic.

Background: Family function plays a pivotal role in self-management among patients with early chronic kidney disease (CKD), which has been especially important during the COVID-19 pandemic. Previous studies have investigated the relationships between family function and self-management using total scores through self-report questionnaires while ignoring the different components in both family function and self-management. The specific objective of this study was to explore the network structure of family function and self-management at the component level. Methods: A total of 360 patients with early CKD from three tertiary hospitals were enrolled in our cross-sectional survey from September to December 2021 in China. Components of family function were measured by the Family Adaptation Partnership Growth and Resolve Index, and components of self-management were measured by the Chronic Kidney Disease Self-management Instrument. Network analysis was used to establish the network structure. Results: Edges across the community of family function and self-management were mainly positive. Edges between F3 "Growth" and M1 "Self-integration", F2 "Partnership" and M3 "Seeking social support," F5 "Resolve" and M3 "Seeking social support" were the strongest. F3 "Growth" had the greatest positive bridge expected influence of family function community (0.12), and M3 "Seeking social support" had the greatest positive bridge expected influence of self-management community (0.16). Conclusion: We explored the potential pathways between different components of family function and self-management among patients with early CKD during the COVID-19 pandemic and found fine-grained relationships between them. The two nodes F3 "Growth" and M3 "Seeking social support" may provide a new idea from the perspective of family function for interventions to improve self-management.

Investigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: A physiologically based pharmacokinetic/pharmacodynamic analysis.

AIMS: Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the combination of ritonavir and nifedipine can potentially cause drug-drug interactions. This study provides guidance on nifedipine treatment during and after coadministration with ritonavir-containing regimens, using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for 3 formations of nifedipine were developed based on the Simcyp nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release and controlled-release formulations in patients. Various nifedipine regimens were investigated when coadministered with or without ritonavir. RESULTS: PBPK/PD models for 3 formulations of nifedipine were successfully established. The predicted maximum concentration (Cmax ), area under plasma concentration-time curve (AUC), maximum reduction in SBP and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSION: Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.

Safety of different carotid artery revascularization strategies in the coronary artery bypass graft population: study protocol for a systematic review and network meta-analysis.

BACKGROUND: Concomitant significant carotid artery occlusive diseases (CAOD) increase the risk of perioperative stroke and death in patients who undergo coronary artery bypass graft (CABG). Although several surgical strategies can be used in the management of such patients, controversy still surrounds which is the best option for CABG patients with accompanying CAOD. METHODS: Literature searches will be conducted covering articles published in PubMed, the Cochrane Central Register of Controlled Trials, Web of Science, and Embase between January 1989 and December 2019. Search results will be limited to articles published in English. Six surgical strategies using carotid endarterectomy (CEA) or carotid artery stenting (CAS) with different timings (i.e., before, after, or combined with CABG) will be evaluated. Randomized controlled trials and non-randomized studies comparing these strategies will be included. The quality of studies will be critically appraised using the Cochrane risk-of-bias tool or ROBINS-I tool. Since CEA and CAS have comparable effectiveness for the treatment of significant CAOD, we will integrate direct and indirect evidence using network meta-analysis (NMA) to create hierarchies of the six surgical strategies based on their perioperative safety. The primary outcomes will be the probability of perioperative stroke and the probability of perioperative death. Additionally, we will analyze the probability of perioperative myocardial infarction (MI) as a secondary outcome. Pairwise meta-analyses and Bayesian network meta-analyses will be performed for all related outcome measures. Subgroup analyses, sensitivity analyses, and network meta-regression will be conducted to assess the robustness of the findings. DISCUSSION: This NMA will summarize the direct and indirect evidence of perioperative safety with the aim of providing a ranking of the various surgical strategies. The results of this meta-analysis will provide useful information on optimal surgical management of CABG patients with concomitant significant CAOD. TRIAL REGISTRATION NUMBER: PROSPERO CRD42020162611.

Mechanistic examination of methimazole-induced hepatotoxicity in patients with Grave's disease: a metabolomic approach.

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.