Withania somnifera) has been demonstrated to reduce anxiety and stress, allowing the body to settle down and prepare for sleep. This study will be a double-blind, randomized, placebo-controlled interventional study in NRS population.Nonrestorative sleep (NRS) is one of the cardinal symptoms of insomnia and can occur independent of other components of insomnia. Among the sleep disturbances, NRS has been little studied in the general population, even though this symptom plays an important role in several medical conditions associated with chronic inflammation such as heart disease, fibromyalgia, and chronic fatigue syndrome, as well as various sleep disorders. There is paucity in the literature about effective treatments for NRS. Ashwagandha (The NRS participants are identified using Restorative Sleep Questionnaire-weekly version (RSQ-W) questionnaire. Actigraphy and polysomnography are used for the objective assessment of sleep. The other assessments used are Hamilton Anxiety Depression Scale (HADS), World Health Organization Quality of Life (WHOQOL) scales, and C-reactive protein. Routine blood and urine analyses will be conducted to assess the safety of treatment. Duration of study for each participant will be 50 days with “day one” for screening followed by randomization for the treatment. The duration for medicine/placebo intake shall be 42 days.Primary outcome will be to evaluate effect of daily supplement of ashwagandha extract compared with placebo in subjects with NRS at 6 weeks from baseline, as assessed by the total score of RSQ-W.CTRI/2017/02/007801 This results in daytime fatigue. In a Swedish survey of 1550 randomly selected subjects from entire Swedish population, almost one-third felt the need for the treatment and yet had not consulted healthcare provider. Insomnia symptoms are highly heterogeneous in terms of causes and manifestations. Recent studies have suggested that NRS symptoms may or may not be present along with insomnia symptoms such as difficulty in initiating and/or maintaining sleep (DIS and/or DMS). Thus, sleep disorders may be grouped as pure DIS and/or DMS, only NRS, and combination of DIS and/or DMS with NRS.Disturbed sleep is one the commonest encounters of day-to-day life in the fast moving society. NRS has been little studied in the general population even though it influences several medical conditions such as heart disease, fibromyalgia, and chronic fatigue syndrome, as well as various sleep disorders. When compared with subjects who have only DIS/DMS, subjects with NRS reported more frequently a variety of daytime impairment  and consulted a physician twice as frequently for their sleeping difficulties. According to International Classification of Sleep Disorders (ICSD), NRS is an associated feature in many intrinsic sleep disorders such as sleep- related breathing disorders and Parasomnias. Other conditions, such as chronic fatigue syndrome and depression, have increased peripheral inflammatory markers and NRS as common features. This underscores the causative relationship between systemic inflammation and NRS.NRS can be defined as a moderate to severe complaint of being unrefreshed upon awakening (even if the sleep duration is sufficient according to the subject) occurring at least 3 nights per week during a period of at least 1 month. Despite recent advances in the development of newer hypnotics in modern medicine, a significant proportion of subjects with sleep disturbances, both locally and internationally, consume herbal hypnotic regularly. Therefore, there is always a search for a candidate molecule for the better management of NRS.Currently available treatments for insomnia, including pharmacologic managements and psychological therapy, are designed for DIS and/or DMS rather than NRS, even though NRS is associated with a greater level of functional impairment.Given the multifactorial involvement in NRS, it seems logical that a medicine that would cause reduction in stress, has antidepressant property, reduces peripheral inflammatory activity, and also help in improving physical performance will be useful in treating NRS.Withania somnifera) has shown to be effective in reduction of chronic inflammation markers such as C-reactive protein (CRP). It was shown to have mild anti-anxiety and anti-depressant effect and effective in reducing postchemotherapy fatigue in breast cancer subjects.–14 Thus, Ashwagandha would very likely have an impact on “NRS.” The investigational product studied in this clinical study is an extract of Ashwagandha (W somnifera) developed by M/s Arjuna Natural Extracts Ltd., Aluva, Kerala, India, that is standardized to contain about 35% glycowithanolides.In multiple clinical trials, Ashwagandha .The secondary objective will be to compare Ashwagandha and placebo groups on change from baseline up to 6 weeks by actigraphy parameters , nocturnal polysomnogram parameters (only in a subset of 30 subjects) such as sleep onset latency (SOL), wakefulness after sleep onset (WASO), TST, Micro-arousal index and time spent in individual sleep stage, quality of life scores using WHOQOL-BREF scale, depression, and anxiety scores using Hospital Anxiety and Depression Scale and CRP levels.2.2NRS (with or without DIS and/or DMS) is strongly associated with stress, anxiety, depression, daytime fatigue, and increased CRP. Ashwagandha was shown to be effective in relieving stress and depression. It is also effective in reducing fatigue and inflammatory markers such as CRP levels. Thus, it is proposed that Ashwagandha would likely be effective in reducing NRS.2.3www.ctri.nic.in) (CTRI registration number: CTRI/2017/02/007801). The study will be conducted according to the Declaration of Helsinki 2013, the ICH-GCP E6  1996, and ICMR-National Ethical Guidelines for Biomedical and Health Research, 2006. The investigational product will be Ashwagandha extract 300 mg in size “0” capsule of M/s Arjuna Natural Extracts Ltd., Aluva, Kerala, India, and matching placebo in size “0” capsule for reference group.This is a prospective, randomized, double-blind, parallel, placebo-controlled, single-center, clinical study. The study will be conducted at International Institute of Sleep Sciences, Thane, Maharashtra, India. The study protocol  is approved by institutional ethics committees and registered with Clinical Trials Registry- India  will take the informed consent before enrolling the subjects and will take all necessary precautions in protecting the confidentiality of the subjects. The subjects will be identified throughout and after the completion of the study only by the allotted randomization number to protect the confidentiality. The PI delegated pharmacist will dispense the study products. As this study is double blinded, the PI and the subject will be blinded toward the interventions. If a need to know arises in which case knowing the identity of interventions is necessary, the PI will be permitted to unblind the subject. Adequate subject enrollment would be achieved by those visiting the site, educational pamphlets, and by study camps conducted in nearby places. The enrolled subjects would be assigned to either of the 2 study groups (75 in each study group). Subjects will be instructed to take 2 capsules of Ashwagandha extract 300 mg or matching placebo once daily in the evening 2 hours before food with water.2.4Differences of 10 points and 15 points for RSQ-W total score are considered as clinically significant and clinically highly significant, respectively. Assuming standard deviation of 25 points, these differences correspond to standardize effect size of 0.4  and 0.6 (medium-to-large), respectively, as per Cohen recommendation. The difference of 10 points for RSQ-W total score (range 0–100 points) also translates to about 1-point change on 5-point Likert scale in 4 of 9 items of the RSQ-W. Similarly, the difference of 15 points for RSQ-W total score translates to about 1-point change in 5 of 9 items of the RSQ-W.Group-sequential method will be used to determine the sample size. The planned sample size of 150 subjects (75 in each study treatment group) will be required to detect a difference of 10 points in change in RSQ-W total score at 6 weeks from the baseline between the study treatment groups, assuming a standard deviation of 25 points and a 15% drop-out rate, to achieve 80% statistical power at 5% (2-sided) level of significance. Two interim analyses are planned to occur after completion of the study of 50 subjects and 150 subjects. If the analysis turns out to have a statistically nonsignificant difference, then the enrollment may extend to 236 subjects. The final analysis will be performed when all 236 subjects complete the study.2.5This will be a parallel arm treatment study and all the enrolled subjects will be instructed to take study medication for a treatment period of 6 weeks. There will be a total of 8 to 9 visits and/or follow ups: screening, randomization , follow-up (visit 2 or day 1), follow-up (visit 3 or day 8), follow-up (visit 4 or day 15), follow-up (visit 5 or day 22), follow-up (visit 6 or day 29), follow-up (visit 7 or day 36), follow-up (visit 8 or day 43), and end of study visit (visit 9 or day 50). Laboratory investigation of all the efficacy and safety parameters will be conducted screening and end of the study. Visits 1,3,7,8, and 9 are mandatory for physical presence at investigation site. Visits 4, 5, and 6 can be done via telephone as per subject's convenience. Visit 2 is only for subjects who will be undergoing polysomnography evaluation.2.6A total of 150 subjects either male or female with age 18 to 65 years will be enrolled in this study. The study eligibility criteria were chosen to maximize generalizability of the results, while taking into account safety and well-being of the participants. The inclusion and exclusion criteria are summarized in Table 2.7W somnifera, Solanaceae) and is manufactured by Arjuna Natural Extracts Ltd, Aluva, Kerala, India. Harvested dried roots of Ashwagandha, visually identified by a qualified botanist, are used to manufacture the extract. The extraction solvent used was ethanol: water with a proportion of 70:30 with a raw material to extract ratio of 13:1. The extract was standardized by HPLC to contain 35% glycowithanolides. The analysis of heavy metals was done with ICP-MS and conforms to EU standards . The microbial assay was done using AOAC, BAM method and conforms to EU standards . Identically colored and similar sized placebo capsules were used as the placebo.The investigational product used in this study is a proprietary detoxified root extract of Ashwagandha (Ashwagandha extract or matching placebo capsules will be given as two 300 mg capsules once daily in the evening 2 hours before food with water. The dosage of Ashwagandha extract (Shoden) capsules is standardized to contain 21 mg of glycowithanolides per dose. No dose modification will be allowed in the study. Subjects needing concomitant medication will be managed as per the exclusion criteria of the study. Those subjects having adverse events (AEs) that require standard treatments will be discontinued. Investigational product accountability and telephonic follow-up are used to monitor adherence to protocol.2.8A Data Monitoring Committee (DMC) will review the safety of the study and the results of the interim analyses and make appropriate recommendations to the trial steering committee. The DMC will be independent from the sponsor and do not have any competing interests. The members have experience in reviewing clinical trial data and have statistical analysis background. Requests for granting public access to the full protocol, participant-level dataset, and statistical code will be as per the SOP of the DMC, which can be sourced with a detailed request to the committee.2.9P value of ≤.0002 for the first analysis and ≤.012 for the second analysis. These boundaries are obtained using O’Brien–Fleming spending function and based on an overall significance level of 5%. That is, the study is likely to be stopped for strong efficacy signal at the first and second interim analysis if the observed mean difference between the study treatment groups is at least 26 points and 12 points, respectively . The study may also be stopped due to futility at any interim analyses on discretion of the DMC. If we do not get a desired statistical difference with the analysis of 150 subjects, then we will continue the enrollment up to 236 subjects and the final analysis will be performed when all 236 subjects complete the study, using a critical P value of ≤.0475.Interim analyses for efficacy are planned after 50 and 150 subjects complete the 6-week assessment for the primary outcome (or discontinue the study) using a critical 2.10No AEs have been reported with the use of the product till now in various clinical studies conducted earlier in subjects but as a precautionary measure we are monitoring the routine hematological, biochemical, and urine analysis in the in-house laboratory. In addition, the subjects would be asked an open question like “Have you noticed any change in your health since your last visit?” For all AEs, the investigator will pursue and obtain information about the type, severity, date of onset, treatment given, duration, outcome, causality as assessed by WHO criteria, and decide on whether the AE is serious or not. The serious adverse event (SAE) will be recorded on SAE form and reported to the Ethics Committee and to the Sponsor's representative. The sponsor has taken adequate insurance in case of any need for post trial care or compensation to those who suffer from harm as a result of participation in the trial.3Measures include demographic data, vital signs , etc. The primary and secondary study efficacy outcomes are listed in Table 3.1RSQ-W is a validated scale for measuring refreshing quality of sleep. It has 9 items with answers scaled from 1 to 5. Some items are reversed scored. The total score is an average score based on all 9 items and rescaled to a 0 to 100 scale, using the following transformation: RSQ-W Total Score = (RSQ-W average score across completed items – 1) X 25.3.2WHOQOL-BREF is a 26-item, self-administered, cross-culturally validated questionnaire in which items are rated on a 5-point scale. The 26 items measure the following broad domains: physical health, psychological health, social relationships, and environment. Domain scores are scaled in a positive direction . The mean score of items within each domain is used to calculate the domain score. Mean scores are then multiplied by 4. The second transformation method described in the manual converts domain scores to a 0 to 100 scale. The study will use the English version.3.3Hospital and Anxiety Scale (HADS) is a 14-item cross culturally validated scale with 7 items each in 2 subscales for evaluation of symptoms of anxiety (HADS-A) and depression (HADS-D). It detects symptoms of anxiety and depression, rather than making a diagnosis of the syndrome, and excludes symptoms that may arise from physical illness, insomnia, or fatigue. Each item is scored (0–3) according to severity, with a maximum possible score of 21 for each subscale. A score of 0 to 7 indicates no anxiety or depression, a score of 8 to 10 indicates a borderline case, and a score of 11+ indicates presence of anxiety and/or depression. The study will be using English version for the study.3.4Actigraphy is a noninvasive method of monitoring human rest/activity cycles. It is validated against gold standard Nocturnal Polysomnogram. Using software algorithms, sleep parameters such as latency to sleep, sleep duration, awakenings per night, and sleep efficiency are calculated. We will be able to distinguish between 3 groups  using actigraphy. Another advantage of actigraphy will be assessment of sleep in subject's own natural environment.3.5Nocturnal polysomnography (NPSG) is considered a gold standard test for objective measurements of sleep parameters such as total bed time, TST, sleep efficiency, SOL, WASO, micro arousal index, % of each sleep stage , apnea/hypopnea index (AHI), and periodic limb movement index (PLMI). The NPSG monitors many body functions, including brain (EEG), eye movements (EOG), muscle activity or skeletal muscle activation (EMG), and heart rhythm (ECG) during sleep. Recordings will be taken from bedtime to awakening in the morning and continuous audiovisual infra red monitoring of the subjects. Sleep stages shall be manually scored according to guidelines in American Academy of Sleep Medicine (AASM) Manual for the Scoring of sleep and Associated events in 30-second epoch page.3.6Serum CRP, a systemic marker of inflammation, is associated with an increased risk for a host of chronic diseases. Reduction in the CRP level would suggest reduction in chronic inflammation.3.7P value of < .05 will be considered as statistically significant. Standard statistical tests will be used to analyze the data obtained. For efficacy analysis both, modified intention-to-treat (mITT) analysis and per-protocol (PP) analysis will be done. The PP analysis will be considered as definitive, while the mITT analysis will be considered as supportive during the trial analysis.The data will be collected from paper case report forms  by the investigator and given to the statistician who will analyze the data for demographics, efficacy, and safety. Data will be presented as mean ± SD/SE or number (percentage). Descriptive statistics will be used for different variables at baseline. 4The quality of sleep is one of the major hurdles that sleep therapists face in today's society. NRS is one of the indicators of poor sleep quality that results in day time fatigue and lethargy.W somnifera), also commonly known as Indian ginseng, is a shrub plant belonging to the Solanaceae family. The various plant parts of  of Ashwagandha have been used by traditional Indian Ayurvedic medicine for thousands of years to help with inflammation, sexual issues, nerve tissue damage, stress, anxiety, insomnia, and many other ailments. The major phytochemical constituents reported from Ashwagandha are alkaloids , steroidal lactones , saponins containing an additional acyl group (sitoindoside VII and VIII), withanolides with a glucose at carbon 27 also known as glycol-withanolides (sitoindoside IX and X), and amino acids such as aspartic acid, proline, tyrosine, alanine, glycine, etc. A lot of herbal supplements are commercially available containing majority of alkaloids and small amount of withaferine. The pharmacological activity of such products has been claimed as due to presence of alkaloids and/or withaferine. European Food Safety Authority (EFSA) has categorized some of the alkaloids of Ashwagandha as toxic and harmful. These include anaferine, anahygrine, withanine, sominiferine, somnine, tropine, etc. Apart from alkaloids, withaferine A has also been categorized as cytotoxic lactones by EFSA.Ashwagandha  in society, its resultant, and the lack of high-quality evidence for the efficacy of the commonly used medication. It is anticipated that this study will result in evidence-based treatment of subjects suffering from nonrefreshing sleep. If negative, the results of this study will still be critical for further efforts to elucidate epidemiology, pathophysiology, and new treatment targets for NRS.5NRS is relatively common and yet underexplored issue. There is a paucity of knowledge about its prevalence, clinical implications, and treatment. This study will be the first of epidemiological studies to explore the prevalence of this entity in Indian population. To our knowledge, this will be the first study to explore objective correlates of NRS using actigraphy, which gives us the advantage of measuring these in subject's own environment. Ashwagandha has been shown to be a useful supplement in many conditions such as postchemotherapy fatigue in double-blind, randomized studies. This study will also be the first to explore specific changes in sleep quality.This study will be limited to educated people who can read and/or understand English. Although an argument can be made in defense of this limitation, NRS has shown to be more prevalent in educated, younger demographic. Due to financial constraints, NPSG will not be performed in all populations.The authors deeply acknowledge the gracious help of M/s Arjuna Natural Extracts Ltd., Aluva, Kerala, India, for providing Ashwagandha extract capsule and financial assistance to conduct the study.Conceptualization: Abhijit Deshpande, Nushafreen Irani, Rathna Balakrishnan.Data curation: Abhijit Deshpande, Nushafreen Irani.Formal analysis: Abhijit Deshpande.Funding acquisition: Abhijit Deshpande.Investigation: Abhijit Deshpande, Nushafreen Irani.Methodology: Abhijit Deshpande, Rathna Balakrishnan.Project administration: Nushafreen Irani, Rathna Balakrishnan.Resources: Abhijit Deshpande.Software: Abhijit Deshpande.Supervision: Abhijit Deshpande, Nushafreen Irani, Rathna Balakrishnan.Validation: Abhijit Deshpande.Visualization: Abhijit Deshpande.Writing – original draft: Abhijit Deshpande.Writing – review & editing: Abhijit Deshpande, Nushafreen Irani, Rathna Balakrishnan.


Background: The association between age and health-related quality of life (HRQoL) is still under debate. While some research shows older age is associated with better HRQoL, other studies show no or negative association between age and HRQoL. In addition, while the association between age and HRQoL may depend on race, ethnicity, gender, and their intersections, most previous research on this link has been performed in predominantly White Middle Class. Objective: To explore gender differences in the association between age and mental and physical HRQoL in a sample of economically disadvantaged African American (AA) older adults. Methods: This cross-sectional survey was conducted in South Los Angeles between 2015 to 2018. A total number of 740 economically disadvantaged AA older adults (age ≥ 55 years) were enrolled in this study, using non-random sampling. This includes 266 AA men and 474 AA women. The independent variable of interest was age. Dependent variables of interest were physical component scores (PCS) and mental component scores (MCS), two main summary scores of the HRQoL, measured using Short Form-12 (SF-12). Gender was the moderator. Socioeconomic status  were covariates. Linear regression models were used to analyze the data. Results: AA women reported worse PCS; however, gender did not impact MCS. In the pooled sample, high age was associated with better PCS and MCS. In the pooled sample, a significant interaction was found between gender and age on PCS, suggesting a stronger effect of age on PCS for AA men than AA women. In gender-stratified models, older age was associated with better PCS for AA men but not AA women. Older age was similarly and positively associated with better MCS for AA men and women. Conclusions: There may be some gender differences in the implications of ageing for the physical HRQoL of AA older adults. It is unclear how old age may have a boosting effect on physical HRQoL for AA men but not AA women. Future research should test gender differences in the effect of age on physical health indicators such as chronic disease as well as cognitive processes involved in the evaluation of own’s health in AA men and women. Health-Related Quality of Life (HRQoL) predicts a wide range of health outcomes, including falls , health There is no agreement on how older age influences HRQoL ,21,22. WFor example, falls may be a mechanism that links age to HRQoL . In a stSome research suggests that not only race and ethnicity  but alsoIn line with the global trends, the American population is undergoing an unprecedented ageing process, which is accompanied with and increased life expectancy and presence of multimorbidity. Increased life expectancy combined with an increase in prevalence of non-communicable diseases increases the number of years that the population of older adults live . As a reTo better understand whether gender alters meanings and correlates of subjective health measures in low-income AA older adults ,44,45,46This was a cross-sectional survey of economically disadvantaged AA older adults in South Los Angeles. The study was performed between 2015 and 2018.The data collection included structured face-to-face interviews and a comprehensive assessment of medications. The interview collected data on demographic factors (age and gender), SES , and HRQoL.The study used a non-random sampling strategy to recruit AA older adults from economically disadvantaged areas in South Los Angeles. Using a convenience sampling, participants were eligible if they were AA or Black, were 55 years or older, could complete an interview in English, and were living in SPA6. Institutionalized participants were excluded from the study. Other exclusion criteria included being enrolled to any clinical trial. This sampling resulted in 740 economically disadvantaged AAs aged 55 years and older. Demographics of our participants were comparable to those of AA older adults in South Los Angeles. In our sample, only 35% had a high school diploma. With a similar pattern, in the California Health Interview Survey (CHIS) data, 37% of AA older adults in South Los Angeles had a high school diploma. Regarding the health status of our participants, about one third described their SRH as fair or poor. Again, similarly, CHIS data show that 38% of AA older adults with the same age group living in South Los Angeles report fair or poor SRH . The HRQoL was measured using SF-12v2, which is a 12-item measure. This measure generates two summary scores and eight sub-domains . Summary scores include the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores. Bodily Pain (BP), General Health (GH), Vitality (VT), and Social Functioning (SF) with one item each; and physical Functioning (PF), Mental Health (MH), Role Physical (RP), and Role Emotional (RE) domains, each with two items. To score the SF-12v2, we followed the method proposed by the original authors. The summary scores are calculated from z-scores of the 8 subscales. All scales contribute to the scorings of PCS and MCS, using weights from principal component analysis on the SF-36 scales. The norm-based scoring that is commonly used for SF-12v2 produces scores with a mean of 50 and a standard deviation of 10 for the US population. A higher score indicates better HRQoL ,58,59,60Age was treated as an interval variable. Educational attainment and financial difficulty were the SES covariates in this study. Educational attainment was operationalized as an interval level variable (years of schooling). Higher scores indicated more years of education. Financial difficulty was measured using three items. These items asked about the frequency of not having enough money to afford (1) food, (2) clothing, and (3) paying bills. Items were on a 5-level response scale ranging from 1 (never) to 5 . A total “financial difficulty” score was calculated, with a score ranging from 3 to 15. A high score was indicative of more financial difficulty. These items are consistent with Pearlin’s list of chronic financial difficulties of low SES individuals . .t Values, and p Values were reported. We ruled out multicollinearity between our predictors. We also tested the homoscedasticity of our outcomes, defined as having equal statistical variances. We replicated our model for self-rated health as outcome . For descriptive purposes, means, standard deviation (SD), and frequencies (%) were reported, both in the pooled sample and by gender. We used the independent samples t test and the Chi-squared test to compare our study variables between AA men and AA women. We also ran the Pearson correlation test to explore correlations between study variables in the pooled sample and by gender. For multivariable analysis, we used eight linear regression models, four for PCS and four for MCS as the outcome. In our models, age was the main independent variable, either PCS or MCS was the main outcome, SES  were the covariates, and gender was the moderator. From linear regression models, b (regression coefficient), standard errors (SE),  outcome .The study protocol was approved by the Institutional Review Board (IRB) of the Charles R. Drew University of Medicine and Science (CDU), Los Angeles. All participants signed a written informed consent before being enrolled in the study. Participants received a financial incentive.A total number of 740 economically disadvantaged AA older adults who were at least 55 years old entered to this study. From this number, 474 were AA women and 266 were AA men. Average age of the participants was 71.73 (SD = 8.37). Mean educational attainment of this sample was 12.74 (SD = 2.24). On average, their PCS was considerably lower than average US population , however, their MCS was about average US population (52.28 ± 10.93).In the pooled sample, a gender-by-age interaction was found in the model with PCS as the outcome, suggesting that the positive association between age and PCS is stronger for AA men than AA women. In the pooled sample, gender and age did not interact on MCS as the outcome, suggesting that the positive association between age and MCS does not differ between AA men and AA women.In a sample of economically disadvantaged AA older adults in LA, the current study showed two findings. First, age was positively, not negatively, associated with HRQoL in the pooled sample. This pattern was consistent for PCS and MCS and could be replicated for SRH, another well accepted subjective measure of health . Second,Our first finding on the positive association of age with physical and mental HRQoL, which could be replicated for SRH, is similar to some, but not all, studies. In a study that involved 247 older adults composed of 154 Whites, 90 AAs, and 3 Asians, participants reported an improvement in the HRQOL over a two-year follow up period. The study showed that the AAs had greater improvements in mental HRQoL compared to Whites . Overall, age has shown inconsistent effects on HRQoL across studies . Even wiThe observed positive associations between age and PCS/MCS in this study may also be due to the mortality cross-over that happens in AAs, compared to Whites ,78,79,80Among studies on population differences in determinants of subjective health, there are fewer studies on HRQoL and more studies on SRH. In a recent study in AA adults, for women, SRH was found to operate like a sponge; it absorbed more affective and contextual information compared to AA men . Other sGender differences exist in subjective measures of well-being and health . In mainly White samples, poor SRH predicted risk of mortality of men better than women ,68. In oThere are also studies that do not confirm major gender differences in meanings of SRH. In another study spanning 12 years from the Health and Retirement Study (HRS), males and females were compared for trajectories and determinants of SRH. The study, which was mainly composed of Whites, did not show gender differences in the SRH levels at baseline; however, SRH declined faster for men than women over time. Onset of development of CMC, health behaviors such as smoking, and rate of retirement explained the observed gender difference in trajectory of SRH over time .In a study that used the 2002–2015 National Health Interview Survey (NHIS) data, ordered logistic regression models were applied to predict SRH as a function of two dozen health conditions including CMC, physical symptoms, mental health, function, health care use, and health behaviors by gender. The study found almost no evidence supporting the sponge hypothesis. The study failed to show systematic gender variation in the structure of SRH. The study showed that men and women use a wide-range of health-related frames of reference, mostly in a similar way, to make a judgment regarding their own health. The following gender differences were observed: at mid-life and older ages, men have a higher tendency than women to weigh physical functioning and negative health behaviors as a factor in SRH. The study suggested that only through mid-adulthood, women report worse SRH than men. This pattern is reversed in older ages. The study also showed that the female disadvantage in SRH is fully due to SES differences. The study argued that SRH can be used to measure gender differences in health . A studyGender, race/ethnicity, SES, and their intersections change how subjective measures such as SRH and HRQoL reflect health problems such as CMC, depression, and mortality. In other words, poor status in subjective measures do not have the same meaning across groups ,64,65,66study, causal associations are not plausible. This study did not control several factors such as income, history of psychiatric disorders, chronic diseases. Unbalanced sample size between AA men and AA women may have resulted in differential statistical power between AA men and AA women. This is not a concern, as we found stronger association in the smaller group . In addition, with the convenience sampling in that area and excluded institutionalized participants, the results may have over-estimated the HRQoL or underestimated the effects of covariates on the outcome variables. In addition, we only focused on physical and mental HRQoL. Other researchers may also focus on subscales of HRQoL, which were not of interest here. We can also not rule out the possibility that gender differences in response styles result in the observed gender differences in HRQoL. Our study failed to explain possible self-report differences on the data collection. These limitations should be addressed in future studies examining older AA adults’ HRQoL. Despite these limitations, this study contributes to the literature on the intersectional effects of race, gender, and age on populations’ HRQoL. This study is unable to make a distinction between age- and cohort- differences. Although, as all participants were at least 55 years old, participants were at most one generation different from each other. Particularly in studies that use a cross-sectional design, the association between age and HRQoL may be confounded with cohort effect. Thus, the results may not all be due to aging, but some of it may be due to variations across generations. This issue can be studied in future studies with multiple observations over time. In summation, our findings suggest that among economically disadvantaged AA older adults, age is positively associated with physical and mental HRQoL. Low-income older AA men and women, however, differ in the association of age and physical HRQoL. Age may have a stronger effect on physical HRQoL for economically disadvantaged older AA men than for AA women. The results invite researchers to study how age-related changes in HRQoL differ between AA older men and women.


Background and objectives: Ionizing radiation (IR) has been of immense benefit to man, especially for medical purposes (diagnostic imaging and radiotherapy). However, the risks of toxicity in healthy normal cells, leading to cellular damage as well as early and late side effects, have been major drawbacks. The aim of this study was to evaluate the radioprotective effect of hesperidin against IR-induced damage. Materials and Methods: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were applied in reporting this study. A search was conducted using the electronic databases PubMed, Scopus, Embase, Google Scholar, and www.ClinicalTrials.gov for information about completed or ongoing clinical trials. Results: From our search results, 24 studies involving rats, mice, and cultured human and animal cells were included. An experimental case—control design was used in all studies. The studies showed that the administration of hesperidin reduced oxidative stress and inflammation in all investigated tissues. Furthermore, it increased 30-day and 60-day survival rates and protected against DNA damage. The best radioprotection was obtained when hesperidin was administered before irradiation. Conclusions: The results of the included studies support the antioxidant, anti-inflammatory, and antiapoptotic abilities of hesperidin as a potential radioprotective agent against IR-induced damage. We recommend future clinical trials for more insights. Since the discovery of ionizing radiation (IR) in the early 1900s, its use has been on the increase. Nowadays, the use of IR can be found in industrial and agricultural sectors. However, it is mostly utilized in medicine for diagnostic as well as treatment aims. The use of IR for diagnostic purposes is responsible for the majority of radiation doses received by man . MoreoveDespite the numerous benefits of IR to man, the risks of toxicity to healthy normal cells leading to cellular damage as well as early and late side effects have been major drawbacks. IR causes damage to cells via direct and indirect effects. Direct effects occur when IR interacts directly with DNA. Indirect effects take place as a result of the interaction between free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), and neighboring DNA molecules . The mosIn addition to radiation exposure for medical purposes, several side effects due to radiation exposure from nuclear accidents as well as radiation disasters have been reported. The Hiroshima and Nagasaki events during World War II led to the deaths of over 150,000 people who were exposed to sublethal radiation doses .Most radiation-induced side effects are due to the free radicals produced by IR in cells . RadioprFlavonoids of varying phenolic structures are present in natural substances with varying phenolic structures such as fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine . It has Hesperidin  . A compuStudies that were conducted to determine the radioprotective effect of hesperidin and were published in the English language;Studies in which ionizing radiation was used; andExperimental and clinical studies with full texts.The articles retrieved were based on the following inclusion criteria:Studies in which hesperidin was not used;Studies in which hesperidin was used in combination with other agents;Studies that made use of other forms of radiation such as ultraviolet (UV), fluorescence, cosmic, etc.;Studies that evaluated the effect of hesperidin with chemotherapy instead of radiation therapy; andConference abstracts, simulation studies, review articles, case reports, letters, editorials, unpublished data, articles without full texts, and non-English articles.We excluded studies based on the following criteria:All retrieved articles from electronic as well as manual searches were entered into endnote software . Thereafter, duplicates were removed. Afterwards, two authors (A.E.M. and G.O.) independently reviewed the titles and abstracts of the retrieved studies for eligibility. Studies were then selected based on the predetermined inclusion and exclusion criteria. For any disagreements concerning the inclusion of studies, all authors agreed on a consensus based on factual evidence.Data from each eligible study were extracted by A.E.M. and G.O. and checked by F.E. and D.S. The following information was obtained: Author name, year of publication, subject, organ (or tissue) of interest, radiation type and dose, hesperidin dose, as well as time for outcome assessment. Furthermore, the main outcomes were summarized and included.www.ClinicalTrials.gov showed that there were no completed or ongoing clinical trials evaluating the radioprotective effect of hesperidin. From these figures, 143 records were retained after removing duplicates. Following careful examination and screening of their titles and abstracts as well as the application of the inclusion and exclusion criteria, a further 114 records were excluded. The full texts of the remaining 29 records were assessed. We excluded two articles for non-English language publication, while three more records were removed for not having full texts. Finally, a total of 24 studies were included in this systematic review.The PRISMA flow diagram showing our search results is presented in 99mTc-MIBI) radiopharmaceuticals), and X-ray radiation was used in 3 studies. The doses of the radiation were between 1 and 18 Gy. Hesperidin was administered orally in 18 studies and intraperitoneally in 2 studies.The summary of data showing the characteristics of included studies is presented in A hesperidin dose of 100 mg/kg body weight was mostly used in the included studies to assess its radioprotective effect. In addition, this dose has been shown to be the most effective in reducing the healing time of radiation-induced wounds by two days . ResultsDifferent effective hesperidin doses have also been reported in several studies. In a study by Hosseinimehr and Nemati, a hesperidin dose of 80 mg/kg showed a maximum reduction in the frequencies of micronucleated polychromatic erythrocytes (MnPCEs) . In a laKalpana et al. detected maximum protection against radiation-induced reproductive death for a hesperidin concentration in a cell medium of 16.38 μM (9.99 mg/L) . In anotIn all included studies, there was no reported case of toxicity or side effects following the administration of hesperidin. In an in vivo/in vitro study by Hosseinimehr et al., five human subjects each received a hesperidin dose of 250 mg/kg orally before collection of their blood samples. They showed no adverse signs 0 (before), 1, 2, and 3 h post-hesperidin ingestion .In a study by Rezaeyan et al., rats treated with 100 mg/kg hesperidin before exposure to an 18-Gy single-dose X-ray showed significant improvement in survival rates compared to those in the radiation group . A 60-day follow-up indicated that five rats survived in the radiation group, while eight survived in the hesperidin-pretreated group .Hesperidin also improved survival in a study investigating its protective effect against radiation-induced lung damage. Rats were administered 100 mg/kg hesperidin orally for seven consecutive days before exposure to 18-Gy γ-rays. After a 60-day period of observation, 4 out of 10 rats in the radiation group survived, while 7 out of 10 rats survived in the hesperidin + radiation group .In evaluating the radioprotective effect of hesperidin against radiation-induced hepatic damage, Kalpana et al. showed that mice pretreatment with 25 mg/kg hesperidin before exposure to 10-Gy γ-rays increased the median survival period to 15 days compared to the nontreated groups (6 days) exposed to the same radiation dose. Daily monitoring of these rats was done for 30 days .Exposure to IR can affect cellular components of living tissues, leading to early and late side effects. The severity of IR-induced complications on normal tissues varies with radiation dose as well as cell or organ type . Early eOne of the strategies for countering radiation-induced damage is the use of radioprotectors. The efficacy of natural radioprotective agents such as hesperidin has been explored in recent times. Thus, in the present study, using a systematic review design, we searched for studies that made use of hesperidin as a radioprotective agent against IR-induced damage.Results from the included studies showed that hesperidin demonstrated a protective effect against both gamma and X-rays in the healthy tissue of mice, rats, and cultured human and animal cells . These eVEGF) gene induction [Skin, the body’s largest organ, is inevitably exposed to IR during radiotherapy. It has been observed that bone marrow and skin epithelia have high susceptibility to IR-induced side effects . It has nduction .Cardiovascular diseases are the leading causes of mortality worldwide . It has Promising radioprotective effects have been observed for some natural antioxidants, such as melatonin, selenium, Coenzyme Q10, α-tocopherol, caffeic acid, and ascorbic acid. . VariousThe present review has some limitations. First, we reviewed studies that used animals as well as cultured human and animal cells due to the nonavailability of clinical trials. Furthermore, in the studies included, the radioprotective effect of hesperidin was only investigated in healthy tissues. It would be desirable to observe these effects in tumor cells.In the results of the included studies in this review, it was shown that hesperidin has the potential to be an effective radioprotector against IR-induced damage to cellular components of healthy tissues. It showed promising antioxidant, anti-inflammatory, and as antiapoptotic abilities. There were no reported side effects due to its administration. We suggest future clinical trials to further assess its efficacy as well as its optimal dose. This is necessary in order to assess the clinical effects of experimental melatonin doses as well as for more insight into possible variations between experimental outcomes using cells or animals and those in humans. Comparative studies with other radioprotectors will be required in order to investigate its effectiveness. The effects of hesperidin treatment on cancer cells exposed to ionizing radiation should also be investigated. Lastly, more studies of the molecular mechanisms of radioprotection by hesperidin would be desirable.


Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urinary system disease in the male population. Recent studies have shown that traditional Chinese medicine (TCM) can alleviate the pain caused by CP/CPPS to a certain extent and improve the quality of life of patients. In this systematic review, we aim to evaluate the effectiveness and safety of TCM for chronic prostatitis/chronic pelvic pain syndrome.We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to May 2019. The quality of the included randomized controlled trials (RCTs) will be evaluated with the risk of bias (ROB) tool and evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE). STATA 13.0 and Revman 5.3 will be used to perform a systematic review and meta-analysis to synthesize direct and indirect evidence.This systematic review will evaluate the efficacy and safety of TCM for treating chronic prostatitis/chronic pelvic pain syndrome. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process trial.PROSPERO CRD42019131527 Epidemiological investigations have shown that 2.2% to 13.8% of adult men are suffering from it, and approximately 30% to 50% of men would suffer from it in particular periods of their lives. Related literature reports that the prevalence of CP/CPPS and the related symptoms of it in China is as high as 46.6%.,5 Its impacts not only deteriorate the patients’ physical and psychological health, but also the social economy, which, because of the high incidence and the recurrence. Thus, the National Institutes of Health (NIH) has listed CP as one of the chronic diseases that affect the quality of life of residents, which include myocardial infarction, unstable angina, and active Crohn disease.Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a common urinary system disease in the male population, has the symptoms of repeated, long-term pain and discomfortableness around pelvic floor area and lumbosacral portion, besides, varying degrees of lower urinary tract symptoms  would also become visible.,8 At present, there is no specific therapy for this disease in modern medicine and we mainly adopt antibiotics, α-blockers, etc., however, multicenter clinical studies have shown that the curative effect of single treatment mode is limited or even invalid.–11 In addition, due to the specificity of the anatomical structure of prostate—the deeper intima of the capsule, it is easy to cause local microcirculation disturbance, blockage of blood stasis, drainage blocked. All the factors above make the disease become recurrent and chronic.The pathogenesis of CP/CPPS is complicated which has not yet been completely illuminated. Literature reports that there are kind of connections between prostate hyperplasia and CP/CPPS.,14 Yin deficiency and heat, qi stagnation and blood stasis is its main pathogenic factor. Through the application of traditional Chinese medicine in the treatment of CP/CPPS's unique diagnosis and treatment system, clinical efficacy is significant.,16 Modern research has shown that effective active ingredients in traditional Chinese medicine can improve the blood supply of peripheral blood vessels and achieve therapeutic purposes.,18 Through the action mechanism of multifaceted and multitarget, TCM regulates the body function as a whole and has unique advantages in the treatment of CP/CPPS. After preliminary search and analysis of database, we found that the frequency of randomized controlled trials of TCM treatment in CP/CPPS has been showing an increasing trend. Previous clinical trials have shown that TCM could ameliorate pain and improve the quality of lives in patients who suffer from CP/CPPS, and these effects are sustained.,20 However, due to the limitation of the scale and sample size of the clinical centers, the current level of evidence-based medical evidence is still not sufficient. Therefore, we hope to evaluate the efficacy and safety of TCM in treating CP/CPPS by using network meta-analysis, which aim to provide sufficient evidence for its clinical application.As the most important part of Chinese medicine, Chinese herbal medicine has been widely used in clinical trials of CP/CPPS in recent years. TCM believes that the cause of CP/CPPS is mainly in the kidney.2http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019131527). The protocol follows the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) statement guidelines. We will describe the changes in our full review if needed.This systematic review protocol has been registered on PROSPERO as CRD42019131527. . The cases which relate to prostatic hyperplasia, prostate cancer or other prostate-related diseases would be excluded. In addition, there are no limitation in region, citizenship, nationality, and source of cases.2.1.32.1.3.1The drug composition, the dose-specific Chinese medicine preparation, or the combined western medicine are used as experimental interventions. Both prescription and Chinese patent medicines will be included. Other traditional Chinese medicine treatments such as intravenous medication, acupuncture, and massage will be limited.2.1.3.2As for the control interventions, who accepted simple western medicine can be used as a control intervention or didn’t get any treatment as a blank control would be adopted. However, once they had accepted the therapy of TCM, the trials will be rejected.2.1.42.1.4.1The National Institutes of Health's Symptom Score Index (NIH-CPSI) score for CP/CPPS will be used as the primary outcome measure. Every dimensions  of NIH-CPSI will be evaluated, and the lower the total score, the lighter the clinical symptoms of the patient.2.1.4.2Secondary outcomes include: changes in international prostate symptom scores (IPSS) before and after treatment; changes in international erectile function scores (IIEF-5) before and after treatment; comparison of effective rates between groups and the incidence of adverse events.2.2Database Search: PubMed, Cochrane Library, AMED, EMbase, World SciNet, Nature, Science online and China National Knowledge Infrastructure (CNKI), China Biomedical Literature CD-ROM Database (CBM), China Resources Database. Search for clinical research literature on TCM CP/CPPS published in domestic and foreign biomedical journals from the establishment of the library to May 2019. Based on the standards of the Cochrane Collaboration Workbook of the International Evidence-Based Medicine Center, a manual and computer-based method will be used to conduct related literature searches. The search terms include: chronic prostatitis, chronic pelvic floor pain syndrome, non-bacterial prostatitis, Chinese medicine, traditional Chinese medicine, proprietary Chinese medicine, Chinese herbal medicine. Manually search for topics, abstracts, etc. related to the research of Chinese Journal of Male Science, Chinese TCM, and TCM. The complete PubMed search strategy is summarized in Table 2.32.3.1Two investigators used EndnoteX7 software to conduct a preliminary assessment of the title and abstract of each document in the database based on the established criteria for inclusion in the study to select eligible studies. After a preliminary assessment, the full text of the selected literature would be evaluated, and the uncontrolled study, no randomization, inconsistent evaluation criteria, and similar data would be excluded. Any differences in screening that occurred during the screening study would be discussed in order to get consensus, if it still cannot be resolved, then the third author would be intervened.2.3.2Two investigators independently extracted information from the included literature. The extracted content includes research design, random hiding and blinding, basic information of the included cases, intervention methods, observation indicators, and test results of the treatment group and the control group. The extracted literature data will be filled in a unified data statistics table. For studies that provide baseline and posttreatment data, we will estimate the change values by the method recommended by Cochrane. The details of selection process will be shown in the PRISMA flow chart Fig. .2.3.3Two investigators will independently evaluate the methodological quality of the included literature by using the Cochrane Collaboration ROB tool which includes whether the random method is correct, whether blinding is used, whether it is hidden, whether it is lost or quit, whether it uses Intent-To-Treat (ITT) analysis, whether the data results are accurate, and other risks of bias. According to the relevant standards in the Cochrane Intervention System Evaluation Manual, it will be divided into low risk, high risk, and unclear.2.3.4In the event of data loss during the screening and extraction of literature data, first, we will actively investigate the cause of data loss. Then we will contact the experimental research author by telephone, mail, etc. to achieve the purpose of supplementing the missing data. If the lost data cannot be retrieved, we will only extract and analyze the useful data, besides, we will indicate the situation.2.3.5α = 0.1). If there is no heterogeneity, a fixed effect model will be used. If there is significant heterogeneity between a group of studies, we will explore the reasons for the existence of heterogeneity from various aspects such as the characteristics of the subjects and the degree of variation of the interventions. Sensitivity analysis or meta-regression and subgroup analysis to explore possible sources of heterogeneity when necessary. We will use qualitative analysis of the funnel plot and graph symmetry to assess publication bias. Quantitative methods such as Begg testing and Egger testing will be used to help assess publication bias in the application.The numerical variable will be expressed as the normalized mean difference (SMD) with a confidence interval (CI) of 95%. The heterogeneity of each pairwise comparison will be tested by chi-square test (test level 2.3.6If there is significant heterogeneity between a group of studies, we will explore the reasons for the existence of heterogeneity from various aspects such as the characteristics of the subjects and the degree of variation of the interventions. Sensitivity analysis or subgroup analysis is performed as necessary to explain heterogeneity.2.3.7The forest map and funnel plot were drawn and analyzed using Rev Man5.3 software, and the funnel plot was used to analyze potential publication bias.2.3.8The quality of evidence for the main outcomes will also be assessed with the GRADE approach. The evaluation included bias risk; heterogeneity; indirectness; imprecision; publication bias. And each level of evidence will be made “very low,” “low,” “moderate,” or “high” judgment.3 Studies have shown that drug intervention can improve the overall NIH-CPSI score and ameliorate most of the symptoms of CP/CPPS patients to a certain extent, but there is no single drug can continue to significantly ameliorate all symptoms of CP/CPPS patients.,23 TCM has a profound theoretical foundation and abundant clinical experience in the treatment of CP/CPPS. TCM therapy mainly achieves therapeutic effects by stimulating the body's righteousness and regulating the balance of qi and blood. In recent years, TCM therapy has been widely used in clinical trials of CP/CPPS. Recent studies have shown that TCM can alleviate the pain caused by CP/CPPS to a certain extent and improve the quality of lives of patients.At present, there are vast of therapies in treating CP/CPPS, however, the efficacy is still unsatisfactory due to the particularity of the anatomical structure of prostate.Although abundant studies have evaluated the effectiveness of TCM in treating CP/CPPS, evaluation and comparison between various treatments are still insufficient. To the best of our knowledge, a systematic review and meta-analysis has not been used in recent years to compare the effectiveness of TCM in the treatment of CP/CPPS. The results of meta-analysis can provide a possible ranking for TCM treatment of CP/CPPS. We hope that the results will provide clinicians with the best options for treating CP/CPPS and provide them with research directions. Due to the limited number of relevant high-quality studies and the few sample size included, the strength of the arguments of the conclusions is to some degree limited. Therefore, we hope that more large-scale, high-quality randomized controlled trials should be necessary in the future. Besides, improving the quality of the original research and conducting high-quality multicenter randomized controlled trials to explore the clinical efficacy of TCM treatment of CP/CPPS is also indispensable, through which could make the conclusion more objective and reasonable.Conceptualization: Yahui Xue.Data curation: Yahui Xue, Yongqiang Li.Formal analysis: Yahui Xue, Yunyun Duan.Funding acquisition: Yunyun Duan, Yongqiang Li.Supervision: Xiaoyong Gong, Wei Zheng.Visualization: Xiaoyong Gong.Validation: Wei Zheng.Project administration: Yongqiang LiWriting – review & editing: Wei Zheng.Writing – original draft: Yongqiang Li.


N = 64) who experienced a traumatic event between the start (Time 1) and end (Time 2) of a semester. We included three measures of change from pre- to post-trauma: (1) Actual PTG (change scores in measures of PTG domains), (2) perceived general growth , and (3) perceived PTG (self-reports of PTG on the posttraumatic growth inventory). The results revealed perceived general growth and actual PTG were significantly correlated, suggesting that participants’ perceptions of change were accurate. However, perceived PTG was not significantly related to either actual PTG or perceived general growth. Further, increases in actual PTG and perceived general growth were significantly related to decreases in distress and unrelated to coping. By contrast, higher levels of perceived PTG were significantly related to increases in distress and higher levels of avoidance coping. Our results suggest perceived PTG may be more of a coping process than an accurate recall of posttraumatic change.Recent research has distinguished between actual posttraumatic growth (PTG) and perceived PTG. We used a prospective research design to measure both actual and perceived PTG in an attempt to replicate and extend previous findings. We examined college students ( Since its introduction in the mid-1990s, a plethora of research has focused on the possibility that people may experience positive changes after a traumatic event .Research in psychology gives us reason to suspect that self-reports of PTG may be biased and sometimes even illusory . Foperceived PTG. The distinction between actual PTG and perceived PTG is a crucial one, and it is paramount that researchers recognize this distinction . A metae, 2014, ).It is similarly crucial that we understand the nature of perceived PTG and how it differs from actual PTG. For instance, what is the value of perceived PTG? Is it something clinicians should try to foster? Social psychological research has found that overinflated perceptions of oneself are related to better psychological adjustment . Alterngeneral change over time, with no references to change resulting from trauma. This latter lack of reference to change resulting from a trauma is what distinguishes perceived general growth from perceived PTG. In summary, the current study design yields three primary measures of changes, (1) actual PTG, (2) perceived general growth, and (3) perceived PTG. We tested three hypotheses that follow from our aforementioned questions about the nature of perceived PTG. The first two hypotheses are based on the notion that perceived PTG is a different construct than actual or perceived change. The first hypothesis is that actual PTG and perceived general growth will be positively related to each other; by contrast, perceived PTG will be unrelated to these two measures. The second hypothesis is that actual PTG and perceived general growth will be positively related to changes in PTG-domain measures; by contrast, perceived PTG will be unrelated to changes in PTG-domain measures. The third hypothesis concerns the notion that perceived PTG is, at least partly, a coping mechanism. The third hypothesis is that actual PTG and perceived general growth will be related to decreases in distress and posttraumatic stress symptoms at Time 2, and unrelated to coping; by contrast, perceived PTG will be related to increases in distress and posttraumatic stress symptoms at Time 2, and increased use of coping.In the current study, we used a research design very similar to the one employed by Frazier et al. (2009) —a prospeN = 282; 90 male) were recruited from a large university in the southern United States and received partial course credit for participating. The average age was 19.58 years . The ethnicity profile of the final sample was 43% White, non-Hispanic, 22% African-American, 24% Hispanic, 6% Asian, 1% Native American, and 4% Other. A total of 221 (78%) of participants completed Time 2. There were no significant differences between completers (completed Time 1 and Time 2) and noncompleters (completed Time 1 only) on any of the variables included in the study, including age, gender, and ethnicity , with one exception. Completers reported significantly higher levels of distress on the depression, anxiety, and stress scales (DASS)  than did noncompleters , t (279) = 2.03, p = 0.04, Cohen’s d = 0.29. Sixty-four of the 221 participants (29%) who completed Time 2 reported an intervening trauma. This subsample was 76% female, with an average age of 19.68 years , and was 44% White, non-Hispanic, 21% African-American, 22% Hispanic, 8% Asian, and 5% Other.Participants , [ (2009), , the cur (2009), ). The C-Actual PTG—Secondary Measures. We used the same five measures used by Frazier et al. (2009), [ (2009), . For all (2009), ) was use (2009), ) was cho (2009), ; e.g., “ (2009), ; e.g., “ (2009), ; e.g., “Perceived General Growth. At Time 2 only, we gave the participants a modified version of the C-PTGI, which we call the C-PTGI-Past. The C-PTGI-Past is identical to the C-PTGI , with the only difference occurring in the instructions. The C-PTGI asks respondents to refer to the past two weeks, whereas the C-PTGI-Past asks respondents to refer to “…your life at the beginning of the semester”. Hence, the C-PTGI-Past assesses respondents’ perception of how they think they were doing at Time 1. We then subtracted the C-PTGI-Past total score from the C-PTGI administered at Time 2 total score to assess perceived general change.Coping. We used the brief COPE  to measIntervening Trauma. We used the LEC-5  to assePosttraumatic Stress Symptoms (PTSS). We used the 20-item PTSD checklist , a commDistress. We used the 19-item depression, anxiety, and stress scales  to asseWe conducted a cross-sectional, longitudinal, and prospective research design in which participants completed measures during the first three weeks of the semester (Time 1) and the last three weeks of the semester (Time 2). At Time 1, participants completed the C-PTGI, the five secondary measures that assess the domains of PTG, the BCOPE (coping), and the DASS (distress). At Time 2, participants completed the DASS, followed by the LEC-5, which was used to identify each participant’s most stressful event they experienced since Time 1. A frequency count of intervening traumatic events is reported in r = 0.38) with the five secondary measures of actual PTG, cross-sectionally at Time 2. We wanted to make certain we replicated these findings in the current sample, with some additional analyses. Since change scores in our measures are a central part of our hypotheses, we (1) examined correlations between the C-PTGI and the five secondary measures of actual PTG at Time 2  = 0.59, p < 0.001 . Hence, participants’ reflections of how they think they were doing three months earlier only accounted for 35% of the variance in how they were actually doing three months prior.Means and standard deviations for all variables are included in r et al.  in the cTo test our hypotheses, we examined correlations between actual PTG, perceived general growth, perceived PTG, and changes in the secondary measures of actual PTG, changes in distress, and coping. Since the PTGI is intended to assess growth from traumatic events  , who onlThe results mostly supported the second hypothesis. As can be seen in The results mostly supported the third hypothesis. As can be seen in The preliminary results demonstrated the solid validity of our primary measure of actual PTG, which replicated and extended similar findings reported in Frazier et al. (2009) . ParticiOur results support the Janus–Face model of PTG , which N = 64) was only slightly more than half the sample size in the Frazier et al. study (N = 120). However, the full sample had a much larger sample size and we obtained the same pattern of results, regardless of which sample we examined. A third limitation is we did not replicate all of the findings reported in Frazier et al. (2009) [r = 0.22); this same correlation was not significant in the current study . This discrepancy suggests multiple possibilities, including that this association is spurious and/or this association varies, depending on one or more factors. Second, Frazier et al. found a positive correlation (r = 0.29) between Time 2 PTGI scores and changes in religious commitment ; this same correlation was not significant in the current study . Third, Frazier et al. found Time 2 PTGI scores were strongly correlated with Time 2 positive reframing coping (r = 0.52); this correlation was not significant in the current study . One possibility for this failure to replicate is that the way we used the BCOPE was as an assessment of general coping tendencies, whereas Frazier et al. used the BCOPE to examine coping specific to the traumatic event. A fourth limitation is our use of an undergraduate sample. An undergraduate sample has the advantage of elevated rates of trauma exposure but comes at the cost of restricted ranges of age, intelligence, and socioeconomic status. The fifth limitation is that, according to Calhoun and Tedeschi (1998) [The current study has some limitations that are worthy of note. The first limitation is the relatively short time period between the intervening trauma and the assessment of perceived PTG. Genuine PTG can take months or sometimes years after a trauma to occur. Prospective studies that have longer-term follow-ups are ideal to assess changes that result from trauma. The second limitation is our limited statistical power. The intervening trauma sample in the current study (. (2009) . First, i (1998) , only evThe measurement of psychological constructs is a challenging endeavor. Unfortunately, we cannot slip a thermometer under a participant’s tongue and get an objective, precise measurement of PTG. In psychology, more times than not, we have to rely on self-reports for measurement. There is growing empirical evidence that self-reports of PTG are contaminated by a number of motivated cognitive biases. It is crucial that we recognize the distinction between perceived PTG and actual PTG. The results of the current study support this distinction. We encourage researchers to recognize this distinction and continue examining the nature and value of perceived PTG versus actual PTG. Such research is vital to our understanding of the nature of PTG and our ability to help trauma victims recover, grow, and flourish.


Awe is an emotion experience when individuals encounter with such powerful stimulate beyond their own understanding. Guided by conceptual analysis of awe as a trait positive emotion, we tested the hypothesis that dispositional awe results in an improvement of individual's self-transcendence meaning of life (STML) and affects future time perspective, and increase prosocial behavior. Mediational data demonstrate that the effects of awe on prosociality are explained, by improving STML self and future time perspective. These findings indicate that awe may help situate individuals within broader social contexts and enhance collective concern. People usually experience a sense of awe when they encounter scenes such as temples and waterfalls. The experience of a sense of awe accompanied by a decline in self-importance makes people pay more attention to their role in society . Also, perception of future time may be another important factor in the effect of awe on prosocial behaviors Chen, . After eIn addition, STML refers to the transcendence of self (not self-centered), and presented as a transcendental attitude toward life Li, . STML isProsocial behaviors are actions that individuals engage in to benefit others or the collective; such actions include self-sacrifice, donating, helping behaviors, and sharing  refers to transcendence of self (not self-centered), and individuals believe that gain and loss are dialectical, inevitable and meaningful, presented as a transcendental attitude toward life that is focus others more than themselves and not afraid of loss Li, , 2006. TStudies have confirmed that a sense of awe will be accompanied with a strong self-transcendence emotional experience, enabling individuals to pursue spiritual world and become more altruistic  from 2 universities in Guangdong Province of China participated in this research. There were 956 students from science and engineering colleges (such as the School of Computer Science) and 2,391 students from human and social science colleges (such as the School of Business Administration). There were 753 freshmen, 900 sophomores, 843 juniors, and 851 seniors.First, the researchers distributed questionnaire notices and test schedules to 18 colleges  participating in the survey. Second, according to the research plan, the test was conducted collectively in class, all of the students were required to fill in written informed consent and return them. Finally, the questionnaire was carefully checked to eliminate invalid responses. All the participants received a small gift for their participation. A counselor or class teacher was trained to proctor the test. The training content included the test instructions and precautions. All the procedures were in accordance with the ethical guidelines of the American Psychological Association (APA) and were approved by the Institutional Review Board (IRB) at School of Education, Guangzhou University.Dispositional Positive Emotion Scales (DPES) , anonymous , dire , emotional , compliant , and altruism . The participants were asked to rate the extent to which the statements described themselves on a 5-point scale ranging from 1  to 5 (Describes me well). The average score for the 26 items was calculated, with a higher score indicating a higher level of prosocial behavior. The Cronbach's alpha for this scale was 0.92.The Prosocial Tendencies Measure (PTM) was developed by Carlo and Randall , revisedstrongly disagree) to 5 (strongly agree). The Cronbach's α for this scale was 0.78.Future time perspective was measured by the 13-item Future Time Perspective subscale in the Zimbardo Time Perspective Inventory (ZTPI_F), which was developed by  to 4 (strongly agree), where higher scores reflect greater STML, no reversed scoring. The Cronbach's alpha for this scale was 0.81.Self-transcendence meaning of life was measured by the Self-transcendence Meaning of Life Scale (SMLS), which was developed by Li , 2006. TSPSS21.0 and Mplus 7.0 were used to analyze the data. First, we used correlation analyses to explore the correlations between the main variables. Second, we tested hypotheses using structural equation modeling (SEM), and demographic variables (gender and grade) were considered covariates in the models. Finally, we used mediation analyses to examine theoretical model, and then used a robust method of maximum likelihood because the dependent variable was ordinal. An RMSEA value below 0.08 and a CFI value over 0.90 indicate a good fit , STML , and prosocial behavior . Future time perspective  and STML  were also positively associated with prosocial behavior.p < 0.001). This finding supported our first hypothesis.We used Mplus 7.0 to create a latent variable for prosocial behavior by using the six dimensions: public, anonymous, dire, emotional, compliant, and altruism. We then used SEM to examine the relationship between awe and prosocial behaviors. The results showed that awe was positively associated with prosocial behavior , and the 95% CI for the indirect effect  did not include zero. Awe was positively associated with future time perspective , and future time perspective was positively associated with prosocial behavior We used SEM  to determine whether future time perspective and STML (latent variables are divided into two dimensions: obtain the meaning of the failure and detachment from success or failure) simultaneously mediated the effect of dispositional awe influencing prosocial tendencies. The fit indices were p < 0.001), and the 95% CI for the indirect effect  did not include zero. Awe was positively associated with STML , and STML was positively associated with prosocial behavior . After accounting for the mediating variables of future time perspective and STML, the direct effect of awe on prosocial behavior decreased from β = 0.44 (p < 0.001) to β = 0.21 (p < 0.001). The model results are shown in As expected, STML significantly mediated the positive association between awe and prosocial behavior .That is, STML not only helps to reduce poor adaptation but also promotes mental health and prosocial behavior  and time points, thus providing a deep examination of the causal relationship between dispositional awe and prosocial behavior.Second, from the perspective of the research objective, this study mainly used a convenient sampling method, and research was carried out on late-adolescent college students. Therefore, the conclusions of this study cannot be generalized to all youths or adults. Future research can further increase the ecological validity of these findings by expanding the age range of the sample and the group type of the sample .Individuals with high levels of dispositional awe show more prosocial tendencies.Dispositional awe can indirectly influence prosocial tendencies through future time perspective.Dispositional awe may also indirectly influence individuals' prosocial tendencies through STML.This study has certain enlightenment to education. It can encourage young people to balance their behaviors from the future time frame by cultivating awe, and put STML or life education into adolescent mental health education content system so as to promote youth development.This project is approved by the Ethics Review Committee (IRB) of Education School, Guangzhou University, accords with the principle of ethics. All participants have filled written informed consent before study.J-JL, KD, and Y-GN: conceptualization. Y-JW and KD: data curation. J-JL and KD: formal analysis, methodology, software and writing—original draft. KD and Y-GN: investigation. J-JL and Y-JW: project administration. KD, Y-JW, and Y-GN: resources. Y-GN: supervision. Y-JW and Y-GN: writing—review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Supplemental Digital Content is available in the text Ischemic stroke, hemorrhagic stroke, and acute myocardial infarction (AMI) are diseases with golden hour. This study aimed to identify and compare factors that affect in-hospital mortality in patients with stroke and AMI who admitted via the emergency department.This study used the Korean National Health Insurance claims data from 2002 to 2013. The study sample included 7693 patients who had an ischemic stroke, 2828 patients who had a hemorrhagic stroke, and 4916 patients with AMI who were admitted via the emergency departments of a superior general hospital and general hospital, did not transfer to another hospital or come from another hospital, and were aged ≥20 years. This study was analyzed by using Cox's proportional hazards frailty model.Five hundred (6.5%) of 7693 patients with ischemic stroke, 569 (20.1%) of 2828 patients with hemorrhagic stroke, and 399 (8.1%) of 4916 patients with AMI were dead. The clinical factors were associated with in-hospital mortality such as age, CCI, hypertension, and diabetes of patient characteristics. In treatment characteristics, performing PCI and weekday admission was associated with in-hospital mortality . In hospital characteristics, the volume, the proportion of transferred patient to other hospital and ratio of beds per one nurse was associated with in-hospital mortality.Clinical factors of patient characteristics, intervention such as performing PCI and reducing ICP of treatment characteristics, and the volume, transferred rate, and the number of nurse of hospital characteristics were associated with in-hospital mortality. Until 1980s, basic approach for measuring of quality of care was to use a model of Donabedian in aspects of structure, process, and outcome. According to this theory, structure, process, and outcome can be indicator of quality of care. However, looking at history of quality assurance,–8 approach for measuring of quality of care changed gradually that quality of care measured in terms of structure in early stage, and measured in aspect of process, and tendency have showed that measuring of quality of care emphasized on outcomes. Measuring structure and process is relative easy but there is a limitation in terms of indirect assessment. In contrast, measuring outcomes as quality of care has an advantage that can directly evaluate an effectiveness of quality of care. However, the three dimensions are intertwined, but their relative utility depends on context. Outcomes that are not linked to specific medical practices provide little guidance for developing quality-improvement strategies. Furthermore, comparing outcomes across groups frequently requires adjustment for patient risk and the recognition that some patients are sicker than others. For these reasons, Lisa Iezzoni provides a conceptual model of the summation of patient factors, treatment effects, and random events that produce health outcomes.,12 This conceptual model is referred to as the “Algebra Effectiveness.” This model is based on the viewpoint that in-hospital patient outcome is caused by the sum of three components. To assess hospital net quality, factors such as patient factors are removed that could affect health outcome.The growing demand for health care, increasing treatment costs, constrained resources, and evidence of variations in clinical practice have increased the interest in measuring and improving the quality of health care in many countries. Especially stroke is the first leading cause of mortality as single disease in Korea, and is the second leading cause of death worldwide.In Korea, to improve quality of care for stroke and acute myocardial infarction (AMI), the Health Insurance Review and Assessment Service (HIRA) demonstrated pay for performance (P4P) from July 2007 to December 2010 for AMI and stroke for superior general hospitals. Despite several advances in AMI and stroke care over the last decade, Cardiovascular and cerebrovascular diseases accounts for a quarter of the total mortality. These diseases were the second and third leading causes of mortality, being responsible for 52.4 and 48.2 deaths per 1,000,000 people in Korea, respectively.The aim of this study was to identify and compare patient, treatment, and hospital characteristics that affect the in-hospital mortality of patients with who were admitted via the emergency department due to stroke and AMI by an application of algebra effectiveness model.22.1 These data include information on 10,250,340 patients. These subjects represent a stratified random sample selected according to age, sex, region, health insurance type, income quintile, and individual total medical costs based on the year 2002. The database includes information on reimbursement for each medical service, including basic patient information, an identifier for the clinic or hospital, a disease code, costs incurred, results of health screening, personal/family history, health behaviors, and information related to death. These data are publicly available for research purposes. Ethical approval for this study was granted by the institutional review board of the Graduate School of Public Health, Yonsei University (2-1040939-AB-N-01-2016-402).The dataset was obtained from the Korean National Health Insurance (KNHI) claims database from 2002 to 2013. The National Health Insurance Corporation collects cohort data representative of the country's population.2.2International Classification of Diseases, 10th Revision (ICD-10); medication information; and clinical test information. According to the assessment report for AMI and stroke quality, in cases of ischemic stroke and AMI, the administration rates of anticoagulants and antiplatelet agents within 48 h and aspirin within 24 h are both almost close to 100%. In the case of AMI, almost all patients with suspected AMI received tests for cardiac enzymes such as creatine kinase MB fraction (CK-MB), troponins T and I, and myoglobin. In the case of hemorrhagic stroke, approximately 90% of these patients received intravenous antihypertensive drugs according to the guideline for hemorrhagic stroke. Otherwise, patients received mannitol to control their conditions or craniotomy to decrease intracranial pressure as intervention. The final study sample with ischemic stroke included 7693 participants, the final study sample with hemorrhagic stroke included 2828 participants, and the final study sample with AMI included 4916 participants .The total number of individuals admitted to acute care hospitals, including superior general hospitals and general hospitals, via the emergency department without dropping by other health-care institutions due to ischemic stroke, hemorrhagic stroke, and AMI. The Korean health-care delivery system is classified into 3 steps based on fee-for-services as the reimbursement mechanism as follows: clinics function as primary care institutions, hospitals function as secondary care institutions, and general hospitals function as tertiary care institutions. Our study sample was included only patients who utilized general hospitals, 20 years old or more, and was not transferred to other hospitals. Because clinics were likely to receive only low-risk or a limited number of patients, and in case of transferring patients, each hospital's net quality or performance cannot be measured, and time to treatment was delayed. To determine real stroke and AMI patients, patients with stroke and AMI as a principal or secondary diagnosis were identified by searching for codes of the 2.32.3.1The dependent variable in the present study was mortality upon in-hospital admission, and at 7 and 30 days after admission. Death was assumed to be the outcome of interest. Death was determined by linking inpatient records with death certificate records from the national death registry. The death certificate records indicated only the month and year of death; we had to determine whether the patient was dead at discharge. We defined in-hospital, 7-day, and 30-day mortalities as follows: First, we matched the discharge and death dates. If the discharge data month/year was the same as the death date, we determined if the patients acquired discharge medication or used any medical services after the discharge date. If they did not, we included them as cases as mortalities.2.3.2Patient, treatment, and hospital characteristics were classified as covariates. Patient characteristics included age; sex; health insurance type ; income level; residential area ; Charlson comorbidity index ; arrival route (by emergency team/others); disability status (none/mild/severe); presence or absence of hypertension/hypertensive complications , diabetic complications  and hyperlipidemia; and admission on a weekend or weekday. Treatment characteristics included administration of an intervention such as embolization, balloon, or stent (yes/no); administration of intravenous thrombolytic agents in case of ischemic diseases; use of intensive care unit service (yes/no); and administration of surgical procedures (yes/no) in case of hemorrhagic stroke. Hospital characteristics included ownership , total number of patients admitted via the emergency department because of a corresponding condition per year (quintiles 1–5), proportion of transferred patients to another hospital (<5/5–9/10–14/15–19/≥20), number of beds (quintiles 1–5), patient-to-physician ratio (2.5:1/ 3.5:1/ 5.5:1/ 8.5:1/ >8.5:1), patient-to-nurse ratio (2.0:1/ 2.5:1/ 3.0:1/ 3.5:1/ 4.0:1/ 4.5:1/ >6.0:1), and hospital function . Only the comorbidity component of the CCI was calculated from entry of cohort to before occurrence of interested conditions. In addition, when we calculated CCI, we extracted diabetes scores. The weekend effect was investigated by determining whether patients were admitted via the emergency department on a Saturday or Sunday. In addition, patients who were admitted on an official national holiday were regarded as weekend admissions. The definition of variables shows the variables that used in this study .2.4P-values among the hospitals. The variance and P values were 0.126 and 0.050 for ischemic stroke, 0.081 and 0.04 for AMI, and 0.109 and 0.021 for hemorrhagic stroke, respectively.Descriptive statistics were computed for all variables as follows: Frequencies and percentages of categorical variables were determined by using the chi-square test. The cumulative incidence for each dependent was estimated by using the Kaplan-Meier product limit method with log-rank tests. To investigate the association between patient/treatment/hospital characteristics and mortality, we performed a survival analysis by using Cox's proportional hazards frailty model, which included random effects to account for covariate hierarchy. This approach used a random effect to test for a hospital effect. This random effect can be thought of as a “frailty,” which increases a hospital's susceptibility to a short survival time when it is large and decreases this susceptibility when it is small. We determined the mortality variance and t|x) = zλ0 (t)exp (xβ) describes the frailty model, where x is the covariate matrix, β is the fixed effect vector, and z is a random variable representing an unknown random effect related to each hospital, with unit mean and variance ξ. These random effects act multiplicatively on the baseline hazard, and large ξ values reflect a great degree of heterogeneity among hospitals. For model distribution purposes, we assumed that the frailties were distributed according to a gamma distribution. One attractive feature of the gamma distribution is that it is mathematically tractable. All the statistical analyses were performed by using SAS 9.4 .The equation λ  of hypertension was 22.7% to 28.5%, but the PAR of diabetes was 14.6%. PCI was one of the most important processes. Moreover, considering that the cumulative mortality was the greatest of all three conditions, performing PCI was the most effective way of reducing the risk of mortality. For the patients admitted to a superior general hospital because of ischemic stroke and AMI, we could observe the weekend effect.–24 Especially in the case of AMI, if we consider that performing PCI could decrease the risk of mortality, the availability of personal resources that can perform a PCI during a weekend or holiday might be a critical factor.The HR of mortality was higher for the patients admitted to the intensive care unit than for those who were not in all three diseases. Admission in the intensive care unit might proxy for disease severity itself. However, the risk of mortality among the patients admitted to the intensive care unit was highest in ischemic stroke, followed by AMI, and the lowest in hemorrhagic stroke. The difference in admission rate between the patients admitted to the intensive care unit and those who were not was the greatest in ischemic stroke, followed by AMI and then hemorrhagic stroke. We thought the difference likely reflects the difference in disease severity between the two patient groups. Performing percutaneous coronary intervention (PCI) reduced the risk of mortality in AMI. We observed a steady increase in cumulative mortality regardless of an acute or chronic phase. Our findings suggest that the overall hospital quality was more important during the whole admission period relative to the other factors of ischemic stroke. Hospitals with private funding are likely to invest in improving quality of care. Therefore, considering the characteristic of ischemic stroke, we thought that the characteristic of funding sources is associated with mortality. The patient-to-nurse ratio was associated with mortality in ischemic stroke. We thought this variable was likely to represent the overall quality of care provided by hospitals. AMI and hemorrhagic stroke are diseases that need specialized techniques such as PCI or craniotomy. In these two diseases, hospital volume and transfer rate to another hospital were associated with mortality. This finding was consistent with those of previous studies.–29 In addition, in the case of AMI, the patient-to-physician ratio was associated with mortality for some groups. Considering these results, we think organizational or individual competence might be a critical factor. In hemorrhagic stroke, the patient-to-nurse or physician ratio was greater, but the hazard ratio was smaller. This finding contradicts the general idea. Thus, this study performed two tests to resolve the issues that led to these results.In case of ischemic stroke, the risk of mortality was higher for the patients admitted to hospitals with public sources of funding or to hospitals with sources of funding for educational purposes than for those admitted to hospitals with private funding. The hospitals with public funding tended to be weaker financially than the other hospitals, which leads to poor quality of care. Although this study tried to identify throughout real patients by using medication and clinical test information, the diagnostic accuracy might have been compromised in the study. In addition, we could not consider the time of first medical contact, the time to electrocardiogram (ECG) and PCI or thrombolysis, because this information can be obtained from medical records. Third was to define dependent variable. This study determined the death date by examining whether the patient received discharge medication and/or used medical services after discharge. Although the death date month/year and the discharge date month/year were identical, it is possible that some patients were discharged against medical advice, did not take discharge medication, and did not use medical services after discharge. Finally, in stroke and AMI, pre-hospital intervention is one of the most important factors. However, this study could not consider pre-hospital intervention because this study used claims data.Some issues could be raised related with the study methods. First limitation was an issue related to data source. These data were extracted from a national health insurance claims database from 2002 to 2013. These subjects represent a stratified random sample selected according to age, sex, region, health insurance type, income quintile, and individual total medical cost based on the year 2002. These data were not from a representative organization. Therefore, the definitions of the hospital characteristics could not be generalized. Second was the selection of the study sample. The study data were obtained from a claims database. To determine the study sample, we used ICD-10 code as primary diagnostic criteria. The diagnostic accuracy in the KNHI claims data is roughly 70%.Despite these limitations, this study used a representative data and included all data on all-cause mortality. This study used socioeconomic status, which could affect mortality, unlike studies that used administrative data. In addition, this study used a robust study design and Cox's proportional hazard frailty model to investigate factors at the individual, treatment, and hospital levels that could impact mortality.In conclusions, hypertension, diabetes, and dyslipidemia were associated with increased risk of mortality in stroke and AMI. These factors are preventable; thus, policies should focus on primary prevention by changing to healthy lifestyles. In AMI, performing PCI was strongly associated with reduced risk of mortality. In hospital factors, the ratio of number of patient per one nurse was associated with mortality in ischemic stroke. The volume was associated with mortality in all three diseases, and the transferred rate was associated with mortality in hemorrhagic stroke. To secure experts, we need policies that can supply experts and train the experts at national level who can perform intervention such as PCI. In case of diseases that organizational and hospital staff's competence is important, an introduction of system is needed that can share the list of organization which can manage patients with these diseases between institution.This study was based on Kyoung Hee Cho's doctoral dissertation.Conceptualization: Kyoung Hee Cho.Formal analysis: Kyoung Hee Cho, Chung Mo Nam.Investigation: Kyoung Hee Cho.Methodology: Kyoung Hee Cho, Chung Mo Nam.Project administration: Eun-Cheol Park.Supervision: Eun-Cheol Park.Validation: Chung Mo Nam.Writing – original draft: Kyoung Hee Cho.Writing – review & editing: Sang Gyu Lee, Tae Hyun Kim, Seon-Heui Lee, Eun-Cheol Park.