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 genome-wide DNA methylation profiles among neurosurgery patients with and without post-operative delirium.

AIMS: There is no previous study demonstrating the differences of genome-wide DNA methylation (DNAm) profiles between patients with and without postoperative delirium (POD). We aimed to discover epigenetic (DNAm) markers that are associated with POD in blood obtained from patients before and after neurosurgery. METHODS: Pre- and post-surgical blood DNA samples from 37 patients, including 10 POD cases, were analyzed using the Illumina EPIC array genome-wide platform. We examined DNAm differences in blood from patients with and without POD. Enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also conducted. RESULTS: When POD cases were tested for DNAm change before and after surgery, enrichment analyses showed many relevant signals with statistical significance in immune response related-pathways and inflammatory cytokine related-pathways such as "cellular response to cytokine stimulus", "regulation of immune system process", "regulation of cell activation", and "regulation of cytokine production". Furthermore, after excluding the potential effect of common factors related to surgery and anesthesia between POD cases and non-POD controls, the enrichment analyses showed significant signals such as "immune response" and "T cell activation", which are same pathways previously identified from an independent non-surgical inpatient cohort. CONCLUSIONS: Our first genome-wide DNAm investigation of POD showed promising signals related to immune response, inflammatory response and other relevant signals considered to be associated with delirium pathophysiology. Our data supports the hypothesis that epigenetics play an important role in the pathophysiological mechanism of delirium and suggest the potential usefulness of an epigenetics-based biomarker of POD.

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.

Mortality among patients with sepsis associated with a bispectral electroencephalography (BSEEG) score.

We have previously developed a bispectral electroencephalography (BSEEG) device, which was shown to be effective in detecting delirium and predicting patient outcomes. In this study we aimed to apply the BSEEG approach for a sepsis. This was a retrospective cohort study conducted at a single center. Sepsis-positive cases were identified based on retrospective chart review. EEG raw data and calculated BSEEG scores were obtained in the previous studies. The relationship between BSEEG scores and sepsis was analyzed, as well as the relationship among sepsis, BSEEG score, and mortality. Data were analyzed from 628 patients. The BSEEG score from the first encounter (1st BSEEG) showed a significant difference between patients with and without sepsis (p = 0.0062), although AUC was very small indicating that it is not suitable for detection purpose. Sepsis patients with high BSEEG scores showed the highest mortality, and non-sepsis patients with low BSEEG scores showed the lowest mortality. Mortality of non-sepsis patients with high BSEEG scores was as bad as that of sepsis patients with low BSEEG scores. Even adjusting for age, gender, comorbidity, and sepsis status, BSEEG remained a significant predictor of mortality (p = 0.008). These data are demonstrating its usefulness as a potential tool for identification of patients at high risk and management of sepsis.

DNA methylation in the TNF-alpha gene decreases along with aging among delirium inpatients.

It has been suggested that aging and inflammation play key roles in the development of delirium. In the present study, we investigated the differences of the DNAm patterns in the TNF gene between patients with delirium and without. The data and samples derived from previous and ongoing cohort studies were analyzed. DNAm levels of the TNF gene were analyzed using the Illumina EPIC array genome-wide method and pyrosequencing method. Correlations between age and DNAm levels of each CpG were calculated. Several CpG in the TNF gene in blood showed negative correlation between their DNAm and age in delirium cases both with the EPIC array and by the pyrosequencing method. However, there was no CpG that had significant correlation between their DNAm and age regardless of delirium status among buccal samples. On the other hand, among peripheral blood mononuclear cells samples, it was found that several CpG showed negative correlation between their DNAm and age in delirium cases. The evidence of DNAm change in the TNF gene among delirious subjects was demonstrated.

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.

New Cutoff Scores for Delirium Screening Tools to Predict Patient Mortality.

BACKGROUND/OBJECTIVES: Detecting delirium is important to identify patients with a high risk of poor outcomes. Although many different kinds of screening instruments for delirium exist, there is no solid consensus about which methods are the most effective. In addition, it is important to find the most useful tools in predicting outcomes such as mortality. DESIGN: Retrospective cohort study. SETTING: University of Iowa Hospitals and Clinics. PARTICIPANTS: A total of 1,125 adult inpatients (mean age = 67.7; median age = 69). MEASUREMENTS: Post hoc analyses were performed based on existing data from the Confusion Assessment Method for Intensive Care Unit (CAM-ICU), Delirium Rating Scale-Revised-98 (DRS), and the Delirium Observation Screening Scale (DOSS). Correlation among these scales and relationships between 365-day mortality and each scale were evaluated. RESULTS: A positive result on the CAM-ICU ("CAM-ICU positive") was associated with higher DRS and DOSS scores. A DRS score = 9/10 was the best cutoff to detect CAM-ICU positive, and DOSS = 2/3 was the best cutoff to detect CAM-ICU positive. CAM-ICU positive was associated with high 365-day mortality. DRS score = 9/10 and DOSS score = 0/1 were found to differentiate mortality risk the most significantly. Higher DRS and DOSS scores significantly coincided with a decrease in a patient's survival rate at 365 days. CONCLUSION: The best DRS and DOSS cutoff scores to differentiate 365-day mortality risk were lower than those commonly used to detect delirium in the literature. New cutoff scores for the DRS and DOSS might be useful in differentiating risk of mortality among hospital patients.

The Role of Nurses in Primary Care: Managing Alcohol-Abusing Patients.

Nurses work on the front lines of primary health care delivery in many settings. The unique characteristics of nursing care put nurses in an excellent position to identify, assess, counsel, and monitor clients with alcohol problems.