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Background The anterior communicating artery (AComm) region is the most common site of intracranial aneurysms, with increased rupture risk compared with other locations. Overall, flow diverters present as a safe and efficacious treatment for intracranial aneurysms, but there is paucity of data for their use in the treatment of unruptured AComm aneurysms. We present the largest multicentric analysis evaluating the outcomes of flow diverters in AComm aneurysm treatment. Methods Databases from 10 centers were retrospectively reviewed for unruptured AComm aneurysms treated with flow diverters. Demographics, clinical presentation, radiographic characteristics, procedural complications, and outcomes were assessed. Results A total of 144 patients harboring 147 AComm aneurysms were treated between January 2012 and December 2021. Seventy-four were women (51.4%) and median age was 60 (IQR 50–67) years. All were unruptured AComm aneurysms. Half of the cohort had similar anterior cerebral artery sizes (51.4%). The most common morphology was saccular (94.6%), with a branch involvement in 32.7% of cases. Median vessel diameter was 2.4 mm, and the Pipeline Flex was the most prevalent device (32.7%). Median follow-up time was 17 months, with complete occlusion in 86.4% at the last follow-up. Functional independence (modified Rankin Scale score 0–2) was reported in 95.1%. Intraprocedural complications occurred in 5.6%, and postoperative complications were noted in 9.7% of cases. Combined major complication and mortality rate was 2.1%. Conclusions Our study suggests that flow diverters are a useful treatment for AComm aneurysms. Mid-term results indicated favorable aneurysm occlusion with a good safety profile. Additional prospective studies with longer follow-up periods and independent adjudication are warranted to better assess these results.

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle–specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

AbstractIntroductionCytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). Measuring cell‐mediated immunity (CMI) may inform the risk of CMV infection after antiviral prophylaxis and predict relapse after CMV treatment.MethodsWe serially assessed CMV CMI using the QuantiFERON‐CMV assay (QF‐CMV; Qiagen, Germantown, MD) in two cohorts of SOTRs: during valganciclovir prophylaxis and during treatment of CMV viremia. Results of CMI were correlated with post‐prophylaxis CMV infection and post‐treatment relapse, respectively.ResultsOnly one (4.2%) of 24 CMV D+/R‐ patients demonstrated positive QF‐CMV by the end of valganciclovir prophylaxis. Four (16.6%) patients developed post‐prophylaxis CMV infection; all four had undetectable QF‐CMV at end of prophylaxis. Among 20 patients treated for CMV infection, 18 (90%) developed QF‐CMV levels >.2 IU/mL by end of antiviral treatment and none developed CMV relapse. In contrast, the single patient who relapsed after completing treatment had a CMV CMI <.2 IU/ml (p = .0036).ConclusionSince CMV D+/R‐ SOTRs are unlikely to develop adequate CMV CMI while receiving valganciclovir prophylaxis, the utility of CMV CMI monitoring for risk stratification during time of prophylaxis had limited value. Conversely, CMV CMI testing may be a useful marker of the risk of CMV relapse after antiviral treatment.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Background: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. Design: A prospective, observational cohort study. Methods: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. Results: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml (P = 0.003) and -55.6 ng/ml (P = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 (r = 0.64, P = 0.002; r = 0.58, P = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. Conclusion: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

INTRODUCTION: Endoscopic sleeve gastroplasty (ESG) has gained popularity over the past decade and has been adopted in both academic and private institutions globally. We present outcomes of the largest cohort of patients from the United States undergoing ESG and evaluate these according to obesity class. METHODS: We performed a retrospective analysis of adult patients who underwent ESG. Medical information was abstracted from the electronic record with weight records up to 2 years after ESG. Percent total body weight loss (%TBWL) at 6, 12, 18, and 24 months was calculated based on baseline weight at the procedure. SPSS (version 29.0) was used for all statistical analyses. RESULTS: A total of 1,506 patients from 7 sites were included (501 Class I obesity, 546 Class II, and 459 Class III). Baseline demographics differed according to obesity class due to differences in age, body mass index (BMI), height, sex distribution, and race. As early as 6 months post-ESG, mean BMI for each class dropped to the next lower class and remained there through 2 years. %TWBL achieved in the Class III group was significantly greater when compared with other classes at all time points. At 12 months, 83.2% and 60.9% of patients had ≥10% and ≥15% TBWL for all classes. There were no differences in adverse events between classes. DISCUSSION: Real-world data from a large cohort of patients of all BMI classes across the United States shows significant and sustained weight loss with ESG. ESG is safe to perform in a higher obesity class with acceptable midterm efficacy.