Faculty Bibliography

Among the ways by which oncogenic KRAS upregulates glycolysis in cancer is direct interaction of KRAS4A with hexokinase 1 (HK1), but the mechanism is unknown. HK1 associates with the outer mitochondrial membrane (OMM) where its allosteric regulation depends on homodimerization. Using affinity capture, FRET, and blue native gels, we show that KRAS4A enhances oligomerization of HK1 on the OMM. Modeling the HK1/KRAS4A complex with AlphaFold3 predicts that the membrane association sequences of both HK1 and KRAS4A are oriented toward the OMM. Super-resolution microscopy showed colocalization of HK1 and KRAS4A on the OMM with HK1 enriched at discrete locations. Single-molecule tracking reveals HK1 diffusing freely along the OMM and dwelling at discrete regions where two molecules can be seen to colocalize transiently. KRAS4A expression decreased the diffusion coefficient of HK1 on the organelle. Thus, KRAS4A alters the dynamics of HK1 on the OMM and promotes oligomerization.

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disorder that can involve the esophagus, potentially leading to complications such as stricture or stenosis. Diagnosis of MMP is challenging owing to overlapping clinical features with other subepithelial blistering diseases and limitations of current diagnostic techniques. Although direct immunofluorescence (DIF) remains the gold standard, it requires fresh tissue samples, which are not always available, particularly in cases without active mucosal or cutaneous lesions. Complement fragment 4d (C4d) immunohistochemistry (IHC) on formalin-fixed tissue has demonstrated diagnostic utility in bullous pemphigoid but has been less explored in MMP. This case highlights that C4d IHC may serve as a useful ancillary test to support MMP diagnosis, especially for mucosal or esophageal biopsies received in formalin, offering a potential diagnostic pathway when fresh biopsy samples are unavailable.

BACKGROUND:Patients with Cushing's syndrome (CS) have a high prevalence of cardiovascular disease, and other recognized risk factors for atrial fibrillation/flutter (AF/AFL); however, the prevalence of AF/AFL has not been well characterized in this population. METHODS:We conducted a retrospective matched-cohort study using the Clalit Health Services database, including patients with CS and 1:5 matched controls. We assessed the risk of new-onset AF/AFL overall and according to disease etiology and remission status. Pre-existing AF/AFL was defined as >30 days before CS, and new-onset as within 30 days or thereafter. RESULTS:The cohort included 609 patients with CS and 3018 controls. Pre-existing AF/AFL was more common among patients with CS than controls (3.6% vs. 2.1%; OR 1.70, 95% CI 1.04-2.78). During a mean follow-up of 15 years, patients with CS had a significantly higher risk of developing new-onset AF/AFL compared with controls (HR 1.55, 95% CI 1.19-2.03). This increased risk was observed in both Cushing's disease (CD) (HR 1.53, 95% CI 1.01-2.32) and adrenal CS (HR 1.70, 95% CI 1.06-2.74). AF/AFL risk did not significantly differ according to remission status, although a trend toward lower risk was observed. Multivariate analysis identified older age at diagnosis, male sex, hypertension, vascular disease, and higher BMI as predictors for new-onset AF/AFL. CONCLUSION/CONCLUSIONS:CS is associated with an increased risk of AF/AFL. This elevated risk is observed across both CD and adrenal CS and persists despite disease remission, underscoring the need for heightened awareness and close cardiovascular surveillance in this population. The increased risk of AF/AFL appears to be primarily driven by coexisting cardiovascular comorbidities rather than cortisol excess or other CS-specific features.

BACKGROUND:Atopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune differences remain poorly understood. METHODS:We performed single-cell multi-omics profiling of peripheral blood mononuclear cells (PBMCs) from 29 AD patients and 29 matched healthy controls (HC), spanning pediatric (0-17 years), adult (18-59 years), and geriatric (≥60 years) groups. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we simultaneously quantified transcriptomic (RNA) and surface proteomic (ADT) profiles across ~280,000 immune cells. Integrated analyses identified 30 immune subsets for cell-type proportion and differential expression analyses. Machine-learning classifiers were trained on significant gene and protein features to distinguish AD subgroups by age. RESULTS:Compared with HC, AD blood showed enrichment of CD14+ monocytes, plasmacytoid dendritic cells, and CD4+ proliferating T cells, and differential gene expression analysis of AD vs HC revealed downstream Th2-associated signatures shared across all age groups. Within AD, pediatric patients had increased γδ T cells, naïve CD4+, and naïve CD8+ T cells, while geriatric patients exhibited more CD4+ cytotoxic and CD8+ central memory T cells, indicating a shift from naive to effector predominance with aging. Transcriptomic and proteomic analyses revealed distinct programs: pediatric AD was enriched for IL-10 and cytokine-cytokine receptor signaling; adult AD demonstrated activation of metabolic and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Th1/Th17 pathways; and geriatric AD exhibited reduced adaptive immune activity but increased innate signaling. Machine-learning models based on differentially expressed genes and proteins accurately classified AD age groups (transcript-based F1 = 0.70, AUC = 0.79), identifying stable markers such as IRF2, PDK4, ZFP90, CD21, CD94, and CD122. CONCLUSIONS:Single-cell multi-omics profiling revealed age-specific transcriptional and immunological programs overlaid on a shared Th2-driven inflammatory foundation in AD. Rather than discrete disease states, pediatric, adult, and geriatric AD each exhibited distinct molecular signatures: developmental and cytoskeletal in children, stress-response and chronic inflammatory in adults, and innate and metabolic in geriatric individuals. These findings support age-group molecular subtyping and age-tailored therapeutic strategies across the AD lifespan.

BACKGROUND/UNASSIGNED:The coronavirus disease 2019 (COVID-19) pandemic spurred a tremendous increase in the adoption and use of remote patient monitoring (RPM) for hypertension (HTN) management. However, limited evidence exists on the associations between frequency of utilization and uncontrolled blood pressure (BP). OBJECTIVES/UNASSIGNED:The present study comprehensively explores the associations between RPM use frequency and uncontrolled BP among a metropolitan-dwelling sample of hypertensive patients. METHODS/UNASSIGNED:Of 2,920 participants from a single urban health system, we employed a range of analytical perspectives to evaluate the RPM utilization-uncontrolled BP relationship across widely used engagement metrics: Frequency of BP transmission, digitally enabled clinician interactions, patient portal interactions, and a composite measure of utilization. Our dichotomized primary and secondary endpoints were BP >140/90 mm Hg and BP >130/80 mm Hg. RESULTS/UNASSIGNED:Fifty-nine percent of participants were females (59%), one-third (37%) were ≥65 years old, and Hispanic patients were most represented (39%). Our primary uncontrolled BP endpoint demonstrated strong adjusted associations with suboptimal RPM use across dichotomized measures: Low BP transmission (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.41-2.96), low clinician interactions (OR: 1.83, 95% CI: 1.43-2.36), low patient portal interactions (OR: 1.83, 95% 1.46-2.30), and low overall engagement (OR: 3.50, 95% 2.77-4.46). Our causal evaluations mirrored these findings, showing moderate causal associations after comprehensive adjustment for confounding. Assessments using other data types, such as continuous and quartiles, showed significant associations and an apparent dose-response relationship, though not at a similar magnitude. CONCLUSION/UNASSIGNED:We observed strong associations between low RPM utilization and uncontrolled BP, with promising implications for patients with collectively high RPM use. These findings highlight the need to strengthen digital inclusion initiatives to improve RPM uptake and support existing efforts aimed at developing RPM clinical practice guidelines and expanding RPM reimbursement policies. Further research is warranted across diverse utilization components to better understand the linkages between engagement frequency and improved clinical outcomes.

OBJECTIVE:or Purpose: To investigate the potential association of semaglutide and neovascular age-related macular degeneration (NVAMD) DESIGN: Retrospective study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network during the study period from 12/1/2017-12/31/2024 SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Adults with type 2 diabetes (T2D) on semaglutide, other glucagon-like peptide-1 receptor agonists (GLP-1RAs) (dulaglutide, exenatide), or non-GLP-1RAs (empagliflozin, sitagliptin, glipizide) METHODS, INTERVENTION OR TESTING: The association between semaglutide and NVAMD was assessed using two approaches: an active-comparator cohort design and a self-controlled case-series (SCCS) analysis. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). A random-effects meta-analysis was used to generate network-wide HR and IRR estimates. MAIN OUTCOME MEASURES/METHODS:Two definitions of NVAMD, one based on condition codes alone (NVAMD-C) or condition codes and procedures (NVAMD-CP). RESULTS:A total of 227,971 new users of semaglutide were included in the study. The risk of NVAMD among semaglutide users was similar to users of dulaglutide (NVAMD-C HR 0.57, 95% CI 0.21 to 1.57, P=.28; NVAMD-CP HR 0.25, 95% CI 0.05 to 1.27, P=.10), empagliflozin (NVAMD-C HR 0.98, 95% CI 0.54 to 1.79, P=.94; NVAMD-CP HR 0.79, 95% CI 0.38 to 1.64, P=.52), sitagliptin (NVAMD-C HR 2.08, 95% CI 0.90 to 4.83, P=.09; NVAMD-CP HR 1.80, 95% CI 0.55 to 5.86, P=.33), and glipizide (NVAMD-C HR 0.83, 95% CI 0.35 to 2.02, P=0.69; NVAMD-CP HR 0.50, 95% CI 0.21 to 1.19, P=.12). There was no evidence of increased or decreased risk for NVAMD associated with semaglutide exposure (NVAMD-C: incidence rate ratio [IRR] 0.92, 95% CI 0.67 to 1.26, P=.60; NVAMD-CP IRR 1.02, 95% CI 0.76 to 1.36, P=.92) nor any of the other GLP-1RA or non-GLP-1RAs. CONCLUSIONS:We detected no differences in the risk of NVAMD associated with semaglutide use among adults with T2D.

OBJECTIVE:receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS:Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS:receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE/CONCLUSIONS:receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

BACKGROUND:Artificial intelligence (AI)-enabled "ambient" documentation may reduce clinician administrative burdens and improve care delivery, but implementation in clinical practice is complex. AIM/OBJECTIVE:To evaluate the implementation of commercially available ambient documentation tools in multi-specialty ambulatory clinical workflows at an academic medical center. SETTING/METHODS:A large urban academic health system in New York City. PARTICIPANTS/METHODS:Ninety-seven ambulatory clinicians across specialties. PROGRAM DESCRIPTION/METHODS:A multidisciplinary team conducted a 6-month proof-of-concept structured evaluation of two commercially available ambient documentation tools through initial vendor evaluations, technical review and integration with the electronic health record (EHR), clinician training and onboarding, implementation and technical support, and structured evaluation based on objective and key results (OKR) metrics. A single-group, pre-post evaluation of the impact of the tools on clinician EHR-based efficiency was conducted on a subset of participating clinicians. PROGRAM EVALUATION/RESULTS:Compared to the 3-month period immediately prior to initiating the ambient trial, clinicians experienced a 0.35-min-per-note and a 2.07-min-per-day reduction in documentation time. "Vendor B" showed higher utilization rates and superior user experience compared to "Vendor A." Implementation challenges included workflow integration, training resource requirements, data interoperability and analytics, and ongoing technical support needs. DISCUSSION/CONCLUSIONS:Ambient documentation shows promise in reducing documentation burden, but its success depends on technical stability and integration, product fit and support for clinicians, and adequate implementation resourcing. A multidisciplinary approach with clear metrics, strong vendor partnership and executive sponsorship, and ongoing technical support enables scalability.

BACKGROUND/UNASSIGNED:This study evaluates outcomes following internal fixation of unstable distal clavicle fractures (DCFs) with or without coracoclavicular (CC) stabilization. METHODS/UNASSIGNED:A retrospective review was conducted for patients who underwent open repair of unstable DCFs at a single institution from 2017 to 2024. Fixation techniques included locking plate alone (P) or plate with CC stabilization [transcoracoid suture button (P + B), coracoid anchor (P + A)]. Collected variables included demographics, clinical details, patient-reported outcome measurement information system (PROMIS) scores, American Shoulder and Elbow Surgeons (ASES) scores, and Visual Analog Scale (VAS) Pain. RESULTS/UNASSIGNED:Seventeen patients with DCFs (17 shoulders;11 males, 6 females; mean age 45 [23-78] years) were followed for an average of 32.0 (3.4-69.3) months. Fixation groups included P (6), P + B (8), and P + A (3). Neer types included IIA (4), IIB (6), and V (7). Mean outcome scores were PROMIS upper extremity 49.2 ± 10.5, pain interference 47.0 ± 7.2, pain intensity 39.3 ± 7.0, ASES 89.3 ± 14.3, and VAS 1.5 ± 2.2. Three patients (18%) experienced postoperative issues: plate prominence (2) and shoulder stiffness (1); none required reoperation. DISCUSSION/UNASSIGNED:The addition of CC stabilization to locking plate fixation in high-risk unstable DCFs results in favorable outcomes and predictable healing rates. LEVEL OF EVIDENCE/UNASSIGNED:IV, case series.