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.

Feasibility and Clinical Significance of In Vivo Cholesterol Crystal Detection Using Optical Coherence Tomography.

OBJECTIVE: Cholesterol crystals (CCs) are frequently found at the site of acute myocardial infarctions (AMIs), but the role of CCs in the onset of AMI remains unclear due to the lack of validated in vivo imaging tools. The aim of this study was to validate the ability of optical coherence tomography (OCT) to detect CCs and to compare the prevalence and distribution of CCs in patients with AMIs and stable angina pectoris. Approach and Results: CC assessment using OCT were compared with histopathology results in 45 coronary samples. We investigated 152 consecutive patients with AMIs and 41 patients with single vessel-diseased stable angina pectoris. Based on the presence of plaque ruptures (PR), AMI patients were divided into 2 groups: those with PR (n=112) and those without PR (n=40). CCs invading fibrous caps were defined as superficial-type CCs. A multivariable logistic regression analysis was performed to determine PR predictors. The sensitivity and specificity of OCT for detecting CCs were 68% and 92%, respectively. The prevalence of plaques with CCs was higher in the AMI with PR group (AMI with PR 81%, AMI without PR 48%, stable angina pectoris 39%, P<0.01). A multivariable logistic model showed that superficial-type CCs and thin-cap fibroatheromas were positive predictors for PR. CONCLUSIONS: OCT has a high specificity and modest sensitivity for the detection of CCs. The combination of CCs invading fibrous cap and thin-cap fibroatheromas detected by OCT may better identify rupture-prone plaques.

Implications of multiple late gadolinium enhancement lesions on the frequency of left ventricular reverse remodeling and prognosis in patients with non-ischemic cardiomyopathy.

BACKGROUND: Non-ischemic cardiomyopathy (NICM) is a heterogeneous disease, and its prognosis varies. Although late gadolinium enhancement (LGE)-cardiovascular magnetic resonance (CMR) demonstrates a linear pattern in the mid-wall of the septum or multiple LGE lesions in patients with NICM, the therapeutic response and prognosis of multiple LGE lesions have not been elucidated. This study aimed to investigate the frequency of left ventricular (LV) reverse remodeling (LVRR) and prognosis in patients with NICM who have multiple LGE lesions. METHODS: This single-center retrospective study included 101 consecutive patients with NICM who were divided into 3 groups according to LGE-CMR results: patients without LGE (no LGE group = 48 patients), patients with a typical mid-wall LGE pattern (n = 29 patients), and patients with multiple LGE lesions (n = 24 patients). LVRR was defined as an increase in LV ejection fraction (LVEF) ≥ 10 % and a final value of LVEF > 35 %, which was accompanied by a decrease in LV end-systolic volume ≥ 15 % at 12-month follow-up using echocardiography. The frequency of composite cardiac events, defined as sudden cardiac death (SCD), aborted SCD (non-fatal ventricular fibrillation, sustained ventricular tachycardia, or adequate implantable cardioverter-defibrillator therapies), and heart failure death or hospitalization for worsening heart failure, were summarized and compared between the groups. RESULTS: Among the 3 groups, the frequency of LVRR was significantly lower in the multiple lesions group than in the no LGE and mid-wall groups (no LGE vs. mid-wall vs. multiple lesions: 49 % vs. 52 % vs. 19 %, p = 0.03). There were 24 composite cardiac events among the patients: 2 in patients without LGE (hospitalization for worsening heart failure; 2), 7 in patients of the mid-wall group (SCD; 1, aborted SCD; 1 and hospitalization for worsening heart failure; 5), and 15 in patients of the multiple lesions group (SCD; 1, aborted SCD; 8 and hospitalization for worsening heart failure; 6). The multiple LGE lesions was an independent predictor of composite cardiac events (hazard ratio: 11.40 [95 % confidence intervals: 1.49-92.01], p = 0.020). CONCLUSIONS: Patients with multiple LGE lesions have a higher risk of cardiac events and poorer LVRR. The LGE pattern may be useful for an improved risk stratification in patients with NICM.

Expression of Cyclophilin A in Coronary Artery Plaque with Intraplaque Hemorrhage Is More Frequent in Deceased Patients Who Had Impaired Kidney Function.

Patients with impaired kidney function have a high frequency of intraplaque hemorrhage (IPH) in their coronary arteries. Levels of cyclophilin A (CyPA), an indirect matrix metalloproteinase inducer, are increased in deceased patients who had impaired kidney function. In this study, we have examined the relationship between IPH and CyPA.We examined 47 samples of coronary plaque from 27 cadavers with coronary stenosis. These sections, all with > 50% coronary stenosis, were stained with an antibody against CyPA and the expression of CyPA was semi-quantified. Cadavers and plaques were classified into one of two groups depending on the presence or absence of IPH. IPH was defined as the presence of red blood cells stained with hematoxylin and eosin (HE) indicative of overt acute hemorrhage.In an individual analysis, estimation of glomerular filtration rate (eGFR) in the IPH group was significantly lower than that in the non-IPH group (P = 0.002). In a histological analysis, the percentage of stained area of CyPA in the IPH group was significantly higher than that in the non-IPH group (P < 0.0001).IPH was associated with a significantly higher expression of CyPA in this study. In addition, patients with IPH in their coronary arteries had significantly impaired kidney function.

Prognostic Value of Human Peripheral Monocyte Subsets for Future Coronary Events in Patients Without Significant Coronary Artery Stenosis.

BACKGROUND: Monocytes in human peripheral blood are heterogeneous and can be divided into 2 groups, inflammatory and pro-inflammatory, according to the differential expression of CD14 and CD16. Pro-inflammatory monocytes (CD14+CD16+) seem to contribute to the development of coronary artery disease. This study aimed to investigate the involvement of specific human peripheral monocyte subsets in the development of future coronary events.Methods and Results:We enrolled 271 patients who were suspected to have either stable angina pectoris or silent myocardial ischemia and underwent coronary angiography (CAG). Two monocyte subsets (CD14+CD16-and CD14+CD16+) were measured by flow cytometry. Patients who did not undergo coronary artery revascularization at initial CAG were followed as the medical therapy group, which included 136 patients among whom 15 had future coronary events. The frequency of CD14+CD16+monocytes was significantly higher in patients who had future coronary events than in those who did not (P<0.01). Furthermore, the frequencies of CD14+CD16+monocyte were not significantly different between patients who had future coronary events and those who underwent coronary revascularization at initial CAG (P<0.33). Multivariate analysis revealed that the frequency of CD14+CD16+monocytes was an independent predictor for future coronary events (P<0.01). CONCLUSIONS: An increase in the abundance of human peripheral pro-inflammatory monocytes is related to the development of future coronary events.

Combination of Lesion Stenosis and Myocardial Supply Area Assessed by Coronary Computed Tomography Angiography for Prediction of Myocardial Ischemia.

Recent clinical studies revealed that anatomical information assessed by coronary computed tomography angiography (CTA) may be used effectively to diagnose coronary artery disease (CAD). However, a physiological assessment, demonstrating myocardial ischemia, is required to justify a therapeutic strategy for CAD. This study aimed to investigate whether using CTA to assess myocardial supply area can improve the prediction of myocardial ischemia.We analyzed 201 vessels with moderate (luminal narrowing ≥ 50%, < 70%) and severe (luminal narrowing ≥ 70%, < 99%) stenosis on CTA from 174 patients, who were suspected of having stable angina and underwent measurement of fractional flow reserve (FFR). The myocardial area supplied by the coronary artery, distal to the stenosis, was evaluated with CTA, as reported previously (modified Alberta Provincial Project for Outcome Assessment in Coronary Heart score) and was classified into 3 groups (large, medium, and small).Both percentage area stenosis and myocardial supply area were significantly correlated with FFR (r = -0.46, P < 0.01, and r = -0.45, P < 0.01). Among patients who had coronary plaques, with moderate stenosis and a small myocardial supply area, only 3 of 42 lesions (7%) were identified as ischemic; deviation from the ischemic threshold (FFR = 0.80) was P < 0.01. The combined assessment of lesion stenosis and myocardial supply area, using CTA, improved the prediction of myocardial ischemia significantly compared to lesion stenosis alone (77% versus 59%, P < 0.01).Adding the assessment of myocardial supply area to standard CTA might help predict myocardial ischemia in patients with stable angina pectoris.

Local Matrix Metalloproteinase 9 Level Determines Early Clinical Presentation of ST-Segment-Elevation Myocardial Infarction.

OBJECTIVE: Early clinical presentation of ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction affects patient management. Although local inflammatory activities are involved in the onset of MI, little is known about their impact on early clinical presentation. This study aimed to investigate whether local inflammatory activities affect early clinical presentation. APPROACH AND RESULTS: This study comprised 94 and 17 patients with MI (STEMI, 69; non-STEMI, 25) and stable angina pectoris, respectively. We simultaneously investigated the culprit lesion morphologies using optical coherence tomography and inflammatory activities assessed by shedding matrix metalloproteinase 9 (MMP-9) and myeloperoxidase into the coronary circulation before and after stenting. Prevalence of plaque rupture, thin-cap fibroatheroma, and lipid arc or macrophage count was higher in patients with STEMI and non-STEMI than in those with stable angina pectoris. Red thrombus was frequently observed in STEMI compared with others. Local MMP-9 levels were significantly higher than systemic levels (systemic, 42.0 [27.9-73.2] ng/mL versus prestent local, 69.1 [32.2-152.3] ng/mL versus poststent local, 68.0 [35.6-133.3] ng/mL; P<0.01). Poststent local MMP-9 level was significantly elevated in patients with STEMI (STEMI, 109.9 [54.5-197.8] ng/mL versus non-STEMI: 52.9 [33.0-79.5] ng/mL; stable angina pectoris, 28.3 [14.2-40.0] ng/mL; P<0.01), whereas no difference was observed in the myeloperoxidase level. Poststent local MMP-9 and the presence of red thrombus are the independent determinants for STEMI in multivariate analysis. CONCLUSIONS: Local MMP-9 level could determine the early clinical presentation in patients with MI. Local inflammatory activity for atherosclerosis needs increased attention.

Association of Toll-Like Receptor 4 on Human Monocyte Subsets and Vulnerability Characteristics of Coronary Plaque as Assessed by 64-Slice Multidetector Computed Tomography.

BACKGROUND: Although Toll-like receptor 4 (TLR-4) is involved in monocyte activation in patients with accelerated forms of atherosclerosis, the relationship between the expression of TLR-4 on circulating monocytes and coronary plaque vulnerability has not previously been evaluated. We investigated this relationship using 64-slice multidetector computed tomography (MDCT) in patients with stable angina pectoris (SAP).Methods and Results:We enrolled 65 patients with SAP who underwent MDCT. Three monocyte subsets (CD14++CD16-, CD14++CD16+, and CD14+CD16+) and expression of TLR-4 were measured by flow cytometry. Intracoronary plaques were assessed by 64-slice MDCT. We defined vulnerability of intracoronary plaques according to the presence of positive remodeling (remodeling index >1.05) and/or low CT attenuation (<35 HU). The circulating CD14++CD16+monocytes more frequently expressed TLR-4 than CD14++CD16-and CD14+CD16+monocytes (P<0.001). The relative proportion of the expression of TLR-4 on CD14++CD16+monocytes was significantly greater in patients with vulnerable plaque compared with those without (10.4 [4.1-14.5] % vs. 4.5 [2.8-7.8] %, P=0.012). In addition, the relative proportion of TLR-4 expression on CD14++CD16+monocytes positively correlated with the remodeling index (r=0.28, P=0.025) and negatively correlated with CT attenuation value (r=-0.31, P=0.013). CONCLUSIONS: Upregulation of TLR-4 on CD14++CD16+monocytes might be associated with coronary plaque vulnerability in patients with SAP.

Optimal threshold of postintervention minimum stent area to predict in-stent restenosis in small coronary arteries: An optical coherence tomography analysis.

OBJECTIVES: The aim of this study was to determine the best threshold of postintervention minimum stent area (MSA) assessed by optical coherence tomography (OCT) to predict long-term in-stent restenosis (ISR) for 2.5 mm-diameter everolimus-eluting stents (EES). BACKGROUND: Percutaneous coronary intervention (PCI) for small coronary arteries remains challenging. Stent underexpansion is a strong predictor of late ISR. METHODS: We performed a retrospective analysis of 69 lesions in 69 patients undergoing PCI with 2.5 mm-diameter stents using OCT for the assessment of postintervention MSA and subsequent 9-month angiographic follow-up. RESULTS: The rates of angiographic ISR and target lesion revascularization were 7.2% and 1.4%. The postintervention OCT-MSA of EES < 3.5 mm(2) for predicting ISR yielded a sensitivity of 80%, specificity of 71%, positive predictive value of 18%, and negative predictive value of 98%. There was a marginally significant trend between increasing MSA quartiles and decreasing ISR rate (P for trend = 0.07). CONCLUSIONS: Postintervention OCT-MSA of 3.5 mm(2) best predicted 9-month ISR following PCI with 2.5-mm-diameter EES. Further large, prospective, observational studies are warranted that validate this result. © 2015 Wiley Periodicals, Inc.

European Society of Cardiology (ESC) Congress Report from London 2015.

The Annual Congress of the European Society of Cardiology (ESC) was held in London from 29 August to 2 September 2015. It is the leading conference in cardiology in the world, with presentations on the latest scientific discoveries, innovations, technology, education, and clinical practices. More than 32,000 delegates and 5,000 exhibitors from 140 countries participated, sharing a number of scientific presentations, including 28 clinical hot lines, 18 clinical trial updates, 20 registry studies, 12 basic and translational science hot line studies, and 4,533 abstract studies. Japan had the highest number of accepted abstracts at the Congress, indicating the great contribution of Japanese scientists and the Japanese Circulation Society.

Circulating CD14++CD16+ Monocyte Subsets as a Surrogate Marker of the Therapeutic Effect of Corticosteroid Therapy in Patients With Cardiac Sarcoidosis.

BACKGROUND: We aimed to evaluate whether specific monocyte subsets could serve as surrogate markers of disease activity in cardiac sarcoidosis (CS) evaluated by 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). METHODS AND RESULTS: We studied 28 patients with CS (8 men; mean age: 61±9 years) diagnosed according to consensus criteria. We divided the patients into 2 groups: known CS receiving corticosteroid therapy (Rx(+); n=13) and new-onset CS (Rx(-); n=15), and analyzed 3 distinct monocyte subsets (CD14+CD16-, CD14++CD16+, and CD14+ -CD16+). Monocyte subsets were also analyzed in 10 Rx(-) patients before and 12 weeks after starting corticosteroid therapy. Inflammatory activity was quantified by 18F-FDG PET using the coefficient of variation (COV) of the standardized uptake value (SUV). The proportion of CD14++CD16+ monocytes in Rx(+) patients (10.8 [0.2-23.5] %) was significantly lower than in Rx(-) patients (23.0 [11.5-38.4] %, P=0.001). After corticosteroid therapy, the COV of the SUV was significantly improved from 0.32 [0.14-0.62] to 0.17 [0.04-0.43] (P=0.017). The proportion of CD14++16+ monocytes showed a significant decrease from 22.2 [8.8-38.4] % to 8.4 [1.8-16.8] % (P=0.001). The decrease in the proportion of CD14++16+ monocytes significantly correlated with the decrease in the COV of the SUV (r=0.495, P=0.027). CONCLUSIONS: CD14++16+ monocytes are a possible surrogate marker of the therapeutic effect of corticosteroid therapy in CS.

Long-term outcome after deferral of revascularization in patients with intermediate coronary stenosis and gray-zone fractional flow reserve.

BACKGROUND: A strategy of deferred percutaneous coronary intervention for coronary stenosis with fractional flow reserve (FFR) 0.75-0.80, termed the gray zone, remains a matter of debate. The aim of this study was to assess the safety of deferring revascularization for patients with FFR 0.75-0.80 compared with those with FFR >0.80. METHODS AND RESULTS: We assessed 3-year clinical outcome in 150 patients with angiographically intermediate stenosis who had revascularization deferred on the basis of FFR ≥ 0.75 (FFR 0.75-0.80, n=56; FFR >0.80, n=94). Target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR) was evaluated during follow-up. Cardiac death was observed in 1 patient with FFR 0.75-0.80. There was no target vessel-related MI in either group. The incidence of ischemia-driven TVR was higher in patients with FFR 0.75-0.80 than in those with FFR >0.80 (14% vs. 3%, P=0.020). TVF-free survival was significantly worse for the patients with FFR 0.75-0.80 than those with FFR >0.80 (hazard ratio, 5.2; 95% confidence intervals: 1.4-19.5; P=0.015). CONCLUSIONS: Patients with FFR 0.75-0.80 were at higher risk of TVF mainly due to TVR than those with FFR >0.80.

Feasibility of optical coronary tomography in quantitative measurement of coronary arteries with lipid-rich plaque.

BACKGROUND: The aim of the present study was to evaluate the feasibility of optical coherence tomography (OCT) for measurement of vessel area in coronary arteries with lipid-rich plaque as compared with intravascular ultrasound (IVUS). METHODS AND RESULTS: We investigated 80 coronary artery segments with lipid-rich plaque on OCT and non-attenuated plaque on IVUS. According to the lipid arc on OCT, the plaques were classified into 4 groups: group 1, lipid arc ≤90°; group 2, 90°270°. Vessel circular arcs that could not be identified due to OCT signal attenuation were interpolated using an approximating algorithm. OCT-measured vessel area was well-correlated with IVUS-measured vessel area (R=0.834, P<0.001). On Bland-Altman plot, there was a good agreement between OCT-measured vessel area and IVUS-measured vessel area, although mean difference and limits of agreement increased with increase of lipid arc (mean difference in groups 1-4: -0.21, -0.31, -1.02, and -2.13 mm(2); lower limit: -1.49, -3.22, -5.24, and -9.25 mm(2); and upper limit: 1.07, 2.60, 3.20, and 4.99 mm(2)). Intra-observer (R=0.97-0.99, P<0.001) and inter-observer (R=0.97-0.99, P<0.001) reproducibility for OCT measurement of vessel area was excellent. CONCLUSIONS: Like IVUS, OCT can be used to measure vessel area in coronary arteries with lipid-rich plaque.

Effect of direct renin inhibitor on left ventricular remodeling in patients with primary acute myocardial infarction.

Some patients with acute myocardial infarction (AMI) have a poor prognosis due to left ventricular remodeling (LVR), resulting in the recurrence of congestive heart failure even when therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) has been initiated. We investigated the effect of early administration of the direct renin inhibitor (DRI) aliskiren in combination with an ACEI or an ARB on LVR using cardiac magnetic resonance (CMR) imaging in patients with AMI.Twenty-one consecutive patients were treated with an ACEI or an ARB (non-DRI group), and another 21 consecutive patients received aliskiren 150 mg/day combined with an ACEI or an ARB (DRI group). CMR imaging was performed 7 days after AMI and 10 months later.CMR imaging revealed no significant changes in LV end-systolic volume, LV end-diastolic volume, or LV ejection fraction between the patients with and without DRI aliskiren. In the DRI group, plasma renin activity was significantly lower in both the acute and chronic phases; however, aldosterone levels were significantly lower in the acute but not the chronic phase.A low dose of aliskiren may be insufficient to maintain suppression of aldosterone under current standard therapies with an ACEI or an ARB and ß-blocker in patients with primary AMI, and results in no attenuation of LVR.

Genome-wide DNA methylation analysis in female veterans with military sexual trauma and comorbid PTSD/MDD.

BACKGROUND: Military sexual trauma (MST) is a prevalent issue within the U.S. military. Victims are more likely to develop comorbid diseases such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Nonetheless, not everyone who suffers from MST develops PTSD and/or MDD. DNA methylation, which can regulate gene expression, might give us insight into the molecular mechanisms behind this discrepancy. Therefore, we sought to identify genomic loci and enriched biological pathways that differ between patients with and without MST, PTSD, and MDD. METHODS: Saliva samples were collected from 113 female veterans. Following DNA extraction and processing, DNA methylation levels were measured through the Infinium HumanMethylationEPIC BeadChip array. We used limma and bump hunting methods to generate the differentially methylated positions and differentially methylated regions (DMRs), respectively. Concurrently, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome to find enriched pathways. RESULTS: A DMR close to the transcription start site of ZFP57 was differentially methylated between subjects with and without PTSD, replicating previous findings and emphasizing the potential role of ZFP57 in PTSD susceptibility. In the pathway analyses, none survived multiple correction, although top GO terms included some potentially relevant to MST, PTSD, and MDD etiology. CONCLUSION: We conducted one of the first DNA methylation analyses investigating MST along with PTSD and MDD. In addition, we found one DMR near ZFP57 to be associated with PTSD. The replication of this finding indicates further investigation of ZFP57 in PTSD may be warranted.

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.

Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography.

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

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.

Low Energy Intake Diagnosed Using the Harris-Benedict Equation Is Associated with Poor Prognosis in Elderly Heart Failure Patients.

INTRODUCTION: Insufficient nutrient intake is a strong independent predictor of mortality in elderly patients with heart failure. However, it is unclear to what extent energy intake affects their prognosis. This study investigated the association between patient outcomes and actual measured energy intake in elderly patients (≥65 years) with heart failure. METHODS: This study enrolled 139 elderly patients who were hospitalized with worsening heart failure at Shingu Municipal Medical Center, Shingu, Japan, between May 2017 and April 2018. Energy intake was evaluated for three days (from three days prior to the day of discharge until the day of discharge). Based on basal energy expenditure calculated using the Harris-Benedict equation, the patients were classified into a low-energy group (n = 38) and a high-energy group (n = 101). We assessed the prognosis in terms of both all-cause mortality and readmission due to worsening heart failure as a primary outcome. RESULTS: Compared to the patients in the high-energy group, the patients in the low-energy group were predominantly female, less frequently had smoking habits and ischemic heart diseases, and had a higher left ventricular ejection fraction. The low-energy group had higher mortality than the high-energy group (p = 0.028), although the two groups showed equivalent event rates of the primary outcome (p = 0.569). CONCLUSION: Calculations based on the Harris-Benedict equation revealed no significant difference in the primary outcome between the two groups, with a secondary outcome that showed worse mortality in the low-energy group. Given this result, energy requirement-based assessments using the Harris-Benedict equation might help in the management of elderly heart failure patients in terms of improved life outcomes.