Uterine fibroid (UF) driver mutations in Mediator complex subunit 12 (MED12) trigger genomic instability and tumor development through unknown mechanisms. Herein, we show that MED12 mutations trigger aberrant R-loop-induced replication stress, suggesting a possible route to genomic instability and a novel therapeutic vulnerability in this dominant UF subclass. Immunohistochemical analyses of patient-matched tissue samples revealed that MED12 mutation-positive UFs, compared to MED12 mutation-negative UFs and myometrium, exhibited significantly higher levels of R-loops and activated markers of Ataxia Telangiectasia and Rad3-related (ATR) kinase-dependent replication stress signaling in situ. Single molecule DNA fiber analysis revealed that primary cells from MED12 mutation-positive UFs, compared to those from patient-matched MED12 mutation-negative UFs and myometrium, exhibited defects in replication fork dynamics, including reduced fork speeds, increased and decreased numbers of stalled and restarted forks, respectively, and increased asymmetrical bidirectional forks. Notably, these phenotypes were recapitulated and functionally linked in cultured uterine smooth muscle cells following chemical inhibition of Mediator-associated CDK8/19 kinase activity that is known to be disrupted by UF driver mutations in MED12. Thus, Mediator kinase inhibition triggered enhanced R-loop formation and replication stress leading to an S-phase cell cycle delay, phenotypes that were rescued by overexpression of the R-loop resolving enzyme RNaseH. Altogether, these findings reveal MED12-mutant UFs to be uniquely characterized by aberrant R-loop induced replication stress, suggesting a possible basis for genomic instability and new avenues for therapeutic intervention that involve the replication stress phenotype in this dominant UF subtype.
OBJECTIVE: To assess the change in competitiveness of obstetrics and gynecology programs over 20 years using a normalized competitive index. METHODS: Obstetrics and gynecology match data were obtained from the National Resident Matching Program (NRMP) for 2003–2022. Applicant metrics (United States Medical Licensing Examination scores, score percentiles, research output and experiences, and work and volunteer experiences) were obtained from the NRMP and the Association of American Medical Colleges (2007–2021). The competitive index was calculated using the number of positions available divided by match rate each year between 2003 and 2022. The normalized competitive index was calculated by dividing the yearly competitive index by the average competitive index over 20 years. Data were analyzed using univariate analysis and linear regressions. RESULTS: When comparing the two decades (2003–2012 vs 2013–2022), applicants (1,539±242 vs 1,902±144; P<.001), positions (1,173±31 vs 1,345±98; P<.001), and number of programs ranked per applicant (13±1.4 vs 15±0.6; P<.001) have increased. While the match rate did not significantly change from 2003 to 2022 (75.5%±9.9% vs 70.5%±1.6%; P=.14), the normalized competitive index increased (R2=0.92, P<.001), indicating increased competitiveness. Applicant metrics increased over time, including research output (2.4±0.8 vs 5.0±0.7; P=.002) and work experiences (2.9±0.2 vs 3.6±0.1; P=.002; R2=0.98, P<.001). CONCLUSION: Despite an increase in obstetrics and gynecology applicants and applicant metrics, match rates remain unchanged. However, the competitiveness of programs has significantly increased, as demonstrated by the normalized competitive index, applicants per position, and applicant metrics. The normalized competitive index is a useful metric for applicants to determine program or applicant competitiveness, especially when used alongside applicant metrics.
INTRODUCTION: Management of endometriosis is complex and varies among providers. This study investigates patterns in the management of endometriosis among Obstetrics and Gynecology physicians in the United States. METHODS: The Institutional Review Board reviewed and approved this study. A national online survey was sent to 5000 members of the American College of Obstetrics and Gynecology. It included 22 questions designed to assess the medical, surgical, and pain management of endometriosis. Variations in management were assessed using Fisher exact test and Mann-Whitney test. RESULTS: The adjusted response rate was 24.5%. The most common initial treatment for pelvic pain and suspected endometriosis was continuous combined oral contraceptives (COCs) (58%). When medical management fails, 52% of respondents opt for surgical management; 45% of respondents treat with excision while 42% treat with cautery ablation. Most indicated they offer postoperative hormone suppression, including continuous COCs (45%) or gonadotropin-releasing hormone agonists with add-back therapy (27%). The majority prescribe nonsteroidal anti-inflammatory drugs to treat endometriosis-related pain while a minority opt for alternative treatments such as opioids, acupuncture, and psychological support. 82% of physicians believe there is a need for women with endometriosis to have psychosocial care; however, only 15% routinely refer patients for psychological counseling. Importantly, 72% of respondents indicated they do not feel adequately trained to provide care for psychosocial aspects of endometriosis. CONCLUSION: The majority of responding providers are practicing evidence-based care for the treatment of endometriosis. Although most physicians recognize the need for a multidisciplinary approach to the treatment of endometriosis-related pain, only a minority recommend alternative treatments.
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