Realization of the T Lineage Program Involves GATA-3 Induction of Bcl11b and Repression of Cdkn2b Expression.

The zinc-finger transcription factor GATA-3 plays a crucial role during early T cell development and also dictates later T cell differentiation outcomes. However, its role and collaboration with the Notch signaling pathway in the induction of T lineage specification and commitment have not been fully elucidated. We show that GATA-3 deficiency in mouse hematopoietic progenitors results in an early block in T cell development despite the presence of Notch signals, with a failure to upregulate Bcl11b expression, leading to a diversion along a myeloid, but not a B cell, lineage fate. GATA-3 deficiency in the presence of Notch signaling results in the apoptosis of early T lineage cells, as seen with inhibition of CDK4/6 (cyclin-dependent kinases 4 and 6) function, and dysregulated cyclin-dependent kinase inhibitor 2b (Cdkn2b) expression. We also show that GATA-3 induces Bcl11b, and together with Bcl11b represses Cdkn2b expression; however, loss of Cdkn2b failed to rescue the developmental block of GATA-3-deficient T cell progenitor. Our findings provide a signaling and transcriptional network by which the T lineage program in response to Notch signals is realized.

Operative Time and Accrual of Postoperative Complications in Minimally Invasive Versus Open Myomectomy.

STUDY OBJECTIVE: To compare the prevalence and accrual of 30-day postoperative complications by operative time for open myomectomy (OM) and minimally invasive myomectomy (MIM). DESIGN: Retrospective cohort study SETTING: Hospitals participating in the National Surgical Quality Improvement Program database from January 2015 to December 2021. PATIENTS: Female patients aged ≥18 years undergoing OM or MIM. INTERVENTIONS: Patients were categorized into OM and MIM cohorts. Covariates associated with operative time and composite complications were identified using general linear model and chi-square or Fisher's exact test as appropriate. Adjusted spline regression was performed as a test of linearity between operative time and composite complications. Adjusted risk ratios of 30-day postoperative individual, minor, major, and composite complications by 60-minute operative time increments were estimated using Poisson regression with robust error variance. MEASUREMENTS AND MAIN RESULTS: Of 27 728 patients, 11 071 underwent MIM and 16 657 underwent OM. Mean operative times (SD) were 164.6 (82.0) for MIM and 129.2 (67.0) for OM. Raw composite complication rates were 5.5% for MIM and 15.8% for OM. Adjusted spline regression demonstrated linearity between operative time and relative risk of composite postoperative complications for both MIM and OM. MIM had higher adjusted relative risk (aRR, 95% CI) compared to OM of blood transfusion (1.55, 1.45-1.64 versus 1.29, 1.25-1.34), overall minor complications (1.13, 1.03-1.23 versus 1.01, 0.92-1.10), and overall major complications (1.43, 1.35-1.51 versus 1.27, 1.12-1.32). Operative time had greater impact on risk of composite complications for MIM than OM, reaching aRR 2.0 at 296 minutes versus 461 minutes for OM. CONCLUSION: OM has a higher overall rate of composite, minor, and major complications compared to MIM. While operative time is independently and linearly associated with postoperative complications with myomectomy regardless of approach, optimizing surgical efficiency for MIM may be more critical than for OM.

Safety of Same-Day Discharge Versus Hospital Admission in Minimally Invasive Myomectomy.

STUDY OBJECTIVE: To compare postoperative complication rates between same-day discharge patients and patients admitted to hospital after minimally invasive myomectomy, stratified by patient demographics and perioperative variables including myoma burden. DESIGN: Retrospective cohort study. Setting Hospitals participating in the National Surgical Quality Improvement Program database from January 2015 to December 2019. PATIENTS: Female patients aged ≥18 years undergoing minimally invasive myomectomy. INTERVENTIONS: Patients were categorized into either the same-day discharge or admitted patient cohort. Univariate comparisons of demographics, perioperative variables, and 30-day postoperative complications were performed. Multivariate logistic regression was used to 1) identify demographic and perioperative factors associated with admission, and 2) compare postoperative complication rates of same-day discharge patients with those of admitted patients while adjusting for demographic and perioperative factors. MEASUREMENTS AND MAIN RESULTS: Eight thousand one hundred patients were recruited during the study period. The overall rate of same-day discharge was 57.2% in 2015 and 65.0% in 2019. The same-day discharge rate was 64.6% for patients with a smaller myoma burden (1-4 fibroids and ≤250 grams, Current Procedural Terminology 58545) and 56.8% for larger myoma burden (≥5 fibroids or >250 grams, Current Procedural Terminology 58546). Age, race, American Society of Anesthesiologists classification III or IV, preoperative hematocrit <36%, hypertension, diabetes, bleeding disorder, and increasing operative time were associated with admission to hospital. After adjusting for these variables, composite postoperative complication rates were similar between admitted patients and patients who were discharged the same day regardless of myoma burden (adjusted OR [aOR], 0.66; 95% confidence interval [CI] 0.18-2.47 for low myoma burden and aOR, 0.91; 95% CI 0.18-4.63 for high myoma burden). Admitted patients with both low (aOR, 9.1; 95% CI 2.27-37.04) and high (aOR, 8.24; 95% CI 1.59-42.49) myoma burdens were significantly more likely to receive a blood transfusion compared to same-day discharge patients. CONCLUSION: Same-day discharge after minimally invasive myomectomy, regardless of myoma burden, is associated with low complication rates. Our findings may aid in shared decision making on discharge planning.

Laparoscopically Confirmed Endometriosis and Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Prior research suggests that women with endometriosis are at greater risk of coronary heart disease. Therefore, our objective was to prospectively investigate the association between laparoscopically confirmed endometriosis and risk of incident stroke during 28 years of follow-up. METHODS: Participants in the NHSII cohort study (Nurses' Health Study II) were followed from 1989 when they were between the ages of 25 to 42 until 2017 for development of incident stroke (ischemic and hemorrhagic). Cox proportional hazard models were used to calculate hazard ratios and 95% CI, with adjustment for potential confounding variables (alcohol intake, body mass index at age 18, current body mass index, age at menarche, menstrual cycle pattern in adolescence, current menstrual cycle pattern, parity, oral contraceptive use history, smoking history, diet quality, physical activity, NSAID use, aspirin use, race/ethnicity, and income). We estimated the proportion of the total association mediated by history of hypertension, hypercholesterolemia, hysterectomy/oophorectomy, and hormone therapy. We also tested for effect modification by age (<50, ≥50 years), infertility history, body mass index (<25, ≥25 kg/m2), and menopausal status. RESULTS: We documented 893 incident cases of stroke during 2 770 152 person-years of follow-up. Women with laparoscopically confirmed endometriosis had a 34% greater risk of stroke in multivariable-adjusted models (hazard ratio, 1.34 [95% CI, 1.10-1.62]), compared to those without a history of endometriosis. Of the total association of endometriosis with risk of stroke, the largest proportion was attributed to hysterectomy/oophorectomy (39% mediated [95% CI, 14%-71%]) and hormone therapy (16% mediated [95% CI, 5%-40%]). We observed no differences in the relationship between endometriosis and stroke by age, infertility history, body mass index, or menopausal status. CONCLUSIONS: We observed that women with endometriosis were at elevated risk of stroke. Women and their health care providers should be aware of endometriosis history, maximize primary cardiovascular prevention, and discuss signs and symptoms of cardiovascular disease.

Maximising the potential of neuroimmunology.

Technological developments in recent years have led to a surge in advances in neuroimmunology, making real progress towards improving human health. With the scale of the challenges ahead, realising this potential requires a collaborative effort. The neuroscience, immunology and wider scientific community, both academia and industry, must come together to pool together ideas, experiences and resources.

The Epidemiology of Brachial Plexus Birth Palsy in the United States: Declining Incidence and Evolving Risk Factors.

BACKGROUND: The epidemiology of brachial plexus birth palsy (BPBP) in the United States may be changing over time due to population-level changes in obstetric care. METHODS: The Kids' Inpatient Database from 1997 to 2012 was analyzed. Annual estimates of BPBP incidence and disease determinant distribution were calculated for the general population and the study population with BPBP. Long-term trends were analyzed. A multivariate logistic regression model was used to quantify the risk associated with each determinant. RESULTS: The database yielded a combined total of 5,564,628 sample births extrapolated to 23,385,597 population births. The population incidence of BPBP dropped 47.1% over the 16-year study period, from 1.7 to 0.9 cases per 1000 live births (P<0.001). Female, black, and Hispanic subgroups had moderately increased risks of BPBP. Among children with BPBP, 55.0% had no identifiable risk factor. Shoulder dystocia was the strongest risk factor for BPBP in the regression model [odds ratio (OR), 113.2; P<0.001], although the risk of sustaining a BPBP in the setting of shoulder dystocia decreased from 10.7% in 1997 to 8.3% in 2012 (P=0.006). Birth hypoxia was independently associated with BPBP (OR, 3.1; P<0.001). Cesarean delivery (OR, 0.16; P<0.001) and multiple gestation birth (OR, 0.45; P<0.001) were associated with lower incidence of BPBP. Notably, the rate of cesarean delivery increased by 62.8% during the study period, from 20.9% in 1997 to 34.0% in 2012 (P<0.001). CONCLUSIONS: Over a 16-year period, the incidence of BPBP fell dramatically, paralleled by a significant increase in the rate of cesarean delivery. Systemic changes in obstetric practice may have contributed to these trends. As more than half of BPBP cases have no identifiable risk factor, prospective investigation of established risk factors and characterization of new disease determinants are needed to more reliably identify infants at greatest risk. Racial and geographic inequalities in disease burden should be investigated to identify interventional targets. LEVEL OF EVIDENCE: Level III-case series.

An overview of the intrathymic intricacies of T cell development.

The generation of a functional and diverse repertoire of T cells occurs in the thymus from precursors arriving from the bone marrow. In this article, we introduce the various stages of mouse thymocyte development and highlight recent work using various in vivo, and, where appropriate, in vitro models of T cell development that led to discoveries in the regulation afforded by transcription factors and receptor-ligand signaling pathways in specifying, maintaining, and promoting the T cell lineage and the production of T cells. This review also discusses the role of the thymic microenvironment in providing a niche for the successful development of T cells. In particular, we focus on advances in Notch signaling and developments in Notch ligand interactions in this process.

Association Between Body Mass Index, Uterine Size, and Operative Morbidity in Women Undergoing Minimally Invasive Hysterectomy.

STUDY OBJECTIVE: Although the selection of an approach to minimally invasive hysterectomy is relatively straightforward in an ideal patient scenario, it is more difficult in patients who pose operative challenges such as high body mass index (BMI) and enlarged uteri. The objective of this study was to explore the association between surgical approach and operative morbidity after minimally invasive hysterectomy and examine whether the association varies based on patient BMI and uterine size. DESIGN: Retrospective cohort (Canadian Task Force classification II-2). SETTING: Data abstracted from the American College of Surgeons National Safety and Quality Improvement Project registry. PATIENTS: Thirty-six thousand seven hundred fifty-seven women undergoing vaginal, laparoscopic-assisted vaginal, or total laparoscopic hysterectomy for benign indications between January 2005 and December 2012. INTERVENTIONS: Associations between surgical approach, BMI, and operative morbidity were examined, stratifying by uterine size (< or >250 g) and adjusting for covariates. Adjusted means, rate ratios, or odds ratios with 95% confidence intervals (CI) were calculated using linear, Poisson, or logistic regression. MEASUREMENTS AND MAIN RESULTS: Operative times were shortest in women undergoing vaginal hysterectomy regardless of BMI or uterine size (all p < .02). Although operative time increased with BMI, the association varied with uterine size in women undergoing vaginal hysterectomy; increasing BMI had a minimal impact on operative time with small uteri <250 g but lengthened operative time in uteri >250 g. Compared with vaginal hysterectomy, total laparoscopic hysterectomy had lower odds of blood transfusion (all p < .02) and shorter hospitalizations (all p < .03) regardless of uterine size or BMI. Stratifying by uterine size, the association was strongest in morbidly obese women with small uteri; women with uteri <250 g and BMI >40 kg/m2 had 76% lower odds of blood transfusion (95% CI, 0.10-0.54) and 18% shorter hospitalization (95% CI, 0.75-0.90) after laparoscopic hysterectomy compared with vaginal hysterectomy. CONCLUSION: Major operative morbidity after minimally invasive hysterectomy is rare regardless of the surgical approach. A vaginal approach to hysterectomy is associated with the shortest operative times, but increasing BMI results in a rapid escalation of operative time in women with large uteri. Total laparoscopic hysterectomy is associated with shorter hospitalizations and lower odds of blood transfusion across the BMI spectrum, particularly in women with small uteri. Laparoscopic-assisted vaginal hysterectomy appears to confer no specific advantage over the vaginal or laparoscopic approaches.

Induction of T-cell development by Delta-like 4-expressing fibroblasts.

The thymus provides a unique environment for the induction of T-cell lineage commitment and differentiation, which is predicted by specific Notch ligand-receptor interactions on epithelial cells and lymphoid progenitors, respectively. Accordingly, a bone marrow-derived stromal cell line (OP9) ectopically expressing the Notch ligand Delta-like 1 (Dll1) or Dll4 (OP9-DL1 and OP9-DL4, respectively) gains the ability to recapitulate thymus-like function, supporting T-cell differentiation of both mouse and human progenitors. In this study, we extend these findings by demonstrating that, unlike the NIH3T3 cell line, mouse primary fibroblasts made to express Dll4 (mFibro-DL4) acquire the capacity to promote and support T-cell development from hematopoietic stem cells (HSCs) into TCRαß(+), CD4(+) and CD8(+) T-lineage cells. However, mFibro-DL4 cells showed a lower efficiency of T-cell generation than OP9-DL4 cells did. Nevertheless, progenitor T-cells (CD117(+) CD44(+) CD25(+)) generated in HSC/mFibro-DL4 co-cultures, when intravenously transferred into immunodeficient (Rag2(-/-) γc(-/-)) mice, home to the thymus, undergo differentiation, and give rise to mature T-cells that go on to populate the periphery. Surprisingly, primary human fibroblast cells expressing Dll4 showed very low efficiency in supporting human T-lineage differentiation, which could not be improved by blocking myelopoiesis. Nevertheless, mFibro-DL4 cells could support human T-cell lineage differentiation. Our results provide a functional framework for the induction of T-cell development using easily accessible fibroblasts made to express Dll4. These cells, which are amenable for in vitro applications, can be further utilized in the design of individualized systems for T-cell production, with implications for the treatment of immunodeficiencies.

Role of recycling, Mindbomb1 association, and exclusion from lipid rafts of δ-like 4 for effective Notch signaling to drive T cell development.

Intrathymic T cell development is predicated on the Notch1 ligand Delta-like (Dll) 4. However, both Dll4 and Dll1 can support T cell development in vitro. Endocytosis of Dll1 is important for Notch activation, whereas currently there is no evidence for the role of Dll4 endocytosis in T cell development. To elucidate this, we generated Dll4 constructs that modify or inhibit endocytosis. Our results show that targeting the intracellular domain affects Dll4's ability to induce Notch target gene expression, support efficient T cell development, and inhibit B cell development. Dll4 function relies on a combination of factors, which include strong Mindbomb1 (Mib1) association, ubiquitination, and internalization and recycling back to the cell surface, to engage Notch1 effectively. Distinct membrane localization and the Delta/Serrate/Lag2 (DSL) domain were important for Dll4 function. These features are consistent with a "recycling" model, but not in opposition to a "mechano-transduction" model, whereby Dll4 is able to engage Notch and create a pulling force required to activate signaling, leading to the induction of T-lineage development. Taken together, in contrast to Dll1, Dll4 does not localize to lipid rafts and shows stronger association with Mib1 and increased Notch1 uptake, which likely account for its superior ability to induce T cell development.

Effect of surgery for endometrioma on ovarian function.

Endometriosis affects a significant proportion of reproductive-aged women. The impact of the disease on ovarian function is an important consideration when planning treatment in women who want to retain the potential of future childbearing. This review will specifically address the association between endometriomas and diminished ovarian reserve, with a particular focus on the impact of surgical endometrioma resection on ovarian function. The existing literature supports an adverse effect of ovarian endometriomas on spontaneous ovulation rates, markers of ovarian reserve, and response to ovarian stimulation, although data on clinical pregnancy and live birth rates remain inconsistent. Surgical removal of endometriomas may worsen ovarian function by removing healthy ovarian cortex or compromising blood flow to the ovary. It is evident that surgical excision of endometriomas acutely impairs ovarian function as measured by ovarian reserve markers; whether this represents progressive or long term impairment remains the subject of ongoing investigation.

Racial and socioeconomic disparities in fertility treatment provision for patients with polycystic ovary syndrome.

OBJECTIVE: To assess whether provision of fertility treatment for patients with polycystic ovary syndrome (PCOS) varies by patient and physician level demographics. DESIGN: Retrospective cohort study SUBJECTS: Patients at a university health system seeking care for PCOS and infertility from 2007-2021. EXPOSURE: Patient age, BMI, race, ethnicity, estimated household income, primary insurance payor, provider sex, and provider medical specialty. MAIN OUTCOME MEASURES: Prescriptions for fertility treatment, including clomiphene citrate, letrozole, and injectable gonadotropins. Differences in patient and physician demographics between patients who did and did not receive a prescription were identified with univariable analysis. Multilevel mixed-effects logistic regression was performed to determine associations between patient and physician demographics and prescription receipt. RESULTS: 3,435 patients with PCOS and infertility were identified with a mean age of 31.1 +/- 5.7 years. Of the 68.8% of patients who received a prescription, 47.8% of prescriptions were clomiphene citrate, 38.6% letrozole, and 13.7% injectable gonadotropins. There were lower odds of prescription receipt for Black patients compared to White patients (aOR 0.75, 95% CI 0.61-0.93), those with estimated household income below the federal poverty level (FPL) compared to above the national median (aOR 0.71, 95% CI 0.46-0.97), and those with public compared to commercial insurance (aOR 0.53, 95% CI 0.40-0.71). These disparities persisted in a subanalysis of patients prescribed oral medications only with lower odds of prescription receipt for Black compared to White patients (aOR 0.74, 95% CI 0.57-0.95), those with estimated household income below the FPL compared to above the national median (aOR 0.93, 95% CI 0.87-0.98), and those with public compared to commercial insurance (aOR 0.57, 95% CI 0.42-0.76). Black patients waited on average 153.3 days longer than White patients from initial visit to prescription receipt. Patients had lower odds of receiving any prescription from family medicine physicians (aOR 0.36, 95% CI 0.24-0.52) and general internal medicine physicians (aOR 0.55, 95% CI 0.42-0.73) compared to reproductive endocrinologists. CONCLUSION: Racial and socioeconomic disparities exist in the provision of infertility treatments for patients with PCOS. Fewer primary care physicians engaged in first-line fertility treatment, indicating an opportunity for physician education to improve access to fertility care.

Plasma adipokines and endometriosis risk: a prospective nested case-control investigation from the Nurses' Health Study II.

STUDY QUESTION: Do higher leptin levels and lower adiponectin levels predict subsequent development of endometriosis? SUMMARY ANSWER: Plasma leptin and adiponectin levels were not associated with laparoscopically confirmed endometriosis when collected prior to disease diagnosis. WHAT IS KNOWN ALREADY: Case-control studies have identified altered levels of the inflammatory adipokines leptin and adiponectin in women with endometriosis, but it remains unclear whether inflammation results in endometriosis or whether the presence of endometriosis creates an inflammatory state. STUDY DESIGN, SIZE, DURATION: Nested, matched, case-control study within the prospective Nurses' Health Study II (NHS II) cohort. Blood samples were collected between 1996 and 1999 from 29 611 female nurses within the cohort. Women who reported endometriosis before blood collection were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Plasma leptin and adiponectin levels were assayed by ELISA. Three hundred and fifty cases of laparoscopically confirmed endometriosis were matched 1:2 with 694 controls of comparable race, age, infertility history, menopausal status and time of blood draw. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models adjusting for matching factors and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for BMI, there were no statistically significant associations between endometriosis and leptin [RR = 1.2; 95% CI = 0.7-2.0; P-value, test for linear trend (P(trend)) = 0.72], adiponectin (RR = 0.8; 95% CI = 0.5-1.2; P(trend) = 0.48) or the leptin to adiponectin ratio (RR = 0.8; 95% CI = 0.4-1.4; P(trend) = 0.14) when comparing the upper with the lower quartile. Results were unaltered when analyses were stratified by BMI or restricted to cases diagnosed ≥ 4 years after blood draw. To evaluate statistical significance and limit the role of chance to the gold standard of 5%, we present 95% CIs about the RRs, and for P-values calculated for linear tests of trend and tests of heterogeneity, we have set the α-level to be 0.05 (i.e. <0.05 is considered to be statistically significant). LIMITATIONS AND REASONS FOR CAUTION: A limitation of this study is the inability to differentiate the time of endometriosis 'diagnosis' from the time of disease 'onset' due to the impossibility in identifying a precise time point at which the disease process was first initiated at a molecular or cellular level. Additional limitations include lack of information regarding stage of endometriosis and the possibility of asymptomatic disease in the control population. WIDER IMPLICATIONS OF THE FINDINGS: The mean age at diagnosis of endometriosis in the study population is 41.7, ≈ 10 years older than the mean age of diagnosis in the general population. While this may limit the generalizability of the results, there is no reason to suspect that the association between adipokines and endometriosis risk should differ at a younger age of diagnosis in an adult population.

Body size and endometriosis: results from 20 years of follow-up within the Nurses' Health Study II prospective cohort.

STUDY QUESTION: Is there a relationship between body mass index (BMI), body shape and endometriosis? SUMMARY ANSWER: Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. WHAT IS KNOWN ALREADY: The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, METHODS AND SETTING: Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend <0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35-39.9 kg/m(2) and ≥ 40 kg/m(2) had a 55% (95% CI 0.30-0.67) and a 62% (95% CI 0.23-0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5-22.4 kg/m(2)). Rates of endometriosis were nearly 3-fold higher in women with waist-to-hip ratios <0.60 (RR = 2.78, 95% CI 1.38-5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79, although the sample size for this category was very small. LIMITATIONS AND REASONS FOR CAUTION: Although women with undiagnosed endometriosis certainly remain in the comparison population even in this prospective cohort study, the community prevalence of endometriosis in an asymptomatic population is very low. Moreover, the characteristics of this small proportion of undiagnosed cases are diluted among the >90 000 women accurately defined as being endometriosis-free and are, therefore, unlikely to impact on effect estimation. Although geographically diverse, the NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations. WIDER IMPLICATIONS OF THE STUDY: The results of this study suggest that endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution.

Notch receptor-ligand interactions during T cell development, a ligand endocytosis-driven mechanism.

Notch signaling plays an important role during the development of different cell types and tissues. The role of Notch signaling in lymphocyte development, in particular in the development and commitment to the T cell lineage, has been the focus of research for many years. Notch signaling is absolutely required during the commitment and early stages of T cell development. Activation of the Notch signaling pathway is initiated by ligand-receptor interactions and appears to require active endocytosis of Notch ligands. Studies addressing the mechanism underlying endocytosis of Notch ligands have helped to identify the main players important and necessary for this process. Here, we review the Notch ligands, and the proposed models of Notch activation by Notch ligand endocytosis, highlighting key molecules involved. In particular, we discuss recent studies on Notch ligands involved in T cell development, current studies aimed at elucidating the relevance of Notch ligand endocytosis during T cell development and the identification of key players necessary for ligand endocytosis in the thymus and during T cell development.

Direct comparison of Dll1- and Dll4-mediated Notch activation levels shows differential lymphomyeloid lineage commitment outcomes.

In the thymus, Notch signaling is essential for T lymphopoiesis, with Delta-like (Dll)4 uniquely involved in this process. However, using cocultures, either Dll4 or Dll1 were shown to support T lymphopoiesis. To address which Dll is more effective at inducing hematopoietic progenitor cells to give rise to T lineage cells in vitro, we generated OP9 cells expressing a series of incrementally discrete and equivalent levels of Dll1 or Dll4. In keeping with previous findings, OP9 cells expressing high levels of either Dll1 or Dll4 gave rise to T lineage cells with similar efficacy, and prevented the differentiation of B and myeloid-lineage cells. However, at limiting levels, Dll4 maintained its ability to inhibit B lineage choice and induce T lineage commitment and differentiation at lower levels than Dll1. This manifest property of Dll4 is evident despite lower levels of steady-state surface expression than Dll1 on OP9 cells. The heightened effectiveness of Dll4 over Dll1 also corresponded to the induction of Notch target genes, and inhibition of B and myeloid-specific transcription factors. Furthermore, we show that OP9 cells expressing levels of Dll4 equivalent to those present in thymic epithelial cells, as expected, gave rise to T lineage cells, but were also permissive for the differentiation of myeloid cells; whereas, still inhibiting B lymphopoiesis. Our findings show that Dll4 expressed at physiological levels on OP9 cells is functionally distinct from similarly expressed levels of Dll1, illustrating the unique properties of Dll4 in supporting the combined T lineage and specific myeloid-lineage outcomes that underpin its function within the thymus.

Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation.

We show that Indian Hedgehog (Ihh) regulates T-cell development and homeostasis in both fetal and adult thymus, controlling thymocyte number. Fetal Ihh(-/-) thymi had reduced differentiation to double-positive (DP) cell and reduced cell numbers compared with wild-type littermates. Surprisingly, fetal Ihh(+/-) thymi had increased thymocyte numbers and proportion of DP cells relative to wild type, indicating that Ihh also negatively regulates thymocyte development. In vitro treatment of thymus explants with exogenous recombinant Hedgehog protein promoted thymocyte development in Ihh(-/-) thymi but inhibited thymocyte development in Ihh(+/-), confirming both positive and negative regulatory functions of Ihh. Analysis of Rag(-/-)Ihh(+/-) thymi showed that Ihh promotes T-cell development before pre-T-cell receptor (pre-TCR) signaling, but negatively regulates T-cell development only after pre-TCR signaling has taken place. We show that Ihh is most highly expressed by the DP population and that Ihh produced by DP cells feeds back to negatively regulate the differentiation and proliferation of their double-negative progenitors. Thus, differentiation from double-negative to DP cell, and hence the size of the DP population, is dependent on the concentration of Ihh in the thymus. Analysis of Ihh conditional knockout and heterozygote adult mice showed that Ihh also influences thymocyte number in the adult.

Risk factors for atypical hyperplasia and endometrial cancer in the infertility population: a case-control study.

OBJECTIVE: To estimate the incidence and identify risk factors for atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in American women undergoing infertility evaluation. DESIGN: Case-control study. SETTING: Academic reproductive endocrinology and infertility practice. PATIENTS: Female patients (18-50 years) seeking infertility evaluation from January 1, 2009 to December 1, 2018. Patients with known genetic predisposition to cancer or prior cancer diagnosis were excluded. Cases were defined as patients diagnosed with AH or EC during infertility workup (n = 22). Controls without AH or EC were randomly selected in a 10:1 ratio (n = 220) from all women undergoing infertility evaluation in the same year. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Incidence of AH or EC and odds of AH or EC accounting for age, race, body mass index (BMI), and ovulatory dysfunction. RESULTS: Twenty-two cases of AH or EC were identified among 11,569 women undergoing infertility evaluation (incidence 2 per 1,000 women, 95% confidence interval [CI] 1.2-2.9 per 1,000). Of these women, 68% had a BMI ≥30 kg/m2 compared with 25% of controls. In multivariable analyses, women with a BMI ≥30 kg/m2 were 5.9 times more likely to be diagnosed with AH or EC (adjusted odds ratio 5.9, 95% CI 2.0-17.2). Women with ovulatory dysfunction were 3.4 times more likely to be diagnosed with AH or EC (adjusted odds ratio 3.4, 95% CI 1.1-10.1). CONCLUSIONS: The incidence of AH and EC in a population of women undergoing infertility evaluation is 10 times that in the general population of premenopausal women. Obesity is the strongest independent risk factor for AH and EC in women with infertility.

Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030.

Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.

Bariatric surgery and fertility.

PURPOSE OF REVIEW: Bariatric surgery is the most reliable way to sustain weight loss in the morbidly obese. Reproductive age women comprise the majority of bariatric patients, and many may be interested in conceiving after surgery. The purpose of this review is to synthesize the recent literature on bariatric surgery and fertility to assist providers in patient counseling. RECENT FINDINGS: Obesity adversely impacts fecundability and IVF outcomes through a variety of mechanisms. The body of literature on reproductive outcome after bariatric surgery is sparse and of mixed quality. Bariatric surgery has been shown to improve menstrual cyclicity in anovulatory women, but little is published on the impact of surgical weight loss on spontaneous or IVF-treatment-related pregnancy rates. The increased risk of miscarriage in obese women may decline after bariatric surgery. There are currently insufficient data to support recommendations regarding the ideal timing for pregnancy after bariatric surgery. SUMMARY: Obesity has been shown to adversely impact fertility, and weight loss is associated with significant improvement in many parameters of reproductive function. Further research is required as to the specific impact of surgical weight loss on pregnancy and miscarriage rates, as well as the optimal timing of pregnancy after bariatric surgery.