Faculty Bibliography

OBJECTIVES/OBJECTIVE:Documentation of gender identity (GI) and anatomy data in the electronic health record (EHR) is a proposed standard of care for transgender populations. However, there is limited research on implementation of proposed best practices, particularly anatomy data collection. This study aims to characterize factors that influence patient preferences and comfort around the collection and documentation of GI and anatomy in EHRs. MATERIALS AND METHODS/METHODS:From November 2023 to January 2024, 17 one-on-one, semi-structured virtual interviews were conducted with transgender adults residing in the Metropolitan New York area. Transcriptions were analyzed using inductive thematic analysis. RESULTS:Themes clustered around comfort and preferences for data collection processes and outcomes. Factors that influenced preferences and comfort around anatomy data were distinct from those impacting GI documentation preferences and comfort. The tension between the categories of GI and sex assigned at birth impacted anatomy data documentation preferences. Clinical context emerged as a consistent factor that impacts both preferences and comfort of GI and anatomy data documentation. DISCUSSION AND CONCLUSION/CONCLUSIONS:GI data collection efforts in clinical settings must consider the implication of anatomy data collection when determining data collection best practice methodologies. Anticipated and experienced stigma remain significant hurdles to patient comfort and willingness to collect GI and anatomy data, and their impact on actual data collection should be further elucidated among diverse gender identities. Clinical data collection methods, tools, and education warrant ongoing research investment to further elucidate best practices.

PURPOSE OF REVIEW/OBJECTIVE:The science and practice of xenotransplantation is advancing more rapidly than the regulatory infrastructure that will be necessary to ensure the promise of alleviating the organ shortage can be safely and equitably met. RECENT FINDINGS/RESULTS:While countries leading the way have developed some regulatory guidance to support first in human "compassionate use" xenotransplant interventions and the first clinical trials, existing legislative, regulatory, and operational frameworks for human allotransplantation have not been explicitly extended to nonhuman animal organs. SUMMARY/CONCLUSIONS:To address safety concerns and other ethics challenges unique to xenotransplantation, existing policies must be amended and new policies must be implemented to protect patients and ensure equitable access to xenotransplantation.

Castration-resistant prostate cancer (CRPC) is largely dependent on the androgen receptor (AR) for growth and often exhibits hyperactive PI3K signaling, most frequently due to PTEN loss. Therapeutic pressure from anti-AR therapies can induce trans-differentiation toward an AR-independent phenotype. Recently, different subtypes of AR-independent CRPC have been redefined, with the stem cell-like (SCL) subtype emerging as one of the most prevalent. Elucidation of the epigenetic mechanisms controlling the maintenance of these distinct CRPC cell states could pave the way for effective combinatorial therapies for CRPC. In this study, we identified a key role for the histone methyltransferase KMT2D in establishing the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) that are essential for the AR transcriptional output in AR-dependent CRPC cell lines, patient derived organoids, and patient samples. Unexpectedly, KMT2D maintained the identity of the AR-low CRPC-SCL subtype and controlled activity of AP-1 TFs such as FOSL1, which acts as a master regulator of this subtype. Single cell transcriptomics and chromatin assays underscored the role of KMT2D in sustaining a mixed lineage cell state via AP-1 and FOXA1. The combined suppression of PI3K/AKT and KMT2D reduced cell proliferation in prostate cancer cells and patient-derived organoids in both CRPC-AR and CRPC-SCL subtypes. Altogether, these results unveil KMT2D as a major mediator of the epigenetic landscape in subtype-specific CRPC, contributing to tumor growth and therapeutic response.

OBJECTIVE:To describe the current state of AAGL-FMIGS fellowship programs, assessing case volume, case types, and differences among programs. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Fellowships in Minimally Invasive Gynecologic Surgery (FMIGS) in the United States. PARTICIPANTS/METHODS:All fellows who started and completed an AAGL-FMIGS fellowship in the U.S. between 2020 to 2024. INTERVENTIONS/METHODS:n/a RESULTS: During the study period, 130 fellows completed a 2 or 3-year fellowship from start to finish among 52 fellowships. The median number of total cases completed in a 2-year fellowship was 510 [IQR 428-586]. The most common procedure was hysterectomy (median 210 [IQR 174-255]), followed by peritoneal procedures, which included retroperitoneal dissection and adhesiolysis (median 125 [IQR 91-167]), and endometriosis procedures (median 89 [IQR 56-132]). The medians for other case types were as follows: myomectomies (including hysteroscopic) 62 [IQR 40-95], adnexal surgeries 39 [IQR 25-67], and hysteroscopies (excluding hysteroscopic myomectomy) 45 [IQR 35-77]. Among the 130 fellows, 67% (n= 87) had FMIGS-trained Program Directors and 33% (n= 43) had non-FMIGS-trained Program Directors. Fellows from programs with FMIGS-trained Program Directors had greater surgical volume compared to fellows with non-FMIGS-trained Program Directors (median number of cases per fellow of 537 [IQR 468-620] vs 464 [IQR 367-551], p=.03). Furthermore, fellows from programs with FMIGS-trained Program Directors compared to those with non-FMIGS-trained Program Directors, completed a median of 108 vs. 58 endometriosis surgeries (p=.01), 71 vs. 44 myomectomies (p = .01), 52 vs. 39 hysteroscopies (p=.06), and 215 vs. 187 hysterectomies (p=.27), respectively. CONCLUSION/CONCLUSIONS:Adopting the ACGME case log system provided greater insight into the volume and types of cases completed in AAGL-FMIGS programs. Overall, AAGL-FMIGS programs have robust surgical volume with Program Director training affecting volume and case types. Fellows from programs with FMIGS-trained Program Directors have significantly greater total case volume, myomectomies, and endometriosis surgeries.

PURPOSE/OBJECTIVE:Examine sex-specific differences in Intracranial Aneurysms (IA) rupture at presentation and to retrospectively benchmark sex-stratified versus pooled classification models for their ability to discriminate rupture status, using a cross-sectional cohort. METHODS:We retrospectively analyzed 203 patients (46 males, 157 females) with 303 IAs from a single-center, IRB-approved registry. Of these, 76 IAs were ruptured and 227 unruptured at presentation. Clinical data and lesion characteristics were summarized into patient-level variables and used to develop sex-specific logistic regression models. Adjusted Odds ratios (ORs) were produced for clinical covariates. Cross-application assessed generalizability across sexes. RESULTS:Among females, 58.7% of ruptures were < 5 mm, with a median ruptured size of 4.2 mm at Anterior Communicating Artery (ACOM). Rupture likelihood in females peaked between ages 40 and 59 (aORs = 2.8 and 1.7), coinciding with perimenopause. In males, ACOM was the most frequent rupture site; although males had higher mean hemoglobin levels (14.1 vs. 12.5 g/dL, p < 0.0001), hemoglobin contributed less to rupture compared to sex-specific models incorporating age, location, and metabolic factors (hemoglobin concentration, blood glucose). Metabolic factors contributed significantly to the female-specific model, achieving strong discrimination (AUC-ROC: 0.80), while the male-specific model underperformed (AUC-ROC: 0.50), due to limited rupture events (n = 19). Cross-application of features between sexes drastically reduced performance, providing the first computational evidence that male and female rupture mechanisms represent distinct biological feature spaces requiring separate modeling architectures CONCLUSION: Women in this cohort more often presented with rupture IAs at smaller sizes and at midlife ages than men. These sex-specific patterns, though strictly cross-sectional and associative rather than predictive, highlight potential biological and clinical contributors to rupture presentation and may partly explain misclassification by pooled risk models. Future longitudinal, multicenter studies with balanced cohorts are required to validate these findings and to develop robust rupture-risk prediction tools that incorporate sex as a biological variable.

BACKGROUND:Few studies have evaluated the ototoxic effects of in utero antiretroviral (ARV) exposure on hearing in children HIV-exposed uninfected (CHEU). Concerns have been identified for some ARVs: tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine (3TC), zidovudine (ZDV) and atazanavir (ATV). The aims are to describe hearing outcomes in 5-year-old CHEU in the Surveillance Monitoring for Antiretroviral Therapy Toxicities study and evaluate their association with in utero ARV exposures. METHODS:Hearing evaluations including pure-tone thresholds and distortion product otoacoustic emissions (DPOAEs) were completed in CHEU at 5 years. Log-binomial regression models were fit to assess associations of maternal ARV exposures with risk of sensorineural hearing loss (SNHL) and incomplete DPOAE responses. RESULTS:Among 1078 CHEU, 13% had SNHL. Among those exposed to <13 weeks gestation, there was 28% higher risk (95% confidence interval: -37% to 158%) of SNHL with TDF/FTC with ATV and 38% lower risk (95% confidence interval: -68% to 19%) with ZDV/3TC without ATV than for regimens containing TDF/FTC without ATV. There was a higher risk of incomplete DPOAE responses for ZDV/3TC without ATV and a lower risk for TDF/FTC with ATV. For CHEU with first ARV exposure at 13-26 weeks gestation, those exposed to TDF/FTC with ATV or ZDV/3TC without ATV had a lower risk for SNHL compared with TDF/FTC without ATV. Despite nontrivial relative risks, all confidence intervals were wide. CONCLUSIONS:While SNHL was relatively common, there were no consistent associations between in utero ARV exposure and SNHL or incomplete DPOAEs. Further research is needed on ARV exposures and other hearing measures in CHEU.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and current therapies show limited efficacy. Ligands and receptors of the TIGIT axis were analyzed using multicolor flow cytometry of tumor and blood samples, immunohistochemistry from primary tumors, and single-cell RNA sequencing from primary tumors and liver metastasis from patients with various stages of PDAC. The effect of soluble and plate-bound Nectin-4 on T cell function was tested in vitro. Further, patient-derived PDAC organoids were treated with the standard of care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin. TIGIT expression was increased on tumor-infiltrating conventional and regulatory T cells compared with T cells from matched blood. Nectin-4, but not CD155 expression was associated with poor outcome. Nectin-4 was exclusively expressed by tumor cells and correlated with low immune infiltration. Notably, Nectin-4 inhibited T cell effector cytokine production in vitro. Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscores Nectin-4 as a novel therapeutic target and provides the rationale to test this agent in PDAC patients.

Contemporary surgical techniques and alloplastic implants have made ossiculoplasty a safe and well-tolerated procedure in the past several decades. There has been significant evolution in types and materials of prostheses used to reconstruct the ossicular chain. Generally, the presence of an intact stapes may predict better outcomes, but this is not always the case. A wide range of underlying disease burden can lead to variable audiologic outcomes that are difficult to predict preoperatively. Though rare, intraoperative or postoperative complications can be bothersome and may require revision surgery.