Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Aims Transcatheter mitral valve replacement (TMVR) with the Tendyne Mitral Valve System is a treatment option for patients with severe symptomatic mitral regurgitation (MR) unsuitable for conventional mitral valve surgery or transcatheter edge-to-edge repair (TEER). This study sought to evaluate the safety and effectiveness of TMVR through 5-year follow-up. Methods and Results The Tendyne Expanded Clinical Study is a prospective, single-arm, multicentre study that enrolled patients between November 2014 and June 2020. The study enrolled 191 patients (mean age 74.1 ± 8.0 years, 62.8% male, 70.2% New York Heart Association Class (NYHA) class III/IV, 88.5% secondary MR), of whom 186 (97.4%) underwent TMVR with Tendyne. MR grade decreased from ≥3+ in 99.5% patients at baseline to grade ≤1+ in 95.3% at 5 years. In those patients surviving to 5 years (n = 49), durable symptomatic improvement was evidenced by 73.5% patients being in NYHA class I/II at 5 years. The Kansas City Cardiomyopathy Questionnaire overall summary score increased from 48.5 ± 22.5 points at baseline to 67.6 ± 21.5 points at 5 years. Serious adverse events that occurred through 5 years included life-threatening bleeding (11.5%), fatal bleeding (2.6%), renal insufficiency/failure (28.8%), endocarditis (7.3%), device thrombosis (5.8%), and new onset atrial fibrillation (13.1%). No structural device degeneration or device embolism occurred through 5 years. Conclusions The Tendyne TMVR was effective at achieving immediate and sustainable elimination of MR, which was associated with symptomatic improvement and absence of structural valve degeneration in a high-risk cohort over 5 years. These findings support TMVR with the Tendyne System as an alternative for patients with appropriate mitral valve anatomy and symptomatic secondary MR unsuitable for mitral surgery or TEER.

Abstract Purpose Bronchiectasis is a condition characterized by chronic cough, recurrent infections, and progressive airway damage that is rising in prevalence. While often idiopathic, a subset of patients have a genetic cause such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or alpha-1-antitrypsin deficiency (A1ATD). Genetic causes for bronchiectasis should be considered in patients with diffuse bronchiectasis involving ≥2 lobes, especially in those with early onset of symptoms, recurrent otitis media or chronic rhinosinusitis, infertility, organ laterality defects (e.g., situs inversus), exocrine pancreatic insufficiency or family history of bronchiectasis. Genetic testing may impact management decisions. Methods The Mayo Clinic Center for Individualized Medicine developed the Program for Rare and Undiagnosed Diseases (PRaUD) Genetic Testing and Counseling Unit (GTAC) provides abbreviated, point-of-care genetic counseling, and DNA sequencing-based testing. Patients with bronchiectasis evaluated by GTAC underwent exome or genome-based 52-gene panels which included PCD, CF, and A1ATD (SERPINA1)-associated genes. Sequencing panes results were reviewed and interpreted by a multidisciplinary team including genetic counselors, geneticists, and pulmonologists. Results From July 2022 to December 2025, 203 patients were identified; 163 patients completed testing (74% female, 93% white). A molecular diagnosis was confirmed in 10.4% (17/163) of cases, with known pathogenic variants identified in RSPH4A, SERPINA1 (A1ATD), and CFTR (CF). Variants of uncertain significance (VUS) were identified in 24% of patients. Notably, 11.6% (19/163) were identified as CF carriers, a rate significantly higher than the general European-ancestry population (∼4%). Clinical management was impacted for two patients, including the initiation of targeted CFTR modulator therapy in one patient with CF-related disorder (CFTRD) and one CFTR pathogenic variant heterozygote. Conclusions Genetic counselor-supported DNA sequencing for bronchiectasis led to an increased identification of genes that cause bronchiectasis. Interestingly, we found a high rate of CFTR heterozygote variant carriers in our clinic cohort, this aligns with the findings of other studies that CFTR variant carriers can have an increased frequency of bronchiectasis. The identification of pathogenic variants and VUS helps facilitate a diagnosis or potential genetic cause in a significant proportion of patients and highlights the need for further research in understanding the epidemiology of CF, PCD, and A1ATD-related variant genotypes in patients with bronchiectasis. Clinical Implications Comprehensive DNA sequencing, combined with genetic counseling and support from genetic counselors in partnership with pulmonologists can advance precision diagnostics and care for patients with bronchiectasis. This abstract is funded by: None

Abstract Genetic counseling assistants (GCAs) support genetic counselors (GCs) and genetics clinic workflows, but their potential roles in pretest genetic counseling for rare diseases have not been explored. A pilot within the Mayo Clinic Center for Individualized Medicine's Genetic Testing and Counseling Clinic (GTAC), which offers predefined tests for patients with rare disease, explored the impact of GCA pretest education on appointment time and patient questions. After training, GCAs met GTAC patients prior to the GC to provide scripted information on genetics concepts, the visit purpose, and the test including result types and disclosure plans. Data from the pilot and a control group were collected and analyzed using descriptive statistics and two‐sided t ‐tests. Patient cohort characteristics did not differ between the two models. When a GCA provided pretest education, the GC spent an average of 11.2 minutes less with the patient during their session compared to visits completed solely by the GC ( p < 0.0001). Total appointment time was not impacted by GCA education. Questions asked to GCAs were often not within GCA scope to answer (72.7%), and some patients asked repetitive questions to both the GC and GCA (63.2%). Reduction in GC time per patient could lead to increased accessibility by allowing additional patients to be seen in a day. Similar models may support GCA professional development while allowing GCs to remove repetitive education from their genetic counseling sessions, leading to less burnout and/or increased job satisfaction. Impact on administrative workflows, access, revenue, patient satisfaction and outcomes and GC/GCA satisfaction and benefits can continue to be explored when trialing models incorporating GCAs in pretest education roles.

Objective This study aims to identify factors associated with patient global assessment (PtGA) and physician global assessment (PhGA) and discordance between them in systemic sclerosis (SSc). Methods Data from adults with early SSc (<5 years) from the Collaborative National Quality and Efficacy Registry were included. PtGA and PhGA (0–10 scale), clinical evaluations, and patient‐reported outcomes (PROs) were collected every six months. Multivariable mixed‐effects linear regression identified factors associated with PtGA and PhGA using (1) clinical variables and (2) clinical variables plus PROs. Relative weight analysis (RWA) determined the relative importance of each variable. Discordance (≥2 points between PtGA and PhGA) was assessed using multinomial mixed‐effects logistic regression. Results Among 956 patients (83% women, 33% limited disease), mean PtGA and PhGA at enrollment were 4.2 (SD 2.6) and 3.4 (SD 2.0), respectively ( P < 0.001). RWA of clinical variables identified modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class as most influential for both global assessments. After including PROs, PtGA was most influenced by measures of pain, skin symptoms, and physical function. Discordance occurred in 53% of patients (35% PtGA worse, 18% PhGA worse). Worse PtGA was associated with higher overall pain and discomfort. Worse PhGA was associated with higher mRSS, worse NYHA class, higher pain interference, and lower diffusing capacity of the lung. Conclusion Discordance between PtGA and PhGA occurs commonly, highlighting the need for comprehensive symptom management and measurement of disease burden in this complex disease. In SSc, differences in PtGA and PhGA reflect dissimilar weighting of data elements.

Morel-Lavallee lesions (MLLs) are traumatic closed degloving injuries with operative intervention (OI), especially excisional debridement, remaining the mainstay of treatment. However, high-quality evidence describing operative techniques and outcomes remains limited. This study aimed to characterize current OI practices and associated outcomes, especially among patients undergoing excisional debridement, hypothesizing an increased risk of wound complications with this approach for MLLs. Methods This prospective (2021-2024), multicenter, observational study was conducted across 15 trauma centers and included patients diagnosed with MLL who underwent OI. The association between operative technique (eg, excisional debridement) and the primary outcome of wound complications was evaluated. Wound complications were defined as cellulitis, deep wound infection, skin necrosis, necrotizing soft tissue infection (NSTI), and/or organized hematoma. Results Of 88 MLL patients undergoing OI, 36 (40.9%) had excisional debridement, with 4 (11.1%) limited excision to skin, 20 (55.6%) extended to subcutaneous tissue, and 12 (33.3%) down to muscle. Excisional debridement had higher rates of skin necrosis (22.2% vs. 1.9%, P = .002). Although overall rates of wound complications were statistically similar between cohorts (33.3% vs. 17.3%, P = .098), univariate analysis demonstrated excisional debridement had increased risk of wound complications (OR 2.52, CI 1.07-5.97, P = .035). Conclusion This prospective multicenter study over three years demonstrated that a fifth of MLLs undergoing excisional debridement developed postoperative skin necrosis. Excisional debridement also had a more than two-fold increased risk of wound complications compared to other OIs. These findings underscore the importance of investigating alternative operative techniques, such as incision and drainage or minimally invasive debridement methods.

Abstract Background Anti‐M antibodies were described as rarely eliciting hemolytic disease of the fetus and newborn (HDFN) in pregnancy. More recent literature, primarily from Asia, reports severe HDFN attributed to maternal anti‐M. The objective of this study is to determine if there is a difference in the frequency and/or severity of anti‐M HDFN among subjects who self‐report as Asian compared to non‐Asian. Methods Retrospective data were collected from 18 sites. Fetuses/neonates affected by HDFN were categorized as unaffected, mild, moderate, or severe based on clinical management and outcomes. Results Anti‐M was identified in 557 obstetric patients. Among 332 neonates with complete data for analysis, anti‐M was detected in isolation during the pregnancies of 210 (63.3%) neonates; 198 (94.3%) were unaffected by HDFN. The overall frequency of HDFN was 6.5% (2/31) in Asian patients and 5.6% (10/179) in non‐Asian patients. The frequency of severe HDFN was 6.5% (2/31) among Asian patients and 0.6% (1/179) among non‐Asian patients. Among non‐Asian patients, eight (4.5%) were mild and one (0.6%) was moderate. Of 63 pregnancies with anti‐M and ABO incompatibility, 6 (9.5%) were associated with mild HDFN and 57 (90.5%) were unaffected. Of 49 pregnancies with anti‐M and non‐ABO antibody(s), 6 (12.2%) were associated with mild HDFN and 43 (87.8%) were unaffected. One case (10.0%) of HDFN (mild) occurred in the presence of anti‐M, additional antibody(s), and ABO incompatibility. Conclusion In this study, severe anti‐M HDFN was rare in non‐Asian subjects. There is a signal that Asian patients are at greater risk for severe anti‐M HDFN.

Abstract Specialized immune niches located in the stroma-tumor junction promote interactions between tumor-resident antigen-presenting cells and effector lymphocytes that are required for immunotherapy efficacy. We have hypothesized that this stromal-based immune crosstalk may be regulated by provisional extracellular matrix signals, analogous to the early-stages of wound healing where provisional matrix hosts robust immune activity. A cardinal provisional matrix remodeling event, the regulated proteolysis of the large proteoglycan versican (VCAN) generates an immunomodulatory fragment (matrikine), versikine, that engages adaptive immunity. We have previously shown that VCAN proteolysis correlates with T-cell infiltration across multiple solid and liquid cancers with the most immune-evasive cancers showing low to negligible rates of VCAN proteolysis (e.g., 0% in pancreatic adenocarcinoma). A recent clinical trial generated informative prospective data linking VCAN proteolysis with immunotherapy outcomes: patients whose metastatic colorectal tumors categorized as VCAN proteolysis-weak (VPW, 60% of cases) demonstrated inferior responses to checkpoint inhibition (CPI, pembrolizumab) and worse outcomes compared to VCAN proteolysis-predominant (VPP, 40%) cases. Leveraging these prospective trial data, we hypothesized that versikine therapy may rationally reverse the immunosuppression associated with the prevalent VPW phenotype. To tailor versikine therapy to specific human biomarker-stratified tumor phenotypes, we studied experimental models replicating partially T-permissive VPW-VCANlo human cancers and poor-prognosis, immune-exclusionary VPW-VCANhi cancers. Across VPW-like tumors, versikine promoted the stromal accumulation of CD40lghiIcoshiFoxp3neg Tfh-like CD4+ T cells that engaged dendritic cells (DC) and CD8+ T cells in “immune triads” even at baseline (prior to CPI), concurrently with the intratumoral expansion of activated CD8+ T cells expressing cytolytic molecules (granzymes, perforin). In VPW-VCANlo tumors, versikine delivered as LNP-mRNA or recombinant protein demonstrated monotherapy activity, dependent on Batf3-lineage DC and CD8+ T cells. When combined with single-agent CPI, versikine cured most VPW-VCANlo tumors with memory to tumor re-challenge. In VPW-VCANhi tumors, versikine synergized with combination immunotherapy modulating “mature DCs enriched in immunoregulatory molecules” (mregDC). Our data provide mechanistic rationale for the biomarker-stratified, therapeutic restoration of a provisional matrix-regulated immune signaling network to reverse resistance to CPI. Moreover, the data highlight the need to reevaluate prior approaches to globally disrupt tumor stroma in favor of biomarker-driven, pathway-focused harnessing of stromal signals that modulate anti-tumor immunity. Citation Format: Daniel J. Lagal, Duncan Hong, Athanasios Papadas, Emma Geatches, George Yacu, Surabhi Naik, Alicia Gibbons, Alexander Cicala, Kersi Pestonjamasp, Peter Toth, Kristina Matkowskyj, Dustin A. Deming, Fotis Asimakopoulos. Biomarker-driven restoration of tumor provisional matrix signaling network reverses resistance to checkpoint inhibition immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6746.

ABSTRACT Recent advances in the diagnosis and management of reflux disease were the central focus of the inaugural Gatherings in Esophagology (GiE), which convened experts across gastroenterology, surgery, otolaryngology, pulmonology, and basic research. The sessions highlighted innovations in reflux monitoring—including high‐resolution manometry, wireless pH monitoring, and novel salivary biomarkers—while critically evaluating their diagnostic accuracy and clinical utility. Presentations explored the limitations of traditional proton‐pump inhibitor therapy, the emergence of potassium‐competitive acid blockers as a new class of acid suppressants, and the evolving role of adjunctive treatments such as mucosal protectants, reflux reducers, and neuromodulators for refractory symptoms. The discourse extended to advanced interventional procedures, including transoral incisionless fundoplication, magnetic sphincter augmentation, and the RefluxStop device, with discussion of patient selection, efficacy, and complication management. Discussants emphasized the pathophysiology and management of extraesophageal manifestations of reflux, the interplay between reflux and pulmonary disease, and the diagnostic challenges in pediatric populations. The meeting also addressed the integration of behavioral therapies, the role of the microbiome, and the application of artificial intelligence in reflux diagnostics. Collectively, these insights underscore a shift toward precision medicine in reflux disease, emphasizing individualized diagnostic strategies and tailored therapeutic approaches to improve patient outcomes.