Time spent away from bed is associated with oral hygiene and oral function: A cross-sectional and multi-institutional study.

BACKGROUND: Spending time away from bed is important in older adults. Not doing so can lead to functional decline rapidly. OBJECTIVE: To investigate the association between oral function and time spent away from bed in older adults living in nursing homes. METHODS: We enrolled 748 adults aged ≥65 years across eight nursing homes between April 2022 and March 2023. 'Problems with oral hygiene' and 'problems with oral function' were the dependent variables in the multiple regression analyses to determine their association with time spent away from bed. RESULTS: We selected 304 participants (76 men; mean age, 86.3 ± 7.5 years) and divided them into three groups: group S (< 4 h), group M (4 to < 6 h) and group L (≥ 6 h), with 28, 23 and 253 participants, respectively. Comparison of the characteristics between the groups demonstrated significant differences in the Barthel index (p < .001), time spent away from bed (p < .001), history of aspiration pneumonia (p < .001), confirmation of meals and food forms (p = .010), problems with oral hygiene (p = .014), and problems with oral function (p = .002). Based on multiple regression analyses, 'problems with oral hygiene' (p < .001) and 'problems with oral function' (p < .001) were significantly associated with time spent away from bed. CONCLUSIONS: The time spent away from bed was significantly associated with both oral hygiene and function in older adults, suggesting the importance of extending the time that older adults spend away from bed.

Comparison survey on family caregivers of older persons in Japan and Thailand.

BACKGROUND: While rapid population ageing is occurring worldwide, its speed is especially prominent in Asian countries. In Asia, cultural diversity might significantly affect care burden; however, few studies have investigated the differences in care burden, and mental, physical and social conditions among Asian countries. This study aimed to clarify the situations of and differences in family caregivers (FCs) of older persons in Japan and Thailand, and evaluate the factors associated with care burden in both countries. METHODS: A cross-national survey of 217 in-home FCs was conducted in Japan and Thailand and mainly included items regarding care burden and psychosocial conditions. Differences between the two countries were obtained, and the factors associated with care burden were analysed by multiple regression analyses. RESULTS: The FCs' and care receivers' mean ages (64.8 ± 11.1 and 84.8 ± 8.6 years, respectively) in Japan were significantly higher than the mean ages (49.1 ± 13.3 and 77.1 ± 9.5 years) in Thailand. In Japan, FCs had more severe care burden, loneliness, and stress compared to those in Thailand. In Thailand, FCs had more social connections and informal support than those in Japan. The factors associated with care burden were different in each country; thus, severe stress, low emotional care preparation, and low willingness to continue care at home were significantly associated with severe care burden in Japan, whereas poor relationships with care receivers, few social connections, low confidence in providing care, low emotional care preparation, and lack of informal support were significantly associated with severe care burden in Thailand. CONCLUSIONS: Despite there being a long-term care insurance system in Japan, which is absent in Thailand, care burden and psychosocial conditions of FCs might be worse in Japan. There was a clear difference in the factors associated with care burden between Japan and Thailand.

Effects of a virtual reality intervention on dementia care education among acute care nurses in Japan: A non-randomised controlled trial.

This study aimed to evaluate the effects of a virtual reality intervention for dementia care education in Japanese acute care nurses. Non-randomised controlled trial was used to assess the effectiveness of the intervention pre- and post-intervention and at a 1-month follow-up. This study enrolled 20 and 19 nurses in the intervention and control groups, respectively. Generalized estimating equation analyses revealed significant differences in scores on the Dementia Nursing Competency Scale in Acute Hospitals and Staff Experiences of Working with Dementia Residents questionnaire in the intervention group. A post hoc test revealed significantly higher scores on the Dementia Nursing Competency Scale in Acute Hospitals at 1 month after compared with pre-intervention. Staff Experiences of Working with Dementia Residents questionnaire scores were significantly lower at pre- than that at post-intervention and 1 month after intervention. These findings could improve competency of dementia nursing care and attitudes toward people with dementia.

The Impact of Cognitive Impairment on Disaster Preparedness: A Cross-sectional Study of Older Adults over the Age of 75 Requiring Special Care in Japan.

Disaster preparedness is the most important measure that can be taken to reduce damage. However, disaster preparedness is predicted to be difficult for older adults with cognitive impairment. Thus, we investigated the effects on disaster preparedness of cognitive impairment in persons requiring special care who are 75 or older. The survey included subject characteristics such as demographic indicators, physical function, cognitive function impairments, community involvement, and disaster preparedness. Cross-sectional data from 711 subjects were divided into two groups, a cognitive impairment group and an unimpaired group. Next, to show the effects of subject characteristics in each group on disaster preparedness, a binomial logistic regression analysis was performed. Then, the effects on disaster preparedness were compared between the two groups. This study showed that persons requiring special care who are 75 or older, and have the characteristics of "living alone," "requiring care," and "needing mobility assistance" in addition to cognitive impairment, have increased difficulty making disaster preparedness. Government officials and community supporters therefore need to recognize that these people should be supported on a priority basis, and to provide continuing support for disaster preparedness.

Impact of Motivation for Eating Habits, Appetite and Food Satisfaction, and Food Consciousness on Food Intake and Weight Loss in Older Nursing Home Patients.

BACKGROUND: This study analyzed data from the Long-term care Information system For Evidence (LIFE) database to examine the effects of motivation to eat, appetite and food satisfaction, and food consciousness on food intake and weight loss. METHODS: Of the 748 nursing home residents enrolled in the LIFE database, 336 met the eligibility criteria for this cross-sectional study. Motivation to eat, appetite and food satisfaction, and food consciousness were rated on five-point Likert scales (e.g., good, fair, normal, not so good, and not good). We applied Spearman rank correlation coefficient and multiple regression analyses to analyze the relationships between these three items, daily energy and protein intake, and body weight loss over 6 months. RESULTS: The mean participant age was 87.4±8.1 years and 259 (77%) were female. The required levels of care included-level 1, 1 (0%); level 2, 4 (1%); level 3, 107 (32%); level 4, 135 (40%); and level 5, 89 (27%). The mean daily energy intake was 28.2±7.8 kcal/kg. The mean daily protein intake was 1.1±0.3 g/kg. The mean weight loss over six months was 1.2±0.7 kg. We observed strong positive correlations among motivation to eat, appetite and food satisfaction, and food consciousness (r>0.8). These three items were significantly associated with higher daily energy intake but not with daily protein intake. Only appetite and food satisfaction were significantly associated with lower weight loss over six months. CONCLUSION: The observed associations of appetite and food satisfaction suggest that these factors may be more important to assess than motivation to eat or food consciousness among older adult residents of long-term care facilities.

Psychological and physiological responses to odor-evoked autobiographic memory.

OBJECTIVE: The "Proust phenomenon" occurs when a certain smell evokes a specific memory. Recent studies have demonstrated that odor-evoked autobiographic memories are more emotional than those elicited by other sensory stimuli because of the direct neural communication between the olfactory system and the amygdala. The amygdala is known to regulate various physiological activities including the endocrine and immune systems; therefore, odor-evoked autobiographic memory may trigger various psychological and physiological responses; however, the responses elicited by this memory remains obscure. In this study, we aimed to investigate the psychological and physiological responses accompanying odor-evoked autobiographic memory. METHODS: We recruited healthy male and female volunteers and investigated changes in their mood states and autonomic nervous, endocrine, and immune activities when autobiographic memory was evoked in the participants by asking them to smell an odor(s) that was nostalgic to them. RESULTS: The autobiographic memories associated with positive emotion resulted in increased positive mood states, such as comfort and happiness, and decreased negative mood states, such as anxiety. Furthermore, heart rate was decreased, skin-conductance level was increased, and peripheral interleukin-2 level was decreased after smelling the nostalgic odor. These psychological and physiological responses were significantly correlated. CONCLUSIONS: The present study suggests that odor-evoked autobiographic memory along with a positive feeling induce various physiological responses, including the autonomic nervous and immune activities. To the best of our knowledge, the present study is the first to observe an interaction between odor-evoked autobiographic memories and immune function.

Association between perceived happiness levels and peripheral circulating pro-inflammatory cytokine levels in middle-aged adults in Japan.

OBJECTIVES: The idea that perceived happiness may be associated with health and well-being is a recent topic of focus. However, the neurobiological mechanisms underlying the positive effects of happiness on psychological and physiological wellness remain obscure. In this study, we attempted to clarify the association between systemic inflammation and happiness. METHODS: We recruited 160 healthy volunteers for experiment 1 and compared peripheral inflammatory markers, namely the concentrations of pro-inflammatory cytokines in the serum, between perceived high-happiness and low-happiness groups. Subsequently, we recruited 7 romantic couples for experiment 2 and investigated changes in peripheral pro-inflammatory cytokine levels after the evocation of happiness, which was induced by warm physical contact with the partner. RESULTS: We found that circulating levels of interferon-γ (IFN-γ), which can affect brain functions and induce depressive symptoms, were lower in the high-happiness group than in the low-happiness group. A negative correlation between the levels of perceived happiness and IFN-γ concentrations was also observed. Furthermore, we also found that experimentally induced happiness could reduce peripheral IFN-γ levels. CONCLUSIONS: These results revealed an association between the perception of happiness and systemic inflammation. Increased happiness may suppress the peripheral circulation of pro-inflammatory cytokines.

Disaster Preparedness of Persons Requiring Special Care Ages 75 Years and Older Living in Areas at High Risk of Earthquake Disasters: A Cross-Sectional Study From the Pacific Coast Region of Western Japan.

OBJECTIVE: The aims of this study were to examine the preparedness of vulnerable people ages 75 years and older and to clarify the characteristics of older adults that are associated with disaster preparedness. METHODS: We conducted interviews with persons requiring special care ages 75 years and older living in coastal communities of western Japan, where earthquakes and tsunami disasters are a concern. The survey included participant characteristics such as demographic indicators, physical function, health status, community involvement, and disaster preparedness. Binomial logistic regression analysis was performed with participant characteristics as independent variables and disaster preparedness as the dependent variables. RESULTS: The characteristics related to disaster preparedness were age, family composition, cognitive function, level of interaction with neighbors, and participation in community activities. CONCLUSIONS: Being female, living alone, and having cognitive impairment were factors that led to decreased disaster preparedness. However, it was suggested that close human interactions in the community facilitated preparedness. Community engagement is crucial in reducing disaster damage and recovering effectively. In order to facilitate preparedness measures for persons requiring special care ages 75 and older, it is important to establish community preparedness.

Brain and autonomic association accompanying stochastic decision-making.

To examine the functional association between brain and autonomic activities accompanying decision-making, we simultaneously recorded regional cerebral blood flow using (15)O-water positron emission tomography and event-related brain potentials (ERPs) time-locked to feedback of reward and punishment, as well as cardiovascular parameters, during a stochastic decision-making task. We manipulated the uncertainty of outcomes in the task; specifically, we compared a condition with high predictability of reward/punishment (contingent-reward condition) and a condition with low predictability of reward/punishment (random-reward condition). The anterior cingulate cortex (ACC) was commonly activated in both conditions. Compared with the contingent-reward condition, the orbitofrontal and right dorsolateral prefrontal cortices and dorsal striatum were activated in the random-reward condition, where subjects had to continue to seek contingency between stimuli and reward/punishment. Activation of these brain regions correlated with a positive component of ERPs locked to feedback signals (feedback-related positivity), which showed an association with behavioral decision-making in the contingent-reward condition. Furthermore, cardiovascular responses were attenuated in the random-reward condition, where continuous attention and contingency monitoring were needed, and such attenuation of cardiovascular responses was mediated by vagal activity that was governed by the rostral ACC. These findings suggest that the prefrontal-striatal network provides a neural basis for decision-making and modulation over the peripheral autonomic activity accompanying decision-making.

Regulation of natural killer cell redistribution by prefrontal cortex during stochastic learning.

Acute stress elicits redistribution of lymphocyte subsets, especially natural killer (NK) cells, probably for preparatory defense against potential invasion of antigens in fight-flight situations. We previously reported that regulation of lymphocyte redistribution is based on the evaluation of the controllability of a stressor (Kimura, K., Ohira, H., Isowa, T., Matsunaga, M., Murashima, S. 2007. Regulation of lymphocytes redistribution via autonomic nervous activity during stochastic learning. Brain Behav. Immun. 21, 921-934; Ohira, H., Isowa, T., Nomura, M., Ichikawa, N., Kimura, K., Miyakoshi, M., Iidaka, T., Fukuyama, S., Nakajima, T., Yamada, J. 2008. Imaging brain and immune association accompanying cognitive appraisal of an acute stressor. Neuroimage 39, 500-514). Specifially, lymphocyte redistribution is somewhat attenuated when a stressor is uncontrollable, probably to save biological energy in a situation where appropriate coping is unclear. We infer that this phenomenon might reflect top-down regulation over peripheral immune function by higher-ordered brain regions. To investigate the neural basis of such a phenomenon, we simultaneously recorded regional cerebral blood flow using (15)O-water positron emission tomography and cardiovascular (blood pressure and heart rate), neuroendocrine (epinephrine, norepinephrine, and adrenocorticotropic hormone), and immune (proportions of NK cells and helper T cells in blood) indices in 16 male subjects who performed a stochastic learning task with manipulation of controllability (controllable vs. uncontrollable). Consistent with previous studies, the proportion of peripheral NK cells was attenuated in an uncontrollable stress condition. The dorsolateral prefrontal and orbitofrontal cortices were activated in the uncontrollable situation but not in the controllable condition, and additionally, these prefrontal brain regions significantly correlated with the degree of redistribution of NK cells in the uncontrollable condition. The results of the study suggest these brain regions are involved in both evaluation of the controllability of a stressor and regulation of immune function.

Association of polymorphism in the human mu-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception.

Recent studies in psychoneuroimmunology have indicated that proinflammatory cytokines cause several diseases and behaviors that overlap symptomatically with depression. It is known that the endogenous opioid peptide beta-endorphin regulates proinflammatory cytokine secretion from peripheral immune cells via mu-opioid receptor-dependent mechanisms. Therefore, it is possible that the functional polymorphism of the mu-opioid receptor gene (OPRM1, SNP: A118G) influences peripheral circulating proinflammatory cytokine levels and the health-related quality of life (QOL) even in healthy populations. In this study, we compared the serum concentrations of several proinflammatory cytokines (interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma)) and the health-related QOL between OPRM1 genotypes. Interestingly, serum concentrations of IL-6, TNF-alpha, and IFN-gamma were significantly lower and the general health score was significantly higher in carriers of the G allele, who show a strong binding of beta-endorphin to the mu-opioid receptor as compared to individuals without the G allele. Correlation analysis indicated that the general health score was negatively correlated with the IL-6 serum concentration. These results suggest that the sensitive endogenous opioid system in carriers of the G allele may suppress proinflammatory cytokine secretion from peripheral immune cells; consequently, it may influence the health perception.

Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men.

A short (S) variant, compared to a long (L) variant, of the promoter region of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been related to emotional hyper-reactivity. We tested whether the 5HTTLPR could modulate acute stress responses in the brain and, the cardiovascular and neuroendocrine systems. Ten Japanese male participants carrying double copies of the S alleles and 10 Japanese males carrying S and L alleles conducted a mental arithmetic task, and their regional cerebral blood flow by (15)O positron emission tomography and cardiovascular and neuroendocrine parameters were measured. During the acute stress task, the participants with the SS alleles showed stronger reactivity in blood pressure and secretion of epinephrine, compared to the participants with the SL and LL alleles. Furthermore, the SS carriers showed greater activation in stress-related brain regions such as the hypothalamus, cerebellum, midbrain, and pulvinar compared to the SL and LL carriers during the acute stress task. The present findings indicated that the S allele of the 5HTTLPR is associated with greater brain and physiological reactivity to acute stress in Japanese men.

Profiling of serum proteins influenced by warm partner contact in healthy couples.

OBJECTIVES: Warm physical contact may positively influence our health and well-being; however, it has not been investigated yet whether serum proteins are influenced by warm physical contact in healthy couples. In this study, we focused on psychological and physiological effects of warm partner contact in healthy couples. METHODS: When participants freely kissed and hugged their romantic partners, they were asked to subjectively evaluate their present emotions. Furthermore, changes of serum proteins were determined by using ProteinChip surface enhanced laser desorption/ionization-time-of-flight-mass spectrometry (SELDI-TOF-MS). We characterized these proteins by using biochemical techniques combined with gel filtration high performance liquid chromatography (HPLC), reverse-phase HPLC, and sequencing analyses. RESULTS: Romantic couples became happier and less irritated after kissing and hugging. Accompanying these psychological changes, SELDI-TOF-MS indicated that the intensities of 66-k Da, 11.7-k Da, and 5.9-k Da serum proteins were increased. These proteins were identified as serum albumin and beta2-microglobulin, and probably fibrinogen fragment. The feeling of happiness positively correlated and the feeling of irritation negatively correlated with intensities of serum albumin and beta2-microglobulin. CONCLUSION: These results suggest that psychological stress may be reduced and we may feel happiness when we kiss and hug a romantic partner. Furthermore, these results also suggest that warm partner contact influences peripheral circulating proteins, more importantly, may promote health and well-being.

Associations among central nervous, endocrine, and immune activities when positive emotions are elicited by looking at a favorite person.

Recent studies on psychoneuroimmunology have indicated that positive psychological events are related to immune functions; however, limited information is available regarding associations among the central nervous, endocrine, and immune systems when positive emotions are elicited. In the present study, we demonstrated associations among these systems by simultaneously recording brain, endocrine, and immune activities when positive emotions were evoked in participants as they watched films featuring their favorite persons. Interestingly, the activity of peripheral circulating natural killer cells and the peripheral dopamine level were elevated while participants experienced positive emotions, and these values were positively correlated. The following brain regions were significantly activated in the positive condition relative to the control condition: medial prefrontal cortex, thalamus, hypothalamus, subcallosal gyrus, posterior cingulate cortex, superior temporal gyrus, and cerebellum. Further, covariate analyses indicated that these brain regions were temporally associated with endocrine and immune activities. These results suggest that while an individual experiences positive emotions, the central nervous, endocrine, and immune systems may be interrelated and attraction for favorite persons may be associated with the activation of the innate immune function via the dopaminergic system.

Association study between reward dependence temperament and a polymorphism in the phenylethanolamine N-methyltransferase gene in a Japanese female population.

Cloninger's theory is that specific dimensions of temperament are associated with single neurotransmitter systems, and it is based on neurophysiologic and genetic approaches to the human traits. It suggests that overexpression of temperament could cause psychiatric illness. Based on this theory, we examined the correlation between reward dependence (RD) trait, measured with the Temperament and Character Inventory, and 5 polymorphisms in genes of norepinephrine pathways, ADRB1, COMT, PNMT, SLC18A1, and SLC6A2, in 85 Japanese female nursing students. We found that rs3764351 in PNMT was significantly associated with RD on Fisher's exact test (P = .029, P(corr) = .236). When haplotype analysis was performed for rs3764351 and rs876493 polymorphisms in the 5' flanking region of PNMT, 3 haplotypes were identified. Rs3764351 itself appeared to be correlated with RD in the present study of a specific population, although we could not demonstrate an association between RD and any of the haplotypes. Our findings have implications for the understanding of temperament using neurophysiologic approaches.

The temporal redistribution pattern of NK cells under acute stress based on CD62L adhesion molecule expression.

Recent studies demonstrated that an acute psychological stressor elicited transient changes in lymphocyte redistribution. Earlier studies had established that CD3-CD16+CD56+ natural killer cells (NK cells) increased remarkably in peripheral blood circulation and that the amount of lymphocyte redistribution in NK cells was dependent on the CD62L expression density. Specifically, CD62L- cells were mobilized more pronouncedly than were CD62L+ cells. These results led us to hypothesize that such different reactivity causes different temporal characteristics between CD62L+ and CD62L- lymphocyte subsets. The present study was conducted to examine this issue. Ten female participants experienced a 10-minute baseline period and performed a 10-minute mental arithmetic task as an acute psychological stressor. Blood samples for measuring the proportions of CD62L+ or CD62L- NK cells and CD62L+ or CD62L- T cells were obtained immediately after each period and every 2 min during the task. As expected, CD62L+ and CD62L- NK cells showed different reactivity in response to the stressor and showed different temporal characteristics. That is, the elevation of CD62L- NK cells reached a significant level at 1 min after the initiation of the stressor, while CD62L+ NK cells took 8 min to show a tendency of elevation. Although CD3+ T cells showed different reactivity between CD62L cell types, they did not show different temporal characteristics. These findings suggest that the expression of CD62L modulates not only the amount of redistribution but also the temporal characteristics of the redistribution of NK cells.

Immune, endocrine and cardiovascular responses to controllable and uncontrollable acute stress.

This study, using a triadic-yoked design, clarified the effects of controllability of acute stress on responses of immune, cardiovascular (heart rate and blood pressure), and cortisol activities. Forty-three women in their follicular phase completed a mental arithmetic task as a stressor in which controllability was manipulated by correct or yoked-bogus feedback. The task decreased proportions of CD3+ T cells, CD4+ T cells, and CD19+ B cells, whereas it increased the numbers of white blood cells, lymphocytes, natural killer (NK) cells, and NK cell activity (NKCA). Our main hypothesis that greater immune and cardiovascular responses to the task would be obtained under the uncontrollable condition than under the controllable condition was not supported. However, the uncontrollable stress condition, but not the controllable situation, led to higher correlations between heart rate or blood pressure, and various immune parameters. On the other hand, parameters of heart rate variability reflecting sympathetic and parasympathetic activities showed significant correlations only with NKCA. These results suggest that immune responses were most directly associated with cardiovascular activities under the uncontrollable condition.

Prolonged Effects of Acute Stress on Decision-Making under Risk: A Human Psychophysiological Study.

This study investigates the prolonged effects of physiological responses induced by acute stress on risk-taking in decision-making. Participants were divided into a Stress group (N = 14) and a Control group (N = 12). The Trier Social Stress Test was administered as an acute stressor, and reading was administered as a control task; thereafter, participants performed a decision-making task in which they needed to choose a sure option or a gamble option in Gain and Loss frame trials 2 h after (non-) exposure to the stressor. Increased cortisol, adrenaline, heart rate (HR), and subjective stress levels validated acute stress manipulation. Stressed participants made fewer risky choices only in the Gain domain, whereas no effect of stress was shown in the Loss domain. Deceleration of HR reflecting attention was greater for Gains compared with Losses only in the Stress group. Risk avoidance was determined by increased levels of cortisol caused by acute stress. These results suggest that processes regarding glucocorticoid might be involved in the prolonged effects of acute stress on the evaluation of risks and the monitoring of outcomes in decision-making.

Temporal variation of acute stress responses in sympathetic nervous and immune systems.

Sympathetic nervous activity plays a prominent role in acute stress responses in the immune system, enhancement of innate immunity and suppression of specific immunity. The present study was conducted to examine the temporal characteristics of such immune responses to acute stress and to determine their association with sympathetic activity in detail. For this purpose, 15 female undergraduates engaged in a continuous mental arithmetic task for 14 min, and we collected their blood samples for immune indices (CD3+ T cells, CD4+ T cells, NK cells) each 3 min during the task and saliva samples before and after the task. Our results showed that the proportion of Natural Killer cells (NK cells) increased even 2 min after initiation of the task, whereas proportions of CD3+ and CD4+ lymphocytes decreased 8 min after initiation of the task. Moreover, we found significant correlations between cardiovascular activity and the variations of immune indices.

Serotonin transporter gene polymorphism modulates inflammatory cytokine responses during acute stress.

Cytokines are important mediators of various stress-related modulations of immune function. A major genetic factor determining inter-individual differences in stress reactivity is polymorphisms of the serotonin (5-hydroxytryptamine, 5HT) transporter (5HTT) gene. A short (S) variant, compared with a long (L) variant, of the promoter region of the 5HTT gene-linked polymorphic region (5HTTLPR) has been related to emotional and stress hyper-reactivity. The present study examined whether the 5HTTLPR can modulate responses of inflammatory cytokines under acute stress. Nine Japanese male participants carrying two copies of the S alleles and nine Japanese males carrying S and L alleles underwent the Trier Social Stress Test (TSST). Inflammatory cytokines, endocrine parameters, heart rate and subjective stress were measured before, during and after the task. The participants carrying the SS alleles, but not those carrying the SL alleles, showed a significant increase of IL-1ß immediately after TSST. This hyper-reactivity to acute stress in individuals with the SS alleles was also observed in their heart rate and cortisol levels. These results suggest that the S allele of the 5HTTLPR is consistently associated with stress reactivity in multi-level stress-related biological systems.