Extracellular Vesicle MicroRNAs as Predictive Biomarkers in Postoperative Delirium after Spine Surgery; Preliminary Study.

Postoperative Delirium (POD) can cause poor patient outcomes in older adults who undergo surgery. In this study, we tested plasma extracellular vesicle (EV) miRNAs obtained before the delirium event to find predictive POD biomarkers after spine surgery. We recruited patients who are over 70 years old and have undergone spine surgery. Finally, POD patients (n=31) were included, with no-POD patients matched in age, sex, medical history, and type of surgery (n=31). Peripheral blood was collected from patients in the operating room after the operation was completed. EVs were isolated from plasma, and the 798 miRNA expression level from EVs was measured using a NanoString platform. Sixty-two patients were included in the study; all were Korean, 67.7% were females, and the median age was 75 years. Preoperative medical history was not statistically different between no-POD and POD patients except for hypertension and the American Society of Anesthesiologists (ASA) physical status. From the miRNA profiling, we identified 142 significantly differentially expressed miRNAs in POD patients compared to no-POD patients, which are associated with psychological/neurological disorders. The top 10 differentially expressed miRNAs including miR-548ar-5p and miR-627-5p were all upregulated in POD patients and the results were validated using qRT-PCR from the independent sets of samples (n=96). We demonstrated the potential of plasma EV-miRNAs as predictive biomarkers to identify the risk group of POD after spine surgery. It also provides opportunities for future studies investigating the role of EV-miRNAs in delirium pathology.

Salivary Cortisol and Melatonin, Sleep, and Behavioral Patterns in Older Adults Living With Dementia.

BACKGROUND: Over half of the older adults living with dementia have behavioral and psychological symptoms of dementia (BPSD), including sleep disturbance; however, little is known about physiological markers. Salivary cortisol and melatonin have been identified as potential biomarkers of BPSD, with evidence suggesting a relationship between these biomarkers and various behavioral factors, as well as sleep and activity patterns. OBJECTIVES: The aim of this study was to investigate the time-dependent changes in salivary cortisol and melatonin levels in older adults with dementia, their relationship with the sleep-wake cycle, and their correlation with BPSD symptoms and behavioral factors. METHODS: This observational study conducted in Seoul and Gyeonggi-do, South Korea, used data from 172 older adults with dementia, measuring sleep and activity patterns for 2 weeks using a wearable device, in addition to administering questionnaires for neuropsychiatric and psychological symptoms-the Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, and Cornell Scale for Depression in Dementia. Salivary cortisol and melatonin levels were measured at four time points and divided into four groups based on a dual-trajectory model. Differences among the groups were analyzed using one-way analysis of variance. RESULTS: The participants showed normal but heterogeneous patterns of salivary cortisol and melatonin levels. Dual-trajectory pattern analysis showed that higher levels of melatonin during the daytime were correlated with poor nighttime sleep efficiency and decreased disinhibited behaviors, and higher levels of cortisol at all four time points were associated with decreased physical activity. DISCUSSION: Measuring and analyzing periodic changes in cortisol and melatonin levels can predict various behavioral symptoms (e.g., sleep disturbances, activity counts, and disinhibition) in older adults with dementia. A study with an experimental design is needed to discover the direct physiological interactions between cortisol, melatonin, and these symptoms.

Assessment of Risk Factors for Postoperative Delirium in Older Adults Who Underwent Spinal Surgery and Identifying Associated Biomarkers Using Exosomal Protein.

PURPOSE: With an increase in the aging population, the number of patients with degenerative spinal diseases undergoing surgery has risen, as has the incidence of postoperative delirium. This study aimed to investigate the risk factors affecting postoperative delirium in older adults who had undergone spine surgery and to identify the associated biomarkers. METHODS: This study is a prospective study. Data of 100 patients aged ≥ 70 years who underwent spinal surgery were analyzed. Demographic data, medical history, clinical characteristics, cognitive function, depression symptoms, functional status, frailty, and nutritional status were investigated to identify the risk factors for delirium. The Confusion Assessment Method, Delirium Rating Scale-R-98, and Nursing Delirium Scale were also used for diagnosing delirium. To discover the biomarkers, urine extracellular vesicles (EVs) were analyzed for tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light, and glial fibrillary acidic protein using digital immunoassay technology. RESULTS: Nine patients were excluded, and data obtained from the remaining 91 were analyzed. Among them, 18 (19.8%) developed delirium. Differences were observed between participants with and without delirium in the contexts of a history of mental disorder and use of benzodiazepines (p = .005 and p = .026, respectively). Tau and UCH-L1-concentrations of urine EVs-were comparatively higher in participants with severe delirium than that in participants without delirium (p = .002 and p = .001, respectively). CONCLUSION: These findings can assist clinicians in accurately identifying the risk factors before surgery, classifying high-risk patients, and predicting and detecting delirium in older patients. Moreover, urine EV analysis revealed that postoperative delirium following spinal surgery is most likely associated with brain damage.

Cytokine associated with severity of depressive symptoms in female nurses in Korea.

Background: Depression has been associated with the risk of developing physical illnesses and diseases. Inflammatory hypotheses of immunoactive and dysregulated cytokine production have been proposed to describe this association; however, data pertaining to the high prevalence of depression among nurses are limited. Objective: This study aimed to use a comprehensive immune-profiling approach to determine whether an abnormal profile of circulating cytokines could be identified in nurses with self-reported depression and whether this profile is associated with the severity of depression. Methods: We investigated a cohort of 157 female nurses in Korea. The self-report Patient Health Questionnaire was used to measure the depression levels of nurses. In addition, peripheral blood samples were collected and used to measure the cytokine profile using the Luminex multiplexing system. Generalized gamma regression analyses were conducted to evaluate the association between cytokine and depressive symptoms. Results: Regarding severity of depressive symptoms, 28.0% of nurses had moderately severe depression while 9.6% had severe depression. Moderately-severe depressive symptoms in nurses were associated with elevated levels of interleukin-6 (B = 0.460, p = 0.003), interleukin-8 (B = 0.273, p = 0.001), and interleukin-18 (B = 0.236, p = 0.023), whereas interferon-gamma levels (B = -0.585, p = 0.003) showed the opposite profile. Participants with severe depressive symptoms presented decreased interferon-gamma levels (B = -1.254, p < 0.001). Conclusion: This study demonstrated that proinflammatory cytokines were associated with depression among nurses. This calls for early detection and intervention, considering the mechanisms linking depression to physical illness and disease.

External validation of subclassification system and progression pattern analysis in hepatocelluar carcinoma with macroscopic vascular invasion.

BACKGROUND AND PURPOSE: The present study aimed to validate the performance of a previously proposed subclassification model to predict prognosis after combined transarterial chemoembolization (TACE) and external beam radiotherapy (RT) for hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) in an independent cohort that received the same first-line treatment for the patients with the similar disease extent characteristics, and analyzed the progression patterns as well as progression-free survival (PFS). MATERIALS AND METHODS: This study was conducted using prospectively collected data from the XXXXX HCC registry for newly diagnosed, previously untreated HCC between 2005 and 2018. Finally, 417 patients who satisfied the eligibility criteria were included and analyzed. RESULTS: The median PFS and overall survival (OS) were 5.2 and 13.9 months, respectively. Similar to a previous study, subclassification of patients into very low-, low-, intermediate-, and high-risk groups showed a median OS of 98.4, 18.3, 9.7, and 5.8 months, respectively (P < 0.001). Additionally, subclassification of patients into the very low-, low-, intermediate-, and high-risk groups showed median PFS of 18.7, 6.7, 3.3, and 2.3 months, respectively (p < 0.001). Overall, intrahepatic progression was the most common pattern of progression; however, extrahepatic progression was more common in the intermediate- and high-risk groups. CONCLUSION: The previously proposed subclassification model was successfully validated in an independent cohort. Treatment modification should be considered in the intermediate- and high-risk patient groups because of their frequent extrahepatic as well as intrahepatic progressions after combined TACE and RT.

Association between inflammatory cytokines and caregiving distress in family caregivers of cancer patients.

PURPOSE: Caregivers of cancer patients experience distress that can manifest as caregiving burden, burnout, depression, and fatigue. Caregiving distress affects physical health in various ways such as causing the dysregulation of inflammatory functions. We examined the relationships between psychological distress experienced by and inflammatory cytokine levels of family caregivers of cancer patients. METHODS: A descriptive, cross-sectional study involving 93 family caregivers of cancer patients was conducted. Self-report questionnaires were used to measure the distress variables, which included the caregiving burden, burnout, depression, and fatigue, and peripheral blood samples were collected to measure the IL-6, IL-10, and TNF-α levels. Multiple linear regression analyses were conducted to evaluate the impact of caregivers' distress on their inflammatory cytokine levels. RESULTS: Inflammatory cytokine levels were negatively correlated with caregiving distress. High fatigue levels (B = - 0.047, p = 0.026) and additional days of care provided per week (B = - 0.048, p = 0.009) was associated with low IL-6 levels. High depression levels (B = - 0.250, p = 0.007), high fatigue levels (B = - 0.054, p = 0.027), and more days of care provided per week (B = - 0.048, p = 0.033) were associated with low TNF-α levels. The age of the caregiver (B = - 0.011, p = 0.020) and days of care provided per week (B = - 0.138, p = 0.031) were associated factors for IL-10 levels. CONCLUSION: The inflammatory responses were associated with the distress in family caregiving for cancer patients. Thus, interventions are needed to support caregivers and manage their caregiving distress.

Effect of Ezetimibe on Glucose Metabolism and Inflammatory Markers in Adipose Tissue.

Despite numerous studies, the effects of ezetimibe on glucose metabolism are poorly understood. Here, we aimed to investigate the effects of ezetimibe on glucose metabolism and the expression of inflammatory markers. Thirteen rats were randomly assigned to an ezetimibe (n = 6) or control group (n = 7). The control group received a high fat diet (HFD; 60 Kcal%), whereas the ezetimibe group received an HFD (60 Kcal%) containing 160 mg/kg of ezetimibe. After 14 weeks, adipose and liver tissues, along with plasma, were collected and comparatively analyzed. The effects of combination therapy with ezetimibe and statins on glucose metabolism were investigated over a 1-year period using data from patients with hyperlipidemia. Several indices of glucose metabolism partially improved in the ezetimibe group. The sizes of adipocytes and the accumulation of pro-inflammatory cytokines were reduced in the ezetimibe group. Ezetimibe treatment induced anti-inflammatory cytokines and fatty acid oxidation in adipocytes and reduced serum levels of free fatty acids. Clinical data analysis revealed that statin monotherapy significantly increased insulin resistance. However, combination therapy with ezetimibe and statins did not increase insulin resistance. In conclusion, ezetimibe was found to reduce the sizes of adipocytes in visceral fat and serum levels of free fatty acids, to induce fatty acid oxidation, to improve adipocytic inflammation, and to partially improve glycemic index values.

Erratum: Pro-inflammatory Cytokine Levels and Cancer-related Fatigue in Breast Cancer Survivors: Effects of an Exercise Adherence Program.

[This corrects the article on p. 205 in vol. 23, PMID: 32395379.].

Pro-inflammatory Cytokine Levels and Cancer-related Fatigue in Breast Cancer Survivors: Effects of an Exercise Adherence Program.

PURPOSE: This study aimed to determine the effect of an exercise intervention on subjective cancer-related fatigue (CRF) and pro-inflammatory cytokine levels in breast cancer survivors (BCS). METHODS: BCS with greater than moderate CRF (≥ 4) were recruited and randomly assigned to experimental or control groups. The experimental group participated in a 12-week exercise adherence program (Better Life after Cancer - Energy, Strength, and Support; BLESS). Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) levels were determined at 3 time points (M1: baseline, M2: post-intervention, and M4: 6 months after intervention). Subjective fatigue was measured using the Korean version of the revised Piper Fatigue Scale. RESULTS: In this analysis of participants with physiological fatigue measures available (19 experimental, 21 control), there were no statistically significant differences in IL-6 (F = 1.157, p = 0.341), TNF-α levels (F = 0.878, p = 0.436), and level of fatigue (F = 2.067, p = 0.118) between the 2 groups at baseline. Fatigue in the experimental group showed statistically significant improvement compared to the control only at M2 (p = 0.022). There was no significant relationship between subjective and physiological fatigue at the 3 measurement points. CONCLUSION: The BLESS intervention improved CRF in BCS immediately at post-intervention, and this study presents clinical feasibility for the management of CRF in BCS in the early survivorship phase who are already experiencing fatigue.

The Possible Influence of Mediterranean Diet on Extracellular Vesicle miRNA Expression in Breast Cancer Survivors.

The Mediterranean diet (MD) has been reported to have beneficial effects on breast cancer and cardiovascular diseases. Recently, microRNAs (miRNAs) have been suggested as biomarkers for the diagnosis and disease prognosis in cancer and cardiovascular diseases. We evaluated the influence of the MD on the plasma-derived extracellular vesicle miRNA signature of overweight breast cancer survivors. Sixteen participants instructed to adhere to the MD for eight weeks were included in this study. To curate differentially expressed miRNAs after MD intervention, we employed two methods: significance analysis of microarrays and DESeq2. The selected miRNAs were analyzed using ingenuity pathway analysis. After an eight-week intervention, body mass index, waist circumference, fasting glucose, fasting insulin, and homeostatic model assessment for insulin resistance were significantly improved. Expression levels of 798 miRNAs were comprehensively analyzed, and 42 extracellular vesicle miRNAs were significantly differentially regulated after the eight-week MD (36 were up and 6 were down-regulated). We also identified enriched pathways in genes regulated by differentially expressed 42 miRNAs, which include signaling associated with breast cancer, energy metabolism, glucose metabolism, and insulin. Our study indicates that extracellular vesicle miRNAs differentially expressed as a result of the MD might be involved in the mechanisms that relate to cardiometabolic risk factors in overweight breast cancer survivors.

Visceral adiposity and expression of clock genes in peripheral blood mononuclear cells: A pilot study.

Increasing evidence suggests a close interrelationship between disrupted circadian rhythms and obesity and metabolic disturbances. In particular, abdominal obesity, which contributes to the pathogenesis of metabolic disease, is associated with disrupted clock gene expression. However, little is known about the relationship between clock gene expression and accurate computed tomography (CT)-based measurements of visceral adiposity. Therefore, we examined the relationship between expression of clock genes in peripheral blood mononuclear cells (PBMCs) with visceral and subcutaneous adiposity in 75 healthy overweight or obese individuals. PBMCs were obtained from blood samples collected at 8 AM, and gene expression was analyzed by real-time reverse transcription polymerase chain reaction. Visceral and subcutaneous adiposity were measured by CT. Our results showed that visceral fat area was significantly positively correlated with BMAL1 and CRY1 mRNA levels and significantly negatively correlated with CLOCK, PER2, PER3 and CRY2 mRNA levels. In contrast, subcutaneous fat area was not correlated with the expression of any of the clock genes analyzed. After adjusting for multiple variables, visceral fat area was significantly associated with the expression of BMAL1, PER2 and CRY1. Taken together, our results indicate that visceral adiposity, but not subcutaneous adiposity, correlates with expression of clock genes in PBMCs.