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ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel–related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.

ABSTRACT Genetic variation at the TMEM106B locus has been associated with Alzheimer’s disease (AD) and related neurodegenerative phenotypes, yet its haplotypic architecture remains incompletely resolved. We refined the genetic landscape of TMEM106B by integrating AD-GWAS summary statistics (∼978K individuals) with haplotype analyses in 5,873 Dutch genomes including AD-cases, age-matched controls, and cognitively healthy centenarians. In addition to the known linkage disequilibrium (LD) block defining risk and protective haplotypes characterized by the amino acid substitution at residue 185 (Threonine/Serine), we identify a second conditionally independent LD block. Together these form four haplotypes (T1-T4), with T3 strongly enriched in centenarians. Long-read whole-genome sequencing in 493 individuals reveals haplotype-linked structural variation and methylation patterns, including a ∼19 Kbp genomic rearrangement carried by T3. These findings indicate that the TMEM106B locus comprises multiple haplotypes defined by methylation patterns and structural variants, offering insights into GWAS associations with AD risk and preserved cognition at extreme age.

AbstractLiver transplantation is becoming increasingly common in the United States, with very favorable 1- and 5-year survival rates. With increasing long-term survival rates, postprocedural vascular complications can occur with increased frequency. Familiarity with posttransplant vascular anatomy is essential for interventional radiologists dealing with this patient population. This article discusses the posttransplant venous, arterial, and biliary anatomy and the implications for minimally invasive interventions.

OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.

AbstractNew understanding of the lymphatic system as well as increasing recognition of its importance in various pathologies have increased the opportunity to perform lymphatic interventions. Advancement in our understanding of the lymphatic system anatomy, including variations, combined with improved imaging has renewed interest in both surgical and interventional management of a wide range of complex lymphatic pathologies. It is important for the proceduralist to recognize the anatomy, variability, and physiology of the lymphatic system, including lower extremity lymphatic drainage, cisterna chyli location, and thoracic duct drainage. The purpose of this study is to convey the practical aspects of performing lymphatic interventions in an effort to improve the speed and reliability of these procedures.

We evaluated the energy consumption of a 3T MRI using a central monitoring system, focusing on hospital energy costs during peak winter months from 2021 to 2023. We analyzed consumption during non-productive phases like end-of-day standby and assessed their impact. For active use, we compared standard and AI-enhanced protocols on phantoms, scheduling high-demand protocols during off-peak hours to benefit from lower energy prices. Standard protocols consumed 3.4 to 15 kWh, while optimized protocols used 2.3 to 10.6 kWh, reducing consumption by 32% on average. Savings per scan ranged from EUR 0.03 to EUR 3.7. The electrical consumption of a brain MRI protocol is equivalent to that of 3–4 knee protocols or 2–3 lumbar spine protocols. Using AI-optimized protocols and management, 41 protocols can be completed in 12 h, up from 30, reducing daily costs by EUR 2.38 to EUR 29.18. Annually, AI-optimized protocols could save 7900 to 8800 kWh per MRI unit, totaling 10,500 to 11,600 MWh across France’s MRI fleet, equivalent to the yearly consumption of about 4700 to 5300 people. Optimizing MRI resource use can expand patient access while significantly reducing the associated energy footprint. These findings support the implementation of more sustainable practices in medical imaging without compromising care quality.

Introduction Intravenous thrombolysis with tissue plasminogen activator (tPA) and endovascular therapy (ET) represent the cornerstone of modern stroke management. Despite advancements in these therapies, a subset of patients fails to achieve optimal recanalization (TICI 2b‐3), which is associated with poor functional outcomes and higher mortality rates. As a result, there has been growing interest in adjunctive pharmacologic interventions that could enhance the efficacy of ET. The efficacy and safety of tirofiban as an adjunct to ET have not been conclusively established, with existing studies yielding inconsistent results. Methods We conducted a systematic review and meta‐analysis to assess the efficacy and safety of tirofiban in patients undergoing thrombectomy. A comprehensive search was carried out across PubMed, Embase, and the Cochrane Library for studies published through August 2024. For each outcome, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and heterogeneity was evaluated using the I² statistic. Statistical analyses were performed using R. Results The meta‐analysis included 21 studies evaluating the effect of tirofiban plus ET on successful recanalization (TICI 2b‐3), showing a significant benefit with an odds ratio (OR) of 1.41 (95% CI 1.21‐1.65, p < 0.01), with low heterogeneity (I² = 25%). For excellent functional recovery (mRS 0‐1), 14 studies were analyzed, demonstrating a significant improvement with an OR of 1.17 (95% CI 1.03‐1.34, p = 0.02), and moderate heterogeneity (I² = 37%). In assessing good functional recovery (mRS 0‐2), 25 studies were pooled, and showed a significant effect of tirofiban plus ET with an OR of 1.30 (95% CI 1.19‐1.44, p < 0.01), with low heterogeneity (I² = 24%). Mortality outcomes across multiple studies revealed a significant reduction in mortality (OR 0.70, 95% CI 0.59‐0.84, p < 0.01), with moderate heterogeneity (I² = 44%). Lastly, for symptomatic intracranial hemorrhage (sICH), no significant difference was observed (OR 0.88, 95% CI 0.75‐1.04, p = 0.14), and heterogeneity was low (I² = 12%). Conclusion In conclusion, the meta‐analysis demonstrates that the addition of tirofiban to Endovascular Therapy (ET) significantly improves successful recanalization and functional recovery (mRS 0‐1 and mRS 0‐2) while reducing mortality, with low to moderate heterogeneity across the included studies. However, no significant difference in the risk of symptomatic intracranial hemorrhage (sICH) was observed. These findings suggest that Tirofiban plus ET may enhance clinical outcomes in patients undergoing treatment for acute ischemic stroke.