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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 Background Post‐transplant malignancy is a major determinant of long‐term outcomes after solid organ transplantation. Whether simultaneous pancreas–kidney (SPK) transplantation confers a differential post‐transplant cancer risk compared With kidney transplantation alone (KA) remains uncertain. Methods We conducted a retrospective propensity score–matched cohort study of adult transplant recipients at three Mayo Clinic sites between 2001 and 2017. SPK recipients ( n = 484) were matched 1:1 with KA recipients using propensity scores. The primary outcome was post‐transplant cancer incidence analyzed using Fine–Gray competing risks regression with death as a competing event. Standardized incidence ratios (SIRs) were calculated relative to the US general population. Cox proportional hazards models with cancer modeled as a time‐varying covariate evaluated associations with mortality and death‐censored graft failure. Results Over a median follow‐up of 10 years, overall cancer incidence was similar between SPK and KA recipients (subdistribution hazard ratio [sHR] 0.80, 95% CI 0.63–1.02; p = 0.07). The observed trend toward lower cancer incidence in SPK recipients was driven by a lower incidence of non‐melanoma skin cancer (NMSC) (sHR 0.72, 95% CI 0.53–0.97; p = 0.03), which was attenuated after age adjustment (sHR 0.76, p = 0.07). Incidence of other malignancies did not differ between groups. Compared with the US general population, cancer risk excluding NMSC was approximately twofold higher in both cohorts (SIR 2.18 for SPK vs. 2.23 for KA). Incident malignancy was strongly associated with increased mortality (HR 3.40 in KA and 2.07 in SPK) but not with a statistically significant increase in graft failure. Conclusions In this propensity score–matched cohort study, overall post‐transplant malignancy incidence was comparable between SPK and KA recipients. Both groups experienced substantially elevated cancer risk relative to the general population, and incident malignancy was strongly associated with mortality. These findings suggest that malignancy risk is driven primarily by shared immunologic and demographic factors rather than transplant type.

ABSTRACT Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA ( n = 35) or alloHSCT ( n = 31). Baseline characteristics such as genetics, co‐morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow‐up from therapy initiation was 18 months (95% CI: 11–26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real‐world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05–0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant‐eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score‐based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

Background: Rheumatic heart disease (RHD) remains a prevalent cause of valvular heart pathology worldwide, especially in younger populations of low- and middle-income countries. Tricuspid valve (TV) involvement in RHD is usually secondary to left-sided valvular lesions and is often underdiagnosed, since two-dimensional echocardiography (2DE) has limited ability to visualize the complex tricuspid anatomy. Compared with 2DE, three-dimensional echocardiography (3DE) provides an en face visualization of the tricuspid valve, enabling direct planimetric measurements and detailed commissural assessment, and offers advantages for evaluating complex valvular heart disease (VHD). Thus, this study aimed to assess baseline characteristics and valvular morphology in patients with rheumatic tricuspid valve disease using 3DE. Methods: A prospective cohort single-center study conducted between April 2022 and April 2023 included 34 patients with rheumatic TV involvement. Baseline demographics, morphological features, and hemodynamic parameters were assessed using transthoracic 3DE. Results: The mean age of included patients was 45.5 ± 9.1 years, and 88.2% were female. Most patients had associated left-sided valvular involvement (mitral or combined mitral and aortic). Commissural fusion (50%), leaflet thickening (82.4%), restricted mobility (85.3%), and coaptation loss (58.8%) were predominantly noted. The mean diastolic TV gradient was 3.9 ± 3.4 mmHg, planimetry area 3.3 ± 1.7 cm2, and estimated pulmonary artery systolic pressure 43.3 ± 19.5 mmHg. Mean right ventricular (RV) global longitudinal strain was –23.6 ± 6.1%. Conclusion: Rheumatic TV involvement is characterized by commissural fusion, leaflet thickening, and coaptation loss, highlighting the diagnostic value of 3DE in identifying morphological patterns that may guide intervention planning.

Abstract Introduction High disease burden has been associated with reduced efficacy and resistance to BCMA CAR-T therapy in relapsed/refractory multiple myeloma (van de Donk, Blood Cancer Discov, 2021; Martin, J Clin Oncol, 2023). While CAR-T cells can still induce remissions in these patients, outcomes are often worse compared to those with a lower tumor load. In addition to tumor debulking, novel strategies are needed to improve responses and durability of CAR-T cells in these patients. We previously demonstrated that immunomodulatory drugs (IMiDs) improve in vivo responses to T cell engagers (TCE) in high tumor burden setting by boosting T cell activation (Meermeier, Blood Cancer Discov, 2021; Meermeier, Blood, in press). IMiDs have also been shown to promote CAR-T cell antitumor activity in moderate to low tumor burden conditions (E:T ratios ≥1:1) (Yan, J Transl Med, 2024; Wang, Clin Cancer Res, 2018). We hypothesized that combining CAR-T with an IMiD may improve CAR-T function in high tumor burden setting. Methods We generated murine anti-BCMA.CD28 CAR-T cells by transducing Con-A stimulated T lymphocytes extracted from hCRBN+ mice, expanded with IL-7 and IL-15 to express a memory phenotype. We then tested CAR-T, or untransduced T cells, ability to kill in vitro IMiD resistant, hCRBN-, Vk*MYC myeloma cells in low (E:T 1:1) and high (E:T 1:≥5) tumor burden, with and without pomalidomide (POM) and IL-2. Tumor killing and T cell phenotype were assessed by flow cytometry at 24-72 hours. This controlled system allowed us to focus on putative CAR-T cell intrinsic impact of IMiDs. Results In low tumor burden setting, CAR-T effectively killed tumor at all timepoints, with or without POM; addition of POM increased T cell number, confirming that IMiDs support CAR-T expansion. Unexpectedly, in high tumor burden (E:T 1:≥5), adding POM diminished CAR-T mediated killing over time and hindered CAR-T expansion. Moreover, combination with POM decreased granzyme B, while increased expression of exhaustion marker TOX, ultimately leading to CAR-T apoptosis. This phenotype was further intensified by increasing concentrations of IL-2 in the co-culture, resulting in increased expression of CAR-T expressing LAG-3, TIM-3, and TIGIT, suggesting that CAR-T cells may be overactivated by POM and IL-2. Our manufacturing protocol preferentially expands memory CAR-T cells, favored for their durability, proliferative capacity, and considered to rapidly expand upon encounter with antigen. We reasoned that CAR-T are already sufficiently activated by CAR/CD3z stimulation, especially with a CD28 co-stimulatory domain (versus 4-1BB), known promote rapid, effector memory expansion upon activation (Kawalekar, Immunity, 2016). Activation is intensified by high tumor burden where antigen is highly abundant. We hypothesize under intense, sustained antigen exposure in high tumor burden, the addition of POM paradoxically triggers activation induced cell death (AICD). Conclusion Although it is well accepted that POM can boost T cell function and proliferation, we demonstrate that in high tumor burden, POM drives memory CAR-T to increase exhaustion markers and apoptotic cell death by overactivation, further exacerbated by exogenous IL-2. Interestingly, we have shown opposite effects of preclinically combining POM with TCE therapy in high tumor burden, based on dosing schedule. Concomitant administration transiently boosted T cell activation improving response rates but rapidly led to T cell exhaustion (Meermeier, Blood Cancer Discov, 2021). In contrast, IMiD pretreatment in the context of step-up dosing TCE administration improved T cell fitness and longevity (Meermeier, Blood, in press).The effect of IMiDs on T cells transcriptional program is likely to differ depending on differentiation stage and mode of T cell activation. Memory cells have more sensitive TCR signaling (Kumar, Immunity, 2011) and can be hyperactivated, leading to AICD. Thus, timing of IMiD administration, when tumor burden is low, may be a critical consideration as different T cell subsets require different levels of activation. Conversely, TCE provide only initial activation via TCR signaling, therefore POM may help in providing necessary co-stimulation in this setting. Future studies will evaluate different co-stimulatory domains and test in vivo effects of POM on CAR-T expansion and persistence, particularly as CAR-T cells diminish over time as tumor burden increases.

Abstract Background: Although progression-free survival (PFS) in early-stage (ES) classic Hodgkin Lymphoma (cHL) is high, there remains a subset of patients (pts) at higher risk of worse outcomes, particularly in those with unfavorable risk disease. Leveraging pt-level data from within the HoLISTIC (Hodgkin Lymphoma International STudy for Individual Care) Consortium, the E-HIPI was developed in clinical trial pts and validated in real-world registry pts to predict 2-year (y) PFS (Rodday. NEJM Evidence 2025). Continuous, objective, and readily measurable pre-treatment variables were considered, with sex, maximum tumor diameter, albumin, and hemoglobin included as significant predictors. Using the E-HIPI, interactive calculators for pt risk, comparison, and stratification were created (https://rtools.mayo.edu/holistic_ehipi/). Although the E-HIPI was developed and validated in both unfavorable and favorable ES cHL pts, the clinical predictors are primarily markers of unfavorable disease. In the development and initial validation cohorts, 2y PFS was 93.7% and 90.3%, respectively, the C-statistic was 0.63 in both cohorts, calibration was strong with slight underprediction of events in the validation cohort, and the E-HIPI outperformed the historic binary classification of patients as favorable or unfavorable using EORTC criteria. However, since pts in the original E-HIPI development and validation were primarily treated with ABVD chemotherapy protocols, additional validation is needed, particularly among pts with unfavorable ES cHL who were treated initially with more intensive chemotherapeutic platforms (e.g., BEACOPP-based). Thus, we conducted an external validation of the E-HIPI in pts treated on recent unfavorable ES cHL GHSG trials. Methods: The validation cohort included 2367 adults (ages 18 to 60y) with newly-diagnosed unfavorable cHL from randomized phase 3 trials conducted by the GHSG (HD14 von Tresckow. JCO 2012; and HD17 Borchmann. Lancet 2021). We calculated the predicted probability of 2y PFS events based on the E-HIPI model equation (scale 1-100%). Model performance was assessed using discrimination and calibration. Discrimination, which is the model's ability to separate high and low risk pts, was assessed using Harrell's C-statistic. Calibration, which is the model's ability to accurately predict absolute risk, was assessed by comparing observed and predicted probabilities of 2y PFS events within quintiles of predicted probabilities and estimating calibration-in-the-large (predicted minus observed event rate) and the calibration slope. Results: For pts treated on unfavorable GHSG trials, mean age was 33y, 95% had stage II disease, mean baseline E-HIPI score (i.e., predicted 2y PFS event rate) was 6.0% (SD=2.3%), and the observed 2y PFS rate was 96.2% (95%CI: 95.4-97.0%). The C-statistic was 0.65 (95% CI: 0.59-0.70), calibration-in-the-large was 0.02, and the calibration slope was 1.08 (95% CI: 0.52, 1.64). Within the lowest risk E-HIPI quintile, the observed 2y PFS event rate was 1.6%, compared with 6.1% in the highest risk quintile. Conclusions: In external validation of the recently published E-HIPI in pts with cHL treated on unfavorable GHSG trials using more intensive BEACOPP-based protocols, discrimination was similar to the original development and validation cohorts. Collectively, the E-HIPI is a treatment-agnostic prediction tool across varied treatment regimens for unfavorable ES cHL pts. Better 2y PFS in the GHSG trials than in the E-HIPI development and initial validation cohorts may have contributed to mild misclassification, likely reflecting differences in treatment regimens. This may be resolved with recalibration or incorporating granular treatment variables into future models. Additional research is needed to understand E-HIPI performance in pts with favorable disease who have even lower event rates as well as to more fully predict individualized pt outcomes across varied chemotherapy platforms and radiation received for all ES cHL pts.

Introduction The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer’s disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient’s trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes. Methods This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included. All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process. Ethics and dissemination Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO registration number CRD42024562389.