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• What is the primary question addressed by this study? Can the bispectral EEG (BSEEG) method predict patient mortality regardless of age, delirium motor subtype, and device type? • What is the main finding of this study? The BSEEG score measured early in the hospitalization was shown to be capable of capturing high mortality risk among patients. • What is the meaning of the finding? The BSEEG method has a potential to be useful in identifying patients at high risk for poor outcomes with the objective scoring by a simple, easy to use, point-of-care device. : Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes. : We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups. : A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16–1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06–1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12–1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05–1.67], which remained significant after adjustment for the same covariates. : We found that the BSEEG method is capable of capturing patients at high mortality risk. [ABSTRACT FROM AUTHOR]

We previously reported the association between DNA methylation (DNAm) of pro-inflammatory cytokine genes and age. In addition, neurotrophic factors are known to be associated with age and neurocognitive disorders. Therefore, we hypothesized that DNAm of neurotrophic genes change with age, especially in delirium patients. DNAm was analyzed using the Illumina HumanMethylation450 or HumanMethylationEPIC BeadChip Kit in 3 independent cohorts: blood from 383 Grady Trauma Project subjects, brain from 21 neurosurgery patients, and blood from 87 inpatients with and without delirium. Both blood and brain samples showed that most of the DNAm of neurotrophic genes were positively correlated with age. Furthermore, DNAm of neurotrophic genes was more positively correlated with age in delirium cases than in non-delirium controls. These findings support our hypothesis that the neurotrophic genes may be epigenetically modulated with age, and this process may be contributing to the pathophysiology of delirium. • Neurotrophic genes' DNAm were positively correlated with age in blood and brain. • Neurotrophic genes' DNAm were positively correlated with age in delirious patients. • Neurotrophic genes may be modulated with aging epigenetically. [ABSTRACT FROM AUTHOR]

Previously our study has shown that the DNA methylation (DNAm) levels at CpG sites in the pro-inflammatory cytokine gene, TNF-alpha , decrease along with aging, suggesting the potential role of DNAm in aging and heightened inflammatory process leading to increased risk for delirium. However, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, we examined genome-wide DNAm differences in blood between patients with delirium and controls to identify useful epigenetic biomarkers for delirium. Data from a total of 87 subjects (43 delirium cases) were analyzed by a genome-wide DNAm case-control association study. A genome-wide significant CpG site near the gene of LDLRAD4 was identified (p = 5.07E-8). In addition, over-representation analysis showed several significant pathways with a false discovery rate adjusted p -value < 0.05. The top pathway with a Gene Ontology term was immune response, and the second top pathway with a Kyoto Encyclopedia of Genes and Genomes term was cholinergic synapse. Significant DNAm differences related to immune/inflammatory response were shown both at gene and pathway levels between patients with delirium and non-delirium controls. This finding indicates that DNAm status in blood has the potential to be used as epigenetic biomarkers for delirium. • A genome-wide significant CpG site near the gene of LDLRAD4 was identified from the genome-wide DNAm investigation of delirium. • Several significant pathways related to immune/inflammatory response/cholinergic function were identified. • DNA methylation status in blood may be used as epigenetic biomarkers for delirium. [ABSTRACT FROM AUTHOR]

To investigate the relationship between history of anti-inflammatory medication use and delirium risk, as well as long-term mortality. 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. 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]). 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. • History of NSAIDs use was associated with decreased delirium risk and mortality. • It might be possible that NSAIDs has benefits for patients to prevent delirium and decrease mortality. • Subjects with a history of glucosamine use had lower prevalence of delirium. [ABSTRACT FROM AUTHOR]