Faculty Bibliography

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.

BACKGROUND/UNASSIGNED:We investigated racial and ethnic disparities in telehealth counseling among Medicaid-insured patients in outpatient substance use disorder (SUD) treatment clinics and assessed whether the clinic-level proportion of Medicaid-insured patients moderated these disparities. METHODS/UNASSIGNED:Using New York State (NYS) Medicaid and statewide treatment registry data, we analyzed 24,814 admission episodes across 399 outpatient SUD clinics during the first 6 months of COVID-19 (April-September 2020). Our outcome measure was the number of tele-counseling sessions within the first 90 days of treatment. Key independent variables included beneficiary race/ethnicity and the clinic-level proportion of Medicaid-insured patients, divided into four quartiles: lowest, second, third, and highest. Mixed effects negative binomial models assessed the associations between race/ethnicity, Medicaid proportions, and telehealth use, with interaction terms evaluating the moderating role of Medicaid proportions. RESULTS/UNASSIGNED:Black and Latinx patients received fewer telehealth sessions than non-Latinx White patients, with adjusted incidence rate ratios (aIRRs) of 0.86 (95% CI: 0.82, 0.91) for Black patients and 0.93 (95% CI: 0.88, 0.98) for Latinx patients. Black patients at clinics with the highest Medicaid proportions had higher telehealth usage rates compared to those at clinics with the lowest Medicaid proportions (aIRR, 1.20; 95% CI, 1.03-1.41). Patients in clinics with the highest Medicaid proportions were more likely to use individual telehealth counseling (aIRR, 1.02-1.88; 95% CI, 1.01-3.04). CONCLUSIONS/UNASSIGNED:Significant racial disparities in telehealth use exist, with variations persisting across clinics with different Medicaid proportions. Targeted interventions are needed to address these access gaps.

BACKGROUND:Hepatic artery infusion with floxuridine is a treatment option for patients with colorectal liver metastases or intrahepatic cholangiocarcinoma. Outcomes from newer centers are understudied. Predictive markers are needed, and quantitative circulating tumor DNA is an emerging candidate method for predicting response in patients receiving hepatic artery infusion. We aimed to describe safety, feasibility, early oncologic outcomes, and quantitative circulating tumor DNA dynamics in patients treated with hepatic artery infusion at a newly established program. METHODS:Single-institution analysis of patients who underwent hepatic artery infusion pump placement (April 2022-April 2024) was conducted. Primary outcomes included safety and feasibility (receiving ≥1 cycle of floxuridine). Secondary outcomes included radiographic response (Response Evaluation Criteria in Solid Tumors 1.1), relative dose intensity of floxuridine received, and quantitative circulating tumor DNA response. RESULTS:A total of 36 patients underwent hepatic artery infusion pump placement (colorectal liver metastases: 32; cholangiocarcinoma: 4). Technical success was 100%. Feasibility was 97%. One patient experienced mortality at 90 days from disease progression. Three patients (8%) experienced a total of 5 hepatic artery infusion pump-specific complications (pump pocket [n = 3], hemorrhage [n = 1], biliary sclerosis [n = 1]). Median relative dose intensity was 68.5% (colorectal liver metastases: 68.3%; cholangiocarcinoma 72.5.0%). For the 27 patients who underwent floxuridine therapy with available postoperative imaging, disease control rate was 97% (partial response: n = 15; stable disease: n = 11). Quantitative circulating tumor DNA was obtained from 16 patients (44%). Circulating tumor DNA dynamics appeared to correlate with and precede radiographic response. CONCLUSIONS:Implementation of a new hepatic artery infusion program is safe and feasible with promising early oncologic outcomes. Circulating tumor DNA tracking is achievable and dynamic changes in circulating tumor DNA may correlate with radiographic response to treatment.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This study aimed to evaluate whether a 6-month (limited) course of early IVIG is an effective strategy for relapse prevention in children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) versus only acute therapies or other early immunotherapies. METHODS:This was a retrospective multicenter observational study of pediatric MOGAD patients from the US Network of Pediatric Multiple Sclerosis Centers with disease onset between October 1996 and December 2022. Controls were matched to limited early IVIG subjects using a 3:1 ratio. Hazard ratios of time to relapse and rate ratios of annualized relapse rate were calculated. The cumulative probability of remaining relapse-free was evaluated with the Kaplan-Meier method. RESULTS:We identified 130 unique control subjects treated before second attack with acute treatments only used in matching, 18 subjects treated with limited early IVIG, and 23 subjects treated with other early immunotherapy. The time to relapse was not different between either the limited early IVIG group and control group (HR 0.60 [0.22, 1.66], p = 0.32) or other early immunotherapy group (HR 0.98 [0.27, 3.6], p = 0.98). The limited early IVIG group showed a lower annualized relapse rate, although not statistically significant (RR 0.44 [0.17, 1.14], p = 0.09) compared with controls and a similar annualized relapse rate compared with the other early immunotherapy group (RR 0.56 [0.19, 1.69], p = 0.30). DISCUSSION/CONCLUSIONS:Although underpowered, our results suggest that the use of a limited, 6-month course of early IVIG may reduce the risk of multiphasic disease in pediatric MOGAD.

Cancer is a systemic disease with complications beyond the primary tumor site. Among them, thrombosis is the second leading cause of death in patients with certain cancers (e.g., pancreatic ductal adenocarcinoma [PDAC]) and advanced-stage disease. Here, we demonstrate that pro-thrombotic small extracellular vesicles (sEVs) are secreted by C-X-C motif chemokine 13 (CXCL13)-reprogrammed interstitial macrophages in the non-metastatic lung microenvironment of multiple cancers, a niche that we define as the pro-thrombotic niche (PTN). These sEVs package clustered integrin β₂ that dimerizes with integrin α_X and interacts with platelet-bound glycoprotein (GP)Ib to induce platelet aggregation. Blocking integrin β₂ decreases both sEV-induced thrombosis and lung metastasis. Importantly, sEV-β₂ levels are elevated in the plasma of PDAC patients prior to thrombotic events compared with patients with no history of thrombosis. We show that lung PTN establishment is a systemic consequence of cancer progression and identify sEV-β₂ as a prognostic biomarker of thrombosis risk as well as a target to prevent thrombosis and metastasis.

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.

BackgroundAdvances in STN-DBS technology, among which directional stimulation, improved Parkinson's disease (PD) treatment efficacy, while increasing the clinical programming complexity. Lead localization software may aid the stimulation contact selection process.ObjectiveWe aimed to assess the concordance between imaging-suggested (IGP) and conventional-programming (CP) selected stimulation contacts one year after surgery and its impact on motor outcomes.MethodsSixty-four PD patients with bilateral STN-DBS were enrolled. Lead localization was reconstructed with Brainlab^TM software. For each electrode, the vertical contact level and, when applicable, the directionality predicted by the lead reconstruction software to be the most effective were established and compared to the stimulation parameters clinically activated one-year post-surgery. IGP/CP concordance ratio was calculated for both stimulation level and directional contacts. Post-operative modifications of PD motor symptoms severity were compared among groups of concordant and discordant IGP/CP programming.ResultsOne-year post-surgery, IGP/CP concordance was 80% for active stimulation vertical contact level and 51% for directionality. No significant difference in motor outcomes was found between IGP/CP concordant and discordant patients for contact level activation, whereas patients with concordant IGP/CP active directional stimulation (c-Direction) showed superior motor outcomes at one-year follow-up than those discordant (d-Direction) (UPDRS-III stimulation-induced improvement: c-Direction = -25.66 ± 13.74 vs. d-Direction = -12.54 ± 11.86; p = 0.011).ConclusionsVisual reconstruction software correctly predicted the most clinically effective stimulation contact levels in most patients. Imaging therefore facilitates classic STN-DBS clinical programming while assuring similar outcomes. Moreover, better motor outcomes were reached by patients with concordant IGP/CP directional parameters, suggesting that visualization can represent an added value in particular for directional stimulation programming.

OBJECTIVES/OBJECTIVE:To evaluate the yield of CT-guided biopsy of 18F-piflufolastat PET avid osseous lesions in suspected prostate metastases. METHODS:Retrospective review of computed tomography guided biopsies targeting 18F-piflufolastat avid lesions on PET/CT or PET/MR performed between 2022 and 2024. Demographics, image modality, biopsy system, number of cores, lesion location, lean body mass corrected SUV (SUL) and pathology were recorded. Biopsied lesions were compared to the PROMISE (prostate cancer molecular imaging standardized evaluation) scoring system, version 2. RESULTS:Eighteen patients were included, average age 68.7 years. Lesions were defined as: ≥ 50 % sclerotic (n = 10), <50 % sclerotic (n = 7), occult (n = 0), and lytic (n = 1). A technically successful pathologic diagnosis was made in 94 % of biopsies (n = 17). Histopathological diagnosis included: metastatic prostate adenocarcinoma (n = 12), benign with fibrotic/densely sclerotic bone or normocellular bone marrow (n = 5), and metastatic non-small cell lung carcinoma (n = 1). The median SUL on PET for all patients was 7.9 (IQR 13.3), 2.6 (0.3) for benign biopsies, and 8.8 (12.5) for malignant biopsies. Major identifiable differences between biopsies yielding a metastatic versus benign diagnosis included: higher SUL (p-value = 0.03), target lesion volume (p-value = 0.01), and higher incidence of sclerotic lesions (p value = 0.003); however, multivariate analysis did not find these to be statistically significant predictors (p-value >0.05). The prostate cancer lesion biopsy positive group had significantly higher PROMISE scores than the negative group (p = 0.03). CONCLUSION/CONCLUSIONS:CT-guided biopsy of bone lesions demonstrating avidity for 18F-piflufolastat can be performed with a high diagnostic yield.