Low blood concentration of alcohol enhances activity related to stopping failure in the right inferior frontal cortex.

This study investigated the effects of low doses of alcohol, which are acceptable for driving a car, on inhibitory control and neural processing using the stop-signal task (SST) in 17 healthy right-handed social drinkers. The study employed simultaneous functional magnetic resonance imaging and electromyography (EMG) recordings to assess behavioral and neural responses under conditions of low-dose alcohol (breath-alcohol concentration of 0.15 mg/L) and placebo. The results demonstrated that even a small amount of alcohol consumption prolonged Go reaction times in the SST and modified stopping behavior, as evidenced by a decrease in the frequency and magnitude of partial response EMG that did not result in button pressing during successful inhibitory control. Furthermore, alcohol intake enhanced neural activity during failed inhibitory responses in the right inferior frontal cortex, suggesting its potential role in behavioral adaptation following stop-signal failure. These findings suggest that even low levels of alcohol consumption within legal driving limits can greatly impact both the cognitive performance and brain activity involved in inhibiting responses. This research provides important evidence on the neurobehavioral effects of low-dose alcohol consumption, with implications for understanding the biological basis of impaired motor control and decision-making and potentially informing legal guidelines on alcohol consumption.

The relationships between motor behavior and sensory gating in the ball rotation task.

During voluntary muscle contraction, sensory information induced by electrostimulation of the nerves supplying the contracting muscle is inhibited and the amplitude of the corresponding somatosensory evoked potential (SEP) decreases. This phenomenon is called "gating." The reduction of the SEP amplitude is reportedly significantly larger when task performance is high. However, the relationship between dexterous movement skills and gating remains unclear. In this study, we investigated through a ball rotation (BR) task how dexterous movement skills affect the SEP amplitudes. Thirty healthy subjects performed the BR task comprising the rotation of two wooden balls as quickly as possible. We estimated the median number of ball rotations for each participant and classified the participants into two (fast and slow) groups based on the results. Moreover, we recorded SEPs, while the subjects performed BR tasks or rested. SEP amplitude reduction (P45) was significantly larger in the fast than in the slow group. We also observed that the P45 amplitude during the BR task was attenuated even more so in the case of the participants with better dexterous movement skills. Our results suggest that the participants with better dexterous movement skills might display stronger somatosensory information suppression because of increasing the motor cortex activity and the afferent input during the BR task.

Out-of-pocket payment and patients' treatment choice for assisted reproductive technology by household income: a conjoint analysis using an online social research panel in Japan.

BACKGROUND: Economic disparities affect access to assisted reproductive technology (ART) treatment in many countries. At the time of this survey, Japan provided partial reimbursement for ART treatment only for those in low- or middle-income classes due to limited governmental budgets. However, the optimal level of financial support by income class remains unclear. METHODS: We conducted a conjoint analysis of ART in Japan in January 2020. We recruited 824 women with fertility problems aged 25 to 44 years via an online social research panel. They completed a questionnaire of 16 hypothetical scenarios measuring six relevant ART attributes (i.e., out-of-pocket payment, pregnancy rate, risk of adverse effects, number of visits to outpatient clinics, consultation hours and kindness of staff) and their relations to treatment choice. RESULTS: Mixed-effect logistic regression models showed that all six attributes significantly influenced treatment preferences, with participants valuing out-of-pocket payment the most, followed by pregnancy rates and kindness of staff. Significant interactions occurred between high household income (≥ 8 million JPY) and high out-of-pocket payment (≥ 500,000 JPY). However, the average marginal probability of the highest-income patients (i.e., ≥ 10 million JPY, ineligible for the subsidy) receiving ART treatment at the average cost of 400,000 JPY was 47%, compared to 56 - 61% of other income participants, who opted to receive ART at an average cost of 100,000 JPY after a 300,000 JPY subsidy. CONCLUSION: Our results suggest that out-of-pocket payment is the primary determinant in patients' decision to opt for ART treatment. High-income patients were more likely to choose treatment, even at a high cost, but their income-based ineligibility for government financial support might discourage some from receiving treatment.

Household income and medical help-seeking for fertility problems among a representative population in Japan.

BACKGROUND: Fertility treatments help many infertile couples to have children. However, disparities exist in access to fertility tests and treatments. We investigated the association between household income and medical help-seeking for fertility in Japan. METHODS: We conducted a cross-sectional study using nationally representative data from the National Fertility Survey 2015. Respondents were 6598 married women younger than 50 years old. The primary outcome was medical help-seeking for fertility among those who experienced fertility problems. Multiple logistic regression models were used to assess the association between household income and medical help-seeking, adjusting for age, length of marriage, educational level, employment status, number of children, childbearing desires, living with parents, and region of residence. RESULTS: Among 2253 (34%) women who experienced fertility problems, 1154 (51%) sought medical help. The proportion of help-seekers increased linearly from 43% in the low-income group (< 4 million Japanese yen [JPY]) to 59% in the high-income group (≥ 8 million JPY) (P for trend < 0.001). Respondents with upper-middle (6-8 million JPY) or high household income were more likely to seek medical help, compared to those with low household income: adjusted odds ratio [aOR] 1.37 (95% confidence interval [CI]: 1.00-1.86) and aOR 1.78 (95% CI: 1.29-2.47), respectively. CONCLUSIONS: We found that higher household income was associated with a higher probability of seeking medical help among Japanese women who experienced fertility problem. Along with policy discussion about additional financial support, further studies from societal, cultural, or psychological views are required.

Fertility treatments have helped millions of people to have a child. Although financial factors are known to play an important role in the decision to use fertility treatments, no previous studies have investigated how socioeconomic factors affect medical help-seeking for fertility in Japan. Therefore, we assessed the association between household income and medical help-seeking among couples with fertility problems in Japan, using nationally representative data from the National Fertility Survey 2015. Of the 6598 respondents (married women under 50 years old), one-third (2253) reported worrying about fertility problems, and half of those women (1154) sought medical help for fertility-related issues. The proportion of help-seekers was highest (59%) among those with high household income and lowest (43%) among those with low household income with a significant linear trend. Even after accounting for age, length of marriage, educational level, employment status, and other possibly related factors, those with higher household income were more likely to seek medical help for fertility tests and treatments. Japan provides various sources of financial support for fertility-related care, such as health insurance coverage for tests and early-stage treatments and partial subsidies for assisted reproductive technology treatments. However, the results indicate that further policy discussion about additional financial support and further studies focusing on barriers to care in Japan could help improve the situations for those with fertility problems.

Cumulative live birth rate according to the number of receiving governmental subsidies for assisted reproductive technology in Saitama Prefecture, Japan: A retrospective study using individual data for governmental subsidies.

PURPOSE: We investigated the cumulative live birth rate (CLBR) in women receiving governmental subsidies for assisted reproductive technology (ART) in Saitama Prefecture, Japan. METHODS: Women who applied for subsidies from Saitama Prefectural Government for the first time in 2016 were enrolled and followed up until the end of 2017. Treatment information, including live birth, was obtained from the Japanese ART registry by linking it with unique identification numbers for treatment. Patients' factors associated with having a live birth were investigated. RESULTS: Of 1,072 women (2,513 applications), 495 (46.2%) had a live birth with 8 (1.6%) twin pregnancies. The CLBR over six subsidized cycles was 53.7% for women aged <40 years, and 17.2% over three subsidized cycles for women 40-42 years; highest among women <35 years (58.4%), followed by those aged 35-39 years (49.3%). Multivariate analysis revealed patient age as the only independent factor for having a live birth. CONCLUSIONS: The CLBR of women receiving subsidies for ART was greatest in women aged <35 years. Effective policies for promoting ART among younger couples who seek infertility treatment are essential.

Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction.

Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase (CS) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial CS (eCS) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of eCS in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca2+ oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of eCS enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that eCS suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.

Correction: Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death.

Protein crystallization in human tissue rarely occurs. Charcot-Leyden crystals (CLCs) were described in various eosinophilic diseases >150 years ago, but our understanding of CLC formation still remains limited. In this study, we demonstrate that CLCs observed in varied inflamed human tissues are closely associated with eosinophil cell-free granules and nuclear envelope/plasma membrane disintegration with release of filamentous chromatin (extracellular traps), typical morphologies of a regulated pathway of extracellular trap cell death (ETosis). During the process of eosinophil ETosis, eccentrically localized cytoplasmic and perinuclear CLC protein (galectin-10) is homogeneously redistributed in the cytoplasm. Rapid (1-2 minutes) formation of intracytoplasmic CLCs was observed using time-lapse imaging. Plasma membrane rupture enabled the release of both intracellularly formed CLCs and soluble galectin-10 that further contributed to formation of CLCs extracellularly, in parallel with the expulsion of free intact granules and extracellular traps. CLC formation and galectin-10 release were dependent on nicotinamide adenine dinucleotide phosphate oxidase activation. To our knowledge, this is the first demonstration of natural formation of CLCs in association with an active physiological process (ie, ETosis). These results indicate that dynamic changes in intracellular localization and release of galectin-10 contribute to CLC formation in vivo and suggest that CLC/galectin-10 might serve as an indicator of ETosis.

Promoting fertility awareness and preconception health using a chatbot: a randomized controlled trial.

RESEARCH QUESTION: What are the effects of using a fertility education chatbot, i.e. automatic conversation programme, on knowledge, intentions to improve preconception behaviour and anxiety? DESIGN: A three-armed, randomized controlled trial was conducted using an online social research panel. Participants included 927 women aged 20-34 years who were randomly allocated to one of three groups: a fertility education chatbot (intervention group), a document about fertility and preconception health (control group 1) or a document about an irrelevant topic (control group 2). Participants' scores on the Cardiff Fertility Knowledge Scale and the State-Trait Anxiety Inventory, their intentions to optimize preconception behaviours, e.g. taking folic acid, and the free-text feedback provided by chatbot users were assessed. RESULTS: A repeated-measures analysis of variance showed significant fertility knowledge gains after the intervention in the intervention group (+9.1 points) and control group 1 (+14.9 points) but no significant change in control group 2 (+1.1 points). Post-test increases in the intentions to optimize behaviours were significantly higher in the intervention group than in control group 2, and were similar to those in control group 1. Post-test state anxiety scores were significantly lower in the intervention group than in control group 1 and control group 2. User feedbacks about the chatbot suggested technical limitations, e.g. low comprehension of users' words, and pros and cons of using the chatbot, e.g. convenient versus coldness. CONCLUSIONS: Providing fertility education using a chatbot improved fertility knowledge and intentions to optimize preconception behaviour without increasing anxiety, but the improvement in knowledge was small. Further technical development and exploration of personal affinity for technology is required.

Membrane protein CD9 is repositioned and released to enhance uterine function.

Tetraspanin CD9 is essential for sperm-egg fusion and also contributes to uterine repair through microexosome formation. Microexosomes share CD9 with exosomes and are released from eggs and uterine epithelial cells. However, the mechanism for the formation of microexosomes remains unknown. To address this issue, we examined membrane localization and extracellular release of CD9 proteins using uterine epithelial cells and secretions in mice and humans. In mice, CD9 localized predominantly on the basal region of the plasma membrane and relocated to the apical region upon embryo implantation. Furthermore, extracellular CD9 proteins were detected in uterine secretions of mice and women undergoing infertility treatment, but were below detectable levels in supernatants of pluripotent stem cells. Ultrastructural analysis demonstrated that membrane projections were shortened and the number of mitochondria was reduced in uterine epithelial cells lacking Cd9 genes. Our results suggest that CD9 repositioning and release affect both membrane structures and mitochondrial state in the uterus, and contribute to female fertility.

Degradation of phosphate polymer polyP enhances lactic fermentation in mice.

In bacteria, a polymer of inorganic phosphate (Pi) (inorganic polyphosphate; polyP) is enzymatically produced and consumed as an alternative phosphate donor for adenosine triphosphate (ATP) production to protect against nutrient starvation. In vertebrates, polyP has been dismissed as a "molecular fossil" due to the lack of any known physiological function. Here, we have explored its possible role by producing transgenic (TG) mice widely expressing Saccharomyces cerevisiae exopolyphosphatase 1 (ScPPX1), which catalyzes hydrolytic polyP degradation. TG mice were produced and displayed reduced mitochondrial respiration in muscles. In female TG mice, the blood concentration of lactic acid was enhanced, whereas ATP storage in liver and brain tissues was reduced significantly. Thus, we suggested that the elongation of polyP reduces the intracellular Pi concentration, suppresses anaerobic lactic acid production, and sustains mitochondrial respiration. Our results provide an insight into the physiological role of polyP in mammals, particularly in females.

Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus.

STUDY QUESTION: What were the risks with regard to the pregnancy outcomes of patients who conceived by frozen-thawed embryo transfer (FET) during a hormone replacement cycle (HRC-FET)? SUMMARY ANSWER: The patients who conceived by HRC-FET had increased risks of hypertensive disorders of pregnancy (HDP) and placenta accreta and a reduced risk of gestational diabetes mellitus (GDM) in comparison to those who conceived by FET during a natural ovulatory cycle (NC-FET). WHAT IS KNOWN ALREADY: Previous studies have shown that pregnancy and live-birth rates after HRC-FET and NC-FET are comparable. Little has been clarified regarding the association between endometrium preparation and other pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of patients who conceived after HRC-FET and those who conceived after NC-FET was performed based on the Japanese assisted reproductive technology registry in 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: The pregnancy outcomes were compared between NC-FET (n = 29 760) and HRC-FET (n = 75 474) cycles. Multiple logistic regression analyses were performed to investigate the potential confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: The pregnancy rate (32.1% vs 36.1%) and the live birth rate among pregnancies (67.1% vs 71.9%) in HRC-FET cycles were significantly lower than those in NC-FET cycles. A multiple logistic regression analysis showed that pregnancies after HRC-FET had increased odds of HDPs [adjusted odds ratio, 1.43; 95% confidence interval (CI), 1.14-1.80] and placenta accreta (adjusted odds ratio, 6.91; 95% CI, 2.87-16.66) and decreased odds for GDM (adjusted odds ratio, 0.52; 95% CI, 0.40-0.68) in comparison to pregnancies after NC-FET. LIMITATIONS, REASONS FOR CAUTION: Our study was retrospective in nature, and some cases were excluded due to missing data. The implication of bias and residual confounding factors such as body mass index, alcohol consumption, and smoking habits should be considered in other observational studies. WIDER IMPLICATIONS OF THE FINDINGS: Pregnancies following HRC-FET are associated with higher risks of HDPs and placenta accreta and a lower risk of GDM. The association between the endometrium preparation method and obstetrical complication merits further attention. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained for this work. The authors declare no conflicts of interest in association with the present study. TRIAL REGISTRATION NUMBER: Not applicable.

Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure.

STUDY QUESTION: Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)? SUMMARY ANSWER: PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups. WHAT IS KNOWN ALREADY: PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40-50% and 5-25% in patients with RPL, respectively. STUDY DESIGN, SIZE, DURATION: A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35-36, 37-38, 39-40 or 41-42 years) were selected for PGT-A groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted. MAIN RESULT AND THE ROLE OF CHANCE: There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16-13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28-10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02-0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03-0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients. LIMITATIONS, REASONS FOR CAUTION: The sample size was too small to find any significant advantage for improving the live birth rate and reducing the clinical miscarriage rate per patient. Further study is necessary. WIDER IMPLICATION OF THE FINDINGS: A large portion of pregnancy losses in the RPL group might be due to aneuploidy, since PGT-A reduced the overall incidence of pregnancy loss in these patients. Although PGT-A did not improve the live birth rate per patient, it did have the advantage of reducing the number of embryo transfers required to achieve a similar number live births compared with those not undergoing PGT-A. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Japan Society of Obstetrics and Gynecology and grants from the Japanese Ministry of Education, Science, and Technology. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Male subfertility and the risk of major birth defects in children born after in vitro fertilization and intracytoplasmic sperm injection: a retrospective cohort study.

BACKGROUND: Children born after intracytoplasmic sperm injection (ICSI) are at increased risk of specific major birth defects compared with children born after in vitro fertilization (IVF). However, whether this risk is due to the treatment itself (i.e., IVF or ICSI) or underlying male subfertility is unknown. This study investigated the associations between male subfertility and the risk of major birth defects in children born after IVF and ICSI. METHODS: We conducted a retrospective cohort study using data from the Japanese assisted reproductive technology registry between 2007 and 2014. Fresh embryo transfer cycles registered from 2007 to 2014 that resulted in singleton live births, still births, or selective terminations were included (n = 59,971). Major birth defects were defined by the US Centers for Disease Control and Prevention guidelines, excluding chromosomal abnormalities. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using generalized estimating equations adjusting for potential confounders. RESULTS: Major birth defects were reported in 626/59,971 (1.04%) cases. Among IVF cycles, male subfertility was associated with significantly greater risks of hypospadias (3/3163 [0.09%] vs 4/28,671 [0.01%], adjusted OR = 6.85, 95% CI 2.05-22.9, P = 0.002) and atrial septal defects (4/3163 [0.13%] vs 9/28,671 [0.03%], adjusted OR = 3.98, 95% CI 1.12-14.1, P = 0.03) compared with fertile men. Subgroup analysis using sperm parameters showed that oligozoospermia (i.e., sperm concentrations < 15 million/mL) was significantly associated with a greater risk of ventricular septal defects compared with normal sperm concentrations in IVF pregnancies (5/868 [0.58%] vs 60/28,090 [0.21%], adjusted OR = 2.68, 95% CI 1.15-6.27, P = 0.02), and severe oligozoospermia (i.e., sperm concentrations < 5 million/mL) was significantly associated with an increased risk of hypospadias compared with normal sperm concentrations in ICSI pregnancies (5/3136 [0.16%] vs 5/16,865 [0.03%], adjusted OR = 3.88, 95% CI 1.14-13.2, P = 0.03). CONCLUSIONS: The results of this exploratory study suggest that underlying male subfertility may play a role in the risk of major birth defects related to ICSI and IVF. Further research, including systematic reviews adjusting for confounders, is required to confirm the associations between male subfertility and major cardiac and urogenital birth defects.

Assisted reproductive technology in Japan: A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology.

PURPOSE: The Japan Society of Obstetrics and Gynecology started an online cycle-based assisted reproductive technology (ART) registry system in 2007. This report presents the characteristics and treatment outcomes of ART registered for the cycles practiced during 2016. METHODS: Cycle-specific information for all ART cycles implemented in participating ART facilities were collected. A descriptive analysis was conducted for the registry database of 2016. RESULTS: In total, 447 790 treatment cycles and 54 110 neonates (one in 18.1 neonates born in Japan) were reported in 2016. The mean patients' age was 38.1 years (SD = 4.5). Among the egg retrieval cycles, 104 575 of 251 399 (41.6%) were freeze-all cycles without fresh embryo transfers (ET), while fresh ET was performed in 64 497 cycles (58.4%). A total of 187 132 frozen-thawed ET cycles were reported, resulting in 62 432 pregnancies and 44 484 neonates born. Single ET was selected for 81.0% of fresh transfers and 82.7% of frozen cycles, resulting in singleton pregnancy/live birth rates of 97.0%/96.4% and 96.7%/96.4%, respectively. CONCLUSION: The total ART cycles and subsequent live births continued to increase in 2016. Single ET was performed more than 80%, and ET has shifted from using fresh embryos to frozen ones.

Two-year follow-up of a randomized controlled trial: knowledge and reproductive outcome after online fertility education.

STUDY QUESTION: What are the long-term effects of fertility education on knowledge and reproductive outcome? SUMMARY ANSWER: Participants in the intervention group retained some knowledge after 2 years and the partnered women had a new child more quickly than the comparison group. WHAT IS KNOWN ALREADY: Fertility education improves knowledge, at least in the short-term. Attitudes toward childbearing and its timing can change after exposure to educational materials. STUDY DESIGN, SIZE, DURATION: Participants were recruited via an online social research panel. In the original randomized controlled trial (RCT), knowledge of reproductive-aged participants was assessed before (T1) and immediately after (T2) receiving one of three information brochures: fertility (intervention group), healthy pre-pregnancy (focused on intake of folic acid during pregnancy, control group 1), or family policies in Japan (childcare provision, control group 2). The present follow-up study was conducted 2 years later in January 2017 (T3) with the same participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the T1 participants (n = 1455), 383 men and 360 women (51%) responded to the T3 survey. Fertility knowledge measured with the Japanese version of the Cardiff Fertility Knowledge Scale (CFKS-J) and fertility status (e.g. new births, new medical consultations, and the timing of new birth) was assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline (T1) characteristics of the T3 participants were well balanced between groups, but T3 participants were older, married, and more educated compared to those lost to follow-up. A repeated-measures analysis of variance showed significant knowledge gains among the intervention group from T1 to T3 (11.2% and 7.0% among men and women, respectively) but no significant change over time for the control groups. There were no differences between groups in the incidence of new births or new medical consultations. However, subgroup analysis showed that timing of new births was accelerated for partnered individuals in the intervention group. Specifically, the proportion of partnered participants at T1 who had a new birth in the first year subsequent to presentation of information was higher in the intervention group versus control group 1 (folic acid): 8.8% versus 1.4% (P = 0.09) among men and 10.6% versus 2.3% (P = 0.03) among women, respectively. The odds ratios (adjusted for age) were 7.8 (95% CI: 0.86-70.7) and 5.2 (95% CI: 1.09-25.0) among men and women, respectively. The timing of births and the proportion of new births during the 2-year follow-up period in the intervention group were similar to that of control group 2 (family policy). The incidence of new medical consultation was higher in the male intervention group (12.0%) than in male control group 2 (family policy, 1.5%, P = 0.04) but similar among women in all groups. LIMITATIONS REASONS FOR CAUTION: First, the high attrition rate may limit the generalizability of these findings for longer-term acquisition of fertility knowledge, especially when applied to younger people who were more likely to be lost to follow-up. Second, this is a 2-year follow-up study and the results may change in the longer-term. Finally, we relied on self-reported questionnaire data and there is a possibility that some women were unknowingly pregnant at T1 but this risk should be distributed equally in the three groups through randomization. WIDER IMPLICATIONS OF THE FINDINGS: Effects of one-time education were limited but retained beyond baseline levels. Importantly, education was found to potentially accelerate decision-making about achieving births in partnered subgroups compared to receiving healthy pre-pregnancy information. However, this finding should be confirmed in future stratified RCTs designed to evaluate effects in these subgroups. Follow-up 'booster' education sessions might help people retain knowledge and facilitate reproductive decisions for longer. In view of the high attrition rate, especially among young populations, novel educational strategies to retain young people in fertility education cohorts should be explored. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by National Center for Child Health and Development, the Daiwa Anglo-Japanese Foundation, Pfizer Health Research Foundation, and the Japan Society for the Promotion of Science. E.M. reports joint research funds from a public interest incorporated foundation '1 more Baby Ohendan.'

Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following intrauterine insemination.

PURPOSE: This study aimed to evaluate the effect of advanced paternal age on pregnancy outcomes and sperm parameters following intrauterine insemination (IUI). We used IUI data rather than assisted reproductive technology data, which might mask the effects of sperm impairments. METHODS: We retrospectively analyzed 1576 IUI cycles in women under 40 years old between April 2012 and May 2016 at the National Center for Child Health and Development in Japan. The main outcomes were clinical pregnancy and live birth. RESULTS: The mean male age was significantly lower in cycles that resulted in pregnancy compared with those without pregnancy (38.0 vs 39.1 years; P < 0.001), with a similar trend for live-birth cycles. However, there was no relationship between advanced paternal age and pregnancy outcomes after adjusting for confounding factors and correlations within patients using generalized estimating equations, and the age of the female partner was the only factor affecting pregnancy rate. Furthermore, advanced paternal age had no effect on sperm parameters. CONCLUSIONS: Advanced paternal age alone does not adversely affect pregnancy or live-birth rates or sperm parameters following IUI.

Assisted reproductive technology in Japan: a summary report for 2015 by The Ethics Committee of The Japan Society of Obstetrics and Gynecology.

Purpose: The Japan Society of Obstetrics and Gynecology (JSOG) implemented an assisted reproductive technology (ART) registry system in 1986. Here are reported the characteristics and treatment outcomes of ART cycles that were registered in 2015. Methods: JSOG has requested all participating ART facilities to register cycle-specific information for all ART cycles since 2007. A descriptive analysis was performed by using the registry database for 2015. Results: In total, 424 151 cycles and 51 001 neonates (1 in 19.7 neonates born in Japan) were registered in 2015. The patients' mean age was 38.2 years (standard deviation = 4.5). Among the fresh cycles, 94 158 of 244 718 (38.5%) egg retrieval cycles were cycles with freeze-all embryos or oocytes, while fresh embryo transfer (ET) was performed in 70 254 cycles, signaling a decrease from 2014. There were 169 898 frozen-thawed ET cycles, resulting in 56 355 pregnancies and 40 599 neonates. Single ET was performed at a rate of 79.7% for fresh and 81.8% for frozen cycles and the singleton pregnancy/live birth rates were 96.9%/96.5% and 96.8%/96.4% for the respective cycles. Conclusion: The total ART cycles and live births resulting from ART has been increasing in Japan. Single ET was performed at a rate of almost 80% and ET cycles have shifted from fresh to frozen cycles.

Thermal spin current from a ferromagnet to silicon by Seebeck spin tunnelling.

Heat generation by electric current, which is ubiquitous in electronic devices and circuits, raises energy consumption and will become increasingly problematic in future generations of high-density electronics. The control and re-use of heat are therefore important topics for existing and emerging technologies, including spintronics. Recently it was reported that heat flow within a ferromagnet can produce a flow of spin angular momentum-a spin current-and an associated voltage. This spin Seebeck effect has been observed in metallic, insulating and semiconductor ferromagnets with temperature gradients across them. Here we describe and report the demonstration of Seebeck spin tunnelling-a distinctly different thermal spin flow, of purely interfacial nature-generated in a tunnel contact between electrodes of different temperatures when at least one of the electrodes is a ferromagnet. The Seebeck spin current is governed by the energy derivative of the tunnel spin polarization. By exploiting this in ferromagnet-oxide-silicon tunnel junctions, we observe thermal transfer of spins from the ferromagnet to the silicon without a net tunnel charge current. The induced spin accumulation scales linearly with heating power and changes sign when the temperature differential is reversed. This thermal spin current can be used by itself, or in combination with electrical spin injection, to increase device efficiency. The results highlight the engineering of heat transport in spintronic devices and facilitate the functional use of heat.