Aspirin Use and Risk of Alzheimer's Disease: A 2-Sample Mendelian Randomization Study.

BACKGROUND: Observational studies have shown inconsistent findings of the relationships between aspirin use and the risk of Alzheimer's disease (AD). OBJECTIVE: Since residual confounding and reverse causality were challenging issues inherent in observational studies, we conducted a 2-sample Mendelian randomization analysis (MR) to investigate whether aspirin use was causally associated with the risk of AD. METHODS: We conducted 2-sample MR analyses utilizing summary genetic association statistics to estimate the potential causal relationship between aspirin use and AD. Single-nucleotide variants associated with aspirin use in a genome-wide association study (GWAS) of UK Biobank were considered as genetic proxies for aspirin use. The GWAS summary-level data of AD were derived from a meta-analysis of GWAS data from the International Genomics of Alzheimer's Project (IGAP) stage I. RESULTS: Univariable MR analysis based on these two large GWAS data sources showed that genetically proxied aspirin use was associated with a decreased risk of AD (Odds Ratio (OR): 0.87; 95%CI: 0.77-0.99). In multivariate MR analyses, the causal estimates remained significant after adjusting for chronic pain, inflammation, heart failure (OR = 0.88, 95%CI = 0.78-0.98), or stroke (OR = 0.87, 95%CI = 0.77-0.99), but was attenuated when adjusting for coronary heart disease, blood pressure, and blood lipids. CONCLUSION: Findings from this MR analysis suggest a genetic protective effect of aspirin use on AD, possibly influenced by coronary heart disease, blood pressure, and lipid levels.

Ischemic stroke after COVID-19 bivalent vaccine administration in patients aged 65 years and older: analysis of nation-wide patient electronic health records in the United States.

Importance: The Centers for Disease Control and Prevention (CDC) announced in January 2023 that they were investigating a potential connection between administration of the Pfizer novel coronavirus disease-2019 (COVID-19) bivalent vaccine booster and ischemic stroke (IS). Objective: To explore the relationship between Pfizer bivalent booster administration and IS in older patients in the United States and compare it to other COVID-19 vaccines. Design: A retrospective cohort study was conducted to compare hazard of IS among patients aged 65 years or over who received the Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent COVID-19 booster vaccine 1-21 and 22-42 days after vaccination. Setting: Patient data were collected from TriNetX, a cloud-based analytics platform that includes electronic health record data from over 90 million unique patients in the United States. Participants: Patients in the United States aged 65 years or over at the time of administration of a Pfizer bivalent (n = 43,216), Moderna bivalent (n = 4,267), or Pfizer/Moderna monovalent (n = 100,583) booster were included for analysis. Cohorts were propensity-score matched by demographic factors and risk factors for IS and severe COVID-19. Exposures: Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent COVID-19 booster administration. Main outcomes: The hazard ratio (HR) and 95% confidence interval (CI) for IS in the cohorts at 1-21 and 22-42 days after administration. Results: After matching, the Pfizer bivalent cohort included 4,267 patients, with an average age of 73.7 years (44.43% male, 76.59% white). The Moderna bivalent cohort included 4,267 patients, with an average age of 74.0 years (44.08% male, 77.39% white). There was no significant difference in the hazard of IS encounters between the Pfizer bivalent versus Moderna bivalent cohorts at 1-21- or 22-42-days post-administration: HR = 0.59 (0.31, 1.11), 0.73 (0.33, 1.60). The hazard for IS was lower in the Pfizer bivalent cohort than in the Pfizer/Moderna monovalent cohort at both timepoints: HR = 0.24 (0.19, 0.29), 0.25 (0.20, 0.31). Conclusions and relevance: Older adults administered the Pfizer bivalent booster had similar hazard for IS encounters compared to those administered the Moderna bivalent booster vaccine, but lower hazard than those administered the Pfizer/Moderna monovalent boosters.

Ischemic stroke after COVID-19 bivalent vaccine administration in patients aged 65 years and older in the United States.

The Centers for Disease Control and Prevention announced in January 2023 a potential connection between administration of the Pfizer novel coronavirus disease-2019 (COVID-19) bivalent vaccine booster and ischemic stroke (IS). A retrospective cohort study was conducted to compare the hazard of IS in patients aged 65 years and over administered the Pfizer bivalent booster versus those administered the Pfizer/Moderna monovalent or Moderna bivalent boosters. De-identified patient electronic health data were collected from TriNetX, a cloud-based analytics platform that includes data from over 90 million unique patients in the United States. Patients aged 65 years and over at the time of administration of a Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent booster were included for analysis. Cohorts were propensity-score matched. The hazard ratios (HR) and 95% confidence intervals (CI) for IS between matched cohorts at 1-21 and 22-42 days after booster administration were calculated. There was reduced hazard of IS in the Pfizer bivalent cohort compared to the monovalent cohort at both timepoints: 1-21 days after vaccination (HR: 0.54, 95% CI: 0.47-0.62), and 22-42 days after vaccination (HR: 0.62, 95% CI: 0.54-0.72) (n = 79,036 patients per cohort). There was reduced hazard of IS in the Pfizer bivalent cohort compared to the Moderna bivalent cohort at 1-21 days after vaccination (HR: 0.75, 95% CI: 0.58-0.96) (n = 26,962 patients per cohort). This analysis provides no evidence that the Pfizer bivalent vaccine is associated with increased hazard of IS compared to the monovalent or Moderna bivalent vaccines.

Drug repurposing for reducing the risk of cataract extraction in patients with diabetes mellitus: integration of artificial intelligence-based drug prediction and clinical corroboration.

Diabetes mellitus (DM) increases the incidence of age-related cataracts. Currently, no medication is approved or known to delay clinical cataract progression. Using a novel approach based on AI, we searched for drugs with potential cataract surgery-suppressing effects. We developed a drug discovery strategy that combines AI-based potential candidate prediction among 2650 Food and Drug Administration (FDA)-approved drugs with clinical corroboration leveraging multicenter electronic health records (EHRs) of approximately 800,000 cataract patients from the TriNetX platform. Among the top-10 AI-predicted repurposed candidate drugs, we identified three DM diagnostic ICD code groups, such as cataract patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), or hyperglycemia, and conducted retrospective cohort analyses to evaluate the efficacy of these candidate drugs in reducing the risk of cataract extraction. Aspirin, melatonin, and ibuprofen were associated with a reduced 5-, 10-, and 20-year cataract extraction risk in all types of diabetes. Acetylcysteine was associated with a reduced 5-, 10-, and 20-year cataract extraction risk in T2DM and hyperglycemia but not in T1DM patient groups. The suppressive effects of aspirin, acetylcysteine, and ibuprofen waned over time, while those of melatonin became stronger in both genders. Thus, the four repositioned drugs have the potential to delay cataract progression in both genders. All four drugs share the ability to directly or indirectly inhibit cyclooxygenase-2 (COX-2), an enzyme that is increased by multiple cataractogenic stimuli.

Suicidal ideation and suicide attempt following ketamine prescription in patients with treatment-resistant depression: a nation-wide cohort study.

Ketamine, including esketamine, is an effective treatment for patients with treatment-resistant depression (TRD); however, its long-term efficacy in real-world populations remains poorly characterized. This is a retrospective cohort study using TriNetX US Collaborative Network, a platform aggregating electronic health records (EHRs) data from 93 million patients from 56 health care organizations in the US, and the study population includes 321,367 patients with a diagnosis of TRD who were prescribed relevant treatment in their EHRs. The prescription of ketamine (including esketamine) was associated with significant decreased risk of suicidal ideation compared to prescription of other common antidepressants: HR = 0.65 (95% CI: 0.53 - 0.81) at 1 day - 7 days, 0.78 (95% CI: 0.66 - 0.92) at 1 day - 30 days, 0.81 (95% CI: 0.70 - 0.92) at 1 day - 90 days, 0.82 (95% CI: 0.72 - 0.92) at 1 day - 180 days, and 0.83 (95% CI: 0.74 - 0.93) at 1 day - 270 days. This trend was especially robust among adults over 24 years of age, males, and White patients with TRD. No significant difference was observed for suicide attempts, except significantly increased risk for adolescents (aged 10-24) at 1 day - 30 days with HR = 2.22 (95% CI: 1.01-4.87). This study provides real-world evidence that ketamine has long-term benefits in mitigating suicidal ideation in patients with treatment-resistant depression. Future work should focus on optimizing dosage regimens for ketamine, understanding the mechanism, and the difference in various demographic subpopulations.

Area-level socioeconomic status is positively correlated with glioblastoma incidence and prognosis in the United States.

In the United States, an individual's access to resources, insurance status, and wealth are critical social determinants that affect both the risk and outcomes of many diseases. One disease for which the correlation with socioeconomic status (SES) is less well-characterized is glioblastoma (GBM), a devastating brain malignancy. The aim of this study was to review the current literature characterizing the relationship between area-level SES and both GBM incidence and prognosis in the United States. A query of multiple databases was performed to identify the existing data on SES and GBM incidence or prognosis. Papers were filtered by relevant terms and topics. A narrative review was then constructed to summarize the current body of knowledge on this topic. We obtained a total of three papers that analyze SES and GBM incidence, which all report a positive correlation between area-level SES and GBM incidence. In addition, we found 14 papers that focus on SES and GBM prognosis, either overall survival or GBM-specific survival. Those studies that analyze data from greater than 1,530 patients report a positive correlation between area-level SES and individual prognosis, while those with smaller study populations report no significant relationship. Our report underlines the strong association between SES and GBM incidence and highlights the need for large study populations to assess SES and GBM prognosis to ideally guide interventions that improve outcomes. Further studies are needed to determine underlying socio-economic stresses on GBM risk and outcomes to identify opportunities for intervention.

Repurposing ketamine to treat cocaine use disorder: integration of artificial intelligence-based prediction, expert evaluation, clinical corroboration and mechanism of action analyses.

BACKGROUND AND AIMS: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment. DESIGN: Our drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD. SETTING: The study utilized TriNetX to access EHRs from more than 90 million patients world-wide. Genetic- and functional-level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases. PARTICIPANTS: A total of 7742 CUD patients who received anesthesia (3871 ketamine-exposed and 3871 anesthetic-controlled) and 7910 CUD patients with depression (3955 ketamine-exposed and 3955 antidepressant-controlled) were identified after propensity score-matching. MEASUREMENTS: EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription. FINDINGS: Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42-2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling and cocaine abuse/dependence. CONCLUSIONS: Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder.

Association of Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study.

BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD. OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients. METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders. RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.81 [0.70,0.94], and 0.76 [0.70,0.92]. CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.

Potential effect of antidepressants on remission from cocaine use disorder - A nationwide matched retrospective cohort study.

BACKGROUND: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration-approved pharmacotherapy. Depressive disorders are common psychiatric comorbidity amongst individuals with CUD. METHODS: A retrospective cohort study was conducted among 161,544 patients diagnosed with CUD and depression to evaluate the effectiveness of 13 antidepressants on CUD remission. For any antidepressant found to be associated with CUD remission that had an additional indication, we conducted an additional analysis to evaluate the effectiveness of the candidate drug in patients with CUD with that indication. We then analyzed publicly genomic and functional databases to identify potential explanatory mechanisms of action of the candidate drug in the treatment of CUD. RESULTS: Among these antidepressants, bupropion was associated with higher rates of CUD remission compared to propensity-score matched patients prescribed other antidepressants: hazard ratio (HR) and 95% confidence interval (CI) 1.57 (95% CI: 1.27-1.94). Bupropion is also approved for smoking cessation. We identified CUD patients with co-occurring nicotine dependence and observed that patients prescribed bupropion displayed a higher rate of CUD remission compared to matched individuals prescribed other drugs for nicotine dependence: 1.38 (95% CI: 1.11-1.71). Genetic and functional analyses revealed that bupropion interacts with four protein-encoding genes (COMT, DRD2, SLC6A3, and SLC6A4) which are also associated with CUD and targets CUD-associated pathways including serotonergic synapses, cocaine addiction, and dopaminergic synapses. CONCLUSIONS: Our findings suggest that bupropion might be considered a treatment for improving CUD remission in patients with CUD and co-occurring depression or nicotine dependence.