Exploring the Relationship Between Atorvastatin and Memory Loss: A Comprehensive Analysis Integrating Real-World Pharmacovigilance and Mendelian Randomization.

BACKGROUND AND OBJECTIVE: Atorvastatin is a drug widely used to prevent cardiovascular and cerebrovascular diseases. Current observational studies suggest that atorvastatin may be associated with cognitive dysfunction (especially memory loss). However, some studies have suggested that dyslipidemia may be an important factor in cognitive dysfunction. The purpose of this study was to perform a pharmacovigilance analysis using real-world data from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess whether memory loss is an adverse effect of atorvastatin and to further clarify its causality through Mendelian randomization (MR). METHODS: We extracted real-world data from the FAERS database (Quarter 1 2004 to Quarter 1 2023). Disproportionality analysis methods and measures of association such as the reporting odds ratio (OR), proportional reporting ratio, Bayesian confidence interval progressive neural network, and polynomial Gamma Poisson distribution reduction were used to assess whether memory loss was an adverse effect of atorvastatin. In addition, we used MR to evaluate causality in depth. RESULTS: In the pharmacovigilance analysis of atorvastatin, we extracted four datasets of clinical symptoms associated with memory loss from the FAERS database [Amnesia (n = 1196), Memory impairment (n = 840), Transient global amnesia (n = 38), and Retrograde amnesia (n = 9)]. The reporting OR, proportional reporting ratio, Bayesian confidence interval progressive neural network, and Gamma Poisson distribution reduction all showed positive results for amnesia, transient global amnesia, and retrograde amnesia, while the reporting OR and Bayesian confidence interval progressive neural network also showed positive results for memory disorders. Thus, memory loss was a frequent side effect of atorvastatin. The MR analyses were used to further evaluate the association between statins and memory loss. The results of the MR analysis (statins and memory loss) are as follows: Ivw (mre) (ß = 0.11 [OR = 1.11], P = 0.01 < 0.05) and the OR and ß directions of MR-Egger and weighted mode were the same. The results of the MR analysis (statins and mitochondrial DNA copy number) are as follows: Ivw(mre) (ß = -0.03 [OR = 0.96], P < 0.01) and the OR and ß direction of MR-Egger and weighted mode are the same. The results of the MR analysis (DNA copy number and memory loss) are as follows: Ivw(ß = - 0.06 [OR = 0.94], P = 0.04 < 0.05) and the OR and ß direction of MR-Egger and weighted mode were the same. The pleiotropy test did not find horizontal diversity in our results. CONCLUSIONS: This study suggests that memory loss is a notable adverse event associated with atorvastatin and provides evidence indicating a potential causal relationship between atorvastatin and memory loss. We also found that statins may further affect memory by affecting mitochondrial function. Therefore, in the clinical use of atorvastatin, it is important to carefully monitor the changes in cognitive function of patients. Second, a pharmacovigilance analysis combined with MR was used in this study to provide a new approach for the study of adverse drug reactions. This comprehensive analysis method helps to evaluate the safety of drugs and the risk of adverse reactions more comprehensively and provides doctors with a more accurate clinical decision-making basis.

Association between atorvastatin and erectile dysfunction: a comprehensive analysis incorporating real-world pharmacovigilance and Mendelian randomization.

Background: Atorvastatin is a commonly prescribed medication for the prevention of cardiovascular diseases. Recent observational studies have suggested a potential association between atorvastatin use and the occurrence of Erectile Dysfunction (ED). In this study, we aimed to explore the relationship between atorvastatin and ED using real-world data from the FAERS database and employed Mendelian randomization to assess causality. Methods: To evaluate the disproportionality of atorvastatin in relation to ED, we conducted several pharmacovigilance analyses, including odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence propagation neural network (BCPNN), and gamma-Poisson contractile apparatus (GPS). Additionally, we employed Mendelian randomization to investigate the causal relationship between atorvastatin and ED. Results: Pharmacovigilance disproportionality analysis revealed a significant association between atorvastatin and ED, as indicated by the following results: ROR [3.707078559, 95% CI (3.33250349, 4.123756054)], PRR [3.702969038, χ2 (669.2853829)], IC [1.870490139, IC025 (1.702813857)], and EBGM [3.656567867, EBGM05 (3.28709656)]. Furthermore, the two-sample Mendelian randomization analysis provided evidence supporting a causal relationship between atorvastatin use and ED, with an inverse variance weighted estimate of ß = 3.17 (OR = 23.91, p = 0.02 < 0.05). Conclusion: Based on comprehensive analyses incorporating pharmacovigilance and Mendelian randomization, our findings suggest that atorvastatin use is associated with an increased risk of ED and indicate a causal relationship. These results emphasize the importance of considering potential adverse effects, such as ED, when prescribing atorvastatin for cardiovascular disease prevention. Further research and clinical monitoring are warranted to better understand the underlying mechanisms and develop appropriate strategies to mitigate this side effect.

Association between Lipid-Lowering Drugs and Traumatic Subdural Hemorrhage: A Mendelian Randomization Study.

BACKGROUND: There are current clinical observations that atorvastatin may promote subdural hematoma resorption. We aimed to assess the causal effects of lipid-lowering agents 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, Proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors and Niemann-Pick C1-like protein 1 (NPC1L1) inhibitors on traumatic subdural hematomas. METHODS: We used genetic instruments to proxy lipid-lowering drug exposure, with genetic instruments being genetic variants within or near low-density lipoprotein (LDL cholesterol)-associated drug target genes. These were analyzed by using a two-sample Mendelian randomization (MR) study. RESULTS: A causal relationship was found between HMGCR inhibitors and traumatic subdural hematoma (Inverse variance weighted (ß = -0.7593341 (Odds Ratio (OR) = 0.4679779), p = 0.008366947 < 0.05)). However, no causal relationship was found between PCSK9 inhibitors and NPC1L1 inhibitors and traumatic subdural hematoma (PCSK9 inhibitors: Inverse variance weighted (ß = 0.23897796 (OR = 1.2699505), p = 0.1126327), NPC1L1 inhibitors: Inverse variance weighted (ß = -0.02118558 (OR = 0.9790373), p = 0.9701686)). Sensitivity analysis of the data revealed good stability of the results. CONCLUSIONS: This two-sample MR study suggests a potential causal relationship between HMGCR inhibition (atorvastatin) and traumatic subdural hemorrhage.

Mechanical stability of polarization signatures in biological tissue characterization.

Mueller matrix imaging polarimetry (MMIP) is a promising technique for investigating structural abnormalities in pathological diagnosis. The characterization stability of polarization signatures, described by Mueller matrix parameters (MMPs), correlates with the mechanical state of the biological medium. In this study, we developed an MMIP system capable of applying quantitative forces to samples and measuring the resulting polarization signatures. Mechanical stretching experiments were conducted on a mimicking phantom and a tissue sample at different force scales. We analyzed the textural features and data distribution of MMP images and evaluated the force effect on the characterization of MMPs using the structural similarity index. The results demonstrate that changes in the mechanical microenvironment (CMM) can cause textural fluctuations in MMP images, interfering with the stability of polarization signatures. Specifically, parameters of anisotropic orientation, retardance, and optical rotation are the most sensitive to CMM, inducing a dramatic change in the overall image texture, while other parameters (e.g., polarization, diattenuation, and depolarization) exhibit locality in their response to CMM. For some MMPs, CMM can enhance regional textural contrasts. This study elucidates the mechanical stability of polarization signatures in biological tissue characterization and provides a valuable reference for further research toward minimizing CMM influence.

Association of hemicolectomy with survival in stage II colorectal cancer: a retrospective cohort study.

To compare the oncological survival outcomes of partial colectomy (PC) and hemicolectomy (HC) in patients with stage II colon cancer. A total of 18,795 patients with stage II colon cancer who underwent hemicolectomy (n = 12,022) or partial colectomy (n = 6773) from 2010 to 2019 were included in the the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were compared between the two groups, and the threshold of harvested lymph nodes was determined. The results showed that age, gender, race, tumor site, scope of regional lymph nodes, postoperative chemotherapy, postoperative radiotherapy, harvested lymph nodes, and tumor size were significantly different between the PC and HC groups (all P < 0.05). The OS rate was slightly lower in hemicolectomy patients than in partial colectomy patients (69.9% vs. 74.5%, respectively, P < 0.001), but CSS was similar between the two groups (87.9% vs. 88.1%, respectively, P = 0.32). After propensity score matching (PSM) was performed, the OS and CSS rates in the two groups were significantly different (CSS 84.3% vs. 88.0%, P < 0.001; OS 62.2% vs. 72.5%, P < 0.001). The survminer R package determined that the optimum threshold for the harvested lymph node count in stage II colon cancer patients was 16. CSS was significantly different between patients with ≥ 12 lymph nodes harvested and patients with ≥ 16 lymph nodes harvested (P = 0.043). Univariate and multivariate Cox regression and survival analyses of stage II colon cancer patients showed that the survival benefit of stage II colon cancer patients receiving partial colectomy was superior to that of patients receiving hemicolectomy. Partial colectomy has significant oncological benefits over hemicolectomy in the treatment of stage II colon cancer patients, even in the case of pT4b or tumor deposits. Removal of 16 lymph nodes during colectomy for stage II colon cancer correlated with improved survival, and this threshold was more effective than the standard threshold of 12 lymph nodes in distinguishing between patients with good and poor prognoses.

Polarization clustering of biological structures with Mueller matrix parameters.

Mueller matrix imaging polarimetry (MMIP) is a promising technique for the characterization of biological tissues, including the classification of microstructures in pathological diagnosis. To expand the parameter space of Mueller matrix parameters, we propose new vector parameters (VPs) according to the Mueller matrix polar decomposition method. We measure invasive bladder cancer (IBC) with extensive necrosis and high-grade ductal carcinoma in situ (DCIS) with MMIP, and the regions of cancer cells and fibrotic stroma are classified with the VPs. Then the proposed and existing VPs are mapped on the Poincaré sphere with 3D visualization, and an indicator of spatial feature is defined based on the minimum enclosing sphere to evaluate the classification capability of the VPs. For both IBC and DCIS, the results show that the proposed VPs exhibit evident contrast between the regions of cancer cells and fibrotic stroma. This study broadens the fundamental Mueller matrix parameters and helps to improve the characterization ability of the MMIP technique.

Study of the spatial scale stability of Mueller matrix parameters for textural characterization of biological tissues.

Mueller matrix imaging polarimetry (MMIP) is a promising technique for the textural characterization of biological tissue structures. To reveal the influence of imaging magnification on the robustness of Mueller matrix parameters (MMPs), the spatial scale stability of MMPs was studied. We established a new MMIP detector and derived the mathematical model of the spatial scale stability of MMPs. The biological tissues with well-defined structural components were imaged under different magnifications. Then, we compared and analyzed the textural features of the MMPs in the resulting images. The experimental results match the predictions of the mathematical model in these aspects: (a) magnification exhibits a strong nonlinear effect on the textural contrasts of MMPs images; (b) higher magnification does not necessarily lead to superior contrast for textural characterization; and (c) for different biological tissues, MMPs contrasts can be optimized differently, with some showing superior results. This study provides a reference for the experimental design and operation of the MMIP technique and is helpful for improving the characterization ability of MMPs.

Protective Effect of Retrograde Reperfusion Against Hepatic Autophagy Impairment in Rat Liver Transplantation.

The retrograde reperfusion (RTR) technique was introduced in orthotopic liver transplantation (OLT) to improve initial postoperative liver function, but the related mechanisms remain unexplained. We investigated the influences of different reperfusion sequences, including initial portal reperfusion (IPR) and RTR, on hepatic ischemia/reperfusion (I/R) injury and autophagic activity in a simplified rat orthotopic liver transplantation (ROLT) model. METHODS: First, we established an ROLT model of male Sprague-Dawley rats to simulate either the IPR or RTR technique. The operative times and survival rates until postoperative day (POD) 7 were recorded. Liver enzyme levels, histologic damage, and in situ apoptosis were assessed. Second, we evaluated differences in the autophagic flux of liver grafts at 1, 2, and 6 hours after reperfusion between the IPR and RTR techniques. All experimental procedures involving animals were approved by the Institutional Animal Ethics Committee of the 900th Hospital of PLA. RESULTS: In the first experiment, all animals survived to POD 7. In contrast to the IPR sequence, the RTR technique decreased the extent of graft I/R injury. In the second experiment, reperfusion markedly impaired the autophagic flux of ischemic liver grafts, but the RTR technique could alleviate and postpone the reduction in autophagy after I/R. CONCLUSIONS: A feasible modified ROLT model with the cuff method was described and could flexibly simulate 2 reperfusion techniques: IPR and RTR. The use of the RTR sequence exhibited a protective effect against I/R injury and impairment of autophagy in liver grafts.

Glycochenodeoxycholic acid impairs transcription factor E3 -dependent autophagy-lysosome machinery by disrupting reactive oxygen species homeostasis in L02 cells.

Cholestasis represents pathophysiologic syndromes defined as impaired bile flow from the liver. As an outcome, bile acids accumulate and promote hepatocyte injury, followed by liver cirrhosis and liver failure. Glycochenodeoxycholic acid (GCDCA) is relatively toxic and highly concentrated in bile and serum after cholestasis. However, the mechanism underlying GCDCA-induced hepatotoxicity remains unclear. In this study, we found that GCDCA inhibits autophagosome formation and impairs lysosomal function by inhibiting lysosomal proteolysis and increasing lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to the death of L02 human hepatocyte cells. Notably, through tandem mass tag (TMT)-based quantitative proteomic analysis and database searches, 313 differentially expressed proteins were identified, of which 71 were increased and 242 were decreased in the GCDCA group compared with those in the control group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GCDCA suppressed the signaling pathway of transcription factor E3 (TFE3), which was the most closely associated with autophagic flux impairment. In contrast, GCDCA-inhibited lysosomal function and autophagic flux were efficiently attenuated by TFE3 overexpression. Specifically, the decreased expression of TFE3 was closely related to the disruption of reactive oxygen species (ROS) homeostasis, which could be prevented by inhibiting intracellular ROS with N-acetyl cysteine (NAC). In summary, our study is the first to demonstrate that manipulation of ROS/TFE3 signaling may be a therapeutic approach for antagonizing GCDCA-induced hepatotoxicity.

Nonlinear Ion Harmonics in the Paul Trap with Added Octopole Field: Theoretical Characterization and New Insight into Nonlinear Resonance Effect.

The nonlinear harmonics within the ion motion are the fingerprint of the nonlinear fields. They are exclusively introduced by these nonlinear fields and are responsible to some specific nonlinear effects such as nonlinear resonance effect. In this article, the ion motion in the quadrupole field with a weak superimposed octopole component, described by the nonlinear Mathieu equation (NME), was studied by using the analytical harmonic balance (HB) method. Good accuracy of the HB method, which was comparable with that of the numerical fourth-order Runge-Kutta (4th RK), was achieved in the entire first stability region, except for the points at the stability boundary (i.e., ß = 1) and at the nonlinear resonance condition (i.e., ß = 0.5). Using the HB method, the nonlinear 3ß harmonic series introduced by the octopole component and the resultant nonlinear resonance effect were characterized. At nonlinear resonance, obvious resonant peaks were observed in the nonlinear 3ß series of ion motion, but were not found in the natural harmonics. In addition, both resonant excitation and absorption peaks could be observed, simultaneously. These are two unique features of the nonlinear resonance, distinguishing it from the normal resonance. Finally, an approximation equation was given to describe the corresponding working parameter, q nr , at nonlinear resonance. This equation can help avoid the sensitivity degradation due to the operation of ion traps at the nonlinear resonance condition.

A Theoretical Method for Characterizing Nonlinear Effects in Paul Traps with Added Octopole Field.

In comparison with numerical methods, theoretical characterizations of ion motion in the nonlinear Paul traps always suffer from low accuracy and little applicability. To overcome the difficulties, the theoretical harmonic balance (HB) method was developed, and was validated by the numerical fourth-order Runge-Kutta (4th RK) method. Using the HB method, analytical ion trajectory and ion motion frequency in the superimposed octopole field, ε, were obtained by solving the nonlinear Mathieu equation (NME). The obtained accuracy of the HB method was comparable with that of the 4th RK method at the Mathieu parameter, q = 0.6, and the applicable q values could be extended to the entire first stability region with satisfactory accuracy. Two sorts of nonlinear effects of ion motion were studied, including ion frequency shift, Δß, and ion amplitude variation, Δ(C(2n)/C0) (n ≠ 0). New phenomena regarding Δß were observed, although extensive studies have been performed based on the pseudo-potential well (PW) model. For instance, the |Δß| at ε = 0.1 and ε = -0.1 were found to be different, but they were the same in the PW model. This is the first time the nonlinear effects regarding Δ(C(2n)/C0) (n ≠ 0) are studied, and the associated study has been a challenge for both theoretical and numerical methods. The nonlinear effects of Δ(C(2n)/C0) (n ≠ 0) and Δß were found to share some similarities at q < 0.6: both of them were proportional to ε, and the square of the initial ion displacement, z(0)(2).

Plasma-based ambient sampling/ionization/transmission integrated source for mass spectrometry.

Better sensitivity and interface of ambient sampling/ionization mass spectrometry remain a challenge. Herein, a novel, plasma-based, ambient sampling/ionization/transmission (PASIT) integrated source in a pin-to-funnel configuration was developed for the sensitive analysis of complex samples. With the funnel sleeve directly affected by direct-current discharge plasma, PASIT combines the ability to sample/ionize analyte molecules and then efficiently collect/transport charged mass species under atmospheric pressure and consequently shows an improved sensitivity. The integrated source enhances the signal intensity by more than 2 orders of magnitude compared with the previous pin-to-plate plasma source without significant background addition. A surface limit of detection (LOD) of 130 fmol mm-(2) (S/N = 3) has been achieved for clenbuterol on filter paper with an argon carrier gas. Demonstrated applications include the direct determination of active ingredients from drugs and symbolic compounds from natural plants and cholesterol from mouse brain tissue sections.