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Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [¹⁸F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [¹⁸F]flortaucipir (ADNI), [¹⁸F]MK‐6240 (CPAS), and [¹⁸F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([¹⁸F]flortaucipir) and AIBL ([¹⁸F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [¹⁸F]flortaucipir and [¹⁸F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([¹⁸F]PI‐2620) are underway.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

A 32-fold accelerated real-time cine MRI sequence (radial sampling) demonstrated better temporal resolution and image quality than a 16-fold sequence (Cartesian sampling) in patients with cardiac implantable electronic devices and arrhythmias.

Abstract Background Obesity is strongly associated with the development of heart failure (HF) with preserved ejection fraction (HFpEF). Beyond increased body mass index (BMI), an abundance of epicardial adipose tissue (EAT) may play a role in its pathophysiology. Purpose To study the associations between increased EAT, functional status and invasive exercise hemodynamics in a large cohort of HFpEF patients. Methods This is a sub-analysis from a large randomized clinical trial that investigated an atrial shunt device in patients with HF with left ventricular ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25mmHg. At baseline, all patients underwent echocardiography, 6-minute walk distance (6-MWD) test, Kansas City Cardiomyopathy Questionnaire (KCCQ) and invasive hemodynamic assessment at rest and during supine ergometry. EAT thickness was measured on the free wall of the right ventricle on echocardiography, expressed in mm and patients were divided according to EAT tertiles. Results In total, 566 patients were examined. Their mean age was 72±8 years, 62% were women, mean BMI was 33±6 kg/m2 and mean EAT thickness was 6.0±2.4 mm, ranging from 1.7 to 17.2 mm. With increasing EAT thickness tertiles, 6-MWD and KCCQ overall summary score were significantly lower (320 vs. 315 vs. 287m, p=.01; 51 vs. 45 vs. 41, p=.003; respectively, Figure 1A-B). The association between increased EAT and lower KCCQ score was independent of BMI (p=.004, β: -2.6), whereas the association with lower 6-MWD was not independent of BMI (p=.1, β: -6.9). At rest, invasive hemodynamics were not different across EAT tertiles. At peak exercise, patients in the highest EAT thickness tertile had higher PCWP and PCWP to right atrial pressure gradient, as compared to patients in the first and second EAT thickness tertiles (36±8 vs. 34±8 mmHg, p=.009; 18±7 vs. 16±7 mmHg, p=.002, respectively, Figure 1C). Conclusion Excess EAT is common in patients with HFpEF and is associated with lower functional status and with higher left-sided filling pressures at peak exercise. These data suggest that EAT plays a significant role in functional status and exercise hemodynamics in HFpEF.Figure 1

Background: The arteriovenous fistula (AVF) is a requirement for hemodialysis therapy in end-stage kidney disease (ESKD) patients. A consequence of AVF creation is compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in ESKD patients, which worsens in dialysis patients. Currently, no suitable uremic large animal models exist to investigate the underlying mechanisms of AVF-induced cardiac remodeling. Research Question: This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Methods: Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. The AVF was created by anastomosis of the left common carotid artery to the left external jugular vein. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac MRI was performed at 14-, 28-, and 42-days post-PTA. Results: Increased end-diastolic volumes were observed in the left and right ventricles at day 42 vs 14 (200.8ml to 249.5ml, p=0.0457, and 204.6ml to 260.0ml, p=0.0268 respectively), while systolic function was preserved. Left ventricle (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the free wall of the LV at day 42 vs control, senescence markers showed increased p16 expression (fold change 10.21, p=0.0086) and decreased p21 expression (fold change 0.07, p=0.0357). The LV showed perivascular fibrosis (0.2% to 0.59%, p=0.021), via picrosirius red, reduced collagen-type IV expression (fold change 0.81, p=0.0089), and increased MMP2 levels (fold change 14.33, p=0.0213). Cardiomyocyte cross-sectional area was increased (from 800.9 µm 2 to 1250.0 µm 2 , p=0.0296), without CD4+ or CD68+ cell LV infiltration. Conclusion: In conclusion, AVF creation leads to modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model of uremic kidney disease can now be used to evaluate mechanisms of AVF induced cardiac disease and test the efficacy of therapeutics like senolytics and anti-fibrotic agents.

Background: The prevalence of cardiac implantable electronic devices (CIED) is increasing, with over 300,000 new implants annually in the U.S. Stress cardiac magnetic resonance (CMR) has proven as a powerful modality for myocardial characterization, enabling accurate diagnosis of different cardiac conditions. In patients without devices, CMR findings have also demonstrated prognostic value for major adverse cardiovascular events (MACE) and guide clinical decision-making. However, its use in CIED patients has historically been limited due to safety and image quality concerns. Hypothesis: We aimed to evaluate the prognostic value of CMR imaging using wideband sequences in CIED patients. Methods: CIED patients referred for clinical CMR were included prospectively and retrospectively between January 2020 and February 2025. All patients underwent a stress CMR protocol, which included cine, wideband late gadolinium enhancement (LGE), wideband T1 mapping, and wideband stress/rest perfusion imaging. Clinical follow-up is ongoing. The primary endpoint was the occurrence of MACE, defined as the composite of myocardial infarction, heart failure hospitalization, implantable cardioverter defibrillator (ICD) therapy, cardiac death, revascularization, or heart transplant. Results: A total of 89 patients were included (median age 69.0 [58.0–75.5] years; 62.9% male). Device types included pacemakers (33.7%), ICDs (48.3%), and cardiac resynchronization therapy devices (16.9%). Over a median of follow-up of 613 days [355-991], 21 patients experienced a MACE. In unadjusted models, higher left ventricular ejection fraction (LVEF) (per 5%) was significantly associated with a lower risk of MACE (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.65–0.95; p=0.016), as was higher stress myocardial blood flow (MBF) (per 0.25 mL/g/min increase: OR 0.78, 95% CI 0.60–0.98; p=0.05). In contrast, greater LV myocardial mass (per 10 g) was significantly associated with a higher risk of MACE (OR 1.27, 95% CI 1.08–1.52; p = 0.006), figure 1. Conclusion: The use of wideband sequences enabled the assessment of prognostic imaging value in CIED patients. LVEF remains a strong and consistent predictor of MACE in this population and LV mass was significantly associated with higher rates of MACE reflecting the influence of underlying cardiomyopathy. While stress perfusion CMR imaging showed promising trends, further studies with longer follow-up are needed to clarify its prognostic value in this population.

Abstract Purpose: The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences. Experimental Design: Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters. Results: Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival. Conclusions: Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization. See related commentary by Salgado and Kok, p. 2133

Candida krusei empyema is a rare but serious manifestation of invasive candidiasis, characterized by intrinsic resistance to fluconazole, biofilm formation, and high mortality, with limited case-level data to inform management. This review aims to systematically identify and synthesize all reported English-language cases of Candida krusei empyema from January 2005 to June 2025 using PubMed, ScienceDirect, OVID MEDLINE, and Gale OneFile and perform descriptive analysis on them. Screening, data extraction, and eligibility assessment were performed, and those articles not clearly meeting eligibility criteria were reviewed by additional reviewers with consensus resolution. Seven publications (six individual cases and two cohorts) were included. We additionally describe the clinical course, management, and outcome of a 70-year-old bilateral lung transplant patient who developed persistent C. krusei empyema despite optimized antifungal therapy. Patients ranged from 11 to 74 years of age (median 62.5 years). Predisposing factors included esophageal perforation (n = 4), post-transplant hemorrhage (n = 1), community-acquired empyema (n = 1), and thoracic surgery (n = 1). Empiric fluconazole was switched to caspofungin (3/4), with others receiving amphotericin B, voriconazole, or combination therapy. Source control varied: chest tube drainage (n = 3), percutaneous catheter (n = 3), and surgical decortication (n = 2). Mortality was 14.3% (1/7). In the absence of clear guidelines and robust literature, the management approach remains heterogeneous. Optimal care requires early recognition, aggressive multimodal antifungal therapy, and effective source control tailored to patient risk. Standardized antifungal protocols and larger case series are needed to guide clinicians in managing this challenging infection.

Importance Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. Objective To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. Design, Setting, and Participants This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. Interventions Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. Main Outcomes and Measures Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer’s Disease Rating Scale (iADRS) and Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. Results Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score ( R 2 , 0.73 [95% CI, 0.37-0.97]) and CDR-SB score ( R 2 , 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 ( R 2 , 0.86 [95% CI, 0.73-0.97]), p-tau181 ( R 2 , 0.88 [95% CI, 0.77-0.97]), and GFAP ( R 2 , 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL ( R 2 , 0.03 [95% CI, 0.00-0.54]). Conclusions and Relevance The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. Trial Registration ClinicalTrials.gov Identifier: NCT04437511