Rel Family Transcription Factor NFAT5 Upregulates COX2 via HIF-1α Activity in Ishikawa and HEC1a Cells.

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.

Tokophobia: Psychopathology and Diagnostic Consideration of Ten Cases.

Tokophobia is regarded as the intensive fear of childbirth that some pregnant women have. However, little is known about the psychopathological details of tokophobia (fear of childbirth). Between 2020 and 2021, a total of 10 pregnant women (nine nulliparae and one multipara) with a strong fear of childbirth were referred by obstetricians. Semi-structured psychopathological interviews were conducted, and two cases were judged to have obsession, three an overvalued idea, and one secondary delusion. Three were characterised by both obsession and overvalued idea and one by both obsession and secondary delusion. In total, six cases had features of an overvalued idea. All of the participants except one had a lifetime history of a specific phobia. In addition, their history included social phobia in two cases, panic disorder in one case, obsessive-compulsive disorder (other than tokophobia) in two cases, depressive disorder in two cases, bipolar disorder in two cases, and PTSD in six cases. To conclude, this study showed that tokophobia was not a phobic disorder but a kind of overvalued idea that requires specific assessment and treatment.

Risk Factors for Alcohol Consumption after Starting Assisted Reproductive Technology Treatment among Japanese Women: Japan-Female Employment and Mental Health in Assisted Reproductive Technology (J-FEMA) Study.

AIMS: To determine the association between drinking habits and social factors among women undergoing assisted reproductive technology (ART) treatment in Japan. METHODS: The study participants who provided answers for the questionnaire concerning alcohol consumption were 1017 female patients undergoing ART treatment were enrolled in the Japan-Female Employment and Mental Health in assisted reproductive technology (J-FEMA) study between August and December 2018. Patient characteristics, including demographic, clinical, and socioeconomic status, were assessed using a self-administered questionnaire which was distributed only once during the period, regardless of their first or follow-up examination. We defined current drinkers who drank ≥46 g of ethanol per week as the habitual drinking group. The risk factors for habitual drinking were analyzed using multivariable-adjusted logistic regression. RESULTS: The proportion of habitual drinkers was 15.5% in this study population. The multivariable-adjusted odds ratios (95% confidence interval) for habitual drinking were 2.27 (0.99-5.21) for women aged ≥35 years versus those <35 years, 4.26 (1.98-9.16) for women having partners who currently drink compared to those with partners without current drinking, 1.84 (1.08-3.12) for women without a history of childbirth versus those with, and 1.77 (1.00-3.14) for working women compared with those not working. CONCLUSIONS: In our study, habitual drinking among women undergoing ART treatment was significantly associated with older age, no history of childbirth, partner's current drinking status, and working.

An AsCas12f-based compact genome-editing tool derived by deep mutational scanning and structural analysis.

SpCas9 and AsCas12a are widely utilized as genome-editing tools in human cells. However, their relatively large size poses a limitation for delivery by cargo-size-limited adeno-associated virus (AAV) vectors. The type V-F Cas12f from Acidibacillus sulfuroxidans is exceptionally compact (422 amino acids) and has been harnessed as a compact genome-editing tool. Here, we developed an approach, combining deep mutational scanning and structure-informed design, to successfully generate two AsCas12f activity-enhanced (enAsCas12f) variants. Remarkably, the enAsCas12f variants exhibited genome-editing activities in human cells comparable with those of SpCas9 and AsCas12a. The cryoelectron microscopy (cryo-EM) structures revealed that the mutations stabilize the dimer formation and reinforce interactions with nucleic acids to enhance their DNA cleavage activities. Moreover, enAsCas12f packaged with partner genes in an all-in-one AAV vector exhibited efficient knock-in/knock-out activities and transcriptional activation in mice. Taken together, enAsCas12f variants could offer a minimal genome-editing platform for in vivo gene therapy.

Is Your Pregnancy Unwanted or Unhappy? Psychological Correlates of a Cluster of Pregnant Women Who Need Professional Care.

BACKGROUND: A negative response towards a current pregnancy consists of two elements: unwantedness of and unhappiness about the current pregnancy. Little is clear about whether pregnant women can be categorized in terms of unwantedness and unhappiness as well as what the correlates are of these categories. METHODS: An internet survey of 696 women in their first trimester of pregnancy examined the participants' intention of and emotional reaction towards pregnancy, borderline personality traits, adult attachment style, depression, fear of childbirth, obsessive-compulsive symptoms, fetal bonding disorder, avoidance of taking part in child care, and consideration about termination of pregnancy (TOP). About one third of the participants were followed up with in their second trimester. RESULTS: Two-step cluster analysis using the participants' intention of and emotional reaction towards pregnancy revealed three groups of pregnant women: those who wanted and were happy about the pregnancy (Cluster 1), those who were unhappy about the pregnancy (Cluster 2), and those who did not intend to be pregnant but were happy about pregnancy (Cluster 3). Cluster 2 women, but not Cluster 3 women, were likely to be single, with borderline personality traits as well as unstable adult attachment styles, accompanied by depression, fear of childbirth, obsessive-compulsive symptoms, and fetal bonding disorder. They were more likely to avoid caring for the baby after childbirth and consider TOP. CONCLUSION: Expectant women who were unhappy about their pregnancy were at risk of psychological adjustment and need specific perinatal mental health assessment and care.

Tokophobia: Case Reports and Narratives of Ten Japanese Women.

Intense fear of childbirth by expectant women is called tokophobia. Because there are no qualitative studies targeting women with an intense fear of childbirth in Japan, it is unknown whether there is any link between the type of fear of objects/situations among tokophobic women and their psychological/demographic background. Furthermore, there is no available summary of the lived experience of Japanese women with tokophobia. This study aims to identify the intensity patterns of various types of fear among the participants and summarize the lived experience of having intense fear of childbirth. A qualitative descriptive study was conducted using a semi-structured interview. Pregnant women with an intense fear of childbirth participated in individual interviews facilitated by a psychiatrist and a midwife. Audio recordings of the interviews were transcribed and analyzed using a content analysis approach. The number of participants was ten. The types of feared objects varied individually and these were categorized as being related to either prospective or retrospective fear. The participants' experiences were grouped into three categories: difficulty in daily life, preoccupied negative expectation towards childbirth, and psychological adaptation to the upcoming childbirth. The results imply that women with tokophobia continuously suffer from fear in their daily life; hence, a special approach is needed to detect and reduce their fear.

Cervical Cerclage to Prevent Intrauterine Balloon Prolapse.

Intrauterine balloon prolapse sometimes occurs, and the intrauterine balloon must be reinserted. Furthermore, intrauterine balloon tamponade (IBT) failure can necessitate additional invasive procedures. We report a case of cervical cerclage with IBT for placenta previa with a cervical dilation. In our case, emergency cesarean section was performed at 35 + 4 weeks of gestation because of persistent hemorrhage. During the operation, we performed IBT to prevent further postpartum hemorrhage. However, immediately after the operation, uterine cervical dilatation was 6 cm, which resulted in cervical dilation and prolapse of the intrauterine balloon. Therefore, we performed cervical cerclage using absorbable sutures with IBT and blood transfusion. We speculated that the intrauterine balloon might have induced cervical canal ripening during the operation. Our case suggested that cervical cerclage with IBT is a useful method to prevent intrauterine balloon prolapse in cases with cervical dilation.

Relationships between Depression, Fear of Childbirth, and Obsessive-Compulsive Symptoms among Pregnant Women under the COVID-19 Pandemic in Japan.

Little is known about the causality of antenatal depression (AND). We focused on the causal relationships between AND, fear of childbirth (FOC), and obsessive-compulsive symptoms (OCS) during the COVID-19 pandemic in Japan. We also examined whether the perceived threat of COVID-19 is associated with AND. Participants were recruited for an Internet survey conducted in December 2020. A total of 245 pregnant women completed the online survey at 12 to 15 weeks' gestational age (Time 1) and approximately 10 weeks later (Time 2). AND was estimated using the first two diagnostic items of Major Depressive Episode. The estimated prevalence of AND was 4.5% and 2.9% at Time 1 and Time 2, respectively. At both time points, no association was found between AND and the perception of COVID-19 threat. Structural equation modeling showed that AND predicted OCS (ß = 0.16, p < 0.001), which, in turn, predicted FOC (ß = 0.09, p = 0.042); FOC, in turn, predicted AND (ß = 0.23, p < 0.001). AND, OCS, and FOC were predicted by borderline personality traits. Insecure adult attachment influenced AND and FOC via the perceived negative impact of the current pregnancy. Perinatal care providers should assess the personality and perception of pregnancy to prevent depression and pay attention to symptoms such as FOC and OCS in addition to those of depression.

Distal 2q duplication in a patient with intellectual disability.

We report on a patient with a distal 16.4-Mb duplication at 2q36.3-qter, who presented with severe intellectual disability, microcephaly, brachycephaly, prominent forehead, hypertelorism, prominent eyes, thin upper lip, and progenia. Copy number analysis using whole exome data detected a distal 2q duplication. This is the first report describing a distal 2q duplication at the molecular level.

Constitutive activation of estrogen receptor α signaling in muscle prolongs exercise endurance in mice.

Estrogen is a female hormone that plays a role in various tissues, although the mechanism in skeletal muscle has not been fully clarified. We previously showed that systemic administration of estrogen for 10 weeks ameliorated decreased exercise endurance in ovariectomized mice. To assess whether a long-term and muscle-specific activation of estrogen signaling modulates muscle function, we constructed an expression plasmid for a constitutively active estrogen receptor α (caERα) under the control of muscle creatine kinase (Mck) gene promoter/enhancer. In C2C12 mouse myoblastic cells, transfection of the Mck-caERα plasmid elevated the estrogen response element-driven transcription in a ligand-independent manner. Using this construct, we generated Mck-caERα transgenic mice, in which caERα is predominantly expressed in muscle. Treadmill running test revealed that female Mck-caERα mice exhibit a prolonged running time and distance compared with the wild-type mice. Moreover, microarray expression analysis revealed that the genes related to lipid metabolism, insulin signaling, and growth factor signaling were particularly upregulated in the quadriceps femoris muscle of Mck-caERα mice. These results suggest that estrogen signaling potentiates exercise endurance in skeletal muscle through modulating the expression of metabolism-associated genes.

Structure and engineering of the minimal type VI CRISPR-Cas13bt3.

Type VI CRISPR-Cas13 effector enzymes catalyze RNA-guided RNA cleavage and have been harnessed for various technologies, such as RNA detection, targeting, and editing. Recent studies identified Cas13bt3 (also known as Cas13X.1) as a miniature Cas13 enzyme, which can be used for knockdown and editing of target transcripts in mammalian cells. However, the action mechanism of the compact Cas13bt3 remains unknown. Here, we report the structures of the Cas13bt3-guide RNA complex and the Cas13bt3-guide RNA-target RNA complex. The structures revealed how Cas13bt3 recognizes the guide RNA and its target RNA and provided insights into the activation mechanism of Cas13bt3, which is distinct from those of the other Cas13a/d enzymes. Furthermore, we rationally engineered enhanced Cas13bt3 variants and ultracompact RNA base editors. Overall, this study improves our mechanistic understanding of the CRISPR-Cas13 enzymes and paves the way for the development of efficient Cas13-mediated transcriptome modulation technologies.

Development of a Scale for COVID-19 Stigma and Its Psychometric Properties: A Study among Pregnant Japanese Women.

Background: Stigma towards COVID-19 may negatively impact people who suffer from it and those supporting and treating them. Objective: To develop and validate a scale to assess 11-item COVID-19−related stigma. Methods: A total of 696 pregnant women at a gestational age of 12 to 15 weeks were surveyed using an online survey with a newly developed scale for COVID-19 stigma and other variables. The internal consistency of the scale was calculated using omega indices. We also examined the measurement invariance of the scale. Results: Exploratory factor analyses (EFAs) of the scale items were conducted using a halved sample (n = 350). Confirmatory factor analyses (CFAs) among the other halved sample (n = 346) compared the single-, two-, three-, and four-factor structure models derived from the EFAs. The best model included the following three-factor structure (χ2/df = 2.718, CFI = 0.960, RMSEA = 0.071): Omnidirectional Avoidance, Attributional Avoidance, and Hostility. Its internal consistency was excellent (all omega indices > 0.70). The three-factor structure model showed configuration, measurement, and structural invariances between primiparas and multiparas, and between younger (less than 32 years) and older women (32 years or older). Fear of childbirth, mother−fetal bonding, obsessive compulsive symptoms, depression, adult attachment self-model, and borderline personality traits were not significantly correlated with the Omnidirectional Avoidance subscale but correlated with the Attributional Avoidance and Hostility subscales (p < 0.001). Conclusion: The findings suggested that our scale for COVID-19 stigma was robust in its factor structure, as well as in construct validity.

Risk factors for infertility treatment-associated harassment among working women: a Japan-Female Employment and Mental health in assisted reproductive technology (J-FEMA) study.

PURPOSE: This study aims to elucidate the risk factors of infertility treatment-associated harassment (I-harassment) among Japanese working women. METHODS: The study participants were 1103 female patients who enrolled in the Japan-Female Employment and Mental Health in artificial reproductive technology (J-FEMA) study. Of the 1727 female patients, 1103 female patients were working during the initiation of infertility treatment and were still working during the survey. Risk factors for I-harassment were analyzed using a multivariable logistic regression model. RESULTS: In this study, 82 female patients (7.4%) experienced I-harassment. The risk was significantly higher in those who had more in vitro fertilization (IVF) cycles than those who had fewer IVF cycles (OR, 1.06; 95% CI, 1.01-1.10). Similarly, those who disclosed their infertility treatment to their workplace were at significantly higher risk for I-harassment than those who did not (OR, 1.80; 95% CI, 1.03-3.15). CONCLUSION: This study found that 7.4% of female patients experienced I-harassment after infertility treatment initiation. Those female patients who "experienced more IVF cycles," and "disclosed their infertility treatment in their workplace" should be carefully followed up by healthcare professionals to prevent I-harassment.

Fetal heart rate evolution patterns in cerebral palsy associated with umbilical cord complications: a nationwide study.

BACKGROUND: The aim of the present study was to clarify fetal heart rate (FHR) evolution patterns in infants with cerebral palsy (CP) according to different types of umbilical cord complications. METHODS: This case-control study included children born: with a birth weight ≥2000 g, at gestational age ≥33 weeks, with disability due to CP, and between 2009 and 2014. Obstetric characteristics and FHR patterns were compared among patients with CP associated with (126 cases) and without (594 controls) umbilical cord complications. RESULTS: There were 32 umbilical cord prolapse cases and 94 cases with coexistent antenatal umbilical cord complications. Compared with the control group, the persistent non-reassuring pattern was more frequent in cases with coexistent antenatal umbilical cord complications (p = 0.012). A reassuring FHR pattern was observed on admission, but resulted in prolonged deceleration, especially during the first stage of labor, and was significantly identified in 69% of cases with umbilical cord prolapse and 35% of cases with antenatal cord complications, compared to 17% of control cases (p < 0.001). CONCLUSION: Hypercoiled cord and abnormal placental umbilical cord insertion, may be associated with CP due to acute hypoxic-ischemic injury as well as sub-acute or chronic adverse events during pregnancy, while umbilical cord prolapse may be characterized by acute hypoxic-ischemic injury during delivery.

Depressive and anxiety symptoms among Japanese cancer survivors: Japan cancer survivorship research project.

BACKGROUND: This study aimed to clarify predictors of depressive symptoms and anxiety symptoms after cancer diagnosis among Japanese cancer survivors (CSs). METHODS: As part of a Japanese cancer survivorship research project commissioned by the Ministry of Health, Labour and Welfare (MHLW) of Japan, we conducted a web-based nationwide survey of CSs in 2018. We analyzed the risk factors for depressive and anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale Japanese version (HADS). RESULTS: Of 1,234 Japanese CSs, mean score of HADS-depression and HADS-anxiety were 4.08 and 4.78, respectively. At the time of the study, the number of CSs with symptoms of depression and anxiety were 111 (9.0%) and 269 (21.8%), respectively. After multivariable analysis, CSs ≥ 60 years old (reference: ≤ 39 years old, odds ratios (OR): 0.39, 95%CI: 0.17-0.90) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.55, 95%CI: 0.32-0.96) had lower odds for depressive symptoms. And CSs ≥ 60 years old (reference: ≤ 39 years old, OR: 0.27, 95%CI: 0.15-0.49) and those ≥ 10 years from cancer diagnosis (reference: 0-4 years, OR: 0.62, 95%CI: 0.42-0.90) also had lower odds for anxiety symptoms. CSs who received chemotherapy (OR: 1.56, 95%CI: 1.10-2.20) had higher odds for anxiety symptoms. CONCLUSIONS: Based on manifestation of symptoms, CSs who were younger, closer to the time of cancer diagnosis, had advanced-staged cancer, or received chemotherapy may be at higher risk for depressive or anxiety symptoms. Those CSs who have higher risk for depression and anxiety symptoms, should be followed-up more carefully for better cancer survivorship, by medical professionals, companies, and society.

The retrospective study for effectiveness of cervical cerclage in preventing recurrent preterm birth.

OBJECTIVE: This study aimed to clarify the effectiveness of cervical cerclage in preventing recurrent preterm births. MATERIALS AND METHODS: A retrospective study was conducted using the perinatal registration database of the Japan Society of Obstetrics and Gynecology for the Perinatal Center from 2014 to 2016. The efficacies of history-indicated, ultrasound-indicated, and physical examination-indicated cerclage as preventive treatments for women with a history of preterm birth were evaluated by comparing cerclage and non-cerclage cases. Fisher's exact test was performed to evaluate any significant differences in patient backgrounds. Prior to the evaluation, propensity score matching was performed for history-indicated and ultrasound-indicated cerclage patients. RESULTS: For this study, 6060 multiparous women with a history of preterm birth were reviewed. After excluding 17 patients with unknown indications for cervical cerclage, 6043 patients were included in the study. History-indicated and ultrasound-indicated cerclage did not reduce the risk of preterm birth in subsequent pregnancies for any of the pregnancy periods (p = 0.413, p = 1.000). In contrast, physical examination-indicated cerclage significantly reduced the risk of subsequent preterm births for all pregnancy periods (p < 0.001). CONCLUSION: Subsequent preterm births were effectively prevented only in physical examination-indicated cerclage cases. For history- or ultrasound-indicated cerclage, statistically significant differences in subsequent preterm births were not evident.

Identification of a Novel Oncogenic Fusion Gene SPON1-TRIM29 in Clinical Ovarian Cancer That Promotes Cell and Tumor Growth and Enhances Chemoresistance in A2780 Cells.

Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript SPON1-TRIM29 in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing SPON1-TRIM29 exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of SPON1-TRIM29 fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that SPON1-TRIM29-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the SPON1-TRIM29 fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript.

Retrospective study of the recurrence risk of preterm birth in Japan.

BACKGROUND: A history of preterm birth is a risk factor for preterm birth in a future pregnancy, and there are some reports of prevention methods, such as the administration of progesterone. However, the rate of recurrence of preterm birth in Japan has not been clarified, and there is no data for judging whether these preventive methods are effective. OBJECTIVE: To clarify the risk of recurrence of preterm birth and preterm prelabor rupture of membranes (pPROM) in Japan. MATERIALS AND METHODS: A retrospective study was conducted using the perinatal registration database of the Japan Obstetrics and Gynecology Society for the Perinatal Center from 2014 to 2016. There were 704,418 subjects, of which 190,990 were excluded those with unknown maternal information, those under the age of 20 years, those with perinatal disease related to preterm birth, and first-time mothers. RESULTS: Logistic model unavailable and multivariate analysis were performed. An analysis of the preterm birth history indicated the risk of preterm birth in the current pregnancy, and the odds ratio for preterm birth recurrence once, twice, and three times or more was 3.3, 6.6, and 7.8, respectively. As a secondary analysis, we analyzed whether the history of pPROM is a risk factor of recurrence of pPROM and found a significant association with an odds ratio of 3.4. CONCLUSION: Having a preterm birth history increases the risk of recurrence of preterm birth, and the risk of recurrent preterm birth increases as the number of preterm births increases. Although this report is intended for high-risk pregnancies wherein the rate of preterm birth is high, as previously reported, our data indicate that in Japan, preterm birth is a risk factor of recurrent preterm birth.

Can digital health technologies exacerbate the health gap? A clustering analysis of mothers' opinions toward digitizing the maternal and child health handbook.

BACKGROUND: The use of mobile health has increased worldwide, but along with its increased utilization comes the risk of the digital divide, inequity in access to information and communications technologies, exerting greater influence on health inequity caused by socioeconomic determinants of health. There is a growing need to investigate whether the digitization of existing health interventions has a risk of worsening the health gap. METHODS: We investigated the attitudes of mothers and pregnant women toward digitization of the Maternal and Child Health Handbook (MCHH), a popular personal health record (PHR) used by almost every pregnant woman or mother in Japan, using a cross-sectional survey. We determined sociodemographic factors associated with favorable opinions toward digitization using a multivariate regression model. We then grouped the participants using partitioning around medoids clustering, a machine-learning approach, to interpret their varying attitudes toward digitization in light of their sociodemographic characteristics as well as their affinity toward the paper MCHH. FINDINGS: Higher income and educational level, older age, and less reliance on the MCHH were significantly associated with favorable opinion toward digitization. Clustering analysis identified four latent clusters. The cluster with the highest socioeconomic status (SES) was the most favorable toward digitization, while two clusters with the lowest SES, one of which relied heavily on the paper MCHH, were less favorable of digitization compared to the high SES cluster. The final cluster was comprised of mothers with the experience of raising multiple children and did not rely heavily on the MCHH. INTERPRETATION: Our study identified a socioeconomic divide in opinions toward digitization of an existing health intervention. A hasty digitization may result in an unbalanced uptake of the digitized health intervention among different social classes.