Citations

ABSTRACT Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid neoplasms shaped by genetic lesions and immune dysregulation, both of which contribute to disease progression and poor outcomes. Existing prognostic systems, such as IPSS‐R and IPSS‐M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi‐center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia‐free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS‐R, IPSS‐M, and bi‐allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time‐dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS‐high cases demonstrated reduced cytotoxic T‐cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS‐high cases to multikinase and NF‐κB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction. Trial Registration: #201709072RINC, #202109078RINB, #202207050RINB

Importance Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes. Objective To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy. Design, Setting, and Participants This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded. Exposures Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF). Main Outcomes and Measures Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes. Results A total of 78 patients with cNORSE (mean [95% CI] age, 37 [30-41] years; 44 female [56%]) and 2 independent cohorts of 211 patients (mean [95% CI] age, 69 [66-71] years; 128 female [61%]) and 73 patients (mean [95% CI] age, 56 [45-65] years; 39 male [53%]) with eSE were included. NfL concentrations were markedly elevated in cNORSE—approximately 10-fold higher in CSF and 4-fold higher in serum—compared with the eSE cohorts (CSF: median [IQR], 6408 [1503-22 963] pg/mL compared with 694 [219-2389] pg/mL; serum: median [IQR], 231 [99-855] pg/mL compared with 55 [20-135] pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median [IQR], 11 [7-19 ] and 7 [5-14 ] pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median [IQR], 101 [51-137] pg/mL), week 2 (median [IQR], 197 [117-324] pg/mL), and week 3 (median [IQR], 598 [163-1000] pg/mL) after onset ( P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve [AUROC], 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03). Conclusions and Relevance Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.

Abstract Aims Heart failure is prevalent; however, there is no cost-effective screening option. Against formal echocardiography, we assessed the diagnostic performance of focused cardiac ultrasound (FoCUS), performed by novice users guided and interpreted by artificial intelligence (AI) for the assessment of left ventricular ejection fraction (LVEF). Methods and results We prospectively enrolled 496 adults referred for diagnostic echocardiography. Novice operators (without clinical or imaging experience) underwent a 4-h imaging workshop, then performed FoCUS using a point-of-care device (Philips Lumify) utilizing real-time AI-image guidance (UltraSight). Images were assessed by AI-image interpretation software (Mayo Clinic), and two expert blinded echocardiologists. Median age was 67, 39% female, and body mass index range 17–56 kg/m2. Forty-one subjects (8.3%) exhibited moderate or greater LV dilatation and 28 (5.6%) had LVEF <40%. The median scan time was 4 min (IQR 3–5). Adequate views were achieved in 95.0% and 97.4% of subjects for AI interpretation and expert analysis, respectively. A two-step diagnostic screening process for low EF in which only abnormal AI reads or uninterpretable scans were reviewed by experts (15.1%) had a sensitivity 96.2%, specificity 95.4%, PPV 54.3%, and NPV 99.8%. A subsequent prospective validation study of 344 subjects demonstrated similar results (sensitivity 100%, specificity 99.4%). Conclusion In this early feasibility investigation, AI-guidance technology embedded on a handheld device, enabled novice users without clinical or imaging experience to acquire sufficient quality images to accurately assess LVEF with minimal training. The technology evaluated in this study may hold promise for AI-guidance and interpretation to facilitate low-cost screening for cardiac dysfunction.

ABSTRACT Introduction Frailty is increasingly recognized as an important determinant of outcomes in cardiovascular disease, yet its population‐level impact among patients hospitalized with cardiac implantable electronic device (CIED) infections remains incompletely defined. We examined the prevalence of frailty and its association with clinical outcomes and utilization of transvenous lead removal (TLR) in a contemporary national cohort. Methods and Results We analyzed the National Readmissions Database from 2016–2021 to identify adults hospitalized for CIED infections. Frailty was defined using the Johns Hopkins adjusted clinical groups frailty‐defining diagnoses. Of 288,402 patients hospitalized with CIED infections, 25.1% were classified as frail. Frail patients experienced significantly higher in‐hospital mortality (10.8% vs. 4.6%), 30‐day mortality (9.2% vs. 5.5%), complications, longer length of stay, lower rates of discharge home, and higher 30‐day readmissions compared with non‐frail patients (all p < 0.01). TLR was performed less frequently in frail patients (10.8% vs. 13.4%; adjusted odds ratio [aOR] 0.80, 95% CI 0.76–0.83). On adjusted analyses, TLR was independently associated with lower in‐hospital mortality, 30‐day mortality, and 30‐day readmissions in both frail and non‐frail patients. Conclusion Among patients hospitalized with CIED infections, TLR was independently associated with lower mortality and readmissions in both frail and non‐frail patients, despite lower utilization in frail individuals. Frailty was common (25.1%) and independently associated with significantly worse outcomes. These findings highlight important associations between frailty, treatment patterns, and outcomes that warrant prospective evaluation.

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.

Background Medical providers often face challenges in accurately predicting the survival of critically sick patients. Optimistic forecasts can lead to the overuse of resources, while overly cautious predictions might restrict treatments. This study examines the role of specific psychological factors, analyzed realistically and holistically, in predicting survival outcomes for intensive care unit patients. Methods This single-center cohort study evaluated health care providers (e.g., physicians, residents and fellows, and advanced practice practitioners) using two 7-d clinical vignettes. Providers assessed the need for mechanical ventilation (MV), renal replacement therapy (RRT), a percutaneous endoscopic gastrostomy (PEG) tube, or palliative care. Psychological factors were measured using scales that assessed ambiguity tolerance, rationality versus emotional defensiveness, anxiety related to uncertainty, decision-making style, and risk taking. These psychological traits were analyzed using a more realistic and holistic approach, employing cluster techniques. Providers also determined whether they had enough information to evaluate the patient’s condition and compared their survival estimates to APACHE II scores. Results In general, engagement in MV and RRT was common by day 2, although physicians were significantly less likely to recommend RRT. Providers generally suggested starting a palliative care consultation by day 6, with a noticeable shift on day 4. Three distinct composite psychological groups emerged: optimistic denial individuals (ODI), optimistic providers (OP), and resilient providers (RP). While these composite psychological groups did not significantly influence engagement in mechanical therapies, they did affect palliative care decisions: RP were more likely to request palliative care, whereas ODI were much less likely to do so. In contrast, individual psychological traits had nonsignificant correlations with the decision to use therapies. Providers initially overestimated survival probabilities during the first 3 d compared with APACHE II survival estimates. However, after day 4, this trend reversed, with providers becoming significantly more pessimistic versus the predictive score and increasingly requesting palliative care involvement. Conclusions Providers’ psychological profiles, rather than their clinical experience, significantly influenced decisions about organ-support therapies and palliative care. Survival estimates showed a biphasic pattern: initially, providers overestimated survival compared with APACHE II predictions, then became more pessimistic and more likely to consult palliative care after day 4. Highlights Intensive care unit survival predictions by providers followed a biphasic pattern: optimistic early on, then increasingly pessimistic after day 4. Psychological traits such as denial and ambiguity tolerance influenced palliative care decisions more than clinical experience did. Resilient providers were more likely to initiate timely palliative care, while denial-prone providers delayed it. Clinicians and critical care teams should be aware of how their psychological makeup can affect patient care decisions and outcomes.

PURPOSE 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

Abstract Background Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative tumors with limited treatment options at recurrence. Early studies suggest IDH inhibition has therapeutic activity. We evaluated clinical outcomes associated with IDH-1 inhibitor ivosidenib in recurrent IDH-1-mutant gliomas and molecular predictors of response. Methods We retrospectively analyzed adults treated with ivosidenib from January 2021 to August 2025 with predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted. Prior anticancer treatments, toxicities, enhancement status at ivosidenib initiation, and genomic alterations were collected. The primary endpoint was progression-free survival (PFS); secondary analyses evaluated associations between PFS, genomic complexity, and CDKN2A/B homozygous deletion. Results Ninety-two adults, median age 43, were included: 61 astrocytomas and 31 oligodendrogliomas, mostly grade 2. Before ivosidenib, 69 had surgery, 64 chemotherapy, and 64 radiation. Median time from diagnosis to ivosidenib was 4.8 years, with median of two prior progressions. Median treatment duration was 5.8 months. Median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, 14.0 and 6.9 months for oligodendroglioma grades 2-3. Increasing genomic complexity was associated with shorter PFS in univariate analysis. Patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months. Two patients with homozygous deletion had median PFS of 0.6 months. Conclusions In this retrospective analysis of predominantly recurrent IDH-1-mutant glioma, ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles. These findings support a context-dependent benefit of IDH inhibition in recurrent disease.

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