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Cardiovascular disease (CVD) remains the leading cause of death worldwide and is a major driver of critical illness, resulting in admission to cardiac intensive care units (CICUs). Patients with acute, life-threatening CVD often experience episodes of acute decompensation characterized by high symptom burden that may portend progressive loss of function, significantly impair quality of life (QOL), and involve high-intensity, technologically advanced therapies to sustain life. Despite these advances, up to 30% of patients die during CICU hospitalizations, and those who survive may subsequently face persistent functional impairment and psychosocial distress. During critical CVD (CCVD), patients often endure prognostic uncertainty and face complex decisions regarding life-sustaining therapies alongside refractory symptoms. Thus, care that focuses exclusively on disease-directed or life-prolonging therapies is often insufficient to address the full spectrum of patient and caregiver needs. When integrated alongside intensive cardiovascular care, palliative care (PC) offers a complementary and essential approach to the management of CCVD to inform therapeutic decisions, improve QOL, and address psychosocial and spiritual well-being. In this article, a multidisciplinary team featuring PC clinicians (physicians, nurse practitioners, social worker, psychologist, and chaplain), cardiologists, cardiac surgeons, cardiothoracic anesthesiologists, and intensivists present evidence-based guidance in a “Top Ten Tips” format to support PC clinicians caring for CICU patients and their caregivers.

BACKGROUND: It is unknown whether cardiac resynchronization therapy (CRT) improves systemic metabolomic profile by enhancing left ventricular function. The observational cohort study aimed to investigate the effect of CRT on left ventricular ejection fraction (LVEF) and circulating plasma metabolites in patients who had heart failure with reduced LVEF. METHODS: We prospectively screened patients with ischemic cardiomyopathy and nonischemic cardiomyopathy who received CRT with a defibrillator for LVEF ≤35% according to current guidelines. Clinical assessment included echocardiography and device interrogation. Blood samples for metabolomic analysis were collected before CRT and at 6-month follow-up. Plasma was subjected to gas chromatography-mass spectrometry and 1 H nuclear magnetic resonance-based metabolomic analysis. RESULTS: Totally 92 patients were enrolled, with a mean age of 67.3±11.3 years (37.0% female). LVEF was significantly improved from 28.9±7.6% at baseline to 36.0±11.3% at 6 months ( P <0.001) and to 40.1±12.6% at 12 months ( P <0.001). After CRT, 42 metabolite features were significantly decreased compared with the baseline. The ketone bodies, including 3-hydroxybutyrate ( P <0.001) and acetone ( P =0.01), were reduced. A branched-chain amino acid, isoleucine, was also decreased after CRT ( P =0.01). These metabolomic changes were mainly observed in the nonischemic cardiomyopathy group, while the metabolomic profile in the ischemic cardiomyopathy group was characterized by enhanced amino acid oxidation and elevated levels of lactate and pyruvate. The improvement in LVEF positively correlated with the ratio of changes in ketone bodies and isoleucine. CONCLUSIONS: CRT may modulate the systemic plasma metabolomic profile, which correlated with improvement in left ventricular function in patients with severe heart failure with reduced ejection fraction.

ABSTRACT Background While vaccination is a key strategy to mitigate the severity of coronavirus disease 2019 (COVID‐19) in children, the risk factors for symptomatic, medically attended (hereon referred to as “symptomatic”) COVID‐19 and the impact of vaccination are not well defined among pediatric solid organ transplant recipients (PSOTR). Methods PSOTR aged six months through 21 years at 11 centers in the Pediatric Infectious Diseases Transplant Network (PIDTRAN) were analyzed retrospectively for symptomatic COVID‐19 between July 2021 and May 2023. Using a Cox proportional hazards model, risk factors associated with COVID‐19‐associated hospitalization, in‐hospital oxygen use, mechanical ventilation, and the impact of COVID‐19 vaccination were analyzed. Results Of 1370 PSOTR, 410 (29%) had symptomatic COVID‐19 infection. Among those with symptomatic infection, 115 (28%) were hospitalized, 35 required in‐hospital oxygen, and three required mechanical ventilation. In the study, 45% were unvaccinated against COVID‐19. Compared to unvaccinated PSOTR, incompletely vaccinated PSOTR had 56% lower hazard (95% CI 0.26, 0.72, p = 0.001) of COVID‐19‐associated hospitalization whereas completely vaccinated did not have a statistically significant difference in hazard of hospitalization. Receipt of at least one dose of the bivalent vaccine was also associated with 92.5% lower hazard (95% CI 0.010, 0.55, p = 0.011) of hospitalization. Risk factors for hospitalization included chronic kidney disease, underlying heart disease, neurodevelopmental delay, and lymphocytopenia. Conclusions Most PSOTR with symptomatic COVID‐19 did not require hospitalization or respiratory support. Several comorbidities and lymphocytopenia are associated with severe COVID‐19 in PSOTR. COVID‐19 vaccination, mostly, protected PSOTR against COVID‐19‐associated hospitalization, but vaccine uptake among PSOTR was low. image

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.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

ABSTRACT As a principal metabolite of ginsenosides, compound K (CK) exhibits remarkable antioxidant, anti‐inflammatory, antidiabetic, and anticancer bioactivities. However, CK is naturally scarce in ginseng and its industrial application is limited by the lack of efficient deglycosylating enzymes for large‐scale CK bioproduction. Here, we report a synthetic biology‐driven approach for high‐yield CK production via recombinant β‐glycosidase‐mediated bioconversion of the polar ginsenoside Rb1. The β‑glycosidase‐encoding gene was introduced into Escherichia coli BL21 (DE3), and the resulting engineered strain produced 2.1 g/L β‑glycosidase in shake flasks and 10.1 g/L in a 5‐L fermentor. The crude β‐glycosidase exhibited excellent enzymatic activity; at a concentration of 1.5 g/L, it converted 95% of the Rb1 substrate (initial concentration 10 g/L) to CK within 4 h. In vitro studies demonstrated CK's high cytocompatibility and potent anti‐aging effects, including suppression of reactive oxygen species ( via upregulation of superoxide dismutase, catalase, and glutathione peroxidase), enhanced collagen I, Ⅲ and elastin synthesis, and matrix metalloproteinase‐1 inhibition. These findings highlight CK as a promising candidate for anti‐wrinkle formulations, supported by the feasibility of scalable bioproduction.

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.

Abstract TAR DNA-binding protein 43 (TDP-43) pathology frequently co-occurs with Tau neurofibrillary tangles (NFTs) and amyloid β plaques in Alzheimer’s disease (AD), driving significant clinical heterogeneity. Whether TDP-43 engages autonomous molecular programs or instead amplifies Tau-driven neurodegeneration remains difficult to resolve, largely because these pathologies often co-occur. To separate these overlapping signatures, we generated regionally resolved transcriptomic profiles from cognitively normal controls (Controls), neuropathologically defined cohorts of AD, AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE), and frontotemporal lobar degeneration (FTLD-TDP), categorizing them by their distinct TDP-43 subtypes (types α and β for AD/LATE; types A and B for FTLD-TDP). By integrating transcriptomic profiles with quantitative measures of phosphorylated TDP-43 (pTDP-43) and Tau (pTau), we separated pathology-associated signals within mixed disease contexts. We found that TDP-43 is linked to distinct transcriptomic programs in AD/LATE that are largely uncoupled from Tau burden and diverge from those observed in FTLD-TDP. These signatures showed regional specificity, with transcriptomic remodeling occurring in the amygdala across both diseases, whereas frontal cortex alterations were largely restricted to FTLD-TDP. Furthermore, by stratifying cases by TDP-43 morphological subtype, we unmasked specific biological trajectories, from immune activation to unique cellular vulnerabilities, that are not apparent in unstratified cohorts. Together, our findings provide a framework for decoupling mixed proteinopathies and demonstrate that TDP-43 shapes autonomous, subtype-dependent transcriptional landscapes in AD.

Abstract Hematoxylin and eosin (H&E) slides are routinely available in cancer care, but molecular profiling often requires additional tissue processing and turnaround time. We introduce HistoMethyl, a DNA methylation-aware pathology foundation model that aligns whole-slide histopathology with matched genome-scale methylation beta-value profiles during pre-training while requiring only an H&E slide at inference. We evaluated HistoMethyl across four task groups: gene mutation prediction, morphology-associated classification, overall survival prediction, and direct DNA methylation beta-value recovery. Evaluation spanned TCGA cross-validation, a disease-held-out lower-grade glioma cohort, and external cohort validation in CPTAC glioblastoma and SurGen rectal adenocarcinoma, totaling 14 cancer cohorts and 81 gene mutation tasks. The best-performing configuration improved mean mutation AUROC by 5.03 percentage points. By converting DNA methylation supervision into an H&E-only representation, His-toMethyl could support an early molecular triage layer that helps prioritize cases for confirmatory sequencing, methylation profiling, immunohistochemistry, and molecular tumor board review. These image-only predictions are intended to accelerate downstream molecular testing and tissue allocation while leaving final diagnosis and treatment selection anchored in validated molecular assays.