Racial Disparities in Surgical Treatment of Uterine Fibroids During the COVID-19 Pandemic.

Objective: Analyze the association between race and surgery performed for uterine fibroids during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Retrospective exploratory cross-sectional study of patients with fibroids who underwent surgery during the COVID-19 pandemic. We compared the type of surgery performed (minimally invasive hysterectomy [MIH], uterine-sparing procedure [USP], or total abdominal hysterectomy [TAH]) by White versus non-White patients. Absolute percentage differences were estimated with multinomial logistic regression adjusting for age, body mass index (BMI), parity, comorbidities, and maximum fibroid diameter. Results: Of 350 subjects, the racial composition was 1.7% Asian, 23.4% Black, and 74.9% White. Non-White patients had greater fibroid burden by mean maximum fibroid diameter, mean uterine weight, and mean fibroid weight. Although MIH occurred more frequently among White patients (7.5% points higher [95% confidence interval (CI) = -3.1 to 18.2]), USP and TAH were more commonly conducted for non-White patients (3.4% points higher [95% CI = -10.4 to 3.6] and 4.2% points higher [95% CI = -13.2 to 4.8], respectively). The overall complication rate was 18.6%, which was 6% points lower (95% CI = -15.8 to 3.7) among White patients. Conclusion: During the COVID-19 pandemic at a single-site institution, non-White patients were more likely to undergo a uterine-sparing procedure for surgical treatment of uterine fibroids, abdominal procedures, including both hysterectomy and myomectomy, and experience surgery-related complications.

Loss of mTORC1 signalling impairs ß-cell homeostasis and insulin processing.

Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that ß-cell-specific loss of mTORC1 causes diabetes and ß-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (ßraKO) and inducible (MIP-ßraKOf/f) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates ß-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates ß-cell proliferation. Restoration of both pathways partially recovers ß-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in ß-cells and identify downstream pathways driving ß-cell mass, function and insulin processing.

4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls ß-Cell Mass.

The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and ß-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and ß-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of ß-cells.