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Abstract Background NT-proBNP levels are associated with disease severity and outcomes in patients with HF across the spectrum of LVEF. Recently, it has been suggested that the effectiveness of certain treatments may vary by NT-proBNP level with greater benefit from omecamtiv mecarbil, and smaller benefit from vericiguat, in patients with higher NT-proBNP levels. We examined the benefit of sacubitril/valsartan on outcomes across the range of NT-proBNP levels in patients with HFrEF/HFmrEF/HFpEF. Purpose To evaluate clinical outcomes, and the efficacy of sacubitril/valsartan, according to NT-proBNP levels, in patients with HFrEF/HFmrEF/HFpEF, using the pooled dataset of participants in the PARADIGM-HF and PARAGON-HF trials. Methods The PARADIGM-HF (n=8399) and PARAGON-HF (n=4822) trials enrolled patients with HF, functional limitation, and elevated NT-proBNP levels. Patients with LVEF ≤40% were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10mg twice daily in PARADIGM-HF, and those with LVEF ≥45% to sacubitril/valsartan 200 mg twice daily or valsartan 160mg twice daily in PARAGON-HF. Patients were categorized by quintiles of NT-proBNP level and using NT-proBNP as a continuous variable, analysed using restricted cubic splines. The primary outcome in the present study was the composite of cardiovascular death or HF hospitalization. Results Among the 13195 patients in the pooled PARADIGM-HF and PARAGON-HF dataset, 13142 (99.6%) patients with baseline NT-proBNP were analysed. Patients with higher NT-proBNP levels were more often male, had lower body mass index and LVEF, worse New York Heart Association functional class, worse kidney function, and more atrial fibrillation, while age was similar across NT-proBNP levels. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP level: quintile 1, 5.9 (95%CI 5.3-6.5); quintile 2, 7.5 (95%CI 6.9-8.2); quintile 3, 9.0 (95%CI 8.2-9.7); quintile 4, 12.0 (95%CI 11.1-12.9); and quintile 5, 20.8 (95%CI 19.6-22.2) (Figure 1). Similar trends were observed for other outcomes. The benefit of sacubitril/valsartan was consistent across NT-proBNP levels: the hazard ratio for the primary outcome in NT-proBNP quintile 1 was 0.79 (95%CI 0.65-0.96); quintile 2, 0.87 (95%CI 0.72-1.04); quintile 3, 0.79 (95%CI 0.66-0.93); quintile 4, 0.85 (95%CI 0.73-0.99); and quintile 5, 0.86 (95%CI 0.76-0.97), P-interaction=0.86. The consistent benefit of sacubitril/valsartan was also seen when NT-proBNP was analysed as a continuous variable (Figure 2). The absolute benefit was greatest in quintile 5 of NT-proBNP; the number needed to treat for quintile 5 was 16 versus 37 for the quintile 1 for the primary endpoint. Conclusions Patients with higher NT-proBNP had worse outcomes, but the benefits of sacubitril valsartan were consistent across the range of NT-proBNP levels of participants in PARADIGM-HF and PARAGON-HF.Kaplan-Meier curvesEffect of sac/val across NT-proBNP range

Abstract Background Concerns have been raised about the appropriateness of use and safety of beta-blockers (BBs) in patients with heart failure and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). However, randomized trial evidence is still lacking. Purpose To perform an observational analysis of the association between BB use and clinical outcomes in a large dataset of patients with HFmrEF and HFpEF. Methods We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The associations between baseline BB use and outcomes were analyzed. The primary outcome was the composite of cardiovascular death or HF hospitalization. Results Among the 16,951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13,400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12,812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1-Q3: 2.5-5.0) mg with BB continuation rates of 95.1% at 1 year and 93.1% at 2 years (in patients who survived more than 1 and 2 years, respectively). Overall, the hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR: 0.98 [95% CI: 0.91-1.05]) but among patients with HFmrEF, BB users had a lower HR (0.84 [95% CI 0.71-0.98]), whereas in HFpEF the HR was similar BB users and non-users (0.99 [95% CI 0.92-1.08]). However, after comprehensive adjustment for known prognostic variables, including NT-proBNP, BB use was associated with a better outcome in the overall cohort (HR 0.81 [0.74-0.88]), and this association was maintained across the range of LVEF (Figure 1). In subgroup analyses, the risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, with or without a history of hypertension, or with or without a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (Figure 2). Conclusions Although this is an observational analysis of non-randomized treatment, there was no suggestion that BB use was associated with worse HF outcomes even after extensive adjustment for other prognostic variables. Figure Legends Figure 1. Association between beta-blocker use and outcomes across the range of LVEF. Risk in beta-blocker users versus non-users is shown as an adjusted continuous hazard ratio Figure 2. Association between beta-blocker use and non-use in the overall population and clinically relevant patient subgroups, shown as an adjusted hazard ratio (HR). The outcome analyzed was the composite of CV death or HF hospitalization (primary outcome)Figure 1Figure 2

Background Acute ischemic stroke arising from medium vessel occlusions (MeVO) poses substantial challenges in treatment and management. This study aims to elucidate the outcomes and factors contributing to achieving excellent recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] 2c–3) versus successful recanalization (mTICI 2b) in patients with MeVO stroke undergoing mechanical thrombectomy (MT). Methods We conducted a multinational study analyzing data from the MAD‐MT (Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy) registry, encompassing 37 centers across North America, Asia, and Europe, collected between September 2017 and July 2023. The study included acute ischemic stroke patients with MeVO treated with MT, with or without intravenous thrombolysis, who achieved mTICI 2b–3 post‐MT. Results Among 1463 patients with successful recanalization (mTICI 2b–3), 523 achieved mTICI 2b recanalization, and 940 achieved mTICI 2c–3. Distal occlusions exhibited higher odds of excellent recanalization compared with proximal MeVO vessel occlusions (odds ratio, 1.58; 95% CI, 1.17–2.15; P = 0.003). Cardioembolic stroke pathogenesis was associated with a higher likelihood of excellent recanalization (1.67; 95% CI, 1.07–2.59; P = 0.018). Patients achieving mTICI 2c–3 recanalization demonstrated lower initial National Institutes of Health Stroke Scale scores, significant improvements in postprocedural National Institutes of Health Stroke Scale shift, and a higher percentage of favorable 90‐day outcomes compared with those with mTICI 2b. However, no significant difference in 90‐day mortality rates was observed. Conclusion This study underscores that among patients with MeVO stroke with successful recanalization (mTICI 2b–3) there is higher likelihood of achieving excellent recanalization (mTICI 2c–3) in distal occlusions and cardioembolic pathogenesis. mTICI 2c–3 scores post‐MT correlate with improved clinical outcomes compared with mTICI 2b, affirming the superiority of excellent recanalization over successful recanalization in patients with MeVO stroke. Further prospective studies and randomized controlled trials are warranted for validation.

Background: Patients with skin lesions suspicious for skin cancer or atypical melanocytic nevi of uncertain malignant potential often present to dermatologists, who may have variable dermoscopy triage clinical experience. Objective: To evaluate the clinical utility of a digital dermoscopy image-based artificial intelligence algorithm (DDI-AI device) on the diagnosis and management of skin cancers by dermatologists. Methods: Thirty-six United States board-certified dermatologists evaluated 50 clinical images and 50 digital dermoscopy images of the same skin lesions (25 malignant and 25 benign), first without and then with knowledge of the DDI-AI device output. Participants indicated whether they thought the lesion was likely benign (unremarkable) or malignant (suspicious). Results: The management sensitivity of dermatologists using the DDI-AI device was 91.1%, compared to 84.3% with DDI, and 70.0% with clinical images. The management specificity was 71.0%, compared to 68.4% and 64.9%, respectively. The diagnostic sensitivity of dermatologists using the DDI-AI device was 86.1%, compared to 78.8% with DDI, and 63.4% with clinical images. Diagnostic specificity using the DDI-AI device increased to 80.7%, compared to 75.9% and 73.6%, respectively. Conclusion: The use of the DDI-AI device may quickly, safely, and effectively improve dermoscopy performance, skin cancer diagnosis, and management when used by dermatologists, independent of training and experience.

Abstract Background: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo. Methods: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications. Results: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30–1.00, p = 0.048), functional independence (OR = 2.52, 95% CI = 1.02–6.20, p = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03–0.54, p = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups. Conclusion: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the study’s observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

Abstract Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0 mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints—low (<1.7 mg/dL) and low normal (<2.0 mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0 mg/dL to learn if survival can be improved.