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Importance: It is widely known that individuals with adverse childhood experiences (ACEs) have an increased risk of abusing their own children, thereby perpetuating the cycle of violence. However, the association between ACEs and elder abuse perpetration has not been fully examined., Objective: To examine the association between ACEs and elder abuse and the mediating factors., Design, Setting, and Participants: This cross-sectional study used data collected via the self-administered Japan COVID-19 and Society Internet Survey from September 12 to October 19, 2022. Men and women aged 20 to 64 years who responded to related questions were included. Data were analyzed from July 2023 to April 2024., Exposures: ACEs, defined as the experience of any of 7 items-interpersonal loss (parental loss and parental divorce), family psychopathology (parental mental disease and violence in family), abuse (physical and psychological abuse), and neglect-before the age of 18 years., Main Outcomes and Measures: The primary outcome was the perpetration of physical and/or psychological abuse against an older person (aged ≥65 years) self-reported via questionnaire. The direct and indirect effect estimates were determined using logistic regression analyses., Results: Of a total of 13 318 participants (mean [SD] age, 41.1 [12.1] years; 6634 female [49.8%]), 1133 (8.5%) reported perpetrating violence against older adults. Compared with individuals without ACEs, the odds ratios (ORs) for perpetrating violence were 3.22 (95% CI, 2.74-3.79) for those with 1 ACE and 7.65 (95% CI, 6.41-9.13) for those with 2 or more ACEs. In the mediation analysis, factors with large indirect effect estimates included depression (OR, 1.13; 95% CI, 1.11-1.14; proportion mediated [PM], 18.6%), mental illness other than depression (OR, 1.12; 95% CI, 1.10-1.14; PM, 17.3%), and self-rated health (OR, 1.04; 95% CI, 1.03-1.05; PM, 6.0%)., Conclusions and Relevance: These findings suggest that intergenerational cycles of violence may extend to any vulnerable group, not only children but also older adults. Further research into the prevention of ACEs and breaking these cycles of violence is warranted.

Importance: There are limited data on whether the vulnerabilities and impacts of social isolation vary across populations., Objective: To explore the association between social isolation and mortality due to all causes, cardiovascular diseases (CVD), and malignant neoplasms focusing on heterogeneity by sociodemographic factors., Design, Setting, and Participants: This cohort study used a moderator-wide approach to examine the heterogeneity in the association of social isolation with all-cause, CVD, and malignant neoplasm mortality using baseline data from the Japan Gerontological Evaluation Study in 2010 and 2011. Eligible participants were adults aged 65 years or older without heart disease, stroke, cancer, or impaired activity of daily living across 12 Japanese municipalities. Follow-up continued until December 31, 2017, identifying 6-year all-cause, cardiovascular disease (CVD), and malignant neoplasm mortality. Logistic regression assessed effect modification by age, gender, education, income, population density, marital status, and employment on mortality associations. Data analysis was performed from September 13, 2023, to March 17, 2024., Exposure: Social isolation, determined by a 3-item scale (scores of 2 or 3 indicating isolation) was the primary exposure variable., Main Outcomes and Measures: Six-year all-cause, CVD, and malignant neoplasms mortality., Results: This study included 37 604 older adults, with a mean (SD) age of 73.5 (5.9) years (21 073 women [56.0%]). A total of 10 094 participants (26.8%) were classified as experiencing social isolation. Social isolation was associated with increased all-cause (odds ratio [OR], 1.20 [95% CI, 1.09-1.32]), CVD (OR, 1.22 [95% CI, 0.98-1.52]), and malignant neoplasm mortality (OR, 1.14 [95% CI, 1.01-1.28]). Stratified analysis showed associations of social isolation with all-cause and malignant neoplasm mortality among people with high income (highest tertile all cause: OR, 1.27 [95% CI, 1.06-1.53]; malignant neoplasm: OR, 1.27 [95% CI, 1.02-1.60]), living in areas with high population density (highest tertile all cause: OR, 1.47 [95% CI, 1.26-1.72]; malignant neoplasm: OR, 1.38 [95% CI, 1.11-1.70]), not married (all cause: OR, 1.33 [95% CI, 1.15-1.53]; malignant neoplasm: OR, 1.25 [95% CI, 1.02-1.52]), and retirees (all cause: OR, 1.27 [95% CI, 1.14-1.43]; malignant neoplasm: OR, 1.27 [95% CI, 1.10-1.48]). Formal testing for effect modification indicated modification by population density and employment for all-cause mortality and by household income and employment for neoplasm mortality., Conclusions and Relevance: Social isolation was associated with increased risks of all-cause, CVD, and malignant neoplasm mortality, with associations varying across populations. This study fills an important gap in research on social isolation, emphasizing its varied associations across demographic and socioeconomic groups.

Background: Community-level group sports participation is a structural aspect of social capital that can potentially impact individual health in a contextual manner. This study aimed to investigate contextual relationship between the community-level prevalence of group sports participation and the risk of all-cause, cardiovascular disease (CVD), and cancer mortality in older adults., Methods: In this 7-year longitudinal cohort study, data from the Japan Gerontological Evaluation Study, a nationwide survey encompassing 43,088 functionally independent older adults residing in 311 communities, were used. Cause of death data were derived from the Japanese governmental agency, The Ministry of Health, Labour and Welfare, for secondary use. "Participation" was defined as engaging in group sports for one or more days per month. To analyze the data, a two-level survival analysis was employed, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated., Results: Among the participants, 5,711 (13.3%) deaths were identified, with 1,311 related to CVD and 2,349 to cancer. The average group sports participation rate was 28.3% (range, 10.0-52.7%). After adjusting for individual-level group sports participation and potential confounders, a higher community-level group sports participation rate was found to be significantly associated with a lower risk of both all-cause mortality (HR: 0.89, 95% CI: 0.83-0.95) and cancer mortality (HR: 0.89, 95% CI: 0.81-0.98) for every 10% point increase in the participation rate. For CVD mortality, the association became less significant in the model adjusted for all covariates (HR: 0.94, 95% CI: 0.82-1.09)., Conclusions: Our findings support the existence of a preventive relationship between community-level group sports participation and the occurrence of all-cause and cancer mortality among older individuals. Promoting group sports within communities holds promise as an effective population-based strategy for extending life expectancy, regardless of individual participation in these groups., (© 2024. The Author(s).)

Housing tenure is an important aspect to determine health. However, even though renters tend to have more socioeconomic disadvantages than homeowners, mortality risk between private and public renters compared with homeowners remains unclear. Japanese public rented housing, such as the Urban Renaissance Agency, has been developed for supplying an adequate living environment since 1950s. This study aimed to examine the mortality risk among older Japanese residents living in private and public rented houses compared with those living in owner-occupied houses using 9-year follow-up data. This study drew upon a 9-year follow-up of participants in the Japan Gerontological Evaluation Study, a population-based cohort study of Japanese independent adults aged ≥ 65 years. Mortality from 2010 to 2019 was analyzed for 44,007 respondents. Housing tenure was defined by a questionnaire. Cox regression models were used for calculating the hazard ratio for mortality. Bonferroni correction was used to account for multiple testing between rental houses. Overall, 10,638 deaths occurred during the follow-up period. Compared with housing owners, all rental housing groups had a significantly higher risk of mortality. Among renters, participants who lived in public rental housing had the lowest risk of mortality even after adjusting for sociodemographic characteristics, health status, social status, and environmental status. Multiple testing among renters with Bonferroni correction showed that public renters had 0.80 times (95% CI 0.72-0.89) lower mortality risk than private renters. Although Japanese older adults living in public rental housing had a higher mortality risk than homeowners, this risk was lower than that among private renters. A positive neighborhood environment based on well-planned urban development may have contributed to this result. The results suggest that planned urban development lowers the risk of mortality in older renters in Japan., (© 2024. The Author(s).)

Importance: Because shopping malls are considered safe places for walking, several mall walking programs have been developed. Research on the association between the use of walking programs and the number of daily steps taken is limited., Objective: To evaluate the association between use of a smartphone-based shopping mall walking program and daily steps taken after the COVID-19 pandemic., Design, Setting, and Participants: This cohort study evaluated a nationwide longitudinal data set of 217 344 registered smartphone app users at least 18 years of age residing in Japan. Daily step counts were collected from January 1 to December 31, 2021., Exposures: The mall walking program Mall Challenge integrated a global positioning system with a smartphone app's incentive system to reward achieving a goal of 1000 daily steps with lottery-based coupons to win from 0 to 500 shopping points (1 point equaled 1 yen or approximately US $0.01)., Main Outcomes and Measures: Daily step records were collected from the smartphone app's walking program and adjusted for gender and age. Multilevel analyses using mixed-effect linear regression models were used to estimate the coefficients for the association between daily participation in the walking program and daily step counts. Cross-level interaction terms of age and gender by walking program participation were included in one model., Results: Among the 217 344 registered mall app users (23 638 110 daily step records; 154 616 [71.1%] women; 18 014 [8.3%] participants 65 years or older, and 199 330 [91.7%] adults younger than 65 years), the mean (SD) daily steps were 7415 (4686) on walking program participation days and 5281 (4339) on days without participation in the program. Walking program participation days were associated with 1219 additional daily steps (95% CI, 1205-1232) compared with nonparticipation days after adjusting for gender and age. By geographic region, participation in the walking program was associated with 1130 (95% CI, 1113-1146) more steps in rural malls, 1403 (95% CI, 1379-1428) more steps in suburban malls, and 1433 (95% CI, 1408-1457) more steps in urban malls than nonparticipation. Moreover, participation in the walking program was associated with 1422 (95% CI, 1405-1439) more steps in large malls and 1059 (95% CI, 1041-1077) more steps in small malls compared with nonparticipation. Regarding cross-level interactions, women were associated with walking 728 (95% CI, 698-758) more steps than men, and older adults were associated with walking 228 (95% CI, 183-273) more steps than younger adults on walking program participation days., Conclusions and Relevance: This cohort study found that the use of a smartphone-based mall walking program combined with physical shopping mall facilities and lottery-based digital incentive coupons may motivate people to increase their daily number of walking steps.

Background: Disaster-related relocation is associated with depression and post-traumatic stress disorder, especially in older adults. Disaster-related relocation often deprives survivors of opportunities for social group participation, potentially deteriorating their mental health. On the contrary, the relocation could also be an opportunity for optimizing social relationships, ending/reducing unwanted participation. This study examined the potential mediation effects of changing participation for the link of disaster-related relocation to mental health., Methods: We analyzed a pre-post disaster dataset of functionally independent older adults from the Japan Gerontological Evaluation Study. Following the 2013 survey, a follow-up survey was conducted seven months after the 2016 Kumamoto earthquake (n = 828)., Results: The causal mediation analyses indicated that compared to no relocation, the relative risk for experiencing major depressive episodes among those relocating to temporary housing was 3.79 [95% confidence interval: 1.70-6.64] (natural direct effect). By contrast, the relative risk for those renewing (either ceased or started) group participation was 0.60 [95% CI: 0.34-0.94] (natural indirect effect)., Conclusions: Optimization of social ties according to a renewal of group participation status might have protected older adults in temporary housing against depression., (© 2023. BioMed Central Ltd., part of Springer Nature.)

People have a preference for, and feel better in, beautiful natural environments. However, there are no epidemiological studies on the association between neighborhood beauty and neuroimaging measures. We aimed to determine association between neighborhood beauty and regional brain volume. Participants were 476 community-dwelling older adults from the Neuron to Environmental Impact across Generations (NEIGE) study. Subjective neighborhood beauty was assessed through participants’ perception of beautiful scenery within 1 km of their home. Objective measures of neighborhood indicators (green spaces, blue spaces, and plant diversity) within 1 km of participants’ homes were obtained using a geographic information system. Volumes of brain regions associated with experience of beauty were measured using magnetic resonance imaging. We estimated associations between neighborhood beauty and regional brain volume using linear regression. Of the participants, 42% rated their neighborhoods as very beautiful, and 17% rated them as not at all beautiful. Higher subjective neighborhood beauty was associated with larger bilateral medial orbitofrontal cortex and insula volumes (all p for trend < 0.01). Brain volume was not associated with objective neighborhood measures. Subjective neighborhood beauty was associated with brain regions related to rewards and decision making, suggesting that these brain regions underpin the perception of neighborhood beauty.

Objectives: Elder abuse is a public health issue that is thought to have increased during the COVID-19 pandemic due to lockdowns and behavioral restrictions. This study examines the association between elder abuse and refrainment from daily activities during the pandemic., Methods: We used data from a self-administered mail survey conducted by the Japan Gerontological Evaluation Study (JAGES) from November 2020 to February 2021 in 11 municipalities. Our participants included 18,263 older adults (age ≥65 years) who were independent in their daily lives. Logistic regression analysis was conducted to evaluate the association between elder abuse and refrainment from 10 daily activities, and the total number of refrained behaviors., Results: Experiences of abuse were reported by 288 participants (1.6%). The risk of elder abuse was 1.37 times (95% confidence interval, 1.04-1.81) higher among those who refrained from shopping for food and daily necessities and 1.60 times (1.20-2.13) higher among those who refrained from interaction with neighbors, than those who did not. Also, a dose-response relationship was observed where the risk of abuse increased with the number of restrictions., Conclusion: The risk of elder abuse increased as the number of refrained behaviors increased which suggests that refrainment from multiple behaviors may significantly increase the risk of elder abuse, compared with refrainment from a single behavior. To avoid increasing the risk of abuse in likely future pandemics, it is necessary to maintain social connections without face-to-face contact, or with adequate infection control measures., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 The Authors.)

Mental health is important in older age; neighborhood environment is considered a protective factor of depression. Research has established that a critical indicator of neighborhood environment, street connectivity, is related to older people's health. However, little is known about the relationship between street connectivity and depression. We examined the relationship between street connectivity and depression among older people. Using Japan Gerontological Evaluation Study 2013-2016, the target population comprised 24,141 independent older people without depression (Geriatric Depression Scale scores below 5) in 2013. The outcome variable was depression in 2016; the explanatory variable was street connectivity calculated by intersection density and space syntax within 800 m around the subject's neighborhood in 2013. We used logistic regression analysis to calculate the odds ratio and 95% confidence interval for the new occurrence of depression among participants in 2016. This analysis demonstrated incidence of new depression after 3 years that is 17% and 14% lower among participations living in high-intersection density and high-street-connectivity areas, respectively, than those living in low-intersection density and low-street-connectivity areas. The association held after adjusting for physical activities and social interaction. Given the established connection between street connectivity and mental health, the findings can contribute to healthy urban planning., (© 2022. The Author(s).)

Background: Urbanization and population aging may affect prevalence of chronic pain from various causes. This cross-sectional study aimed to investigate the prevalence of chronic musculoskeletal pain, including some subtypes, in independent Japanese older people, and whether population density and population aging rate explained prevalence and differences in pain levels between municipalities., Methods: We analyzed data from 12,883 independent older people living in 58 municipalities who completed mailed questionnaires and did not need support for daily living. We identified three types of pain: "chronic musculoskeletal pain" lasting ≥ 3 months (overall and in each part of the body), "chronic widespread-type pain" in the spinal and peripheral area, and "chronic multisite pain" in at least three sites. The latter two were measured using new definitions. These types of pain are correlated with depressive symptoms and we therefore examined the construct validity of the definitions by comparing the Geriatric Depression Scale score. We also used analysis of covariance to compare the prevalence of these three types of pain between municipalities. Odds ratios, median odds ratios, and the municipal variance in prevalence of chronic musculoskeletal pain were estimated by Bayesian multilevel logistic regression analysis using the Markov Chain Monte Carlo method., Results: The construct validity of the definitions of chronic widespread-type pain and chronic multisite pain was confirmed. The prevalence of the three types of pain (chronic musculoskeletal, widespread, and multisite pain) was 39.0%, 13.9%, and 10.3%, respectively. Chronic musculoskeletal pain showed a higher prevalence among older people and women. Individuals in underpopulated, suburban, or metropolitan areas tended to have more pain than those in urban areas, but this was not statistically significant (odds ratio [95% credible interval] 1.15 [0.86-1.51], 1.17 [0.93-1.43], 1.17 [0.94-1.46]). Population density and population aging rate did not explain the differences between municipalities., Conclusions: The prevalence of chronic musculoskeletal pain was consistent with previous global reports. Areas with overpopulation and depopulation tended to have higher pain prevalence, but population density and population aging rate did not explain municipal variance. Further research is needed to identify other factors that contribute to regional variance., (© 2022. The Author(s).)

Background: As the understanding of the association between community-level education and dementia is insufficient, this study examined the contextual association of community-level prevalence of low educational attainment on the risk of dementia incidence. With this study, we further explored the potential differences in the aforementioned associations for urban and non-urban areas., Methods: We analyzed 6 years of prospective cohort data from the Japan Gerontological Evaluation Study, beginning with the baseline data collected between 2010 and 2012, for 51,186 physically and cognitively independent individuals aged ≥65 years (23,785 men and 27,401 women) from 346 communities in 16 municipalities across 7 prefectures. We assessed dementia incidence using available data from the long-term care insurance system in Japan. We dichotomized education years as ≤9 and ≥ 10 years and aggregated individual-level educational attainment as a community-level independent variable. Model 1 covariates were age and sex. Income, residential years, disease, alcohol, smoking, social isolation, and population density were added in Model 2. We conducted multiple imputation to address the missing data. We performed a two-level (community and individual) survival analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: The results indicate that the cumulative incidence of dementia during the follow-up period was 10.6%. The mean proportion with educational attainment of ≤9 years was 40.8% (range: 5.1-87.3%). Low community-level educational attainment was significantly associated with higher dementia incidence (HR: 1.04; 95% CI: 1.01-1.07), estimated by 10 percentage points of low educational attainment after adjusting for individual-level educational years and covariates. While the association was significant in non-urban areas (HR: 1.07; 1.02-1.13), there was no association in urban areas (HR: 1.03; 0.99-1.06)., Conclusions: Older people living in communities with low educational attainment among their age demographic develop dementia more often compared with those living in areas with high educational attainment after adjusting for individual-level educational attainment and covariates; the association was pronounced in non-urban areas. Securing education for adolescents as a life course and population approach could thus be crucial in preventing dementia later in life among older people living in non-urban areas., (© 2021. The Author(s).)

Background: The causal effect of physical activity on reducing dementia risk has been questioned due to the possibility of reverse causation. This study examined the potential causal effects of physical activity on reducing dementia risk using residency in a snowy area as an instrumental variable (IV) representing the physical activity of older adults., Methods: We used cohort data from the Japan Gerontological Evaluation Study, a longitudinal cohort enrolling people aged 65 or older who were physically and cognitively independent in 2013; study participants were followed for an average of 5.7 years. Participants in the present study included 73,260 individuals living in 19 municipalities in Japan. Physical activity was measured by self-report questionnaires and the incidence of dementia was ascertained by linking participants to the public registries of long-term care insurance. IV estimation was obtained from a piecewise Cox proportional hazard model using a two-stage regression procedure., Results: During the study period, we ascertained 8714 cases (11.9%) of dementia onset. In the IV analysis, we found that the frequency of physical activity per week was negatively associated with dementia risk, though the association weakened over time (Year 1: hazard ratio = 0.53, 95% confidence interval: 0.39-0.74; Year 4: 0.69, 0.53-0.90; Year 6: 0.85, 0.66-1.10)., Conclusions: Our IV analysis indicated a potential causal effect of physical activity on reducing dementia risk that persisted for at least 4 years of follow-up. Thus, we conclude that physical activity should be recommended for older adults to reduce dementia risk., (© 2021. The Author(s).)

The relationship between chemical concentrations in indoor air and the human sense of comfort and relaxation have been reported. We investigated the effect of the sum of volatile organic compounds (ΣVOCs; sum of 79 VOCs) on the level of relaxation in two laboratory houses with almost identical interior and exterior appearances. The electroencephalogram (EEG) was monitored to evaluate the degree of personal relaxation objectively. The experiments were conducted in laboratory houses (LH) A and B with lower and higher levels of ΣVOCs, respectively. A total of 168 healthy volunteers participated, who each performed the task for 20 min, followed by a 10-min break, and EEG was measured during the break. Simultaneously as subjective evaluations, the participants were asked to fill a questionnaire regarding the intensity of odor and preference for the air quality in each LH. The subjective evaluation showed a significant association between ΣVOCs and participants' relaxation (OR: 2.86, 95%CI: 1.24-6.61), and the objective evaluation indicated that the participants were more relaxed in the LH with lower levels of ΣVOCs than that with higher levels (OR: 3.03, 95%CI: 1.23-7.50). Therefore, the reduction of ΣVOCs and odors in indoor air would have an effect, which is the promotion of relaxation.

Background: Rurality can reflect many aspects of the community, including community characteristics that may be associated with mental health. In this study, we focused on geographical units to address multiple layers of a rural environment. By evaluating rurality at both the municipality and neighborhood (i.e., a smaller unit within a municipality) levels in Japan, we aimed to elucidate the relationship between depression and rurality. To explore the mechanisms linking rurality and depression, we examined how the association between rurality and depression can be explained by community social capital according to geographical units., Methods: We used cross-sectional data from the 2016 wave of the Japan Gerontological Evaluation Study involving 144,822 respondents aged 65 years or older residing in 937 neighborhoods across 39 municipalities. The population density quintile for municipality-level rurality and the quintile for the time required to reach densely inhabited districts for neighborhood-level rurality were used. We calculated the prevalence ratios of depressive symptoms by gender using a three-level (individual, neighborhood, and municipality) Poisson regression. Community social capital was assessed using three components: civic participation, social cohesion, and reciprocity., Results: The prevalence of depressive symptoms was higher in municipalities with lower population density than those with the highest population density; the ratios were 1.22 (95% confidence intervals: 1.15, 1.30) for men and 1.22 (1.13, 1.31) for women. In contrast, when evaluating rurality at the neighborhood level, the prevalence of depressive symptoms was 0.9 times lower for men in rural areas; no such association was observed for women. In rural municipalities, community civic participation was associated with an increased risk of depressive symptoms. In rural neighborhoods, community social cohesion and reciprocity were linked to a lower risk of depressive symptoms., Conclusions: The association between rurality and depression varied according to geographical unit. In rural municipalities, the risk of depression may be higher for both men and women, and the presence of an environment conducive to civic participation may contribute to a higher risk of depression, as observed in this study. The risk of depression in men may be lower in rural neighborhoods in Japan, which may be related to high social cohesion and reciprocity., (© 2021. The Author(s).)

Background: The current study aimed to investigate the contextual effect of volunteer group participation on subsequent depressive symptoms in older people., Methods: We analyzed the longitudinal data of 37,552 people aged 65 years and older in 24 municipalities surveyed in the Japan Gerontological Evaluation Study. Volunteer group participation of older people was assessed in 2013 by one question and depressive symptoms were assessed by the Geriatric Depression Scale 15 in 2016. To investigate a contextual effect, we aggregated individual-level volunteer group participation by each residence area as a community-level independent variable. We conducted a two-level multilevel Poisson regression analysis using the Random Intercepts and Fixed Slopes Model., Results: The average proportion of community-level volunteer group participation was 10.6%. The results of the Poisson regression analysis showed that community-level volunteer group participation reduced the risk for the onset of depressive symptoms by 13% with a 10 percentage point increase in participation, after adjusting for sex, age, population density, total annual sunshine hours and annual rainfall (incident rate ratio, 0.87; 95% confidence interval, 0.78-0.98)., Conclusions: Older people living in areas with higher volunteer group participation had a lower risk of developing depressive symptoms regardless of whether or not they participated in a volunteer group.

Sidewalks are indispensable environmental resources for daily life in that they encourage physical activity. However, the proportion of sidewalk coverage is low even in developed countries. We examined the association between neighborhood sidewalk environment and dementia in Japan. We conducted a 3-year follow-up (2010-2013) among participants in the Japan Gerontological Evaluation Study, a population-based cohort study of community-dwelling older adults. We ascertained the incidence of dementia for 76,053 participants from the public long-term care insurance system. We calculated sidewalk coverage (sidewalk area as a percentage of road area) within 436 residential neighborhood units using geographic information systems. Multilevel survival models were used to estimate hazard ratios for the incidence of dementia. During follow-up, 5,310 dementia cases were found. In urban areas, compared with the lowest quartile of sidewalk coverage, the hazard ratio was 0.42 (95% confidence interval: 0.33, 0.54) for the highest quartile, adjusting for individual covariates. After successive adjustments for other neighborhood factors (land slope; numbers of hospitals, grocery stores, parks, railway stations, and bus stops; educational level; and unemployment rate), the hazard ratio remained statistically significant (hazard ratio = 0.71, 95% confidence interval: 0.54, 0.92). Living in a neighborhood with a high level of sidewalk installation was associated with low dementia incidence in urban areas., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Farmers may have an increased risk for poor mental health. In connection with this, factors specific to the neighborhood environment such as farm density and the type of agriculture, might be important for mental wellbeing. In this study we aimed to clarify the cross-level interaction on depressive symptoms between farm density at the neighborhood level by type of agriculture and the longest occupation of individuals (farmer or non-farmer)., Methods: Data came from the 2016 wave of the Japan Gerontological Evaluation Study (JAGES) that were linked to governmental agricultural data. Information was analyzed from 147,549 respondents aged 65 years or older, residing in 1024 neighborhoods in 39 municipalities. We calculated farm (crop or animal husbandry) density at the neighborhood level, dividing the number of agricultural management entities by the population. Three-level (individual, neighborhood, and municipality) Poisson regression analysis was used to calculate the prevalence rate ratios of depressive symptoms., Results: The prevalence of depressive symptoms was higher among individuals whose longest occupation was farmer compared to non-farmer. The estimated probability of depressive symptoms by a cross-level interaction analysis showed that among farmers of both genders, those who were residing in neighborhoods where the farm density was low had a higher prevalence of depressive symptoms, regardless of the type of agriculture. The slope of the relationship between depressive symptoms and animal husbandry farm density varied by occupation, with a higher prevalence of depressive symptoms observed in male farmers compared to male non-farmers., Conclusions: The high prevalence of depressive symptoms among farmers in neighborhoods with a low farm density may reflect a scarcity of formal and informal social support in such communities. The health effects of the neighborhood environment on farmers, such as farm density, which may vary by the type of agriculture, should be further researched.

Depression among older adults is one of the most critical public health issues. The proximity of elementary schools has been positively associated with neighborhood social cohesion and quality of life. However, no studies have identified an association between the proximity of elementary school and older adults' mental health. Therefore, this study aimed to examine the association between the proximity of elementary schools, one of the core facilities of neighborhood communities in Japan, and depression in older adults. A total of 131,871 participants (63,430 men 73.7 ± 6.1 years, 68,441 women 73.8 ± 6.2 years) were analyzed from the Japan Gerontological Evaluation Study (JAGES) 2016 survey. Logistic regression analysis showed that there was no association between distance to elementary school and depression among males. However, among females, compared with the participants living within 400 m from the nearest elementary school, the odds ratio of depression for those living between 400 and 799 m and more than 800 m away were 1.06 (95% confidence interval (CI) 1.00-1.12) and 1.07 (95% CI 1.00-1.15), respectively. The findings may be useful when considering the design of communities around elementary schools and the planning of facilities as a population-based approach to promote mental health of older women.

Depression in older adults is a public health challenge. We aimed to clarify the relationship between depression in older adults and three types of neighborhood greenspaces: trees, grasslands, and fields. We utilized data from the Japan Gerontological Evaluation Study (JAGES) performed in 2016. Multilevel logistic regression analysis was used for non-stratified and stratified analyses for the urban-rural regions. The target population comprised 126,878 older adults (age ≥ 65 years) who responded to the depression questions and were living in 881 neighborhoods in Japan. Depression was diagnosed based on a Geriatric Depression Scale score ≥5, and 20.4% of the study population had depression. In the pre-stratification analysis, areas with more greenspaces revealed lower odds of depression (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.85-0.95). In urban areas, more trees correlated with lower odds of depression (OR 0.94, 95% CI 0.89-1.00). In rural areas, moderate amounts of grassland were associated with lower odds of depression compared to areas with fewer grasslands (OR 0.91, 95% CI 0.83-1.00). We found that urban areas with higher tree density and rural areas with moderate amounts of grassland were associated with lower odds of depression.

This study examined the longitudinal association between the change in the step count of older adults and the neighborhood-built environment (BE) in Yokohama, Japan. We analyzed pedometer data in March 2016 and March 2019 that were acquired from 21,557 older adults aged 65-79 years at baseline, who lived in 758 neighborhoods in Yokohama City and participated in the Yokohama Walking Point Program (YWPP). Six BE variables were computed, for each of which neighborhoods were classified into quartiles. Using multilevel regression analysis, we examined the association between the BE variables, baseline step count, and change in step count. Higher population density, lower intersection density, and the second shortest quartile of the average distance to the nearest railway station were associated with a higher baseline step count. A lower intersection density and shorter average distance to the nearest railway station were associated with a smaller decline. The lowest quartile of population density was inversely associated with step-count decline. In conclusion, the neighborhood BEs were not only associated with their step count at baseline, but also widened the disparity of the step count over the three years. These findings would contribute to creating age-friendly cities where older adults can maintain and promote their health.

Herein, the concentrations of formic acid, acetic acid, and ammonia in samples of indoor air for 47 new houses were measured two weeks after completion. The houses were fabricated with light-gauge steel structures. The measurements were performed in living rooms and bedrooms without furniture and outdoors. Air samples were analyzed using ion chromatography. The mean values were 28 (living room), 30 (bedroom), and 20 μg m -3 (outdoor air) for formic acid; 166 (living room), 151 (bedroom), and 51 μg m -3 (outdoor air) for acetic acid; and 73 (living room), 76 (bedroom), and 21 μg m -3 (outdoor air) for ammonia. The total values of the three substances accounted for 39.4-40.7% of the sum of chemical compound values. The analyzed compounds were indicated by two principal components (PC), PC1 (30.1%) and PC2 (9%), with 39.1% total variance. Formic acid, acetic acid, and ammonia were positively aligned with PC1 and negatively aligned with PC2. Factors such as room temperature, aldehydes, and phthalates were positively aligned with PC1 and negatively aligned with PC2. Furthermore, concentrations of formic acid, acetic acid, and ammonia were significantly and positively correlated with room temperature ( p < 0.05).

Background: With the aim to prevent sick building syndrome and worsening of allergic symptoms, primarily resulting from the indoor environment, the relationships among people's residential environment in recent years, their lifestyle habits, their awareness, and their symptoms were investigated using an online survey., Methods: In the survey, respondents experiencing symptoms specific to sick building syndrome, although they were not diagnosed with sick building syndrome, were categorized in the pre-sick building syndrome group. The relationships among individual characteristics, residential environment, and individual awareness were analyzed., Results: Results showed that the prevalence of pre-sick building syndrome was high among young (aged 20-29 years) population of both sexes. In addition, "condensation," "moisture," "musty odors" in the house, and the "use of deodorant and fragrance" were all significantly associated with pre-sick building syndrome. Conversely, there was no significant association with recently built "wooden" houses that are highly airtight and have thermal insulation., Conclusions: Efficient "ventilation" plans and "ventilation" improvement and air conditioning systems to prevent mold and condensation in rooms are necessary to maintain a good, indoor environment that is beneficial for health. Efforts should also be made to encourage individuals to regularly clean and effectively ventilate their homes.

Few studies have focused on a relationship between the built environment and musculoskeletal pain. This study aimed to investigate an association between neighborhood walkability and knee and low back pain in older people. Data were derived from the Japan Gerontological Evaluation Study (JAGES) 2013, a population-based study of independently living people ≥65 years old. A cross-sectional multilevel analysis was performed, of 22,892 participants in 792 neighborhoods. Neighborhood walkability was assessed by residents' perceptions and population density. Dependent variables were knee and low back pain restricting daily activities within the past year. The prevalence of knee pain was 26.2% and of low back pain 29.3%. After adjusting for sociodemographic covariates, the prevalence ratio (PR) of knee and low back pain was significantly lower in neighborhoods with better access to parks and sidewalks, good access to fresh food stores, and higher population densities. After additionally adjusting for population density, easier walking in neighborhoods without slopes or stairs was significantly inversely correlated with knee pain (PR 0.91, 95% confidence interval 0.85-0.99). Neighborhoods with walkability enhanced by good access to parks and sidewalks and fresh food stores, easy walking without slopes or stairs, and high population densities, had lower prevalences of knee and low back pain among older people. Further studies should examine environmental determinants of pain.

Purpose: Community-level group participation is a structural aspect of social capital that may have a contextual influence on individual health. We investigated the contextual effect of community-level prevalence of sports group participation on the risk of cognitive impairment among older individuals., Methods: We analyzed prospective cohort data from the Japan Gerontological Evaluation Study, a nationwide survey of 40,308 functionally independent older individuals from 346 communities. Cognitive impairment was assessed by the nationally standardized dementia scale proposed by the Ministry of Health, Labour and Welfare of Japan. Participation in a sports group 1 d per month or more frequently was defined as "participation." We applied a two-level multilevel survival analysis to calculate hazard ratios (HR) and 95% confidence intervals (CI)., Results: The cumulative incidence of cognitive impairment during the 6-yr follow-up period was 9.8%. The mean proportion of sports group participation was 25.2% (range, 0.0%-56.5%). Higher prevalence of community-level sports group participation was associated with a lower risk of cognitive impairment (HR, 0.92; 95% CI, 0.86-0.99, estimated by 10 percentage points of participation proportion) after adjusting for individual-level sports group participation, sex, age, disease, obesity, social isolation, alcohol, smoking, education, income, depression, daily walking time, population density, and sunlight hours. We found cross-level interaction between individual- and community-level sports group participation (HR, 0.87; 95% CI, 0.76-0.99)., Conclusions: We found a contextual preventive effect of community-level sports group participation on developing cognitive impairment among older individuals. Furthermore, the benefit may favor sports group participants. Therefore, promoting sports groups in a community setting may be effective as a population-based strategy for the prevention of dementia.

Recently, people have become increasingly aware of potential health issues related to indoor environments. In this study, we measure the concentrations of various volatile organic compounds, carbonyl compounds, and semi-volatile organic compounds, as well as the ventilation rates, in 49 new houses with light-gauge steel structures one week after completion. The proper indoor air quality of new residential environments can be ensured by characterizing people's exposure to certain chemicals and assessing future risks. Our results show that the concentrations of the measured compounds were lower than the guideline values set by the Ministry of Health, Labour and Welfare of Japan, and would continue to decrease. However, we observed that unregulated compounds, assumed to be substitutes for regulated solvents, contributed substantially to the total volatile organic compounds. To reduce indoor chemical exposure risks, the concentrations of these unregulated compounds should also be minimized. In addition, their sources need to be identified, and manufacture and use must be monitored. We believe it is important to select low-emission building materials for reducing residents' exposure to indoor chemicals.

This study sought to clarify the association between food store availability and the incidence of disability in older adults. This study utilized a population-based cohort study of independent Japanese adults aged ≥65 years, which was a 6 year follow-up of participants in the Japan Gerontological Evaluation Study. A total of 31,273 respondents were extracted. Food store availability was evaluated based on the existence of food stores within 500/1000 m of the home. We utilized participant-reported subjective measurement as well as geographic information system-based objective measurement for the evaluation. The incidence of disability was determined using municipal data on eligibility for long-term care insurance benefits. There were 7643 (24.4%) community-dwelling participants with low subjective food store availability and 5673 (18.1%) with low objective food store availability. During the follow-up period of 6 years, the cumulative incidence of disability was 20.9%, with a significant association between low subjective food store availability and increased disability. Participants who reported low subjective food store availability had a significantly higher likelihood of developing disability (hazard ratio = 1.18, 95% confidence interval: 1.11-1.25) than those who reported high subjective food store availability after adjusting for age, sex, sociodemographic status, environmental status, walking and going out, dietary food intake, body mass index, and comorbidities. Low subjective food store availability was associated with early onset of disability. Accessibility of food stores might contribute to maintaining a disability-free life., Competing Interests: The authors declare no conflicts of interest.

Mobility management is a transportation policy aiming to change travel behavior from car use to sustainable transportation modes while increasing people's physical activity. Providing pedometers and visualizing step counts, popular interventions in public health practice, may constitute a mobility management program. However, the ease of modal shifts and changeability of walking habits differ across neighborhood environments. Using questionnaire data from 2023 middle-aged and older participants from Yokohama, Japan, in May 2017, this study examined (1) the relationship between the physical and social environments of Yokohama Walking Point Program participants who volunteered to use free pedometers and their modal shifts from cars to walking and public transport, and (2) whether participants' modal shifts were associated with increases in step counts. Multivariate categorical regression analyses identified the frequency of greetings and conversations with neighbors as well as health motivation as important explanatory variables in both analyses. Participants living in neighborhoods far from railway stations and in neighborhoods with a high bus stop density tended to shift to walking and public transport, a modal shift that was highly associated with increased step counts. These results suggest that mobility management should be promoted in collaboration with public health and city planning professionals.

This cross-sectional study aimed to compare access to the nearest food stores with perceived access associated with intake frequencies of vegetables/fruits and meat/fish among older Japanese people. We used intake frequencies of vegetables/fruits and meat/fish from a self-administered questionnaire in the Japan Gerontological Evaluation Study among 83,384 adults aged over 65 years. We defined distance over 1 km as poor objective access in community level. We performed multilevel regression analysis to investigate the association of objective and perceived access with intake frequencies of vegetables/fruits and meat/fish, respectively. Participants who lived in poor objective access had a significantly higher intake frequency of vegetables/fruits than those who lived in good access. In contrast, residents with poor perceived access consumed lower frequent intake of vegetables/fruits (beta coefficient (standard error) 0.086 (0.021) for objective access; -0.093 (0.009) for perceived access). There was no significant association between objective access and intake frequency of meat/fish, but poor perceived access showed a significant association with lower intake frequency of meat/fish. There was inconsistency between objective and perceived measurement of access to food stores associated with dietary habits among older Japanese adults. Food access needs to be comprehensively assessed, while considering characteristics of measurements.

Background: Previous research has linked lower availability of food stores selling fruits and vegetables to unhealthy diet. However, the longitudinal association between the availability of healthy food stores and mortality is unknown. This study examined the association between neighborhood availability of food stores and mortality by driving status among older adults., Methods: This study drew upon a three-year follow up of participants in the Japan Gerontological Evaluation Study, a population-based cohort study of Japanese adults aged 65 years or older. Mortality from 2010 to 2013 was analyzed for 49,511 respondents. Neighborhood availability of food stores was defined as the number of food stores selling fruits and vegetables within a 500-m or 1-km radius of a person's residence. Both subjective (participant-reported) and objective (geographic information system-based) measurements were used to assess this variable. Cox regression models were used to estimate hazard ratios (HR) for mortality., Results: A total of 2049 deaths occurred during the follow up. Lower subjective availability of food stores was significantly associated with increased mortality. Compared with participants reporting the highest availability, the age- and sex-adjusted HR for those reporting the lowest availability was 1.28 (95% CI: 1.04-1.58; p = 0.02). The association remained significant after adjustment for sociodemographic (education, income, cohabitation, marital status, and employment status) and environmental (driving status, use of public transportation, and study site) status (HR = 1.24, 95% CI: 1.01-1.53, p = 0.04). This association was stronger among non-car users, among whom the HR for those reporting the lowest availability of food stores was 1.61 (95% CI: 1.08-2.41, p = 0.02). In contrast, no significant association was seen between objective availability and mortality., Conclusions: Lower availability of healthy food stores measured subjectively, but not objectively, was associated with mortality, especially among non-car users. Considering the decline in mobility with age, living in a neighborhood with many options for procuring fruits and vegetables within walking distance may be important for healthy aging.

Purpose: Community-level group participation is a structural aspect of social capital that may have a contextual influence on an individual's health. Herein, we sought to investigate a contextual relationship between community-level prevalence of sports group participation and depressive symptoms in older individuals., Methods: We used data from the 2010 Japan Gerontological Evaluation Study, a population-based, cross-sectional study of individuals 65 yr or older without long-term care needs in Japan. Overall, 74,681 participants in 516 communities were analyzed. Depressive symptoms were diagnosed as a 15-item Geriatric Depression Scale score of ≥5. Participation in a sports group 1 d·month or more often was defined as "participation." For this study, we applied two-level multilevel Poisson regression analysis stratified by sex, calculated prevalence ratios (PR), and 95% confidence intervals (CI)., Results: Overall, 17,420 individuals (23.3%) had depressive symptoms, and 16,915 (22.6%) participated in a sports group. Higher prevalence of community-level sports group participation had a statistically significant relationship with a lower likelihood of depressive symptoms (male: PR, 0.89 (95% CI, 0.85-0.92); female: PR, 0.96 (95% CI, 0.92-0.99), estimated by 10% of participation proportion) after adjusting for individual-level sports group participation, age, diseases, family form, alcohol, smoking, education, equivalent income, and population density. We found statistically significant cross-level interaction terms in male participants only (PR, 0.86; 95% CI, 0.77-0.95)., Conclusions: We found a contextual preventive relationship between community-level sports group participation and depressive symptoms in older individuals. Therefore, promoting sports groups in a community may be effective as a population-based strategy for the prevention of depression in older individuals. Furthermore, the benefit may favor male sports group participants.

Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS)., (© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bacterial access to the gut immune system is a crucial process to promote host immune responses. The probiotic L-92 strain of Lactobacillus acidophilus exerts anti-allergic immunomodulatory effects upon oral administration in mice. Here, we show that microfold cells (M cells) are responsible for L-92 internalization for evoking L-92-mediated immune responses. L-92 specifically bound to uromodulin, a glycosylphosphatidylinositol-anchored protein expressed exclusively on M cells among intestinal epithelial cells. Internalization of L-92 into M cells was significantly reduced in uromodulin-deficient (Umod-/-) mice compared to Umod+/+ mice. Furthermore, the binding of L-92 to uromodulin was significantly decreased after removal of surface layer protein A (SlpA) from the bacteria. Our study thus revealed a crucial role of uromodulin on the M-cell surface for the uptake of SlpA-positive lactic acid bacteria into M cells, possibly leading to subsequent delivery of the bacteria to dendritic cells closely associated with M cells for immunomodulation. Our study also shed light on the possibility that SlpA and uromodulin could be used as vehicle and target, respectively, for efficient mucosal vaccine delivery., (© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies have found an association between neighborhood characteristics (i.e., aspects of the physical and social environment) and the incidence of cardiovascular disease (CVD) and elevated CVD risk. This study investigated the relationship between neighborhood characteristics and CVD risk among older people in Japan where research on this association is scarce. Data came from the Japan Gerontological Evaluation Study project; questionnaire data collected from 3,810 people aged 65 years or older living in 20 primary school districts in Aichi prefecture, Japan, was linked to a computed composite CVD risk score based on biomarker data (i.e., hemoglobin A1c, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and estimated glomerular filtration rate). A sex-stratified multilevel linear regression analysis revealed that for male participants, living in neighborhoods with a higher perceived occurrence of traffic accidents and reduced personal safety was associated with an elevated CVD risk (coefficient = 1.08 per interquartile range increase, 95% confidence interval [CI] = 0.30 to 1.86) whereas males living in neighborhoods with a higher perceived proximity of exercise facilities had a lower risk (coefficient = -1.00, 95% CI = -1.78 to -0.21). For females, there was no statistically significant association between neighborhood characteristics and CVD risk. This study suggests that aspects of the neighborhood environment might be important for CVD morbidity and mortality in Japan, particularly among men., Competing Interests: The authors have declared that no competing interests exist.

M cells in the follicle-associated epithelium (FAE) of Peyer's patches (PPs) serve as a main portal for external antigens and function as a sentinel in mucosal immune responses. The scarcity of these cells has hampered identification of M cell-specific molecules. Recent efforts have begun to provide insight into antigen transcytosis and differentiation of M cells; however, the molecular mechanisms underlying these processes are not fully elucidated. Small non-coding RNAs including microRNA (miRNA) have been reported to regulate gene expression and control various biological processes such as cellular differentiation and function. To evaluate the expression of miRNAs in FAE, including M cells, we previously performed microarray analysis comparing intestinal villous epithelium (VE) and PP FAE. Here we confirmed FAE specific miRNA expression levels by quantitative PCR. To gain insight into miRNA function, we generated mice with intestinal epithelial cell-specific deletion of Dicer1 (DicerΔIEC) and analyzed intestinal phenotypes, including M-cell differentiation, morphology and function. DicerΔIEC mice had a marked decrease in M cells compared to control floxed Dicer mice, suggesting an essential role of miRNAs in maturation of these cells. Furthermore, transmission electron microscopic analysis revealed that depletion of miRNA caused the loss of endosomal structures in M cells. In addition, antigen uptake by M cells was impaired in DicerΔIEC mice. These results suggest that miRNAs play a significant role in M cell differentiation and help secure mucosal immune homeostasis.

Establishing methods for the assessment of fetal exposure to chemicals is important for the prevention or prediction of the child's future disease risk. In the present study, we aimed to determine the influence of molecular weight on the likelihood of chemical transfer from mother to fetus via the placenta. The correlation between molecular weight and placental transfer rates of congeners/isomers of polychlorinated biphenyls (PCBs) and dioxins was examined. Twenty-nine sample sets of maternal blood, umbilical cord, and umbilical cord blood were used to measure PCB concentration, and 41 sample sets were used to analyze dioxins. Placental transfer rates were calculated using the concentrations of PCBs, dioxins, and their congeners/isomers within these sample sets. Transfer rate correlated negatively with molecular weight for PCB congeners, normalized using wet and lipid weights. The transfer rates of PCB or dioxin congeners differed from those of total PCBs or dioxins. The transfer rate for dioxin congeners did not always correlate significantly with molecular weight, perhaps because of the small sample size or other factors. Further improvement of the analytical methods for dioxin congeners is required. The findings of the present study suggested that PCBs, dioxins, or their congeners with lower molecular weights are more likely to be transferred from mother to fetus via the placenta. Consideration of chemical molecular weight and transfer rate could therefore contribute to the assessment of fetal exposure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Microfold (M) cells are intestinal epithelial cells specialized for sampling and transport of luminal antigens to gut-associated lymphoid tissue for initiation of both mucosal and systemic immune responses. Therefore, M-cell targeted vaccination has the potential to be a better immunization strategy. Glycoprotein 2 (GP2), an antigen uptake receptor for FimH(+) bacteria on M cells, can be a good target for this purpose. Aptamers are oligonucleotides that bind to a variety of target molecules with high specificity and affinity. Together with its low toxic feature, aptamers serves as a tool of molecular-targeted delivery. In this study, we used Systematic Evolution of Ligands by EXponential enrichment (SELEX) to isolate aptamers specific to murine GP2 (mGP2). After ten rounds of SELEX, eleven different aptamer sequences were selected. Among them, the most frequently appeared sequence (~60%) were aptamer NO. 1 (Apt1), and the second most (~7%) were aptamer NO. 5 (Apt5). In vitro binding experiment confirmed that only Apt1 and Apt5 specifically bound to mGP2 among eleven aptamers initially selected. Apt1 showed the strongest affinity with mGP2, with the Kd value of 110±2.6 nM evaluated by BIACORE. Binding assays with mutants of Apt1 suggest that, in addition to the loop structure, the nucleotide sequence, AAAUA, in the loop is important for binding to mGP2. Furthermore, this aptamer was able to bind to mGP2 expressed on the cell surface. These results suggest that this mGP2-specific aptamer could serve as a valuable tool for testing M-cell-targeted vaccine delivery in the murine model system.