Faculty Bibliography

OBJECTIVE/UNASSIGNED:Timely use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) is vital for managing type 2 diabetes (T2DM) and preventing cardiovascular and renal complications. However, socioeconomic barriers and prescribing inertia may disproportionately affect disadvantaged populations. We examined racial and ethnic differences in the initiation of SGLT2i among Medicaid patients with T2DM. METHODS/UNASSIGNED:Adult participants 18-64 with T2DM and prescribed with metformin were drawn from MarketScan Multistate Medicaid Database (2015-2022) for this retrospective cohort study. We used a Cox proportional hazards model, adjusted for age, sex, type of Medicaid coverage, and comorbidities, to assess time to SGLT2i initiation. RESULTS/UNASSIGNED:Among 13 744 Medicaid patients, non-Hispanic Black patients had an 18% lower rate of SGLT2i initiation compared with non-Hispanic White patients (hazard ratio [HR] = 0.82; 95%CI: 0.75-0.90). This disparity was most pronounced among patients without pre-existing atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease (HR = 0.79; 95%CI: 0.71-0.87). No significant racial/ethnic differences were observed among patients with these conditions. CONCLUSIONS/UNASSIGNED:Significant delays in SGLT2i initiation among Black Medicaid patients-particularly in early stage of diabetes-may increase their risk for long-term complications. Addressing structural barriers through targeted interventions is essential to promote equity in diabetes care.

Pathological deposition of endogenous material within tissues represents a central, unifying mechanism across a broad spectrum of prevalent human diseases. Atherosclerosis and Alzheimer's disease (AD) exemplify this paradigm: atherosclerosis is driven by subendothelial accumulation of apolipoprotein B-containing lipoproteins, cholesterol crystals, and hydroxyapatite, while AD is characterized by cerebral deposition of misfolded amyloid-β (Aβ) and/or hyperphosphorylated tau. Emerging evidence implicates substantial lipid dyshomeostasis in AD pathogenesis, including lipid-droplet-accumulating microglia and widespread lipidomic disruption, blurring the categorical boundary between "lipid" and "protein" deposition diseases. Apolipoprotein A-I (apoA-I) dysfunction bridges both domains: post-translational modifications and point mutations impair reverse cholesterol transport in atherosclerosis and simultaneously promote apoA-I amyloid fibril formation in systemic amyloidosis. Across atherosclerosis, AD, systemic amyloidoses, immune complex-mediated nephropathies, crystal arthropathies, and lysosomal storage disorders, shared pathophysiologic processes emerge: production-clearance imbalance, conformational transitions favoring aggregation or crystallization, microenvironmental modulation by extracellular matrix components, and chronic sterile inflammatory responses driven by NLRP3 inflammasome activation. In this review, we synthesize deposition biology using atherosclerosis and AD as primary paradigms, integrate mechanistic insights from related disorders, highlight convergent molecular pathways including NLRP3, proteostasis, and glymphatic clearance, and discuss diagnostic and therapeutic strategies. A conceptual framework unifying these conditions as variations on a common deposition theme is proposed to guide broadly applicable precision therapies.

PURPOSE/OBJECTIVE:EA1181 (ClinicalTrials.gov identifier: NCT04266249) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point-3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)-will be reported when data mature. METHODS:Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS:A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER-]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER- tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION/CONCLUSIONS:Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER- and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (n = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (n = 5) and RNA-based fusion profiling (n = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5-75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (n = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.

BACKGROUND:People with multiple sclerosis (pwMS) treated with anti-CD20 monoclonal antibodies have an elevated infection risk, yet long-term comparative data with oral fumarates are limited. OBJECTIVE:To compare infection incidence, healthcare resource utilization, and relapse outcomes among pwMS receiving fumarate or anti-CD20 therapy for ⩾2 years. METHODS:This retrospective propensity-matched (1:2) analysis used US Komodo Health claims (1 January 2016-31 May 2022) for pwMS aged 18-64 years with ⩾2 years of continuous follow-up. Outcomes were assessed using Poisson generalized linear models. RESULTS: = 0.021). CONCLUSIONS:Fumarate therapy was associated with a lower infection risk versus anti-CD20s. The infection rate in the fumarates group remained relatively stable over time, but it progressively increased in the anti-CD20 group, with the most prominent differences observed at year 4 and beyond.

BACKGROUND/UNASSIGNED:It is unknown how the increased range of motion and improved gait mechanics provided by total ankle arthroplasty (TAA) affects the progression of subtalar arthritis compared with ankle arthrodesis (AA). We hypothesized that patients treated with TAA would have a lower incidence of postoperative subtalar arthrodesis (SA) compared to AA. METHODS/UNASSIGNED: <.05. RESULTS/UNASSIGNED: > .05). In a multivariate analysis, AA remained associated with increased risk of requiring SA (OR = 1.90, CI = 1.01-3.56). CONCLUSION/UNASSIGNED:In this study, we found a significantly higher incidence of subtalar arthrodesis following AA compared with TAA. Surgeons may consider the risk of progression to SA when deciding between TAA and AA for patients with advanced ankle arthritis, particularly in preoperative counseling for patients without existing subtalar arthritis, as TAA may offer an opportunity to mitigate this risk. LEVEL OF EVIDENCE/UNASSIGNED:Level III, retrospective comparative study.

CONTEXT/BACKGROUND:Osteopathic manipulative treatment (OMT) utilizes manual techniques to address somatic dysfunctions (SDs) and promote physiologic function. Although SDs commonly develop following traumatic injury, the role of OMT in postinjury remains incompletely characterized. Patients recovering from trauma frequently experience persistent pain and functional limitations requiring ongoing healthcare utilization. To address this need, we established a novel OMT for trauma program (OTP) to complement interventions for patients with subacute and chronic postinjury pain and mobility impairments. OBJECTIVES/OBJECTIVE:This study aims to evaluate the growth and effectiveness of the novel OTP over its first 3 years. METHODS:We retrospectively analyzed data for all patients treated at the OTP between January 1, 2021 and December 31, 2023. The outcomes included patient volume, relative value units (RVUs), and referral patterns as well as changes in pain, mobility, and other subjective improvement patients attributed to OMT. We performed subgroup analyses of patients who reported a mechanism of injury (MOI, "Injured") and those who did not ("No MOI"). Data are presented as percentages or medians (interquartile range [IQR]). RESULTS:During its first 3 years, the OTP provided 279 OMT sessions for 95 patients (41 [43.16 %] male and 54 [56.84 %] female; median 52 [41.50-64.50] years-old), applying a trauma-informed biomechanical OMT model. Quarterly patient encounters, RVUs generated, and new patient referrals increased per calendar-year quarter (CYQ; r=0.74, 0.62 and 0.56 with p=0.0028, 0.028, and 0.016, respectively). Referral patterns shifted from trauma/acute care surgery (T/ACS) and Physical Medicine and Rehabilitation (PM&R; 51.85 to 25.0 % and 33.33 to 2.78 %) toward OTP patient referrals and Primary Care referrals (0-19.44 % and 11.11-47.22 %). Median pain scores decreased immediately following the first OMT session (3 [2-5] on a 10-point pain scale). OTP patients whose first follow-up was within the study period (61, 64.21 %) reported a similar decrease between OMT sessions #1 and #2 (4 [3-6]). All patients reported improved mobility immediately after OMT. Additional benefits that patients attributed to the OTP included improvements in daily activity level (75.41 %), mood (60.66 %), sleep quality (36.07 %), and pain-free periods (36.07 %). The rate of immediate post-OMT complications (universally described as musculoskeletal discomfort or pain) was 2.87 %. We detected no significant differences during subgroup analyses. Median pain scores improved similarly between Injured and No MOI subgroups immediately after OMT session #1 (3 [2-5] vs. 3.5 [1.5-4.25], p=0.337) and between OMT sessions #1 and 2 (4 [3-6] vs. 4 [1.5-6], p=0.363). CONCLUSIONS:Our data demonstrate that not only is it possible to integrate a novel OTP into a level 1 trauma center but also that such a program is likely to grow significantly over time and consistently provide potentially beneficial OMT services for patients who do and do not identify a MOI. Programs like the OTP may provide a distinct modality to help improve postinjury pain and mobility limitations, among other potential benefits, although further analysis is necessary to assess causality. The present data informed updates to OTP operations, including the implementation of prospective, higher-fidelity data collection to enable more detailed and accurate analyses. Further research, including comparative studies, is warranted to explore the potential benefits of OMT for the trauma population.

BACKGROUND:Social determinants of health (SDOH) influence cancer prevention and outcomes. Among SDOH, economic stability-including food insecurity, income, employment, and housing stability-has a major impact on health. However, data linking food security status with cancer screening completion remain limited. We examined whether lower food security status was associated with lower completion of colorectal, breast, cervical, and prostate cancer screening. METHODS:We performed a retrospective analysis of the 2018-2023 National Health Interview Survey. Analyses were limited to cancer-specific complete-case cohorts: colorectal (N = 59,849), breast (N = 30,867), cervical (N = 56,229), and prostate (N = 20,518). Food security was categorized as high, marginal, or low/very low. Screening completion was the dependent variable. Multivariable logistic regression estimated adjusted odds ratios (aORs) for screening by food security status, controlling for sociodemographic and clinical covariates. Sensitivity analyses used age-stratified eligibility definitions across survey years. RESULTS:Compared with high food security, marginal food security was associated with lower odds of screening across cancers (aOR range, 0.63-0.88), and low/very low food security showed similar or larger deficits (aOR range, 0.60-0.88). Associations were significant for all four cancers and were similar in sensitivity analyses. CONCLUSIONS:Lower food security status was associated with lower completion of cancer screening. Addressing food insecurity may improve screening equity and reduce cancer disparities. IMPACT/CONCLUSIONS:Lower food security status was associated with lower completion of guideline-recommended screening across four cancers, even after multivariable adjustment. Future work should test whether interventions addressing food insecurity can improve screening.

BACKGROUND:Tracheal intubation is a common yet high risk procedure in the critically ill with as many as half experiencing peri-intubation adverse outcomes. RESEARCH QUESTION/OBJECTIVE:We aimed to evaluate the comparative effectiveness and safety of various sedative agents used for endotracheal intubation of the critically ill patient in the emergency department, intensive care unit, operating room, and pre-hospital setting. STUDY DESIGN & METHODS/METHODS:We conducted a network meta-analysis and systematic review of randomized controlled trials. We searched MEDLINE, EMBASE, PubMed, Cochrane, and trial registries from inception to December 10, 2025 for Randomized controlled trials (RCTs) comparing two or more sedative agents in critically ill adults or children undergoing endotracheal intubation. Outcomes of interest were hemodynamic instability during intubation, hypoxemia, cardiac arrest, mortality, intensive care unit and hospital length of stay, vasopressor use, adrenal insufficiency, and first-pass success. Reviewers screened, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool independently and in duplicate. We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates. RESULTS:We included 21 RCTs enrolling 6,031 patients across Intensive Care Unit, Emergency Department, Operating Room, and pre-hospital settings. Compared with etomidate, there is probably more hemodynamic instability during intubation with ketamine (RR 1.31, 95% CI 1.15-1.48; moderate certainty). Ketamine-propofol may decrease hemodynamic instability during intubation compared with etomidate (RR 0.44, 95% CI 0.27-0.72; low certainty) and ketamine (RR 0.34, 95% CI 0.21-0.56; low certainty). Compared with etomidate, ketamine may decrease the need for the initiation of post-intubation continuous infusion vasopressors (RR 0.80, 95% CI 0.50-1.28; low certainty). Etomidate caused increased adrenal suppression compared with other agents. INTERPRETATION/CONCLUSIONS:When considering sedation agents for endotracheal intubation of the critically ill, etomidate probably causes less hemodynamic instability during intubation when compared with ketamine. However, etomidate may increase the need for the initiation of post-intubation continuous infusion vasopressors when compared with ketamine and increases adrenal suppression. The clinical importance of these competing effects remains uncertain. Ketamine-propofol may decrease hemodynamic instability during intubation when compared with etomidate and ketamine though the available evidence is too limited and uncertain to support firm conclusions and further randomized trials are needed.