Nonrestorative Sleep Mediates the Influence of Adverse Childhood Experiences on Psychological Distress, Physical Health, Mental Health, and Activity Limitation: A Longitudinal Study for the General Population in Japan

Nonrestorative Sleep Mediates the Influence of Adverse Childhood Experiences on Psychological Distress, Physical Health, Mental Health, and Activity Limitation: A Longitudinal Study for the General Population in Japan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Nonrestorative Sleep Mediates the Influence of Adverse Childhood Experiences on Psychological Distress, Physical Health, Mental Health, and Activity Limitation: A Longitudinal Study for the General Population in Japan Megumi, Kentaro, Takahiro, Ryo, Takuya, Shingo, Aoi, Kentaro, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4314857/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: This study explores the associations between adverse childhood experiences (ACEs), health problems, and increased daytime inactivity, emphasizing nonrestorative sleep (NRS), a subjective perception of unrefreshing sleep, as a significant contributing factor. Methods: A longitudinal online survey utilizing data from the Japan COVID-19 and Society Internet Survey was employed. The Kessler distress scale (K6) served as the primary outcome measure, with a score of K6 ≥ 13 indicating psychological distress. Health-Related Quality of Life-4 was utilized to assess mentally unhealthy days, physically unhealthy days, and days with activity limitation, indicating mental health problems, physical health problems, and daytime inactivity if exceeding 14 days monthly, respectively. NRS frequency within the past 30 days was evaluated on a 5-point scale, with "usually" (16 days or more) indicating NRS presence. ACEs were identified when four or more items from a validated ACEs list were selected. A causal mediation analysis was performed. Results: Among the 17,042 participants, 52.8% were male, averaging 50.35 years of age (SD = 17.73). Approximately 11.1% reported four or more ACEs. Notably, 16.7% met NRS criteria, while 9.6% met psychological distress criteria. The proportions of individuals with physical health problems, mental health problems, and activity limitations were 6.4%, 6.2%, and 4.2%, respectively. Significant mediational pathways via NRS were observed from ACEs to psychological distress (RR = 1.14, 95% CI = 1.08–1.19, p < 0.001), physical health problems (RR = 1.30, 95% CI = 1.21–1.40, p < 0.001), mental health problems (RR = 1.20, 95% CI = 1.13–1.28, p < 0.001), and daytime inactivity (RR = 1.27, 95% CI = 1.17–1.37, p < 0.001). Conclusion: This study suggests that NRS mediates the impact of ACEs on mental or physical health issues and daytime inactivity. Further research is needed to determine whether targeting NRS can alleviate ACE-associated health problems. Psychiatry non-restorative sleep adverse childhood experiences mental health physical health activity limitations Figures Figure 1 Figure 2 Introduction Adverse childhood experiences (ACEs) encompass traumatic experiences endured by children and adolescents, including abuse, violence, and neglect 1 . These experiences precipitate diverse health issues and functional impairment 2 . A comprehensive survey unveiled odds ratios (ORs) for attempted suicide of 1.8, 3.0, 6.6, and 12.2 in individuals with one, two, three, and four or more ACEs, respectively, in contrast to those without ACEs 3 . A systematic review and meta-analysis indicated that approximately 13% (ranging from 1–38% across studies) of the general populace underwent four or more ACEs 4 . Furthermore, the probability of encountering various health issues, such as cardiovascular disease, cancer, respiratory disease, mental health issues, and substance use, was significantly elevated among those with four or more ACEs, with ORs ranging from 1.25 to exceeding 30 4 . Given the irreversibility of ACE exposure, priority should be given to identifying and modifying intermediate factors adversely affecting health pathways. Nonrestorative sleep (NRS), characterized by a subjective sensation of restlessness, exhibits a prevalence ranging from 2–16% within the general population 5 – 8 . This condition is closely linked to ACEs and various health complications, often manifesting as a consequence of sleep-related disorders, including insomnia, circadian rhythm sleep-wake disorder, insufficient sleep syndrome, sleep-related breathing disorders, central disorders of hypersomnolence, and nightmare disorder 7 – 9 . These disorders are notably more prevalent among individuals with ACEs 10 – 12 . NRS is also associated with mental health issues, notably depression 13 , with a higher propensity to precipitate depression compared to other insomnia-related symptoms such as difficulty initiating and maintaining sleep 14 . Moreover, NRS is associated with various physical health issues, encompassing asthma, laryngopharyngitis, obesity, diabetes, dyslipidemia, hypertension, and increased all-cause mortality rates 15 – 18 . Daytime inactivity emerges as a comparable risk factor for NRS as sleep disorders, with a likelihood of being more pronounced among individuals experiencing NRS than those who do not 13 , 19 . Its severity parallels that observed in individuals with insomnia 19 . However, there remains a gap in understanding the longitudinal mediation effects of ACEs on mental health, physical health, and activity, particularly using NRS. Notably, a longitudinal investigation involving soldiers exposed to combat situations delineated a pathway linking ACEs to mental health issues and functional impairment through sleep disturbances 20 . Yet, given the predominant young adult demographic and the unique health challenges inherent to combat exposure 20 , uncertainties persist regarding the generalizability of these findings beyond this specific cohort 21 – 23 . Therefore, this study aimed to examine, using a longitudinal design in the general population, the hypothesis that four or more ACEs predict the presence of mental health, physical health, and activity issues via the presence of NRS. Methods Participants and setting This study, conducted within the framework of the Japan COVID-19 and Society Internet Survey (JACSIS study), focused on examining changes or trends across specific time points during the COVID-19 pandemic. The JACSIS study is an online survey of the general population in Japan through Rakuten Insight Corporation and contains one of the most extensive pooled panels, approximately 2.2 million, in Japan 24 . From the data collected during the stated periods beginning in February 2022, we used data from those who participated in February (Time 1; T1) and September to October (Time 2; T2) 2022. The study included individuals aged 16–79 who took part in both of the data collection in February and October 2022. Participants with erroneous responses were excluded, defined as those who did not correct the dummy question or selected all alternatives to the medication or comorbidity confirmation questions. Additionally, those who answered "Unknown" or "Refuse to respond" to the income level question were excluded. Measurement Independent variable ACEs were assessed using the Adverse Childhood Experience in Japan (ACE-J) 25 , which consists of a 15-item checklist of various adverse experiences encountered before 18 years of age. These items were adapted from the CDC-Kaiser ACE questionnaire 26 to fit the Japanese context better. The ACE-J includes comprehensive adverse experiences, such as parental death, parental divorce or separation, mental illness in the household, addiction in the household, mother being treated violently, emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect, childhood poverty, bullying, hospitalization due to chronic disease, and natural disasters. Those who experienced four or more episodes were identified as having ACEs 3 , 25 , 27 . Data on ACEs were collected at T1. Mediation variable To assess the frequency of NRS, the survey question used was “How many days in the past 30 days have you felt NRS?” with response options being “None,” “Rarely (less than one day),” “Sometimes (2 to 4 days),” “Often (5 to 15 days),” and “Usually (16 days or more)” 28 . For the primary analysis, participants who selected “Often (5 to 15 days)” and “Usually (16 days or more)” were identified as experiencing NRS. In the sensitivity analysis, however, the criteria were broadened to include those who answered “Sometimes (2 to 4 days)” or more. NRS data were collected at T1. Outcome variables The Kessler-distress scale (K6), which measures the degree of psychological distress, was used as the primary outcome measure. Scores range from 0 to 24, with high scores indicating severe psychological distress 29 – 31 . According to a previous study, those who scored 13 or higher were identified as having psychological distress 29 . The threshold of 5 was also applied as mild psychological distress for sensitivity analysis 32 . K6 was collected at T1 and T2. K6 at T1 was used as a covariate to adjust for the original intensity of psychological distress, ensuring that it did not influence NRS or K6 at T2. In addition to the Kessler-distress scale, we used three specific questions from the Health-Related Quality of Life-4 questionnaire developed by the Center for Disease Control and Prevention as outcome variables 33 , 34 . These questions were designed to assess the number of unhealthy days experienced in three different ways over the past 30 days: physically, mentally, and activity limitations. Specifically, we recorded the number of days the participants felt physically unwell, the days they experienced mental health problems, and the days on which their activities were limited because of health problems. A higher number of days for these questions indicates a more severe health condition. For our analysis, we defined those who reported having 14 days or more as having physical health problems, mental health problems, and daytime inactivity 35 . All outcome variables were collected at T2. Covariates Demographic information was used as covariates: age, sex (male or female), educational level, and income level. Educational level was divided into two categories: high school graduates or lower and post-high school education, in accordance with a previous survey that reported an association between educational level and mental health, such as anxiety in Japan 36 . Those who selected “Others” were categorized into the latter. Income level was divided into the two categories based on the average household income 37 : < ¥ 6,000,000 and ≥ ¥ 6,000,000. Comorbidities associated with sleep and psychological distress were used as covariates: diabetes 38 , 39 , angina and myocardial infarction 40 , 41 , stroke 42 , 43 , chronic kidney disease 44 , 45 , chronic hepatitis or cirrhosis 46 , 47 , immune abnormalities and dysfunction 48 , 49 , cancer and malignancies 50 , 51 , asthma or chronic obstructive pulmonary disease, 52 – 54 and chronic pain 55 , 56 . In the study, each comorbidity status was categorized based on the participant’s response to the following options: “None,” “Not currently, but previously,” “Currently present (in hospital and taking medication),” “Currently present (in hospital but no medication),” and “Currently present (not in a hospital).” A comorbidity was considered “present” if the response was either “None” or “Not currently, but previously.” Body mass index 57 , 58 , drinking 59 , 60 , and smoking 61 , 62 were used as covariates. Participants who answered “None” to the frequency of drinking questions (options: “None, “1 time per month or less,” “2–4 times per month,” “2–3 times per week,” and “4 times per week or more”) were categorized as non-drinkers. Those who chose any option other than “None” were categorized as drinkers. For smoking status, the participants were classified based on their responses to the smoking frequency question. Those who selected “I have not smoked,” “I have smoked but not habitually,” or “I have smoked habitually but quit now” were categorized as non-smokers. In contrast, participants who chose, “I smoke sometimes” or “I smoke almost every day” were categorized as smokers. Covariates were collected at T1. Analyses All analyses were performed using Stata 18. The threshold for the p-value was set at 0.05. After excluding those who were lost to follow-up from the dataset, the mean and standard deviation (SD) for continuous variables and the number and proportion for categorical variables were calculated. Risk risks (RR) were calculated with and without covariates to confirm the risks of NRS and ACEs to outcomes, such as psychological distress, physical health problems, mental health problems, and daytime inactivity. The RRs were calculated based on a previous study using Stata commands 63 . Causal mediation analyses were performed to confirm the pathway from ACEs at T1 (independent variable) to outcomes at T2 through the NRS at T1 (mediation variable), with adjustments for covariates (Fig. 1 ). Proportion mediated and proportion eliminated were also calculated. Sensitivity analyses were performed to assess the robustness of the findings. These analyses included: 1) applying a lower threshold for K6, considering scores of 5 or higher rather than 13 or higher; 2) modifying the frequency threshold for the negative response style to “Sometimes (2 to 4 days)” rather than “Often (5 to 15 days)”; and 3) restricting the analysis to participants who scored below 13 on the K6 at baseline (T1) to eliminate the possibility that originally existing psychological distress could influence NRS or psychological distress at T2. Ethics This study was conducted in accordance with the principles of the Declaration of Helsinki. The Osaka International Cancer Institute Research Ethics Committee (20084-8) and the Ethics Committee of the National Center of Neurology and Psychiatry(A2022-049)permitted the study. All participants agreed to participate in the study after obtaining informed consent through an online system. Results Participants Of the 33,000 participants, 17,042 were analyzed after excluding 15,958 individuals (Fig. 2 ). Table 1 shows the characteristics of participants. The mean age was 50.35 (SD = 17.73). About 52.8% were males. A total of 11.1% reported having ACEs, and 16.7% reported often or usually experiencing NRS. The mean K6 at T1 was 5.06 (SD = 5.74), and the proportion of individuals with psychological distress was 11.9%. The mean K6 at T2 was 4.20 (SD = 5.42), and the proportion of individuals with psychological distress was 9.6%. The mean number of physically unhealthy days was 2.60 (SD = 6.19), and the proportion of those with physical health problems was 6.4%. The mean number of mentally unhealthy days was 2.37 (SD = 6.11), and the proportion of mental health problems was 6.2%. The mean number of days with activity limitation was 1.84 (SD = 5.23), and the proportion of daytime inactivity or more was 4.2%. Table 1 Characteristic mean / n SD / % Age 50.35 17.13 Sex male 8998 52.8% female 8044 47.2% Educational level high school graduate or lower 4514 26.5% post-high school education 12528 73.5% Income level < ¥ 6,000,000 8584 50.4% ≥ ¥ 6,000,000 8458 49.6% Comorbidity Diabetes 1196 7.0% Angina pectoris/myocardial infarction 432 2.5% Stroke 217 1.3% CKD 297 1.7% Chronic hepatitis/cirrhosis 201 1.2% Immune abnormalities/ dysfunction 360 2.1% Cancer/ Malignancies 380 2.2% Asthma/ COPD 673 4.0% Chronic pain 2669 15.7% BMI 22.44 5.74 Drinking 11880 69.7% Smoking 3260 19.1% ACEs 1.48 1.73 ≥ 4 1893 11.1% NRS Often or more 2837 16.7% Sometimes or more 6982 41.0% Never 6352 37.3% Rarely 3708 21.8% Sometimes 4145 24.3% Often 1664 9.8% Usually 1173 6.9% K6 at Time 1 5.06 5.74 ≥ 13 at Time 1 (Psychological distress) 2030 11.9% ≥ 5 at Time 1 (Mild psychological distress) 7016 41.2% K6 at Time 2 4.20 5.42 ≥ 13 at Time 2 (Psychological distress) 1643 9.6% ≥ 5 at Time 2 (Mild psychological distress) 5847 34.3% HRQoL4 Physically unhealthy days 2.60 6.19 ≥ 14 days (Physical health problems) 1085 6.4% Mentally unhealthy days 2.37 6.11 ≥ 14 days (Mental health problems) 1052 6.2% Days with activity limitation 1.84 5.23 ≥ 14 days (Daytime inactivity) 723 4.2% n, number; SD, Standard Deviation; CKD, Chronic Kidney Disease; COPD, Chronic Obstructive Pulmonary Disease; BMI, Body Mass Index; ACEs, Adverse Childhood Experiences; NRS, Nonrestorative Sleep; K6, Kessler distress scale; HRQoL4, Independent association between psychological distress, unhealthy days, ACEs, and NRS As Table 2 shows, ACEs was significantly associated with psychological distress, physical health problems, mental health problems, and daytime inactivity in both the crude and adjusted analyses. Adjusted analyses revealed that experience of ACEs was significantly associated with psychological distress (RR = 2.77, 95% CI = 2.51–3.05, p < 0.001), physical health problems (RR = 2.64, 95% CI = 2.33–3.01, p < 0.001), mental health problems (RR = 3.20, 95% CI = 2.82–3.62, p < 0.001), and daytime inactivity (RR = 3.30, 95% CI = 2.83–3.85, p < 0.001). Similarly, the NRS score was significantly associated with psychological distress, physical health problems, mental health problems, and daytime inactivity in both the crude and adjusted analyses. Adjusted analyses revealed that NRS was significantly associated with psychological distress (RR = 1.58, 95% CI = 1.43–1.73, p < 0.001), physical health problems (RR = 2.80, 95% CI = 2.39–3.27, p < 0.001), mental health problems (RR = 2.75, 95% CI = 2.36–3.23, p < 0.001), and daytime inactivity (RR = 2.91, 95% CI = 2.39–3.53, p < 0.001) (Table 2 ). Table 2 Associations between ACEs and NRS and outcomes Psychological distress Physical health problems Mental health problems Daytime inactivity ACEs Crude RR = 3.22 (95% CI = 2.92–3.54), p < 0.001 RR = 2.73 (95% CI = 2.40–3.10), p < 0.001 RR = 3.58 (95% CI = 3.17–4.04), p < 0.001 RR = 3.43 (95% CI = 2.95–3.99), p < 0.001 Adjusted RR = 2.77, (95% CI = 2.51–3.05), p < 0.001 RR = 2.64 (95% CI = 2.33–3.01), p < 0.001 RR = 3.20 (95% CI = 2.82–3.62), p < 0.001 RR = 3.30 (95% CI = 2.83–3.85), p < 0.001 NRS Crude RR = 5.00 (95% CI = 4.58–5.46), p < 0.001 RR = 3.94 (95% CI = 3.52–4.14), p < 0.001 RR = 6.47 (95% CI = 5.77–7.26), p < 0.001 RR = 5.31 (95% CI = 4.61–6.11), p < 0.001 Adjusted RR = 1.58 (95% CI = 1.43–1.73), p < 0.001 RR = 2.80 (95% CI = 2.39–3.27), p < 0.001 RR = 2.75 (95% CI = 2.36–3.23), p < 0.001 RR = 2.91 (95% CI = 2.39–3.53), p < 0.001 ACEs, Adverse childhood experiences; NRS, non-restorative sleep; RR, Relative risk; 95% CI, 95% confidence interval The association between ACEs and psychological distress, physical health problems, mental health problems, and daytime inactivity via NRS Table 3 presents the results of the mediational analyses. ACEs’ significant natural indirect effect on psychological distress via NRS was observed (RR = 1.14, 95% CI = 1.08–1.19, p < 0.001). The proportion mediated was 28.2% (95% CI = 17.5–38.8%, p < 0.001), and the proportion eliminated was 31.5%. ACEs’ significant natural indirect effect on physical health problems via NRS was observed (RR = 1.30, 95% CI = 1.21–1.40, p < 0.001). The proportion mediated was 46.3% (95% CI = 33.4–59.2%, p < 0.001), and the proportion eliminated was 64.5%. ACEs’ significant natural indirect effect on mental health problems via NRS was observed (RR = 1.20, 95% CI = 1.13–1.28, p < 0.001). The proportion mediated was 30.7% (95% CI = 20.5–40.9%, p < 0.001), and the proportion eliminated was 33.1%. ACEs’ significant natural indirect effect on daytime inactivity via NRS was observed (RR = 1.27, 95% CI = 1.17–1.38, p < 0.001). The proportion mediated was 39.5% (95% CI = 25.9% – 53.0%, p < 0.001), and the proportion eliminated was 51.4%. Table 3 Causal mediation analyses from ACEs to outcomes via NRS Psychological distress Physical health problems Mental health problems Daytime inactivity NIE RR = 1.14 (95% CI = 1.08–1.19), p < 0.001 RR = 1.30 (95% CI = 1.21–1.40), p < 0.001 RR = 1.20 (95% CI = 1.13–1.28), p < 0.001 RR = 1.27 (95% CI = 1.17–1.38), p < 0.001 NDE RR = 1.54 (95% CI = 1.37–1.74), p < 0.001 RR = 1.54 (95% CI = 1.31–1.82), p < 0.001 RR = 1.87 (95% CI = 1.59–2.18), p < 0.001 RR = 1.72 (95% CI = 1.41–2.09), p < 0.001 TE RR = 1.75 (95% CI = 1.57–1.96), p < 0.001 RR = 2.01 (95% CI = 1.73–2.33), p < 0.001 RR = 2.25 (95% CI = 1.95–2.59), p < 0.001 RR = 2.19 (95% CI = 1.83–2.61), p < 0.001 PM 28.2% (95% CI = 17.5% – 38.8%), p < 0.001 46.3% (95% CI = 33.4% – 59.2%), p < 0.001 30.7% (95% CI = 20.5% – 40.9%), p < 0.001 39.5% (95% CI = 26.0% – 53.0%), p < 0.001 PE 31.5% 64.5% 33.1% 51.4% NDE, natural direct effect; NIE, natural indirect effect; TE, total effect; PM, proportion mediated; PE, proportion eliminated. These similar associations were maintained when the same analyses were performed with the threshold K6 ≥ 5 instead of ≥ 13 as mild psychological distress (Additional file 1) and the threshold of “Sometimes (2 to 4 days)” instead of “Often (5 to 15 days)” as NRS (Additional file 2), and when the data was limited in participants without psychological distress at T1 (Additional file 3). 64 Discussion This is the first longitudinal study to investigate the mediating role of NRS in the relationship between ACEs health outcomes in the general population. This study suggests that NRS mediates the impact of ACEs on psychological distress, physical health issues, psychological health issues, and daytime inactivity. The estimated proportion of the effect mediated by the NRS ranged from approximately 28–46%. The present study further revealed that the adverse effects of ACEs on these health outcomes could be partially mitigated by approximately 31–62% if the frequency of NRS in the past 30 days was reduced to fewer than 5 days. A previous longitudinal study revealed that ACEs predict mental health issues and functional disability through sleep issues in soldiers 20 . Our study indicated that these associations can be applied to the general population. Our results were also consistent with the associations observed in multiple cross-sectional studies of adolescents 65 , university undergraduates 66 , 67 , and older people 64 , 65 . Our results indicated that the mediational relationships previously claimed in the subpopulation can be applied to the general population. Potential physiological and behavioral mechanisms may underlie the association between ACEs and NRS scores. As an example of a physiological mechanism, cortisol dysregulation, which interrupts sleep, 68 was observed in patients with ACEs 69 , 70 . ACEs cause subsequent hypothalamic-pituitary-adrenal axis dysregulation 71 , resulting in sleep disturbance. 72 Individuals with a history of multiple ACEs can be more prone to NRS due to their lifestyle habits that negatively impact sleep. Such habits, commonly observed in patients with multiple ACEs, include an irregular life rhythm 73 , 74 and extended screen time 75 . These behaviors have been consistently linked to sleep disturbances 76 – 79 . Multiple studies support the association of NRS with mental health 13 , 14 , physical health 16 – 18 , 80 – 83 , and daytime impairment 7 , 19 . NRS may predispose individuals to mental health issues by increasing their vulnerability to stressful events 84 , 85 and impairing emotion regulation 86 . It is also suspected that NRS contributes to physical health issues by promoting unhealthy behavioral patterns. Poor sleep conditions have been linked to reduced physical activity 82 , 87 , suboptimal dietary behaviors 82 , and the consumption of unhealthy food 88 , 89 . Additionally, NRS may influence various biological processes that detrimentally affect physical health, such as elevating blood pressure 17 , disrupting metabolism 16 , and weakening the immune system 90 , which in turn can lead to a range of health issues. Furthermore, NRS-induced executive dysfunction and diminished performance can result in daytime inactivity 91 , 92 . Given that the NRS could be a modifiable risk factor, interventions targeting NRS could be crucial in preventing or mitigating health issues among individuals affected by multiple ACEs. Sleep hygiene education emphasizing the importance of restorative sleep and modification of detrimental habits, such as irregular life rhythms 73 , 74 and prolonged screen time 75 , could potentially enhance health outcomes by improving the NRS. Furthermore, interventions for individual sleep dysfunctions, such as pharmacotherapy (e.g., orexin receptor agonist, melatonin agonists, benzodiazepine receptor agonist, etc.), cognitive behavioral therapy for insomnia, light therapy, and continuous positive airway pressure 93 – 98 , may lessen NRS and improve health outcomes. Future research should examine the efficacy of such interventions in improving NRS and longitudinal health outcomes in individuals with ACEs. This study had some limitations. First, the predictive strengths of ACEs and NRS for physical health issues, mental health issues, and daytime inactivity might be overestimated. This potential overestimation arose because these outcome variables at T1 were not included as covariates, although the K6 at T1 was included. Therefore, the reported effect sizes should be interpreted with caution. Second, there may have been an unadjusted potential bias. Nevertheless, this study had notable strengths, including its large sample size and longitudinal design. Conclusions This study identified NRS as a mediator of the pathway from ACEs to mental health, physical health, and daytime impairment within the general population using a longitudinal design over an eight-month interval. Regrettably, ACEs are immutable, given their nature as past events. Nonetheless, our findings suggest that NRS treatment can alleviate health issues in individuals with ACEs. Therefore, targeted interventions for NRS could potentially prevent or alleviate these health issues and the associated functional impairments. Abbreviations Adverse childhood experiences (ACEs) Nonrestorative sleep (NRS) Kessler distress scale (K6) Odds ratios (ORs) Japan COVID-19 and Society Internet Survey (JACSIS study) Adverse Childhood Experience in Japan (ACE-J) Standard deviation (SD) Risk risks (RRs) Declarations Ethics approval and consent to participate This study was conducted in accordance with the principles of the Declaration of Helsinki. The Osaka International Cancer Institute Research Ethics Committee (20084-8) and the Ethics Committee of the National Center of Neurology and Psychiatry（A2022-049）permitted the study. All participants agreed to participate in the study after obtaining informed consent through an online system. Consent for publication Not applicable. Availability of data and materials No data are available. Competing Interests The authors declare no conflict of interest. Author contributions Conceptualization: MH, KM, TT, RO, TY, SK, AK, KN, TU, MI, JK, MF, and KK. Data collection: TT and RO. Formal analysis: MH. Data interpretation: MH, KM, and KK. Original Draft preparation: MH and KM. Review and editing: all authors. Super vision: KK. Acknowledgement This study was supported by the following grants: the Japan Society for the Promotion of Science (JSPS) KAKENHI Grants (17H03589, 19K10671, 19K10446, 18H03107, 18H03062, 19H03860, 21H0485, 19K19439, 22K15764), Research Support Program to Apply the Wisdom of the University to tackle COVID-19 Related Emergency Problems, the University of Tsukuba, Health Labour Sciences Research Grant ( 19FA1005 ; 19FG2001; 19FA1012), and the Japan Agency for Medical Research and Development (AMED; 2033648). References Adverse childhood experiences (ACEs). https://www.cdc.gov/violenceprevention/aces/index.html (2023). Hughes, K. et al. Health and financial costs of adverse childhood experiences in 28 European countries: a systematic review and meta-analysis. Lancet Public Health 6 , e848–e857 (2021). Felitti, V. J. et al. 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no competing interests.","formattedTitle":"\u003cp\u003eNonrestorative Sleep Mediates the Influence of Adverse Childhood Experiences on Psychological Distress, Physical Health, Mental Health, and Activity Limitation: A Longitudinal Study for the General Population in Japan\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdverse childhood experiences (ACEs) encompass traumatic experiences endured by children and adolescents, including abuse, violence, and neglect\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. These experiences precipitate diverse health issues and functional impairment\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. A comprehensive survey unveiled odds ratios (ORs) for attempted suicide of 1.8, 3.0, 6.6, and 12.2 in individuals with one, two, three, and four or more ACEs, respectively, in contrast to those without ACEs\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. A systematic review and meta-analysis indicated that approximately 13% (ranging from 1\u0026ndash;38% across studies) of the general populace underwent four or more ACEs\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Furthermore, the probability of encountering various health issues, such as cardiovascular disease, cancer, respiratory disease, mental health issues, and substance use, was significantly elevated among those with four or more ACEs, with ORs ranging from 1.25 to exceeding 30\u003csup\u003e4\u003c/sup\u003e. Given the irreversibility of ACE exposure, priority should be given to identifying and modifying intermediate factors adversely affecting health pathways.\u003c/p\u003e \u003cp\u003eNonrestorative sleep (NRS), characterized by a subjective sensation of restlessness, exhibits a prevalence ranging from 2\u0026ndash;16% within the general population\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. This condition is closely linked to ACEs and various health complications, often manifesting as a consequence of sleep-related disorders, including insomnia, circadian rhythm sleep-wake disorder, insufficient sleep syndrome, sleep-related breathing disorders, central disorders of hypersomnolence, and nightmare disorder\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. These disorders are notably more prevalent among individuals with ACEs\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. NRS is also associated with mental health issues, notably depression\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, with a higher propensity to precipitate depression compared to other insomnia-related symptoms such as difficulty initiating and maintaining sleep\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Moreover, NRS is associated with various physical health issues, encompassing asthma, laryngopharyngitis, obesity, diabetes, dyslipidemia, hypertension, and increased all-cause mortality rates\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Daytime inactivity emerges as a comparable risk factor for NRS as sleep disorders, with a likelihood of being more pronounced among individuals experiencing NRS than those who do not\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Its severity parallels that observed in individuals with insomnia\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, there remains a gap in understanding the longitudinal mediation effects of ACEs on mental health, physical health, and activity, particularly using NRS. Notably, a longitudinal investigation involving soldiers exposed to combat situations delineated a pathway linking ACEs to mental health issues and functional impairment through sleep disturbances\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Yet, given the predominant young adult demographic and the unique health challenges inherent to combat exposure\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, uncertainties persist regarding the generalizability of these findings beyond this specific cohort\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Therefore, this study aimed to examine, using a longitudinal design in the general population, the hypothesis that four or more ACEs predict the presence of mental health, physical health, and activity issues via the presence of NRS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants and setting\u003c/h2\u003e \u003cp\u003eThis study, conducted within the framework of the Japan COVID-19 and Society Internet Survey (JACSIS study), focused on examining changes or trends across specific time points during the COVID-19 pandemic. The JACSIS study is an online survey of the general population in Japan through Rakuten Insight Corporation and contains one of the most extensive pooled panels, approximately 2.2\u0026nbsp;million, in Japan\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. From the data collected during the stated periods beginning in February 2022, we used data from those who participated in February (Time 1; T1) and September to October (Time 2; T2) 2022.\u003c/p\u003e \u003cp\u003eThe study included individuals aged 16\u0026ndash;79 who took part in both of the data collection in February and October 2022. Participants with erroneous responses were excluded, defined as those who did not correct the dummy question or selected all alternatives to the medication or comorbidity confirmation questions. Additionally, those who answered \"Unknown\" or \"Refuse to respond\" to the income level question were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMeasurement\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eIndependent variable\u003c/h2\u003e \u003cp\u003eACEs were assessed using the Adverse Childhood Experience in Japan (ACE-J)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, which consists of a 15-item checklist of various adverse experiences encountered before 18 years of age. These items were adapted from the CDC-Kaiser ACE questionnaire\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e to fit the Japanese context better. The ACE-J includes comprehensive adverse experiences, such as parental death, parental divorce or separation, mental illness in the household, addiction in the household, mother being treated violently, emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect, childhood poverty, bullying, hospitalization due to chronic disease, and natural disasters. Those who experienced four or more episodes were identified as having ACEs\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Data on ACEs were collected at T1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eMediation variable\u003c/h2\u003e \u003cp\u003eTo assess the frequency of NRS, the survey question used was \u0026ldquo;How many days in the past 30 days have you felt NRS?\u0026rdquo; with response options being \u0026ldquo;None,\u0026rdquo; \u0026ldquo;Rarely (less than one day),\u0026rdquo; \u0026ldquo;Sometimes (2 to 4 days),\u0026rdquo; \u0026ldquo;Often (5 to 15 days),\u0026rdquo; and \u0026ldquo;Usually (16 days or more)\u0026rdquo;\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. For the primary analysis, participants who selected \u0026ldquo;Often (5 to 15 days)\u0026rdquo; and \u0026ldquo;Usually (16 days or more)\u0026rdquo; were identified as experiencing NRS. In the sensitivity analysis, however, the criteria were broadened to include those who answered \u0026ldquo;Sometimes (2 to 4 days)\u0026rdquo; or more. NRS data were collected at T1.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eOutcome variables\u003c/h2\u003e \u003cp\u003eThe Kessler-distress scale (K6), which measures the degree of psychological distress, was used as the primary outcome measure. Scores range from 0 to 24, with high scores indicating severe psychological distress\u003csup\u003e\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. According to a previous study, those who scored 13 or higher were identified as having psychological distress\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. The threshold of 5 was also applied as mild psychological distress for sensitivity analysis\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. K6 was collected at T1 and T2. K6 at T1 was used as a covariate to adjust for the original intensity of psychological distress, ensuring that it did not influence NRS or K6 at T2.\u003c/p\u003e \u003cp\u003eIn addition to the Kessler-distress scale, we used three specific questions from the Health-Related Quality of Life-4 questionnaire developed by the Center for Disease Control and Prevention as outcome variables\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. These questions were designed to assess the number of unhealthy days experienced in three different ways over the past 30 days: physically, mentally, and activity limitations. Specifically, we recorded the number of days the participants felt physically unwell, the days they experienced mental health problems, and the days on which their activities were limited because of health problems. A higher number of days for these questions indicates a more severe health condition. For our analysis, we defined those who reported having 14 days or more as having physical health problems, mental health problems, and daytime inactivity\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. All outcome variables were collected at T2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCovariates\u003c/h2\u003e \u003cp\u003eDemographic information was used as covariates: age, sex (male or female), educational level, and income level. Educational level was divided into two categories: high school graduates or lower and post-high school education, in accordance with a previous survey that reported an association between educational level and mental health, such as anxiety in Japan\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Those who selected \u0026ldquo;Others\u0026rdquo; were categorized into the latter. Income level was divided into the two categories based on the average household income\u003csup\u003e37\u003c/sup\u003e: \u0026lt; \u0026yen; 6,000,000 and \u0026ge; \u0026yen; 6,000,000.\u003c/p\u003e \u003cp\u003eComorbidities associated with sleep and psychological distress were used as covariates: diabetes\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, angina and myocardial infarction\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, stroke\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, chronic kidney disease\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, chronic hepatitis or cirrhosis\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e, immune abnormalities and dysfunction\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, cancer and malignancies\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e, asthma or chronic obstructive pulmonary disease,\u003csup\u003e\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e and chronic pain\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. In the study, each comorbidity status was categorized based on the participant\u0026rsquo;s response to the following options: \u0026ldquo;None,\u0026rdquo; \u0026ldquo;Not currently, but previously,\u0026rdquo; \u0026ldquo;Currently present (in hospital and taking medication),\u0026rdquo; \u0026ldquo;Currently present (in hospital but no medication),\u0026rdquo; and \u0026ldquo;Currently present (not in a hospital).\u0026rdquo; A comorbidity was considered \u0026ldquo;present\u0026rdquo; if the response was either \u0026ldquo;None\u0026rdquo; or \u0026ldquo;Not currently, but previously.\u0026rdquo; Body mass index\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e, drinking\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, and smoking\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e were used as covariates. Participants who answered \u0026ldquo;None\u0026rdquo; to the frequency of drinking questions (options: \u0026ldquo;None, \u0026ldquo;1 time per month or less,\u0026rdquo; \u0026ldquo;2\u0026ndash;4 times per month,\u0026rdquo; \u0026ldquo;2\u0026ndash;3 times per week,\u0026rdquo; and \u0026ldquo;4 times per week or more\u0026rdquo;) were categorized as non-drinkers. Those who chose any option other than \u0026ldquo;None\u0026rdquo; were categorized as drinkers. For smoking status, the participants were classified based on their responses to the smoking frequency question. Those who selected \u0026ldquo;I have not smoked,\u0026rdquo; \u0026ldquo;I have smoked but not habitually,\u0026rdquo; or \u0026ldquo;I have smoked habitually but quit now\u0026rdquo; were categorized as non-smokers. In contrast, participants who chose, \u0026ldquo;I smoke sometimes\u0026rdquo; or \u0026ldquo;I smoke almost every day\u0026rdquo; were categorized as smokers. Covariates were collected at T1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eAnalyses\u003c/h2\u003e \u003cp\u003eAll analyses were performed using Stata 18. The threshold for the p-value was set at 0.05.\u003c/p\u003e \u003cp\u003eAfter excluding those who were lost to follow-up from the dataset, the mean and standard deviation (SD) for continuous variables and the number and proportion for categorical variables were calculated.\u003c/p\u003e \u003cp\u003eRisk risks (RR) were calculated with and without covariates to confirm the risks of NRS and ACEs to outcomes, such as psychological distress, physical health problems, mental health problems, and daytime inactivity. The RRs were calculated based on a previous study using Stata commands\u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCausal mediation analyses were performed to confirm the pathway from ACEs at T1 (independent variable) to outcomes at T2 through the NRS at T1 (mediation variable), with adjustments for covariates (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Proportion mediated and proportion eliminated were also calculated. Sensitivity analyses were performed to assess the robustness of the findings. These analyses included: 1) applying a lower threshold for K6, considering scores of 5 or higher rather than 13 or higher; 2) modifying the frequency threshold for the negative response style to \u0026ldquo;Sometimes (2 to 4 days)\u0026rdquo; rather than \u0026ldquo;Often (5 to 15 days)\u0026rdquo;; and 3) restricting the analysis to participants who scored below 13 on the K6 at baseline (T1) to eliminate the possibility that originally existing psychological distress could influence NRS or psychological distress at T2.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e\u0026lt;\u003c/b\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e\u0026gt;\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEthics\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki. The Osaka International Cancer Institute Research Ethics Committee (20084-8) and the Ethics Committee of the National Center of Neurology and Psychiatry(A2022-049)permitted the study. All participants agreed to participate in the study after obtaining informed consent through an online system.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eOf the 33,000 participants, 17,042 were analyzed after excluding 15,958 individuals (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the characteristics of participants. The mean age was 50.35 (SD\u0026thinsp;=\u0026thinsp;17.73). About 52.8% were males. A total of 11.1% reported having ACEs, and 16.7% reported often or usually experiencing NRS. The mean K6 at T1 was 5.06 (SD\u0026thinsp;=\u0026thinsp;5.74), and the proportion of individuals with psychological distress was 11.9%. The mean K6 at T2 was 4.20 (SD\u0026thinsp;=\u0026thinsp;5.42), and the proportion of individuals with psychological distress was 9.6%. The mean number of physically unhealthy days was 2.60 (SD\u0026thinsp;=\u0026thinsp;6.19), and the proportion of those with physical health problems was 6.4%. The mean number of mentally unhealthy days was 2.37 (SD\u0026thinsp;=\u0026thinsp;6.11), and the proportion of mental health problems was 6.2%. The mean number of days with activity limitation was 1.84 (SD\u0026thinsp;=\u0026thinsp;5.23), and the proportion of daytime inactivity or more was 4.2%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emean / n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSD / %\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e17.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e52.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e47.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducational level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehigh school graduate or lower\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e26.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epost-high school education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e73.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncome level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; \u0026yen; 6,000,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e50.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; \u0026yen; 6,000,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8458\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e49.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e7.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngina pectoris/myocardial infarction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCKD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic hepatitis/cirrhosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune abnormalities/ dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer/ Malignancies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma/ COPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e673\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e4.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e15.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e5.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrinking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11880\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e69.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e19.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e11.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOften or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2837\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e16.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSometimes or more\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6982\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e41.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6352\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e37.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRarely\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e21.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSometimes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e24.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOften\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e9.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUsually\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e6.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK6 at Time 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;13 at Time 1 (Psychological distress)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 5 at Time 1 (Mild psychological distress)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK6 at Time 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 13 at Time 2 (Psychological distress)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 5 at Time 2 (Mild psychological distress)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5847\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRQoL4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysically unhealthy days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 14 days (Physical health problems)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMentally unhealthy days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;14 days (Mental health problems)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays with activity limitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;14 days (Daytime inactivity)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e723\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003en, number; SD, Standard Deviation; CKD, Chronic Kidney Disease; COPD, Chronic Obstructive Pulmonary Disease; BMI, Body Mass Index; ACEs, Adverse Childhood Experiences; NRS, Nonrestorative Sleep; K6, Kessler distress scale; HRQoL4,\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lt;Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eIndependent association between psychological distress, unhealthy days, ACEs, and NRS\u003c/h2\u003e \u003cp\u003eAs Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows, ACEs was significantly associated with psychological distress, physical health problems, mental health problems, and daytime inactivity in both the crude and adjusted analyses. Adjusted analyses revealed that experience of ACEs was significantly associated with psychological distress (RR\u0026thinsp;=\u0026thinsp;2.77, 95% CI\u0026thinsp;=\u0026thinsp;2.51\u0026ndash;3.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), physical health problems (RR\u0026thinsp;=\u0026thinsp;2.64, 95% CI\u0026thinsp;=\u0026thinsp;2.33\u0026ndash;3.01, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), mental health problems (RR\u0026thinsp;=\u0026thinsp;3.20, 95% CI\u0026thinsp;=\u0026thinsp;2.82\u0026ndash;3.62, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and daytime inactivity (RR\u0026thinsp;=\u0026thinsp;3.30, 95% CI\u0026thinsp;=\u0026thinsp;2.83\u0026ndash;3.85, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, the NRS score was significantly associated with psychological distress, physical health problems, mental health problems, and daytime inactivity in both the crude and adjusted analyses. Adjusted analyses revealed that NRS was significantly associated with psychological distress (RR\u0026thinsp;=\u0026thinsp;1.58, 95% CI\u0026thinsp;=\u0026thinsp;1.43\u0026ndash;1.73, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), physical health problems (RR\u0026thinsp;=\u0026thinsp;2.80, 95% CI\u0026thinsp;=\u0026thinsp;2.39\u0026ndash;3.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), mental health problems (RR\u0026thinsp;=\u0026thinsp;2.75, 95% CI\u0026thinsp;=\u0026thinsp;2.36\u0026ndash;3.23, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and daytime inactivity (RR\u0026thinsp;=\u0026thinsp;2.91, 95% CI\u0026thinsp;=\u0026thinsp;2.39\u0026ndash;3.53, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociations between ACEs and NRS and outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePsychological distress\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhysical health problems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMental health problems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDaytime inactivity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eACEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrude\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.22 (95% CI\u0026thinsp;=\u0026thinsp;2.92\u0026ndash;3.54), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.73 (95% CI\u0026thinsp;=\u0026thinsp;2.40\u0026ndash;3.10), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.58 (95% CI\u0026thinsp;=\u0026thinsp;3.17\u0026ndash;4.04), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.43 (95% CI\u0026thinsp;=\u0026thinsp;2.95\u0026ndash;3.99), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjusted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.77, (95% CI\u0026thinsp;=\u0026thinsp;2.51\u0026ndash;3.05), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.64 (95% CI\u0026thinsp;=\u0026thinsp;2.33\u0026ndash;3.01), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.20 (95% CI\u0026thinsp;=\u0026thinsp;2.82\u0026ndash;3.62), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.30 (95% CI\u0026thinsp;=\u0026thinsp;2.83\u0026ndash;3.85), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCrude\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;5.00 (95% CI\u0026thinsp;=\u0026thinsp;4.58\u0026ndash;5.46), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;3.94 (95% CI\u0026thinsp;=\u0026thinsp;3.52\u0026ndash;4.14), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;6.47 (95% CI\u0026thinsp;=\u0026thinsp;5.77\u0026ndash;7.26), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;5.31 (95% CI\u0026thinsp;=\u0026thinsp;4.61\u0026ndash;6.11), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdjusted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.58 (95% CI\u0026thinsp;=\u0026thinsp;1.43\u0026ndash;1.73), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.80 (95% CI\u0026thinsp;=\u0026thinsp;2.39\u0026ndash;3.27), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.75 (95% CI\u0026thinsp;=\u0026thinsp;2.36\u0026ndash;3.23), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.91 (95% CI\u0026thinsp;=\u0026thinsp;2.39\u0026ndash;3.53), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eACEs, Adverse childhood experiences; NRS, non-restorative sleep; RR, Relative risk; 95% CI, 95% confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u0026lt;Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe association between ACEs and psychological distress, physical health problems, mental health problems, and daytime inactivity via NRS\u003c/b\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of the mediational analyses. ACEs\u0026rsquo; significant natural indirect effect on psychological distress via NRS was observed (RR\u0026thinsp;=\u0026thinsp;1.14, 95% CI\u0026thinsp;=\u0026thinsp;1.08\u0026ndash;1.19, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The proportion mediated was 28.2% (95% CI\u0026thinsp;=\u0026thinsp;17.5\u0026ndash;38.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the proportion eliminated was 31.5%. ACEs\u0026rsquo; significant natural indirect effect on physical health problems via NRS was observed (RR\u0026thinsp;=\u0026thinsp;1.30, 95% CI\u0026thinsp;=\u0026thinsp;1.21\u0026ndash;1.40, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The proportion mediated was 46.3% (95% CI\u0026thinsp;=\u0026thinsp;33.4\u0026ndash;59.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the proportion eliminated was 64.5%. ACEs\u0026rsquo; significant natural indirect effect on mental health problems via NRS was observed (RR\u0026thinsp;=\u0026thinsp;1.20, 95% CI\u0026thinsp;=\u0026thinsp;1.13\u0026ndash;1.28, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The proportion mediated was 30.7% (95% CI\u0026thinsp;=\u0026thinsp;20.5\u0026ndash;40.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the proportion eliminated was 33.1%. ACEs\u0026rsquo; significant natural indirect effect on daytime inactivity via NRS was observed (RR\u0026thinsp;=\u0026thinsp;1.27, 95% CI\u0026thinsp;=\u0026thinsp;1.17\u0026ndash;1.38, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The proportion mediated was 39.5% (95% CI\u0026thinsp;=\u0026thinsp;25.9% \u0026ndash; 53.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the proportion eliminated was 51.4%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCausal mediation analyses from ACEs to outcomes via NRS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePsychological distress\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhysical health problems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMental health problems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDaytime inactivity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.14 (95% CI\u0026thinsp;=\u0026thinsp;1.08\u0026ndash;1.19), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.30 (95% CI\u0026thinsp;=\u0026thinsp;1.21\u0026ndash;1.40), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.20 (95% CI\u0026thinsp;=\u0026thinsp;1.13\u0026ndash;1.28), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.27 (95% CI\u0026thinsp;=\u0026thinsp;1.17\u0026ndash;1.38), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNDE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.54 (95% CI\u0026thinsp;=\u0026thinsp;1.37\u0026ndash;1.74), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.54 (95% CI\u0026thinsp;=\u0026thinsp;1.31\u0026ndash;1.82), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.87 (95% CI\u0026thinsp;=\u0026thinsp;1.59\u0026ndash;2.18), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.72 (95% CI\u0026thinsp;=\u0026thinsp;1.41\u0026ndash;2.09), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;1.75 (95% CI\u0026thinsp;=\u0026thinsp;1.57\u0026ndash;1.96), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.01 (95% CI\u0026thinsp;=\u0026thinsp;1.73\u0026ndash;2.33), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.25 (95% CI\u0026thinsp;=\u0026thinsp;1.95\u0026ndash;2.59), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;2.19 (95% CI\u0026thinsp;=\u0026thinsp;1.83\u0026ndash;2.61), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.2% (95% CI\u0026thinsp;=\u0026thinsp;17.5% \u0026ndash; 38.8%), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46.3% (95% CI\u0026thinsp;=\u0026thinsp;33.4% \u0026ndash; 59.2%), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.7% (95% CI\u0026thinsp;=\u0026thinsp;20.5% \u0026ndash; 40.9%), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.5% (95% CI\u0026thinsp;=\u0026thinsp;26.0% \u0026ndash; 53.0%), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNDE, natural direct effect; NIE, natural indirect effect; TE, total effect; PM, proportion mediated; PE, proportion eliminated.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThese similar associations were maintained when the same analyses were performed with the threshold K6\u0026thinsp;\u0026ge;\u0026thinsp;5 instead of \u0026ge;\u0026thinsp;13 as mild psychological distress (Additional file 1) and the threshold of \u0026ldquo;Sometimes (2 to 4 days)\u0026rdquo; instead of \u0026ldquo;Often (5 to 15 days)\u0026rdquo; as NRS (Additional file 2), and when the data was limited in participants without psychological distress at T1 (Additional file 3).\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Additional file 1\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Additional file 2\u0026gt;\u003c/p\u003e \u003cp\u003e\u0026lt;Additional file 3\u0026gt;\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first longitudinal study to investigate the mediating role of NRS in the relationship between ACEs health outcomes in the general population. This study suggests that NRS mediates the impact of ACEs on psychological distress, physical health issues, psychological health issues, and daytime inactivity. The estimated proportion of the effect mediated by the NRS ranged from approximately 28\u0026ndash;46%. The present study further revealed that the adverse effects of ACEs on these health outcomes could be partially mitigated by approximately 31\u0026ndash;62% if the frequency of NRS in the past 30 days was reduced to fewer than 5 days.\u003c/p\u003e \u003cp\u003eA previous longitudinal study revealed that ACEs predict mental health issues and functional disability through sleep issues in soldiers\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Our study indicated that these associations can be applied to the general population. Our results were also consistent with the associations observed in multiple cross-sectional studies of adolescents\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e, university undergraduates\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e, and older people\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e,\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e. Our results indicated that the mediational relationships previously claimed in the subpopulation can be applied to the general population.\u003c/p\u003e \u003cp\u003ePotential physiological and behavioral mechanisms may underlie the association between ACEs and NRS scores. As an example of a physiological mechanism, cortisol dysregulation, which interrupts sleep,\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e was observed in patients with ACEs\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e,\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e. ACEs cause subsequent hypothalamic-pituitary-adrenal axis dysregulation\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e, resulting in sleep disturbance.\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e Individuals with a history of multiple ACEs can be more prone to NRS due to their lifestyle habits that negatively impact sleep. Such habits, commonly observed in patients with multiple ACEs, include an irregular life rhythm\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e and extended screen time\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e. These behaviors have been consistently linked to sleep disturbances\u003csup\u003e\u003cspan additionalcitationids=\"CR77 CR78\" citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMultiple studies support the association of NRS with mental health\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, physical health\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan additionalcitationids=\"CR81 CR82\" citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e, and daytime impairment\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. NRS may predispose individuals to mental health issues by increasing their vulnerability to stressful events\u003csup\u003e\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e,\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u003c/sup\u003e and impairing emotion regulation\u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u003c/sup\u003e. It is also suspected that NRS contributes to physical health issues by promoting unhealthy behavioral patterns. Poor sleep conditions have been linked to reduced physical activity\u003csup\u003e\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e,\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e\u003c/sup\u003e, suboptimal dietary behaviors\u003csup\u003e\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e, and the consumption of unhealthy food\u003csup\u003e\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e,\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u003c/sup\u003e. Additionally, NRS may influence various biological processes that detrimentally affect physical health, such as elevating blood pressure\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, disrupting metabolism\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, and weakening the immune system\u003csup\u003e\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u003c/sup\u003e, which in turn can lead to a range of health issues. Furthermore, NRS-induced executive dysfunction and diminished performance can result in daytime inactivity\u003csup\u003e\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e,\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e\u003c/sup\u003e. Given that the NRS could be a modifiable risk factor, interventions targeting NRS could be crucial in preventing or mitigating health issues among individuals affected by multiple ACEs. Sleep hygiene education emphasizing the importance of restorative sleep and modification of detrimental habits, such as irregular life rhythms\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e and prolonged screen time\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e, could potentially enhance health outcomes by improving the NRS. Furthermore, interventions for individual sleep dysfunctions, such as pharmacotherapy (e.g., orexin receptor agonist, melatonin agonists, benzodiazepine receptor agonist, etc.), cognitive behavioral therapy for insomnia, light therapy, and continuous positive airway pressure\u003csup\u003e\u003cspan additionalcitationids=\"CR94 CR95 CR96 CR97\" citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR98\" class=\"CitationRef\"\u003e98\u003c/span\u003e\u003c/sup\u003e, may lessen NRS and improve health outcomes. Future research should examine the efficacy of such interventions in improving NRS and longitudinal health outcomes in individuals with ACEs.\u003c/p\u003e \u003cp\u003eThis study had some limitations. First, the predictive strengths of ACEs and NRS for physical health issues, mental health issues, and daytime inactivity might be overestimated. This potential overestimation arose because these outcome variables at T1 were not included as covariates, although the K6 at T1 was included. Therefore, the reported effect sizes should be interpreted with caution. Second, there may have been an unadjusted potential bias. Nevertheless, this study had notable strengths, including its large sample size and longitudinal design.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study identified NRS as a mediator of the pathway from ACEs to mental health, physical health, and daytime impairment within the general population using a longitudinal design over an eight-month interval. Regrettably, ACEs are immutable, given their nature as past events. Nonetheless, our findings suggest that NRS treatment can alleviate health issues in individuals with ACEs. Therefore, targeted interventions for NRS could potentially prevent or alleviate these health issues and the associated functional impairments.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAdverse childhood experiences (ACEs)\u003c/p\u003e\n\u003cp\u003eNonrestorative sleep (NRS)\u003c/p\u003e\n\u003cp\u003eKessler distress scale (K6)\u003c/p\u003e\n\u003cp\u003eOdds ratios (ORs)\u003c/p\u003e\n\u003cp\u003eJapan COVID-19 and Society Internet Survey (JACSIS study)\u003c/p\u003e\n\u003cp\u003eAdverse Childhood Experience in Japan (ACE-J)\u003c/p\u003e\n\u003cp\u003eStandard deviation (SD)\u003c/p\u003e\n\u003cp\u003eRisk risks (RRs)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki. The Osaka International Cancer Institute Research Ethics Committee (20084-8) and the Ethics Committee of the National Center of Neurology and Psychiatry（A2022-049）permitted the study. All participants agreed to participate in the study after obtaining informed consent through an online system.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data are available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: MH, KM, TT, RO, TY, SK, AK, KN, TU, MI, JK, MF, and KK. Data collection: TT and RO. Formal analysis: MH. Data\u0026nbsp;interpretation:\u0026nbsp;MH, KM, and KK. Original Draft preparation: MH and KM. Review and editing: all authors. Super vision: KK.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the following grants: the Japan Society for the Promotion of Science (JSPS) KAKENHI Grants (17H03589, 19K10671, 19K10446, 18H03107, 18H03062,\u0026nbsp;19H03860, 21H0485, 19K19439, 22K15764), Research Support Program to Apply the Wisdom of the University to tackle COVID-19 Related Emergency Problems,\u0026nbsp;the University of Tsukuba,\u0026nbsp;Health Labour Sciences Research Grant (\u003cstrong\u003e19FA1005\u003c/strong\u003e; 19FG2001; 19FA1012), and the Japan Agency for Medical Research and Development (AMED; 2033648).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAdverse childhood experiences (ACEs). https://www.cdc.gov/violenceprevention/aces/index.html (2023).\u003c/li\u003e\n \u003cli\u003eHughes, K. \u003cem\u003eet al.\u003c/em\u003e Health and financial costs of adverse childhood experiences in 28 European countries: a systematic review and meta-analysis. \u003cem\u003eLancet Public Health\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, e848\u0026ndash;e857 (2021).\u003c/li\u003e\n \u003cli\u003eFelitti, V. 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Sleep Med.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 307\u0026ndash;349 (2017).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"00f6f18a-47a4-45ee-87bc-832fc2c22a52","identifier":"10.13039/501100001691","name":"Japan Society for the Promotion of Science","awardNumber":"17H03589, 19K10671, 19K10446, 18H03107, 18H03062, 19H03860, 21H0485, 19K19439, 22K15764","order_by":0},{"identity":"5ee9ec64-d9cc-4d93-ae50-b332edfe6ed1","identifier":"10.13039/100009619","name":"Japan Agency for Medical Research and Development","awardNumber":"2033648","order_by":1},{"identity":"a0b37711-6d15-4815-9168-60f877c0eb2f","identifier":"10.13039/501100006559","name":"University of Tsukuba","awardNumber":"19FA1005; 19FG2001; 19FA1012","order_by":2}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"National Center of Neurology and Psychiatry","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"non-restorative sleep, adverse childhood experiences, mental health, physical health, activity limitations","lastPublishedDoi":"10.21203/rs.3.rs-4314857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4314857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cem\u003e \u003c/em\u003eThis study explores the associations between adverse childhood experiences (ACEs), \u0026nbsp;\u0026nbsp;health problems, and increased daytime inactivity, emphasizing nonrestorative sleep (NRS), a subjective perception of unrefreshing sleep, as a significant contributing factor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cem\u003e \u003c/em\u003eA longitudinal online survey utilizing data from the Japan COVID-19 and Society Internet Survey was employed. The Kessler distress scale (K6) served as the primary outcome measure, with a score of K6 ≥ 13 indicating psychological distress. Health-Related Quality of Life-4 was utilized to assess mentally unhealthy days, physically unhealthy days, and days with activity limitation, indicating mental health problems, physical health problems, and daytime inactivity if exceeding 14 days monthly, respectively. NRS frequency within the past 30 days was evaluated on a 5-point scale, with \"usually\" (16 days or more) indicating NRS presence. ACEs were identified when four or more items from a validated ACEs list were selected. A causal mediation analysis was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong the 17,042 participants, 52.8% were male, averaging 50.35 years of age (SD = 17.73). Approximately 11.1% reported four or more ACEs. Notably, 16.7% met NRS criteria, while 9.6% met psychological distress criteria. The proportions of individuals with physical health problems, mental health problems, and activity limitations were 6.4%, 6.2%, and 4.2%, respectively. Significant mediational pathways via NRS were observed from ACEs to psychological distress (RR = 1.14, 95% CI = 1.08–1.19, p \u0026lt; 0.001), physical health problems (RR = 1.30, 95% CI = 1.21–1.40, p \u0026lt; 0.001), mental health problems (RR = 1.20, 95% CI = 1.13–1.28, p \u0026lt; 0.001), and daytime inactivity (RR = 1.27, 95% CI = 1.17–1.37, p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This study suggests that NRS mediates the impact of ACEs on mental or physical health issues and daytime inactivity. Further research is needed to determine whether targeting NRS can alleviate ACE-associated health problems.\u003c/p\u003e","manuscriptTitle":"Nonrestorative Sleep Mediates the Influence of Adverse Childhood Experiences on Psychological Distress, Physical Health, Mental Health, and Activity Limitation: A Longitudinal Study for the General Population in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-26 02:09:36","doi":"10.21203/rs.3.rs-4314857/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98cf31e2-75e2-4837-a2e4-b2ce9131177f","owner":[],"postedDate":"April 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31075877,"name":"Psychiatry"}],"tags":[],"updatedAt":"2024-05-10T11:07:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-26 02:09:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4314857","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4314857","identity":"rs-4314857","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}