Citations

ABSTRACT Aims In the absence of randomized trial evidence, we performed a large observational analysis of the association between beta-blocker (BB) use and clinical outcomes in patients with heart failure (HF) and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). Methods and results We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The primary outcome was the composite of cardiovascular death or HF hospitalization. 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 93.1% at 2 years (in survivors). The unadjusted hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR 0.98, 95% confidence interval [CI] 0.91–1.05), but the adjusted HR was lower in BB users than non-users (0.81, 95% CI 0.74–0.88), and this association was maintained across LVEF (pinteraction = 0.88). In subgroup analyses, the adjusted risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, hypertension, or 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 (pintreraction = 0.02). Conclusions In this observational analysis of non-randomized BB treatment, there was no suggestion that BB use was associated with worse HF outcomes in HFmrEF/HFpEF, even after extensive adjustment for other prognostic variables.

Abstract INTRODUCTION Multi‐omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP‐AD) expanded brain multi‐omics profiling to multi‐ethnic donors. RESULTS We generated multi‐omics data and curated and harmonized phenotypic data from BA ( n = 306), LA ( n = 326), or BA and LA ( n = 4) brain donors plus non‐Hispanic White ( n = 252) and other ( n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION The inclusion of traditionally underrepresented groups in multi‐omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. Highlights Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi‐ethnic populations. Brain multi‐omics data is generated from Black American, Latin American, and non‐Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

OBJECTIVE Lumbar decompression and/or fusion surgery is a common operation for symptomatic lumbar spondylolisthesis refractory to conservative management. Multiyear follow-up of patient outcomes can be difficult to obtain but allows for identification of preoperative patient characteristics associated with durable pain relief, improved functional outcome, and higher patient satisfaction. METHODS A query of the Quality Outcomes Database (QOD) low-grade spondylolisthesis module for patients who underwent surgery for grade 1 lumbar spondylolisthesis (from July 2014 to June 2016 at the 12 highest-enrolling sites) was used to identify patient satisfaction, as measured with the North American Spine Society (NASS) questionnaire, which uses a scale of 1–4. Patients were considered satisfied if they had a score ≤ 2. Multivariable logistic regression was performed to identify baseline demographic and clinical predictors of long-term satisfaction 5 years after surgery. RESULTS Of 573 eligible patients from a cohort of 608, patient satisfaction data were available for 81.2%. Satisfaction (NASS score of 1 or 2) was reported by 389 patients (83.7%) at 5-year follow-up. Satisfied patients were predominantly White and ambulation independent and had lower baseline BMI, lower back pain levels, lower Oswestry Disability Index (ODI) scores, and greater EQ-5D index scores at baseline when compared to the unsatisfied group. No significant differences in reoperation rates between groups were reported at 5 years. On multivariate analysis, patients who were independently ambulating at baseline had greater odds of long-term satisfaction (OR 1.12, p = 0.04). Patients who had higher 5-year ODI scores (OR 0.99, p < 0.01) and were uninsured (OR 0.43, p = 0.01) were less likely to report long-term satisfaction. CONCLUSIONS Lumbar surgery for the treatment of grade 1 spondylolisthesis can provide lasting pain relief with high patient satisfaction. Baseline independent ambulation is associated with a higher long-term satisfaction rate after surgery. Higher ODI scores at 5-year follow-up and uninsured status are associated with lower postoperative long-term satisfaction.

Abstract Objective Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes ( CAPN3 , COL6A1 , COL6A2 , and COL6A3 ) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1 , though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Interpretation The expert‐reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case‐level data that help clarify disputed or novel LGMD associations.

OBJECTIVE The role of stereotactic radiosurgery (SRS) in the management of intracranial dural arteriovenous fistula (dAVF) is unclear given the rarity of this lesion and the variability in treatment paradigms. This study describes a 3-decade experience with the SRS technique and its outcomes for patients with dAVF. METHODS The authors conducted a retrospective analysis of patients with dAVF who had undergone single-fraction SRS in the period from 1990 to 2021. The imaging modality initially used for targeting was angiography alone, then angiography plus MRI, and most recently MRI alone. RESULTS Two hundred twenty-two patients underwent SRS alone (n = 56, 25%) or SRS plus embolization (n = 166, 75%), depending on the severity of symptoms or the presence of cortical venous drainage (CVD). Most patients were women (64%), and the median patient age was 60 years. Common presenting symptoms were pulsatile bruit (55%), visual change or chemosis (21%), headache (10%), and intracerebral hemorrhage (5%). The most frequent dAVF location was the transverse or sigmoid sinus (44%), followed by the cavernous sinus (24%), jugular bulb (9%), and torcula (5%). CVD was noted in 28% of cases, and venous ectasia in 5%. Borden dAVF types among the patients were I (72%), II (20%), and III (8%). Cognard dAVF types among the patients were I (44%), IIa (27%), IIb (5%), IIa+b (15%), III (4%), and IV (5%). The median SRS treatment volume was 7.6 cm3; the median margin and maximum doses were 18 and 36 Gy, respectively. Follow-up after SRS was available for 209 patients (median follow-up 31 months). Obliteration was noted in 75% of the patients (110/147) with follow-up vascular imaging; the median time to obliteration was 37 months. Multivariate analysis revealed that a cavernous sinus dAVF location was predictive of radiological obliteration (HR 1.86, 95% CI 1.08–3.18, p = 0.024). The absence of CVD was predictive of obliteration in subgroup analysis of non–cavernous sinus dAVF (HR 0.53, 95% CI 0.29–0.98, p = 0.04). Symptoms resolved in 86% of patients (160/185) with clinical follow-up. Twelve patients (5.4%) had complications related to angiography for SRS planning (n = 2, 0.9%), embolization (n = 3, 1.4%), post-SRS hemorrhage (n = 1, 0.5%), delayed sinus thrombosis (n = 1, 0.5%), radiation-induced tumors (n = 2, 0.9%), and chronic encapsulated expanding hematoma (n = 3, 1.4%). CONCLUSIONS SRS alone or in conjunction with embolization provided obliteration and symptom relief for the majority of patients with dAVF, with a low rate of procedure-related morbidity. Patients are at risk for late radiation-related complications, which can require treatment many years after SRS.

OBJECTIVE Following resection of posterior superior frontal gyrus (PSFG) tumors, patients can experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, the authors sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology. METHODS This was a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon. RESULTS A total of 106 consecutive patients undergoing 123 procedures (21 biopsies, 102 resections) fulfilled inclusion and exclusion criteria. Anaplastic astrocytomas were the most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 27%) (p < 0.0001). The biopsy cohort was more likely to have tumor involvement outside the PSFG (90% vs 62%) (p = 0.011), most commonly in the motor cortex (67% vs 31%) (p = 0.005). Seizures were the most common presenting symptom in the resection cohort (p = 0.017), while motor deficits were more common in the biopsy cohort (58% vs 29%) (p < 0.001). Immediate postoperative neurological deficits occurred in 71 cases (58%), but only 3 of the deficits were permanent at 6 months of follow-up (2%). Postoperative SMA syndrome occurred in 48 cases (47%) and was significantly associated with involvement of the motor cortex (p = 0.018) or cingulate gyrus (p = 0.023), which were also significant in multivariate analysis as risk factors for SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p = 0.51). There were no perioperative deaths, but corpus callosum involvement (p < 0.001), contrast enhancement (p = 0.003), and glioblastoma pathology (p = 0.038) predicted worse overall survival in patients undergoing resection. CONCLUSIONS Nearly half of all patients undergoing resection of PSFG-region tumors experience a postoperative SMA syndrome. Individuals with corpus callosum and/or motor cortex involvement may be at an increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement—in addition to pathology—might serve as predictors of overall survival within this patient population.

OBJECTIVE Stereoelectroencephalography (SEEG) has become the predominant method for intracranial seizure localization. When imaging, semiology, and scalp EEG findings are not in full agreement or definitively localizing, implanted SEEG recordings are used to test candidate seizure onset zones (SOZs). Discovered SOZs may then be targeted for resection, laser ablation, or neurostimulation. If an SOZ is eloquent, resection and ablation are both contraindicated, so identifying functional representation is crucial for therapeutic decision-making. The authors present a novel functional brain mapping technique that utilizes task-based electrophysiological changes in SEEG during behavioral tasks and test this in pediatric and adult patients. METHODS SEEG was recorded in 20 patients with epilepsy who ranged in age from 6 to 39 years (12 female, 18 of 20 patients < 21 years of age) and underwent implanted monitoring to identify seizure onset. Each performed 1) visually cued simple repetitive movements of the hand, foot, or tongue while electromyography was recorded; and 2) simple picture-naming or verb-generation speech tasks while audio was recorded. Broadband changes in the power spectrum of the SEEG recording were compared between behavior and rest. RESULTS Electrophysiological functional mapping of movement and/or speech areas was completed in all 20 patients. Eloquent representation was identified in both cortex and white matter and generally corresponded to classically described functional anatomical organization as well as other clinical mapping results. Robust maps of brain activity were identified in healthy brain, regions of developmental or acquired structural abnormality, and SOZs. CONCLUSIONS Task-based electrophysiological mapping using broadband changes in the SEEG signal reliably identifies movement and speech representation in pediatric and adult epilepsy patients.

Abstract There are limited data assessing the risk scores for primary treatment failure (PTF) in patients with classical Hodgkin lymphoma (cHL; PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs) is a multicenter retrospective cohort of patients with PTF-cHL (aged ≥15 years) diagnosed on or after 1 January 2005, at 15 US medical centers. PTF was defined as 1 of the following patterns of failure: (1) progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); (2) partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); (3) progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR; early relapse [ER]). A total of 478 patients were included in the analysis. Among these, 217 (45%) were PP, 86 (18%) were PR/SD, and 175 (37%) were ER. The 6-month and 1-year cumulative incidence of nonrelapse mortality after auto-HCT were 0.9% and 1.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) after auto-HCT were 4.33 and 10.09 years, respectively. Although those not in CR at the time of auto-HCT were associated with inferior PFS and OS, advanced age and diagnosis before 2011 were associated with inferior OS. This study showcases the safety and long-term efficacy of auto-HCT, even in patients with high-risk disease who are traditionally considered chemotherapy refractory, and will serve as a benchmark for the ongoing transplant vs no transplant trials.

The efficacy and safety of extracorporeal membrane oxygenation (ECMO) support during transcatheter aortic valve replacement (TAVR) remains unknown. We conducted a meta-analysis to compare benefit and risk of ECMO in TAVR patients. Bibliographic databases were searched from inception to January 1, 2024. Included studies involved patients ≥18 years old undergoing TAVR and using ECMO emergently or prophylactically. Mortality and procedure success were primary outcomes. Peri- or postoperative complications were the secondary outcomes. We identified 11 observational studies, including 2,275 participants (415 ECMO and 1,860 non-ECMO). The unadjusted mortality risk in ECMO-supported patient was higher than non-ECMO patients (odds ratio [OR] 1.73). The mortality unadjusted risk remained high (OR 3.89) and statistically significant for prophylactic ECMO. Prophylactic ECMO had lower mortality risk compared with emergent ECMO (OR 0.17). Extracorporeal membrane oxygenation-supported patients had lower procedural success rate (OR 0.10). Extracorporeal membrane oxygenation patients undergoing TAVR had significantly increased risk of bleeding (OR 3.32), renal failure (OR 2.38), postoperative myocardial infarction (OR 1.89), and stroke (OR 2.32) compared with non-ECMO patients. Clinical results are not improved by ECMO support in patients with high-risk TAVR. Prophylactic ECMO outperforms emergent. Overall, ECMO support increases mortality and postoperative complications. Transcatheter aortic valve replacement outcomes may improve with prophylactic ECMO in high-risk situations.