Bispectral EEG (BSEEG) Algorithm Captures High Mortality Risk Among 1,077 Patients: Its Relationship to Delirium Motor Subtype.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We found that the BSEEG method is capable of capturing patients at high mortality risk.

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.

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.

Milnacipran influences the indexes of I-metaiodobenzylguanidine scintigraphy in elderly depressed patients.

AIM: This study investigated whether or not and how much milnacipran influences the indexes of I-metaiodobenzylguanidine (I-MIBG) scintigraphy, early heart-to-mediastinum (H/M) ratio, delayed H/M ratio, and wash-out rate. METHODS: Six elderly depressed patients participated in the study. All six patients met the diagnostic criteria for a major depressive disorder. They were taking milnacipran for their depression. They needed differential diagnosis for Lewy body diseases due to their symptomatology. I-MIBG scintigraphy was performed twice for each subject, once under prescription of milnacipran and the other without prescription of milnacipran. RESULTS: Both early and delayed phase H/M ratio were significantly lower when taking milnacipran (early phase H/M ratio, P < 0.01, Cohen's d 1.62; delayed phase H/M ratio, P < 0.005, Cohen's d 1.98) than when not taking the drug. Wash-out rate (%) was significantly higher when taking milnacipran (P < 0.05, Cohen's d 2.31) than when off the drug. CONCLUSION: Taking milnacipran substantially influences the indexes of I-MIBG scintigraphy, indicating that taking the drug possibly causes a false-positive result for Lewy body diseases diagnosis.

Obsessive-compulsive disorder after traumatic injury to the right frontal and left temporal lobes: A case report.

Background: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder affecting many behaviors in daily life. Hyperactivity of the fronto-striato-thalamic circuit via the orbitofrontal cortex (OFC) is assumed to play a major role in the pathophysiology of OCD; however, its pathogenesis is not fully understood. Several reports have described the development of OCD after traumatic brain injury (TBI); however, the pathogenesis of post-TBI OCD remains unknown. Moreover, patients with TBI often have a variety of sequelae, including cognitive dysfunction and mood disorders, which make the diagnosis and treatment of OCD more complex. Case presentation: We report the case of a 17-year-old Japanese male who developed OCD after traffic trauma. The patient developed a fear of contamination and checking compulsion after injuring his right OFC and left temporal lobe when he ran into a running truck during a suicide attempt. We believe that the patient's fear of contamination can be diagnosed as true post-TBI OCD. However, his memory impairment was significant, and we considered his checking compulsion to be strongly influenced by cognitive dysfunction due to TBI. We attempted behavioral therapy for OCD; however, sufficient results were not achieved because of the interference from the sequelae of TBI. Conclusion: It is not rare for OCD symptoms to appear after TBI. Differentiating the OCD symptoms induced by brain injury or cognitive dysfunction associated with TBI is important to determine a treatment strategy.

Idiopathic basal ganglia calcification presenting with obsessive-compulsive symptoms: A case report.

Background: Idiopathic basal ganglia calcification (IBGC), also known as Farh's disease, is a rare neurodegenerative disorder characterized by calcification of the basal ganglia and other brain regions. This disease usually occurs in middle-aged patients and presents with various neurological and psychiatric symptoms. The exact prevalence is unknown; however, population genomic data analysis suggests a prevalence of at least 4.5/10,000 to 3.3/1000, indicating that the disease is more common than previously thought and remains underdiagnosed. Case Presentation: We report the case of a middle-aged Japanese man who attempted suicide twice because of obsessive-compulsive ideation caused by trivial triggers. The patient's psychiatric symptoms resolved relatively quickly after hospitalization, and imaging and genetic testing led to a diagnosis of IBGC. Conclusion: This case report illustrates the importance of including IBGC in the differential diagnosis of psychiatric symptoms that initially develop in middle-aged patients.

Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.

The Bispectral Electroencephalography Method Quantifies Postoperative Delirium-Like States in Young and Aged Male Mice After Head-Mount Implantation Surgery.

Delirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults, although there are few quantitative monitoring methods in the clinical setting. We developed a bispectral electroencephalography (BSEEG) method capable of detecting delirium and can quantify the severity of delirium using a novel algorithm. Preclinical application of this novel BSEEG method can capture a delirium-like state in mice following lipopolysaccharide administration. However, its application to postoperative delirium (POD) has not yet been validated in animal experiments. This study aimed to create a POD model in mice with the BSEEG method by monitoring BSEEG scores following EEG head-mount implantation surgery and throughout the recovery. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) male mice for quantitative evaluation of POD-like states. Postoperatively, both groups displayed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by postoperative day (PO-Day) 3. Conversely, aged mice exhibited prolonged increases in postoperative BSEEG scores and it reached steady states only after PO-Day 8. This study suggests that the BSEEG method can be utilized as a quantitative measure of POD and assess the effect of aging on recovery from POD in the preclinical model.

The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology.

AIM: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery. METHOD: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia. RESULT: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3. CONCLUSION: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD.

Epigenetic signals associated with delirium replicated across four independent cohorts.

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

Comparative efficacy and safety of suvorexant and lemborexant for insomnia treatment.

Aim: Although suvorexant and lemborexant, which have orexin receptor antagonist activity, are used as sleep medications in Japan, no report has directly compared their efficacy and safety. This study compared the efficacy and safety of the drugs. Methods: This retrospective cohort study included patients who presented to the Outpatient Department of Psychiatry at Tottori University Hospital between December 1, 2020, and December 31, 2021. Information was obtained from 108 patients who were newly treated with suvorexant or lemborexant. Data were analyzed after excluding one case of discontinuation due to a post-administration allergic reaction. Improvement in sleep status after administration was assessed retrospectively from medical records by using the Clinical Global Impressions-Improvement (CGI-I) Scale, which is a subscale of the Clinical Global Impressions (CGI) Scale. The incidence of side-effects was obtained from the medical records of the patient's first visit after administration. Results: There was no significant difference between the CGI-I scores in the suvorexant (mean [SD], 3.05 [0.93]) and lemborexant groups (mean [SD], 3.38 [0.83]) (p = 0.10). The incidence of side-effects with continued treatment was not significantly different between the suvorexant group (12.5%) and the lemborexant group (2.9%) (p = 0.10). Patients who switched from suvorexant to lemborexant had CGI-I scores ≤4, and no side-effects were observed after switching to lemborexant. Conclusion: There was no difference in effectiveness between suvorexant and lemborexant. However, lemborexant might cause side-effects less frequently than suvorexant, at least in the early stages of treatment.

Adequate diagnosis of the cause of Parkinsonism and treatment in an elderly patient with schizophrenia: A case report.

Background: Parkinsonism is frequently observed in patients with schizophrenia, and most patients are diagnosed with drug-induced parkinsonism. However, comorbidity with idiopathic Parkinson's disease or Parkinson-plus syndrome is also possible. The pathophysiology and treatment for each of these are entirely different, thus an appropriate diagnosis is required. However, distinguishing them based on clinical symptoms alone is often difficult, and many cases are misdiagnosed. Additionally, Parkinsonism is frequently mistaken for negative symptoms. Case Description: We report a case of 68-year-old woman diagnosed with schizophrenia, who was admitted to a welfare center. At approximately age 60, the patient experienced motivation reduction, a loss of appetite, and pain in the extremities. In her mid-60s, tremor and muscle rigidity appeared; nuclear medicine testing was performed for a detailed examination, resulting in a diagnosis of levodopa-responsive Parkinson's syndrome. Notably, the patient's parkinsonism and emotional symptoms, which had been considered negative symptoms thus far, improved with levodopa treatment. Conclusion: This case report illustrates the importance of properly diagnosing the cause of parkinsonism in patients with schizophrenia.

Trends and Characteristics of Suicide-Related Behaviors Before and After the COVID-19 Epidemic in Tottori, Japan: A Retrospective Study.

Background: In Japan, the number of suicides has increased since the coronavirus disease (COVID-19) epidemic. However, only a few studies have examined the trends among individuals who attempted suicide. In this study, we examined the background characteristics and motives of individuals who attempted suicide and visited the emergency room because of suicide-related behavior before and after the spread of COVID-19. Methods: This single-center retrospective observational study collected information from electronic medical records. We included patients who presented to the emergency department of Tottori University Hospital with suicide-related behaviors between May 1, 2017, to August 31, 2022. The period from May 1, 2017, through December 31, 2019, was designated as 'the period before COVID-19" (before-period), and that from January 1, 2020, through August 31, 2022, was designated as "the period after COVID-19" (after-period). We compared the total number of cases, their background, and motives for suicide-related behaviors between the before- and after-periods. Results: The total number of suicide events was 304. Of these, 182 and 122 occurred during the before-period and after-period, respectively. The incidence of the F3 category of the International Classification of Diseases, 10th Revision, increased, while that of the F4 and F6 categories decreased during the after-period. The proportion of suicide attempts due to health problems decreased and that of work problems increased during the after-period. Conclusion: The total number of suicide-related behaviors decreased after the COVID-19 pandemic. This may be because patients with psychiatric disorders other than depression and schizophrenia often engage in suicidal behavior through non-fatal methods, such as drug overdose and wrist-cutting, which may have led them to refrain from seeing a doctor. The proportion of suicidal motivation due to work-related fatigue has increased, perhaps because the quality and quantity of work changed significantly due to COVID-19.

A Prospective Randomized Study of the Herbal Medicine Yokukansan for Preventing Delirium After Gastrointestinal Cancer Surgery.

Background: Yokukansan, the Chinese Herbal Medicine, may be effective for treating postoperative delirium. However, there is no sufficient evidence supporting this notion. This study aimed to investigate whether yokukansan was effective for preventing delirium after gastrointestinal cancer surgery by the prospective randomized study. Methods: This was a double-blind, randomized, controlled trial. Patients aged 75 years or older who underwent surgery between May 2017 and December 2019 were randomized to the yokukansan or anchusan (another Herbal Medicine) group. They received treatments with oral intake of assigned medicine from the day before surgery until postoperative day 3. Then, the incidence of postoperative delirium was compared. A psychiatrist diagnosed patients with postoperative delirium. Results: Seventy-seven patients were enrolled in this study, and the full analysis set comprised 68 patients. In total, 25 of 68 (36.8%) patients presented with postoperative delirium. Specifically, 13 (37.1%) patients in the control group and 12 (36.4%) in the yokukansan group were diagnosed with postoperative delirium. However, the results did not differ significantly in both groups. Moreover, there was no remarkable difference in terms of delirium severity, and adverse events correlated with the medications were not observed. Conclusion: Yokukansan was ineffective in preventing delirium after gastrointestinal cancer surgery.

Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity.

BACKGROUND: Metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin's potential mechanism of action for longevity is through its epigenetic modifications. METHODS: To test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers. RESULTS: Enrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin's mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance (p < 5E-08). CONCLUSION: This study may elucidate metformin's potential role in longevity through epigenetic modifications and other possible mechanisms of action.

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.

Genome-wide DNA methylation analysis of post-operative delirium with brain, blood, saliva, and buccal samples from neurosurgery patients.

OBJECTIVE: No previous study demonstrates the difference in the genome-wide DNA methylation status of post-operative delirium (POD) using human brain tissue obtained from neurosurgery and multiple peripheral tissues such as blood, saliva, and buccal samples from the same individuals. We aimed to identify epigenetic marks of DNA methylation in the brain and peripheral tissues to elucidate the potential pathophysiological mechanism of POD. METHODS: The four tissue types (brain, blood, saliva, buccal) of DNA samples from up to 40 patients, including 11 POD cases, were analyzed using Illumina EPIC array. DNAm differences between patients with and without POD were examined. We also conducted enrichment analysis based on the top DNAm signals. RESULTS: The most different CpG site between control and POD was found at cg16526133 near the ADAMTS9 gene from the brain tissue(p = 8.66E-08). However, there are no CpG sites to reach the genome-wide significant level. The enrichment analysis based on the 1000 top hit CpG site (p < 0.05) on the four tissues showed several intriguing pathways. In the brain, there are pathways including "positive regulation of glial cell differentiation". Blood samples showed also pathways related to immune function. Besides, both saliva and the buccal sample showed pathways related to circadian rhythm, although these findings were not FDR significant. CONCLUSION: Enrichment analysis found several intriguing pathways related to potential delirium pathophysiology. Present data may further support the role of epigenetics, especially DNA methylation, in the molecular mechanisms of delirium pathogenesis.

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.

Stress increases blood beta-hydroxybutyrate levels and prefrontal cortex NLRP3 activity jointly in a rodent model.

AIM: This study aimed to assess the response of endogenous beta-hydroxybutyrate to psychological stress, and its association with nucleotide-binding domain, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome, and stress-induced behavior. METHODS: Male C57BL/6J mice were subjected to 1-hour restraint stress to examine changes in the endogenous beta-hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10-day social defeat stress to the male C57BL/6J mice. RESULTS: One-hour restraint stress rapidly increased beta-hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta-hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression- and anxiety-like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta-hydroxybutyrate levels. Among the social defeat model mice, those with high beta-hydroxybutyrate levels tended to have more depression- and anxiety-like behavior. CONCLUSIONS: The increased blood beta-hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta-hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta-hydroxybutyrate levels tend to exhibit increased depression- and anxiety-like behaviors; thus, an increase in blood beta-hydroxybutyrate levels due to stress may indicate stress vulnerability.