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    Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer
    (Springer Nature, 2023) Mondal, Tanmoy; Gaur, Himanshu; Wamba, Brice E. N.; Michalak, Abby Grace; Stout, Camryn; Watson, Matthew R.; Aleixo, Sophia L.; Singh, Arjun; Condello, Salvatore; Faller, Roland; Leiserowitz, Gary Scott; Bhatnagar, Sanchita; Tushir-Singh, Jogender; Obstetrics and Gynecology, School of Medicine
    Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.
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    The Present and the Future of Medical Therapies for Adenomyosis: A Narrative Review
    (MDPI, 2023-09-22) Moawad, Gaby; Youssef, Youssef; Fruscalzo, Arrigo; Faysal, Hani; Kheil, Mira; Pirtea, Paul; Guani, Benedetta; Ayoubi, Jean Marc; Feki, Anis; Obstetrics and Gynecology, School of Medicine
    Uterine Adenomyosis is a benign condition characterized by the presence of endometrium-like epithelial and stromal tissue in the myometrium. Several medical treatments have been proposed, but still, no guidelines directing the management of adenomyosis are available. While a hysterectomy is typically regarded as the definitive treatment for adenomyosis, the scarcity of high-quality data leaves patients desiring fertility with limited conservative options. Based on the available data, the levonorgestrel-IUD appears to offer the most favorable outcomes. Other treatments, including GnRH antagonists, dienogest, prolactin, and oxytocin modulators, show promise; however, further data are required to establish their efficacy definitively. Furthermore, there are many emerging therapies that have been developed that seem worthy of consideration in the near future. The aim of this narrative review was to explore the current medical treatments available for adenomyosis and to provide a glimpse of future therapies under assessment. For this scope, we performed a literature search on PubMed and Medline from incept to September 2022 using the keywords: “medical treatment”, “non-steroidal anti-inflammatory”, “progesterone intrauterine device”, “dienogest”, “combined oral contraceptives”, “gonadotropin releasing hormone agonist”, “gonadotropin releasing hormone antagonist”, “danazol”, “aromatase inhibitors”, “ulipristal acetate”, “anti-platelet therapy”, “dopamine”, “oxytocin antagonists”, “STAT3”, “KRAS”, “MAPK”, “micro-RNA”, “mifepristone”, “valproic acid”, “levo-tetrahydropalamatine”, and “andrographolide”. The search was limited to articles in English, with subsequent screening of abstracts. Abstracts were screened to select relevant studies.
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    Objectively assessed sleep-disordered breathing during pregnancy and infant birthweight
    (Elsevier, 2021) Hawkins, Marquis; Parker, Corette B.; Redline, Susan; Larkin, Jacob C.; Zee, Phyllis P.; Grobman, William A.; Silver, Robert M.; Louis, Judette M.; Pien, Grace; Basner, Robert C.; Chung, Judith H.; Haas, David M.; Nhan-Chang, Chia-Ling; Simhan, Hyagriv N.; Blue, Nathan R.; Parry, Samuel; Reddy, Uma; Facco, Francesca; NICHD NuMoM2b; NHLBI NuMoM2b Heart Health Study Networks; Obstetrics and Gynecology, School of Medicine
    Background: Sleep-disordered breathing (SDB) in pregnancy is associated with adverse maternal outcomes. The relationship between SDB and infant birthweight is unclear. This study's primary aim is to determine if objectively measured SDB in pregnancy is associated with infant birthweight. Methods: We measured SDB objectively in early (6-15 weeks' gestation) and mid (22-31 weeks' gestation) pregnancy in a large cohort of nulliparous women. SDB was defined as an Apnea-Hypopnea Index ≥5 and in secondary analyses we also examined measures of nocturnal hypoxemia. We used a modified Poisson regression approach to estimate relative risks (RR) of large-for-gestational-age (LGA: >90th percentile for gestational age) and small-for-gestational-age (SGA: <10th percentile for gestational age) birthweights. Results: The prevalence of early-pregnancy SDB was nearly 4%. The incidence of mid-pregnancy SDB was nearly 6.0%. The prevalence of LGA and SGA was 7.4% and 11.9%, respectively. Early-pregnancy SDB was associated with a higher risk of LGA in unadjusted models (RR 2.2, 95% CI 1.3-3.5) but not BMI-adjusted models (aRR 1.0, 95% CI 0.6-1.8). Mid-pregnancy SDB was not associated with SGA or LGA. Mid-pregnancy nocturnal hypoxemia (% of sleep time <90% oxygen saturation) and increasing nocturnal hypoxemia from early to mid-pregnancy were associated with a higher risk of LGA in BMI-adjusted models. SDB and nocturnal hypoxemia were not associated with SGA. Conclusions: SDB in pregnancy was not associated with an increased risk of LGA or SGA birthweight, independent of BMI. Some measures nocturnal hypoxemia were associated with an increase in LGA risk, independent of BMI.
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    Incremental Propensity Score Effects for Time-Fixed Exposures
    (Wolters Kluwer, 2021) Naimi, Ashley I.; Rudolph, Jacqueline E.; Kennedy, Edward H.; Cartus, Abigail; Kirkpatrick, Sharon I.; Haas, David M.; Simhan, Hyagriv; Bodnar, Lisa M.; Obstetrics and Gynecology, School of Medicine
    When causal inference is of primary interest, a range of target parameters can be chosen to define the causal effect of interest, such as average treatment effects (ATEs). However, ATEs may not always align with the research question at hand. Furthermore, the assumptions needed to interpret estimates as ATEs, such as exchangeability, consistency, and positivity, are often not met. Here, we present the incremental propensity score (incremental PS) approach to quantify the effect of shifting each person’s exposure propensity by some pre-determined amount. Compared to the ATE, incremental PS may better reflect the impact of certain policy interventions, and do not require that positivity hold. Using the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b), we quantified the relation between total vegetable intake and the risk of preeclampsia, and compared it to average treatment effect estimates. The ATE estimates suggested a reduction of between two and three preeclampsia cases per 100 pregnancies for consuming at least 1/2 a cup of vegetables per 1,000 kcal. However, positivity violations obfuscate the interpretation of these results. In contrast, shifting each woman’s exposure propensity by odds ratios ranging from 0.20 to 5.0 yielded no difference in the risk of preeclampsia. Our analyses show the utility of the incremental propensity score effects in addressing public health questions with fewer assumptions.
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    Remote Monitoring Compared With In-Office Surveillance of Blood Pressure in Patients With Pregnancy-Related Hypertension: A Randomized Controlled Trial
    (Wolters Kluwer, 2023) Arkerson, Brittany J.; Finneran, Matthew M.; Harris, Solita R.; Schnorr, Jessica; McElwee, Eliza R.; Demosthenes, Lauren; Sawyer, Renata; Obstetrics and Gynecology, School of Medicine
    Objective: To compare the rate of blood pressure ascertainment within 10 days of postpartum discharge among individuals with hypertensive disorders of pregnancy randomized either to in-office blood pressure assessment or at-home monitoring. Methods: This was a multisite randomized controlled trial of postpartum patients diagnosed with a hypertensive disorder of pregnancy before discharge between April 2021 and September 2021 and was performed at two academic training institutions. Patients were randomized to either an in-office blood pressure check or remote monitoring through a web-enabled smartphone platform. The primary outcome was the rate of any blood pressure ascertainment within 10 days of discharge. Secondary outcomes include rates of initiation of antihypertensive medication, readmission, and additional office or triage visits for hypertension. Assuming a 10-day postdischarge blood pressure ascertainment rate of 50% in the in-office arm, we estimated that 186 participants would provide 80% power to detect a 20% difference in the primary outcome between groups. Results: One hundred ninety-seven patients were randomized (96 remote, 101 in-office). Patients with remote monitoring had higher rates of postpartum blood pressure ascertainment compared with in-office surveillance (91.7% [n=88] vs 58.4% [n=59]; P<.001). There were 11 (11.5%) patients in the intervention arm whose only qualifying blood pressure was a postdischarge in-person ascertainment, yielding a true remote monitoring uptake rate of 80.2%. In those with remote blood pressure uptake (n=77), the median number of blood pressure checks was 15 (interquartile range 6-26) and the median duration of remote monitoring use was 14 days (interquartile range 9-16). There were no differences in rates of readmission for hypertension (5.0% [n=5] vs 4.2% [n=4], P=.792) or initiation of antihypertensive medications after discharge (9.4% [n=9] vs 6.9% [n=7], P=.530). Rates of unscheduled visits were increased in the remote monitoring arm, but this did not reach statistical significance (5.0% [n=5] vs 12.5% [n=12], P=.059). When stratifying the primary outcome by race and randomization group, Black patients had lower rates of blood pressure ascertainment than White patients when assigned to in-office surveillance (41.2% [n=14] vs 69.5% [n=41], P=.007), but there was no difference in the remote management group (92.9% [n=26] vs 92.9% [n=52], P>.99). Conclusion: Remote monitoring can increase postpartum blood pressure ascertainment within 10 days of discharge for women with hypertensive disorders of pregnancy and has the potential to promote health equity.
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    Extract of Artemisia dracunculus L. Modulates Osteoblast Proliferation and Mineralization
    (MDPI, 2023-08-30) Scott, Matthew C.; Bourgeois, Aleah; Yu, Yongmei; Burk, David H.; Smith, Brenda J.; Floyd, Z. Elizabeth; Obstetrics and Gynecology, School of Medicine
    Thiazolidinediones (TZD) significantly improve insulin sensitivity via action on adipocytes. Unfortunately, TZDs also degrade bone by inhibiting osteoblasts. An extract of Artemisia dracunculus L., termed PMI5011, improves blood glucose and insulin sensitivity via skeletal muscle, rather than fat, and may therefore spare bone. Here, we examine the effects of PMI5011 and an identified active compound within PMI5011 (2′,4′-dihydroxy-4-methoxydihydrochalcone, DMC-2) on pre-osteoblasts. We hypothesized that PMI5011 and DMC-2 will not inhibit osteogenesis. To test our hypothesis, MC3T3-E1 cells were induced in osteogenic media with and without PMI5011 or DMC-2. Cell lysates were probed for osteogenic gene expression and protein content and were stained for osteogenic endpoints. Neither compound had an effect on early stain outcomes for alkaline phosphatase or collagen. Contrary to our hypothesis, PMI5011 at 30 µg/mL significantly increases osteogenic gene expression as early as day 1. Further, osteogenic proteins and cell culture mineralization trend higher for PMI5011-treated wells. Treatment with DMC-2 at 1 µg/mL similarly increased osteogenic gene expression and significantly increased mineralization, although protein content did not trend higher. Our data suggest that PMI5011 and DMC-2 have the potential to promote bone health via improved osteoblast maturation and activity.
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    Risks of Uterine Perforation and Expulsion Associated With Intrauterine Devices
    (Wolters Kluwer, 2023) Fassett, Michael J.; Reed, Susan D.; Rothman, Kenneth J.; Pisa, Federica; Schoendorf, Juliane; Wahdan, Yesmean; Peipert, Jeffrey F.; Gatz, Jennifer; Ritchey, Mary E.; Armstrong, Mary Anne; Raine-Bennett, Tina; Postlethwaite, Debbie; Getahun, Darios; Shi, Jiaxiao M.; Xie, Fagen; Chiu, Vicki Y.; Im, Theresa M.; Takhar, Harpreet S.; Wang, Jinyi; Anthony, Mary S.; Obstetrics and Gynecology, School of Medicine
    Objective: The APEX-IUD (Association of Perforation and Expulsion of Intrauterine Devices) study evaluated the association of postpartum timing of intrauterine device (IUD) insertion, breastfeeding, heavy menstrual bleeding, and IUD type (levonorgestrel-releasing vs copper) with risks of uterine perforation and IUD expulsion in usual clinical practice. We summarize the clinically important findings to inform counseling and shared decision making. Methods: APEX-IUD was a real-world (using U.S. health care data) retrospective cohort study of individuals aged 50 years and younger with IUD insertions between 2001 and 2018 and with electronic health record data. Cumulative incidences of uterine perforation and IUD expulsion were calculated. Adjusted hazard ratios (aHRs) and 95% CIs were estimated from proportional hazards models with control of confounding. Results: Among the study population of 326,658, absolute risk of uterine perforation was low overall (cumulative incidence, 0.21% [95% CI 0.19-0.23%] at 1 year and 0.61% [95% CI 0.56-0.66% at 5 years]) but was elevated for IUDs inserted during time intervals within 1 year postpartum, particularly among those between 4 days and 6 weeks postpartum (aHR 6.71, 95% CI 4.80-9.38), relative to nonpostpartum insertions. Among postpartum insertions, IUD expulsion risk was greatest for insertions in the immediate postpartum period (0-3 days after delivery) compared with nonpostpartum (aHR 5.34, 95% CI 4.47-6.39). Postpartum individuals who were breastfeeding had a slightly elevated risk of perforation and lowered risk of expulsion than those not breastfeeding. Among nonpostpartum individuals, those with a heavy menstrual bleeding diagnosis were at greater risk of expulsion than those without (aHR 2.84, 95% CI 2.66-3.03); heavy menstrual bleeding also was associated with a slightly elevated perforation risk. There was a slightly elevated perforation risk and slightly lower expulsion risk associated with levonorgestrel-releasing IUDs compared with copper IUDs. Conclusion: Absolute risk of adverse outcomes with IUD insertion is low. Clinicians should be aware of the differences in risks of uterine perforation and expulsion associated with IUD insertion during specific postpartum time periods and with a heavy menstrual bleeding diagnosis. This information should be incorporated into counseling and decision making for patients considering IUD insertion.
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    Integration of ultrasound simulation to improve medical student knowledge and satisfaction on the obstetrics and gynecology clerkship
    (Elsevier, 2023-06-12) Shanks, Anthony; Darwish, Adrianna; Cook, Myanna; Asencio, Ivana; Rouse, Carrie; Obstetrics and Gynecology, School of Medicine
    Background: There has been increased use of ultrasound in contemporary medical education. Students tend to report a higher sense of satisfaction when ultrasound is incorporated into medical education, but little is known about whether its use leads to an improvement in medical knowledge acquisition independent of the ultrasound skill. In addition, there is no consensus among obstetrics and gynecology clerkships on the most effective way to incorporate ultrasound into the clerkship curriculum. Objective: This project described a method to integrate ultrasound simulation into an obstetrics and gynecology clerkship curriculum. Our hypothesis was that the incorporation of ultrasound simulation in the obstetrics and gynecology clerkship curriculum will lead to an increase in standardized assessments of obstetrics and gynecology knowledge. Study design: A prepost study at a single institution with multiple methods design was employed. Of note, 10 high-yield pathology topics commonly tested on the Association of Professors of Gynecology and Obstetrics quizzes and National Board of Medical Examiners examinations were summarized into study sheets and associated with a representative ultrasound simulation module. All students were provided access to the summary sheets. Students with instruction in ultrasound simulation consisted of the postintervention group and were compared with students that did not have ultrasound simulation (preintervention group). Quiz and examination scores were compared between the groups. In addition, students who accessed the ultrasound simulator were given a survey at the end of their rotation to obtain qualitative information regarding satisfaction and the incorporation of ultrasound into the clerkship curriculum. Results: There was no significant difference in quiz or examination scores between students who had access to the ultrasound simulation and those who did not. Most students found the integration of ultrasound simulation into the obstetrics and gynecology clerkship to be beneficial, to enhance their learning, to boost their confidence in ultrasound skills, and to be a potential substitute for clinical ultrasounds during the rotation. Conclusion: Integration of ultrasound simulation into obstetrics and gynecology clerkships and medical school education is understudied but can be a valuable educational tool. The incorporation of ultrasound into the medical education system is a topic of current studies. This study found that integration was viewed favorably by students, although integration was not associated with an improvement in medical knowledge measured via quiz and examination performance. Our research provided students with a standardized ultrasound education experience, which improved student satisfaction with the obstetrics and gynecology clerkship but did not correlate to increased demonstrated medical knowledge and understanding of examinations. Moving forward, student participants provided various suggestions on how we can continue to enrich medical students' education with the implementation of ultrasound.
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    Using nominal group technique to determine skills that applied improvisation can teach health profession education learners
    (Elsevier, 2023-07-25) Chan, Carolyn A.; Chou, Erica; Graff LaDisa, Anne; Mehta, Ankit; Zelenski, Amy; Longtin, Krista; Obstetrics and Gynecology, School of Medicine
    Objective: Applied improvisation (AI) is an approach used in health professions (HP) education to teach skills essential for clinical practice such as communication, teamwork, and empathy. Little is known about which skills can be developed using AI, or those which an AI should prioritize. Our research aims to identify skills essential to include in an AI curriculum for HP learners. Methods: A modified nominal group technique (NGT) was conducted to identify and prioritize specific skills which can be taught using AI. This involved silent generation of ideas, round robin, discussions, 2-rounds of preliminary voting, and a final ranking survey to determine a prioritized list of skills to include in an AI curriculum for HP learners. Results: Six content experts participated in the NGT meeting. Initially, 83 skills were identified, and through NGT, a final list of 11 skills essential to an AI curriculum were determined including: adaptability, affirmation of others, acceptance, active listening, being present, cooperation, collaboration with other, advancement, compassionate communication, sharpened non-verbal communication, resilience. Conclusion: Essential skills for an AI curriculum relate to adaptability, attunement, collaboration, affirmation, and advancement. Innovation: This study is a novel application of NGT as a strategy to organize an approach to curriculum innovations.
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    Impact of an Online Question Bank on Resident In-Training Exam Performance
    (Sage, 2023-10-09) Scott, Nicole P.; Martin, Terrell W.; Schmidt, Alison M.; Shanks, Anthony L.; Obstetrics and Gynecology, School of Medicine
    OBJECTIVE In-training exams (ITEs) are administered annually to Obstetrics and Gynecology (OBGYN) residents and have been demonstrated to correlate with success on licensing examinations. Our study objective was to determine the impact of a question bank and mock exam on the performance of Council on Resident Education in Obstetrics and Gynecology (CREOG) ITEs. Secondarily, we investigated the correlation between the extent of question bank usage and performance on the exam. METHODS Pre–post intervention study of resident performance on CREOG ITE before and after implementation of the question bank and mock ITE at Indiana University in 2018. Performance was measured as year-to-year improvement in percent correct on ITE exams. Scores were excluded if a resident did not have a prequestion bank score report or if they did not sit for all eligible ITE exams. RESULTS There were 51 OBGYN residents at Indiana University during the study period, with 38 available for analysis (75%). Before implementation, average year-to-year improvement for PGY1-2, PGY2-3 and PGY3-4 classes were 0.60%, 1.0% and −1.6%, respectively. After implementation, all resident classes had significant improvements in ITE scores of 6.6% (P < .01), 9.0% (P < .01), and 7.2% (P < .01), respectively. There was a moderate program-wide correlation between the number of questions completed and the percent improvement on the ITE of R = 0.36 (P = .046). CONCLUSIONS Our study demonstrated that access to a question bank and mock ITE significantly improved CREOG ITE performance of OBGYN residents at Indiana University.