Disparities in the Operative Experience Between Female and Male General Surgery Residents: A Multi-institutional Study From the US ROPE Consortium

OBJECTIVE: To examine differences in resident operative experience between male and female general surgery residents. BACKGROUND: Despite increasing female representation in surgery, sex and gender disparities in residency experience continue to exist. The operative volume of male and female general surgery residents has not been compared on a multi-institutional level. METHODS: Demographic characteristics and case logs were obtained for categorical general surgery graduates between 2010 and 2020 from the US Resident OPerative Experience Consortium database. Univariable, multivariable, and linear regression analyses were performed to compare differences in operative experience between male and female residents. RESULTS: There were 1343 graduates from 20 Accreditation Council for Graduate Medical Education-accredited programs, and 476 (35%) were females. There were no differences in age, race/ethnicity, or proportion pursuing fellowship between groups. Female graduates were less likely to be high-volume residents (27% vs 36%, P \u3c 0.01). On univariable analysis, female graduates performed fewer total cases than male graduates (1140 vs 1177, P \u3c 0.01), largely due to a diminished surgeon junior experience (829 vs 863, P \u3c 0.01). On adjusted multivariable analysis, female sex was negatively associated with being a high-volume resident (OR = 0.74, 95% CI: 0.56 to 0.98, P = 0.03). Over the 11-year study period, the annual total number of cases increased significantly for both groups, but female graduates (+16 cases/year) outpaced male graduates (+13 cases/year, P = 0.02). CONCLUSIONS: Female general surgery graduates performed significantly fewer cases than male graduates. Reassuringly, this gap in operative experience may be narrowing. Further interventions are warranted to promote equitable training opportunities that support and engage female residents

Cbl-b deficiency renders T cells resistant to PD-L1/PD-1 mediated suppression

Abstract The PD-L1/PD-1 pathway is a critical regulator of T cell responses that has become a significant focus in cancer immunotherapy. Cbl-b is an E3 ubiquitin ligase that regulates many aspects of T cell activation. In humans, polymorphisms in the CBLB gene are associated with autoimmunity. Cbl-b deficient (Cbl-b−/−) mice demonstrate spontaneous autoimmunity and enhanced anti-tumor T cell responses. Thus, there is now great interest in manipulating Cbl-b to enhance anti-tumor T cell responses. We now report that, in contrast to WT T cells, in vitro TCR-stimulated proliferative responses of Cbl-b−/− CD4+ and CD8+ T cells are not suppressed by a recombinant PD-L1 fusion protein (PD-L1 Ig) (% suppression in CD4+: WT 40%, Cbl-b 0%, p&amp;lt;0.01; in CD8+: WT 32%, Cbl-b 5%, p&amp;lt;0.05). Moreover, IFN-γ production of Cbl-b−/− CD4+ T cells is less suppressed by PD-L1 Ig than that of WT cells (% Suppression: WT 68%, Cbl-b 20%, p&amp;lt;0.0001). Importantly, PD-1 expression is comparable between Cbl-b−/− and WT T cells. To confirm this PD-L1 resistance in vivo, we used a model of B16 melanoma in which liver metastases develop only when PD-L1/PD-1 immune regulation is functionally intact. We confirmed that WT mice develop numerous liver metastases which are significantly reduced by anti-PD-1 antibody treatment. Strikingly, Cbl-b−/− mice develop only rare liver metastases even in the absence of anti-PD-1. In sum, we report for the first time that Cbl-b−/− T cells are resistant in vitro and in vivo to suppression by PD-L1/PD-1. Our finding of Cbl-b−/− T cell resistance to PD-L1/PD-1-mediated inhibition broadens our understanding of Cbl-b’s role in autoimmunity and suggests a new mechanism by which manipulation of Cbl-b function may lead to enhanced anti-tumor T cell responses.</jats:p

TLR2 tolerance in EAE

Abstract TLR2 expression is enhanced in MS and EAE, but its role in these diseases is controversial. In adoptive transfer EAE, exogenous TLR ligands are not administered yet TLR2-deficient mice have been reported to develop attenuated disease. Despite this evidence for a disease-promoting function of TLR2, others have shown the opposite, i.e. that administration of TLR2 ligands can inhibit EAE in WT mice. To understand this paradox we tested the postulate that although TLR2 signaling may be EAE-promoting, repeated TLR2 ligand administration can lead to diminished TLR2 responsiveness (tolerance) and attenuated disease. To establish our approach, we administered Pam2Cys to SJL/J mice for 5 days and induced TLR2 tolerance that persisted for 4–5 days, reflected in decreased serum TNFα in response to a second TLR2 ligand (p&amp;lt;0.0001 day 1; p&amp;lt;0.01 day 3; p=0.069 day 5). Next, we used this approach to induce TLR2 tolerance in the context of EAE. SJL/J mice received EAE-causing, PLP-reactive LNCs on day 0 and tolerance was induced at various time points. Surprisingly, initiating the TLR2 tolerance protocol at day −2 or day +8 showed no effect on disease. In contrast, initiating the protocol between day +4 and +6 lead to significant inhibition of EAE onset and severity that lasted at least 5 days (p=0.025) and was associated with TLR2 tolerance (p&amp;lt;0.0001). In sum, we have used TLR tolerance as a novel probe to identify a narrow kinetic window in which TLR2 is required for EAE. Additionally, we have demonstrated the potential use of TLR tolerance as a new therapeutic approach in EAE and MS. Ongoing studies will characterize the relevant TLR2-expressing cells in EAE and the potential role of the microbiome in inducing homeostatic TLR tolerance that regulates autoimmunity.</jats:p

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Abstract The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.</jats:p

The Association Between Cardiac Rehabilitation Attendance and Hospital Readmission

Purpose: Cardiac rehabilitation is associated with improved clinical outcomes, but the impact of individual cardiac rehabilitation sessions on readmission rates is less studied. Methods: A retrospective evaluation of the relationship between the number of cardiac rehabilitation sessions completed and all-cause and cardiac readmission rates at 1 year was conducted. The 1-year cardiac readmission counts were modeled via Poisson regression. Results: Of the 347 patients included in the primary analysis, 227 (65%) completed all assigned cardiac rehabilitation sessions. At 1 year, 135 patients (39%) had at least 1 cardiac readmission, and 155 patients (45%) had at least 1 all-cause readmission. The primary result was that every additional cardiac rehabilitation session completed was associated with a 1.75% lower incidence rate of 1-year cardiac readmission (P = .01) and a 2% lower incidence rate of all-cause hospital readmission (P = .001). Conclusion: Regardless of the number of cardiac rehabilitation sessions assigned, each additional session attended was associated with reduced cardiac readmission by 1.75% and all-cause readmission by 2%. </jats:p