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Background: While previous literature suggests that multimorbidity is linked to a higher risk of mortality, evidence is scarce among individuals in middle adulthood. We aimed to examine the association between physical multimorbidity and all-cause mortality among individuals aged 40–64 years at baseline in Japan. Methods: Data were obtained from two cohort studies, the Japan Public Health Center-based Prospective Study (JPHC) and the Japan Epidemiology Collaboration on Occupational Health Study (J-ECOH). The study participants were 144,774 individuals aged 40–64 years at baseline who were followed up for a maximum of 29 and 10 years in the JPHC and J-ECOH, respectively. Multimorbidity was defined as the presence of ≥ 2 of 10 morbidities or conditions based on self-reported information. A Cox proportional hazards model was used to examine the association in relation to all-cause mortality. We calculated pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) using a random-effects meta-analysis model. Cause-specific analysis was performed using the JPHC dataset, which provided a sufficient number of events for mortality due to physical disorders, mental disorders/suicide, and unintentional injuries. Results: During a follow-up of 2,304,375 person-years in the JPHC and 311,637 person-years in the J-ECOH, 23,611 and 275 deaths were recorded, respectively. Participants with vs. without physical multimorbidity at baseline were more likely to die prematurely in both cohorts with a pooled HR of 1.61 (95%CI = 1.29–2.01). Cause-specific analyses among the JPHC participants revealed that physical multimorbidity at baseline was linked with mortality due to physical disorders, mortality due to mental disorders/suicide, and mortality due to unintentional injuries. Conclusions: Physical multimorbidity in middle adulthood is associated with an increased risk of all-cause mortality in Japan. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS: Participants aged 65‐85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS: Of 531 participants, 406 completed the trial. The between‐group difference in composite score changes was 0.047 (95% CI: −0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. Highlights: This trial evaluated the efficacy of multidomain intervention in individuals with MCI.The trial did not show a significant difference in preplanned cognitive outcomes.Interventions had positive effects on a wide range of secondary health outcomes.Those with adequate adherence or high risk of dementia benefited from interventions. [ABSTRACT FROM AUTHOR]

Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/[IL2rg.sup.null] strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin--CD34+ CD38--human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR[alpha][beta]+ T cells and CD4--CD8--and CD8+ TCR[gamma][delta]+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from naive to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein--Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases. human immunology | T-cell development | HLA restriction | Epstein-Barr virus doi/ 10.1073/pnas.1000475107

Abstract Background Gait variables derived from trunk accelerometry may predict the risk of falls; however, their associations with falls are not fully understood. The purpose of the study was to determine which gait variables derived from upper and lower trunk accelerometry are associated with the incidence of falls, and to compare the discriminative ability of gait variables and physical performance. Methods This study was a 1-year prospective study. Older people (n = 73) walked normally while wearing accelerometers attached to the upper and lower trunk. Participants were classified as fallers (n = 16) or non-fallers (n = 57) based on the incidence of falls over 1 year. The harmonic ratio (HR) of the upper and lower trunk was measured. Physical performance was measured in five chair stands and in the timed up and go test. Results The HR of the upper and lower trunk were consistently lower in fallers than non-fallers (P < 0.05). Upper trunk HR, was independently associated with the incidence of falls (P < 0.05) after adjusting for confounding factors including physical performances. Consequently, upper trunk HR showed high discrimination for the risk of falls (AUC = 0.81). Conclusions HR derived from upper trunk accelerometry may predict the risk of falls, independently of physical performance. The discriminative ability of HR for the risk of falls may have some validity, and further studies are needed to confirm the clinical relevance of trunk HR.