NSAIDs use history: impact on the genome-wide DNA methylation profile and possible mechanisms of action.

BACKGROUND AND OBJECTIVE: NSAIDs inhibit cyclooxygenase, but their role in aging and other diseases is not well understood. Our group previously showed the potential benefit of NSAIDs in decreasing the risk of delirium and mortality. Concurrently, epigenetics signals have also been associated with delirium. Therefore, we sought to find differentially methylated genes and biological pathways related to exposure with NSAIDs by comparing the genome-wide DNA methylation profiles of patients with and without a history of NSAIDs use. METHODS: Whole blood samples were collected from 171 patients at the University of Iowa Hospital and Clinics from November 2017 to March 2020. History of NSAIDs use was assessed through a word-search function in the subjects' electronic medical records. DNA was extracted from the blood samples, processed with bisulfite conversion, and analyzed using Illumina's EPIC array. The analysis of top differentially methylated CpG sites and subsequent enrichment analysis were conducted using an established pipeline using R statistical software. RESULTS: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) showed several biological pathways relevant to NSAIDs' function. The identified GO terms included "arachidonic acid metabolic process," while KEGG results included "linoleic acid metabolism," "cellular senescence," and "circadian rhythm." Nonetheless, none of the top GO and KEGG pathways and the top differentially methylated CpG sites reached statistical significance. CONCLUSION: Our results suggest a potential role of epigenetics in the mechanisms of the action of NSAIDs. However, the results should be viewed with caution as exploratory and hypothesis-generating given the lack of statistically significant findings.

Anti-inflammatory medication use associated with reduced delirium risk and all-cause mortality: A retrospective cohort study.

OBJECTIVE: To investigate the relationship between history of anti-inflammatory medication use and delirium risk, as well as long-term mortality. METHODS: In this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Information about anti-inflammatory medication use history including aspirin, NSAIDs, glucosamine, and other anti-inflammatory drugs, was collected. Logistic regression analysis investigated the relationship between anti-inflammatory medications and delirium. Log-rank analysis and cox proportional hazards model investigated the relationship between anti-inflammatory medications and one-year mortality. RESULTS: The data from 1274 subjects were analyzed. The prevalence of delirium was significantly lower in subjects with NSAIDs usage (23.0%) than in those without NSAIDs usage (35.0%) (p < 0.001). Logistic regression analysis controlling for age, sex, dementia status, and hospitalization department showed that the risk of delirium tended to be reduced by a history of NSAIDs use (OR, 0.76 [95% CI, 0.55 to 1.03]). The one-year mortality in the subjects with NSAIDs (survival rate, 0.879 [95% CI, 0.845 to 0.906]) was significantly lower than in the subjects without NSAIDs (survival rate, 0.776 [95% CI, 0.746 to 0.803]) (p < 0.001). A history of NSAIDs use associated with the decreased risk of one-year mortality even after adjustment for age, sex, Charlson Comorbidity Index, delirium status, and hospitalization department (HR, 0.70 [95% CI, 0.51 to 0.96]). CONCLUSION: This study suggested that NSAIDs usage was associated with decreased delirium prevalence and lower one-year mortality. The potential benefit of NSAIDs on delirium risk and mortality were shown.

The potential benefit of metformin to reduce delirium risk and mortality: a retrospective cohort study.

PURPOSE: Metformin has been reported to improve age-related disorders, including dementia, and to lower mortality. This study was conducted to investigate whether metformin use lower delirium risk, as well as long-term mortality. METHODS: In this retrospective cohort study, previously recruited 1,404 subjects were analyzed. The relationship between metformin use and delirium, and the relationship between metformin use and 3-year mortality were investigated. MAIN FINDINGS: 242 subjects were categorized into a type 2 diabetes mellitus (DM)-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for confounding factors. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for confounding factors (HR, 0.69 [95% CI, 0.48 to 0.98]). CONCLUSIONS: Metformin use may lower the risk of delirium and mortality in DM patients.

Evaluation of point-of-care thumb-size bispectral electroencephalography device to quantify delirium severity and predict mortality.

BACKGROUND: We have developed the bispectral electroencephalography (BSEEG) method for detection of delirium and prediction of poor outcomes. AIMS: To improve the BSEEG method by introducing a new EEG device. METHOD: In a prospective cohort study, EEG data were obtained and BSEEG scores were calculated. BSEEG scores were filtered on the basis of standard deviation (s.d.) values to exclude signals with high noise. Both non-filtered and s.d.-filtered BSEEG scores were analysed. BSEEG scores were compared with the results of three delirium screening scales: the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Delirium Rating Scale-Revised-98 (DRS) and the Delirium Observation Screening Scale (DOSS). Additionally, the 365-day mortalities and the length of stay (LOS) in the hospital were analysed. RESULTS: We enrolled 279 elderly participants and obtained 620 BSEEG recordings; 142 participants were categorised as BSEEG-positive, reflecting slower EEG activity. BSEEG scores were higher in the CAM-ICU-positive group than in the CAM-ICU-negative group. There were significant correlations between BSEEG scores and scores on the DRS and the DOSS. The mortality rate of the BSEEG-positive group was significantly higher than that of the BSEEG-negative group. The LOS of the BSEEG-positive group was longer compared with that of the BSEEG-negative group. BSEEG scores after s.d. filtering showed stronger correlations with delirium screening scores and more significant prediction of mortality. CONCLUSIONS: We confirmed the usefulness of the BSEEG method for detection of delirium and of delirium severity, and prediction of patient outcomes with a new EEG device.