MICAL2 Is a Super Enhancer Associated Gene that Promotes Pancreatic Cancer Growth and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed that MICAL2 is a super enhancer-associated gene in human PDAC. MICAL2 is a flavin monooxygenase that induces actin depolymerization and indirectly promotes SRF transcription by modulating the availability of serum response factor coactivators myocardin related transcription factors (MRTF-A and MRTF-B). We found that MICAL2 is overexpressed in PDAC and correlates with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and EMT signaling pathways, contributing to tumor growth and metastasis. In loss and gain of function experiments in human and mouse PDAC cells, we observed that MICAL2 promotes both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 expression also inhibited macropinocytosis. Through in vitro phenotypic analyses, we show that MICAL2, MRTF-A and MRTF-B influence PDAC cell proliferation, migration and promote cell cycle progression. Importantly, we demonstrate that MICAL2 is essential for in vivo tumor growth and metastasis. Interestingly, we find that MRTF-B, but not MRTF-A, phenocopies MICAL2-driven phenotypes in vivo . This study highlights the multiple ways in which MICAL2 impacts PDAC biology and suggests that its inhibition may impede PDAC progression. Our results provide a foundation for future investigations into the role of MICAL2 in PDAC and its potential as a target for therapeutic intervention.

Common misperceptions and public knowledge about intrauterine devices among US-based online respondents.

OBJECTIVES: Misperceptions about intrauterine devices (IUDs) may dissuade potential users and public beliefs are not well understood. We sought to describe public knowledge of mechanism of action, failure rate, and IUD health risks. Secondary objectives included identifying inaccurate information and information sources about IUDs. STUDY DESIGN: We conducted a convenience-based survey of participants living in the United States 18 years and older using Amazon Mechanical Turk and ResearchMatch. We collected information on demographics, reproductive history, and IUD knowledge. We asked about IUD mechanism of action, failure rate, potential health risks, and information sources. We used multivariable logistic regression to test the association between gender and perceived lower (vs. higher) risks of IUDs. RESULTS: We included 1597 individuals with 726 (45.5%) self-reported men and 871 (54.5%) self-reported women. For both hormonal and non-hormonal IUDs, participants most often selected implantation prevention as the primary mechanism of action. In our sample, 55.5% of individuals believed the failure rate was greater than five percent. Weight gain, uterine perforation, and expulsion were cited as health risks likely to occur ≥5% of the time by 42.1%, 34.3%, and 38.4% of participants, respectively. Participants identified healthcare providers as their primary source of contraceptive information. Our multivariable logistic regression analysis revealed women had higher odds of perceiving IUDs as higher risk (aOR=1.35, 95% CI 1.09-1.68) compared to men. CONCLUSIONS: Individuals underestimated IUD effectiveness while overestimating perceived health risks. Our results highlight areas to target education about IUDs to support informed contraceptive decision-making. IMPLICATIONS: Participants misunderstood IUD mechanism of action, underestimated efficacy, and overestimated failure rates and health risks. Providers should begin clinical counseling by assessing baseline knowledge, since mechanism of action, side effect profiles, and concepts like female anatomy should not be assumed to be known.

Availability of mifepristone and misoprostol in Oregon pharmacies: A comparison by rural and urban status.

OBJECTIVES: To evaluate the availability of mifepristone and misoprostol at pharmacies in a state with protective abortion legislation and variation in access by rurality. STUDY DESIGN: Using a secret shopper survey, researchers attempted to contact all community pharmacies in Oregon and evaluate their mifepristone and misoprostol provisions. RESULTS: Among the 444 pharmacies surveyed, mifepristone was planned at 19.2%. Misoprostol was available at 77.5%, but stocking issues and medication ordering impact access, without significant differences by rurality. CONCLUSIONS: Pharmacy engagement and support are key to increasing access to these essential medicines, which may be improved through education and referral programs.

Association between Gestational Age and Perinatal Outcomes in Women with Late Preterm Premature Rupture of Membranes.

OBJECTIVE: The American College of Obstetricians and Gynecologists (ACOG) suggests expectant management until 34 weeks for patients with preterm premature rupture of membranes (PPROM). New data suggest extending to 37 weeks might enhance neonatal outcomes, reducing prematurity-linked issues. This study aims to assess adverse neonatal outcomes across gestational ages in women with PPROM. STUDY DESIGN: A retrospective cohort study was performed using linked vital statistics and the International Classification of Diseases, Ninth Revision data. Gestational age at delivery ranged from 32 to 36 weeks. Outcomes include neonatal intensive care unit (NICU) admission >24 hours, neonatal sepsis, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and neonatal death. Multivariate regression analyses and chi-square tests were employed for statistical comparisons. RESULTS: In this cohort of 28,891 deliveries, there was a statistically significant decline in all studied adverse neonatal outcomes with increasing gestational age, without an increase in neonatal sepsis. At 32 weeks, 93% of newborns were in the NICU >24 hours compared with 81% at 34 weeks and 22% at 36 weeks (p < 0.001). At 32 weeks, 20% had neonatal sepsis compared with 11% at 34 weeks and 3% at 36 weeks (p < 0.001). At 32 weeks, 67% had respiratory distress syndrome compared with 44% at 34 weeks and 12% at 36 weeks (p < 0.001). CONCLUSION: In the setting of PPROM, later gestational age at delivery is associated with decreased rates of adverse neonatal outcomes without an increase in neonatal sepsis. KEY POINTS: · The ACOG recommends expectant management until 34 weeks for patients with PPROM.. · However, expectant management to 37 weeks might improve neonatal outcomes.. · Later gestational age at delivery was associated with decreased rates of adverse neonatal outcomes.. · Later gestational age at delivery was not associated with an increase in neonatal sepsis.. · The management of PPROM is complex and should be individualized..

Prenatal methamphetamine use increases risk of adverse maternal and neonatal outcomes.

BACKGROUND: Although methamphetamine use has been increasing in recent years and occurring within new populations and in broader geographical areas, there is limited research on its use and effect in pregnancy. OBJECTIVE: This study aimed to examine the association between prenatal methamphetamine use and maternal and neonatal outcomes in a large, contemporary birth cohort. STUDY DESIGN: This was a retrospective cohort study using California-linked vital statistics and hospital discharge data from 2008 to 2019. Methamphetamine use was identified using the International Classification of Disease, Ninth Revision and Tenth Revision, codes. Chi-square tests and multivariable Poisson regression models were used to evaluate the associations between methamphetamine use and maternal and neonatal outcomes. RESULTS: A total of 4,775,463 pregnancies met the inclusion criteria, of which 18,473 (0.39%) had methamphetamine use. Compared with individuals without methamphetamine use, individuals with methamphetamine use had an increased risk of nonsevere hypertensive disorders (adjusted risk ratio, 1.81; 95% confidence interval, 1.71-1.90), preeclampsia with severe features (adjusted risk ratio, 3.38; 95% confidence interval, 3.14-3.63), placental abruption (adjusted risk ratio, 3.77; 95% confidence interval, 3.51-4.05), cardiovascular morbidity (adjusted risk ratio, 4.30; 95% confidence interval, 3.79-4.88), and severe maternal morbidity (adjusted risk ratio, 3.53; 95% confidence interval, 3.29-3.77). In addition, adverse neonatal outcomes were increased, including preterm birth at <37 weeks of gestation (adjusted risk ratio, 2.85; 95% confidence interval, 2.77-2.94), neonatal intensive care unit admission (adjusted risk ratio, 2.46; 95% confidence interval, 2.39-2.53), and infant death (adjusted risk ratio, 2.73; 95% confidence interval, 2.35-3.16). CONCLUSION: Methamphetamine use in pregnancy is associated with an increased risk of adverse maternal and neonatal outcomes that persists after adjustment for confounding variables and sociodemographic factors. Our results can inform prenatal and postpartum care for this high-risk, socioeconomically vulnerable population.

Risk of Adverse Neonatal Outcomes After Combined Prenatal Cannabis and Nicotine Exposure.

Importance: The prevalence of cannabis use in pregnancy is rising and is associated with adverse perinatal outcomes. In parallel, combined prenatal use of cannabis and nicotine is also increasing, but little is known about the combined impact of both substances on pregnancy and offspring outcomes compared with each substance alone. Objective: To assess the perinatal outcomes associated with combined cannabis and nicotine exposure compared with each substance alone during pregnancy. Design, Setting, and Participants: This retrospective population-based cohort study included linked hospital discharge data (obtained from the California Department of Health Care Access and Information) and vital statistics (obtained from the California Department of Public Health) from January 1, 2012, through December 31, 2019. Pregnant individuals with singleton gestations and gestational ages of 23 to 42 weeks were included. Data were analyzed from October 14, 2023, to March 4, 2024. Exposures: Cannabis-related diagnosis and prenatal nicotine product use were captured using codes from International Classification of Diseases, Ninth Revision, Clinical Modification, and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification. Main Outcome and Measures: The main outcomes were infant and neonatal death, infants small for gestational age, and preterm delivery. Results were analyzed by multivariable Poisson regression models. Results: A total of 3 129 259 pregnant individuals were included (mean [SD] maternal age 29.3 [6.0] years), of whom 23 007 (0.7%) had a cannabis-related diagnosis, 56 811 (1.8%) had a nicotine-use diagnosis, and 10 312 (0.3%) had both in pregnancy. Compared with nonusers, those with cannabis or nicotine use diagnoses alone had increased rates of infant (0.7% for both) and neonatal (0.3% for both) death, small for gestational age (14.3% and 13.7%, respectively), and preterm delivery (<37 weeks) (12.2% and 12.0%, respectively). Moreover, risks in those with both cannabis and nicotine use were higher for infant death (1.2%; adjusted risk ratio [ARR], 2.18 [95% CI, 1.82-2.62]), neonatal death (0.6%; ARR, 1.76 [95% CI, 1.36-2.28]), small for gestational age (18.0%; ARR, 1.94 [95% CI, 1.86-2.02]), and preterm delivery (17.5%; ARR, 1.83 [95% CI, 1.75-1.91]). Conclusions and Relevance: These findings suggest that co-occurring maternal use of cannabis and nicotine products in pregnancy is associated with an increased risk of infant and neonatal death and maternal and neonatal morbidity compared with use of either substance alone. Given the increasing prevalence of combined cannabis and nicotine use in pregnancy, these findings can help guide health care practitioners with preconception and prenatal counseling, especially regarding the benefits of cessation.

Respiratory distress syndrome is associated with increased morbidity and mortality in late preterm births.

BACKGROUND: Respiratory distress syndrome is strongly associated with prematurity, including late preterm births. Respiratory distress syndrome has been shown to be associated with certain neonatal morbidities and mortality, but these associations are not well described among late preterm births. OBJECTIVE: We sought to determine the association between respiratory distress syndrome and adverse neonatal outcomes among late preterm (34-36 weeks) born singleton neonates. STUDY DESIGN: This is a retrospective cohort study using California's linked vital statistics and patient discharge data (2008-2019). We included singleton, nonanomalous births with a gestational age of 34-36 weeks. Outcomes of interest were interventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, neonatal sepsis, length of hospital stay, neonatal death, and infant death. Chi-square and multivariable Poisson regression analyses were used to examine the association of respiratory distress syndrome with outcomes at each gestational age. Adjusted risk ratio and 95% confidence interval values were estimated. RESULTS: A total of 242,827 births were included, of which 11,312 (4.7%) had respiratory distress syndrome. We found that among neonates with respiratory distress syndrome, necrotizing enterocolitis was higher at 35 weeks (adjusted risk ratio, 3.97 [95% confidence interval, 1.88-8.41]) and 36 weeks (adjusted risk ratio, 4.53 [95% confidence interval, 1.45-14.13]). Intraventricular hemorrhage, retinopathy of prematurity, neonatal sepsis, and length of hospital stay were significantly higher at 34-36 weeks of gestation in neonates with respiratory distress syndrome. Neonatal death was significantly higher among neonates with respiratory distress syndrome at 35 weeks (adjusted risk ratio, 3.04 [95% confidence interval, 1.58-5.85]) and 36 weeks (adjusted risk ratio, 3.25; 95% confidence interval, 1.59-6.68). In addition, infant death was significantly higher at 35 weeks (adjusted risk ratio, 2.27 [95% confidence interval, 1.43-3.61]) and 36 weeks (adjusted risk ratio, 2.60 [95% confidence interval, 1.58-4.28]). CONCLUSION: We found that respiratory distress syndrome was associated with intraventricular hemorrhage, retinopathy of prematurity, and sepsis at 34-36 weeks of gestation, whereas respiratory distress syndrome was associated with neonatal death, infant death, and necrotizing enterocolitis at 35 and 36 weeks. Clinicians should keep these outcomes in mind when making decisions about delivery timing, the potential benefits of antenatal steroids in pregnancies in the late preterm period, and the management of respiratory distress syndrome in late preterm neonates.

Understanding the Pursuit of Third-Line Therapies for Overactive Bladder: A Mixed Methods Study.

IMPORTANCE: Overactive bladder (OAB) affects millions of women in the United States, with negative effects in multiple domains that have an impact on quality of life. Third-line therapies for OAB are as effective or superior to lifestyle/behavior modification and medical management, yet few women access these treatments and often spend more than 36 months to reach these treatments after starting medication. Factors associated with time to reach third-line therapy are not well studied, and little is known about how patients progress through care pathways for OAB. OBJECTIVES: The aim of the study was to determine factors associated with the time spent between second- and third-line therapy for OAB at an academic urogynecology and reconstructive pelvic surgery practice. We sought to identify demographic, treatment, clinical factors, and themes in barriers to receiving treatment for OAB. STUDY DESIGN: This was a mixed methods study consisting of a retrospective cohort study followed by qualitative key informant interviews. RESULTS: Eighty-five total participants were included in the analysis, and 42 (49.5%) spent more than 36 months between initiation of medical management and initial third-line therapy for OAB. No significant (P > 0.05) demographic, clinical, or treatment differences were found between groups. Facilitators and obstacles to receiving third-line therapy were identified among key informants, and a treatment decision framework was developed. CONCLUSIONS: Women often spend more than 36 months to pursue third-line therapy for OAB. Existing objective variables are poor predictors of pursuit of third-line treatment, and leveraging known facilitators and obstacles can be used to develop improved care pathways for OAB.

Third stage of labor: evidence-based practice for prevention of adverse maternal and neonatal outcomes.

The third stage of labor is defined as the time period between delivery of the fetus through delivery of the placenta. During a normal third stage, uterine contractions lead to separation and expulsion of the placenta from the uterus. Postpartum hemorrhage is a relatively common complication of the third stage of labor. Strategies have been studied to mitigate the risk of postpartum hemorrhage, leading to the widespread implementation of active management of the third stage of labor. Initially, active management of the third stage of labor consisted of a bundle of interventions including administration of a uterotonic agent, early cord clamping, controlled cord traction, and external uterine massage. However, the effectiveness of these interventions as a bundle has been questioned, leading to abandonment of some components in recent years. Despite this, upon review of selected international guidelines, we found that the term "active management of the third stage of labor" was still used, but recommendations for and against individual interventions were variable and not necessarily supported by current evidence. In this review, we: (1) examine the physiology of the third stage of labor, (2) present evidence related to interventions that prevent postpartum hemorrhage and promote maternal and neonatal health, (3) review current global guidelines and recommendations for practice, and (4) propose future areas of investigation. The interventions in this review include pharmacologic agents to prevent postpartum hemorrhage, cord clamping, cord milking, cord traction, cord drainage, early skin-to-skin contact, and nipple stimulation. Treatment of complications of the third stage of labor is outside of the scope of this review. We conclude that current evidence supports the use of effective pharmacologic postpartum hemorrhage prophylaxis, delayed cord clamping, early skin-to-skin contact, and controlled cord traction at delivery when feasible. The most effective uterotonic regimens for preventing postpartum hemorrhage after vaginal delivery include oxytocin plus ergometrine; oxytocin plus misoprostol; or carbetocin. After cesarean delivery, carbetocin or oxytocin as a bolus are the most effective regimens. There is inconsistent evidence regarding the use of tranexamic acid in addition to a uterotonic compared with a uterotonic alone for postpartum hemorrhage prevention after all deliveries. Because of differences in patient comorbidities, costs, and availability of resources and staff, decisions to use specific prevention strategies are dependent on patient- and system-level factors. We recommend that the term "active management of the third stage of labor" as a combined intervention no longer be used. Instead, we recommend that "third stage care" be adopted, which promotes the implementation of evidence-based interventions that incorporate practices that are safe and beneficial for both the woman and neonate.

Unhealthy air quality secondary to wildfires is associated with lower blastocyst yield.

OBJECTIVE: To study the impact of unhealthy air quality from the 2020 Oregon wildfires on outcomes for patients undergoing in vitro fertilization (IVF) treatment. DESIGN: A retrospective cohort study. SETTING: A university-based fertility clinic. PATIENTS: Subjects were undergoing IVF treatment from the 6 weeks preceding the wildfires through a 10-day exposure period. Cohorts were classified on the basis of whether subjects experienced patient and/or laboratory exposure to unhealthy air quality. Patient exposure was defined as at least 4 days of ovarian stimulation overlapping with the exposure, and laboratory exposure was defined as at least 2 days of IVF treatment and embryogenesis overlapping with the exposure. The unexposed cohort consisted of remaining subjects without defined exposure, with cycles in the 6 weeks preceding the wildfires. As some subjects had dual exposure and appeared in both patient and laboratory exposure cohorts, each cohort was separately compared with the unexposed control cohort. INTERVENTION: A 10-day period of unhealthy air quality caused by smoke plumes from a wildfire event. MAIN OUTCOME MEASURES: The primary outcome was the blastulation rate. Secondary outcomes included fertilization rate, number of blastocysts obtained, and cycles with no blastocysts frozen or transferred. RESULTS: Sixty-nine subjects underwent ovarian stimulation and IVF treatment during the 6 weeks preceding the wildfires through the 10-day period of unhealthy air quality. Of these, 15 patients were in the laboratory exposure cohort, 16 were in the patient exposure cohort, and 44 were unexposed. Six subjects appeared in both laboratory and patient exposure cohorts. Although neither exposure cohort had significantly decreased blastulation rate compared with the unexposed, the median number of blastocysts obtained was significantly lower in the laboratory exposure cohort than the unexposed group (2 [range 0-14] vs. 4.5 [range 0-21], respectively). The laboratory exposure cohort had significantly more cycles with no blastocysts obtained (3/15 [20%] vs. 1/44 [2%]). There were no significant differences in IVF treatment outcomes between patient exposure and unexposed cohorts. These findings persisted after controlling for age. There were no significant differences in pregnancy outcomes observed after embryo transfer between the exposure group and the unexposed group. CONCLUSION: For a cohort of patients undergoing IVF treatment, an acute episode of outside wildfire smoke exposure during fertilization and embryogenesis was associated with decreased blastocyst yield.

Strengthening the Reproductive Endocrinology and Infertility Curriculum Through Three Interactive Cases.

Introduction: Improved reproductive endocrinology and infertility (REI) curricula are needed to address educational deficiencies both at our institution and on a national level. To improve REI education for OB/GYN residents and medical students, we developed and piloted a curriculum with in-person and virtual flexibility. Methods: We developed three clinical vignettes for a facilitator-led case-based discussion among OB/GYN residents: two office cases and one emergency scenario. Cases were evaluated by content experts and tested before implementation. Pre- and postsurveys included both multiple-choice questions on content and a Likert-scale self-assessment of comfort, satisfaction, and knowledge. Postsurveys were administered immediately postintervention and at a delayed interval. Responses were compared using paired t tests and McNemar tests. Results: Eighteen learners (16 OB/GYN residents and two medical students) participated, the majority in person, of whom 17 (94%) completed a postsurvey. Self-rated proficiency in evaluating and managing irregular menses, infertility, and amenorrhea all improved significantly immediately following the intervention (p < .05 for all). Learners reported significantly more knowledge and comfort with REI compared to other subspecialties following the intervention (p < .05). More learners responded correctly to knowledge questions postintervention (p < .05 for questions 1 and 2, p = .16 for question 3). All learners were satisfied with and enjoyed the curriculum. Eight learners completed the delayed postsurvey and showed sustained improvements in knowledge and competence with REI content. Discussion: Facilitator-guided case-based learning was effective in improving learners' confidence, comfort, and knowledge in managing REI conditions, and improvements were sustained following a delayed interval.

A Web-Based Total Worker Health Intervention for Those Fighting Wildland Fires: Mixed Methods Development and Effectiveness Trial.

BACKGROUND: Fire seasons are longer, with more and larger wildfires, placing increased demands and risks on those fighting wildland fires. There are multiple agencies involved with fighting wildland fires and unique worksite conditions make meeting these workers' needs a challenge. OBJECTIVE: The aim of the study is to develop and establish the effectiveness of a web-based safety and health program for those fighting wildland fires. METHODS: This mixed methods project had 3 phases. The initial qualitative phase assessed the needs of 150 diverse firefighters through interviews and focus groups across 11 US sites to establish and prioritize program content. Interview transcripts were read for thematic content with iterative readings used to identify, code, and rank health and safety issues. The second phase used that information to build a comprehensive Total Worker Health program for those fighting wildfires. The program content was based on the qualitative interview data and consisted of 6 core and 8 elective 30-minute, web-based modules primarily done individually on a smartphone or computer. The final, third phase evaluated the program with a quantitative prospective proof-of-concept, usability, and effectiveness trial among wildland firefighter participants. Effectiveness was assessed with paired 2-tailed t tests for pre- and post-Likert agreement scale survey items, adjusted for multiple comparisons. In addition to assessing mean and SD at baseline and postsurvey, observed effect sizes were calculated (Cohen d). Usability and reaction to the program among firefighters who responded to postsurvey were also assessed. RESULTS: The qualitative themes and subthemes were used to inform the program's content. For the effectiveness trial, 131 firefighters completed the presurvey, and 50 (38.2%) completed the postsurvey. The majority of the participants were White (n=123, 93.9%), male (n=117, 89.3%), with an average age of 41 (SD 12.9) years. Significant increases in knowledge and desired health and safety behaviors were found for both cancer (P<.001) and cardiovascular risk (P=.01), nutrition behaviors (P=.01), hydration or overheating (P=.001), binge drinking (P=.002), and getting medical checkups (P=.001). More than 80% (n=40) of postsurvey respondents agreed or strongly agreed that the program was easy to use and would recommend it to others. CONCLUSIONS: An innovative web-based safety and health promotion program for those fighting wildland fires was feasible, scalable, and usable. It improved the health and safety of those fighting wildland fires. TRIAL REGISTRATION: ClinicalTrials.gov NCT05753358; https://classic.clinicaltrials.gov/ct2/show/NCT05753358.

Changes in hair cortisol concentration in intrauterine device initiators: A prospective cohort study.

OBJECTIVES: Prior studies found increased hair cortisol concentration (a surrogate marker for hypothalamic-pituitary-adrenal axis activation) in users of the levonorgestrel intrauterine device (LNG 52 mg IUD). We evaluated change in hair cortisol and psychometric tests in women initiating a copper (CuT380 IUD) or LNG 52 mg IUD. STUDY DESIGN: We prospectively enrolled healthy women initiating an LNG 52 mg IUD or CuT380 IUD. Participants provided hair and blood samples and completed psychometric inventories (Patient Health Questionnaire-9, Positive and Negative Affect Schedule, and Psychological General Well-Being Index) after IUD insertion and at 6 and 12 months. We used liquid chromatography with tandem mass spectrometry to measure hair cortisol concentrations. We compared hair cortisol concentrations and psychometric test changes from baseline to 6 and 12 months using independent two-sample t tests. RESULTS: We enrolled 39 of our targeted 86 participants (LNG 52 mg IUD 26, CuT380 IUD 13). Thirty-eight subjects (LNG 52 mg IUD 25, CuT380 IUD 13) completed 6 months of follow-up. We found no difference between cohorts in the mean change in hair cortisol concentrations at 6 months (LNG 52 mg IUD n = 21 [-0.01 pg/mg (95% CI -1.26, 1.23); CuT380 IUD n = 13 [-1.31 pg/mg (-3.36, 0.73)]). While psychometric inventory results remained within normal ranges, LNG 52 mg IUD users reported a trend toward more favorable changes over time. CONCLUSIONS: We did not find clinically important differences in hair cortisol concentrations following initiation of a CuT380 IUD or LNG 52 mg IUD; psychometric inventories demonstrated no adverse effect of hormonal IUDs on mood. IMPLICATIONS: Our findings of similar hair cortisol concentrations following the initiation of either the LNG 52 mg IUD or CuT380 IUD suggest that hormonal IUDs do not increase cortisol concentrations or alter stress reactivity, and favorable effects on psychometric inventories provide further reassurance that the LNG 52 mg IUD has no adverse impact on mood. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03499379.

Pancreatic ductal adenocarcinoma induces neural injury that promotes a transcriptomic and functional repair signature by peripheral neuroglia.

Perineural invasion (PNI) is the phenomenon whereby cancer cells invade the space surrounding nerves. PNI occurs frequently in epithelial malignancies, but is especially characteristic of pancreatic ductal adenocarcinoma (PDAC). The presence of PNI portends an increased incidence of local recurrence, metastasis and poorer overall survival. While interactions between tumor cells and nerves have been investigated, the etiology and initiating cues for PNI development is not well understood. Here, we used digital spatial profiling to reveal changes in the transcriptome and to allow for a functional analysis of neural-supportive cell types present within the tumor-nerve microenvironment of PDAC during PNI. We found that hypertrophic tumor-associated nerves within PDAC express transcriptomic signals of nerve damage including programmed cell death, Schwann cell proliferation signaling pathways, as well as macrophage clearance of apoptotic cell debris by phagocytosis. Moreover, we identified that neural hypertrophic regions have increased local neuroglial cell proliferation which was tracked using EdU tumor labeling in KPC mice, as well as frequent TUNEL positivity, suggestive of a high turnover rate. Functional calcium imaging studies using human PDAC organotypic slices confirmed nerve bundles had neuronal activity, as well as contained NGFR+ cells with high sustained calcium levels, which are indicative of apoptosis. This study reveals a common gene expression pattern that characterizes solid tumor-induced damage to local nerves. These data provide new insights into the pathobiology of the tumor-nerve microenvironment during PDAC as well as other gastrointestinal cancers.

Ultrasonographic evaluation of endometrial stripe thickness is insufficient to rule out uterine serous carcinoma.

PURPOSE: Uterine serous carcinoma (USC) is a rare endometrial cancer representing less than 10% of uterine cancers but contributing to up to 50% of the mortality. Delay in diagnosis with this high-grade histology can have significant clinical impact. USC is known to arise in a background of endometrial atrophy. We investigated endometrial stripe (EMS) thickness in USC to evaluate current guidelines for postmenopausal bleeding in the context of this histology. METHODS: Retrospective chart review was conducted using ICD-9 and ICD-10 codes over an 18-year period. We included 139 patients with USC and compared characteristics of patients with EMS ≤ 4 mm and EMS > 4 mm. Chi-square or Fisher's exact tests were used to compare proportions and two-tailed t-tests to compare means. A p-value of < 0.05 was considered statistically significant. RESULTS: Most patients were white, obese, and multiparous. Thirty-two (23%) had an EMS ≤ 4 mm; 107 (77%) had an EMS > 4 mm. There were no statistically significant differences in age at diagnosis or presenting symptoms between groups, and postmenopausal bleeding was the most common symptom in each group. CONCLUSION: Nearly 25% of patients with USC initially evaluated with transvaginal ultrasound were found to have an EMS ≤ 4 mm. If transvaginal ultrasound is used to triage these patients, one in four women will potentially experience a delay in diagnosis that may impact their prognosis.

Adverse Perinatal and Neonatal Outcomes among Adolescent Pregnancies in the United States.

OBJECTIVE: Despite a downward trend in recent years, adolescent pregnancies in the United States remain higher than any other western country. Adolescent pregnancies have been inconsistently associated with adverse perinatal outcomes. The objective of this study is to investigate the association between adolescent pregnancies and adverse perinatal and neonatal outcomes in the United States. STUDY DESIGN: This is a retrospective cohort study of singleton births in the United States from 2014 to 2020 using national vital statistics data. Perinatal outcomes included gestational diabetes, gestational hypertension, preterm delivery <37 weeks (preterm birth [PTB]), cesarean delivery (CD), chorioamnionitis, small for gestational age (SGA), large for gestational age (LGA), and neonatal composite outcome. Chi-square tests were used to compare outcomes among adolescent (13-19 years) versus adult (20-29 years) pregnancies. Multivariable logistic regression models were used to examine association of adolescent pregnancies with perinatal outcomes. For each outcome, we utilized three models: unadjusted logistic regression, adjusted for demographics, and adjusted for demographics and medical comorbidities. Similar analyses were used to compare younger (13-17 years) and older (18-19 years) adolescent pregnancies to adults. RESULTS: In a cohort of 14,014,078 pregnancies, we found that adolescents were at an increased risk of PTB (adjusted odds ratio [aOR]: 1.12, 99% confidence interval (CI): 1.12-1.13) and SGA (aOR: 1.02, 99% CI: 1.01-1.03) compared with adult pregnancies. We also found that multiparous adolescents with a prior history of CD were at an increased risk of CD, compared with adults. For all other outcomes, adult pregnancies were at higher risk for adverse outcomes in the adjusted models. When comparing birth outcomes among adolescents, we found that older adolescents are at an increased risk of PTB, whereas younger adolescents are at an increased risk of both PTB and SGA. CONCLUSION: After adjusting for confounders, our study demonstrates adolescents have an increased risk of PTB and SGA, compared with adults. KEY POINTS: · Adolescents as a whole subgroup have an increased risk of PTB and SGA compared with adults.. · Younger adolescents have a risk of PTB and SGA, whereas older adolescents have a risk of PTB only.. · Adverse birth outcomes in adults are gestational diabetes, chorioamnionitis, LGA, and worse neonatal composite score..

Impact of Prenatal Cannabis Use Disorder on Perinatal Outcomes.

OBJECTIVES: With legislative changes to cannabis legalization and increasing prevalence of use, cannabis is the most commonly used federally illicit drug in pregnancy. Our study aims to assess the perinatal outcomes associated with prenatal cannabis use disorder. METHODS: We conducted a retrospective cohort study using California linked hospital discharge-vital statistics data and included singleton, nonanomalous births occurring between 23 and 42 weeks of gestational age. χ 2 Test and multivariable logistic regression were used for statistical analyses. RESULTS: A total of 2,380,446 patients were included, and 9144 (0.38%) were identified as using cannabis during pregnancy. There was a significantly increased risk for adverse birthing person outcomes, including gestational hypertension (adjusted odds ratio [AOR], 1.19; 95% confidence interval [CI], 1.06-1.34; P = 0.004), preeclampsia (AOR, 1.16; 95% CI, 1.0-1.28; P = 0.006), preterm delivery (AOR, 1.45; 95% CI, 1.35-1.55; P < 0.001), and severe maternal morbidity (AOR, 1.22; 95% CI, 1.02-1.47; P = 0.033). Prenatal cannabis use disorder was also associated with an increased risk of neonatal outcomes including respiratory distress syndrome (AOR, 1.16; 95% CI, 1.07-1.27; P < 0.001), small for gestational age (AOR, 1.47; 95% CI, 1.38-1.56; P < 0.001), neonatal intensive care unit admission (AOR, 1.24; 95% CI, 1.16-1.33; P < 0.001), and infant death (AOR, 1.86; 95% CI, 1.44-2.41; P < 0.001). There was no statistically significant difference in stillbirth (AOR, 0.96; 95% CI, 0.69-1.34; P = 0.80) and hypoglycemia (AOR, 1.22; 95% CI, 1.00-1.49; P = 0.045). CONCLUSIONS: Our study suggests that prenatal cannabis use disorder is associated with increased maternal and neonatal morbidity and mortality. As cannabis use disorder in pregnancy is becoming more prevalent, our findings can help guide preconception and prenatal counseling.

Interpregnancy Interval After Stillbirth and Adverse Perinatal Outcomes.

We used a retrospective cohort of 5,581 individuals to examine the association between interpregnancy interval (IPI) after stillbirth and pregnancy outcomes of preterm birth, preeclampsia, small for gestational age, recurrent stillbirth, infant death, and neonatal intensive care unit admission in the subsequent pregnancy. The IPI was divided in six categories, with 18-23 months as referent. Association between IPI category and adverse outcomes was determined with logistic regression models adjusted for maternal race and ethnicity, age, education, insurance, and gestational age at preceding stillbirth. Adverse perinatal outcome was common in pregnancies after stillbirth, with 26.7% of individuals delivering preterm. None of the IPI categories were associated with increased risk of adverse perinatal outcomes, including the shortest category (IPI less than 3 months). This finding is meaningful for bereaved parents who desire to conceive shortly after stillbirth.