Citations

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

Objective: Patent foramen ovale (PFO) closure is recommended for patients younger than 60 years with embolic stroke of undetermined source (ESUS) or cryptogenic stroke, but it’s role in patients older than 60 years remains unclear. We aim to investigate the benefit of closure in patients older than 60 with ESUS or cryptogenic stroke. Methods: Patients older than 60 years with ESUS or cryptogenic stroke from several large tertiary hospitals were recruited, who received a PFO closure after multidisciplinary brain-heart case conference, compared to age-matched cohort patients with ESUS or cryptogenic stroke. The primary outcome included recurrent ischemic stroke that occurred up to a median follow up of 5 years following PFO closure between two groups. The safety outcome was the occurrence of any complications after PFO closure, including new onset atrial fibrillation (AF). Results: A total of 102 patients (Table 1) were included (mean age 66±4), 56 male (55%), who received a PFO closure. Procedure-related complications, including new onset transient AF were low (1%). After following patients up to 5 years, patients with PFO closure demonstrated a relatively low incidence of recurrent ischemic stroke (3.9%, 4/102), compared to age-matched control cohort with a total of 97 patients (mean age 67±4), which had higher incidence of stroke recurrency (8.2%, 8/97) (Table 2). Kaplan-Meier event curve (Figure 1) reveals a trend of reducing recurrent stroke in patients with PFO closure but not achieved statistical significance. Conclusions: In patients with cryptogenic stroke or ESUS who are older than 60 years, PFO closure demonstrated safety profiles with a noticeable trend of reducing recurrent ischemic stroke compared to their age-matched counterparts. Prospective randomized trials are warranted in this young-older population.

Background: High-grade intracranial atherosclerosis (ICAS) is associated with an elevated risk of recurrent ischemic stroke, particularly in patients with severe stenosis (70–99%). Identifying predictors of early recurrence can inform risk stratification and guide treatment strategies. Methods: The Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) study is a multicenter, international, retrospective cohort analysis pooling data from 35 comprehensive stroke centers. We included hospitalized adult patients with symptomatic ICAS, defined as 50–99% stenosis of an intracranial artery (intracranial vertebral, basilar, distal ICA, or M1 MCA), confirmed by vascular imaging and associated with a qualifying ischemic event. Patients with only high-grade stenosis (70-99%) were included in this analysis. The primary outcome was to determine predictors of recurrent ischemic stroke in the territory of the symptomatic artery within 90 days of the index event. Baseline demographic, clinical, and imaging characteristics were recorded. Multivariable Cox proportional hazards regression with stepwise selection (p < 0.1) was used to identify independent predictors of recurrence; model discrimination was assessed using Harrell’s C-statistics. Results: Among 2,050 patients, 1,476 had high-grade (70-99%) symptomatic ICAS. The mean age was 67 ± 12.5 years, and 767 (55%) were male. Most patients were non-Hispanic (90.1%), taking dual antiplatelet therapy (77.8%), and statins (94.5%). Recurrent stroke occurred in 160 patients (10.8%) within 90 days. In multivariable Cox model, independent predictors of recurrence included atrial fibrillation (HR 2.05; 95% CI, 1.26–3.33; p = 0.004), hyperlipidemia (HR 1.57; 95% CI, 1.10–2.24; p = 0.014), diabetes mellitus (HR 1.36; 95% CI, 0.98–1.88; p = 0.064), and home use of dual antiplatelet therapy (HR 1.60; 95% CI, 1.01–2.54; p = 0.043)(Harrell’s C-statistic=0.62). In patients who underwent perfusion(n=402), mistmatch >10seconds were associated with increased recurrence (HR 1.80; 95% CI 0.95-3.38, p=0.07) and atrial fibrillation (HR 2.06: 95% CI 0.03-4.60, p=0.78) though did not reach statistical significance. Conclusion: In this population, diabetes, hyperlipidemia, atrial fibrillation, and prior use of dual antiplatelet therapy were associated with increased risk of 90-day recurrent ischemic stroke. Perfusion imaging may help identify high-risk patients who could benefit from intensified secondary prevention.

Introduction: Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke (IS) worldwide and carries a high risk of recurrence. Current guidelines favor 90 days of dual antiplatelet therapy (DAPT) for severe symptomatic ICAS, but recurrence remain high. Limited data suggest possible benefit of single antiplatelet plus anticoagulation (SAPT+AC). We compared the effectiveness and safety of DAPT versus SAPT+AC. We hypothesized that DAPT would lower 90-day recurrent IS risk without significantly increasing bleeding. Methods: This substudy of the Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) included patients from 35 centers (Jan 2019–Jun 2024) with symptomatic 50–99% ICAS in the intracranial internal carotid, vertebral, basilar, or M1 segment of the MCA, presenting ≤72 hours from last known well. The primary efficacy outcome was recurrent IS in the same vascular territory at 90 days; the primary safety outcome was severe bleeding (symptomatic intracranial hemorrhage or major extracranial bleeding). Categorical variables were compared using χ 2 and continuous variables with the Student's t test; multivariable Cox regression adjusted for key covariates. Results: Of 2050 BIORISK-ICAS patients, 1658 met criteria (DAPT n=1499; SAPT+AC n=159). Mean age was 67 vs. 73 years, and 44% were women. At 90 days, recurrent IS occurred in 121 DAPT patients (8.07%) vs. 13 SAPT+AC patients (8.17%); unadjusted HR 0.83 (95% CI, 0.50–1.36; p=0.46). After adjustment for age, diabetes, coronary heart disease, atrial fibrillation, active smoking, and borderzone infarct, the adjusted HR was 0.99 (95% CI, 0.52–1.86; p=0.97). Severe bleeding occurred in 34 DAPT patients (2.26%) and 5 SAPT+AC patients (3.14%); unadjusted HR 0.79 (95% CI, 0.28–1.85; p=0.50), adjusted HR 0.66 (95% CI, 0.21–2.09; p=0.47). Conclusions: In patients with symptomatic ICAS, DAPT and SAPT+AC were associated with similar risks of 90-day recurrent ischemic stroke and severe bleeding. Well-powered randomized trials are needed to determine the optimal antithrombotic regimen in this high-risk population.

ABSTRACT The goal of this radiomic analysis is to quantify the sensitivity of radiomic features on computed tomography (CT) image pre‐processing parameters and use machine learning (ML) techniques to identify the radiomic features that are highly predictive of shoulder arthroplasty outcomes. An ML framework auto‐segmented 3D masks of the deltoid muscle and scapula bone from pre‐operative CT images of 1949 primary anatomic total shoulder arthroplasty (aTSA)/reverse total shoulder arthroplasty (rTSA) patients. Radiomic features were extracted after various image pre‐processing protocols and assessed for reproducibility. The radiomic features deemed robust to image pre‐processing were used to train ML predictive outcomes models. Feature importance data were rank‐ordered to identify the radiomic features that were highly predictive of pain, motion, and function before and after aTSA/rTSA. A sensitivity analysis identified 37 deltoid muscle and 38 scapular bone radiomic features that were robust, reproducible, and unique across image pre‐processing parameters. The most predictive deltoid muscle radiomic measurements were normalized volume, elongation, flatness, fat percentage, sphericity, and max 2D diameter column. The most predictive scapular bone radiomic measurements were flatness, sphericity, elongation, max 2D diameter column, and max 2D diameter slice. Radiomic data of the deltoid and scapula were highly predictive of pain, motion, and function before and after aTSA and rTSA. Radiomic data were more predictive than patient comorbidities, diagnosis, and implant type/size data, but less predictive than pre‐operative active range of motion measurements and patient reported outcome measures, 3D measurements from planning software, or patient demographic data. Future work is required to clinically validate these radiomic features before they can be deployed in clinical decision support tools. Level of Evidence Level III, Retrospective Comparative Outcome Study.

Abstract Optimal dosing of prophylactic enoxaparin for individuals ≥150 kg is unknown due to limited inclusion in previous studies. Estimate an optimal weight-based prophylactic enoxaparin dose for individuals ≥150 kg. This multicenter, retrospective study included ≥150 kg adult patients admitted to the hospital between January 2014 and April 2024, who received twice daily prophylactic enoxaparin (goal peak anti-Xa 0.2–0.4 IU/mL). At least one peak anti-Xa was required, obtained 3 to 5 hours after the 3rd consecutive dose. The primary outcome was the range of dosing that produced goal prophylactic peak anti-Xa following linear regression modeling. Secondary outcomes were hospital and intensive care unit (ICU)/progressive care unit (PCU) length of stay (LOS), in-hospital mortality, and VTE/bleed events within 72 hours after an eligible peak anti-Xa. A total of 311 encounters and 388 peak anti-Xa levels were assessed. Patients were 46 (37–55) years old, 53.1% were male, and weighed 183.3 kg (166.1–204.1) with a BMI of 61.3 kg/m2 (54.8–69.4). Creatinine clearance was 179.6 mL/min (126.5–228.2) and patients received 4 doses (4–6) before peak anti-Xa, with a time between of 249 minutes (227–271). Linear regression modeling revealed a statistically significant correlation (r2 = 0.27) between weight-based dose and peak anti-Xa (p < 0.0001). Enoxaparin 0.34 mg/kg (95% CI 0.33–0.36) twice daily was predicted to achieve a peak anti-Xa of 0.3 IU/mL. Hospital LOS was 8 days (4–15), ICU/PCU LOS was 8 days (4–14, n = 158), and only two patients (0.6%) died during hospitalization. One VTE event was observed. Our results suggest an appropriate empiric weight-based prophylactic enoxaparin dose for hospitalized patients ≥150 kg is 0.34 mg/kg twice daily.

Abstract INTRODUCTION The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1 , FLT4 , and VEGFB on AD outcomes. However, these analyses have focused within the non‐Hispanic White (NHW) population. METHODS The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag–mass spectrometry (TMT‐MS) proteomic data. Outcomes included measures of AD pathology and diagnosis. RESULTS Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4 , whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity. DISCUSSION This multi‐omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD. Highlights Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi‐omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is typically detected too late for useful therapeutic interventions; hence, we sought blood biomarkers to detect early-stage disease. Experimental Design: Using mass spectrometry and ELISA on plasma pools from the University of Pennsylvania (Penn) and the Mayo Clinic (Mayo), we identified aminopeptidase N (ANPEP) and polymeric immunoglobulin receptor (PIGR) as increased in early-stage (stage I/II) PDAC plasma compared with controls. We tested ANPEP and PIGR, along with prior data for thrombospondin 2 (THBS2) and carbohydrate antigen 19-9 (CA19-9), in retrospective phase II studies using separate cohorts of PDAC plasmas at different stages versus healthy or nonmalignant disease controls (DC) from Penn (n = 135) and Mayo (n = 537). Results: Comparing healthy controls with stage I/II PDAC, we obtained area under the receiver-operating characteristic curves (AUC) of 0.78 [95% confidence interval (CI), 0.68–0.86]/0.80 (95% CI, 0.74–0.85; ANPEP) and 0.81 (95% CI, 0.70–0.88)/0.86 (95% CI, 0.82–0.90; PIGR) for the Penn/Mayo phase II studies, respectively. In multivariable models, CA19-9/THBS2/ANPEP, CA19-9/THBS2/PIGR, and CA19-9/THBS2/ANPEP/PIGR elicited AUC of 0.94 to 0.96 for Penn and 0.97 for Mayo. Notably, the four-marker panel elicited AUC of 0.87 for the Mayo stage I/II versus DC and 0.91 for stages I to IV versus DC. At a specificity of 95%, a plasma biomarker panel composed of CA19-9 (≥35 U/mL), THBS2 (≥42 ng/mL), ANPEP (≥2,995 ng/mL), and PIGR (≥1,800 ng/mL) yielded a sensitivity of 91.9% for PDAC stages I to IV and 87.5% for PDAC stage I/II. Conclusions: Adding ANPEP and PIGR to a plasma biomarker panel of CA19-9 and THBS2 enhances the detection of early-stage PDAC when comparing cancer versus healthy or nonmalignant DC. Given the concordance of our data in two retrospective phase II studies, assessments in prediagnostic cases are warranted.

Hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet blood pressure control rates remain suboptimal despite the availability of effective therapies. Contemporary guidelines increasingly recommend early use of combination therapy, recognizing that most patients require multiple agents to achieve target blood pressure. Widaplik, a recently Food and Drug Administration-approved fixed-dose, single-pill triple combination of telmisartan, amlodipine, and indapamide, represents the first triple therapy approved for initial treatment of hypertension in adults likely to need multidrug therapy. This review summarizes the pharmacologic rationale for low-dose triple therapy, highlighting complementary mechanisms targeting the renin-angiotensin-aldosterone system, vascular resistance, and sodium retention. We examine evidence from pivotal phase 3 trials demonstrating rapid, sustained blood pressure reductions, higher control rates compared with dual therapy, and favorable tolerability. We also discuss safety considerations, practical limitations, and gaps in evidence, including long-term cardiovascular outcomes. Widaplik represents a paradigm shift toward simplified, early combination therapy aimed at improving hypertension control and reducing cardiovascular risk.