Citations

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Background Contact aspiration remains a frontline approach for mechanical thrombectomy (MT) in acute ischemic stroke (AIS). Early evidence correlates catheter size with procedural efficiency and clinical outcomes. Larger‐bore (LB) aspiration catheters may enhance clot ingestion, increase aspiration force, and facilitate faster and more complete recanalization. However, the transition from standard LB catheters (0.068‐0.072″) to super‐large‐bore (SLB, ≥0.080″) devices has raised questions regarding both safety and clinical benefit. Although the use of SLB catheters is increasing, comparative data on their performance versus LB catheters remain limited. This study aims to evaluate the safety and efficacy of SLB compared with LB catheters including data from a large multicenter international registry. Methods We retrospectively analyzed patients with AIS due to LVO treated at 46 international stroke centers between January 2013 and June 2025. Among eligible patients, propensity score matching (PSM) at a 5:1 ratio was used to balance baseline characteristics between those treated with standard LB catheters and those treated with SLB catheters. Safety endpoints included intraprocedural complications, symptomatic intracranial hemorrhage (sICH), distal embolization, and 90‐day mortality. Efficacy endpoints included functional independence at 90 days (modified Rankin Scale [mRS] 0‐2), successful recanalization (TICI ≥2b), first‐pass effect (TICI ≥2b on the first aspiration attempt), and procedural timing to TICI2b. Results A total of 3,100 patients were included (LB n=3,024; SLB n=67). After PSM (LB n=335; SLB n=67), safety outcomes were comparable between groups in terms of intraprocedural complications occurred (p=0.5), sICH (p>0.9), embolization to new territory (p=0.2), and 90‐day mortality (p>0.9). Efficacy outcomes were similarly consistent for functional independence (mRS 0‐2) (p>0.9), successful recanalization (p>0.9), first‐pass effect (p=0.5), and time to TICI ≥2b (27.6 vs. 24.5 minutes; p=0.9). These findings remained consistent in the subgroup with ICA and M1 occlusions, with no significant differences in safety (intraprocedural complications [p=0.4], sICH [p>0.9], embolization to new territory [p=0.6], or 90‐day mortality [p>0.9], nor in efficacy outcomes (functional independence at 90 days [p>0.9], successful recanalization [p=0.9], first‐pass effect [p=0.6], and time to TICI ≥2b [p=0.9]). Conclusion In this large multicenter analysis, the use of SLB aspiration catheters demonstrated comparable safety and efficacy to standard LB catheters for MT in AIS. Despite theoretical advantages in aspiration dynamics, SLB devices did not confer significant procedural or clinical benefit over LB catheters. These findings suggest that while SLB catheters are a feasible alternative, technical and clinical outcomes remain comparable to LB catheters. Further prospective studies are warranted to clarify potential clinical advantages. image

Aims The aim of this study was to achieve consensus for important topics related to periprosthetic infection (PJI) in orthopaedic oncology, and to identify areas for future research. Methods In January 2024, the Birmingham Orthopaedic Oncology Meeting (BOOM) held in Birmingham, UK, gathered 309 delegates from 53 countries to debate 20 consensus statements on PJI in orthopaedic oncology using a modified Delphi process. Results Of 20 questions and statements on PJI in orthopaedic oncology, none achieved unanimous consensus, 18 achieved strong consensus, one achieved moderate consensus, and one achieved weak consensus. The statements that reached consensus with notable agreement were on the prophylaxis of infection, management of leaking wounds, and surgical strategies for the treatment of PJI. Short-duration antibiotic prophylaxis was deemed as effective as longer courses for lower-risk reconstructions, and aggressive management was recommended for wounds draining beyond five to seven days to prevent deep infection. Furthermore, single-stage, two-stage, and 1.5-stage revision were recognized as valid strategies, with two-stage revision remaining the most reliable. The statements that did not achieve consensus were on the role of debridement, antibiotics, and implant retention and prolonged antibiotic use post-revision. Conclusion The BOOM meeting achieved consensus for important topics on periprosthetic infection in orthopaedic oncology, but highlighted the low quality of the underlying evidence. This study has provided recommendations for the treatment of leaky wounds, duration of postoperative antibiotic prophylaxis, and choice of revision strategy. Cite this article: Bone Joint J 2025;107-B(12):1352–1359.

Background Patients with single-ventricle physiology are often palliated with the Fontan operation, which may involve the creation of a fenestration. We aimed to evaluate differences in cardiopulmonary exercise test (CPET) performance between patients with fenestrated and non-fenestrated Fontan circulation. Methods Patients with a Fontan circulation referred to CPET between 2006 and 2024 were included and were categorised based on their fenestration status at the time of CPET. Logistic regression analyses were performed to assess the impact of fenestration on peak oxygen consumption (VO 2 ), and Cox proportional hazard to evaluate the impact of fenestration on cardiovascular outcomes (death, heart transplant and Fontan-related hospitalisation). Results Of the 184 patients, 141 were classified as non-fenestrated and 43 as fenestrated. The minute ventilation-carbon dioxide production (V E /VCO 2 slope) was higher in the fenestrated (36.9±7.9) versus (33.2±6.2; p=0.009) in the non-fenestrated group. There was no significant difference in predicted VO 2 between groups (non-fenestrated 51.9%±14.4 vs 51.3%±15.6; p=0.7). Resting oxygen saturation was higher in the non-fenestrated group (93%±4.7 compared with fenestrated group 90.1%±5; p<0.001). Fontan fenestration was not significantly associated with the composite outcome; older patient age at the time of the CPET, cirrhosis and ventricular ejection fraction <40% were significantly associated with higher risk, while higher resting systolic blood pressure, left ventricular morphology and higher predicted peak VO 2 were protective. Conclusions The increased hypoxia and reduced ventilatory efficiency associated with Fontan fenestration offset any potential benefits, resulting in similar exercise performance between the groups. Fontan fenestration was not significantly associated with cardiovascular outcomes.

Abstract The advent of high-throughput sequencing has led to an exponential increase in genomic data, highlighting the need for efficient and accurate models to analyze and interpret this information. In this study, we introduce a novel, exomic foundational model that leverages a combination of the human reference genome and multispecies data to improve variant detection and interpretation. Our model utilizes a short-range transformer architecture and is trained on a large dataset of human exomic sequences derived from the Tapestry study. Through a series of ablation studies and scaling experiments, we demonstrate the effectiveness of our model in predicting next token accuracy and identifying clinically pathogenic variants. We also show that our model outperforms existing models in a range of downstream tasks, including variant effect prediction and disease state identification. In fact, our largest sequence transformer for range adaptive nucleotide decoding variant (1B parameters) surpassed previous benchmarks, demonstrating a mean accuracy of 0.880 [an 8.2% improvement over the original nucleotide transformer (NT) and a 7% improvement over NT-v2]. Furthermore, we construct a unique exomic ClinVar dataset to evaluate the model’s performance on pathogenicity and disease states. Our results highlight the potential of this model to improve our understanding of the human exome and its role in disease. The model and its applications have significant implications for genomics-based diagnosis and personalized medicine, including tailored therapeutic development.

Background Recent studies suggest that general surgery (GS) residents perform more operations related to their future specialty compared with their peers. In this multi-institutional study, we examined the process of early specialization among GS residents pursuing a career in vascular surgery (VS). Methods Data from the US Resident OPerative Experience (ROPE) Consortium, comprising 20 Accreditation Council for Graduate Medical Education (ACGME)-accredited GS residency programs across the United States, were queried. Case volume and type were compared between GS residents pursuing vs fellowship and all other residents. Effect size was evaluated using Cohen’s d statistic. Effect size was considered large if d > 0.8, moderate if 0.5 ≤ d < 0.8, small if 0.2 ≤ d < 0.5, and inconsequential if d < 0.2. Results A total of 1343 GS residents graduated from 2010-2020 across all programs participating in ROPE, of which 135 (10.1%) pursued vs fellowship. Total major vascular case volume was significantly greater among residents pursuing vs fellowship (138 [100-207] vs 100 [80-139], P < 0.0001) with a large effect size (d = 1.81). Vascular cases reported in a surgeon chief role (27 [9-53] vs 10 [2-29], P < 0.0001, d = 0.76, moderate effect) and surgeon junior role (107 [79-154] vs 88 [62-118], P < 0.0001, d = 1.00, large effect) were also greater among GS residents pursing a vs specialty. Nearly all vascular operative categories demonstrated similar trends ( P < 0.01 each). Conclusions GS residents pursuing a vs fellowship perform more vascular cases compared with their peers. Given the differences in both surgeon chief and surgeon junior roles, career focus may begin as early as the junior resident years.

Abstract Background and Objectives Lucid episodes (LEs) in advanced dementia are characterized by spontaneous, transient recovery of functional abilities. Despite recent increases in research on this previously understudied phenomenon, standard definitional criteria are lacking, presenting challenges for research. Researchers have proposed a preliminary framework to guide uniform labeling and operationalization of salient data elements for investigating LEs and developing definitional criteria. This study leverages this framework to characterize reports of LEs from caregivers and advance their definition and measurement. Research Design and Methods Family caregivers (N = 259) completed an electronic survey with quantitative and open-ended questions about LEs they witnessed (N = 479 episodes). Respondents were purposively sampled for qualitative interviews. Open-ended question responses (n = 208) and in-depth interviews (n = 24) were analyzed using content analysis. Results Caregiver descriptions suggest that the content and context of LEs are heterogeneous. Descriptions included observable changes from baseline, with behavior or communication that was distinguishable from routine cognitive fluctuations. LEs were sometimes, but not always specified by logically organized actions; recognition or awareness of people, emotions, and surroundings; and insight of their cognitive limitations. Many LEs required deep personal knowledge to attribute it as a meaningful shift. Discussion and Implications Findings suggest that definitional features may universally specify a significant return of ability with more flexible criteria for how this return manifests in observed actions and domains of recovery (i.e., insight, function, and communication). The impact of LEs on observers may be better measured separately, although further research should explore this.