Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population.

Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12-35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.

Relationship Between Life Satisfaction and Psychological Characteristics Among Community-Dwelling Oldest-old: Focusing on Erikson's Developmental Stages and the Big Five Personality Traits.

OBJECTIVE: To clarify the relationship between life satisfaction and the psychological characteristics of the oldest-old, and explore the factors for achieving mental health and longevity. DESIGN: This cross-sectional study conducted questionnaire surveys and face-to-face interviews as part of a larger prospective cohort study. SETTING: Arakawa Ward, a district in Tokyo, Japan. PARTICIPANTS: A total of 247 oldest-old individuals from two age groups, 85+ (aged 85-87 years) and 95+ (aged 95 years or older). MEASUREMENTS: Life satisfaction was assessed using the Satisfaction with Life Scale (SWLS), developmental stages of the elderly (Erikson's 8th and 9th stages, i.e., ego integrity, and gerotranscendence), and the Big Five personality traits (extraversion, agreeableness, openness, conscientiousness, and neuroticism) using the NEO-Five Factor Inventory. Multiple regression analyses were performed to examine the relationship between the SWLS scores and each assessment, controlling for age, sex, education, activities of daily living, depressive symptoms, and cognitive function. RESULTS: The SWLS scores of 85+ were positively correlated with scores of ego integrity, extraversion, and conscientiousness. Contrastingly, the SWLS scores of 95+ were positively correlated with gerotranscendence scores. CONCLUSIONS: Psychological characteristics associated with the level of life satisfaction among community-dwelling oldest-old individuals were identified, but a causal relationship between these factors and life satisfaction was not established. Ego integrity, extraversion, conscientiousness, and gerotranscendence may be associated with enhanced life satisfaction and mental health in the oldest-old. Further, the factors associated with life satisfaction in the 85+ and 95+ age groups varied, suggesting that life satisfaction among the oldest-old has different foundations in different age groups.

Gender and age influence the association between gait speed and mild cognitive impairment in community-dwelling Japanese older adults: from the Japan Prospective Studies Collaboration for Ageing and Dementia (JPSC-AD).

BACKGROUND: Studies have shown that decreased gait speed is associated with impaired cognitive function. However, whether this association is equivalent across ages or genders in the older population remains unclear. Thus, we examined the association between mild cognitive impairment (MCI) and gait speed emphasising the influence of age and gender. METHODS: Overall, 8233 Japanese participants aged ≥65 years were enrolled in this cross-sectional study between 2016 and 2018. After stratification by gender and age group, the participants' gait speeds were divided into quintiles, and the difference in MCI prevalence at each gait speed quintile was calculated. Logistic regression analyses were performed to assess the odds of MCI for each quintile and to assess the influence of age and gender. RESULTS: Males had a consistently higher prevalence of MCI than females. The odds of MCI were increased as gait speed decreased. Logistic regression analyses revealed that in the multivariable-adjusted model 2, the odds ratios (95% confidence interval; CI) for MCI were 2.02 (1.47-2.76) for females and 1.75 (1.29-2.38) for males in the slowest gait speed quintiles compared to the fastest quintile. In the stratified analyses, only males showed an age-dependent increase in the associations between gait speed and MCI, while females exhibited comparable associations across age groups. CONCLUSIONS: Reduced gait speed was associated with increased odds of MCI, and this association may vary according to gender and age. Therefore, gait speed could serve as a valuable screening tool for MCI, with gender- and age-dependent clinical implications.

Increasing light physical activity helps to maintain cognitive function among the community-dwelling oldest old population: a cross-sectional study using actigraph from the Arakawa 85+ study.

AIM: To investigate the influence of replacing sedentary time with physical activity on cognitive function using an isotemporal substitution model in a population of community-dwelling oldest old. METHODS: This cross-sectional study included residents of the Arakawa ward, Tokyo, who were part of a prospective cohort from the Arakawa 85+ study. We measured physical activity in 136 participants using a triaxial actigraph. Cognitive function was measured using the Addenbrooke's Cognitive Examination-III and participants were divided into a "cognitive decline group" (Addenbrooke's Cognitive Examination-III ≤88) and "cognitive maintain group" (Addenbrooke's Cognitive Examination-III ≥89). Physical activity was divided into three categories: sedentary behavior (≤1.5 metabolic equivalents), light physical activity (>1.5 to <3.0 metabolic equivalents), and moderate-to-vigorous physical activity (≥3 metabolic equivalents). Using an isotemporal substitution approach, we applied multiple logistic regression analysis to demonstrate the association between cognitive function and replacing 30 min/day of sedentary behavior with an equal period of light physical activity. Covariates included age, education and the Center for Epidemiologic Studies Depression Scale. RESULTS: Our findings showed that in men, replacing 30 min of sedentary behavior per day with light physical activity was associated with a 1.47-fold increase in the odds of maintaining cognitive function. An association between physical activity and cognitive function was not observed in female participants. CONCLUSIONS: Our results indicate that substituting sedentary behavior with light physical activity could be helpful in maintaining cognitive function in community-dwelling oldest old men. These results highlight the importance of behavioral changes to promote cognition. Geriatr Gerontol Int 2020; 20: 773-778.

A new method of Bayesian causal inference in non-stationary environments.

Bayesian inference is the process of narrowing down the hypotheses (causes) to the one that best explains the observational data (effects). To accurately estimate a cause, a considerable amount of data is required to be observed for as long as possible. However, the object of inference is not always constant. In this case, a method such as exponential moving average (EMA) with a discounting rate is used to improve the ability to respond to a sudden change; it is also necessary to increase the discounting rate. That is, a trade-off is established in which the followability is improved by increasing the discounting rate, but the accuracy is reduced. Here, we propose an extended Bayesian inference (EBI), wherein human-like causal inference is incorporated. We show that both the learning and forgetting effects are introduced into Bayesian inference by incorporating the causal inference. We evaluate the estimation performance of the EBI through the learning task of a dynamically changing Gaussian mixture model. In the evaluation, the EBI performance is compared with those of the EMA and a sequential discounting expectation-maximization algorithm. The EBI was shown to modify the trade-off observed in the EMA.

Correction: Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy.

This article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the article have been modified accordingly.

Pigs with δ-sarcoglycan deficiency exhibit traits of genetic cardiomyopathy.

Genetic cardiomyopathy is a group of intractable cardiovascular disorders involving heterogeneous genetic contribution. This heterogeneity has hindered the development of life-saving therapies for this serious disease. Genetic mutations in dystrophin and its associated glycoproteins cause cardiomuscular dysfunction. Large animal models incorporating these genetic defects are crucial for developing effective medical treatments, such as tissue regeneration and gene therapy. In the present study, we knocked out the δ-sarcoglycan (δ-SG) gene (SGCD) in domestic pig by using a combination of efficient de novo gene editing and somatic cell nuclear transfer. Loss of δ-SG expression in the SGCD knockout pigs caused a concomitant reduction in the levels of α-, ß-, and γ-SG in the cardiac and skeletal sarcolemma, resulting in systolic dysfunction, myocardial tissue degeneration, and sudden death. These animals exhibited symptoms resembling human genetic cardiomyopathy and are thus promising for use in preclinical studies of next-generation therapies.

Extended Bayesian inference incorporating symmetry bias.

We start by proposing a causal induction model that incorporates symmetry bias. This model has two parameters that control the strength of symmetry bias and includes conditional probability and conventional models of causal induction as special cases. We calculated the determination coefficients between assessments by participants in eight types of causal induction experiments and the estimated values using the proposed model. The mean coefficient of determination was 0.93. Thus, it can reproduce causal induction of human judgment with high accuracy. We further propose a human-like Bayesian inference method to replace the conditional probability in Bayesian inference with the aforementioned causal induction model. In this method, two components coexist: the component of Bayesian inference, which updates the degree of confidence for each hypothesis, and the component of inverse Bayesian inference that modifies the model of each hypothesis. In other words, this method allows not only inference but also simultaneous learning. Our study demonstrates that the method addresses unsteady situations where the target of inference occasionally changes not only by making inferences based on knowledge (model) and observation data, but also by modifying the model itself.

Sociopsychological characteristics of late nonagenarians in Japan: the protocol of the Arakawa 95+ study.

AIM: The aim of this study was to examine sociopsychological characteristics of the oldest old in Japan. We conducted a baseline survey of a community-based cohort of persons aged 95 or older. METHODS: Participants were aged 95+ years and resided in Arakawa Ward in Tokyo on 1 January 2016. We mailed a questionnaire to these individuals to assess their physical, mental, and social status. Subsequently, if respondents agreed, we conducted in-home interviews and examined their physical and cognitive function. Also, we mailed non-respondents a simplified version of full questionnaire. Additionally, we examined the basic registered data of the study population and the status of their Long-term Care Insurance. Data at baseline and 1-year follow-up were compared. RESULTS: With regard to Long-term Care Insurance, 423 residents aged 95+ years (78.0%) were on long-term care level, 35 (6.5%) were on support level, and 84 (15.5%) did not require support. At the 1-year follow-up, 275 (50.7%) had the same care level, 107 (19.7%) required a greater level of care, and 131 had died (annual death rate: 24.2%). Compared to the simplified questionnaire group (n = 128) and the full questionnaire-only group (n = 14), a higher proportion of respondents who had completed the full questionnaire and had in-home interviews (n = 26) were men, lived only with a spouse, had higher activities of daily living, and reported more positive feelings and well-being. CONCLUSIONS: In the late nonagenarian population, the annual death rate was high, and care needs increased rapidly. However, some persons maintained the same care level or even showed improvement and successful ageing.

Is it possible to implement community care based on mental health in Japan? A comparison between decade ago and present on Duration of Untreated Psychosis (DUP).

INTRODUCTION: In recent years, the early detection and treatment of the first episode of schizophrenia (FES) has attracted worldwide attention. In Japan, psychiatric care has changed to an open and accessible framework over the past decade. Therefore, the duration of untreated psychosis (DUP) is thought to have been shortened. The purposes of this study were to investigate whether recent DUP periods are shorter than they were 10 years ago and whether the DUP at present differs among psychiatric facilities. We investigated the recent DUP at a psychiatric hospital and its satellite clinic. MATERIAL AND METHODS: We examined the differences in DUP, age, sex, referral pathway, living companions, social participation, and schooling history among 3 groups of FES patients: (i) a psychiatric hospital during 1999-2001 and (ii) during 2009-2011, and (iii) a psychiatric clinic during 2009-2011. RESULTS: The average DUP was 14.3 (SD = 17.5) months for the psychiatric hospital during 1999-2001, 16.0 (SD = 18.7) months for the psychiatric hospital during 2009-2011, and 24.4 (SD = 30.0) months for the psychiatric clinic during 2009-2011. No significant differences were found in the DUP for each facility and during this decade. Also, the differences in the DUP could not be attributed to factors such as living companions or social participation. DISCUSSION: Increases in the numbers of patients and psychiatric clinics have not led to the early detection of FES. To shorten the DUP in the future, closer cooperation among the medical field, the educational field, and the health and welfare will be needed.

Pregnancy and birth survey after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident in Fukushima prefecture.

BACKGROUND: On 11 March 2011, the Great East Japan Earthquake followed by a powerful tsunami hit the Pacific Coast of Northeast Japan and damaged Tokyo Electric Power Company's Fukushima Daiichi Nuclear Power Plant, causing a radiation hazard in Fukushima Prefecture. The objective of this report is to describe some results of a questionnaire-based pregnancy and birth survey conducted by the Radiation Medical Science Center for the Fukushima Health Management Survey. MATERIALS AND METHODS: Questionnaires were sent to women who received maternal and child health handbooks from municipal officers in Fukushima Prefecture between 1 August 2010 and 31 July 2011, with the aim of reaching those who were pregnant at the time of the disaster. Mailing began 18 January 2012. Data were analyzed separately for six geographic areas in Fukushima Prefecture. RESULTS: The total number of women meeting survey criteria was 15,972. The number of responses received to date is 9,298 (58.2%). Data from 8602 respondents were analyzed after excluding 634 invalid responses and 5 induced and 57 spontaneous abortions (less than 22 gestational weeks). The incidences of stillbirth (over 22 completed gestational weeks), preterm birth, low birth weight and congenital anomalies were 0.25%, 4.4%, 8.7% and 2.72%, respectively. These incidences are similar to recent averages elsewhere in Japan. CONCLUSION: Considering the pregnancy and birth survey data in aggregate, our disaster seemed to provoke no significant adverse outcomes over the whole of Fukushima prefecture. But post-disaster prenatal care and support intended for patients' safety and security should be coupled with ongoing surveillance and rigorous data analysis.

[Endocrine profiles and gonadotropin response to Gn-RH of men with testicular cancer].

PURPOSE: To investigate the function of the hypothalamic-pituitary-testicular axis in testicular germ cell tumors, we evaluated gonadotropin responses to gonadotropin-releasing hormone (Gn-RH), semen quality, and serum levels of sex steroid hormones in patients with testicular cancer. PATIENTS AND METHODS: Basal serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and human chorionic gonadotropin-beta (hCG-beta) were measured before and after high orchiectomy in 20 patients with germ cell tumors of the testicle (9 with seminoma and 11 with nonseminomatous tumor). Semen quality and basal serum levels of testosterone, free testosterone, and estradiol were measured before orchiectomy. The Gn-RH test was performed before orchiectomy in all patients and after orchiectomy in patients without detectable gonadotropin levels in pre-operative serum samples. Gonadotropin levels were measured at 0, 30, 60, 90, and 120 minutes after intravenous injection of 100 micrograms of luteinizing hormone-releasing hormone (LH-RH). RESULTS: Serum gonadotropin concentrations were not detectable in 6 of 8 (75%) men with hCG positive tumors or in 4 of 12 (33.3%) men with hCG negative tumors before orchiectomy. Before surgery, 10 men without detectable gonadotropin levels showed complete suppression of the LH and FSH responses to LH-RH and 10 men with detectable gonadotropin levels showed significant increases in the LH and FSH responses (p < 0.01) at 30 minutes. After surgery, the Gn-RH test was performed in 9 men without detectable gonadotropin levels prior to surgery. Seven of these 9 men exhibited significant increases in the LH and FSH responses (p < 0.01) at 30 minutes while no response to LH-RH before or after surgery was seen in 2 men with detectable serum hCG-beta. We observed a significantly lower sperm density (median 7.5 x 10(6)/ml, range 0.4 to 17.8) in men with hCG positive tumors than in men with hCG negative tumors (median 33 x 10(6)/ml, range 0 to 103) (p < 0.002). Although testosterone levels did not differ significantly in men with hCG positive tumors and men with hCG negative tumors, free testosterone levels were significantly higher in men with hCG positive tumors (median 28.4 ng/ml, range 8.5 to 39.8) compared with men with hCG negative tumors (median 18.7 ng/ml, range 4.9 to 24.1) (p < 0.002). Estradiol levels were significantly increased in men with hCG positive tumors (median 44 pg/ml, range 26 to 110) compared with men with hCG negative tumors (median 33.5 pg/ml, range 10 to 87) (p = 0.002). CONCLUSION: The present findings indicate that serum hCG producing testicular cancers are associated with a complete suppression of the gonadotropin response to Gn-RH at the pituitary level, resulting in an inhibition of LH and FSH secretion, and also that serum hCG secreted by testicular cancers may suppresses spermatogenesis and may stimulate androgen and estradiol production by the testes. Since suppressed serum gonadotoropin levels are found in men with hCG non-producing testicular cancers, other factors derived from the tumor may cause downregulation of the gonadotropin response to Gn-RH.