Faculty Bibliography

Brown adipose tissue is an evolutionary innovation in placental mammals that regulates body temperature through adaptive thermogenesis. Cold exposure activates brown adipose tissue thermogenesis through coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation; however, how these processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (SLIT3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. Adipocyte progenitors secrete SLIT3, which is cleaved into functionally distinct SLIT3-N and SLIT3-C fragments that independently promote angiogenesis and sympathetic innervation. We identify PLXNA1 as a receptor for SLIT3-C and demonstrate its essential role in sympathetic innervation of brown adipose tissue. Moreover, we identify BMP1 as the first SLIT protease described in vertebrates. Coordinated neurovascular expansion mediated by distinct SLIT3 fragments provides a bifurcated yet integrated mechanism that ensures a synchronized brown adipose tissue response to environmental challenges. Finally, this study reveals a previously unrecognized role for adipocyte progenitors in regulating tissue innervation.

BACKGROUND:Tools for predicting heart failure (HF) in CKD patients remain limited. We aimed to study whether standard ECG features or heart rate variability parameters predict de novo HF hospitalization in individuals with CKD. METHODS:Utilizing a large NYU ECG database linked with electronic health records (2012-2021), we analyzed a cohort of patients with pre-existing CKD. Besides standard ECG features, we extracted heart rate variability (measures the time between consecutive heart beats in milliseconds) features from the ECGs as predictors. The index ECG was the first ECG performed after the index eGFR date (baseline) and was required to be done prior to initiation of dialysis, end-stage kidney disease (ESKD), or transplant. The primary outcome was time to index HF hospitalization (≥30 days after the index ECG) based on discharge ICD-10 codes. LASSO-penalized Cox regression was used to identify predictors. Sensitivity analyses used Fine-Gray competing risk models for death and ESKD. RESULTS:Among 11,409 individuals (median age: 72; ∼50% male) with a median of 976 days, 880 individuals (8%) experienced an index HF hospitalization. Models incorporating ECG and clinical parameters had excellent discrimination (C-statistic 0.76 in the training set and 0.73 in the validation set). Among ECG features, the PR interval, corrected QT, and T axis were independently associated with higher risks of index HF hospitalization ≥30 days after the index ECG in both primary models (p<0.001 for all) and in models accounting for competing risks (p<0.01 for all). History of arrhythmia (hazard ratio (HR, 1.60, 95% CI: 1.36-1.88), valvular disease (HR1.51, 95% CI: 1.27-1.81), and diabetes (HR 1.41, 95% CI: 1.22-1.65) were the strongest clinical predictors. HRV parameters were not independently associated with HF. CONCLUSIONS:Although ECG-derived HRV indices were not independently associated with risk of HF, several standard ECG features are associated with HF hospitalization in CKD.

BackgroundMisalignment between actual and perceived balance ability provides relevant information to understand functional deficits and fall risk. However, few studies have provided a continuous quantification of misalignment in neurological populations such as people with Parkinson's disease (PD).ObjectiveDetermine whether a continuous quantification of misalignment between actual and perceived balance ability, discordance, relates to functional outcomes such as quality of life and cognition.MethodsActual (gait velocity), and perceived (Activities of Balance Confidence) balance, cognition (measured via a computer-based cognitive assessment), and mobility-related quality of life were captured in a clinical sample of 95 people with PD. Primary outcomes were quality of life and cognitive domains frequently altered in people with PD (global cognition & executive function). Secondary cognitive domains assessed were attention, memory, visuo-spatial, verbal function, and information processing. Linear and non-linear models assessed the relationship between discordance, quality of life, and cognition.ResultsDiscordance related to mobility-related quality of life, such that under-confidence was related to poorer quality of life. Non-linear (quadratic) models were shown to fit the discordance-Global cognition (p = 0.02) data better than linear models such that over- and under-confidence related to poorer cognition. Secondary cognitive domains were not robustly related to discordance.ConclusionsIn a clinical sample of people with PD, discordance was related to mobility-related quality of life and global cognition. Global cognition further exhibited a possible non-linear relationship to discordance indicating that over- or under-confidence may relate to poorer cognition. This work underscores the functional relevance of misalignment of actual and balance abilities.

BACKGROUND:Comparative trials evaluating surgical outcomes are critical in guiding treatment for hallux valgus. However, the statistical stability of these outcomes is not well documented. Purpose The purpose of this study was to evaluate the statistical fragility of comparative studies analyzing minimally invasive surgery (MIS) versus open techniques for hallux valgus correction. STUDY/METHODS:Design A systematic review identified comparative studies assessing MIS versus open hallux valgus correction. METHODS:Outcome data were extracted with Fragility Index (FI) and Continuous Fragility Index (CFI) calculated for significant outcomes, and reverse FI (rFI) and reverse CFI (rCFI) for nonsignificant outcomes. Fragility Quotient (FQ) was calculated for each and compared to the number of patients lost to follow-up (LTFU). RESULTS:Of 628 studies screened, 18 met inclusion criteria, totaling 1,369 patients. Among 88 dichotomous outcomes, the median FI was 2, FQ was 0.021, rFI was 4, and rFQ was 0.072. For 236 continuous outcomes, the median CFI was 8, CFQ was 0.116, rCFI was 19, and rCFQ was 0.280. CONCLUSION/CONCLUSIONS:This is the first study to evaluate fragility in comparative trials on MIS versus open hallux valgus correction and among the first to assess reverse fragility in continuous outcomes. Significant results were more fragile than nonsignificant data and dichotomous outcomes were more fragile than continuous ones with nearly a quarter having an FI lower than the number of patients LTFU. Both outcome types demonstrated considerable statistical fragility supporting the cautious interpretation of MIS vs open hallux valgus findings and the reporting of statistical fragility data alongside P-values to better contextualize the robustness of clinical research.

BACKGROUND:Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC. METHODS:Patients with locally advanced or metastatic PDAC after one prior regimen received 50 mg/m2 subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200 mg intravenously every 3 weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis. RESULTS:Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5 years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83 months, respectively. Exploratory analysis suggested higher baseline CD8+ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit. CONCLUSION/CONCLUSIONS:Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8+ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. (NCT03264404).

BACKGROUND:The number of graduates from accelerated 3-year MD (A3YP) programs has increased over the past decade. Previous work showed that A3YP graduates perform comparably to non-accelerated (4-year) graduates from the same medical schools on mid-year and end-year Accreditation Council of Graduate Medical Education (ACGME) harmonized milestones. In shifting to the residency program perspective, it remains unclear how the performance of A3YP graduates compares to non-accelerated graduates including traditional 4-year, international, and osteopathic medical school graduates. OBJECTIVE:To compare the intern performance of A3YP graduates compared with non-accelerated graduates using mid-year and end-year ACGME milestones in Internal Medicine (IM) residency programs. DESIGN/METHODS:The study employed a retrospective cohort design, hypothesizing that graduates from A3YPs were comparable to non-accelerated graduates in the same program. PARTICIPANTS/METHODS:108 interns who graduated from A3YP were compared to 3,542 interns from non-accelerated programs at the same 34 IM residency programs. MAIN MEASURES/METHODS:Descriptive statistics were provided for ACGME milestone performance. Cross-classified random-effects regression was used to account for residency program effects and estimate group differences. KEY RESULTS/RESULTS:After controlling for residency programs, the milestone ratings of A3YP graduates were higher in all competency domains at mid-year except practice-based learning and improvement (PBLI) at .04 (P = .089) (coefficients ranged from 0.08 for medical knowledge (MK) (P < .001) to 0.23 in professionalism (PROF) (P < .001)). These differences persisted at the end-year period (coefficients ranged from 0.05 in PBLI (P = .039) to 0.17 in PROF (P < .001)) except MK at .02 (P = .656). Patient care differences were 0.15 (P < .001) at mid- and 0.14 (P = .005) at end-year. CONCLUSIONS:This study contributes to the literature demonstrating that interns graduating from A3YP are at least equivalent in terms of milestone assessment and possibly better in the competencies of PC and PROF than their non-accelerated counterparts.

BACKGROUND/UNASSIGNED:Endocrine findings in premature adrenarche have been characterized by elevated DHEAS levels in the past. METHODS/UNASSIGNED:We reviewed 44 female patients, aged 4 to 8 years, with premature adrenarche who were seen at our center between 2019 and 2023. Data were collected on the traditional androgens (DHEA and DHEAS) and novel 11-oxo-androgens. 11-oxo-androgens, DHEAS, and DHEA levels were measured using Liquid chromatography/tandem mass spectrometry (LC/MS-MS) assays in commercial laboratories (Lab Corp). RESULTS/UNASSIGNED:The majority, 89% of patients from the youngest group (4-5year olds), presented with apocrine odor as the only symptom of premature adrenarche. We have demonstrated that DHEA and DHEAS levels were within the normal range in many girls with premature adrenarche, whereas 11-oxo-androgens, particularly 11-hydroxyandrostenedione and 11β-hydroxytestosterone, were elevated. Out of those with normal DHEAS, 75 % had elevated 11-hydroxyandrostenedione, and 77.8% of those patients with normal DHEA had the same elevated oxo-adrogen. Additionally, advanced bone age greater than 1 year compared to chronological age was positively associated with 11-ketotestosterone (Spearman correlation coefficient = 0.32, 95% CI: 0.01-0.57, p=0.0429) and 11β-hydroxy testosterone (Spearman correlation coefficient=0.32, 95% CI: 0.01-0.58, p=0.0395). CONCLUSION/UNASSIGNED:We propose that 11-oxoandrogens are a more sensitive steroid to be measured in premature adrenarche.

OBJECTIVE:Exposure to antidepressants, particularly agents that work through serotonin-reuptake inhibition, may increase potential for bleeding, especially among patients with other bleeding risk factors. There is limited guidance for clinicians in the use of serotonin reuptake inhibitors (SRIs) and other antidepressants in the setting of increased bleeding risk. METHODS:A PubMed literature search was conducted for English-language articles (1992-2024) examining the bleeding risk associated with antidepressants. Physicians from the Association of Medicine and Psychiatry then convened to develop consensus recommendations. RESULTS:Consensus recommendations were established for managing antidepressant use in patients with medical and psychiatric comorbidities. Additionally, a clinical decision algorithm was created to assist clinicians in assessing the appropriateness of antidepressant prescribing in patients at risk for bleeding. CONCLUSIONS:The proposed algorithm can aid clinicians in determining whether antidepressant (including SRI) initiation, discontinuation, or dose adjustment should be considered for patients susceptible to bleeding. These guidelines preserve a role for clinical judgment in selection of treatments that balance the risks and benefits, which may be particularly relevant for patients with complex medical and psychiatric comorbidities. Additional studies are needed to better guide clinical decision making.