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Abstract Introduction This study investigated if acute alcohol exposure produces sex differences in aged rats compared to adult and adolescent rats on ataxia and nonspatial cognition. Materials and Methods Sex- and age-related differences were assessed by using aged, young adult, and adolescent Sprague–Dawley rats. For acute alcohol exposure, animals were administered either 1 or 2 g/kg alcohol via intraperitoneal injection before testing. To examine the effects of acute alcohol exposure on balance and motor control and nonspatial learning, animals underwent behavioral testing in the aerial righting reflex (ARR) and Morris water maze (MWM) tests. Blood alcohol levels were determined 60 min following administration of either 1.0 or 2.0 g/kg alcohol. Results Sex differences were found in the ARR, as aged females were significantly less sensitive to the effect of acute alcohol exposure compared to aged males. Age was also found to significantly affect ARR performance, where aged animals performed worse than younger animals in response to acute alcohol. However, these sex- and age-related differences were not found in the nonspatial MWM test or in blood alcohol concentrations. Conclusions These results indicate that the sex- and age-dependent effects of acute alcohol exposure are task specific. In conclusion, these findings highlight the importance of studying the effects of acute alcohol on the aged population.

AbstractINTRODUCTIONIncreasing evidence indicates that α‐synuclein (αSYN) oligomers are toxic. We sought to determine whether αSYN oligomers were associated with faster cognitive decline in prospectively‐followed patients with dementia with Lewy bodies (DLB).METHODSEight autopsy‐confirmed patients with DLB were selected based on rapid or slow cognitive decline determined by the rate of change of Mini‐Mental State Examination (MMSE) scores. Quantitative neuropathologic analysis of αSYN oligomers, Lewy‐related pathology, phosphorylated tau, and amyloid‐β was conducted in hippocampal subfields (CA1‐4 and subiculum) and the entorhinal cortex.RESULTSDLB with rapid cognitive decline showed greater CA1 αSYN oligomer burden (p = 0.029) and tau burden (p = 0.029) than DLB with slow decline. The groups showed comparable burden of Lewy‐related pathology and amyloid‐β pathology in the hippocampal formation and entorhinal cortex.DISCUSSIONHippocampal accumulation of αSYN oligomers and phosphorylated tau is associated with rapid cognitive decline in DLB. Therapeutic strategies targeting αSYN oligomers warrant further investigation.Highlights Proximity ligation assay (PLA) and digital pathology for oligomer quantification. Abundant α‐synuclein (αSYN) oligomers in CA1 of patients with dementia with Lewy bodies (DLB) with rapid decline. First human brain study linking αSYN oligomers to cognitive trajectory. Potential therapeutic implications of targeting αSYN oligomers in DLB.

ABSTRACT Background Pulmonary vein isolation (PVI) is the mainstay treatment for rhythm control in patients with persistent atrial fibrillation (PsAF). However, due to the complex mechanisms of PsAF, the efficacy of PVI alone remains modest. Spatiotemporal electrogram dispersion (STED) ablation is a promising strategy to enhance outcomes. This study aims to evaluate the efficacy of STED ablation plus PVI versus PVI alone in PsAF ablation. Methods A systematic search was conducted to identify studies published up to November 2024 comparing PVI plus STED ablation (PVI‐STED group) versus PVI alone (PVI group) in patients with PsAF. The primary outcomes were AF recurrence and sinus rhythm (SR) conversion. Results Eleven studies (three randomized controlled trials, three prospective cohorts, five retrospective cohorts) involving 1607 patients (mean age of 63.9 ± 9.3 years) were included. The PVI‐STED group was significantly associated with a lower risk of AF recurrence (OR: 0.40, 95% CI: 0.27–0.59, I ² = 25%) and a higher likelihood of SR conversion (OR: 7.04, 95% CI: 1.62–30.62, I 2 = 79%). No significant differences were observed in procedural time (MD: 27.61 min, 95% CI: −29.12 to 84.33, I ² = 97%), ablation time (MD: 4.4 min, 95% CI: −11.3 to 20.0, I 2 = 98%), or fluoroscopy time (0.25 min, 95% CI: −3.4 to 3.9, I 2 = 95%). The overall rate of AEs in the PVI‐STED group was 1% (95% CI: 1%–3%, I 2 = 0%). Conclusion The PVI‐STED approach demonstrated both efficacy and safety in treating PsAF, as evidenced by reduced AF recurrence and improved SR conversion rates.

Fundamental to medical education, gross anatomy first introduces medical students to human mortality, often provoking stress. Sense of purpose, a key aspect of well-being, may serve as a protective factor. We studied students’ sense of purpose during an anatomy course, examining its links to performance, spirituality, and belief in an afterlife. Fifty medical students who took a 7-week gross anatomy course in 2022 or 2023 completed the Life Engagement Test at the beginning, middle, and end of the course. We collected other data including demographics, religious/spiritual beliefs, and previous exposure to body donors. Practical and final examinations assessed course performance. Strong sense of purpose at the three measurement points was positively correlated with practical exam performance (r = 0.40, P = .004; r = 0.44, P = .003; r = 0.30, P = .047, respectively) but not National Board of Medical Examiners’ anatomy subject exam performance. Staunch believers and non-believers in an afterlife maintained a stable sense of purpose, while students uncertain about the afterlife experienced a decline from the beginning to the middle of the course and even more to the end ( P = .046; P = .008, respectively). These students also had significantly lower practical examination performance as compared to other students (95% CI [−10.84, −0.52]). In conclusion, a strong sense of purpose predicts better performance in a 7-week anatomy course. Both believers and non-believers in an afterlife do well, but students wavering in their beliefs experience a declining sense of purpose and lower grades. Supporting these students when they confront human mortality, including in other contexts such as palliative care/hospice settings, may be beneficial.

Objectives Cervical spine (c-spine) X-ray (XR) remains an important tool for pediatric trauma patients. XR is a low radiation alternative to multidetector CT (MDCT). Our primary aims were to analyze the sensitivity of a negative c-spine XR and to analyze what factors lead to additional imaging after a negative c-spine XR. Methods A retrospective cohort study was conducted at a level 1 pediatric trauma center from 2012 to 2021. We compared the group with negative c-spine XR and no additional imaging to the group with negative c-spine XR followed by additional c-spine MDCT and/or MRI. Results There were 2,081 negative XRs and 1,974 (95%) had their c-spines cleared without additional imaging. No patient required an operation for a clinically significant c-spine injury in this group, and we consider this no missed injuries. The remaining 108 patients had additional c-spine imaging after negative c-spine XR for c-spine clearance (24 MDCT, 76 MRI, 8 MDCT and MRI). Indications for additional c-spine imaging were pain (48.1%), Glasgow Coma Scale (GCS) score ≤14 (43.5%), and paresthesia (8.3%). Patients who received additional imaging were more likely to have a GCS score ≤12 (25.4% vs 4.1%), Injury Severity Score >15 (21.9% vs 8.1%), Level 1 Trauma activation (21% vs 5%), Abbreviated Injury Scale head score of 4 or 5 (29% vs 5%), be intubated (30% vs 2%), and have non-accidental trauma as their mechanism of injury (20% vs 1%) (p value<0.0001, for all). Five patients who received additional imaging were treated with a cervical collar, but no operative intervention. Conclusions In this cohort, screening XR had a sensitivity of 100% for clinically significant c-spine injuries. GCS was the most significant predictor of obtaining additional imaging. A negative XR combined with a normal physical examination in an evaluable pediatric patient is a safe way of clearing the c-spine. Level of evidence Study contains level III evidence.

Abstract The idea that it might be possible to prevent some forms of amyotrophic lateral sclerosis and frontotemporal dementia has finally come of age. The hexanucleotide repeat expansion in the C9orf72 gene accounts for ∼10% of all amyotrophic lateral sclerosis and 10%–15% of all frontotemporal dementia diagnoses, with the two clinical syndromes co-manifesting in a significant number of patients. As a result, clinically unaffected carriers of pathogenic C9orf72 repeat expansions are currently the largest identifiable population at significantly elevated risk for both amyotrophic lateral sclerosis and frontotemporal dementia, and in whom it might be possible to prevent the emergence of clinically manifest disease. Strategies for the design of disease prevention trials among clinically unaffected C9orf72 carriers have begun to emerge separately in the amyotrophic lateral sclerosis and frontotemporal dementia fields. However, recognition of the need to define neurodegenerative diseases based on biology underscores the need to consider all potential clinical manifestations of a C9orf72 repeat expansion together, rather than the traditional siloed approach of focusing on only amyotrophic lateral sclerosis or only frontotemporal dementia. Indeed, emerging clinical and biological markers that might be used to quantify pre-symptomatic disease progression and to predict the short-term risk of phenoconversion to clinically manifest disease are shared across the phenotypic spectrum. Given the anticipated progress in the development of therapeutic strategies to target the C9orf72 repeat expansion, and the enthusiasm for prevention trials among the unaffected C9orf72 repeat expansion carrier population, now is the time to begin work on the design of disease prevention trials. To this end, The Association for Frontotemporal Degeneration and The ALS Association supported a multi-stakeholder workshop (in Washington D.C., June 2024) to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Here we describe recommendations emanating from this workshop for the selection of outcome measures, delineation of eligibility criteria, optimal use of biomarkers and digital health technologies, potential analytic frameworks and relevant regulatory considerations related to C9orf72 disease prevention trials. We also emphasize the importance of the amyotrophic lateral sclerosis and frontotemporal dementia communities working together in partnership with the C9orf72 repeat expansion carrier community, the regulatory authorities and the broader drug development community.

Abstract Thyroid eye disease (TED) is a complex ocular autoimmune disorder primarily associated with Graves’ disease. It leads to significant morbidity due to orbital inflammation, fibrosis, and tissue expansion. While corticosteroids have been the traditional mainstay of therapy, recent advancements in understanding TED pathophysiology have driven the development of targeted treatments. Notably, inhibition of the insulin-like growth factor-1 receptor with teprotumumab has revolutionized TED management, demonstrating efficacy in reducing proptosis and disease severity. Additional emerging therapies, including neonatal Fc receptor inhibitors, thyroid-stimulating hormone receptor blockers, and interleukin-6 receptor antagonists, offer promising alternatives for patients with active and refractory disease. Despite these advancements, challenges remain in disease classification and outcome assessment. As the landscape of TED management continues to evolve, this review provides a comprehensive overview of current and emerging therapies for TED, critically examines gaps in disease evaluation, and highlights the evolving paradigm of patient-centered care. Future efforts should focus on optimizing therapeutic algorithms, refining risk stratification models, guiding personalized treatment, and promoting a multidisciplinary approach, which remain essential in improving outcomes and quality of life for affected individuals.

Abstract Objective We hypothesized that a set of immunohistochemistry (IHC) stains could be used to distinguish Burkitt lymphoma (BL), the quintessential B-cell lymphoma with a germinal center B-cell (GCB) dark zone (DZ) expression signature, from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). This might also be applicable to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 rearrangements (double-hit lymphomas [DHLs]) and triple-hit lymphomas (THLs). Methods A 5-marker IHC algorithm was designed from gene lists that distinguish physiologic DZ from light zone GCBs. Results In training and validation cohorts, we distinguished BL from DLBCL, NOS with high sensitivity and specificity. Because DHLs/THLs are enriched for the gene expression DZ signature (DZsig), we evaluated 19 DHLs/THLs and 4 HGBCLs, NOS. Most (83%) cases were IHC DZ. The NanoString DLBCL90 assay was performed on 34 cases to correlate IHC DZ results with the molecular DZsig. The IHC DZ call was significantly associated with the DZsig (P = .0011). The sensitivity and specificity of IHC to recognize DZsig+ cases among DLBCL, NOS and DHLs with BCL2 rearrangements/THLs were 91% and 100%, respectively. Conclusions The IHC DZ algorithm can support a diagnosis of BL and identifies MYC-BCL2 DHLs/THLs with a molecular DZsig.

ABSTRACTHLA‐C*06:402 differs from HLA‐C*06:02:01:01 by a nine‐nucleotide (TCCTGGCTG) insertion in exon 5.

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.