Citations

Abstract Parkinson’s disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.

ABSTRACT Background Fall risk screening and prevention interventions initiated from the Emergency Department (ED) are endorsed by current national guidelines. We aimed to evaluate the effectiveness of ED‐based multi‐factorial and multi‐component interventions to prevent falls. Methods We conducted a systematic review and meta‐analysis of interventions for fall prevention initiated in the ED for older patients (age ≥ 60 years). Multi‐component and multi‐factorial interventions were included. We excluded studies without a control or comparison group. The published literature was searched from 2019 to May 2024. Risk of bias was assessed with the Newcastle Ottawa tool for observation studies and the Cochrane Risk of Bias v2 for randomized trials. A meta‐analysis was completed for the outcomes with multiple studies. Results The search resulted in 6312 abstracts with 2571 duplicates, for 3741 unique citations. A total of 18 studies were included in the systematic review; 5 were rated as high risk of bias/low quality. The articles were heterogenous in the intervention type (8 multi‐factorial and 8 multi‐component), setting (ED focused vs. outpatient), intervention components (i.e., nurses, physicians, therapists), and size (103–1435 participants). The interventions did not decrease risk of falls at 3 months (risk difference 0.05 95% CI [0.00; 0.09]), 6 months (0.07 [−0.04; 0.18]) or 12 months (−0.02 [−0.11; 0.07]). ED revisits at 1 month (−0.01 [−0.03; 0.00]), 3 months (−0.04 [−0.14; 0.06]), and 12 months (0.02 [−0.05; 0.25]) were also unchanged. Mortality and hospitalization rates were also unaffected. Improvement in functional status was noted in 4 of 5 studies reporting this outcome. Conclusions Multi‐factorial and multi‐component fall prevention interventions initiated from the ED did not decrease falls or recurrent healthcare use. These interventions may improve functional status in older adults at fall risk. Comparisons are limited by the heterogeneity in types of interventions, intervention compliance, and timing of outcomes.

BACKGROUND: Radiofrequency (RF) ablation of premature ventricular complexes (PVCs) originating from the left ventricular summit may be unsuccessful, highlighting the need for alternative approaches. We aimed to assess the efficacy and safety of a novel dual-modality focal catheter in treating left ventricular summit PVCs in patients who had failed previous RF ablation. METHODS: Patients were prospectively enrolled and underwent a redo ablation procedure using an irrigated, contact-force sensing, dual-modality focal catheter (TactiFlex Duo, Abbott) under compassionate use indication. The ablation strategy, including the choice of energy modality (monopolar pulsed field [PF], RF, or both), was left to the operator’s discretion. Safety assessments included serial biomarkers, renal function, and CMR within 36 hours. Efficacy was defined as ≥80% reduction in PVC burden with symptom resolution at 3-month follow-up. RESULTS: Six consecutive patients (4 men; mean age, 53.8±15 years) with symptomatic left ventricular summit PVCs and a prior failed RF ablation (range, 1–2) were prospectively enrolled. All PVCs had an inferior axis, with a left bundle V1 morphology observed in 4 of 6 cases (mean burden, 30.1±5.3%). Acute suppression of PVCs was achieved in all cases. Acute suppression with a single PF application in the great cardiac vein-anterior interventricular vein occurred in 2 patients, while 3 patients required additional RF, PF, or combined RF+PF applications at adjacent sites. One patient with an inaccessible great cardiac vein-anterior interventricular vein was successfully treated in the left ventricular outflow tract with RF+PF application. Transient, reversible left anterior descending vasospasm was observed during PF delivery in 2 of 5 cases that underwent PF application adjacent to a coronary artery, despite pretreatment with intracoronary nitroglycerin without ECG or hemodynamic sequelae. All patients had durable suppression of PVCs at follow-up. CONCLUSIONS: In its first human application, dual-modality ablation was feasible and effective for refractory left ventricular summit PVCs. Transient coronary vasospasm occurred, though it was reversible and without acute clinical consequences.

Abstract Background Knowing the prevalence of patent foramen ovale (PFO) and the increasing number of people who inject drugs (PWID) with right-sided infective endocarditis (RSIE), we aimed to better characterize the syndrome of injection drug use, RSIE, and PFO with systemic embolic events. Method A systematic search across multiple databases was independently screened using predefined criteria (from inception until September 2025). Published cases of adult PWID diagnosed with RSIE and ischemic stroke or other systemic embolic event were included, provided they had PFO assessment. Individuals were excluded if they had cardiac implantable electronic device (CIED) infections or any other conditions associated with systemic or paradoxical embolism. Results The review identified 13 studies with 14 young patients, mostly without comorbidities, predominantly infected with Staphylococcus aureus. In most cases, echocardiography revealed large tricuspid valve vegetations. Neuroimaging confirmed multiple ischemic infarcts, while 5 patients showed emboli outside the central nervous system (4 of them as the only systemic embolism). At least 11 (79%) patients had echocardiographic evidence of right-to-left shunting. Management included cardiac surgery in 6 cases that involved valve replacement or repair, percutaneous PFO closure in 2 cases, and percutaneous mechanical aspiration in 1 case. Three patients (21%) died during hospitalization, and only 27.3% patients had outpatient follow-up. Conclusions RSIE with systemic embolism in PWID with PFO has rarely been reported, affects younger patients without sex predominance, and was usually due to S. aureus with large tricuspid vegetations. Right-to-left shunting was characteristic, and outcomes were poor despite combined medical, surgical, and interventional therapies.

Background/Objectives: Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. Methods: The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. Results: Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines ( p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. Conclusions: The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher. Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast

Abstract Background Accurate synthesis of computed tomography (CT) images from magnetic resonance imaging (MRI) is clinically valuable for cranial applications such as attenuation correction, radiotherapy planning, and image‐guided interventions. However, the heterogeneity of MRI data across magnetic field strengths and pulse sequences limits the generalizability of existing methods, posing a barrier to clinical translation. Purpose This study aims to reformulate cranial CT synthesis as a modular, structurally coupled problem using a deep learning approach, enhancing adaptability across heterogeneous MRI conditions, including different field strengths and sequence protocols. Methods We implemented a cascaded multitask pipeline that jointly models skull segmentation and Hounsfield Unit (HU) regression in anatomically targeted regions. A 3D patch‐based training paradigm shifts the modeling focus from global image translation to localized bone feature extraction. The backbone leverages a residual Mamba‐based state space model within a 3D U‐Net structure to improve spatial representation, while a Transformer U‐Net serves as a widely recognized reference baseline comparison. The model was trained and evaluated in terms of multi‐modal (T1‐weighted and T2‐FLAIR) and cross‐domain transferability from a public 1.5 Tesla brain dataset ( n = 37) to an independent 7 Tesla clinical brain dataset ( n = 44). Performance was assessed using Dice and Jaccard indices for segmentation accuracy and mean absolute error (MAE) for HU regression. Results Quantitative analysis showed that our multitask pipeline, incorporating both morphological and HU map prediction stages, significantly outperformed conventional direct MRI‐to‐CT mapping across all metrics on the public 1.5T dataset (p < 0.05). Consistent performance on an external 7T clinical dataset (p < 0.001) further demonstrated the method's robustness and adaptability across field strengths. Conclusion These findings support that task‐structured training for modality transformation markedly improves both accuracy and generalizability of cranial CT synthesis across heterogeneous MRI conditions. The observed consistency across field strengths validates the robustness of the proposed methodology.

ABSTRACT BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61±19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing. (Australia New Zealand Clinical Trials Registry ACTRN12619001189112) Clinical Perspective What is new? Point-of-care troponin assays with good precision have become available and received regulatory approval as high-sensitivity assays. A pragmatic stepped-wedge cluster randomized trial implementing the validated Siemens VTLi high-sensitivity point-of-care assay into 6 emergency departments investigating ∼60,000 patients, was conducted to ascertain if the rapid turnaround time reduced lengths of stay. Introduction of the VTLi high-sensitivity point-of-care assay into clinical pathways reduced emergency department lengths of stay by an average 13% (47 minutes) without compromising safety. What are the clinical implications? Early decision-making using a point-of-care high-sensitivity troponin assay within a structured clinical pathway was safe. Faster turnaround means troponin results are consistently available when clinicians first seek them. This can facilitate earlier decisions and reduce patient length of stay.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Alzheimer’s disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.