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Introduction: We are trying to create a platform for social innovation to extend life span. Methods: Since 2005, health data (approximately 3000 items per person as of 2020) of approximately 1000 adults have been collected each year during the Iwaki Health Promotion Project. The industry, government, academia, and citizens have involvements in data collection, aiming to build a platform that encourages societal innovation and subsequently extends life expectancy in Aomori. The Iwaki Health Promotion Project has been supported financially by the Japanese government since it was selected as the Center of Innovation program in 2013. Results: Since the numbers of academia, industries, governments, and citizens involved in the Iwaki Health Promotion Project increased over the years, the big data produced during the project has become increasingly pluripotent and adaptable. It has been used to promote public health, which has also created a stronger partnership among companies and research organizations. Consequently, the amount of data collected from the project has gained attention and became more open to companies and researchers participating in the Iwaki Health Promotion Project, resulted in establishing a larger platform. It also led to the acquisition of external funding, publications of numerous research papers, creation of new health examinations, and the establishment of the Health Promotion Center (an institution for cultivating health volunteers). Conclusion: The Iwaki Health Promotion Project aims not only to produce a pluripotent big data but also to improve the average life expectancy of Aomori by creating a large platform in the society. Its positive impact in the future is infinite and will keep growing as long as it is maintained by the society.

With the prevalence of COVID-19, the importance of short-course radiotherapy (RT) in many cancers has been discussed. The aim of this study was to evaluate the results of hypofractionated schedule RT for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We assessed 45 patients with localized gastric MALT lymphoma who underwent RT between 2005 and 2019. The total RT dose ranged from 24-36 Gy in 10-18 fractions (median of 28 Gy/14 fractions). Patients were divided into three groups according to the dose fractionation: Group A, 30-36 Gy in 15-18 fractions; Group B, 26-28 Gy in 13-14 fractions; and Group C, 24-25 Gy in 10 fractions. All the patients achieved complete remission without local recurrence. The 5-year overall, cause-specific, and progression-free survival rates were 97.5%, 100%, and 97.5%, respectively, with a median follow-up period of 82 months. Among the dose fractionation groups, there were no statistically significant differences in local control or incidence of grade 2 or worse adverse events. Results of RT for localized gastric MALT lymphoma showed excellent local control and survival with no serious adverse events, regardless of dose fractionation. In situations where short-term RT is required, a hypofractionated RT schedule of 24-25 Gy in 10 fractions could be an option for RT schedules.

Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03-1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population.

Autism spectrum disorder (ASD) presents with heterogeneous phenotypic and genetic characteristics. Despite investigation into the molecular mechanisms underlying ASD, its etiology remains elusive. In our previous investigation within the Simons Simplex Collection (SSC), we noted increased signals through a genome-wide association study (GWAS) by clustering patients with ASD and reducing the sample size. This study seeks to validate our previous study in a different population, the Simons Foundation Powering Autism Research for Knowledge (SPARK) population, while probing further into the genetic architecture of ASD. We examined data from 2,079 white male subjects and 875 unaffected SPARK siblings. Our methodology encompassed cluster analyses, followed by traditional GWAS and cluster-based GWAS (cGWAS). No significant associations were observed in the conventional GWAS when comparing all patients with all controls. However, in the cGWAS, by comparing patients clustered by phenotypes with controls, we identified 27 chromosomal loci meeting the criteria of p  < 5.0 × 10 ⁻  8 . Remarkably, several of these loci were situated within or in proximity to genes previously implicated as candidates for ASD. Nonetheless, our previous study of the SSC population did not fully replicate the SPARK population. The absence of reproducibility suggests the possibility of false positives within the cGWAS results due to potential technical factors. However, the emergence of multiple signals post-clustering and the association of numerous identified gene regions with ASD and related disorders provide supporting evidence for the validity of cGWAS outcomes.

Background: The Tohoku Medical Megabank Project (TMM) was established to realize personalized healthcare and medicine using genomic and omics data. This study evaluated the validity and reproducibility of food group intakes derived from a self-administered food frequency questionnaire (TMM-FFQ) that included the response option “constitutionally unable to eat/drink it” among community-dwelling Japanese adults.Methods: Participants comprised 89 men and 124 women aged ≥20 years from Miyagi Prefecture. Participants completed weighed food records (WFRs) for 3 consecutive days per season as reference intake and FFQs in 2019 (FFQ1) and 2021 (FFQ3). Spearman’s rank correlation coefficients (CCs) were calculated for correlations between food group intakes estimated from the 12-day WFR and FFQ3 (validity), and for correlations between those estimated from the FFQ1 and FFQ3 (reproducibility). Cross-classification according to quintiles using FFQ and WFR data was also performed.Results: The percentage of participants who chose the “constitutionally unable to eat/drink it” option was non-negligible for some food groups. In the validity analysis, CCs were >0.40 for many food groups; the median across 21 food groups was 0.49 in men and 0.45 in women. The median percentages of cross-classification into exact plus adjacent quintiles were 73.0% in men and 66.9% in women. In the reproducibility analysis, CCs were >0.50 for many food groups; the median across 21 food groups was 0.60 in men and 0.51 in women.Conclusion: The validity of the TMM-FFQ compared with 12-day WFR and the reproducibility of the TMM-FFQ were reasonable for food groups in the TMM cohort studies.

Background: More research is needed to clarify the health effects of dietary carotenoid intakes, and this requires the use of high-quality assessments of habitual dietary intake. Cohort studies from the Tohoku Medical Megabank Organization included a self-administered food frequency questionnaire (TMM-FFQ) for community-dwelling adults. This study evaluated the validity of carotenoid intakes derived from the TMM-FFQ using serum carotenoid concentrations as the gold standard.Methods: In Miyagi Prefecture, 88 men and 124 women aged ≥20 years voluntarily agreed to participate in the study and provided completed TMM-FFQs and blood samples in 2019 and 2021. Carotenoids examined included α-carotene, β-carotene, β-cryptoxanthin, and lycopene. Intraclass correlation coefficients (ICCs) were calculated to assess correlations between serum concentrations in 2019 and 2021. Spearman’s rank correlation coefficients were calculated to evaluate the correlations between energy-adjusted dietary carotenoid intakes from the TMM-FFQ in 2021 and the average serum carotenoid concentrations in 2019 and 2021, with correction for the attenuating effect of random within-individual variation.Results: The ICCs between serum concentrations over the 2 years were >0.50 for all carotenoids. Among men, correlation coefficients were 0.33 for α-carotene, 0.42 for β-carotene, 0.50 for β-cryptoxanthin, and −0.09 for lycopene. Among women, the coefficients were lower than those for men, except for lycopene: 0.11 for α-carotene, 0.23 for β-carotene, 0.21 for β-cryptoxanthin, and 0.28 for lycopene.Conclusion: The TMM-FFQ demonstrated reasonable validity for assessing intakes of α-carotene, β-carotene, and β-cryptoxanthin among men, but not among women, in the TMM cohort studies when using serum concentrations as the gold standard.

Key message Using a gRNA and Agrobacterium -mediated transformation, we performed simultaneous site-directed mutagenesis of two GmPPD loci in soybean. Mutations in GmPPD loci were confirmed in at least 33% of T 2 seeds. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated endonuclease 9 (Cas9) system is a powerful tool for site-directed mutagenesis in crops. Using a single guide RNA (gRNA) and Agrobacterium -mediated transformation, we performed simultaneous site-directed mutagenesis of two homoeologous loci in soybean ( Glycine max ), GmPPD1 and GmPPD2 , which encode the orthologs of Arabidopsis thaliana PEAPOD ( PPD ). Most of the T 1 plants had heterozygous and/or chimeric mutations for the targeted loci. The sequencing analysis of T 1 and T 2 generations indicates that putative mutation induced in the T 0 plant is transmitted to the T 1 generation. The inheritable mutation induced in the T 1 plant was also detected. This result indicates that continuous induction of mutations during T 1 plant development increases the occurrence of mutations in germ cells, which ensures the transmission of mutations to the next generation. Simultaneous site-directed mutagenesis in both GmPPD loci was confirmed in at least 33% of T 2 seeds examined. Approximately 19% of double mutants did not contain the Cas9/gRNA expression construct. Double mutants with frameshift mutations in both GmPPD1 and GmPPD2 had dome-shaped trifoliate leaves, extremely twisted pods, and produced few seeds. Taken together, our data indicate that continuous induction of mutations in the whole plant and advancing generations of transgenic plants enable efficient simultaneous site-directed mutagenesis in duplicated loci in soybean.

Background: The Tohoku Medical Megabank Project has initiated the Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) including genomic and omics investigations and conducted a self-administered food frequency questionnaire with the response option “constitutionally unable to eat or drink it” for individual food items (TMM-FFQ) for pregnant women. This study evaluated the validity of the TMM-FFQ among pregnant women.Methods: Participants comprised 122 pregnant women aged ≥20 years residing in Miyagi Prefecture who completed weighed food records (WFRs) for 3 days as reference intake and the TMM-FFQ during mid-pregnancy. Correlations between nutrient or food group intakes based on the WFR and the TMM-FFQ were calculated using Spearman’s rank correlation coefficients (CCs), adjusting for energy intake and correcting for random within-individual variation of WFR. Cross-classification was also conducted according to quintiles using the WFR and TMM-FFQ data.Results: The percentages of participants who chose the “constitutionally unable to eat or drink it” option were >3% for seven food and drink items. CCs were >0.30 for 31 nutrients; the median across energy and 44 nutrients was 0.41. CCs were >0.30 for 14 food groups; the median across 20 food groups was 0.35. The median percentages of cross-classification into exact plus adjacent quintiles and extreme quintiles were 63.1% and 3.3% for energy and nutrients and 61.9% and 4.1% for food groups, respectively.Conclusion: The validity of the TMM-FFQ compared with the WFR was reasonable for certain nutrients and food groups among pregnant women in the TMM BirThree Cohort Study.

Genomic information from pregnant women and the paternal parent of their fetuses may provide effective biomarkers for preeclampsia (PE). This study investigated the association of parental polygenic risk scores (PRSs) for blood pressure (BP) and PE with PE onset and evaluated predictive performances of PRSs using clinical predictive variables. In the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, 19,836 participants were genotyped using either Affymetrix Axiom Japonica Array v2 (further divided into two cohorts—the PRS training cohort and the internal-validation cohort—at a ratio of 1:2) or Japonica Array NEO (external-validation cohort). PRSs were calculated for systolic BP (SBP), diastolic BP (DBP), and PE and hyperparameters for PRS calculation were optimized in the training cohort. PE onset was associated with maternal SBP-, DBP-, and PE-PRSs and paternal SBP- and DBP-PRSs only in the external-validation cohort. Meta-analysis revealed overall associations with maternal PRSs but highlighted significant heterogeneity between cohorts. Maternal DBP-PRS calculated using “LDpred2” presented the most improvement in prediction models and provided additional predictive information on clinical predictive variables. Paternal DBP-PRS improved prediction models in the internal-validation cohort. In conclusion, Parental PRS, along with clinical predictive variables, is potentially useful for predicting PE.

Adverse pregnancy outcomes (APOs) affect approximately 20% pregnant women, and their incidence is increasing. The aim of this study was to investigate the effect of cardiovascular health (CVH) during pregnancy on APOs. We analyzed data from 14,930 pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. CVH status during pregnancy was assessed using the eight components of Life’s Essential 8. APOs were defined as composite outcomes encompassing preeclampsia, gestational diabetes mellitus, preterm birth, and small for gestational age. The numbers of participants with high, moderate, and low CVH status were 2891 (19.4%), 11,498 (77.0%), and 541 (3.6%), respectively. Poisson regression analyses with robust error variance, which adjusted for maternal age at conception, alcohol consumption, conception via in vitro fertilization, parity, psychological distress, social isolation, and household income, showed a positive association between moderate and low CVH levels and APOs (risk ratio and 95% confidence interval 1.15 [1.03–1.28] and 2.14 [1.78–2.58], respectively). Among pregnant women with low CVH, those who reported social isolation had a higher prevalence of APOs than did those without social isolation (36.4% vs. 27.4%). This difference was attenuated for pregnant women with high CVH status (13.6% vs. 13.1%). In conclusion, CVH status may be useful for assessing the risk of APOs. Socially isolated pregnant women are more vulnerable to the effects of low CVH status.