Citations

ABSTRACT Incomplete aneurysm occlusion after flow disruption treatment strongly depends on the persistence of strong flow into the aneurysm, which in turn depends on the aneurysm and parent artery geometry as well as the device placement. However, at the time of treatment it remains challenging to predict future outcomes (complete or incomplete occlusion). This paper describes a strategy to evaluate the local hemodynamic environment created immediately after flow‐modifying device deployment to treat cerebral aneurysms and connect it to the subsequent long‐term outcomes. The approach is based on the concept of angiographic signatures that can be extracted from DSA sequences or computational models and represented as images that can be used to compare different aneurysmal environments. The methodology is demonstrated on two small series of four experimental rabbit aneurysms each, treated with either intrasaccular flow disruptors or endoluminal flow diverters. Noticeable differences in the angiographic signatures of completely and incompletely occluded aneurysms at follow‐up were observed. Specifically, larger values of mean transit times and longer time‐to‐peaks were observed deeper into the aneurysms that remained incompletely occluded in both series. The findings suggest that angiographic signatures can be used to assess the underlying hemodynamic environment immediately after device implantation and prognosticate the likelihood of future complete or incomplete occlusion.

Abstract The Africa Working Group, under the auspices of the Global Laboratory Quality Initiative of the Association for Diagnostics & Laboratory Medicine (ADLM), conducted several educational workshops in Africa to promote laboratory quality in the region. The challenges faced in maintaining quality in clinical laboratories in low-resource countries may differ from region to region and country to country. To better understand current gaps and inform our engagement with partners in Africa, a needs assessment survey was distributed to 1427 ADLM members in Africa and further disseminated through local partners, resulting in 121 responses from participants across 8 countries in the region. Additionally, interviews were conducted with laboratory professionals from the countries surveyed. The surveys primarily focused on quality management, continuing education, budgeting, infrastructure and funding, supplies, and staffing issues. The data collected from the surveys and interviews strongly indicate that respondents face major challenges in all areas assessed, including lack of funding, lack of equipment, lack of quality control (QC) and external quality assessment (EQA) materials, gaps in quality management, lack of appropriate budgeting, staffing issues, and lack of accessible training/continuing education. Consistent with the primary focus of ADLM;s Global Quality Initiative, improved access to continuing education was identified as the primary need by the participants (58%). The assessment highlights that while a strong role for educational workshops in mitigating some of the challenges continues to exist, there is also an opportunity to broaden the scope of the working groups beyond education.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

Abstract Interstitial cells of Cajal (ICC) regulate gastrointestinal motility by generating electrical slow waves that orchestrate downstream calcium (Ca 2 + ) waves and coordinate smooth muscle contractions. A reduced ICC number has been reported in diabetic gastroparesis patients and in mouse models of delayed gastric emptying (DGE). However, functional changes in ICC propagating across the gastric regions in intact stomach are not well understood. The aim of this study was to develop an imaging approach to visualize ICC Ca 2+ waves in mouse stomach and determine spatiotemporal changes in mice with DGE. Tamoxifen‐treated B6.GCaMP5‐KitCreERT2 female mice were used as non‐diabetic controls (Non‐Db), while mice treated with streptozocin to induce diabetes were categorized as having normal (Db‐NGE) or delayed (Db‐DGE) gastric emptying based on emptying of solids. The ICC Ca 2+ network was imaged from excised intact mouse stomachs and subsequently opened along the lesser curvature and pinned flat. ICC Ca 2+ waves typically propagated along the greater curvature from the fundus–corpus line toward the antrum. The propagation length of ICC Ca 2+ activity was significantly decreased in Db‐DGE compared to Non‐Db and Db‐NGE and correlated to longer GE times. There was also a decrease in frequency, and the velocity was significantly faster in stomachs from Db‐DGE compared to Non‐Db and Db‐NGE. All experimental groups exhibited similar proportions of aberrant Ca 2+ propagation patterns (e.g., retrograde waves), but ectopic initiation only occurred in Db‐DGE stomachs. Thus, DGE is possibly driven by dysfunction in Ca 2+ activity in the ICC network that propagates rapidly over short distances, resulting in uncoordinated, non‐phasic muscle activity. image Key points Dysfunction of the interstitial cells of Cajal (ICC) has been implicated in diabetic gastroparesis but the changes in spatiotemporal properties of ICC network activity are not known. We developed an ex vivo Ca 2+ imaging approach to visualize ICC network activity across the entire stomach and determined changes in ICC Ca 2+ activity in a diabetic mouse model of delayed gastric emptying (GE). Decreased frequency and increased velocity of ICC Ca 2+ activity was observed in stomachs of diabetic mice with delayed GE. Ectopic initiation was a key feature associated with delayed GE. The propagation length of ICC Ca 2+ activity was inversely correlated to GE times and significantly reduced in stomach preparations from diabetic mice with delayed GE.

Abstract Genome-resolved virome analysis remains inaccessible for many samples, including those with clinical relevance, because viral nucleic acid recovered after enrichment is often too scarce to support de novo genome assembly. As a result, many analyses are limited to sparse read-level detection, which cannot recover divergent viruses, resolve strains, or interpret gene-level variation. Here, we developed Low Biomass Viral Sequencing (LBV-Seq), a workflow that couples low-input viral sample handling with modified primary template-directed amplification and short- or long-read sequencing to enable de novo reconstruction of DNA and RNA viral genomes from sub-femtogram to nanogram inputs. LBV-Seq reproducibly captures the same relative community composition, amplifies diverse viruses, and achieved broad genome coverage across nearly all targets regardless of viral genome structure, Baltimore class, abundance, or input mass. Short-read assemblies recovered near-complete genomes from femtogram-scale inputs. Long-read sequencing provided orthogonal support for genome structure, with PacBio HiFi reads spanning large portions of viral genomes and, in some cases, complete small viral genomes. Applied to virus-enriched human duodenal biopsy eluates, LBV-Seq provided proof-of-feasibility for recovering both bacteriophage and eukaryotic viral genomes from low-input biopsy-derived material. In the eluates tested, LBV-Seq recovered co-occurring Alphatorquevirus and Betatorquevirus genomes estimated to be present at roughly 10 copies/µL and at viral masses below 0.1 fg/µL. LBV-Seq enables genome-resolved virome analysis in samples previously limited to detection-based viromics, supporting viral discovery and strain-resolved analyses in settings where viral mass is low, including viruses enriched from human tissue biopsies.

Introduction The Centers for Medicare & Medicaid skilled nursing facility (SNF) 3-day waiver permits patients attributed to an Accountable Care Organization (ACO) to be admitted to an SNF or transitional care unit from an emergency department, outpatient setting, inpatient stay (<3 days), or observational status without Medicare’s requisite 3-day inpatient stay. Methods Our institution’s ACO implemented the waiver program in 2023. We report our experience with implementing the waiver and describe benefits and barriers, as well as interventions developed, outcomes achieved, and opportunities presented for patients and health care facilities. Results Through a streamlined process, patients can more readily access essential care, and health care facilities benefit from enhanced efficiency. Furthermore, the ACO can more effectively manage health care utilization and cost. Although the program offers benefits to patients, their families, and health care facilities, implementing and maintaining the program has challenges, with barriers including underdeveloped workflows, gaps in staff education and communication, difficulties in patient identification, and challenges with specific facility requirements. Conclusions The SNF 3-day rule waiver has been valuable in enhancing patient care and optimizing health care delivery within our ACO. Ongoing efforts to refine processes and address challenges will further improve the program’s effectiveness and sustainability.

Abstract Epilepsy affects more than 50 million individuals globally and has a substantial genetic component that remains to be completely understood. Traditional studies have focused on severe, early onset cases enrolled through clinical or research settings. Recent biobank‐based approaches, leveraging large‐scale population datasets, offer opportunities to explore genetic associations in broader epilepsy phenotypes, including milder, later onset forms. We analyzed data from more than 750 000 individuals across the UK Biobank, All of Us, and Massachusetts General Brigham Biobank, including 20 026 individuals with epilepsy. Rare coding variant burden testing revealed a significant association with LGI1 , a known epilepsy gene. Among the other top 10 associated genes, seven had prior evidence linking them to epilepsy ( GABRG2 , ATP1A3 ), neurological disorders with comorbid seizures ( HTRA2 , KRIT1 , STAG1 ), possible involvement in seizure phenotypes ( ADAM23 ), or roles in neuronal function ( PDCD4 ). Thus, we provide the first statistical evidence for ADAM23 as a candidate gene for epilepsy, based on the suggestive association signal combined with prior biological evidence from both animal (canine and murine) and one recent human epilepsy case study, potentially contributing to human epilepsy through its direct interaction with LGI1 . Phenome‐wide analyses highlighted the pleiotropic effects of epilepsy genes, with LGI1 and ADAM23 predominantly associated with epilepsy, whereas other genes such as KRIT1 , TSC1 , and TSC2 exhibited broader systemic involvement. Our study shows the potential of population‐scale genomic data and suggests that integrating these datasets with deep phenotyping will uncover more novel insights into epilepsy genetics in the future.

Abstract Background Immune-related adverse events disrupt immune checkpoint inhibitor therapy and impact quality of life. Peripheral edema is common among patients with cancer, however the causality of peripheral edema can be unclear in the context of multidrug regimens. Methods PubMed/MEDLINE, Embase, and Web of Science were searched to identify phase 3 randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors reporting peripheral edema incidence. The incidence of edema was calculated according to adverse event, immune checkpoint inhibitor, and treatment patterns. A random-effects meta-analysis pooled odds ratios (ORs) of edema incidence between immune checkpoint inhibitor and non–immune checkpoint inhibitor groups. A systematic review characterizing the interventions for immune-related peripheral edema was also conducted. Results From 58 RCTs (22 590 patients), treatment-related peripheral edema (grade 1-5) occurred in 2.80% (n = 195 of 6969) of patients receiving immune checkpoint inhibitor monotherapy, 4.96% (n = 112 of 2257) of patients receiving immune checkpoint inhibitor with chemotherapy, and 8.73% (n = 205 of 2349) of patients receiving immune checkpoint inhibitor with targeted therapy. Meta-analysis showed immune checkpoint inhibitor monotherapy had lower treatment-related peripheral edema incidence compared with chemotherapy (OR = 0.45, 95% CI = 0.27 to 0.73; P = .001, I2 = 69%) with the lowest relative incidence among programmed cell death protein 1 vs chemotherapy (OR = 0.41, 95% CI = 0.23 to 0.73; P = .003) and immune checkpoint inhibitor vs taxane chemotherapy (OR = 0.32, 95% CI = 0.18 to 0.58; P &lt; .001). A systematic review of treatment outcomes for immune-related peripheral edema among 40 patients (19 studies) revealed 82.5% (n = 33 of 40) of cases received glucocorticoid treatment, and immune checkpoint inhibitors were permanently discontinued in 35% (n = 14 of 40). Conclusions Peripheral edema is a rare but potentially serious adverse event associated with immune checkpoint inhibitors. Immune checkpoint inhibitors likely confer less peripheral edema risk than taxane therapy. To avoid unnecessary treatment interruptions, treatment discontinuation requires careful consideration, particularly when edema develops following immune checkpoint inhibitor combination therapy.