Faculty Bibliography

BACKGROUND/UNASSIGNED:The EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus a CS strategy by age is unknown. METHODS/UNASSIGNED:The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS/UNASSIGNED:=0.06). CONCLUSIONS/UNASSIGNED:In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03042104.

Mandibular distraction osteogenesis (MDO) is a common procedure used to correct upper airway obstruction in patients with Robin sequence. However, analysis of predictors of adverse outcomes after MDO has relied on small single-institution cohorts. This retrospective cohort study leveraged the Epic Cosmos multicenter database to evaluate predictors of morbidity and mortality in patients with Robin sequence undergoing MDO from January 2015 to December 2024. A multivariable logistic regression was used to evaluate associations between perinatal factors, airway anomalies, genetic syndromes, and congenital anomalies affecting the cardiopulmonary, gastrointestinal and central nervous system (CNS), and postoperative outcomes including 1-year mortality, tracheostomy, intensive care unit (ICU) admission within 30 days, 30-day hospital readmission, 30-day emergency department visit, ICU length of stay (LOS), and overall hospital LOS. Across a total of 685 patients, CNS anomalies were statistically significantly associated with 1-year mortality; cardiopulmonary anomalies and bronchomalacia were predictive of tracheostomy; tracheal stenosis was associated with ICU admission; CNS anomalies were associated with 30-day emergency department visit; and no variables were significantly associated with 30-day readmission. Age at surgery was inversely associated with longer ICU LOS and overall LOS, whereas prematurity, prenatal drug exposure, gastroesophageal reflux, and CNS anomalies were associated with longer overall LOS. These results highlight the burden of comorbidities of the airway, cardiopulmonary system, and central nervous system for patients with Robin sequence undergoing MDO and can inform surgeons on the likelihood of adverse events based on the diagnostic characteristics of the patient.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.

OBJECTIVE:HPV vaccination recommendations have expanded to include both sexes and a broadened age range since approval in 2006. These changes and increasing HPV-related head and neck cancer rates support vaccination of older and male patients, necessitating changes in HPV education. We aim to analyze vaccination trends and to identify opportunities for increasing awareness. STUDY DESIGN/METHODS:Cross-sectional study analyzing vaccination trends between 2007 and 2023. SETTING/METHODS:US hospitals and clinics using Epic. METHODS:Using Epic Cosmos, a national database, vaccination trends for patients aged 9 to 45 were stratified by year, demographics, and administering provider specialty. RESULTS:19.6 million HPV vaccinations were administered between 2007 and 2023. The inclusion of males aged 9 to 21 in the recommendations beginning in 2009 corresponded with an 836% increase in vaccinations in this group from 2010 to 2016. Males comprised 49.9% of vaccinated patients aged 9 to 18 in 2023, a percentage that increased annually since 2010. Head and neck cancer prevention became a designated vaccine indication in 2020. Despite broadened indications, total vaccination declined by 47.1% from 2016 to 2023 in patients aged 9 to 26. In 2012, 74.8% of vaccinations were administered in pediatrics and 18.3% in family medicine. In 2023, pediatrics administered 46.6%, family medicine 33.3%, OBGYN 7.1%, and primary care 6.8%. CONCLUSION/CONCLUSIONS:Expanding guidelines have had inconsistent impacts on vaccination trends, as rates decreased in target populations since 2016. Males contribute equally to pediatric but not adult vaccinations. Departments administering vaccines are diversifying, though pediatrics predominates. Gendered and outdated education and marketing could contribute to disparities and discordance with guidelines.

The protein activating molecule in Beclin1-regulated autophagy1 (AMBRA1), discovered in 2007, is crucial for autophagy and plays roles in nervous system development, cell survival, and proliferation. Here, we investigated AMBRA1's involvement in various cellular processes using a systems-based "omics" approach, focusing on melanoma. Transcriptomic analysis of AMBRA1 overexpression or knock-down was shown to result in significant dysregulation of several transcripts. We identified several novel roles for AMBRA1 in a range of cellular pathways including cancer signaling pathways such as MAPK, angiogenesis, tissue growth factor signaling, axon guidance, and Wnt signaling. Furthermore, using yeast two-hybrid assays, we identified novel binding partners which provide evidence of new roles for AMBRA1 in different cellular processes. Ultimately, we conclude that AMBRA1 loss upregulates metastatic genes/proteins highlighting AMBRA1 as a tumor suppressor gene in melanoma.

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.

PURPOSE/OBJECTIVE:Herpes simplex virus (HSV) and varicella zoster virus (VZV) are known causes of chronic and recurrent interstitial keratitis. Determination of active corneal inflammation is important for appropriate management. This study aimed to investigate features of clinically active herpetic interstitial keratitis (HIK) by anterior segment optical coherence tomography (AS-OCT). METHODS:Twenty-seven patients with active HIK (17 with HSV, 10 with VZV) and AS-OCT imaging were retrospectively identified. Five patients also had stromal scarring (SS), presumably from prior HIK episodes. An additional 4 patients with SS, but without a history of HIK, were also identified. The AS-OCT images were analyzed qualitatively, followed by an automated segmentation analysis. Deidentified images were shown to 3 masked graders after a training module, and their diagnoses were compared with slit-lamp diagnoses. RESULTS:Qualitative analysis of AS-OCT images of active HIK revealed anterior stromal hyperreflectivity, often with a hazy border and convex posterior contour comparable with "posterior bowing" historically seen on slit lamp. Borders were sharper and typically more linear for SS. Automated segmentation analyses identified that epithelium overlying the stromal area of interest was thicker in SS than HIK. Survey results revealed a high degree of correlation with slit-lamp diagnoses. CONCLUSIONS:AS-OCT may be a useful adjunct to slit-lamp examination in the evaluation of active inflammation in patients with a history of HIK. Hyperreflectivity, hazy borders, convex contour, and epithelial thickness may be informative. Future studies could elucidate a role for deep learning algorithms in diagnosing active HIK.

Study DesignRetrospective Cohort Study.ObjectivesTo determine the incidence of symptomatic retroperitoneal fluid collections (RFCs) following anterior lumbar interbody fusion (ALIF), characterize clinical presentation, and identify independent predictors and associated complications.MethodsBetween 2014 and 2023, adult patients who underwent 1- to 4-level primary or revision ALIF at a single academic university-affiliated hospital were retrospectively reviewed for postoperative RFCs. Asymptomatic RFCs, <1 year follow-up, and surgical indications for trauma, malignancy, or infection were excluded. Symptomatic RFCs, including lymphoceles, hematomas/seromas, abscesses, and urinomas, were identified on postoperative MRI with final classification based on fluid aspiration when available. Multivariable logistic regression was performed to identify independent predictors of RFCs and associations with postoperative complications.ResultsAmong 553 included patients, 44 (7.97%) developed symptomatic postoperative RFCs, most commonly seromas, presenting with abdominal pain and distension. Multi-level surgeries (aOR: 4.472), estimated blood loss ≥725 mL (aOR: 4.213), intraoperative transfusion (aOR: 3.347), L4-5 fusion (aOR: 3.186), higher ASA class (aOR: 2.291), and venous injury (aOR: 2.051) (all P < 0.05) were independent predictors of RFCs. L3-4 fusion provided a protective effect (aOR: 0.163). RFCs were associated with increased risk of subsequent deep vein thrombosis (DVT; aOR: 4.087, P = 0.007) and incision and drainage (aOR: 9.593, P = 0.005).ConclusionsSymptomatic RFCs occurred postoperatively in 7.97% of ALIF cases. Multi-level fusion, blood loss ≥725 mL, intraoperative transfusion, L4-5 fusion, higher ASA class, and venous injury were independently associated with RFC development. Notably, RFCs increased risk of postoperative DVT by 4 times, underscoring the benefit of early recognition in high-risk patients.