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[H]Imipramine binding to platelet membranes was evaluated in ten autistics, eight schizophrenics and seven normal controls. The schizophrenics and eight out of the ten autistics were maintained on chronic neuroleptic treatment. Diagnosis of autism and schizophrenia was established according to the DSM-III criteria. No significant difference in the maximal binding capacity of [H]imipramine ( B) and K values could be found among the three groups. It seems that the imipramine binding site is intact both in autism and schizophrenia. [ABSTRACT FROM AUTHOR]

Introduction: Placental abruption (PA) is a major obstetric complication associated with worse maternal and neonatal outcomes. Though ultrasound findings may support the diagnosis of PA, the association of such findings to the severity of PA and maternal and neonatal outcomes is not yet clear. We aimed to assess the maternal and neonatal outcomes of PA cases with vs. without related sonographic findings., Methods: In this retrospective cohort study, all deliveries complicated by PA between 2009 and 2022 were included. Placental histopathology, obstetric, and neonatal outcomes were compared between cases of PA with vs. without supporting sonographic findings. A composite of severe neonatal morbidity was compared between the groups, including ≥1 of the following: seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, periventricular leukomalacia, respiratory-distress syndrome, sepsis, anemia, blood transfusion or death., Results: Of the 420 cases with PA eligible for the study, 50 patients (12 %) were in the PA with sonographic features group and 370 (88 %) were in the PA without sonographic features group. The PA with sonographic features group was characterized by significantly higher rates of prematurity (p < 0.001), severe composite adverse neonatal outcome (p < 0.01), and a composite maternal vascular malperfusion lesions in placental histopathology (p = 0.001) In multivariable regression analyses, preterm birth was independently associated with the presence of sonographic features (aOR = 8.79, 95 % CI 2.41-31.93, p < 0.001)., Discussion: PA with supporting sonographic features is associated with higher rates of adverse obstetric and neonatal outcomes and placental lesions. These findings emphasize the importance of sonographic evaluation for every case of PA before deciding upon management., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Male development in mammals depends on the activity of the two SOX gene: Sry and Sox9, in the embryonic testis. As deletion of Enhancer 13 (Enh13) of the Sox9 gene results in XY male-to-female sex reversal, we explored the critical elements necessary for its function and hence, for testis and male development. Here, we demonstrate that while microdeletions of individual transcription factor binding sites (TFBS) in Enh13 lead to normal testicular development, combined microdeletions of just two SRY/SOX binding motifs can alone fully abolish Enh13 activity leading to XY male-to-female sex reversal. This suggests that for proper male development to occur, these few nucleotides of non-coding DNA must be intact. Interestingly, we show that depending on the nature of these TFBS mutations, dramatically different phenotypic outcomes can occur, providing a molecular explanation for the distinct clinical outcomes observed in patients harboring different variants in the same enhancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: There is no clear correlation between abnormal umbilical cord blood gas studies (UCGS) and adverse neonatal outcome in low-risk deliveries. We investigated the need for its routine use in low-risk deliveries., Methods: We retrospectively compared maternal, neonatal, and obstetrical characteristics among low-risk deliveries (2014-2022) between "normal" and "abnormal" pH groups: A:normal pH ≥ 7.15; abnormal pH < 7.15; B: normal pH ≥ 7.15 and base excess (BE) > - 12 mmol/L; abnormal pH < 7.15 and BE ≤ We retrospectively compared 12 mmol/L; C: normal pH ≥ 7.1; abnormal pH < 7.1; D: normal pH > 7.1 and BE > - 12 mmol/L; abnormal pH < 7.1 and BE ≤ - 12 mmol/L., Results: Of 14,338 deliveries, the rates of UCGS were: A-0.3% (n = 43); B-0.07% (n = 10); C-0.11% (n = 17); D-0.03% (n = 4). The primary outcome, composite adverse neonatal outcome (CANO) occurred in 178 neonates with normal UCGS (1.2%) and in only one case with UCGS (2.6%). The sensitivity and specificity of UCGS as a predictor of CANO were high (99.7-99.9%) and low (0.56-0.59%), respectively., Conclusion: UCGS were an uncommon finding in low-risk deliveries and its association with CANO was not clinically relevant. Consequently, its routine use should be considered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The testis is responsible for sperm production and androgen synthesis. Abnormalities in testis development and function lead to disorders of sex development and male infertility. Currently, no in vitro system exists for modelling the testis. Here, we generated testis organoids from neonatal mouse primary testicular cells using transwell inserts and show that these organoids generate tubule-like structures and cellular organization resembling that of the in vivo testis. Gene expression analysis of organoids demonstrates a profile that recapitulates that observed in in vivo testis. Embryonic testicular cells, but not adult testicular cells are also capable of forming organoids. These organoids can be maintained in culture for 8-9 weeks and shows signs of entry into meiosis. We further developed defined media compositions that promote the immature versus mature Sertoli cell and Leydig cell states, enabling organoid maturation in vitro . These testis organoids are a promising model system for basic research of testes development and function, with translational applications for elucidation and treatment of developmental sex disorders and infertility., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Gonadal sex determination in mice is a complex and dynamic process, which is crucial for the development of functional reproductive organs. The expression of genes involved in this process is regulated by a variety of genetic and epigenetic mechanisms. Recently, there has been increasing evidence that transposable elements (TEs), which are a class of mobile genetic elements, play a significant role in regulating gene expression during embryogenesis and organ development. In this study, we aimed to investigate the involvement of TEs in the regulation of gene expression during mouse embryonic gonadal development. Through bioinformatics analysis, we aimed to identify and characterize specific TEs that operate as regulatory elements for sex-specific genes, as well as their potential mechanisms of regulation. We identified TE loci expressed in a time- and sex-specific manner along fetal gonad development that correlate positively and negatively with nearby gene expression, suggesting that their expression is integrated to the gonadal regulatory network. Moreover, chromatin accessibility and histone post-transcriptional modification analyses in differentiating supporting cells revealed that TEs are acquiring a sex-specific signature for promoter-, enhancer-, and silencer-like elements, with some of them being proximal to critical sex-determining genes. Altogether, our study introduces TEs as the new potential players in the gene regulatory network that controls gonadal development in mammals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that they were editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Stévant, Gonen and Poulat.)

The process of aging refers to physiological changes that occur to an organism as time progresses and involves changes to DNA, proteins, metabolism, cells, and organs. Like the rest of the cells in the body, gametes age, and it is well established that there is a decline in reproductive capabilities in females and males with aging. One of the major pathways known to be involved in aging is epigenetic changes. The epigenome is the multitude of chemical modifications performed on DNA and chromatin that affect the ability of chromatin to be transcribed. In this review, we explore the effects of aging on female and male gametes with a focus on the epigenetic changes that occur in gametes throughout aging. Quality decline in oocytes occurs at a relatively early age. Epigenetic changes constitute an important part of oocyte aging. DNA methylation is reduced with age, along with reduced expression of DNA methyltransferases (DNMTs). Histone deacetylases (HDAC) expression is also reduced, and a loss of heterochromatin marks occurs with age. As a consequence of heterochromatin loss, retrotransposon expression is elevated, and aged oocytes suffer from DNA damage. In sperm, aging affects sperm number, motility and fecundity, and epigenetic changes may constitute a part of this process. 5 methyl-cytosine (5mC) methylation is elevated in sperm from aged men, but methylation on Long interspersed nuclear elements (LINE) elements is reduced. Di and trimethylation of histone 3 lysine 9 (H3K9me2/3) is reduced in sperm from aged men and trimethylation of histone 3 lysine 27 (H3K27me3) is elevated. The protamine makeup of sperm from aged men is also changed, with reduced protamine expression and a misbalanced ratio between protamine proteins protamine P1 and protamine P2. The study of epigenetic reproductive aging is recently gaining interest. The current status of the field suggests that many aspects of gamete epigenetic aging are still open for investigation. The clinical applications of these investigations have far-reaching consequences for fertility and sociological human behavior., (© 2023 The Authors. Molecular Reproduction and Development published by Wiley Periodicals LLC.)

Introduction: Late fetal growth restriction (FGR) is associated with mild growth restriction and normal or mild abnormal doppler flows. The cerebroplacental ratio (CPR) has been demonstrated as more sensitive to hypoxia than its individual components in these fetuses. We hypothesized that abnormal CPR in late FGR is reflected in specific placental vascular malperfusion lesions., Methods: Retrospective cohort study of late FGR newborns between 2012 and 2022 in a tertiary hospital. Overall, 361 cases were included: 104 with pathological CPR (study group), and 257 with normal doppler flows (control group). The primary outcome was a composite of maternal vascular malperfusion lesions (MVM) and fetal vascular malperfusion lesions (FVM). Secondary outcomes were macroscopic placental characteristics and various obstetrical and neonatal outcomes., Results: The study group had lower birthweight compared with the normal CPR group (2063.5 ± 470.5 vs. 2351.6 ± 387.4 g. P < 0.0001), higher rates of composite adverse neonatal outcomes (34.2% vs. 22.5%, p < 0.0001), lower mean placental weight (318 ± 71.6 vs. 356.6 ± 76.5 g, p < 0.0001), as well as a higher prevalence of Vascular lesions of MVM (15.3% vs. 5.0%, p = 0.002), villous lesions of FVM (37.5% vs. 24.9%, p = 0.02), and composite FVM lesions (36.5% vs. 25.6%, p = 0.04). On multivariate regression analysis for MVM lesions and composite FVM lesions, abnormal CPR was found as an independent risk factor (aOR 2.17, 95% CI 1.63-4.19, and aOR 1.31, 95% CI 1.09-3.97, respectively)., Discussions: Abnormal CPR in late FGR is reflected in placental histopathologic vascular malperfusion lesions, and the incidence of these lesions is higher than in FGR placentas with normal CPR., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.

Objective: To study the association between prenatal diagnosis of isolated abdominal circumference (AC) below the 10th percentile (AC <10th) in appropriate for gestational age (AGA) neonates and placental vascular lesions., Methods: A prospective study was conducted of healthy women who underwent sonographic fetal biometric measurements, up to 7 days before delivery, and delivered AGA neonates. The study cohort was divided into those with and without prenatal isolated AC <10th. Placental histopathology lesions were classified into maternal and fetal vascular malperfusion (MVM, FVM) lesions., Results: Compared to the AC over 10th percentile group (n = 85), the AC <10th group (n = 85) was characterized by lower maternal body mass index, higher rate of smokers, and increased rate of induced labor (P = 0.029, P = 0.029, P = 0.001, respectively). There were no between-group differences regarding maternal age, gestational age, and neonatal outcome. Mean placental weight was lower in the isolated AC <10th (P < 0.001). The rate of MVM or FVM lesions did not differ between the groups. By multivariate logistic regression analysis, isolated AC <10th was not found to be associated with increased risk for placental vascular lesions., Conclusion: Isolated AC <10th is associated with increased rate of induction of labor; however, it is not associated with increased placental vascular lesions., (© 2022 International Federation of Gynecology and Obstetrics.)

Objectives: It is unclear whether the length of the second stage of labour plays a role in the development of urinary incontinence (UI). This study aimed to investigate the association between the cumulative length of the second stage of labour in multiparous women and UI., Methods: This was a longitudinal cohort study of women who had undergone three vaginal deliveries (VDs) between 2008 and 2017. UI was assessed using the Urinary Distress Inventory (UDI-6) questionnaire. Women with a cumulative length of the second stage of labour for three deliveries in the upper 90th percentile (study group) were compared with women with a cumulative length of the second stage of labour below the 90th percentile (control group). A sample size of 280 women was needed to detect a 15-point difference in the UDI-6 score between the groups., Results: Thirty-one women were included in the study group and 275 women were included in the control group. Demographic and obstetric characteristics were similar in both groups. There was no between-group difference in mean UDI-6 score: 12.3 ± 17.5 in the study group and 14.9 ± 18.2 in the control group (p = 0.55). No association was found between the cumulative length of the second stage of labour and the UDI score. A linear regression model revealed that maternal body mass index was independently associated with UDI-6 score (correlation coefficient 0.67, 95% confidence interval 0.19-1.15; p = 0.006)., Conclusion: The cumulative length of the second stage of labour in multiparous women is not associated with UI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Human milk lactation provides health benefits for both the mother and infant. Patients commonly report stopping breastfeeding sooner than they planned. Interventions with proper accessible counseling and support to the mother can potentially increase lactation rates and duration., Objective: This study aimed to investigate the impact of introducing a smartphone-based daily feedback and counseling platform between women after delivery and a multidisciplinary lactation support team on lactation rates and various maternal and neonatal outcomes. Counseling was provided via a specifically developed application from a multidisciplinary team (obstetricians, nurses, lactation counselors, and psychologist) in an attempt to assist and counsel to maintain lactation., Study Design: This was a prospective, single-center, randomized controlled trial. Women planning to lactate were recruited at postpartum day 1 and were randomized to (1) routine lactation counseling and support (control group) or (2) additional daily detailed counseling and feedback on lactation from the team via the application (App group). The primary outcome was partial or full lactation at 3 months after delivery. The secondary outcomes included lactation at additional time points up to 6 months after delivery. The study was adequately powered to detect a 15% difference in the primary outcome., Results: A total of 197 patients were recruited, 97 in the App group and 100 in the control group. The 2 groups did not differ in any background or delivery characteristics. The App group showed higher rates of lactation 6 weeks after delivery (96.9% vs 82.0%; P<.001) and 3 months after delivery (81.4% vs 69.0%; P=.049) than the control group. Patients in the App group reported excellent satisfaction from the use of the application and their overall postnatal care., Conclusion: Our study has provided further information on the growing efficacy of technology platforms in obstetrical care. The introduction of a smartphone-based daily feedback and counseling platform between postpartum patients and a multidisciplinary lactation support team increased the lactation rates after delivery with excellent patient satisfaction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SOX genesare master regulatory genes controlling development and are fundamental to the establishment of sex determination in a multitude of organisms. The discovery of the master sex-determining gene SRY in 1990 was pivotal for the understanding of how testis development is initiated in mammals. With this discovery, an entire family of SOX factors were uncovered that play crucial roles in cell fate decisions during development. The importance of SOX genes in human reproductive development is evident from the various disorders of sex development (DSD) upon loss or overexpression of SOX gene function. Here, we review the roles that SOX genes play in gonad development and their involvement in DSD. We start with an overview of sex determination and differentiation, DSDs, and the SOX gene family and function. We then provide detailed information and discussion on SOX genes that have been implicated in DSDs, both at the gene and regulatory level. These include SRY, SOX9, SOX3, SOX8, and SOX10. This review provides insights on the crucial balance of SOX gene expression levels needed for gonad development and maintenance and how changes in these levels can lead to DSDs., (© 2022 S. Karger AG, Basel.)

Objectives: To evaluates the effect of different modes of final follicular maturation triggering on the degree of apoptosis of granulosa cells (GCs) and the potential effect on progesterone secretion., Methods: Thirty patients undergoing controlled ovarian hyperstimulation for IVF who received hCG, GnRH agonist, or dual trigger for final follicular maturation were included in the study. Granulosa cells were obtained at the time of oocyte retrieval. The proportion of apoptotic cells was evaluated via TUNEL and immunohistochemistry., Results: The proportion of apoptotic cells was significantly higher in the GnRH agonist-alone group compared to hCG-alone and the dual trigger groups (13.5 ± 1.5% vs. 7.8% ± 1.8 vs. 10.1% ± 2, respectively, P < 0.01). Moreover, the expression of active-caspase-3 was also significantly increased in the GnRH agonist-alone group compared with the hCG-alone and the dual trigger groups (15.5% ± 2.9 vs. 8.4% ± 1.6 vs. 12.7% ± 2.6, respectively, P < 0.01). The progesterone levels measured in the granulosa-luteal cell culture medium after 24 h of incubation were similar between the three groups., Conclusions: The levels of apoptosis are increased after GnRH agonist/dual trigger. The increased apoptosis might be one of the culprit of the subsequent premature demise of the corpus luteum post GnRH agonist trigger., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Traditionally, the diagnosis of preeclampsia requires elevated blood pressure measurements and proteinuria demonstrated in a 24-hour urine collection. This prolonged urine collection is associated with patient discomfort, a delay in diagnosis, and in some cases, hospitalization for further management of outcomes., Objective: We aimed to assess the feasibility, reliability, and association between maternal and neonatal outcomes of pregnancies managed according to a 6-hour vs 24-hour urine protein collection for suspected preeclampsia., Study Design: This was a randomized controlled trial conducted at a tertiary university hospital between January 2019 and January 2021 (ClinicalTrials.gov Identifier: NCT03724786). Patients who were hospitalized for preeclampsia workup were asked to participate and randomized at a 1:1 ratio to 6- and 24-hour urine protein collection groups. Both groups collected urine for 24 hours, during which the collection was also tested after 6-hours. After 24 hours, both results were reviewed by one of the research staff, and either the 6- or 24-hour collection result was reported to the patient's managing physician and was documented in the patient's medical record. Both patient and the managing physician were blinded to group allocation. Unblinding was undertaken in cases of a discrepancy between the results (1 of 2 results of >300 mg protein), and the results were analyzed by intention to treat. The primary study outcome was defined as a composite of adverse maternal outcomes. The sample size was set empirically as per proof on concept design., Results: During the study period, 115 patients participated in the trial, 101 of whom completed the follow-up and were analyzed-51 in the 6-hour group and 50 in the 24-hour group. Patient demographics were similar between the study groups. Unblinding occurred in 7 cases in the 6-hour group, in which the initial 6-hour result ranged from 168 to 475 mg. The rates of composite adverse maternal outcomes were 15.6% and 12.0% in the 6- and 24-hour groups, respectively (P=.59). No significant difference was demonstrated in the rate of adverse neonatal outcomes, cesarean delivery, induction of labor, gestational age at delivery, betamethasone treatment, or neonatal birthweight., Conclusion: Managing pregnancies suspected of preeclampsia with a 6-hour urine protein collection is feasible and associated with similar maternal and neonatal outcomes. In cases where the 6-hour result is in the 168 to 475 mg range, we propose completing a 24-hour collection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Antenatal corticosteroids (ACS) are frequently used to reduce neonatal morbidity in preterm births (PTBs). A 'rescue' dose of ACS can be administer, if the risk of PTB remains. Some reports indicated that repeated doses of ACS might impact placental histology and possibly its function. We aimed to study whether repeated doses of ACS effect placental histopathology and pregnancy outcome., Methods: The medical files and placental reports of all PTB, at 24-33 6 / 7 weeks, between Nov 2008-Dec 2019, were reviewed. The study population was divided into three groups; no-ACS (PTBs without ACS treatment), one-ACS (PTBs after a full or partial ACS course), and rescue-ACS (PTBs after a 'rescue' course of ACS). Placental lesions were classified according to "Amsterdam" criteria into maternal and fetal vascular malperfusion lesions, maternal and fetal inflammatory responses and chronic villitis. Placental lesions and pregnancy outcome were compared between the study groups., Results: The no-ACS group (n = 58) was characterized by increased rates of PTB<28 weeks (p = 0.003), perinatal death (p < 0.001) and composite neonatal infectious morbidity (p = 0.022), as compared to the one-ACS group (n = 331) and the rescue-ACS group (n = 53). Placental MIR lesions were more common among the rescue-ACS group, compared to the one- and no-ACS groups (p = 0.022). Other placental lesions did not differ between the groups. On multivariate logistic regression analysis, MIR lesions were independently associated with rescue-ACS treatment (aOR 3.00, 95% CI 1.10-8/17, p = 0.031)., Discussion: Rescue course of ACS is associated with increased rate of placental maternal inflammatory response. These findings probably result from maternal stress stimuli without an adverse impact on early neonatal outcome., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Placenta-associated pregnancy complications (fetal growth restriction and preeclampsia) are traditionally classified as "early" and "late" due to their different pathophysiology, histopathology, and pregnancy outcomes. As placental abruption (PA) represents another placenta-associated complication, we aimed to study if this categorization can be applied to PA as well. Pregnancy and placental reports of all pregnancies complicated by PA between November 2008 and January 2019 were reviewed. Maternal background, pregnancy outcomes, and placental histopathology were compared between cases of PA < 34 weeks (early PA group) vs. > 34 weeks (late PA group). Placental lesions were classified according to the "Amsterdam" criteria. The primary outcome was severe neonatal morbidity (≥ 1 severe neonatal complications: seizures, IVH, HIE, PVL, blood transfusion, NEC, or death). Included were 305 cases of PA, 71 (23.3%) in the early group and 234 (76.7%) in the late group. The early PA group was characterized by higher rates of vaginal bleeding upon presentation (p = 0.003), DIC (p = 0.018), and severe neonatal morbidity (p < 0.001). The late PA group was characterized by a higher rate of urgent Cesarean deliveries (p < 0.001). The early PA group was characterized by higher rates of placental maternal vascular malperfusion (MVM) lesions (p < 0.001), maternal inflammatory response (MIR) lesions (p < 0.001), placental hemorrhage (p < 0.001), and a lower feto-placental ratio (p < 0.001). Using regression analysis, we found that severe neonatal morbidity was independently associated with early abruption (aOR = 5.3, 95% CI = 3.9-7.6), placental MVM (aOR = 1.5, 95% CI = 1.2-1.9), placental MIR (aOR = 1.9, 95% CI = 1.4-2.3), and inversely associated with antenatal corticosteroids (aOR = 0.9, 95% CI = 0.6-0.98). "Early" and "late" PA significantly differ in their presentation, placental pathology, and pregnancy outcomes.

Sex determination is the process by which an initial bipotential gonad adopts either a testicular or ovarian cell fate. The inability to properly complete this process leads to a group of developmental disorders classified as disorders of sex development (DSD). To date, dozens of genes were shown to play roles in mammalian sex determination, and mutations in these genes can cause DSD in humans or gonadal sex reversal/dysfunction in mice. However, exome sequencing currently provides genetic diagnosis for only less than half of DSD patients. This points towards a major role for the non-coding genome during sex determination. In this review, we highlight recent advances in our understanding of non-coding, cis-acting gene regulatory elements and discuss how they may control transcriptional programmes that underpin sex determination in the context of the 3-dimensional folding of chromatin. As a paradigm, we focus on the Sox9 gene, a prominent pro-male factor and one of the most extensively studied genes in gonadal cell fate determination., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Introduction: We aimed to study the correlation between the extent of placental abruption (PA), as grossly estimated immediately after delivery, and pregnancy outcomes, in correlation with placental histopathology., Materials and Methods: Pregnancy and placental reports of all pregnancies complicated by PA (clinically diagnosed) between 11/2008-12/2018 were reviewed. We compared maternal background, pregnancy outcomes, and placental histopathology between cases of PA divided into three groups according to the extent of abruption: Group 1-<30 %, Group 2-30-49 %, and Group 3->50 % of placental surface. Placental lesions were classified according to the current "Amsterdam" criteria. The primary outcome was defined as a composite of severe neonatal morbidity and included ≥ 1 of the following complications: seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, periventricular leukomalacia, blood transfusion, necrotizing enterocolitis, intrauterine fetal demise, or neonatal death., Results: A total of 260 PA cases were included: 111 (42.7 %) in Group 1, 94 (36.2 %) in Group 2, and 55 (21.1 %) in Group 3. The rate of the primary outcome (7.2 % vs. 11.7 % vs. 27.3 %, p = 0.02) was associated with the degree of PA as well as maternal heavy smoking (p = 0.04), DIC (p = 0.03), umbilical artery Ph <7.1 (p = 0.02), 5-minute Apgar scores <7 (p = 0.03), NICU admissions, placental maternal vascular malperfusion lesions (p = 0.04), and neonatal weights <5th percentile (0.04). In multivariable analysis severe adverse neonatal outcome was independently associated with the percentage of PA (aOR = 1.4, 95 % CI = 1.3-3.9)., Conclusion: The extent of placental abruption, as estimated by the examiner, correlated with DIC and severe neonatal outcomes and may serve as an early alarming sign in deliveries complicated by PA., Competing Interests: Declaration of Competing Interest There is not any financial relationship with any organization or any conflict of interest to report., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY -negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families ( P = 4.4 × 10 -6 ), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations ( P < 1.8 × 10 -4 ). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1 Arg495Gly/Arg495Gly XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor β-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: The incidence of thromboembolic complications is highest in the immediate postpartum period, especially following caesarean delivery (CD). Ambulation following CD is important in their prevention. We examined the effect of an educational protocol on patients' mobility following CD, with the use of digital step counters (pedometers)., Methods: Starting February 2018, we implemented an educational protocol at the maternity ward, which included nurses' tutoring and subsequent patients' education, regarding the importance of early ambulation. Following CD, ambulation was initiated 4 h following surgery (as compared to 6 h prior). Scheduled IV acetaminophen was administered at six-hour intervals for 48 h (as compared to only 24 h prior), while additional analgesics were given upon patient request. We compared maternal demographics, delivery and postpartum course between the pre-protocol group (n = 101) and the post-protocol group (n = 100). All patients were asked to wear pedometers for 48 h following the delivery to assess ambulation., Results: Patients' demographics, surgical and post-partum course were non-significant between the groups, except for surgical length (48.5 ± 14.6 vs. 53.5 ± 15.3 min in the pre and post protocol groups, respectively, p = 0.02). The pre-protocol group was treated with more additional analgesics (p = 0.02). A higher number of steps was taken in the post-protocol group as compared to the pre-protocol group (4394 ± 2985 vs.3551 ± 2931, respectively p = 0.04). In a linear regression analysis in which the number of steps served as the dependent variable, this educational protocol was independently associated with a higher number of steps [coefficient 988 steps, 95% CI 137-1838, p = 0.02], as was smoking, after adjustment for surgical length, emergent surgery, maternal age and body mass index., Conclusion: An educational protocol which included earlier ambulation and regular interval pain control was associated with improved ambulation following CD.

Objective: To assess the effect of a personalized repeated feedback approach using digital step counters (pedometers) on mobility after cesarean delivery in high-risk patients., Methods: This was a randomized controlled trial at a tertiary university hospital. Patients who underwent cesarean delivery and were defined as high risk for thromboembolic events were asked to wear a pedometer around their wrists postpartum for 48 hours. Patients were randomized to the feedback group, which received personalized feedback by the research staff regarding their mobility at three set timepoints, or the control group, which received standard care. The number of steps taken by patients was compared between the groups and served as the primary outcome. Secondary outcomes included patient reported pain, physical and mental recovery, and overall satisfaction. Sample size was predetermined to detect a 25% between-group difference in the primary outcome., Results: From December 2018 to July 2019, 215 patients were recruited, randomized and completed follow-up-108 in the feedback group and 107 in the control group. Patients' demographics and intrapartum course were similar between the groups. The number of steps taken was significantly higher in the feedback group compared with the control group: 5,918±3,116 vs 4,161±2,532 steps, P<.001. Pain scores were similar between the groups, as was analgesic consumption. Patients in the feedback group reported a significantly easier physical and mental postpartum recovery and were significantly more satisfied with their delivery experience. Postpartum complications did not differ between the groups., Conclusion: In high-risk patients after cesarean delivery, mobility was improved by using a personalized feedback approach. Enhanced mobility was not associated with a higher rate of complications or pain and was positively associated with patient satisfaction., Clinical Trial Registration: ClinicalTrials.gov, NCT03724760.

Introduction: Two possible causative pathways have been suggested to participate in the development of placental abruption (PA), an acute inflammatory pathway and placental vascular derived, a chronic pathway. We aimed to study the impact of the inflammatory pathway on maternal and neonatal outcome., Methods: The computerized medical files and placental reports of all pregnancies diagnosed with PA, between 11/2008-1/2019, at 24-42 weeks, were reviewed. Placental lesions were classified according to "Amsterdam" criteria into maternal and fetal vascular malperfusion lesions, acute inflammatory responses and chronic villitis. Composite neonatal morbidity included ≥1 of the following: seizures, intra-ventricular hemorrhage (IVH), hypoxic-ischemic encephalopathy, periventricular leukomalacia (PVL), blood transfusion, necrotizing enterocolitis (NEC), neonatal sepsis, respiratory distress syndrome, or neonatal death. Maternal and neonatal outcome were compared between PA with and without histologic chorioamnionitis (HC)., Results: As compared to the PA without HC group (n = 267), the PA with HC group (n = 77) was characterized by lower gestational age (GA) at delivery (32.9 ± 5.5 vs. 35.6 ± 4.1 weeks, p < 0.001), higher rates of oligohydramnios (p < 0.001), bloody amniotic fluid at labor (p < 0.001), maternal postpartum fever (p < 0.001), longer maternal hospitalization (<0.001), and increased composite adverse neonatal morbidity (41.6% vs. 22.8%, p = 0.002). By multivariate analysis, GA and HC were found to be independently associated with adverse neonatal outcome, aOR 0.63 95% CI 0.43-0.78, p < 0.001, and aOR1.12, 95% CI 1.02-3.87, p = 0.04, respectively., Discussion: The involvement of the inflammatory causative pathway in the development of placental abruption, is associated with increased maternal and neonatal morbidity., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction and Hypothesis: Protracted postpartum urinary retention (P-PUR) is a rare puerperal complication of overt urinary retention that proceeds beyond the 3rd postpartum day. Long-term consequences of P-PUR are poorly reported. The objective of the study was to compare the long-term outcome of patients with P-PUR with a matched control group, using a validated pelvic floor distress questionnaire., Methods: All medical files of women diagnosed with P-PUR between 2005 and 2016 were reviewed. The control group was comprised of women who had a consecutive birth, matched in a 1:2 ratio, by maternal age, parity, neonatal birth weight, analgesia, and route of delivery. All women were evaluated for long-term symptoms of urinary or fecal incontinence and pelvic-organ-prolapse-related complaints by a telephone interview, at least 1 year following their delivery, using the Pelvic Floor Distress Inventory-Short Form (PFDI-20) questionnaire., Results: During the study period, there were 27 cases of P-PUR out of 52,662 deliveries (0.051%). There were no differences between the study group (n = 27) and controls (n = 54) in age, BMI (kg/m 2 ), parity, birth weight, route of delivery, and rate of episiotomy. The majority of patients in both groups opted for epidural analgesia. Second stage of labor was longer in the study group than in controls, 134.1 ± 74.6 min vs. 73.4 ± 71.6 min, respectively, p < 0.001. The scores of the PFDI-20, UDI-6, and POPDI-6 did not differ between the groups. However, the study group had minimally elevated scores on the CARDI-8 scale (1.0 ± 2.6 vs. 0.0 ± 0.0, p = 0.012)., Conclusions: P-PUR is a rare postpartum complication, yet this disturbing condition has negligible if any clinical impact on long-term urogynecologic disorders. These findings carry a reassuring message to both patients and their health care providers.

Objective: Reduced fetal movements (RFM) is an obstetric complaint known to be associated with adverse neonatal outcomes and should serve as an alarming sign in obstetric triage. Whether this assumption holds for twin pregnancies, is still an obstetric enigma, and this complaint is sometimes overlooked in twins. We, therefore, aimed to study neonatal outcomes in twin pregnancies complicated by RFM. We hypothesised that in twin pregnancy, maternal ability to perceive RFM will be limited, and therefore, will not be associated with adverse neonatal outcome., Study Design: Included were all dichorionic twin pregnancies between 2009-2019 who presented to our obstetric triage at a gestational age >34 weeks with an isolated complaint of RFM and delivered during the subsequent two weeks (RFM group). The control group included patients with twin pregnancies (matched for gestational age and maternal age) who presented for routine assessment and reported regular fetal movements throughout pregnancy (no RFM group). Data regarding pregnancy, delivery, and neonatal outcomes were compared between the groups. The primary outcome was a composite of adverse neonatal outcomes, which included one or more of the following: neonatal hypoglycemia, respiratory morbidity, cerebral morbidity, phototherapy, neonatal sepsis, blood transfusions, necrotizing enterocolitis, or neonatal death. Multivariable regression analysis was used to identify independent associations with adverse neonatal outcomes., Results: Maternal demographics and gestational age at delivery did not differ between the RFM group (n = 83 pregnancies and 166 neonates) and the no RFM group (n = 83 pregnancies and 166 neonates). Neonatal birthweights, as well as the rate of birthweights <10th centile, did not differ between the groups. There were 2 cases of fetal demise diagnosed at triage in the RFM group. The rate of the primary outcome, as well as NICU admissions, were significantly higher in the RFM group compared to the no RFM group (29.5 % vs. 19.2 %, p = 0.01 and 32.5 % vs. 19.2 %, p = 0.001). In multivariable analysis RFM (aOR = 1.18, 95 % CI = 1.06-2.73), and GA at delivery (aOR = 0.88, 95 % CI = 0.67-0.97) were associated with adverse neonatal outcome-independent from background confounders., Conclusion: Patients presented to obstetric triage with twin pregnancies and isolated RFM had higher rates of adverse neonatal outcomes and NICU admissions compared to twin pregnancies without RFM., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), is a complex cellular response to ER protein misfolding that involves transcriptional regulatory branches and a PERK-mediated translational regulatory branch. Here we revealed that amino acid biosynthesis regulation is coupled to protein synthesis demands during ER stress. Specifically, we demonstrated that the UPR leads to PERK-dependent induction in the biosynthesis of specific amino acids, and to upregulation of their corresponding tRNA synthetases. Furthermore, we found that sequences of UPR-upregulated proteins are significantly enriched with these UPR-induced amino acids. Interestingly, whereas the UPR leads to repression of ER target proteins, we showed that secreted proteins tended to escape this repression and were highly enriched for the UPR-induced amino acids. Our results unravel coordination between amino acid supply, namely, biosynthesis and tRNA loading, and demand from UPR-induced proteins under ER stress, thus revealing an additional regulatory layer of protein synthesis., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Maintaining average activity within a set-point range constitutes a fundamental property of central neural circuits. However, whether and how activity set points are regulated remains unknown. Integrating genome-scale metabolic modeling and experimental study of neuronal homeostasis, we identified mitochondrial dihydroorotate dehydrogenase (DHODH) as a regulator of activity set points in hippocampal networks. The DHODH inhibitor teriflunomide stably suppressed mean firing rates via synaptic and intrinsic excitability mechanisms by modulating mitochondrial Ca 2+ buffering and spare respiratory capacity. Bi-directional activity perturbations under DHODH blockade triggered firing rate compensation, while stabilizing firing to the lower level, indicating a change in the firing rate set point. In vivo, teriflunomide decreased CA3-CA1 synaptic transmission and CA1 mean firing rate and attenuated susceptibility to seizures, even in the intractable Dravet syndrome epilepsy model. Our results uncover mitochondria as a key regulator of activity set points, demonstrate the differential regulation of set points and compensatory mechanisms, and propose a new strategy to treat epilepsy., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Most major societies do not state a specific recommendation against or in favor of routine umbilical cord gas studies sampling., Objective: We aimed to study the correlation between abnormal umbilical cord gas studies (using 5 different definitions) and adverse neonatal outcomes in scheduled nonlaboring term singleton cesarean deliveries., Study Design: The medical charts, surgical records, and neonatal charts of all singleton cesarean deliveries at 37 0/7 -41 6/7 weeks of gestation between January 2009 and May 2018 from a single tertiary center were reviewed. The cohort of singleton cesarean deliveries was divided into those with "normal" vs "abnormal" umbilical cord gas studies with the 5 different definitions: (1) definition A: pH ≤7.15; (2) definition B: pH ≤7.15 and base excess ≤-12 mmol/L; (3) definition C: pH ≤7.1l (4) definition D: pH ≤7.1 and base excess ≤-12 mmol/L, and (5) definition E: pH <7.0 and base excess ≤-12 mmol/L. Adverse neonatal outcomes included Apgar scores at 5 minutes ≤7, neonatal sepsis, blood transfusion, phototherapy, respiratory morbidity (presence of respiratory distress syndrome, transient tachypnea of the newborn infant, mechanical ventilation, need for respiratory support, or meconium aspiration), cerebral morbidity (presence of intraventricular hemorrhage, seizures, or hypoxic-ischemic encephalopathy), necrotizing enterocolitis, or death. Composite adverse outcome was ≥1 of the aforementioned complications., Results: Overall, 3001 singleton cesarean deliveries were included. The rate of abnormal umbilical cord gas studies with the use of definitions A-E was 2.6%, 0.3%, 1.2%, 0.3%, and 0.1%, respectively. The overall rate of adverse neonatal outcome for the entire cohort was 14.43% (433/3001). There was no correlation between abnormal umbilical cord gas studies and composite adverse neonatal outcome with the use of any of the definitions A-E (P=.2, P=.3, P=.2, P=.3, P=.1, respectively). The sensitivity and specificity of abnormal umbilical cord gas studies as a predictor of composite adverse neonatal outcome were calculated for each of the abnormal umbilical cord gas studies definitions; although the sensitivity was extremely low (0-2.07%), the specificity was high (97.2-99.9%) CONCLUSION: Abnormal umbilical cord gas studies are an uncommon finding in cases of singleton term singleton cesarean deliveries and do not correlate with adverse neonatal outcomes. Therefore, the clinical usefulness and cost-effectiveness of obtaining these studies routinely should be questioned., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-XBP1-mediated transcriptional arms, have been thoroughly investigated. Using ribosome footprint profiling, we performed a deep characterization of gene expression programs involved in the early and late ER stress responses, within WT or PERK -/- Mouse Embryonic Fibroblasts (MEFs). We found that both repression and activation gene expression programs, affecting hundreds of genes, are significantly hampered in the absence of PERK. Specifically, PERK -/- cells do not show global translational inhibition, nor do they specifically activate early gene expression programs upon short exposure to ER stress. Furthermore, while PERK -/- cells do activate/repress late ER-stress response genes, the response is substantially weaker. Importantly, we highlight a widespread PERK-dependent repression program, consisting of ER targeted proteins, including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. This phenomenon occurs in various different cell types, and has a major translational regulatory component. Moreover, we revealed a novel interplay between PERK and the XBP1-ATF6 arms of the UPR, whereby PERK attenuates the expression of a specific subset of XBP1-ATF6 targets, further illuminating the complexity of the integrated ER stress response.

Cis-regulatory elements are critical for the precise spatiotemporal regulation of genes during development. However, identifying functional regulatory sites that drive cell differentiation in vivo has been complicated by the high numbers of cells required for whole-genome epigenetic assays. Here, we identified putative regulatory elements during sex determination by performing ATAC-seq and ChIP-seq for H3K27ac in purified XX and XY gonadal supporting cells before and after sex determination in mice. We show that XX and XY supporting cells initiate sex determination with similar chromatin landscapes and acquire sex-specific regulatory elements as they commit to the male or female fate. To validate our approach, we identified a functional gonad-specific enhancer downstream of Bmp2, an ovary-promoting gene. This work increases our understanding of the complex regulatory network underlying mammalian sex determination and provides a powerful resource for identifying non-coding regulatory elements that could harbor mutations that lead to Disorders of Sexual Development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The bipotential nature of cell types in the early developing gonad and the process of sex determination leading to either testis or ovary differentiation makes this an interesting system in which to study transcriptional regulation of gene expression and cell fate decisions. SOX9 is a transcription factor with multiple roles during development, including being a key player in mediating testis differentiation and therefore subsequent male development. Loss of Sox9 expression in both humans and mice results in XY female development, whereas its inappropriate activation in XX embryonic gonads can give male development. Multiple cases of Disorders of Sex Development in human patients or sex reversal in mice and other vertebrates can be explained by mutations affecting upstream regulators of Sox9 expression, such as the product of the Y chromosome gene Sry that triggers testis differentiation. Other cases are due to mutations in the Sox9 gene itself, including its own regulatory region. Indeed, rearrangements in and around the Sox9 genomic locus indicate the presence of multiple critical enhancers and the complex nature of its regulation. Here we summarize what is known about the role of Sox9 and its regulation during gonad development, including recently discovered critical enhancers. We also discuss higher order chromatin organization and how this might be involved. We end with some interesting future directions that have the potential to further enrich our understanding on the complex, multi-layered regulation controlling Sox9 expression in the gonads., (© 2019 Elsevier Inc. All rights reserved.)

Cell fate decisions require appropriate regulation of key genes. Sox9 , a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9 Although others are redundant, enhancer 13 (Enh13), a 557-base pair element located 565 kilobases 5' from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Previous studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only., Methods: A single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits., Results: The age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 μmol/l vs. 17.5 p = NS) were comparable between the two groups. The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17.3 ng/ml p < 0.001) were significantly decreased in the letrozole group., Conclusions: Opposite to observations in the mouse, we found that VEGF levels were increased and PEDF levels were decreased in the follicular fluid in patients treated with letrozole during the stimulation cycles. Further investigation is required to determine if patients treated with letrozole during the IVF stimulation protocol are at increased risk for developing OHSS as a result of these findings.

Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced-stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor-initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)