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The relationship between fish eating habits and menstrual pain is unknown. Elucidating this relationship can inform dietary guidance for reproductive age women with menstrual pain. The aim of this study was to clarify the relationship between fish intake frequency/preference and menstrual pain. This cross-sectional study was conducted at the Miyagi Regional Center as an adjunct study of the Japan Environment and Children’s Study, and 2060 eligible women (mean age, 31.9 years) participated. Fish intake frequency (“< 1 time/week,” “1 time/week,” “2–3 times/week,” or “≥ 4 times/week”), preference (“like,” “neutral,” or “dislike”), and menstrual pain (no/mild or moderate-to-severe) were assessed at 1.5 years after the last delivery through self-administered questionnaires. The association between fish intake frequency/preference and prevalence of moderate-to-severe menstrual pain was evaluated through logistic regression analyses. Our results show that, compared with the “< 1 time/week” (38.0%) group, the “1 time/week” (26.9%), “2–3 times/week” (27.8%), and “≥ 4 times/week” (23.9%) groups showed a lower prevalence of moderate-to-severe menstrual pain ( p < 0.01). The prevalence of moderate-to-severe menstrual pain was 27.7%, 27.6%, and 34.4% in the “like,” “neutral,” and “dislike” groups, respectively. Multivariate logistic regression showed that frequent fish intake was associated with a lower prevalence of moderate-to-severe menstrual pain (“1 time/week”: odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.41–0.86, “2–3 times/week”: OR = 0.64; 95% CI, 0.45–0.90 and “≥ 4 times/week”: OR = 0.52; 95% CI, 0.34–0.80; trend p = 0.004). Multivariate logistic regression showed no association between fish preference and moderate-to-severe menstrual pain (“dislike” vs “like”: OR = 1.16; 95% CI, 0.78–1.73). There was a significant negative association between fish intake frequency and menstrual pain. It is suggested that fish intake can reduce or prevent menstrual pain.

Leiomyoma arising from the vulva is very rare, and it is difficult to differentiate it from a Bartholin gland cyst and aggressive angiomyxomas. We report a case of vulvar leiomyoma in a juvenile girl. The patient, a 16‐year‐old female, had noted a tender subcutaneous nodule on the right vulva for 2 years. At first, a Bartholin gland cyst was suspected, and she was prescribed antibiotics. However, because of persistent symptoms, the patient was referred to our clinic for further examination. An MRI scan suspected a mesenchymal tumor, and surgical resection was performed. Tumor cells were diffusely positive for anti‐smooth muscle antibodies, HHF35, and Desmin, and leiomyoma was suspected. Immunostaining tests were negative for estrogen receptor and positive for progesterone receptor. The patient exhibited an excellent postoperative course with no evidence of recurrence at the latest follow‐up. Surgical resection is the only curative treatment, and long‐term follow‐up is recommended because of rare reports of recurrence.

In regular IVF, a portion of oocytes exhibit abnormal numbers of pronuclei (PN) that is considered as abnormal fertilization, and they are routinely discarded. However, it is known that abnormal ploidy still does not completely abandon embryo development and implantation. To explore the potential of cytoplasm from those abnormally fertilized oocytes, we developed a novel technique for the transfer of large cytoplasm between pronuclear-stage mouse embryos, and assessed its impact. A large volume of cytoplast could be efficiently transferred in the PN stage using a novel two-step method of pronuclear-stage cytoplasmic transfer (PNCT). PNCT revealed the difference in the cytoplasmic function among abnormally fertilized embryos where the cytoplasm of 3PN was developmentally more competent than 1PN, and the supplementing of fresh 3PN cytoplasm restored the impaired developmental potential of postovulatory “aged” oocytes. PNCT-derived embryos harbored significantly higher mitochondrial DNA copies, ATP content, oxygen consumption rate, and total cells. The difference in cytoplasmic function between 3PN and 1PN mouse oocytes probably attributed to the proper activation via sperm and may impact subsequent epigenetic events. These results imply that PNCT may serve as a potential alternative treatment to whole egg donation for patients with age-related recurrent IVF failure.

We have developed an automated device for the measurement of oxygen consumption rate (OCR) called Chip-sensing Embryo Respiratory Measurement system (CERMs). To verify the safety and the significance of the OCR measurement by CERMs, we conducted comprehensive tests using a mouse model prior to clinical trials in a human in vitro fertilization (IVF) program. Embryo transfer revealed that the OCR measured by CERMs did not compromise the full-term development of mice or their future fertility, and was positively correlated with adenosine triphosphate (ATP) production and the mitochondrial membrane potential (ΔΨm), thereby indirectly reflecting mitochondrial oxidative phosphorylation (OXPHOS) activity. We demonstrated that the OCR is independent of embryo morphology (the size) and number of mitochondria (mitochondrial DNA copy number). The OCR correlated with the total cell numbers, whereas the inner cell mass (ICM) cell numbers and the fetal developmental rate were not. Thus, the OCR may serve as an indicator of the numbers of trophectoderm (TE) cells, rather than number or quality of ICM cells. However, implantation ability was neither correlated with the OCR, nor the embryo size in this model. This can probably be attributed to the limitation that chimeric embryos contain non-physiological high TE cells counts that are beneficial for implantation. CERMs can be safely employed in clinical IVF owing to it being a safe, highly effective, non-invasive, accurate, and quantitative tool for OCR measurement. Utilization of CERMs for clinical testing of human embryos would provide further insights into the nature of oxidative metabolism and embryonic viability.

ObjectivesThis study aimed to examine the association between infertility treatment and neurodevelopment in children at 2 and 3.5 years of age.DesignProspective cohort study.Setting and participantsThe study population consisted of mother–child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Miyagi and Iwate Prefectures, Japan. Pregnant women were recruited in obstetric clinics or hospitals and their children were followed up by the questionnaire.Outcome measuresThe children’s neurodevelopmental outcomes were assessed at 2 and 3.5 years of age using the Ages and Stages Questionnaire, third edition (ASQ-3), which consists of questions on five developmental domains. We performed a multivariate logistic regression analysis of the association between infertility treatment (including ovulation induction (OI), artificial insemination with husband’s sperm (AIH) and assisted reproductive technology (ART)) and the clinical range of ASQ-3.ResultsOf 9655 mother–child pairs, 273 (2.8%) and 487 (5.0%) were conceived through OI/AIH and ART, respectively. The odds of having developmental delays at 2 years of age were higher in children conceived through OI/AIH (OR, 1.36; 95% CI 1.00 to 1.85) and ART (OR, 1.36; 95% CI 1.07 to 1.72) than in those conceived naturally. Additionally, OI/AIH and ART were significantly associated with communication (OR, 1.93; 95% CI 1.25 to 2.98) and gross motor (OR, 1.50; 95% CI 1.08 to 2.09) delays, respectively. There were no statistically significant differences in the odds of having developmental delays at 3.5 years of age in children conceived through OI/AIH (OR, 1.13; 95% CI 0.79 to 1.61) and ART (OR, 1.03; 95% CI 0.78 to 1.37).ConclusionIn this study, we found a significant association between infertility treatment and children’s neurodevelopment at 2 years of age, whereas no statistically significant differences were found at 3.5 years of age.

Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.Sexual development disorders: Variant prevalence in the Japanese populationResearchers in Japan have reported the frequency of mutations related to atypical sexual development in the Japanese population. A team led by Junichi Sugawara of Tohoku University, Sendai, analyzed whole-genome data collected by the Tohoku Medical Megabank Organization from 8380 healthy Japanese people. They screened the genomes for variations in 32 genes linked with central hypogonadism (CHG) and disorders of sex development (DSD), and used bioinformatics to predict the effect of the variants. This revealed 91 potentially pathogenic variants in 25 of the genes, including 28 new variants. The team also estimated the frequency of unaffected carriers of these variants. The analysis provides an overview of the prevalence of these variants in the general Japanese population and also offers valuable data for genetic diagnosis and counseling related to DSD and CHG.

Infertility treatment is a possible factor in hypertensive disorders of pregnancy (HDP). Identifying the characteristics of pregnant women who have undergone infertility treatment and have a potential risk for HDP is valuable for its prevention and treatment. Using data from 12,456 pregnant Japanese women from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, the association between infertility treatment and HDP was analyzed. A multiple logistic regression model showed an association between infertility treatment and HDP (odds ratio, 1.34; 95% confidence interval, 1.05–1.72). In vitro fertilization/intracytoplasmic sperm injection were also associated with HDP. Moreover, these associations were observed even among women who were not overweight and did not smoke. The application of infertility treatment should be carefully considered, even among women with low modifiable risk factors.

Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis–van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as “pathogenic” and “likely pathogenic” by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as “pathogenic” and “likely pathogenic” in InterVar and “pathogenic” in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine.Bone dysplasia: Estimating carrier frequency with bioinformaticsA bioinformatics approach helps estimate carrier frequency of a rare inherited bone disease which causes abnormalities in skeletal shape and structure. Autosomal recessive bone dysplasias affect bone and cartilage development and result from inheriting two mutated genes, one from each parent. Junichi Sugawara, Tohoku University, Sendai, Japan, and colleagues used mutation databases and a bioinformatics tool for variant interpretation to detect 198 pathogenic variants in 54 genes associated with autosomal recessive bone dysplasia in a whole-genome reference panel of 3,552 general Japanese individuals (3.5KJPNv2). They then estimated the frequency of people in the sample carrying bone dysplasia mutations and the expected proportion in whom the disorder could manifest, which compared well with reported incidence rates in the general population. These findings could prove useful for calculating the risk of bone dysplasia in the future children of carrier parents.

Background Uterine leiomyosarcoma (LMS) and undifferentiated endometrial sarcoma (UES) are rare, aggressive malignancies. Both are treated similarly; however, few chemotherapy agents are effective. Recently, the combination of gemcitabine (900 mg/m 2 , days 1 and 8) plus docetaxel (100 mg/m 2 , day 8) with granulocyte colony-stimulating factor (G-CSF, 150 μg/m 2 , days 9–15) has been shown to have activity in LMS. In Japan, neither prophylactic G-CSF at a dose of 150 μg/m 2 nor docetaxel at a dose of 100 mg/m 2 are approved for use. For this reason, we evaluated the combination of 900 mg/m 2 gemcitabine plus 70 mg/m 2 docetaxel regimen without prophylactic G-CSF support in advanced or recurrent LMS and UES in Japanese patients. Methods Eligible women with advanced or recurrent LMS and UES were treated with 900 mg/m 2 gemcitabine on days 1 and 8, plus 70 mg/m 2 docetaxel on day 8, every 3 weeks. The primary endpoint was overall response rate, defined as a complete or partial response. Results Of the eleven women enrolled, 10 were evaluated for a response. One complete response and 2 partial responses were observed (30 %) with an additional 4 (40 %) having stable disease. Mean progression-free survival was 5.4 months (range 1.3–24.8 months), and overall survival was 14 months (range 5.3–38.4 months). Grade 4 neutropenia was the major toxicity (50 %). The median number of cycles was 5 (range 2–18). Twenty-two cycles (44 %) employed G-CSF. Conclusion The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES.