LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Economic Evaluation of Enhanced vs Standard Varenicline Treatment for Tobacco Cessation.

Importance: Smoking is the leading preventable cause of death and illness in the US. Identifying cost-effective smoking cessation treatment may increase the likelihood that health systems deliver such treatment to their patients who smoke. Objective: To evaluate the cost-effectiveness of standard vs enhanced varenicline use (extended varenicline treatment or varenicline in combination with nicotine replacement therapy) among individuals trying to quit smoking. Design, Setting, and Participants: This economic evaluation assesses the Quitting Using Intensive Treatments Study (QUITS), which randomized 1251 study participants who smoked into 4 conditions: (1) 12-week varenicline monotherapy (n = 315); (2) 24-week varenicline monotherapy (n = 311); (3) 12-week varenicline combination treatment with nicotine replacement therapy patch (n = 314); or (4) 24-week varenicline combination treatment with nicotine replacement therapy patch (n = 311). Study enrollment occurred in Madison and Milwaukee, Wisconsin, between November 11, 2017, and July 2, 2020. Statistical analysis took place from May to October 2023. Main Outcomes and Measures: The primary outcome was 7-day point prevalence abstinence (biochemically confirmed with exhaled carbon monoxide level ≤5 ppm) at 52 weeks. The incremental cost-effectiveness ratio (ICER), or cost per additional person who quit smoking, was calculated using decision tree analysis based on abstinence and cost for each arm of the trial. Results: Of the 1251 participants, mean (SD) age was 49.1 (11.9) years, 675 (54.0%) were women, and 881 (70.4%) completed the 52-week follow-up. Tobacco cessation at 52 weeks was 25.1% (79 of 315) for 12-week monotherapy, 24.4% (76 of 311) for 24-week monotherapy, 23.6% (74 of 314) for 12-week combination therapy, and 25.1% (78 of 311) for 24-week combination therapy, respectively. The total mean (SD) cost was $1175 ($365) for 12-week monotherapy, $1374 ($412) for 12-week combination therapy, $2022 ($813) for 24-week monotherapy, and $2118 ($1058) for 24-week combination therapy. The ICER for 12-week varenicline monotherapy was $4681 per individual who quit smoking and $4579 per quality-adjusted life-year (QALY) added. The ICER for 24-week varenicline combination therapy relative to 12-week monotherapy was $92 000 000 per additional individual who quit smoking and $90 000 000 (95% CI, $15 703 to dominated or more costly and less efficacious) per additional QALY. Conclusions and Relevance: This economic evaluation of standard vs enhanced varenicline treatment for smoking cessation suggests that 12-week varenicline monotherapy was the most cost-effective treatment option at the commonly cited threshold of $100 000/QALY. This study provides patients, health care professionals, and other stakeholders with increased understanding of the health and economic impact of more intensive varenicline treatment options.

Discrimination, Smoking, and Cardiovascular Disease Risk: A Moderated Mediation Analysis With MESA.

BACKGROUND: Carotid intima-media thickness (cIMT) and carotid plaque are reliable indicators of cardiovascular disease risk, and research highlights that racial and ethnic minority individuals generally exhibit higher cIMT and carotid plaque than White individuals. At present, the mechanisms driving these disparities among different racial and ethnic and biological sex groups are poorly understood. METHODS AND RESULTS: Data came from the baseline examination of MESA (Multi-Ethnic Study of Atherosclerosis). A total of 6814 participants aged 45 to 84 years free of clinical cardiovascular disease completed assessments on health behavior and perceived discrimination. Four sex-stratified moderated mediation models examined associations between discrimination, cigarette smoking, and mean cIMT and plaque. We hypothesized that cigarette use would mediate the association between discrimination and carotid artery disease features, and that these would differ by race and ethnicity. Indirect effects of discrimination on plaque were observed among Hispanic women such that discrimination was associated with cigarette use and, in turn, higher plaque (ß=0.04 [95% CI, 0.01-0.08]). Indirect effects of discrimination on mean cIMT were found among Hispanic (ß=0.003 [95% CI, 0.0001-0.007]) and White men (ß=0.04 [95% CI, 0.01-0.08]) such that discrimination was associated with cigarette use and, in turn, higher cIMT. Finally, a positive indirect effect of discrimination on plaque was observed among Hispanic men (ß=0.03 [95% CI, 0.004-0.07]). No other racial and ethnic differences were observed. CONCLUSIONS: To understand and address social determinants of cardiovascular disease, researchers must incorporate an intersectional framework that will allow us to understand the complex nature of discrimination and cardiovascular disease risk for individuals of varying intersecting identities and social positions.

Comparative Clinicopathologic and Genomic Analysis of Hepatocellular Neoplasm, Not Otherwise Specified, and Hepatoblastoma.

Accurate diagnosis and treatment of hepatocellular neoplasm, not otherwise specified (HCN-NOS), poses significant challenges. Our study aimed to investigate the clinicopathologic and genomic similarities and differences between HCN-NOS and hepatoblastoma (HB) to guide diagnostic and treatment strategies. The clinicopathologic characteristics of 16 patients with HCN-NOS and 23 patients with HB were compared. Molecular studies, including the OncoKids DNA- and RNA-based next-generation sequencing panel, chromosomal microarray, and targeted Sanger sequencing analyses of CTNNB1 and TERT promoters, were employed. We found that patients with HCN-NOS were older (P < .001) and more frequently classified as high risk (P < .01), yet they showed no significant differences in alpha fetoprotein levels or survival outcomes compared with those with HB. HCN-NOS and HB had a comparable frequency of sequence variants, with CTNNB1 mutations being predominant in both groups. Notably, TERT promoter mutations (37.5%) and rare clinically significant variants (BRAF, NRAS, and KMT2D) were exclusive to HCN-NOS. HCN-NOS demonstrated a higher prevalence of gains in 1q, encompassing the MDM4 locus (17/17 vs 11/24; P < .001), as well as loss/loss of heterozygosity (LOH) of 1p (11/17 vs 6/24; P < .05) and chromosome 11 (7/17 vs 1/24; P < .01) when compared with HB. Furthermore, the recurrent loss/LOH of chromosomes 3, 4p, 9, 15q, and Y was only observed in HCN-NOS. However, no significant differences were noted in gains of chromosomes 2, 8, and 20, or loss/LOH of 4q and 11p between the 2 groups. Notably, no clinically significant gene fusions were detected in either group. In conclusion, our study reveals that HCN-NOS exhibits high-risk clinicopathologic features and greater structural complexity compared with HB. However, patients with HCN-NOS exhibit comparable alpha fetoprotein levels at diagnosis, CTNNB1 mutation rates, and survival outcomes when subjected to aggressive treatment, as compared with those with HB. These findings have the potential to enhance diagnostic accuracy and inform more effective treatments for HCN-NOS.

Survival outcomes and surgical morbidity based on surgical approach to pulmonary metastasectomy in pediatric, adolescent and young adult patients with osteosarcoma.

BACKGROUND: Thoracotomy is considered the standard surgical approach for the management of pulmonary metastases in osteosarcoma (OST). Several studies have identified the advantages of a thoracoscopic approach, however, the clinical significance of thoracotomy compared to thoracoscopy is yet to be evaluated in a randomized trial. AIMS: The primary aim was to determine the survival outcomes in OST patients based on surgical approach for pulmonary metastasectomy (PM) and secondary aim was to assess the post-operative morbidities of OST PM through various surgical approaches. MATERIALS AND METHODS: We conducted a single institution retrospective study to compare survival outcomes and surgical morbidity according to the surgical approach of the management of pulmonary metastases in patients with OST. RESULTS: Sixty-one patients with OST underwent PM. Twenty-one patients were metastatic at diagnosis and underwent PM during primary treatment; nine had thoracotomy, six thoracoscopy, and six combined thoracoscopy with thoracotomy (CTT). Forty-three patients with first pulmonary relapse or progression underwent PM; 18 had thoracotomy, 16 thoracoscopy and nine CTT. There was no difference in survival between surgical approaches. There were significantly more postoperative morbidities associated with thoracotomy for initial PM (pain and postoperative chest tube placement), and for PM at first relapse (pneumothoraces, pain, Foley catheter use and prolonged hospitalizations). CONCLUSION: Our study demonstrates that patients with OST pulmonary metastases have comparable poor outcomes despite varying surgical approaches for PM. There were significantly more postoperative morbidities associated with thoracotomy for PM. Surgical bias and other competing risks could not be assessed given the limitations of a retrospective study and may be addressed in a prospective trial evaluating surgical approach for PM in OST.

Female-specific risk factors of parity and menopause age and risk of carotid plaque: the multi-ethnic study of atherosclerosis.

BACKGROUND: Female-specific factors of grand multiparity (≥5 births) and early menopause age are associated with an increased risk of cardiovascular disease (CVD). However, mechanisms are incompletely understood. Carotid plaque is a marker of subclinical atherosclerosis and associated with increased CVD risk. We evaluated the association of female-specific factors with plaque burden. METHODS: We included 2,313 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis, free of clinical CVD, whose parity and menopause age were ascertained by questionnaires and carotid plaque measured by ultrasound at baseline and 10 years later. Parity was categorized as nulliparity (reference), 1-2, 3-4 and ≥5 live births. Menopause age was categorized as <45, 45-49, 50-54 (reference) and ≥55 years. Multivariable regression was performed to evaluate the association of parity and menopause age with carotid plaque presence (yes/no) and extent [carotid plaque score (CPS)]. RESULTS: The mean age was 64±9 years; 52.3% had prevalent carotid plaque at baseline. Compared to nulliparity, grand multiparity was significantly associated with prevalent carotid plaque after adjustment for CVD risk factors (prevalence ratio 1.17 (95% CI 1.03-1.35)) and progression of CPS over 10 years [percent difference 13% (95% CI 3-23)]. There was not any significant association of menopause age with carotid plaque presence or progression in fully-adjusted models. CONCLUSION: In a multiethnic cohort, grand multiparity was independently associated with carotid plaque presence and progression. Early menopause, a known risk factor for CVD, was not captured by carotid plaque in this study. These findings may have implications for refining CVD risk assessment in women.

Incidental Coronary Artery Calcium on Chest CT in Persons Without Known Atherosclerotic Cardiovascular Disease.

This cross-sectional study examines the expected prevalence of coronary artery calcium (CAC) on chest computed tomography (CT) in people without clinical atherosclerotic cardiovascular disease (ASCVD) by age, sex, and race and ethnicity.

Changes in carotid artery texture by ultrasound and elastin features in a murine model.

Objective: In humans, arterial grayscale ultrasound texture features independently predict adverse cardiovascular disease (CVD) events and change with medical interventions. We performed this study to examine how grayscale ultrasound texture features and elastin fibers change in plaque-free segments of the arterial wall in a murine model prone to atherosclerosis. Methods: A total of 10 Apoetm1Unc/J mice (n = 5 male, n = 5 female) were imaged at 6, 16, and 24 weeks of age. Two mice were euthanized at 6 and 16 weeks and the remaining mice at 24 weeks. Texture features were extracted from the ultrasound images of the distal 1.0 mm of the common carotid artery wall, and elastin measures were extracted from histology images. Two-way analysis of variance was used to evaluate associations between week, sex, and grayscale texture features. Texture feature and elastin number comparisons between weeks were conducted using the sex-by-week two-way interaction contrasts. Sex-specific correlations between the number of elastin fibers and grayscale texture features were analyzed by conducting non-parametric Spearman's rank correlation analyses. Results: Arterial wall homogeneity changed significantly in male mice from 6 to 24 weeks, with a mean (SD) of 0.14 (0.03) units at 6 weeks and 0.18 (0.03) units at 24 weeks (p = 0.026). Spatial gray level dependence matrices-homogeneity (SGLD-HOM) also correlated with carotid artery plaque score (rs = 0.707, p = 0.033). Elastin fibers in the region of interest decreased from 6 to 24 weeks for both male and female mice, although only significantly in male mice. The mean (SD) number of elastin fibers for male mice was 5.32 (1.50) at 6 weeks and 3.59 (0.38) at 24 weeks (p = 0.023). For female mice, the mean (SD) number of elastin fibers was 3.98 (0.38) at 6 weeks and 3.46 (0.19) at 24 weeks (p = 0.051). Conclusion: Grayscale ultrasound texture features that are associated with increased risk for CVD events in humans were used in a murine model, and the grayscale texture feature SGLD-HOM was shown to change in male mice from 6 weeks to 24 weeks. Structural alterations of the arterial wall (change in elastin fiber number) were observed during this time and may differ by sex.

In Vivo Adaptive Bayesian Regularized Lagrangian Carotid Strain Imaging for Murine Carotid Arteries and Its Associations With Histological Findings.

OBJECTIVES: Non-invasive methods for monitoring arterial health and identifying early injury to optimize treatment for patients are desirable. The objective of this study was to demonstrate the use of an adaptive Bayesian regularized Lagrangian carotid strain imaging (ABR-LCSI) algorithm for monitoring of atherogenesis in a murine model and examine associations between the ultrasound strain measures and histology. METHODS: Ultrasound radiofrequency (RF) data were acquired from both the right and left common carotid artery (CCA) of 10 (5 male and 5 female) ApoE tm1Unc/J mice at 6, 16 and 24 wk. Lagrangian accumulated axial, lateral and shear strain images and three strain indices-maximum accumulated strain index (MASI), peak mean strain of full region of interest (ROI) index (PMSRI) and strain at peak axial displacement index (SPADI)-were estimated using the ABR-LCSI algorithm. Mice were euthanized (n = 2 at 6 and 16 wk, n = 6 at 24 wk) for histology examination. RESULTS: Sex-specific differences in strain indices of mice at 6, 16 and 24 wk were observed. For male mice, axial PMSRI and SPADI changed significantly from 6 to 24 wk (mean axial PMSRI at 6 wk = 14.10 ± 5.33% and that at 24 wk = -3.03 ± 5.61%, p < 0.001). For female mice, lateral MASI increased significantly from 6 to 24 wk (mean lateral MASI at 6 wk = 10.26 ± 3.13% and that at 24 wk = 16.42 ± 7.15%, p = 0.048). Both cohorts exhibited strong associations with ex vivo histological findings (male mice: correlation between number of elastin fibers and axial PMSRI: rs = 0.83, p = 0.01; female mice: correlation between shear MASI and plaque score: rs = 0.77, p = 0.009). CONCLUSION: The results indicate that ABR-LCSI can be used to measure arterial wall strain in a murine model and that changes in strain are associated with changes in arterial wall structure and plaque formation.

Epidural Analgesia Is Associated With Reduced Inpatient Opioid Consumption and Length of Stay After Wilms Tumor Resection.

INTRODUCTION: Wilms' tumor (WT) is the most common renal malignancy in children and requires an extensive laparotomy for resection. Epidural analgesia (EA) is commonly used in postoperative pain management, but previous literature suggests it may prolong length of stay (LOS). We hypothesized that EA is associated with prolonged LOS but decreased postoperative opioid use in children undergoing WT resection. MATERIALS AND METHODS: A retrospective chart review was performed for all WT patients who underwent nephrectomy between January 1, 1998, and December 31, 2018, at a tertiary children's hospital. Patients with incomplete records, bilateral WT, caval or cardiac tumor extension, or intubation postoperatively were excluded. Outcomes included postoperative opioid consumption measured in oral morphine equivalents per kilogram, receipt of opioid prescription at discharge, and postoperative LOS. Mann-Whitney and multivariable regression analyses were performed. RESULTS: Overall, 46/77 children undergoing WT resection received EA. Children with EA used significantly less inpatient opioids than children without EA (median 1.0 vs. 3.3 oral morphine equivalents per kilogram; P < 0.001). Comparing patients with EA to patients without, there was no significant difference in opioid discharge prescriptions (57% vs. 39%; P = 0.13) or postoperative LOS (median 5 d vs. 6 d; P = 0.10). Controlling for age and disease stage, EA was associated with shorter LOS by multivariable regression (coefficient -0.73, 95% confidence interval: -1.4, -0.05; P = 0.04). CONCLUSIONS: EA is associated with decreased opioid use in children without an associated increase in postoperative LOS following WT resection. EA should be considered as part of multimodal pain management for children undergoing WT resection.

Cardiovascular and Pulmonary Responses to Acute Use of Electronic Nicotine Delivery Systems and Combustible Cigarettes in Long-Term Users.

BACKGROUND: The acute cardiovascular and pulmonary effects of contemporary electronic nicotine delivery systems (ENDS) in long-term users are not known. RESEARCH QUESTION: What are the cardiovascular and pulmonary responses to an acute 15-min product use challenge with ENDS and combustible cigarettes in regular nicotine-containing product users compared with control participants who do not use tobacco or vape? STUDY DESIGN AND METHODS: Observational challenge study before and after nicotine-containing product use of 395 individuals who used ENDS exclusively (n = 164; exhaled carbon monoxide level, < 5 parts per million [ppm]; positive urine NicCheck I [Mossman Associates] results, 82%; fourth-generation ENDS), participants who smoked cigarettes exclusively (n = 117; carbon monoxide level, > 5 ppm; positive urine NicCheck I results), and control participants (n = 114; carbon monoxide level, < 5 ppm; negative urine NicCheck I results). RESULTS: During the 15-min product challenge, cigarette users took a median of 14.0 puffs (interquartile range [IQR], 9.3 puffs); ENDS users took 9.0 puffs (IQR, 7.5 puffs; P < .001). After product challenge, compared with control participants, ENDS users showed greater increases in adjusted mean differences in systolic BP (5.6 mm Hg [95% CI, 4.4-6.8 mm Hg] vs 2.3 mm Hg [95% CI, 0.8-3.8 mm Hg]; P = .001), diastolic BP (4.2 mm Hg [95% CI, 3.3-5.0 mm Hg] vs 2.0 mm Hg [95% CI, 1.1-3.0 mm Hg; P = .003), and heart rate (4.8 beats/min [95% CI, 4.0-5.6 beats/min] vs -1.3 beats/min [95% CI, -2.2 to -0.3 beats/min]; P < .001) and greater reductions in brachial artery diameter (-0.011 cm [95% CI, -0.013 to 0.009 cm] vs -0.006 cm [95% CI, -0.004 to -0.009 cm]; P = .003), time-domain heart rate variability (-7.2 ms [95% CI, -10.5 to -3.7 ms] vs 3.6 ms [95% CI, 1.6-9.3 ms]; P = .001), and FEV1 (ENDS: -4.1 [95% CI, -5.4 to -2.8] vs control participants: -1.1 [95% CI, -2.7 to 0.6]; P = .005) with values similar to those of cigarette users. ENDS users performed worse than control participants on all exercise parameters, notably metabolic equivalents (METs; adjusted mean difference, 1.28 METs [95% CI, 0.73-1.83 METs]; P < .001) and 60-s heart rate recovery (adjusted mean difference, 2.9 beats/min [95% CI, 0.7-5.0 beats/min]; P = .008). INTERPRETATION: ENDS users had acute worsening of blood pressure, heart rate, and heart rate variability, as well as vasoconstriction, impaired exercise tolerance, and increased airflow obstruction after vaping, compared to control participants. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03863509; URL: www. CLINICALTRIALS: gov.

Methods of arterial stiffness calculation and cardiovascular disease events: the multiethnic study of atherosclerosis.

BACKGROUND: A wide variety of different formulae have been used to calculate local arterial stiffness with little external validation in relationship to cardiovascular events. We compared the associations of several arterial stiffness calculations in a large, multiethnic cohort. METHODS: The multi-ethnic study of atherosclerosis (MESA) is a longitudinal study of 6814 adults without clinical cardiovascular disease (CVD) at enrollment. MESA participants with CVD surveillance through year 2018 and carotid ultrasound ( n  = 5873) or aorta MRI ( n  = 3175) at the baseline exam (2000-2002) were included. We analyzed 21 different calculations of local arterial stiffness. Cross-sectional and longitudinal statistical analyses were performed in addition to Cox hazard modeling for associations with CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, adjudicated angina, and cardiovascular death). RESULTS: Carotid artery stiffness calculations had variable correlations with each other ( r  = 0.56-0.99); aortic stiffness measures were similar ( r  = 0.66-0.99). Nevertheless, for CVD events, the hazard ratio (HR) per standard deviation change were similar for all carotid stiffness calculations with HRs in the range of 1.00-1.10 (equivalence P  < 0.001). For the aorta, aortic distensibility coefficient had a stronger association with CVD events (HR 1.18 [1.02-1.37]) compared to aorta Peterson's elastic modulus (HR 0.98 [0.89-1.07]) and aorta pulse wave velocity (HR 1.00 [0.90-1.11]). HRs between all other aortic stiffness calculations were equivalent ( P  < 0.01). CONCLUSION: Different methods of calculating local arterial stiffness largely gave equivalent results, indicating that the variety of different arterial stiffness calculations in use do not cause inconsistent findings.

Intercostal Nerve Cryoablation is Associated with Reduced Opioid Use in Pediatric Oncology Patients.

INTRODUCTION: Intercostal nerve cryoablation reduces postoperative pain in adults undergoing thoracotomy and children undergoing pectus excavatum repair. We hypothesize that cryoablation is associated with decreased post-thoracotomy pain and opioid use in pediatric oncology patients. METHODS: A single-center retrospective cohort study was performed for oncology patients who underwent thoracotomy from January 1, 2017 to May 31, 2021. Outcomes included postoperative opioid use measured in morphine milligram equivalents per kilogram (MME/kg), pain scores (scale 0-10), and opioid prescription at discharge. Univariable analysis compared patients who received cryoablation to patients who did not receive cryoablation. Multivariable regression analysis controlling for age and prior thoracotomy evaluated associations between cryoablation and postoperative pain. RESULTS: Overall, 32 patients (19 males:13 females) underwent thoracotomy with 16 who underwent >1 thoracotomy resulting in 53 thoracotomies included for analysis. Cryoablation was used in 14 of 53 (26.4%) thoracotomies. Throughout the postoperative hospitalization, patients receiving cryoablation during thoracotomy consumed less opioids compared to patients who did not receive cryoablation (median 0.38 MME/kg, interquartile range [IQR] 0.20-1.15 versus median 1.47 MME/kg, IQR 0.71-4.02, P < 0.01). Maximum pain scores were lower in cryoablation patients (median 6, IQR 5-8) than noncryoablation patients (median 8, IQR 6-10), with a significant difference observed on postoperative day 4 (P = 0.01). Cryoablation patients were also less frequently prescribed opioids at discharge (21.4% versus 58.97%, P = 0.02). Multivariable regression demonstrated that cryoablation was associated with 2.59 MME/kg less opioid use (95% confidence interval -4.56 to -0.63) and decreased likelihood of opioid prescription at discharge (adjusted odds ratio 0.14, 95% confidence interval 0.03-0.67). CONCLUSIONS: Cryoablation is significantly associated with decreased post-thoracotomy pain and opioid use in pediatric cancer patients and should be considered in postoperative pain regimens.

Persistent Asthma Is Associated With Carotid Plaque in MESA.

Background Asthma and atherosclerotic cardiovascular disease share an underlying inflammatory pathophysiology. We hypothesized that persistent asthma is associated with carotid plaque burden, a strong predictor of atherosclerotic cardiovascular disease events. Methods and Results The MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults free of known atherosclerotic cardiovascular disease at baseline. Subtype of asthma was determined at examination 1. Persistent asthma was defined as asthma requiring use of controller medications, and intermittent asthma was defined as asthma without controller medications. B-mode carotid ultrasound was performed to detect carotid plaques (total plaque score [TPS], range 0-12). Multivariable regression modeling with robust variances evaluated the association of asthma subtype and carotid plaque burden. The 5029 participants were a mean (SD) age of 61.6 (10.0) years (53% were women, 26% were Black individuals, 23% were Hispanic individuals, and 12% were Chinese individuals). Carotid plaque was present in 50.5% of participants without asthma (TPS, 1.29 [1.80]), 49.5% of participants with intermittent asthma (TPS, 1.25 [1.76]), and 67% of participants with persistent asthma (TPS, 2.08 [2.35]) (P≤0.003). Participants with persistent asthma had higher interleukin-6 (1.89 [1.61] pg/mL) than participants without asthma (1.52 [1.21] pg/mL; P=0.02). In fully adjusted models, persistent asthma was associated with carotid plaque presence (odds ratio, 1.83 [95% confidence interval, 1.21-2.76]; P<0.001) and TPS (ß=0.66; P<0.01), without attenuation after adjustment for baseline interleukin-6 (P=0.02) or CRP (C-reactive protein) (P=0.01). Conclusions Participants with persistent asthma had higher carotid plaque burden and higher levels of inflammatory biomarkers, compared with participants without asthma. Adjustment for baseline inflammatory biomarkers did not attenuate the association between carotid plaque and asthma subtype, highlighting the increased atherosclerotic cardiovascular disease risk among those with persistent asthma may be multifactorial.

Cholesterol mass efflux capacity and coronary artery calcium: The Multi-Ethnic Study of Atherosclerosis.

We assessed the cross-sectional and longitudinal relationships of high-density lipoprotein (HDL)-mediated cholesterol mass efflux capacity (CMEC) with coronary artery calcium (CAC) score and CAC density. CMEC was measured in 1626 Multi-Ethnic Study of Atherosclerosis (MESA) participants in samples obtained between 2000 and 2002 as part of two nested case-control studies, one with cases of incident cardiovascular disease and the other with cases of carotid plaque progression by ultrasound. Cardiac CT examinations for the presence of CAC were performed at baseline and at two additional examinations. CAC scores (Agatston and volume) and density scores (for those with positive CAC) were calculated. Multivariable linear regression modeling per SD increment of CMEC was used to estimate the associations of CMEC with each of these CAC measures. We found no association between higher CMEC and either lower CAC scores or a higher CAC density. We also found no association between higher CMEC and progression of any of these CAC measures. These findings suggest that HDL-mediated cholesterol efflux may be associated with cardiovascular risk via mechanisms unrelated to burden of calcified plaque.

Methotrexate Inhibits T Cell Proliferation but Not Inflammatory Cytokine Expression to Modulate Immunity in People Living With HIV.

Inflammation associated with increased risk of comorbidities persists in people living with HIV (PWH) on combination antiretroviral therapy (ART). A recent placebo-controlled trial of low-dose methotrexate (MTX) in PWH found that numbers of total CD4 and CD8 T cells decreased in the low-dose MTX arm. In this report we analyzed T cell phenotypes and additional plasma inflammatory indices in samples from the trial. We found that cycling (Ki67+) T cells lacking Bcl-2 were reduced by MTX but plasma inflammatory cytokines were largely unaffected. In a series of in vitro experiments to further investigate the mechanisms of MTX activity, we found that MTX did not inhibit effector cytokine production but inhibited T cell proliferation downstream of mTOR activation, mitochondrial function, and cell cycle entry. This inhibitory effect was reversible with folinic acid, suggesting low-dose MTX exerts anti-inflammatory effects in vivo in PWH largely by blocking T cell proliferation via dihydrofolate reductase inhibition, yet daily administration of folic acid did not rescue this effect in trial participants. Our findings identify the main mechanism of action of this widely used anti-inflammatory medicine in PWH and may provide insight into how MTX works in the setting of other inflammatory conditions.

Optimal lifestyle behaviors and 10-year progression of arterial stiffness: The Multi-Ethnic Study of Atherosclerosis.

Majority of previous studies showed no association between a single health behavior and arterial stiffness, but the benefit of simultaneously having multiple healthy behaviors (optimal lifestyle) on the progression of arterial stiffness is unknown. Among 2810 individuals (age 60.0 ± 9.4, 46.5% male), optimal lifestyle marker (yes/no) on four health behaviors (ie, BMI < 25 kg/m2 , never or former smoker, never or moderate drinker, exercised > 500 METS min/week) across four visits (≈ 5 years) were summed to create an optimal lifestyle score. Carotid arterial stiffness was measured using distensibility coefficient (DC) and Young's elastic modulus (YEM) at visit 1 and after a mean of 9.5 years (visit 5). The association of optimal lifestyle with 10-year percent change in DC and YEM was assessed using multiple linear regression. DC decreased by 5.3% and YEM increased by 24.4% over 10 years. Mean optimal lifestyle score was 9.4 ± 3.1 (range: 0-16). Individuals in quintiles 2-5 of optimal lifestyle score compared to quintile 1 (with the least optimal lifestyle score) did not show slower deceleration of DC [Q2, -0.3% (95% CI: -6.0, 5.4); Q3, -0.01% (-4.5, 4.5); Q4, -0.6% (-5.2, 3.9); Q5, -0.4% (-5.3, 4.4)], trend p-value = .82] or slower progression of YEM [Q2, 0.1% (-7.1, 7.3); Q3, -0.8% (-8.0, 6.5); Q4, 4.5% (-2.3, 11.3); Q5, -0.2% (-8.3, 7.9)], trend p-value = .49] after adjusting for risk factors. The association remained non-significant when stratified by categories of age, sex, race, BP control, and diabetes. Our findings indicate that optimal score on multiple health behaviors may not independently slow arterial stiffness progression.

Grayscale Ultrasound Texture Features of Carotid and Brachial Arteries in People With HIV Infection Before and After Antiretroviral Therapy.

Background We aimed to investigate novel grayscale ultrasound characteristics of the carotid and brachial arteries in people with HIV infection before and after starting initial antiretroviral therapy (ART). Methods and Results We performed grayscale ultrasound image analyses of the common carotid artery (CCA) and brachial artery before and after receipt of 1 of 3 randomly allocated ART regimens. We measured arterial wall echogenicity (grayscale median), contrast (gray-level difference statistic method), and entropy. These measures and their changes were compared with atherosclerotic cardiovascular disease risk factors, measures of HIV disease severity, and inflammatory biomarkers before and after ART. Changes in the grayscale measures were evaluated within and between ART arms. Among 201 ART-naïve people with HIV, higher systolic blood pressure, higher body mass index, lower CD4+ T cells, and non-Hispanic White race and ethnicity were associated independently with lower CCA grayscale median. Changes in each CCA grayscale measure from baseline to 144 weeks correlated with changes in soluble CD163: grayscale median (ρ=-0.17; P=0.044), gray-level difference statistic-contrast (ρ=-0.19; P=0.024), and entropy (ρ=-0.21; P=0.016). Within the atazanavir/ritonavir arm, CCA entropy increased (adjusted ß=0.023 [95% CI, 0.001-0.045]; P=0.04), but no other within-arm changes in grayscale measures were seen. Correlations of brachial artery grayscale measures were weaker. Conclusions In ART-naïve people with HIV, CCA grayscale ultrasound measures were associated with atherosclerotic cardiovascular disease risk factors and lower grayscale median was associated with lower CD4+ T cells. Reductions in soluble CD163 with initial ART were associated with improvements in all 3 CCA grayscale measures, suggesting that reductions in macrophage activation with ART initiation may lead to less arterial injury. Registration URL: https://clinicaltrials.gov/; Unique identifiers: NCT00811954; NCT00851799.

Independent Assessment of the Children's Hepatic Tumors International Collaboration Risk Stratification for Hepatoblastoma and the Association of Tumor Histological Characteristics With Prognosis.

Importance: Hepatoblastoma is the most common pediatric liver malignant neoplasm, and accurate risk stratification is essential for guiding treatment. Objective: To validate the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) in an independent cohort of patients with hepatoblastoma and evaluate the association of pretreatment hepatoblastoma histological subtype with prognosis. Design, Setting, and Participants: This is a single-institution retrospective cohort study of 96 pediatric patients with hepatoblastoma diagnosed and treated between June 1, 2000, and December 31, 2016, with recent therapy and independent of the CHIC-HS discovery cohort. Each patient was assigned a risk group according to CHIC-HS. The histological characteristics of each tumor were assessed based on the International Pediatric Liver Tumor Consensus Classification. Data were analyzed from May 2018 to May 2019. Main Outcomes And Measures: The main outcomes were event-free survival (EFS) and overall survival (OS). Cox regression analysis was used to examine the associations of patient characteristics and tumor histological characteristics with survival. Results: A total of 96 patients (median [range] age, 1.9 [0.4-18] years; 36 [38%] girls and 60 [63%] boys) were assessed, including 15 with very low risk, 28 with low risk, 23 with intermediate risk, and 30 with high risk, according to CHIC-HS criteria. There were a total of 13 cancer-related deaths; median (range) follow-up was 3.5 (0.1-17.8) years for those alive at the last follow-up. The estimated 5-year OS rates were 100% in the very low-risk group, 94.7% (95% CI, 68.1%-99.2%) in the low-risk group, 89.2% (95% CI, 63.1%-97.2%) in the intermediate-risk group, and 57.9% (95% CI, 34.6%-75.5%) in the high-risk group. In a multivariable analysis, we confirmed that CHIC-HS significantly estimated EFS (high-risk group vs very low- and low-risk groups: hazard ratio [HR], 45.59; 95% CI, 9.39-209.5; P < .001) and OS (high-risk group vs very low- and low-risk groups: HR, 21.95; 95% CI, 2.76-174.29; P < .001). In the subcohort of 84 patients for whom pretreatment tumor histological data were available, tumor epithelial histological subtypes were found to be significantly associated with both EFS and OS. Patients in the CHIC-HS high-risk group and with embryonal-only histological subtype had the highest risk of relapse or disease progression (high-risk: HR, 42.62; 95% CI, 9.91-203.9; embryonal: HR, 3.28; 95% CI, 1.21-8.9) and death (high-risk: HR, 18.78; 95% CI, 2.31-152.84; embryonal: HR, 7.12; 95% CI, 1.51-33.52). Conclusions and Relevance: This cohort study found that CHIC-HS performed as expected in an independent cohort that was more recently treated. Incorporation of pretreatment tumor histological data into CHIC-HS may provide additional prognostic value.