Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs.

For infants at low risk for development of food allergies, providers should advise caregivers to introduce potentially allergenic foods with other solid foods between 4 and 6 months of age when children show an interest in eating solids. Infants at high risk for peanut allergy, should be evaluated by an allergy specialist prior to introduction of peanuts and work with providers to create an individualized plan for introduction of peanuts and other allergenic foods as needed.

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Objective: To determine whether there is a relationship between prewash total motile count and live births in couples undergoing IUI. Design: Retrospective review in a single academic center. Setting: Not applicable. Patient(s): Couples with infertility undergoing ovulation induction with IUI between 2010 and 2014. Intervention(s): Not applicable. Main Outcome Measure(s): Live births. Result(s): Our cohort included 310 women who underwent 655 IUI cycles with a cumulative live birth rate (LBR) per couple of 20% and an LBR per cycle of 10%. A analysis yielded no correlation between prewash total motile count (TMC) and live births. No live births occurred with TMC <2 million sperms. Age had a significant negative relationship to LBR. A receiver operating characteristic analysis comparing age and live births indicated a significant decline in live births for women >37 years (90% sensitivity, 70% specificity). The LBR per couple was decreased to 7% in women >37 years compared with 25% in women <37 years. Conclusion(s): Prewash TMC is a poor predictor of live birth. There were no live births with prewash TMC <2 million sperms. The LBR for women >37 years with IUI was significantly lower than women <37 years. (Fertil Steril Ò 2019;111:708-13. Ó2019 by American Society for Reproductive Medicine.) El resumen está disponible en Español al final del artículo.

Purpose The number of in vitro fertilization (IVF) cycles is increasing and the majority of patients undergoing IVF pay out of pocket. Reproductive endocrinology and infertility practitioners employ different business models to help create financial pathways for patients needing IVF but details regarding the different types of business models being used and physician satisfaction with those models have not been described previously. Methods A cross-sectional survey was sent to members of the Society of Reproductive Endocrinology and Infertility. The survey included 30 questions designed to assess demographics, practice patterns, and business models utilized. Results A total of 222/736 (30%) physicians responded to the survey. The majority of physicians offer a-la-carte (67%), bundled services (69%), grants (57%), and cost/risk-sharing (50%). The majority answered that the single ideal business model is bundled services (53%). There was no significant association between financial package offered and region of practice or state-mandated insurance. The largest barrier to care reported was cost with or without state-mandated coverage (94% and 99%, respectively). The majority of practices are satisfied with their business model (75%). Higher physician satisfaction was associated with private practice [69% vs 27%; OR (95%CI) = 3.8 (1.7, 8.6)], male gender [59% vs 30%; OR = 2.4 (1.1, 5.4)], and offering bundled services [83% vs 59%; OR = 2.8 (1.2, 6.7)]. Conclusions Physicians utilize a variety of business models and most are satisfied with their current model. Cost is the major barrier to care in states with and without mandated coverage.