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Proper action of the female sex steroids, 17ß-estradiol (E2) and progesterone (P4) on endometrium is essential for fertility. Beyond its role in regulating the cell cycle, cyclin A2 (CCNA2) also mediates E2 and P4 signaling in vitro, but a potential role in modulating steroid action for proper endometrial tissue development and function is unknown. To fill this gap in our knowledge, we examined human endometrial tissue from fertile and infertile women for CCNA2 expression and correlated this with pregnancy outcome. Functional assessment of CCNA2 was validated in vivo using a conditional Ccna2 uterine deficient mouse model while in vitro function was assessed using human cell culture models. We found that CCNA2 expression was significantly reduced in endometrial tissue, specifically the stromal cells, from women undergoing in vitro fertilization who failed to achieve pregnancy. Conditional deletion of Ccna2 from mouse uterine tissue resulted in an inability to achieve pregnancy which appears to be due to alterations in the process of decidualization, which was confirmed using in vitro models. From these studies, we conclude that CCNA2 expression during the proliferative/regenerative stage of the menstrual cycle acts as a safeguard allowing for proper steroid responsiveness, decidualization and pregnancy. When CCNA2 expression levels are insufficient there is impaired endometrial responsiveness, aberrant decidualization and loss of pregnancy.

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Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

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Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.

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OBJECTIVE: To assess factors impacting obstetric transport and referral processes for pregnant patients experiencing an emergency in a rural state without a perinatal regionalized system of care. DATA SOURCES AND STUDY SETTING: Data is from Critical Access Hospitals (CAHs) without obstetric units and healthcare providers involved in obstetric care and transport at hospitals with varying levels of obstetric capacity in Montana. STUDY DESIGN: This mixed-methods study involved surveying CAHs without obstetric units about the hospitals' capacity for obstetric emergencies and transport policies. Survey data were collected from 32 of 34 CAHs without obstetric units (94% response rate) in the fall of 2021. Subsequent interviews were conducted in the fall and winter of 2022-2023 with 20 hospital and emergency medical services (EMS) personnel to provide further insights into the referral and transport process during obstetric emergencies. DATA COLLECTION/EXTRACTION METHODS: Survey data were collected using REDCap; interviews were conducted via videoconference. We performed descriptive statistics and Fisher's exact tests for quantitative data. We analyzed qualitative data using a three-phase pragmatic analytic approach. PRINCIPAL FINDINGS: The survey of CAHs found 12 of 32 facilities faced difficulties coordinating transport for pregnant patients. Qualitative data indicated this was often due to the state's decentralized transport system. Challenges identified through both quantitative and qualitative data included weather, securing a receiving facility/provider, and coordinating medical transport. Only 10 CAHs reported having written protocols for transporting pregnant patients; of those, four facilities had formal transfer agreements. Qualitative data emphasized variations in awareness and the utility of obstetric transport policies. CONCLUSIONS: A decentralized transport system in a rural state can exacerbate existing challenges faced by providers arranging transport for pregnant patients during an obstetric emergency. State and interfacility policies could enhance the transport process for increased regionalization as well as increased support for and coordination of existing EMS.

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MRKH syndrome, or Mayer-Rokitansky-Küster-Hauser syndrome, a rare congenital disease, manifests as a complete or partial aplasia of the uterus and the vagina's upper two-thirds with normal external genitalia and functioning ovaries. Mayer-Rokitansky-Küster-Hauser syndrome can occur in isolation (type I) or in conjunction with other congenital extragenital deformities affecting the kidneys, skeleton, heart, eyes, or auditory system (type II). The diagnosis of Mayer-Rokitansky-Küster-Hauser syndrome typically relies on imaging studies, with transabdominal ultrasonography serving as the primary modality. However, magnetic resonance imaging is considered the gold standard for detailed assessment of internal genital anatomy. We present the case of an 18-year-old woman without any notable medical history who exhibited primary amenorrhea. Mayer-Rokitansky-Küster-Hauser syndrome type II was suspected on pelvic ultrasound and subsequently confirmed via magnetic resonance imaging. The patient was provided with psychological assistance and planned for vaginoplasty.

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Key Clinical Message: Pituitary apoplexy is a medical and surgical emergency requiring prompt diagnosis and often urgent treatment to manage symptoms and prevent further complications. Abstract: This report describes the successful management of a 37-year-old pregnant woman with a history of pituitary macroadenoma and apoplexy during a twin pregnancy. Presenting with bitemporal vision loss, a common pituitary adenoma symptom, she showed no other alarming signs despite a twin pregnancy. Successful endoscopic resection improved her vision, and postoperative recovery was uneventful. The discussion underscores significance of the diagnostic utility of contrast MRI. The patient's favorable outcome supports endoscopic resection feasibility in pregnant individuals with pituitary apoplexy.

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Key Clinical Message: A surgical MDT approach to high-complexity surgeries can allow maximal resection in order to achieve disease control and excellent functional outcomes, as demonstrated here for a case of hidradenitis suppurativa in a patient with Crohn's disease. Abstract: Hidradenitis suppurativa is an autoimmune disease characterized by abscess and fistula formation with purulent discharge in intertriginous zones, and is associated with inflammatory bowel disease. We present the case of a patient with severe ongoing hidradenitis suppurativa causing osteomyelitis and affecting the perineum, on a background of Crohn's disease previously treated with panprotocolectomy and permanent ileostomy. The hidradenitis suppurativa was having a severe impact on the patient's quality of life, and she had failed to respond to conservative management. The patient opted for a radical two-step procedure: first her coccyx and sacrum were removed. The second step was a radical bilateral anterior vulvectomy and posterior vaginectomy, with preservation of the uterine body and cervix. An anterolateral thigh flap was used to reconstruct the perineum. This complex procedure required the expertise of multiple surgical specialties, including plastic, general, spinal, and gynecological oncology surgeons to achieve maximal disease resection, minimizing the risk of recurrence.

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INTRODUCTION: In light of increased cesarean section rates, the incidence of placenta accreta spectrum (PAS) disorder is increasing. Despite the establishment of clinical practice guidelines offering recommendations for early and effective PAS diagnosis and treatment, antepartum diagnosis of PAS remains a challenge. This ultimately risks poor mental health and poor physical maternal and neonatal health outcomes. CASE DESCRIPTIONS: This case series details the experience of two high-risk patients who remained undiagnosed for PAS until they presented with antenatal hemorrhage, leading ultimately to necessary, complex surgical interventions, which can only be optimally provide in a tertiary care center. Patient 1 is a 37-year-old woman with a history of three cesarean sections, which elevates her risk for PAS. She had placenta previa detected at 19 weeks, and placenta percreta diagnosed upon hemorrhage. During a hysterectomy, invasive placenta was found in the patient's bladder, leading to a cystotomy and right ureteric reimplantation. After discharge, she was diagnosed with a vesicovaginal fistula, and is currently awaiting surgical repair. Patient 2 is a 34-year-old woman with two previous cesarean sections. The patient had complete placenta previa detected at 19- and 32-week gestation scans. She presented with antepartum hemorrhage at 35 weeks and 2 days. An ultrasound showed thin myometrium at the scar site with significant vascularity. A hysterectomy was performed due to placental attachment issues, with significant blood loss. Both patients were at high risk for PAS based on past medical history, risk factors, and pathognomonic imaging findings. DISCUSSION: We highlight the importance of the implementation of clinical guidelines at non-tertiary healthcare centers. We offer clinical-guideline-informed recommendations for radiologists and antenatal care providers to promote early PAS diagnosis and, ultimately, better patient and neonatal outcomes through increased access to adequate care.

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We present the case of a 27-year-old pregnant woman, newly diagnosed with Systemic Lupus Erythematosus (SLE) during pregnancy. The patient delivered a newborn at 38 weeks gestation, who, on the first day of life, manifested complete heart block. This case underscores the clinical challenges associated with neonatal lupus, emphasizing the need for collaborative, multidisciplinary management.

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BACKGROUND: Bedside teaching (BST) is a crucial component of medical education. It entails the interaction of students with patients in outpatient clinics and inpatient wards under the supervision of their tutors in order to improve the clinical skills of the students and, ultimately, patient outcomes. This teaching relies heavily on patients' willingness and cooperation. The aim of this study was to assess the perception of Obstetrics and Gynecology (OB/GYN) patients regarding the presence and participation of medical students in BST. MATERIALS AND METHODS: A cross-sectional survey was conducted among OB/GYN patients at the outpatient clinics and inpatient wards at King Fahd Hospital of the University (KFHU) in Al-Khobar from January 1 to April 30, 2023. Data were collected online through the Google Drive survey tool using a validated and pilot tested questionnaire. Data were analyzed utilizing SPSS version 26.0. Chi-squared test was employed to test for association between two categorical variables. Multiple logistic regression model was used to determine variables associated with positive attitudes. RESULTS: A total of 507 patients completed online questionnaire. A highly positive patients' attitude was observed toward the presence and participation of medical students during BST with a mean score of 81.8 ± 10.4. The acceptance rates were higher for female students compared to male students (91.9% vs 61.7%) and for senior doctors compared to junior doctors (89.9% vs 58.9%). Patients who came to the outpatient clinics were also more likely to accept students' presence than those who went to hospital wards. Age, marital status, and previous clinic visits were positively associated with the acceptance level of the presence and involvement of medical students in BST without a significant difference. CONCLUSION: In general, patients had a good perception of medical students' engagement in their care and that the gender of the medical students/doctors and clinical setting could affect this perception. Raising patients' awareness of their valuable role in male medical students' and doctors' education should be raised, as this will increase their acceptance during BST.

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Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

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A pessary is a medical device that is inserted into the vagina to provide structural support to one or more of the descending vaginal compartments in women with pelvic organ prolapse. It is a common management option offered to women in the short and long term. This article will discuss the current use of vaginal pessaries for POP, the current challenges with their use and common complications seen in practise. It will also discuss the unmet needs in the current products available on the market and suggest ideas for product design, materials and considerations for future development.

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Purpose: This study's aim was to determine the actual status of transitional care for patients with pediatric cancer (PPCs) in Japan by surveying obstetricians/gynecologists. Methods: A questionnaire survey on transitional medicine was conducted in the form of an online questionnaire at 579 major training facilities nationwide, which were registered with the Japanese Society of Obstetrics and Gynecology. Results: While 40% of the facilities had received referrals for PPCs, only 13% provided transitional care specifically for PPCs. The most common problems with referrals were related to "insufficient explanation." In addition, at facilities with no experience treating PPCs, many respondents commented that they did not know how to follow the progression of the disease. Regarding the necessity of obstetrics/gynecology visits for PPCs, more than half of the respondents at facilities with experience treating PPCs answered that such visits were "necessary"; only 1% answered that they were "unnecessary." On the other hand, 37% of the facilities that had no experience treating PPCs answered that it was "necessary," whereas 4% answered that it was "unnecessary." Conclusions: This survey of the actual status of transitional care between pediatrics and obstetrics/gynecology in Japan identified issues to be addressed for the spread of transitional care. The results suggest that, in the future, health care professionals need education to increase their knowledge, and that patient education that leads to patients' awareness of their own self-management is necessary.

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High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a ß-adrenergic receptor-dependent (ß-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the ß-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.

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This is a case of a 70-year-old female with small bowel evisceration through vaginal cuff dehiscence 14 months after hysterectomy. She presented with a loop of ileum herniated through the vagina. The bowel was irreducible and she was taken to the operating room for exploratory laparotomy, reduction of herniated bowel contents, and repair of vaginal cuff. During surgery, the eviscerated bowel had questionable viability and indocyanine green angiography was used to assess perfusion. After the repair of the vaginal cuff, indocyanine green angiography was performed and the bowel was saved from resection. In the discussion, light is shed upon the rarity of vaginal cuff dehiscence and the few cases of small bowel evisceration after a dehiscence. Possible causes of the evisceration, updates to technique, and recommendations for management are also discussed. The ultimate recommendation is for use of indocyanine green angiography in assessment of intestinal viability during surgical exploration for small bowel evisceration.

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OBJECTIVE: To evaluate the performance of different approaches for identifying live births using Transformed Medicaid Statistical Information System Analytic Files (TAF). DATA SOURCES: The primary data source for this study were TAF inpatient (IP), other services (OT), and demographic and eligibility files. These data contain administrative claims for Medicaid enrollees in all 50 states and the District of Columbia from January 1, 2018 to December 31, 2018. STUDY DESIGN: We compared five approaches for identifying live birth counts obtained from the TAF IP and OT data with the Centers for Disease Control and Prevention (CDC) Natality data-the gold standard for birth counts at the state level. DATA COLLECTION/EXTRACTION METHODS: The five approaches used varying combinations of diagnosis and procedure, revenue, and place of service codes to identify live births. Approaches 1 and 2 follow guidance developed by the Centers for Medicare and Medicaid Services (CMS). Approaches 3 and 4 build on the approaches developed by CMS by including all inpatient hospital claims in the OT file and excluding codes related to delivery services for infants, respectively. Approach 5 applied Approach 4 to only the IP file. PRINCIPAL FINDINGS: Approach 4, which included all inpatient hospital claims in the OT file and excluded codes related to infants to identify deliveries, achieved the best match of birth counts relative to CDC birth record data, identifying 1,656,794 live births-a national overcount of 3.6%. Approaches 1 and 3 resulted in larger overcounts of births (20.5% and 4.5%), while Approaches 2 and 5 resulted in undercounts of births (-3.4% and -6.8%). CONCLUSIONS: Including claims from both the IP and OT files, and excluding codes unrelated to the delivery episode and those specific to services rendered to infants improves accuracy of live birth identification in the TAF data.

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BACKGROUND: Numerous factors can influence decisions regarding the type of delivery of human babies. There is an increasing demand for non-medically indicated cesarean sections (CS) (non-miCS) or CS on request (CSor). Therefore, this survey study aimed to identify the factors that may foster the decision of CS among obstetricians. METHODS: After the sample size calculation returned with 132 needed participants, confidence surveys were sent electronically or disseminated in paper form to nearly all obstetricians (around 200) in the province between mid-August 2021 and mid-February 2022. After signing the consent form, obstetricians were able to provide responses to the four sections of the questionnaire. Data from the copies of the paper were entered into Excel by a local data collector. The data analysis was done using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY) and followed the following sequence: summary statistics were done first; then the groups (for and against non-miCS) were compared using analysis of variance (ANOVA); and, finally, regression models were conducted to determine the factors that may affect the favorability of doing non-miCS. RESULTS: A total of 104 obstetricians responded to the survey. Approximately 62.5% of them performed CSor for women who requested it. In addition, more than half (57.7%) agreed that all women had the right and autonomy to choose their mode of delivery. Most providers (65.4) agreed that fear of vaginal delivery (VD) and a bad experience with it are rational reasons for performing a CSor. Unfortunately, some obstetricians (18.3%) faced lawsuits when they refused to perform CSor. As for the factors that may influence the acceptance of obstetricians to non-miCS, it was found that obstetricians who are unsure or refuse to answer (OR=4.30, 95%-CI 1.25-16.29, p=0.025), along with people who do not always perform CSor (OR=4.33, 95%-CI 1.59-12.50, p=0.005) or even refuse it (3.54, 95%-CI 1.05-12.96, p=0.046), are more likely to agree that women have the right to request CSor. CONCLUSION: The surge in CSor rates was mostly correlated with an attempt to escape the fear of VD. However, given the wide discrepancies in obstetricians' opinions in this survey, we cannot draw firm conclusions about the reasons behind this phenomenon. It is also important to explore possible ways to address the problem, such as through litigation with providers who refuse to perform a CSor and through economic reform to protect women from money-grubbing obstetricians.

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Vasomotor symptoms (VMS) are a common and distressing experience during menopause, affecting a significant portion of women. Hormone therapy (HT) has been the traditional treatment, but its limitations and potential risks have led to the search foar non-hormonal alternatives. Recently, the FDA approved Veozah (Fezolinetant) as a promising nonhormonal solution for moderate to severe VMS in menopause. Veozah, an innovative neurokinin 3 (NK3) receptor antagonist, targets the disrupted thermoregulation underlying VMS. It modulates neural activity within the thermoregulatory center by crossing the blood-brain barrier, offering relief from hot flashes and night sweats. Clinical trials, including SKYLIGHT 1TM, SKYLIGHT 2TM, and SKYLIGHT 4TM, have established Fezolinemtant's efficacy and safety profile. The recommended dosage of one 45 mg tablet per day demonstrates proportional pharmacokinetics, with generally mild side effects that require regular monitoring. Fezolinetant's oral availability makes it a convenient and accessible option for women seeking relief from VMS, potentially improving their overall well-being.

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CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.

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Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1-/- embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

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