Faculty Bibliography

Individuals with heritable thoracic aortic disease (HTAD) face a high risk of deadly aortic dissections, but genetic testing identifies causative variants in only a minority of cases. We explored the contribution of non-canonical splice variants (NCVAS) to thoracic aortic disease (TAD) using SpliceAI and sequencing data from diverse cohorts, including 551 early-onset sporadic dissection cases and 437 HTAD probands with exome sequencing, 57 HTAD pedigrees with whole genome sequencing, and select sporadic cases with clinical panel testing. NCVAS were identified in syndromic HTAD genes such as FBN1, SMAD3, and COL3A1, including intronic variants in FBN1 in two Marfan syndrome (MFS) families. Validation in the Penn Medicine BioBank and UK Biobank showed enrichment of NCVAS in HTAD-associated genes among dissections. These findings suggest NCVAS are an underrecognized contributor to TAD, particularly in sporadic dissection and unsolved MFS cases, highlighting the potential of advanced splice prediction tools in genetic diagnostics.

Mutations that accumulate in the human male germline with age are a major driver of genetic diversity and contribute to genetic diseases. However, aging-related male germline mutation rates have not been measured directly in germline cells (sperm) at the level of individuals. We developed a study design in which we recalled 23 sperm donors with prior banked samples to provide new sperm samples. The old and new sequential sperm samples were separated by long timespans, ranging from 10 to 33 years. We profiled these samples by high-fidelity duplex sequencing and demonstrate that direct high-fidelity sequencing of sperm yields cohort-wide mutation rates and patterns consistent with prior family-based (trio) studies. In every individual, we detected an increase in sperm mutation burden between the two sequential samples, yielding individual-specific measurements of germline mutation rate. Deep whole-genome sequencing of sequential sperm samples from two individuals followed by targeted validation measured remarkably stable mosaicism of clonal mutations that likely arose during embryonic and germline development, suggesting that age did not substantially impact the diversity of spermatogonial stem cell pools in these individuals. Our application of high-fidelity and deep whole-genome sequencing to sequential sperm samples provides insight into aging-related mutation processes in the male germline.

Cutaneous melanoma is a malignant neoplasm of melanocytes that most frequently affects the skin. It is the most common malignancy in women of childbearing age, and accounts for almost one-third of all malignancies diagnosed during gestation. The pathophysiology of melanoma, particularly during pregnancy, is not well understood, but there are several ways in which the physiologic state pregnancy may impact melanoma. Based on the available literature, pregnancy does not seem to worsen maternal outcomes with melanoma, and outside of placental and fetal metastases, melanoma does not seem to cause serious obstetric or fetal complications. Treatment of localized melanoma during pregnancy follows guidelines for the general population, but advanced melanoma in pregnancy poses unique challenges given the lack of unifying research and management recommendations. Herein, we review the current literature, highlighting diagnostic clinical pearls and key multidisciplinary management considerations with regard to melanoma in the child-bearing population.

BACKGROUND:The goal of this study was to utilize preoperative computed-tomography(CT) scans to identify differences in the Hounsfield units(HU) of the acromion in patients who did and did not develop a postoperative acromial and scapular-spine fracture(ASF) after primary reverse total shoulder arthroplasty (rTSA). METHODS:A retrospective analysis was performed at a single institution. All patients undergoing a rTSA with either a 135° neck/shaft angle(NSA) humeral inlay design combined with a lateralized center-of-rotation(COR) glenosphere or a 145° NSA onlay combined with a medialized COR glenosphere design between 2011-2021 with a minimum follow-up of 24-months were included. Demographic characteristics and clinical outcome metric scores were recorded. Preoperative CT scans were analyzed to obtain acromion trabecular bone density measurements in HU in each zone of the scapula based on the Levy classification. Radiographic parameters were evaluated to determine their association with ASF. RESULTS:In total 263-patients were included, 140-patients with a 135° NSA humeral-inlay design;123-patients with a 145° NSA humeral-onlay design. There were no significant differences in baseline demographics between cohorts. The rate of ASF was 6.4%(9/140) for the 135° NSA-inlay-design versus 2.4%(3/123) in the 145° NSA-onlay design. In the non-fracture cohort there was a linear increase in bone density from zone-1(173.9HU)→zone-3(396.5HU)(lateral→medial). In the fracture cohort there was a decrease in bone density from zone-1(282.6HU)→zone-3(154.5HU). Measuring preoperative bone density in all Levy specific fracture-zones resulted in an AUC of 0.96 correlating to excellent predictive value. A threshold cutoff of 99.9 resulted in a sensitivity of 91.6% and specificity of 75.3%. A HU of 99.9 in any of the three-zones resulted in OR 5.1(p<0.0001) for sustaining an ASF postoperatively. A threshold of<50HU was associated with an 8-times higher-likelihood of developing a fracture in that specific zone. Greater than 5° of superior tilt in combination with ≥24mm of distalization was associated with an OR 6.4(p=0.0004) of sustaining an ASF. CONCLUSION/CONCLUSIONS:The current study demonstrates an accurate method of measuring HU at each of the described Levy fracture zones with excellent predictability of patients who are at risk of an ASF following rTSA. Additionally, we found that a HU threshold of <50 HU at any of the three Levy zones was associated with a nearly 8 times higher likelihood of developing a fracture in that specific zone. Lastly, we found that >5° of superior tilt in combination with ≥24mm of distalization was associated with 6.4 times higher likelihood of sustaining an ASF agnostic to prosthesis design.

Minoritized groups experience interpersonal, structural, and systemic marginalization that is also perpetuated within academic institutions. This marginalization produces barriers that exclude racial/ethnic minoritized groups within academic medicine from career opportunities and advancement. Racial/ethnic minoritized faculty are often expected to take on additional labor to serve the diversity needs of the program and/or institution that are often unrecognized or undervalued in the tenure or promotion process or detract from additional responsibilities. The unique needs resulting from multiple intersecting identities must be considered when planning initiatives to support minoritized groups in academia. This is detrimental to medicine as it limits innovation, perpetuates health disparities, and prevents the recruitment of scholars/physicians that are representative of the diversity within the U.S. population. Cluster hiring is a newer initiative adopted by many institutions; recently supported by funding from the National Institutes of Health (NIH) to improve diversity and inclusion of racial/ethnic minoritized groups. Here we discuss the elements of the cluster hire process and how they might be particularly relevant to intersectional inclusion and structural change of academic institutions, while also highlighting potential limitations to broad adoption. We conclude with recommendations for the potential need for integration of more culturally informed cluster hiring practices that can be made at the departmental, institutional and national level to positively impact the hiring, retention and advancement of faculty from marginalized populations.

Depression is a common and debilitating disorder affecting millions. First-line treatments fail to achieve remission in about one-third of patients, highlighting a critical treatment need. Transcranial direct current stimulation (tDCS) has emerged as a novel treatment for depression. Therefore, the aim of this review was to provide a comprehensive overview of the last decade of tDCS trials for depression and propose future research directions. To compile studies of the past decade, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) of tDCS for depression. A total of 21 RCTs were included, presenting a moderate effect for active tDCS compared to placebo. We also provided a description of study designs, stimulation parameters, and patients' characteristics. Following, we proposed possible strategies to enhance clinical effectiveness and reduce variability in results, including 1) optimization/personalization of tDCS via spatial and temporal target localization; 2) optimized methodological strategies, including home-based, accelerated tDCS protocols and novel trial designs; and 3) investigate patient profile to identify features that can predict treatment response. In conclusion, tDCS holds promise as a treatment for depression, but variability in trial parameters and outcomes underscores the need for its further optimization. Refining and standardizing protocols may enhance its effectiveness.

High-dimensional multiplexed imaging can reveal the spatial organization of tumour tissues at the molecular level. However, owing to the scale and information complexity of the imaging data, it is challenging to discover and thoroughly characterize the heterogeneity of tumour microenvironments. Here we show that self-supervised representation learning on data from imaging mass cytometry can be leveraged to distinguish morphological differences in tumour microenvironments and to precisely characterize distinct microenvironment signatures. We used self-supervised masked image modelling to train a vision transformer that directly takes high-dimensional multiplexed mass-cytometry images. In contrast with traditional spatial analyses relying on cellular segmentation, the vision transformer is segmentation-free, uses pixel-level information, and retains information on the local morphology and biomarker distribution. By applying the vision transformer to a lung-tumour dataset, we identified and validated a monocytic signature that is associated with poor prognosis.

BACKGROUND:As more transgender adolescents and young adults seek gender-affirming care, questions persist about how their desire for potentially fertility-affecting treatment intersects with their fertility intentions. METHODS:We surveyed 125 individuals born with a uterus and ovaries, living in the United States, initially prescribed gender-affirming testosterone at or before age 18, about their interest in genetically related children and history of fertility preservation and fertility-affecting procedures. RESULTS:Twenty-two percent of respondents did not want children, and 47% wanted children but did not think a genetic relationship was important. Another 8% indicated having genetically related children was important and 17% indicated they did not know. Only 47% recalled counseling about fertility preservation. Those who might want genetically related children were less satisfied when they did not recall counseling (p = .001). Significantly more people in the group who might want genetically related children still had one or both ovaries (100% vs. 86%; p = .03), desired to carry a pregnancy in the future or were unsure (30% vs. 8%; p = .01), and either desired to use their eggs for genetically related children or were unsure (93% vs. 26%; p < .001). CONCLUSIONS:More than one-half of individuals prescribed gender-affirming testosterone as adolescents had no interest in genetically related children. Those who were interested in genetically related children were more likely to have other fertility-preserving interests and behaviors, including potentially desiring a pregnancy and still having one or both ovaries. This finding suggests that fertility-related behaviors of individuals prescribed gender-affirming testosterone are in line with their stated goals.