Citations

Abstract Background While tricuspid regurgitation (TR) is predominantly functional, it can arise from various cardiac conditions. This study aimed to evaluate whether the benefits of tricuspid valve intervention, compared to conservative management, differ based on the underlying etiology. Methods In the TRIGISTRY international cohort, which includes consecutive patients with severe isolated functional TR across 33 centers in 10 countries, we compared mortality rates at 2 years between patients who underwent a tricuspid valve intervention (surgical or transcatheter) versus conservative management according to TR etiology. Patients were classified into three groups: (1) Isolated TR (ITR), defined as left ventricular ejection fraction (LVEF) >60%, systolic pulmonary artery pressure (sPAP) <50 mmHg, and no prior left-heart intervention (LHI); (2) LHI-TR, comprising patients with a history of LHI; and (3) Undetermined TR (UTR), which included those who did not meet the criteria for ITR or LHI, as well as those with missing sPAP data. Given previous findings indicating that intervention provided no survival benefit for patients with a high TRI-SCORE, the present analysis was restricted to individuals with low to intermediate TRI-SCORE (≤5). Survival outcomes between groups were compared using restricted mean survival time (RMST). Results A total of 1,552 patients (72±13 years; 56% female) with severe functional TR and a low (48%) or intermediate (52%) TRI-SCORE were included. Of these, 772 (50%) underwent an intervention, while 780 (50%) were conservatively managed. TR was classified as ITR in 201 patients (13%), LHI in 395 (25%), and UTR in 956 (62%). Overall, patients with ITR exhibited the lowest comorbidity burden, whereas those with UTR had the highest. After adjusting for comorbidities and TRI-SCORE, a survival benefit of a tricuspid valve intervention was observed in patients with ITR (survival estimate: 0.17, 95% CI [0.009, 0.32], P=0.039) and, to a lesser extent, in patients with UTR (survival estimate: 0.09, 95% CI [0.0, 0.184], P=0.048), but not in those with prior LHI (survival estimate: 0.06, 95% CI [-0.08, 0.2], P=0.4). Similar results were found when excluding patients with moderate or greater residual TR after intervention. Conclusion In TRIGISTRY, patients with ITR appeared to derive the greatest benefit from tricuspid valve intervention, followed to a lesser extent by those with UTR, while no benefit was observed in patients with prior LHI. However, the potential influence of unaccounted confounders cannot be excluded, and further studies are needed to better identify patients’ subsets that may derive the most benefit from a tricuspid valve intervention.

Abstract Introduction Endogenous endophthalmitis (EE) is a rarely reported complication of infective endocarditis (IE). In an international series, we sought to determine the clinical and microbiological profile, treatment and outcome of patients presenting with IE-related EE. Methods Cases of EE recorded from 2014 to 2023 in 9 centers in Europe and the United States were collected. Results were compared to a matched control group. Results Sixty-six patients with EE were reported, mean age 65.2± 14.9 years, 71% (n=47) male. Blood cultures were positive in 90% (60 cases) of patients, with a predominance of streptococci (46%, n=30). As compared with the control group (n=264), the EE group presented with more frequent diabetes (34vs 20%, p=0.02), history of cirrhosis (9 vs 3%, p=0.04), glomerulonephritis (15 vs 0.3%, p<0.001), embolism before admission (92 vs 55%, p<0.001), and Janeway lesions (9 vs 1%, p=0.002). Streptococcal infection (46 vs 26%, p= 0.003) was more frequent and enterococcal infection (0 vs 18%, p< 0.001) less frequent in the EE group. The main ocular symptoms were a decrease in visual acuity (96%), red eye (55%) and ocular pain (55%). Treatment of EE consisted of intravitreal antibiotic injection in 55 (83%) patients and vitrectomy in 17 (26%). Improvement of visual acuity was observed in 36 (55%) patients but 43 (65%) still experienced severe impairment at one-year with 20 (30%) patients classified as legally blind. Conclusion EE is a serious complication of IE with severe residual vision impairment. Patients with IE should be evaluated for ocular complications, since early detection of EE is crucial to prevent delays in management and to preserve visual function.Severe endogenous endophthalmitis Endophthalmitis versus control group

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have emerged as promising agents for the management of advanced HCC. By reducing tumour burden, ICIs may serve as a downstaging/bridging tool to improve transplant candidacy. The aim of this study was to assess the safety of patients receiving pre‐LT ICIs. Methods Multicenter, retrospective cohort study from January 2018 to December 2024, including 48 patients who received ICIs prior to LT (ICI cohort). A control cohort (non‐ICI cohort) was built (1:3) using propensity score matching including 144 patients who underwent LT for HCC without prior ICI. Results Within the ICI cohort ( N = 48) rejection occurred in 9 patients (18.8%), all biopsy‐proven, with a median onset of 31 days post‐LT (12.0–182.0). The median washout period was 60 days (13–96). Patients experiencing rejection had shorter washout periods ( p = 0.029). All rejection episodes were successfully managed; two were steroid‐resistant, one requiring re‐transplantation. There were no rejection‐related deaths. Of the 5 patients with HCC recurrence, 60% received ICI for < 90 days ( p = 0.027). Comparison between the ICI and non‐ICI cohort revealed no significant differences in rejection rates (18.8% vs. 19.4%, p = 0.916), graft failure, HCC recurrence, or overall mortality. Overall survival (OS) did not differ between ICI and non‐ICI patients ( p = 0.625) or between those with and without rejection ( p = 0.119). Rejection was not associated with increased mortality, with deaths primarily attributed to infection or HCC recurrence. Conclusion Our results demonstrate that rejection rates were similar in patients receiving ICIs pre‐LT and it can be safely managed.

Abstract Background Left atrial appendage (LAA) closure or amputation is commonly performed in atrial fibrillation (AF) patients undergoing cardiac surgery to reduce stroke risk. It has been shown that LAA closure or amputation results in persistent blood pressure (BP) decrease, which may be due to a surge in atrial natriuretic peptide (ANP) and by suppression of sympathetic activity due to activation of mechanoreceptors by atrial distention. We hypothesize that size of the LAA, a compliant structure, affects atrial distension. Consequently, patients with smaller LAA remnants (i.e. more complete amputation) have more distension of the atrium and a more pronounced BP response upon LAA amputation. Methods We analyzed 33 patients with persistent AF from the MARK AF registry who underwent LAA amputation concomitant to thoracoscopic AF ablation. Systolic BP was measured at baseline, 12 hours (h), 24h, and 48h, 1 month, 1 year, and 2 years postoperatively. Complete amputation was defined as LAA remnant depth &lt;10mm and a remnant LAA was defined as depth ≥ 10 mm on contrast enhanced CT 6 months post surgery. The postoperative LAA remnant/LA volume ratio was calculated by segmenting the atria and quantifying the volume of the contrast pools. T-tests and linear regression analyzed BP changes by remnant size and LAA remnant/LA volume ratio. Results were visualized using a boxplot and scatter plots with regression lines. Results 25/33 Patients had a LAA remnant. Baseline systolic BP was similar with 147 ± 31 mmHg in the complete amputation group vs. 137 ± 23 mmHg in the remnant group, p=0.389. Complete amputation correlated with greater systolic BP reductions in relation to baseline at 12h (-18%, p=0.018), 24h (-14%, p=0.025), 48h (-15%, p=0.028), 1 month (-20%, p=0.024), and 1 year (-16%, p=0.001), Figure 1. BP returned to baseline by 2 years in both groups. Lower LAA remnant/LA volume ratios were significantly associated with greater systolic BP reductions at 12h (β=7.4, p=0.005), 24h (β=9.9, p&lt;0.001), 48h (β=10.1, p=0.002), and 1 month (β=11.1, p=0.01), Figure 2. However, this association was not observed at 1 and 2 years. Conclusion Patients with smaller LAA remnants after LAA amputation experienced a more pronounced transient reduction in blood pressure. Our findings suggest that increased atrial distension—due to the loss of compliant LAA tissue—could play a key role in modulating hemodynamics via sympathoinhibition and suppression of the Renin-Angiotensin-Aldosterone System (RAAS). Further investigation is needed to confirm these results and explore the neurohumoral effects of LAA amputation.Figure 1 Figure 2

Abstract Metabolic disorders such as obesity, type 2 diabetes, and dyslipidaemia are major drivers of cardiovascular risk and have reached epidemic levels in Western populations. Recent advances in clinical research have uncovered unexpected and often beneficial effects of pharmacological classes of metabolic drugs on cardiovascular outcomes, revealing complex interactions between metabolism and cardiac pathology. Despite their clinical efficacy, the molecular and cellular mechanisms through which many of these agents act remain only partially understood. This gap in knowledge underscores the urgent need for fundamental research that not only dissects the biology of metabolic disorders and cardiovascular disease but also reveals the mechanistic basis of existing and emerging therapies, thereby enabling rational therapeutic development. This scientific statement, developed by researchers from the European Society of Cardiology (ESC) Council on Basic Cardiovascular Science and several ESC Working Groups, provides a state-of-the-art overview of the emerging molecular and cellular pathways linking metabolic abnormalities with vascular and cardiac disease. By illuminating these critical connections and unresolved questions, this article aims to catalyse innovation in the prevention and management of cardiovascular disease in the context of metabolic dysfunction and to suggest new directions for future research.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

Introduction: Porokeratosis is a group of keratinization disorders characterized by the histopathological presence of the cornoid lamella, a hallmark feature across all subtypes. The clinical diagnosis of porokeratosis can be challenging due to its similarity to other dermatological conditions. While polarized light dermatoscopy (PLD) enhances diagnostic accuracy, certain features remain difficult to identify. Ultraviolet-induced fluorescence dermatoscopy (UVFD) is a novel imaging technique that may improve the visualization of porokeratosis features, particularly the peripheral keratin rim. Objectives: This study aimed to assess the diagnostic utility of UVFD compared with PLD in identifying the dermatoscopic features of porokeratosis. Methods: In this retrospective study, dermatologists from five institutions in Chile, Brazil, Poland, and the United States contributed with dermatoscopic images of porokeratosis cases. Both PLD and UVFD images were obtained for each lesion. Two independent investigators evaluated each lesion in PLD and UVFD for the presence of peripheral keratin rim, rim continuity, central scaling, follicular plugs, vascular structures, and photodamaged surrounding skin. A third investigator reviewed discrepancies. Frequencies and means were calculated. McNemar’s chi-square was used for comparison. Results: A total of 136 lesions from 35 patients with biopsy-proven porokeratosis were analyzed. UVFD significantly improved the visualization of the peripheral keratin rim (95.6% vs. 66.2% in PLD; P<0.001) and increased identification rates for central scaling, follicular plugs, and interrupted rims. PLD remained superior for detecting vascular structures(P<0.001). Conclusions: UVFD enhances the visualization of key dermatoscopic features of porokeratosis, particularly the peripheral keratin rim and other keratin-related structures.