Neurological and Psychiatric Adverse Events Associated with Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer Patients: Insights from a Pharmacovigilance Study via the FDA Adverse Event Reporting System.

BACKGROUND AND OBJECTIVE: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have revolutionised cancer therapy, particularly breast cancer therapy. However, concerns about their potential to cause neurological and psychiatric adverse events (AEs) have emerged, and these concerns remain underexplored. This study aimed to investigate the signals related to neurological and psychiatric AEs associated with CDK4/6 inhibitor use. METHODS: A retrospective study was performed to analyse reports of AEs associated with the use of CDK4/6 inhibitors (abemaciclib, ribociclib and palbociclib) from the first quarter of 2015 to the fourth quarter of 2023 on the basis of the FDA Adverse Event Reporting System (FAERS). Both the reporting odds ratio (ROR) and the multi-item gamma Poisson shrinker (MGPS) were used for signal detection. The timing of events was assessed with the Weibull shape parameter (WSP). The management, analysis and presentation of the data were performed via Python (version 3.8) and R software (version 4.3.2). RESULTS: A total of 19,001 AE reports in which CDK4/6 inhibitors were identified as the 'primary suspect drug' were included in this study. These events were predominantly observed in patients aged 65 to 85 years. Through an ROR analysis, 85 positive signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors were identified. The MGPS method revealed 61 positive AE signals for neurological and psychiatric AEs associated with CDK4/6 inhibitors. A total of 34 positive AE signals were identified by both the ROR and MGPS analyses. The WSP indicated that the onset times for AEs associated with all three CDK4/6 inhibitors tended to be early in drug therapy, suggesting a propensity for early failure type. CONCLUSION: The present study revealed neurological and psychiatric AEs associated with CDK4/6 inhibitors that often occur early in treatment. Significant signals include spinal cord herniation and cerebral microangiopathy. Close monitoring of these AEs is crucial. Further studies are necessary to verify the connection between CDK4/6 inhibitors and neurological and psychiatric AEs.

Reversing Metabolic Dysfunction-Associated Steatotic Liver Disease Promotes Healthy Pediatric Cardiovascular Structures: The PROC Study.

INTRODUCTION: We investigated the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on cardiovascular structure development in children. METHODS: We followed 1,356 children with the mean age of 6.6 years for 4.5 years in Beijing, China. We assessed the association of MASLD with cardiovascular structure (carotid intima-media thickness and left ventricular mass) outcomes at baseline and follow-up. RESULTS: Over follow-up, 59 children had persistent MASLD, 109 had incident MASLD (progression), and 35 had normalization of liver health. Children with MASLD normalization showed a significantly lower mean development in carotid intima-media thickness (0.161 vs 0.188 mm) and left ventricular mass (4.5 vs 12.4 g) than children with persistent MASLD. DISCUSSION: The control of MASLD was associated with improved cardiovascular structure development.

Validation of "Life's Essential 8" Metrics With Cardiovascular Structural Status in Children: The PROC Study in China.

Background Life's Essential 8 (LE8) metrics for cardiovascular health (CVH) aid primordial prevention in US populations. Methods and Results We conducted a child cohort study (PROC [Beijing Child Growth and Health Cohort]) with baseline (2018-2019) and follow-up (2020-2021) assessments, enrolling disease-free 6- to 10-year-old children from 6 elementary schools in Beijing. We collected LE8-assessed components via questionnaire surveys and 3 cardiovascular structural parameters by 2-dimensional M-mode echocardiography: left ventricular mass (LVM), LVM index, and carotid intima-media thickness. Compared with 1914 participants (mean age, 6.6 years) at baseline, we saw lower mean CVH scores at follow-up (n=1789; 8.5 years). Among LE8 components, diet presented the lowest perfect-score prevalence (5.1%). Only 18.6% of participants had physical activity ≥420 min/wk, 55.9% had nicotine exposure, and 25.2% had abnormal sleep duration. Prevalence of overweight/obesity was 26.8% at baseline and 38.2% at follow-up. We noted optimal blood lipid scores in 30.7%, while 12.9% of children had abnormal fasting glucose. Normal BP was 71.6% at baseline and 60.3% at follow-up. LVM (g), LVM index (g/m2.7), and carotid intima-media thickness (mm) were significantly lower in children with high (56.8, 33.2, 0.35) or moderate CVH scores (60.6, 34.6, 0.36), compared with children with low CVH scores (67.9, 37.1, 0.37). Adjusting for age/sex, LVM (ß=11.8 [95% CI, 3.5-20.0]; P=0.005), LVM index (ß=4.4 [95% CI, 0.5-8.3]; P=0.027), and carotid intima-media thickness (ß=0.016 [95% CI, 0.002-0.030]; P=0.028) were higher in the low-CVH group. Conclusions CVH scores were suboptimal, declining with age. LE8 metrics indicated worse CVH in children with abnormal cardiovascular structural measurements, suggesting the validity of LE8 in assessing child CVH. Registration URL: https://www.chictr.org.cn/index.html; Unique identifier: ChiCTR2100044027.

Discovery of 5-alkyl-2-pyrazol-oxazolidin-4-one derivatives as novel hepatitis B virus capsid assembly modulators.

The "magic methyl effect" strategy was used to design a series of 5-alkyl-2-pyrazol-oxazolidin-4-one derivatives as novel hepatitis B virus (HBV) capsid assembly modulators. Most of these compounds exhibited potent HBV inhibitory activities with low cytotoxicities in HepG2.2.15 cells. The most promising compounds 9d and 10b had single-digit nanomolar IC50 values with a high selectivity index. Compared with the lead compound (3.0%), they caused 15% and 18% decreases in HBe antigen secretion at 1.0 µM, respectively. In addition, compounds 9d and 10b possessed good pharmacokinetic profiles with oral bioavailability values of 56.1% and 48.9%, respectively. These results indicated that the two compounds were potential therapeutic agents for HBV infection.

Distinct hyperuricemia trajectories are associated with different risks of incident diabetes: A prospective cohort study.

BACKGROUND AND AIM: Conflicting results suggest a link between serum uric acid and diabetes and previous studies ignored the effect of continuous exposure of serum uric acid on diabetes risk. This study aims to characterize hyperuricemia trajectories in middle-aged adults and to examine its potential impact on diabetes risk, considering the role of obesity, dyslipidemia, and hypertension. METHODS AND RESULTS: The cohort included 9192 participants who were free of diabetes before 2013. The hyperuricemia trajectories during 2009-2013 were identified by latent class growth models. Incident diabetes during 2014-2018 was used as the outcome. Modified Poisson regression models were used to assess the association of trajectories with diabetes. Furthermore, marginal structural models were used to estimate the mediating effects of the relationship between hyperuricemia trajectories and diabetes. We identified three discrete hyperuricemia trajectories: high-increasing (n = 5794), moderate-stable (n = 2049), and low-stable (n = 1349). During 5 years of follow-up, we documented 379 incident diabetes cases. Compared with the low-stable pattern, the high-increasing pattern had a higher risk of developing diabetes (RR, 1.42; 95% CI: 1.09-1.84). In addition, the percentages of total effect between the high-increasing hyperuricemia pattern and diabetes mediated by obesity, dyslipidemia, and hypertension were 24.41%, 18.26%, and 6.29%. However, the moderate-stable pattern was not associated with an increased risk of diabetes. CONCLUSIONS: These results indicate that the high-increasing hyperuricemia trajectory is significantly associated with an increased risk of diabetes. Furthermore, obesity, dyslipidemia, and hypertension play mediating roles in the relationship between the high-increasing hyperuricemia pattern and increased diabetes risk.

Low expression of HIF1AN accompanied by less immune infiltration is associated with poor prognosis in breast cancer.

Background: Hypoxia-inducible factor 1-alpha (HIF-1α) stability and transcriptional action are reduced by the hypoxia-inducible factor 1-alpha subunit suppressor (HIF1AN). Its inappropriate expression is associated with the development of cancer and immune control. It is yet unknown how HIF1AN, clinical outcomes, and immune involvement in breast cancer (BC) are related. Methods: Using the GEPIA, UALCAN, TIMER, Kaplan-Meier plotter, and TISIDB datasets, a thorough analysis of HIF1AN differential expression, medical prognosis, and the relationship between HIF1AN and tumor-infiltrating immune cells in BC was conducted. Quantitative real-time PCR (qRT-PCR) analysis of BC cells were used for external validation. Results: The findings revealed that, as compared to standard specimens, BC cells had significantly lower levels of HIF1AN expression. Good overall survival (OS) for BC was associated with higher HIF1AN expression. Additionally, in BC, the expression of HIF1AN was closely associated with the chemokines and immune cell infiltration, including neutrophils, macrophages, T helper cells, B cells, Tregs, monocytes, dendritic cells, and NK cells. A high correlation between HIF1AN expression and several immunological indicators of T-cell exhaustion was particularly revealed by the bioinformatic study. Conclusions: HIF1AN is a predictive indicator for breast tumors, and it is useful for predicting survival rates.

Biologically Active 2-Oxazolidinone Derivatives Beyond Antibacterial Activities.

2-Oxazolidinone is well known as a pharmacophore for antibacterial agents represented by two marketed medicines, Linezolid and Tedizolid. On the other hand, there are growing reports on the various biological activities of 2-oxazolidinones beyond antibacterial activities. Therefore, in this review, we provide an overview of the progress of this untraditional area of 2-oxazolidinones in the past 10 years (2011-2021).

Predictors of Influenza Vaccination among Chinese Middle School Students Based on the Health Belief Model: A Mixed-Methods Study.

Influenza vaccination rates among Chinese middle school students are low. This study aims to explore the influencing factors of vaccination among middle school students and promote vaccination. We conducted a mixed-methods study, integrating a questionnaire survey among 9145 middle school students in four cities in China and semi-structured interviews with 35 middle school students to understand their attitudes and perceptions toward vaccination based on the Health Belief Model. We found the overall vaccination rate was 38.2% (3493/9145), with students in Beijing, boarding at school, or senior high school showing higher values than their counterparts (p < 0.05). Multiple logistic regression results showed that non-boarding (OR = 0.46, 95%CI: 0.42−0.51) and perceived barriers (OR = 0.97, 95%CI: 0.96−0.98) were unfavorable factors for influenza vaccination, whereas perceived susceptibility (OR = 1.07, 95%CI: 1.05−1.08), perceived benefits (OR = 1.02, 95%CI: 1.01−1.04), cues to action (OR = 1.08, 95%CI: 1.05−1.11), and self-efficacy (OR = 1.04, 95%CI: 1.02−1.07) were facilitators. Qualitative results indicated that positive health beliefs, school, and the home environment contribute to vaccination. In conclusion, the influenza vaccination rate among middle school students remains low. The concerns about the safety and potential side effects of vaccines are the main barriers to vaccination, underscoring the need for strengthening communication, education, and information among students and their teachers/parents.

Assessment of radiolucent lines in patients with lateral unicompartmental knee arthroplasty and the relationship between these lines and the outcome.

PURPOSE: To assess the radiolucent lines (RLLs) around both tibial and femoral components in patients following lateral unicompartmental knee arthroplasty (UKA). METHODS: We performed a retrospective review of the records of a consecutive series of patients who had undergone lateral UKA. The RLLs were assessed with standard anteroposterior and lateral radiographs post-operatively. The patient-reported outcome measures included the Hospital for Special Surgery (HSS) score and Oxford knee score (OKS). The femoral component position (FCP) and femoral-tibial angle (FTA) were also recorded. RESULTS: A total of 198 UKAs that had appropriate radiographs and outcome scores were reviewed with a median follow-up of 33 (range, 12-71) months. The results suggested that 69 cases (34.8%) had RLLs on the standard radiographs. The incidence rates of femoral and tibial physiological RLLs were 11.6% (23/198) and 26% (52/198), respectively, of which 3% (6/198) concerned both components. All RLLs were considered "physiologic lines" that developed within one year after surgery. There were no significant differences among the types of RLLs in any of the outcome measures. No differences in FCP (P = .359) or FTA (P = .111) at the last follow-up were seen. CONCLUSIONS: It was found that one-third of UKAs had RLLs on radiographs following lateral UKA. All RLLs developed within one year after surgery. As a clinical consequence, the development of RLLs does not affect the short-term outcomes after lateral UKA.

MicroRNA-377-3p alleviates IL-1ß-caused chondrocyte apoptosis and cartilage degradation in osteoarthritis in part by downregulating ITGA6.

Increasing evidence indicates that altered expression of microRNAs (miRNAs) is associated with osteoarthritis (OA) progression. In our study, we demonstrated that miR-377-3p is underexpressed in OA-affected cartilage and IL-1ß-treated chondrocytes. Overexpression of miR-377-3p enhanced chondrocyte proliferation and restrained apoptosis and signs of cartilage matrix degradation and of an inflammatory response. Furthermore, ITGA6 was identified as a target gene of miR-377-3p. The latter was found to directly bind to the 3' untranslated region (3'UTR) of ITGA6 mRNA and downregulate ITGA6. In addition, ITGA6 expression was high in OA-affected tissues and negatively correlated with miR-77-3p expression. Overexpression of ITGA6 reversed the effects of miR-377-3p on IL-1ß-caused chondrocyte apoptosis, cartilage matrix degradation, and the inflammatory response. Moreover, bioinformatic analysis and a luciferase assay indicated that miR-377-3p expression is regulated by long noncoding RNA NEAT1, which binds to miR-377-3p and inactivates it. We showed that NEAT1 was highly expressed in OA-affected cartilage, negatively correlated with miR-377-3p levels, and positively correlated with ITGA6 levels. These findings provide information for the development of future treatments of OA, suggesting that miR-377-3p may be a therapeutic target in OA.

miR-93-5p attenuates IL-1ß-induced chondrocyte apoptosis and cartilage degradation in osteoarthritis partially by targeting TCF4.

MicroRNAs (miRNAs, miRs) are frequently dysregulated in osteoarthritis (OA), but the role of specific miRNAs in OA remains unclear. In this study, we found that miR-93-5p is underexpressed in human and rat OA-affected cartilage (compared with normal cartilage) as well as in IL-1ß-treated chondrocytes. Overexpression of miR-93-5p promoted chondrocyte viability, suppressed chondrocyte apoptosis, and maintained the balance between anabolic and catabolic factors of the extracellular matrix in vitro. Similarly, injection of a miR-93-5p-expressing lentivirus alleviated the destruction of articular cartilage in a rat model of OA (anterior cruciate ligament transection). Furthermore, TCF4 was identified as a direct target gene of miR-93-5p. miR-93-5p directly targeted the 3' untranslated region (3'-UTR) of TCF4 mRNA and repressed TCF4 expression. Overexpression of TCF4 attenuated the effects of miR-93-5p on chondrocyte apoptosis and functions. Finally, analyses of miR-93-5p and TCF4 in OA-affected cartilage tissues revealed that miR-93-5p expression inversely correlated with TCF4 expression. Altogether, these findings indicate that miR-93-5p slows OA progression partially by suppressing TCF4 expression, and this phenomenon may provide novel insights into the function of miRNA in OA.