Citations

Abstract Introduction Underwater endoscopic mucosal resection (uEMR) technique has gained popularity for removal of large non-pedunculated colorectal polyps (LNPCPs) due to high en-bloc resection rates and lower recurrence rates. However, there is no information regarding outcomes of uEMR for giant colorectal polyps. Therefore, we aimed to evaluate the outcomes of uEMR for giant colorectal polyps across multiple centers in North America. Methods We conducted a multicenter retrospective study of adults with giant colorectal polyps undergoing uEMR between January 2019 and November 2025. Giant colorectal polyps were defined as LNPCPs ≥40 mm. Primary outcomes were technical success and rate of recurrent adenoma. Secondary outcomes were severe adverse events (SAEs) and predictors of technical success, recurrence, and SAEs. Results A total of 137 polyps, with mean polyp size 47.6 mm were included. Majority of the lesions were located in right colon (61%, n = 83) with the most common histopathology being high-grade dysplasia (HGD) (31.4%, n = 43). Technical success was achieved in 90.5% (n = 124) with en-bloc resection rate of 11.7% (n = 16). Polyp fibrosis (OR: 0.08) and HGD (OR: 0.15) were independent predictors of inability to achieve technical success. Of 92 (67.1%) patients with follow-up, recurrent polyp was present in 8.7% (n = 8). SAEs were noted in 9.5%, consisting of delayed bleeding (9.5%, n = 13), while no delayed perforation or post polypectomy syndrome was noted. Discussion Our study demonstrates that uEMR is technically feasible for the removal of giant colorectal polyps with an acceptable safety profile and recurrence rate.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

Abstract On average, females have smaller airways than males. The largest discrepancy in airway size occurs during puberty, when endogenous sex hormone concentrations diverge between males and females. Transgender individuals often use gender‐affirming hormone therapy (GAHT) to align physical characteristics with gender identity. It is unknown whether GAHT influences airway size (luminal area and length). We evaluated the large conducting airways before starting GAHT and while undergoing years of GAHT. This retrospective within‐subject study included 12 adult transgender individuals who underwent CT scanning before starting GAHT and again after ≥1 year of GAHT. For each transgender individual, we identified two matched cisgender controls (one male and one female) who also underwent two CT scans over a comparable time interval for longitudinal comparison. We used a three‐dimensional reconstruction of CT imaging to measure luminal areas. Within‐subject changes in airway size between scans were assessed using Student's paired t ‐tests in transgender individuals undergoing feminizing hormone therapy. Variance between scans was assessed using Levene's test. Pre‐scans occurred an average of 2.0 ± 3.1 years before beginning GAHT. Transgender persons were on GAHT for an average of 3.3 ± 1.7 years (range, 1.0 – 6.7 years) at their second scan. We found no significant differences in airway luminal cross‐sectional areas for transgender persons on feminizing hormone therapy. The variance in airway size change between scans was not statistically different between transgender individuals and control subjects. Our findings suggest that the size of large conducting airways might remain unchanged after a period (>1 year) on GAHT.

Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Importance Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) lacks proven relapse-preventive therapies. While clinical trials are ongoing, safety data may be limited and approved drugs are costly. Studies of interleukin 6 receptor blocker (IL-6RB) in MOGAD are limited by small numbers and no comparative studies, contributing to low use. Objective To evaluate the impact of IL-6RB therapy on relapse rates in MOGAD and compare relapse frequency with intravenous immunoglobulin (IVIG). Design, Setting, and Participants This international, multicenter, retrospective cohort study (January 1, 2015, through December 31, 2025) included a historical IVIG-treated cohort of varying doses. The study took place across sites in North and South America (US, Canada, Mexico, Argentina, Brazil, Chile, Colombia, and Peru). Patients with MOGAD (n = 116, no excluded patients) who received at least 1 dose of an IL-6RB were included. These data were analyzed in January 2026. Exposures Tocilizumab or satralizumab. Main Outcomes and Measures Annualized relapse rate (ARR) during IL-6RB therapy, time to next relapse after treatment initiation, and adverse events. Outcomes were compared with the IVIG cohort using inverse probability of treatment weighting (IPTW) adjusted for age, sex, prior ARR, and concomitant therapies. Results A total of 116 patients with MOGAD (89% relapsing) receiving IL-6RB (tocilizumab, 104 [90%] and satralizumab, 12 [10%]) were included; overall, 60.3% were female, 39.7% were male, and 18% were younger than 18 years. The median (IQR) IL-6RB treatment follow-up was 1.4 (0.7-2.5) years and 23 relapses occurred during 241.8 person-years of IL-6RB therapy. The ARR decreased from 0.64 (95% CI, 0.58-0.70) for relapsing MOGAD before IL-6RB to 0.09 (95% CI, 0.06-0.14) during IL-6RB treatment (incidence rate ratio, 0.08; 95% CI, 0.04-0.16). Adverse events occurred in 58 patients (50%), most commonly mild infections, although 10 (9%) had severe infections. In the IVIG cohort (n = 59), 30 relapses occurred over 133.8 person-years (ARR, 0.22; 95% CI, 0.15-0.32). After IPTW, IL-6RB was associated with a lower hazard ratio (HR) than the group who underwent IVIG therapy less than 1 g/kg every 4 weeks (HR, 4.5; 95% CI, 2.0-9.8), with no significant difference vs the group who underwent IVIG 1 g/kg or more every 4 weeks (HR, 2.0; 95% CI, 0.8-4.5). Conclusions and Relevance In this multicenter observational cohort, IL-6RB use in MOGAD was associated with low relapse rates and a favorable safety profile, though severe infections occurred occasionally. Relapse rates were lower than the group who underwent IVIG less than 1 g/kg every 4 weeks but not significantly different from the group who underwent IVIG 1 g/kg or more every 4 weeks. This supports IL-6RB as a potential relapse-prevention therapy in MOGAD; the wide availability and relative affordability of tocilizumab may enable broad global use.

Abstract Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

Background Radionuclide SPECT/computed tomography (CT) is standard for diagnosing transthyretin cardiac amyloidosis (ATTR-CM), but the prognostic value of quantitative metrics remains incompletely defined. We investigated their prognostic utility and additive value beyond existing staging systems. Methods Retrospective study of patients undergoing technetium-99m-pyrophosphate (PYP) SPECT/CT, including consecutive clinically referred patients (October 2023 to 2024) and trial participants with positive scans from January 2022. Myocardial PYP was quantified using standardized uptake values (SUV mean and SUV max ) and volumetric measures [percent injected dose (%ID), cardiac amyloid activity (CAA)]. Major adverse cardiovascular events (MACEs) comprised heart failure hospitalization or death. Cox and Kaplan–Meier analyses assessed associations; likelihood ratio testing and change in area under the curve (AUC) evaluated the additive prognostic value to existing staging systems. Results Among 43 patients with ATTR-CM, 16 experienced MACE over a median 518 days. AUCs ranged from 0.74 to 0.88 at 3 months and 0.56–0.62 at 12 months. All variables trended toward association with MACE: SUV mean ( P = 0.02), SUV max ( P = 0.03), %ID ( P = 0.06), and CAA ( P = 0.06). After age adjustment, cut-points for SUV max (5.8) and SUV mean (3.5) remained associated with MACE. Adding imaging variables to the National Amyloidosis Centre and Columbia staging systems did not significantly improve prognostic accuracy (Δ χ 2 : 0.40–2.48, P = 0.11–0.53). Interobserver reproducibility was high (intraclass correlation coefficients = 0.89–0.99). Conclusion Quantitative Tc-99m–PYP SPECT/CT metrics were associated with short-term outcomes in ATTR-CM, but did not improve established staging systems. Findings are hypothesis-generating and require validation in larger cohorts.

Abstract Rural and low-socioeconomic status women face social determinants of health barriers leading to disproportionately low rates of breast cancer screening and markedly reduced participation in clinical trials. To address this gap, we developed the WeCARE (Women’s Engagement for Cancer Awareness, Resources, and Education) intervention using a community-engaged approach. This paper describes how Community Advisory Board feedback informed the development of Mayo Clinic Health System’s WeCARE intervention components. Their input was systematically analyzed using the Consolidated Framework for Implementation Research (CFIR 2.0) to identify determinants of acceptability, appropriateness, and feasibility and to guide actionable refinements to intervention content and delivery.

Abstract Background and Aims EUS-guided gastroenterostomy (EUS-GE) is an effective option to palliate symptoms of gastric outlet obstruction (GOO). While the jejunum is conventionally targeted (EUS-GJ), targeting the duodenum (EUS-GD) may offer clinical advantages. Outcomes were compared for EUS-GJ and EUS-GD. Methods Adult patients who underwent EUS-GE for GOO between 2020 and 2024 were included and categorized as an EUS-GD if the stent entered the transverse or ascending duodenum or an EUS-GJ if the stent entered more distally. The primary outcome was clinical success (soft diet tolerance at 7 days). Secondary outcomes included adverse events (AEs), stent misdeployment, and unplanned endoscopic reintervention. Baseline demographic variables and outcomes were compared with statistical significance at p < 0.05. Results Of the 139 included patients (median age 67 years (IQR 61–74); 41% female), 105 underwent EUS-GJ and 34 underwent EUS-GD. Clinical success was 98% for EUS-GJ and 94% for EUS-GD (p = 0.25). The misdeployment rate was 7% for EUS-GJ and 0% for EUS-GD (p = 0.19). The AE rate was 22% for EUS-GJ and 12% for EUS-GD (p = 0.23). There were no significant differences for stent obstruction (EUS-GJ 12% vs. EUS-GD 6%), bleeding (2% vs. 6%), perforation (4% vs. 0%), stent migration (1% vs. 0%), infection (3% vs. 0%), and unplanned reintervention (14% vs. 9%). Conclusion Both EUS-GJ and EUS-GD demonstrate high clinical success with no significant differences in adverse event rates. These data can support intraprocedural decision-making for endoscopists performing EUS-GE.