B cell Expansion with NF-κB and T cell Anergy (BENTA) disease is a novel B cell lymphoproliferative disorder caused by germline, gain-of-function mutations in the lymphocyte scaffolding protein CARD11, which drives constitutive NF-κB signaling. Despite dramatic polyclonal expansion of naive and immature B cells, BENTA patients also present with signs of primary immunodeficiency, including markedly reduced percentages of class-switched/memory B cells and poor humoral responses to certain vaccines. Using purified naive B cells from our BENTA patient cohort, here we show that BENTA B cells exhibit intrinsic defects in B cell differentiation. Despite a profound in vitro survival advantage relative to normal donor B cells, BENTA patient B cells were severely impaired in their ability to differentiate into short-lived IgDloCD38hi plasmablasts or CD138+ long-lived plasma cells in response to various stimuli. These defects corresponded with diminished IgG antibody production and correlated with poor induction of specific genes required for plasma cell commitment. These findings provide important mechanistic clues that help explain both B cell lymphocytosis and humoral immunodeficiency in BENTA disease.
Introduction Increasingly, physicians find themselves in demanding leadership positions. However, leadership education for medical trainees remains lacking with most physicians reporting that they are ill-equipped to tackle the challenges of leadership. Here, we set out to describe the Feagin Leadership Program (FLP) and assess its reception and impact on trainees over the past 12 years. Materials and Methods During the 1-year FLP, selected scholars from Duke University, Wake Forest University, and the University of North Carolina participate in five leadership sessions, individual coaching, a leadership forum, and a multidisciplinary team–based capstone project. A 28-question survey with six optional free-response questions was distributed to the Feagin Alumni Network, and descriptive statistics were assessed. Results Since its founding, 212 scholars have graduated from the FLP and 117 (55%) alumni have gone on to surgical specialties. A survey was distributed among all Feagin alumni. A total of 56 (26%) surveys were completed. Forty-three percent (n = 24) had held at least one leadership position since completing the FLP. When asked about the impact of their experience, 96% (n = 54) said that the program encouraged them to pursue a position of leadership within their field, 95% (n = 53) stated that it prepared them for such a position, and 93% (n = 52) stated that the program positively influenced their decision to be involved with current or future positions of leadership. Conclusions Over the last 12 years, the FLP has demonstrated a high perceived impact on personal growth, leadership proficiency, and the decision to pursue leadership positions in medicine. The current dearth of leadership education for surgical trainees can best be addressed with models such as the FLP, with adoption benefiting medical trainees, the medical community, and patients they serve.
Bladder Outlet Obstruction (BOO) is ultimately experienced by ≈90% of men, most commonly secondary to benign prostatic hyperplasia. Inflammation is a critical driver of BOO pathology in the bladder and can be divided into two critical steps; initiation and resolution. While great strides have been made toward understanding initiation of inflammation in the bladder (through the NLRP3 inflammasome), no studies have examined resolution. Resolution is controlled by 5 classes of compounds known as Specialized Pro-resolving Mediators (SPMs), all of which bind to one or more of 7 different receptors. Using immunocytochemistry, we show the presence of 6 of the known SPM receptors in the bladder of control and BOO rats; the 7th has no rodent homolog. The expression was predominantly localized to the urothelia, often with some expression in the smooth muscle, but little to none in the interstitial cells. We next examined the therapeutic potential of the Annexin-A1 resolution system, also present in control and BOO bladders. Using the peptide mimetic Ac2-26, we blocked inflammation-initiating pathways (NLRP3 activation), diminished BOO-induced inflammation (Evans blue dye extravasation), and normalized bladder dysfunction (urodynamics). Excitingly, Ac2-26 also promoted faster and more complete functional recovery after surgical de-obstruction. Together, the results demonstrate that the bladder expresses a wide variety of potential pro-resolving pathways and that modulation of just one of these pathways can alleviate many detrimental aspects of BOO and speed recovery after de-obstruction. This work establishes a precedent for future studies evaluating SPM effectiveness in resolving the many conditions associated with bladder inflammation.
Background: Alternative reservoir placement is increasingly popular during inflatable penile prosthesis (IPP) surgery to prevent intraperitoneal positioning, bowel, bladder, or vascular injury in patients with prior pelvic surgeries. Counter incision (CI) can be used for submuscular reservoir placement in high risk patients, however series exploring the safety remain limited.Methods: A database of IPP surgeries was queried for use of a CI during reservoir placement to compare 90-day clinical outcomes in a retrospective case-control study. Primary outcome was device infections, with secondary outcomes including reservoir herniation, hematoma, device malfunction rates, and operative times.Groups were compared using Kruskal-Wallis and Chi-Squared tests, with multivariate logistic regression models to identify predictors of infectious complications.Results: A total of 534 cases met criteria, of which 51 (9.6%) used a CI for reservoir placement. The CI cohort included significantly more removal and replacements, 45.1% vs. 20.9% (P<0.001). Thirty-one CI patients (61.0%) had undergone prior prostatectomy compared to 134 (27.7%) non-CI patients (P=0.001).The most common reasons for CI were prior prostatectomy and inguinal hernia repair. Median operative time was 17 minutes longer in the CI group (74 vs. 57 minutes, P<0.001). Device infection rates were similar (2.0% vs. 4.1%, P=0.71), as were rates of hematoma (5.9% vs. 2.7%, P=0.19), and device malfunction (0.0% vs. 1.4% P=1.00). Conclusions:Complication rates were similar between CI and non-CI cohorts, even in a subset where approximately half the cases were removal and replacements. For physicians not comfortable with alternative placement through a penoscrotal or infrapubic incision, this offers a reasonable alternative and permits use of three-piece devices in patients with a hostile pelvis.
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