Vertical mother-to-infant transmission of herpes simplex virus 2 is correlated with tropism due to mutations in viral UL13.

Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.

Bivalent mRNA vaccine effectiveness against COVID-19 among older adults in Japan: a test-negative study from the VENUS study.

BACKGROUND: Bivalent COVID-19 vaccines have been implemented worldwide since the booster vaccination campaigns of autumn of 2022, but little is known about their effectiveness. Thus, this study holistically evaluated the effectiveness of bivalent vaccines against infection in older adults in Japan. METHODS: We adopted the test-negative design using COVID-19 test data of individuals, aged ≥ 65 years, residing in three municipalities in Japan, who underwent tests in medical institutions between October 1 and December 30, 2022. Logistic regression analyses were conducted to estimate the odds of testing positive according to vaccination status. Vaccine effectiveness was defined as (1 - odds ratio) × 100%. RESULTS: A total of 3,908 positive and 16,090 negative results were included in the analyses. Receiving a bivalent dose in addition to ≥ 2 monovalent doses was 33.6% (95% confidence interval [CI]: 20.8, 44.3%) more effective than receiving no vaccination, and 18.2% (95% CI: 9.4, 26.0%) more effective than receiving ≥ 2 monovalent doses but not receiving a bivalent vaccination. In addition, the effectiveness peaked at 14-20 days after administration and then gradually declined over time. Furthermore, a bivalent booster dose provided 18.6% (95% CI: 9.9, 26.5%) additional protection among those vaccinated with ≥ 2 monovalent doses, in the absence of a previous infection history. However, we did not find sufficient evidence of effectiveness of bivalent vaccines among previously infected older adults. CONCLUSIONS: Bivalent vaccines are effective against COVID-19 infections among older adults without a history of infection.

Frequency of Going Outdoors and Risk of Poor Oral Health Among Older Japanese Adults: A Longitudinal Cohort From the Japan Gerontological Evaluation Study.

BACKGROUND: The association between the frequency of going outdoors and the risk of poor oral health has been reported in several studies; however, the findings have been inconclusive. METHODS: We conducted a 3-year longitudinal study of 19,972 Japanese adults aged ≥65 years who reported no poor oral condition at baseline in 2013. The respondents rated their frequency of going outdoors in three categories (≤1, 2-3, or ≥4 times/week), and the oral conditions reported in 2016 included tooth loss, chewing difficulty, swallowing difficulty, dry mouth, and composite outcomes. The associations between the frequency of going outdoors and the risk of poor oral health were examined as relative risk ratios (RRs) and 95% confidence intervals (CIs) using multivariable Poisson regression, while mediation analysis was performed to investigate indirect effects. RESULTS: During the follow-up, 32.5% of participants developed poor oral health. In the mediation analysis, indirect effects were observed through low instrumental activities of daily living, depressive symptoms, little social network diversity, and underweight. Compared to going outdoors ≥4 times/week, the multivariable RRs of composite poor oral health conditions were 1.12 (95% CI, 1.05-1.20) for 2-3 times/week and 1.22 (95% CI, 1.07-1.39) for ≤1 time/week (P-trend < 0.001). Similar associations were observed for tooth loss, chewing difficulty, and swallowing difficulty; the corresponding RRs were 1.07 (95% CI, 0.97-1.19) and 1.36 (95% CI, 1.13-1.64) (P-trend = 0.002), 1.18 (95% CI, 1.06-1.32) and 1.30 (95% CI, 1.05-1.60) (P-trend < 0.001), and 1.15 (95% CI, 1.01-1.31) and 1.38 (95% CI, 1.08-1.77) (P-trend = 0.002), respectively. CONCLUSION: The frequency of going outdoors was inversely associated with the risk of poor oral health through several modifiable risk factors in the older population.

Changes in the utilization of outpatient and visiting dental care and per-attendance care cost by age groups during COVID-19 pandemic waves in Japan: A time-series analysis from LIFE study.

BACKGROUND: The influence of the coronavirus disease (COVID-19) pandemic on dental care utilization may have differed according to individual characteristics or type of dental care provision. This study aimed to evaluate the changes in dental care utilization and per-attendance costs by age group and type of dental care during the COVID-19 pandemic in Japan. METHODS: This time-series study used healthcare insurance claims data from 01/07/2019 to 09/27/2021 (143 weeks) from nine municipalities in Japan. Dental care utilization rate per week and average dental care cost per attendance by age groups (0-19y/20-64y/65-74y/≥ 75y) and types of dental care (outpatient/visiting) were used as outcome variables. COVID-19 pandemic waves in Japan were used as predictors: 1st (03/23/2020-05/17/2020), 2nd (06/22/2020-09/27/2020), 3rd (10/26/2020-02/21/2021), 4th (02/22/2021-06/07/2021), and 5th (07/05/2021-09/13/2021) waves. Fixed effect models were employed to estimate the proportional changes. RESULTS: In the fixed effect model, we observed large declines in dental care utilization during the 1st (17.0-22.0%) and 2nd waves (3.0-13.0%) compared to the non-pandemic wave period in all age groups. In contrast, the average dental care cost per attendance increased in all age groups by 5.2-8.6% during the 1st wave. CONCLUSIONS: During the initial wave of the COVID-19 pandemic in Japan, dental care utilization decreased in all age groups, whereas the average dental care cost per attendance increased. The COVID-19 pandemic may have changed the dental care provision pattern towards less frequent and more concentrated dental care to avoid the risk of infection.

A principal component analysis of metabolome and cognitive decline among Japanese older adults: cross-sectional analysis using Tohoku Medical Megabank Cohort Study.

BackgroundDementia is the leading cause of disability and imposes a significant burden on society. Previous studies have suggested an association between metabolites and cognitive decline. Although the metabolite composition differs between Western and Asian populations, studies targeting Asian populations remain scarce.MethodsThis cross-sectional study used data from a cohort survey of community-dwelling older adults aged ≥ 60 years living in Miyagi, Japan, conducted by Tohoku Medical Megabank Organization between 2013 and 2016. Forty-three metabolite variables quantified using nuclear magnetic resonance spectroscopy were used as explanatory variables. Dependent variable was the presence of cognitive decline (≤ 23 points), assessed by the Mini-Mental State Examination. Principal component (PC) analysis was performed to reduce the dimensionality of metabolite variables, followed by logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cognitive decline.ResultsA total of 2,940 participants were included (men: 49.0%, mean age: 67.6 years). Among them, 1.9% showed cognitive decline. The first 12 PC components (PC1-PC12) accounted for 71.7% of the total variance. Multivariate analysis showed that PC1, which mainly represented essential amino acids, was associated with lower odds of cognitive decline (OR = 0.89; 95% CI, 0.80-0.98). PC2, which mainly included ketone bodies, was associated with cognitive decline (OR = 1.29; 95% CI, 1.11-1.51). PC3, which included amino acids, was associated with lower odds of cognitive decline (OR = 0.81; 95% CI, 0.66-0.99).ConclusionAmino acids are protectively associated with cognitive decline, whereas ketone metabolites are associated with higher odds of cognitive decline.

BMI and Cardiometabolic Traits in Japanese: A Mendelian Randomization Study.

BACKGROUND: Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. METHODS: We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The ß-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. RESULTS: In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions. CONCLUSION: The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

Tooth loss mediates the association between smoking and an increased risk of dementia among older adults: The JAGES prospective cohort study.

AIM: Tooth loss has various causes; however, its cause-specific effects on health outcomes remain unclear. This study evaluated whether the association between past/current smoking and risk of dementia was mediated by tooth loss. MATERIALS AND METHODS: This 9-year-follow-up prospective cohort study targeted adults aged ≥65 years. Dementia incidence during 2013-2019, smoking status (never, past/current) in 2010 and the number of remaining teeth (≤19, ≥20) in 2013 were the outcome, exposure and mediator, respectively. We used causal mediation analysis to fit the Cox proportional hazards model and estimated the hazard ratio (HR) and 95% confidence interval (CI) of the natural indirect effect (NIE) of smoking on dementia incidence through tooth loss and their mediated proportions. RESULTS: Among 32,986 participants (mean age 72.6 years [1 SD = 5.4]; men 48.4%), the dementia incidence during follow-up was 2.11/100 person-years. Tooth loss significantly mediated the association between past/current smoking and dementia incidence; the NIE of fewer remaining teeth for past/current smokers compared to never smokers was HR = 1.03 (95% CI: 1.02-1.05), and the mediated proportion was 18.0%. CONCLUSIONS: Tooth loss significantly mediates the association between past/current smoking and an increased risk of dementia among older adults.

Association between consumption of small fish and all-cause mortality among Japanese: the Japan Multi-Institutional Collaborative Cohort Study.

OBJECTIVE: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. DESIGN: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated FFQ. The hazard ratio (HR) and 95 % confidence interval (CI) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. SETTING: The Japan Multi-Institutional Collaborative Cohort Study. PARTICIPANTS: A total of 80 802 participants (34 555 males and 46 247 females), aged 35-69 years. RESULTS: During a mean follow-up of 9·0 years, we identified 2482 deaths including 1495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HR (95 % CI) in females for all-cause mortality according to the intake were 0·68 (0·55, 0·85) for intakes 1-3 times/month, 0·72 (0·57, 0·90) for 1-2 times/week and 0·69 (0·54, 0·88) for ≥ 3 times/week, compared with the rare intake. The corresponding HR (95 % CI) in females for cancer mortality were 0·72 (0·54, 0·96), 0·71 (0·53, 0·96) and 0·64 (0·46, 0·89), respectively. No statistically significant association was observed in males. CONCLUSIONS: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

The association between objective and subjective oral health conditions and the presence of anorexia of aging among Japanese older Adults1.

Anorexia of aging is a risk factor for malnutrition among older adults. This study aimed to evaluate the association between objective and subjective oral health and anorexia among independent older adults. This cross-sectional study targeted independent older adults aged ≥65 years who participated in the Japan Gerontological Evaluation Study conducted in 2022. The outcome variable was the presence of anorexia, as assessed by the Simplified Nutritional Appetite Questionnaire. Exposure variables were dental status (≥20 teeth, 10-19 teeth with/without dentures, and 0-9 teeth with/without dentures) as objective oral health and oral health-related quality of life measured by five items of the short version of the Oral Impacts on Daily Performances (OIDP) (eating, speaking, smiling, emotional stability, and enjoying with others) as subjective oral health. We fitted the Poisson regression model, including possible confounders, and estimated prevalence ratios (PRs) and 95% confidence intervals. Among 19,787 participants (mean age: 74.6 years [1SD = 6.2], male: 48.5%), 9.0% were classified as having anorexia. After adjusting possible confounders, those with ≤19 teeth had a higher proportion of experiencing anorexia compared to those with ≥20 teeth; however, the association was less pronounced among those with dentures (0-9 teeth with dentures: PR = 1.48 [1.31-1.68], and 0-9 teeth without dentures: PR = 2.08 [1.65-2.63]). Even after adjusting for dental status, each item of OIDP was significantly associated with the presence of anorexia (all p < 0.05). The results showed that both objective and subjective poor oral health were significantly associated with a higher probability of developing anorexia of aging. Therefore, improving both objective and subjective oral health through appropriate dental care could contribute to maintaining appetite in later life.

Differences in prevalence of self-reported oral hypofunction between older adult patients with rheumatoid arthritis and the general older population: A cross-sectional study using propensity score matching.

OBJECTIVE: To examine the association between rheumatoid arthritis (RA) and oral hypofunction (OHF) using propensity score matching (PSM) to adjust for differences between older adults with RA and the general older adult population. METHODS: We conducted a cross-sectional survey among 189 older adults with RA in 2019 (mean age, 71.9 ± 3.6) and 47 178 independent older adult residents in 2016 (mean age, 71.6 ± 4.0), respectively. The questionnaire covered information on socio-demographic characteristics and OHF for both groups. Age, sex, educational level and smoking history were used to determine PSM. Prevalence ratios (PRs) and 95% confidence intervals (CIs) of self-reported OHF (fewer remaining teeth, decreased masticatory function, deterioration of swallowing function and oral dryness) were estimated using Poisson regressions. RESULT: OHF was observed in 44.4% of patients with RA and 27.5% of residents. Before PSM, the prevalence of OHF among patients with RA was higher than that of residents (PR, 1.75; 95% CI, 1.50-2.05). After PSM, there were 189 patients with RA and residents, and the prevalence of OHF among patients with RA was still higher (PR, 1.61; 95% CI, 1.22-2.13). Poisson regression showed that the prevalence of 19 or fewer teeth (PR, 1.06; 95% CI, 0.82-1.36), difficulties eating tough foods (PR, 1.18; 95% CI, 0.90-1.55), difficulties swallowing tea or soup (PR, 1.77; 95% CI, 1.19-2.63), and dry mouth (PR, 2.79; 95% CI, 1.90-4.07) was higher among patients with RA than residents. CONCLUSION: Compared with the general older adult population, patients with RA have a higher prevalence of self-reported OHF.

Protein tyrosine kinase Abl promotes hepatitis C virus particle assembly via interaction with viral substrate activator NS5A.

Previously, we reported that knockdown of Abl protein tyrosine kinase by shRNA or pharmacological inhibition suppresses particle assembly of J6/JFH1 strain-derived hepatitis C virus (HCV) in Huh-7.5 cells. However, the detailed mechanism by which Abl regulates HCV replication remained unclear. In this study, we established Abl-deficient (Abl-) cells through genome editing and compared HCV production between Abl- cells expressing WT or kinase-dead Abl and parental Huh-7.5 cells. Our findings revealed that Abl expression was not required from the stages of virus attachment and entry to viral gene expression; however, the kinase activity of Abl was necessary for the assembly of HCV particles. Reconstitution experiments using human embryonic kidney 293T cells revealed that phosphorylation of Tyr412 in the activation loop of Abl was enhanced by coexpression with the viral nonstructural protein 5A (NS5A) and was abrogated by the substitution of NS5A Tyr330 with Phe (Y330F), suggesting that NS5A functions as a substrate activator of Abl. Abl-NS5A association was also attenuated by the Y330F mutation of NS5A or the kinase-dead Abl, and Abl Tyr412 phosphorylation was not enhanced by NS5A bearing a mutation disabling homodimerization, although the association of Abl with NS5A was still observed. Taken together, these results demonstrate that Abl forms a phosphorylation-dependent complex with dimeric NS5A necessary for viral particle assembly, but that Abl is capable of complex formation with monomeric NS5A regardless of tyrosine phosphorylation. Our findings provide the foundation of a molecular basis for a new hepatitis C treatment strategy using Abl inhibitors.

Compliance Trajectory and Patterns of COVID-19 Preventive Measures, Japan, 2020-2022.

COVID-19 remains a global health threat. Compliance with nonpharmaceutical interventions is essential because of limited effectiveness of COVID-19 vaccines, emergence of highly contagious variants, and declining COVID-19 antibody titers over time. We evaluated compliance with 14 nonpharmaceutical intervention-related COVID-19 preventive behaviors, including mask wearing, ventilation, and surface sanitation, in a longitudinal study in Japan using 4 waves of Internet survey data obtained during 2020-2022. Compliance with most preventive behaviors increased or remained stable during the 2-year period, except for surface sanitation and going out behaviors; compliance with ventilation behavior substantially decreased in winter. Compliance patterns identified from latent class analysis showed that the number of persons in the low compliance class decreased, whereas those in the personal hygiene class increased. Our findings reflect the relaxation of mobility restriction policy in Japan, where the COVID-19 pandemic continues. Policymakers should consider behavioral changes caused by new policies to improve COVID-19 prevention strategies.

Moderate-to-vigorous Physical Activity and Sedentary Behavior Are Independently Associated With Renal Function: A Cross-sectional Study.

BACKGROUND: Little is known about whether insufficient moderate-to-vigorous physical activity (MVPA) and longer sedentary behavior (SB) are independently associated with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), whether they interact with known risk factors for CKD, and the effect of replacing sedentary time with an equivalent duration of physical activity on kidney function. METHODS: We examined the cross-sectional association of MVPA and SB with eGFR and CKD in 66,603 Japanese cohort study in 14 areas from 2004 to 2013. MVPA and SB were estimated using a self-reported questionnaire, and CKD was defined as eGFR <60 mL/min/1.73 m2. Multiple linear regression analyses, logistic regression analyses, and an isotemporal substitution model were applied. RESULTS: After adjusting for potential confounders, higher MVPA and longer SB were independently associated with higher eGFR (P for trend MVPA <0.0001) and lower eGFR (P for trend SB <0.0001), and a lower odds ratio (OR) of CKD (adjusted OR of MVPA ≥20 MET·h/day, 0.76; 95% confidence interval [CI], 0.68-0.85 compared to MVPA <5 MET·h/day) and a higher OR of CKD (adjusted OR of SB ≥16 h/day, 1.81; 95% CI, 1.52-2.15 compared to SB <7 h/day), respectively. The negative association between MVPA and CKD was stronger in men, and significant interactions between sex and MVPA were detected. Replacing 1 hour of SB with 1 hour of physical activity was associated with about 3 to 4% lower OR of CKD. CONCLUSION: These findings indicate that replacing SB with physical activity may benefit kidney function, especially in men, adding to the possible evidence on CKD prevention.

Population-Based Impact of Smoking, Drinking, and Genetic Factors on HDL-cholesterol Levels in J-MICC Study Participants.

BACKGROUND: Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS: Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, of which seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS: We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSION: The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

Sex-specific Relationship Between Stress Coping Strategies and All-cause Mortality: Japan Multi-Institutional Collaborative Cohort Study.

BACKGROUND: Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults. METHODS: A total of 79,580 individuals aged 35-69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy ("sometimes," and "often/very often" use versus "very few" use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated. RESULTS: During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs for "sometimes" were 0.81 (95% confidence interval [CI], 0.67-0.97) for emotional expression, 0.79 (95% CI, 0.66-0.95) for emotional support-seeking, and 0.80 (95% CI, 0.66-0.98) for disengagement. Men who "sometimes" used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15-41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (P for interaction = 0.03). CONCLUSION: In a large Japanese sample, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.

GWAS of folate metabolism with gene-environment interaction analysis revealed the possible role of lifestyles in the control of blood folate metabolites in Japanese - the J-MICC Study.

BACKGROUND: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites as well as to detect related gene-environment interactions in Japanese. METHODS: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. RESULTS: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5×10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity > 33% on Hcy (ß = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and < 0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (ß = 0.033, P = 0.048). CONCLUSIONS: The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized CVD prevention.

Adaptor protein 3BP2 regulates dectin-1-mediated cellular signalling to induce cytokine expression and NF-κB activation.

The adaptor protein c-Abl Src homology 3 domain-binding protein-2 (3BP2) is phosphorylated by spleen tyrosine kinase (Syk), and the phosphorylation of Tyr183 is important in the regulation of immune responses. Recently, we reported that 3BP2 plays important roles in phagocytosis and chemokine expression mediated by the Fc receptor for IgG. Although it is well established that various phagocytic cells express Syk-coupled C-type lectin receptors (CLRs) to induce innate immune responses, the functions of 3BP2 and the physiological relevance of the phosphorylation of Tyr183 remain elusive. In this study, we generated genome-edited mice and observed that 3BP2 influenced the development of bone marrow-derived dendritic cells (BMDCs) induced by granulocyte-macrophage colony-stimulating factor. In addition, we found that 3BP2 was critical for cytokine expression induced by Syk-coupled CLRs - dectin-1 and macrophage-inducible C-type lectin. Immunoblotting analyses revealed that 3BP2 was required for the dectin-1-induced activation of NF-κB p65. The impaired expression of cytokines and activation of NF-κB in 3BP2-mutant cells were restored by wild-type 3BP2, suggesting that 3BP2 was involved in the dectin-1-mediated signalling that led to NF-κB activation. Furthermore, we found that the phosphorylation of Tyr183 is not essential for cytokine expression and that 3BP2 in combination with caspase recruitment domain family member 9 activates NF-κB in HEK-293T cells. Collectively, these results indicate that in addition to the development of BMDCs, 3BP2 plays an important role in the dectin-1-induced activation of NF-κB and cytokine expression.

Dental prosthesis use is associated with higher protein intake among older adults with tooth loss.

BACKGROUND: Tooth loss is associated with reduced protein intake, which leads to sarcopenia and frailty in older adults. OBJECTIVE: To evaluate the protective effect of dental prostheses on decreased protein intake in older adults with tooth loss. METHODS: This cross-sectional study was based on a self-reported questionnaire targeting older adults. Data were obtained from the Iwanuma Survey of the Japan Gerontological Evaluation Study. We used % energy intake (%E) of total protein as the outcome and the use of dental prostheses and number of remaining teeth as explanatory variables. We estimated the controlled direct effects of tooth loss by fixing the use/non-use of dental prostheses based on a causal mediation analysis, including possible confounders. RESULTS: Among 2095 participants, the mean age was 81.1 years (1SD = 5.1), and 43.9% were men. The average protein intake was 17.4%E (1SD = 3.4) of the total energy intake. Among participants with ≥20, 10-19 and 0-9 remaining teeth, the average protein intake was 17.7%E, 17.2%E/17.4%E and 17.0%E/15.4%E (with/without a dental prosthesis), respectively. Compared to participants with ≥20 remaining teeth, those with 10-19 remaining teeth without a dental prosthesis did not have a significantly different total protein intake (p > .05). Among those with 0-9 remaining teeth without a dental prosthesis, total protein intake was significantly low (-2.31%, p < .001); however, the use of dental prostheses mitigated the association by 79.4% (p < .001). CONCLUSION: Our results suggest that prosthodontic treatment could contribute to maintaining protein intake in older adults with severe tooth loss.

Lower socio-economic status in adolescence is associated with poor oral health at an older age: Mediation by social and behavioural factors.

AIM: To examine the mediators between lower socio-economic status (SES) in adolescence and oral health at an older age to uncover the underlying mechanisms of the association. METHODS: Participants (n = 21 536) aged ≥65 years from the Japan Gerontological Evaluation Study were evaluated. The dependent variables were self-rated chewing difficulty and having ≤19 remaining teeth. The main independent variable was self-perceived SES in adolescence. The Karlson-Holm-Breen method was used for mediation analysis. RESULTS: Mean age of the participants was 74.8 years (standard deviation = 6.4), and 51.5% were female. Overall, 5598 (26.0%) participants reported chewing difficulty and 9404 (43.7%) had ≤19 remaining teeth. Lower SES in adolescence was associated with a higher prevalence of chewing difficulty (odds ratio [OR] = 1.38, 95%confidence interval [CI] = 1.29-1.48; total effect). After controlling for mediators, OR for lower SES in adolescence was 1.22 (95%CI = 1.13-1.30; direct effect) and 1.13 (95%CI = 1.11-1.16; indirect effect). Mediators, prominently the number of teeth and income, explained 39.3% of the associations. Lower SES in adolescence increased the odds of ≤19 remaining teeth by OR = 1.23 (95% CI = 1.16-1.31; total effect). After controlling for mediators, the OR for lower SES in adolescence was 1.03 (95%CI = 0.97-1.10; direct effect) and 1.19 (95%CI = 1.16-1.23; indirect effect). Mediators, prominently educational attainment, explained 85.0% of the associations. CONCLUSIONS: Lower SES in adolescence was associated with poor oral health at an older age through mediators. Approaches that consider social determinants from the beginning of the life course are required.

[Association between periodontal pocket depth determined during dental check-ups and new onset of diabetes in community residents: the LIFE study].

Objectives　Recent studies have shown a bidirectional association between diabetes and periodontal disease. However, the longitudinal association between periodontal pocket depth and new onset of diabetes remains controversial. Therefore, this study aimed to examine the association between periodontal pocket depth and new onset of diabetes using dental check-up data in a community-based population.Methods　The study comprised 5,163 participants aged≥20 years (mean age±standard deviation, 57.4±13.9 years; women, 66.3%) who underwent dental check-ups between April 2016 and March 2019 in a Tokyo ward. We classified the participants into three groups using community periodontal index codes from dental check-ups: healthy periodontal pocket group, periodontal pocket 4-5 mm group, and periodontal pocket ≥6 mm group. The participants were followed until the end of March 2020. Additionally, data on individuals who developed diabetes in the same ward were acquired from the National Health Insurance and Latter-Stage Older Persons Health Care System using ICD-10 codes. As the study outcome, we identified individuals who developed diabetes after the dental check-up date. Diabetes incidence rates were compared using the log-rank test and Cox regression analysis. Additionally, we performed a sensitivity analysis using a similar framework.Results　The log-rank test showed that the cumulative incidence of diabetes between the three groups was significantly different (P<0.01). A Cox regression analysis model adjusted for sex, age, smoking habits, number of teeth present, and oral hygiene status showed that the diabetes development hazard ratio (HR) for the periodontal pocket ≥6 mm group was 1.44 (95% confidence interval [CI]; 1.04-2.00) when compared with that of the healthy periodontal pocket group. In the sensitivity analysis of individuals aged ≥40 years, the HR for the periodontal pocket ≥6 mm group was 1.55 (95% CI; 1.11-2.16) when compared with that of the healthy periodontal pocket group. Similarly, among men aged ≥40 years, the HR for the periodontal pocket ≥6 mm group was 1.72 (95% CI; 1.04-2.85) when compared with that of the healthy periodontal pocket group. However, no significant association between new onset of diabetes and periodontal pocket depth was found for women aged ≥40 years (HR=1.39, 95% CI; 0.89-2.18).Conclusion　This The study suggests a longitudinal association between periodontal pocket depth and new onset of diabetes. The association was particularly pronounced in men aged ≥40 years. Therefore, men aged <40 years should maintain good oral health through appropriate dental health guidance to prevent the future development of diabetes.