Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses.

The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.

Antidepressant effects of activation of infralimbic cortex via upregulation of BDNF and ß-catenin in an estradiol withdrawal model.

RATIONALE: Clinical and preclinical studies have demonstrated that estradiol withdrawal after delivery is one of important factors involved in the pathogenesis of postpartum depression (PPD). The infralimbic cortex (IL) is related to anxiety and mood disorders. Whether IL neurons mediate PPD is still unclear. OBJECTIVES: This study was to observe the antidepressant effect and expression of BDNF and ß-catenin in IL by allopregnanolone (ALLO) treatment or the selective activation or inhibition of IL neurons using a chemogenetic approach in a pseudopregnancy model of PPD. METHODS: Administration of estradiol combined with progesterone and the abrupt withdrawal of estradiol simulated the pregnancy and early postpartum periods to induce depression in ovariectomized rats. The relative expression levels of ß-catenin and BDNF were observed by western blotting. RESULTS: Immobility time was significantly increased in the forced swim test and open-arm movement was reduced in the elevated plus maze test in the estradiol-withdrawn rats. After ALLO treatment, the immobility time were lower and open-arm traveling times higher than those of the estradiol-withdrawn rats. Meanwhile, the expression level of BDNF or ß-catenin in the IL was reduced significantly in estradiol-withdrawn rats, which was prevented by treatment with ALLO. The hM3Dq chemogenetic activation of pyramidal neurons in the IL reversed the immobility and open-arm travel time trends in the estradiol-withdrawal rat model, but chemogenetic inhibition of IL neurons failed to affect this. Upregulated BDNF and ß-catenin expression and increased c-Fos in the basolateral amygdala were found following IL neuron excitation in model rats. CONCLUSIONS: Our results demonstrated that pseudopregnancy and estradiol withdrawal produced depressive-like behavior and anxiety. ALLO treatment or specific excitement of IL pyramidal neurons relieved abnormal behaviors and upregulated BDNF and ß-catenin expression in the IL in the PPD model, suggesting that hypofunction of IL neurons may be involved in the pathogenesis of PPD.

Exploring the pharmacological mechanism of Glycyrrhiza uralensis against KOA through integrating network pharmacology and experimental assessment.

Knee osteoarthritis (KOA), a major health and economic problem facing older adults worldwide, is a degenerative joint disease. Glycyrrhiza uralensis Fisch. (GC) plays an integral role in many classic Chinese medicine prescriptions for treating knee osteoarthritis. Still, the role of GC in treating KOA is unclear. To explore the pharmacological mechanism of GC against KOA, UPLC-Q-TOF/MS was conducted to detect the main compounds in GC. The therapeutic effect of GC on DMM-induced osteoarthritic mice was assessed by histomorphology, µCT, behavioural tests, and immunohistochemical staining. Network pharmacology and molecular docking were used to predict the potential targets of GC against KOA. The predicted results were verified by immunohistochemical staining Animal experiments showed that GC had a protective effect on DMM-induced KOA, mainly in the improvement of movement disorders, subchondral bone sclerosis and cartilage damage. A variety of flavonoids and triterpenoids were detected in GC via UPLC-Q-TOF/MS, such as Naringenin. Seven core targets (JUN, MAPK3, MAPK1, AKT1, TP53, RELA and STAT3) and three main pathways (IL-17, NF-κB and TNF signalling pathways) were discovered through network pharmacology analysis that closely related to inflammatory response. Interestingly, molecular docking results showed that the active ingredient Naringenin had a good binding effect on anti-inflammatory-related proteins. In the verification experiment, after the intervention of GC, the expression levels of pp65 and F4/80 inflammatory indicators in the knee joint of KOA model mice were significantly downregulated. GC could improve the inflammatory environment in DMM-induced osteoarthritic mice thus alleviating the physiological structure and dysfunction of the knee joint. GC might play an important role in the treatment of knee osteoarthritis.

CT-Based Radiomics Models for Differentiation of Benign and Malignant Thyroid Nodules: A Multicenter Development-and-Validation.

Background: CT is increasingly detecting thyroid nodules. Prior studies indicated a potential role of CT-based radiomics models in characterizing thyroid nodules, although lacked external validation. Objectives: To develop and validate a CT-based radiomics model for the differentiation of benign and malignant thyroid nodules. Methods: This retrospective study included 378 patients (mean age, 46.3±13.9 years; 86 men, 292 women) with 408 resected thyroid nodules (145 benign, 263 malignant) from two centers (center 1: 293 nodules, January 2018-December 2022; center 2: 115 nodules, January 2020-December 2022), who underwent preoperative multiphase neck CT (noncontrast, arterial, and venous phases). Nodules from center 1 were divided into training (n=206) and internal validation (n=87) sets; all nodules from center 2 formed an external validation set. Radiologists assessed nodules for morphologic CT features. Nodules were manually segmented on all phases, and radiomic features were extracted. Conventional (clinical and morphologic CT), noncontrast radiomics, arterial-phase radiomics, venous-phase radiomics, multiphase radiomics, and combined (clinical, morphologic, and multiphase radiomics) models were established using feature selection methods and evaluated by ROC curve analysis, calibration curves, and decision-curve analysis. Results: The combined model included patient age, three morphologic features (cystic change, edge interruption sign, abnormal cervical lymph nodes), and 28 radiomic features (from all three phases). In the external validation set, the combined model had AUC of 0.923 and, at an optimal threshold derived in the training set, sensitivity of 84.0%, specificity of 94.1%, and accuracy of 87.0%. In the external validation set, AUC was significantly higher for the combined model than for the conventional model (0.827), noncontrast radiomics model (0.847), arterial-phase radimoics model (0.826), venous-phase radiomics model (0.773), and multiphase radiomics model (0.824) (all p<.05). In the external validation set, the calibration curves indicated lowest (i.e., best) Brier score for the combined model; in decision-curve analysis, the combined model had the highest net benefit for most of the range of threshold probabilities. Conclusion: A combined model incorporating clinical, morphologic CT, and multiphasic radiomics CT features, exhibited robust performing in differentiating benign and malignant thyroid nodules. Clinical Impact: The combined radiomics model may help guide further management for thyroid nodules detected on CT.

Muscone restores anoikis sensitivity in TMZ-resistant glioblastoma cells by suppressing TOP2A via the EGFR/Integrin ß1/FAK signaling pathway.

BACKGROUND: Temozolomide (TMZ) resistance is the main obstacle faced by glioblastoma multiforme (GBM) treatment. Muscone, one of the primary active pharmacological ingredients of Shexiang (Moschus), can cross the blood-brain barrier (BBB) and is being investigated as an antineoplastic medication. However, muscone treatment for GBM has received little research, and its possible mechanisms are still unclear. PURPOSE: This study aims to evaluate the effect and the potential molecular mechanism of muscone on TMZ-resistant GBM cells. METHODS: The differentially expressed genes (DEGs) between TMZ-resistant GBM cells and TMZ-sensitive GBM cells were screened using GEO2R. By progressively raising the TMZ concentration, a relatively stable TMZ-resistant human GBM cell line was established. The drug-resistance traits of U251-TR cells were assessed via the CCK-8 assay and Western Blot analysis of MGMT and TOP2A expression. Cell viability, cell proliferation, cell migration ability, and drug synergism were detected by the CCK-8 assay, colony formation assay, wound healing assay, and drug interaction relationship test, respectively. Anoikis was quantified by Calcein-AM/EthD-1 staining, MTT assay, and flow cytometry. Measurements of cell cycle arrest, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed using cell cycle staining, Annexin V-FITC/PI labeling, JC-1 assay, and ROS assay, respectively. DNA damage was measured by TUNEL assay, alkaline comet assay, and γ-H2AX foci assay. GEPIA was used to investigate the link between the anoikis marker (FAK)/drug resistance gene and critical proteins in the EGFR/Integrin ß1 signaling pathway. Molecular docking was used to anticipate the probable targets of muscone. The intracellular co-localization and expression of EGFR and FAK were shown using immunofluorescence. The U251-TR cell line stably overexpressing EGFR was constructed using lentiviral transduction to assess the involvement of EGFR-related signaling in anoikis resistance. Western Blot was employed to detect the expression of migration-related proteins, cyclins, anoikis-related proteins, DNA damage/repair-related proteins, and associated pathway proteins. RESULTS: DEGs analysis identified 97 deregulated chemotherapy-resistant genes and 3779 upregulated genes in TMZ-resistant GBM cells. Subsequent experiments verified TMZ resistance and the hyper-expression of DNA repair-related genes (TOP2A and MGMT) in continuously low-dose TMZ-induced U251-TR cells. Muscone exhibited dose-dependent inhibition of U251-TR cell migration and proliferation, and its co-administration with TMZ showed the potential for enhanced therapeutic efficacy. By downregulating FAK, muscone reduced anoikis resistance in anchorage-independent U251-TR cells. It also caused cell cycle arrest in the G2/M phase by upregulating p21 and downregulating CDK1, CDK2, and Cyclin E1. Muscone-induced anoikis was accompanied by mitochondrial membrane potential collapse, ROS production, an increase in the BAX/Bcl-2 ratio, as well as elevated levels of Cytochrome c (Cyt c), cleaved caspase-9, and cleaved caspase-3. These findings indicated that muscone might trigger mitochondrial-dependent anoikis via ROS generation. Moreover, significant DNA damage, DNA double-strand breaks (DSBs), the formation of γ-H2AX foci, and a reduction in TOP2A expression are also associated with muscone-induced anoikis. Overexpression of EGFR in U251-TR cells boosted the expression of Integrin ß1, FAK, ß-Catenin, and TOP2A, whereas muscone suppressed the expression levels of EGFR, Integrin ß1, ß-Catenin, FAK, and TOP2A. Muscone may influence the expression of the key DNA repair enzyme, TOP2A, by suppressing the EGFR/Integrin ß1/FAK pathway. CONCLUSION: We first demonstrated that muscone suppressed TOP2A expression through the EGFR/Integrin ß1/FAK pathway, hence restoring anoikis sensitivity in TMZ-resistant GBM cells. These data suggest that muscone may be a promising co-therapeutic agent for enhancing GBM treatment, particularly in cases of TMZ-resistant GBM with elevated TOP2A expression.

Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

Transcriptional regulation of TacL-mediated lipoteichoic acids biosynthesis by ComE during competence impacts pneumococcal transformation.

Competence development is essential for bacterial transformation since it enables bacteria to take up free DNA from the surrounding environment. The regulation of teichoic acid biosynthesis is tightly controlled during pneumococcal competence; however, the mechanism governing this regulation and its impact on transformation remains poorly understood. We demonstrated that a defect in lipoteichoic acid ligase (TacL)-mediated lipoteichoic acids (LTAs) biosynthesis was associated with impaired pneumococcal transformation. Using a fragment of tacL regulatory probe as bait in a DNA pulldown assay, we successfully identified several regulatory proteins, including ComE. Electrophoretic mobility shift assays revealed that phosphomimetic ComE, but not wild-type ComE, exhibited specific binding to the probe. DNase I footprinting assays revealed the specific binding sequences encompassing around 30 base pairs located 31 base pairs upstream from the start codon of tacL. Expression of tacL was found to be upregulated in the ΔcomE strain, and the addition of exogenous competence-stimulating peptide repressed the tacL transcription in the wild-type strain but not the ΔcomE mutant, indicating that ComE exerted a negative regulatory effect on the transcription of tacL. Mutation in the JH2 region of tacL upstream regulatory sequence led to increased LTAs abundance and displayed higher transformation efficiency. Collectively, our work identified the regulatory mechanisms that control LTAs biosynthesis during competence and thereby unveiled a repression mechanism underlying pneumococcal transformation.

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.

Protective effect of chlorogenic acid on liver injury in heat-stressed meat rabbits.

This study investigated the protective effects of chlorogenic acid (CGA) on production performance and liver function of rabbits under heat stress (HS) condition. A total of 120 healthy New Zealand weaned rabbits with similar initial body weight, were randomly divided into 3 treatments with 20 replicates per treatment and 2 weaned rabbits per replicate: control (CON) group (rabbits were housed at 25 ± 1°C and fed a basal diet), HS group (rabbits were housed at 35 ± 1°C and fed a basal diet), and HS + CGA group (rabbits were housed at 35 ± 1°C and fed a basal diet supplemented with 800 mg/kg CGA). The trial lasted for 28 days. The results showed that HS challenge decreased (p < 0.05) growth performance, induced oxidative stress and hepatic apoptosis, and caused liver damage in rabbits. However, dietary CGA supplementation increased (p < 0.05) body weight gain and feed efficiency, and enhanced (p < 0.05) antioxidative capacity in serum and liver in HS-challenged rabbits; attenuated HS-induced increases in urea nitrogen (p = 0.03), alanine aminotransferase (p = 0.03), aspartate aminotransferase (p = 0.01), caspase-8 (p = 0.02), and caspase-3 (p = 0.04) as well as decrease albumin (p = 0.04). Moreover, supplementation with CGA upregulated Nrf2/HO-1 pathway-related genes expressions, including Nrf2 (p = 0.009), HO-1 (p = 0.03) and SOD1 (p = 0.04) in HS-challenged rabbits. Our findings demonstrated that dietary CGA supplementation could alleviate HS-induced decline in growth performance, and protect against HS-induced liver damage partially through enhancing antioxidant capacity via acting Nrf2/HO-1 pathway and inhibiting hepatic apoptosis in rabbits.

Current situation and prospects for the clean utilization of gold tailings.

Gold tailings are characterized by low-grade, complex composition, fine embedded particle size, environmental pollution, and large land occupation. This paper describes the mineralogical properties of gold tailings, including chemical composition, phase composition, particle size distribution, and microstructure; summarizes the recycling and utilization of components such as mica, feldspar, and valuable metals in gold tailings; reviews harmless treatment measures for harmful elements in gold tailings; and adumbrated the research progress of gold tailings in the application fields of building materials, ceramics, and glass materials. Based on these discussions, a new technology roadmap that combines multistage magnetic separation and cemented filling is proposed for the clean utilization of all components of gold tailings.

Bufei Huoxue capsule attenuates COPD-related inflammation and regulates intestinal microflora, metabolites.

Background: Bufei Huoxue capsule (BFHX) is widely used for the clinical treatment of chronic obstructive pulmonary disease (COPD) in China. Objectives: The aim of this study is to explore the effects on COPD and the underlying mechanism of BFHX. The process and methods: In this study, we established a COPD mouse model through cigarette smoke (CS) exposure in combination with lipopolysaccharide (LPS) intratracheal instillation. Subsequently, BFHX was orally administrated to COPD mice, and their pulmonary function, lung pathology, and lung inflammation, including bronchoalveolar lavage fluid (BALF) cell count and classification and cytokines, were analyzed. In addition, the anti-oxidative stress ability of BFHX was detected by Western blotting, and the bacterial diversity, abundance, and fecal microbiome were examined using 16S rRNA sequencing technology. Outcome: BFHX was shown to improve pulmonary function, suppress lung inflammation, decrease emphysema, and increase anti-oxidative stress, whereas 16S rRNA sequencing indicated that BFHX can dynamically regulate the diversity, composition, and distribution of the intestinal flora microbiome and regulate the lysine degradation and phenylalanine metabolism of COPD mice. These results highlight another treatment option for COPD and provide insights into the mechanism of BFHX.

Effect of memory therapy on enhancing postoperative cognitive function recovery and alleviating mood disturbances in brain glioma patients.

OBJECTIVE: To assess the impact of memory therapy on enhancing recovery of postoperative cognitive function and alleviating mood disturbances in brain glioma patients. METHODS: This retrospective study included 160 brain glioma patients who met the inclusion criteria from August 2019 to July 2022. They were divided into a control group and an observation group according to according to different treatment method, with 80 cases in each group. The control group was given routine rehabilitation, while the observation group received additional memory therapy. The study compared complications between the two groups, focusing on the changes in cognitive function [using the Neurobehavioral Cognitive Status Check Scale (NCSE), Clinical Dementia Score (CDR)], mood disturbances [measured by the State Anxiety Scale (S-AI), Trait Anxiety Scale (T-AI), and Hospital Stress Scale score], health-promoting behaviors [evaluated with the Chinese Version of Health Promotion Lifestyle Scale-II (HPLP-II)], coping styles [assessed through the Medical Response Questionnaire (MCQM)], and cancer-related fatigue [using the Cancer-Related Fatigue Scale (CFS)] before and after intervention were observed. A total of 160 glioma cases were classified into either a good or poor prognosis category, based on their prognosis 12 months post-surgery. Baseline data from both groups were compared, and multivariate logistic regression was employed to analyze the factors influencing outcomes in glioma patients. RESULTS: After intervention, the observation group exhibited higher scores of NCSE, HPLP-II, and CFS, but lower scores on the CDR, S-AI, T-AI and hospital stress scale compared to the control group (all P<0.05). Additionally, within the MCQM, the observation group showed reduced avoidance and yield scores, and an increased facing score, compared to the control group (all P<0.05). No significant difference was observed between the complication rates of the control (8.75%) and observation groups (3.75%) (P>0.05). However, the incidence of adverse prognosis was significantly lower in the observation group compared to the control group (8.75% vs 22.50%) (P<0.05). There were no significant differences in age, maximum tumor diameter, preoperative Karnofsky Performance Status score, gender or lesion location between the poor prognosis group and the good prognosis group (all P>0.05). The poor prognosis group had a higher proportion of patients in clinical stages III-IV and a lower proportion receiving recall therapy compared to good prognosis group (P<0.05). Multivariate logistic regression analysis identified clinical stage (III-IV stage) [OR=3.562 (95% CI: 1.476-8.600)] as a risk factor for poor prognosis after brain glioma surgery (P<0.05), while undergoing memory therapy [ß=0.330 (95% CI: 0.99-0.842)] acted as a protective factor against poor prognosis (P<0.05). CONCLUSION: Memory therapy has been shown to promote postoperative cognitive function recovery in glioma patients, reduce anxiety and stress response, bolster coping mechanisms and health-promoting behavior, diminish cancer-related fatigue, and improve patient prognosis.

Design and analysis of unequal aperture off-axis optical integrator for solar simulators.

The unequal aperture off-axis optical integrator design method is proposed to improve the irradiation uniformity of solar simulators and solve the problem of limited uniformity of optical integrator due to aberrations and uneven distribution of incident radiation. Firstly, the unequal aperture off-axis optical integrator structure is designed based on the scalar diffraction theory to analyze the factors affecting the optical homogenization ability of the optical integrator. Then, the relationship between sub-eye lens aperture and arrangement is explored in combination with Lagrange invariance principle and semi-definite programming theory. Finally, the optimum off-axis amount of sub-eye lens with different ring band is determined from the perspective of geometric optics by using the aberration theory and following the principle of edge light, so as to improve the evenness of optical integrator. The design results are verified by the simulation analysis. The simulation results show that: In the picture plane of optical integrator, the irradiation non-uniformity in the ф 26 mm irradiation plane is 14.87%, which is better than 26.02% in the traditional optical integrator. At the same time, at the effective irradiated surface, the irradiation non-uniformity of 0.53% within the ф 300 mm reaches the irradiation standard of the class A + solar simulator, and the irradiance only decreases by 16.5% compared with the traditional optical integrator, which still meets the index requirement of a solar constant. The goal of improving the evenness of optical integrator is realized without greatly affecting irradiance and without introducing aspherical design.

Patient versus physician preferences for lipid-lowering drug therapy: A discrete choice experiment.

BACKGROUND: The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors offered dyslipidemia patients an alternative to statins for lipid-lowering treatment. Understanding patient and physician preferences for lipid-lowering drugs may promote shared decision-making and improve treatment outcomes. METHODS: This study utilized an online discrete choice experiment (DCE) to assess the relative importance (RI) of six attributes related to lipid-lowering drugs, including frequency of administration, mode of administration, reduction of low-density lipoprotein cholesterol (LDL-C) level, risk of myopathy, risk of liver damage, and out-of-pocket monthly cost. Respondents were recruited from dyslipidemia patients and cardiovascular physicians in China. A mixed logit model and latent class analysis were employed to estimate the preference coefficient, marginal willingness to pay (mWTP), and RI of attributes. Ethical approval has been obtained for this study. RESULTS: A total of 708 patients and 507 physicians participated in the survey. Patients prioritized the 'risk of liver damage' (RI = 23.6%) with 'mode of administration' (RI = 19.2%) and 'frequency of administration' (RI = 18.8%) following closely. Contrarily, physicians prioritized the 'reduction of LDL-C level' (RI = 33.5%), followed by 'risk of liver damage' (RI = 26.0%) and 'risk of myopathy' (RI = 16.1%). Patients placed a higher value on 'frequency of administration' (p < .001) and 'mode of administration' (p < .001) compared to physicians, while physicians valued 'reduction of LDL-C level' (p < .001) and 'risk of myopathy' (p = .012) more than patients. Physicians exhibited higher mWTP than patients for all attributes except frequency and mode of administration. The LCA revealed three distinct patient classes: focus on oral administration, focus on hepatic safety and frequency and focus on hepatic safety and cost. Likewise, three physician classes were identified: frequency-insensitive, efficacy-focused and safety-focused. CONCLUSIONS: The preferences for lipid-lowering drug therapy differed between patients and physicians in China. Physicians should take into account patients' preferences and provide personalized treatment when they formulate lipid-lowering treatment plans. PATIENT OR PUBLIC CONTRIBUTION: Patients participated in the questionnaire design process. They engaged in a focus group discussion to determine attributes and levels and also participated in a pilot survey to assess the comprehensibility of the questionnaires. Additionally, patients were involved in the DCE survey to express their preferences. The findings of patient preference for lipid-lowering drug therapy will promote shared decision-making and optimize the treatment regimen.

Assessing multidisciplinary follow-up pattern efficiency and cost in follow-up care for patients in cervical spondylosis surgery: a non-randomized controlled study.

Background: The use of multidisciplinary treatment programs in out-of-hospital healthcare is a new area of research. Little is known about the benefits of this method in the management of discharged patients undergoing cervical spondylosis surgery. Objective: This study aimed to explore the effect of a contracted-based, multidisciplinary follow-up plan in patients after cervical spondylosis surgery. Methods: This non-blinded non-randomized controlled study was conducted with 88 patients (44 in the intervention group, 44 in the control group). The clinical outcomes, including Neck Disability Index (NDI), pain score (VAS), Self-Efficacy for Managing Chronic Disease 6-item Scale (SECD-6), and 12-Item Short-Form Health Survey (SF-12) score were assessed at the time of discharge, 24-72 h, 1 month, and 3 months post-discharge. The complications, patient satisfaction, and economic indicators were assessed at the final follow-up (3 months). Results: Patients who received contracted follow-up showed greater improvement in neck dysfunction at 24-72 h, 1 month, and 3 months after discharge compared to those who received routine follow-up (p < 0.001). At 1 month after discharge, the intervention group exhibited better self-efficacy (p = 0.001) and quality of life (p < 0.001) than the control group, and these improvements lasted for 3 months. The intervention group reported lower pain scores at 24-72 h and 1 month (p = 0.008; p = 0.026) compared to the control group. The incidence of complications was significantly lower in the intervention group (11.4%) compared to the control group (40.9%). The total satisfaction score was significant difference between the two groups (p < 0.001). Additionally, the intervention group had lower direct medical costs (p < 0.001), direct non-medical costs (p = 0.035), and total costs (p = 0.04) compared to the control group. However, there was no statistically significant difference in indirect costs between the two groups (p = 0.59). Conclusion: A multidisciplinary contract follow-up plan has significant advantages regarding neck disability, self-efficacy, quality of life, postoperative complications, patient satisfaction, and direct costs compared with routine follow-up.

A rationally designed nuclei-targeting FAPI 04-based molecular probe with enhanced tumor uptake for PET/CT and fluorescence imaging.

PURPOSE: Fibroblast activation protein inhibitor (FAPI) -based probes have been widely studied in the diagnosis of various malignant tumors with positron emission tomography/computed tomography (PET/CT). However, current imaging studies of FAPI-based probes face challenges in rapid clearance rate and potential false-negative results. Furthermore, FAPI has been rarely explored in optical imaging. Considering this, further modifications are imperative to improve the properties of FAPI-based probes to address existing limitations and broaden their application scenarios. In this study, we rationally introduced methylene blue (MB) to FAPIs, thereby imparting nuclei-targeting and fluorescence imaging capabilities to the probes. Furthermore, we evaluated the added value of FAPI-based fluorescence imaging to traditional PET/CT, exploring the potential application of FAPI-based probes in intraoperative fluorescence imaging. METHODS: A new FAPI-based probe, namely NOTA-FAPI-MB, was designed for both PET/CT and fluorescence imaging by conjugation of MB. The targeting efficacy of the probe was evaluated on fibroblast activation protein (FAP)-transfected cell line and human primary cancer-associated fibroblasts (CAFs). Subsequently, PET/CT and fluorescence imaging were conducted on tumor-bearing mice. The tumor detection and boundary delineation were assessed by fluorescence imaging of tissues from hepatocellular carcinoma (HCC) patients. RESULTS: NOTA-FAPI-MB demonstrated exceptional targeting ability towards FAP-transfected cells and CAFs in comparison to NOTA-FAPI. This benefit arises from the cationic methylene blue (MB) affinity for anionic nucleic acids. PET/CT imaging of tumor-bearing mice revealed significantly higher tumor uptake of [18F]F-NOTA-FAPI-MB (standard uptake value of 2.20 ± 0.31) compared to [18F]F-FDG (standard uptake value of 1.66 ± 0.14). In vivo fluorescence imaging indicated prolonged retention at the tumor site, with retention lasting up to 24 h. In addition, the fluorescent probes enabled more precise lesion detection and tumor margin delineation than clinically used indocyanine green (ICG), achieving a 100.0% (6/6) tumor-positive rate for NOTA-FAPI-MB while 33.3% (2/6) for ICG. These findings highlighted the potential of NOTA-FAPI-MB in guiding intraoperative surgical procedures. CONCLUSIONS: The NOTA-FAPI-MB was successfully synthesized, in which FAPI and MB simultaneously contributed to the targeting effect. Notably, the nuclear delivery mechanism of the probes improved intracellular retention time and targeting efficacy, broadening the imaging time window for fluorescence imaging. In vivo PET/CT demonstrated favorable performance of NOTA-FAPI-MB compared to [18F]F-FDG. This study highlights the significance of fluorescence imaging as an adjunct technique to PET/CT. Furthermore, the encouraging results obtained from the imaging of human HCC tissues hold promise for the potential application of NOTA-FAPI-MB in intraoperative fluorescent surgery guidance within clinical settings.

Knowledge-Augmented Visual Question Answering With Natural Language Explanation.

Visual question answering with natural language explanation (VQA-NLE) is a challenging task that requires models to not only generate accurate answers but also to provide explanations that justify the relevant decision-making processes. This task is accomplished by generating natural language sentences based on the given question-image pair. However, existing methods often struggle to ensure consistency between the answers and explanations due to their disregard of the crucial interactions between these factors. Moreover, existing methods overlook the potential benefits of incorporating additional knowledge, which hinders their ability to effectively bridge the semantic gap between questions and images, leading to less accurate explanations. In this paper, we present a novel approach denoted the knowledge-based iterative consensus VQA-NLE (KICNLE) model to address these limitations. To maintain consistency, our model incorporates an iterative consensus generator that adopts a multi-iteration generative method, enabling multiple iterations of the answer and explanation in each generation. In each iteration, the current answer is utilized to generate an explanation, which in turn guides the generation of a new answer. Additionally, a knowledge retrieval module is introduced to provide potentially valid candidate knowledge, guide the generation process, effectively bridge the gap between questions and images, and enable the production of high-quality answer-explanation pairs. Extensive experiments conducted on three different datasets demonstrate the superiority of our proposed KICNLE model over competing state-of-the-art approaches. Our code is available at https://github.com/Gary-code/KICNLE.

Differential diagnosis of rare adrenal cellular schwannomas: A case report.

BACKGROUND: Adrenal cellular schwannomas are exceptionally rare stromal tumors that are often misdiagnosed due to the lack of specific radiological, serological, or clinical features. In this report, we describe the differential diagnosis of a rare adrenal cellular schwannoma. METHODS: A 69-year-old man with a history of persistent hypertension, chronic kidney disease, hypertensive heart disease, and cardiac insufficiency was hospitalized due to bilateral lower extremity edema lasting for 3 months. Plain computed tomography at that time revealed a space-occupying lesion in the right adrenal gland. As serum levels of catecholamines, cortisol, and adrenocorticotropic hormone were within normal ranges, the edema was attributed to the chronic kidney disease and cardiac insufficiency, and the patient was referred to our hospital for surgical treatment. Contrast-enhanced computed tomography revealed heterogeneous enhancement in the adrenal mass indicating pheochromocytoma. An irregularly shaped 5 cm mass with a complete capsule in the right adrenal gland was laparoscopically resected. The postoperative histopathological diagnosis was adrenal cellular schwannoma. RESULTS: The postoperative course was unremarkable and the tumor did not recur during 5 years of follow-up. CONCLUSION: Adrenal cellular schwannoma is a very rare tumor that is extremely difficult to preoperatively diagnose. Histological and immunohistochemical analyses are required for differential diagnosis and confirmation. Cellular schwannomas can transform into malignant peripheral nerve sheath tumors, but not often. Consequently, regular postoperative follow-up is required for such patients, especially imaging.