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Meron Teklu, Philip M Parel, Nehal N Mehta National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USACorrespondence: Nehal N MehtaLasker Senior Investigator, Chief, Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Clinical Research Center, Room 5-5140, Bethesda, MD, 20892, USATel +1-301-827-0483Fax +1-301-827-0915Email nehal.mehta@nih.govAbstract: Psoriasis is a common chronic inflammatory condition associated with a higher risk of cardiovascular disease. Psoriasis confers a dose-dependent increase in risk for the metabolic syndrome and its components. The metabolic syndrome and its components have been associated with higher coronary atherosclerosis in psoriasis and cardiovascular events in the general population. In this review, we discuss the role of inflammation and psoriasis in cardiometabolic diseases with a focus on the metabolic syndrome and its components. We highlight the relationship between psoriasis and important cardiovascular risk factors encompassed by obesity, dyslipidemia, insulin resistance and hypertension. Furthermore, we briefly highlight literature on anti-inflammatory therapies and their impact on the components of the metabolic syndrome as well as directly quantified coronary atherosclerosis burden.Keywords: psoriasis, inflammation, metabolic syndrome, atherosclerosis

AimsGenome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.Methods and resultsWe analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio.ConclusionsIn CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.

Objectives: This study sought to examine the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂/PLA2G7) in human inflammation and coronary atherosclerosis.Background: Lp-PLA₂ has emerged as a potential therapeutic target in coronary heart disease. Data supporting Lp-PLA₂ are indirect and confounded by species differences; whether Lp-PLA₂ is causal in coronary heart disease remains in question.Methods: We examined inflammatory regulation of Lp-PLA₂ during experimental endotoxemia in humans, probed the source of Lp-PLA₂ in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7, the gene encoding Lp-PLA₂, with coronary artery calcification.Results: In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA₂ messenger ribonucleic acid decreased transiently, and plasma Lp-PLA₂ mass declined modestly during endotoxemia. In vitro, Lp-PLA₂ expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA₂ activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification.Conclusions: Circulating Lp-PLA₂ did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA₂. Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA₂ to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA₂ as a biomarker of Lp-PLA₂ actions in the vasculature. [ABSTRACT FROM AUTHOR]

Importance: Psoriasis is associated with increased cardiovascular risk, but the underlying pathogenic mechanisms remain unclear. Elucidating these mechanisms can help develop treatment strategies and enhance understanding of the link between peripheral inflammation, such as psoriatic skin lesions, and cardiovascular disease (CVD)., Objective: To explore whether systemic inflammation is a mediator of the association between psoriasis skin disease severity and CVD., Design, Setting, and Participants: This cohort study used data from cross-sectional study (Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative [PACI]), which enrolled patients from January 2013 to February 2022, and an inception cohort study (Stockholm Psoriasis Cohort [SPC]), which enrolled patients from January 2000 to December 2005. The PACI enrolled consecutive patients referred by dermatologists in Maryland, and the SPC enrolled consecutive patients referred from a wide range of practices in Sweden. Patients with prevalent psoriasis from the PACI and patients with incident psoriasis from the SPC were included. Data were analyzed from October 2023 to January 2024., Exposures: Psoriasis skin disease severity was measured using the Psoriasis Area and Severity Index (PASI), and systemic inflammation was measured using glycan biomarker of N-acetyl side chains of acute-phase proteins (GlycA). Mediation analysis was performed by evaluating the associations between exposure, mediator, and outcome in patients with first-tertile and third-tertile PASI scores when GlycA level was set at the level observed in patients with first-tertile PASI., Main Outcomes and Measures: Noncalcified coronary burden (NCB) measured using coronary computed tomography angiography in the PACI and hospitalization for CVD or cardiovascular death in the SPC., Results: Of 260 eligible patients from the PACI, 162 (62.3%) were male, and the median (IQR) age was 51 (41-60) years; of 509 eligible patients from the SPC, 237 (46.6%) were male, and the median (IQR) age was 43 (30-57) years. In both studies, PASI was associated with GlycA level and CVD, and GlycA level was associated with CVD. The direct and indirect (through GlycA) effects of PASI on NCB were estimated at 0.94 (95% CI, 0.26-1.74) and 0.19 (95% CI, 0.02-0.47), respectively. The odds ratios for the direct and indirect effects of PASI on cardiovascular events were estimated at 1.23 (95% CI, 0.70-1.92) and 1.16 (95% CI, 1.04-1.42), respectively., Conclusions and Relevance: In this study, skin disease severity measured using PASI was associated with systemic inflammation, and both PASI and systemic inflammation, measured using GlycA levels, were associated with CVD. The association between PASI and CVD may be mediated by systemic inflammation.

This study investigates the efficacy of predicting age-related macular degeneration (AMD) activity through deep neural networks (DNN) using a cross-instrument training dataset composed of Optical coherence tomography-angiography (OCTA) images from two different manufacturers. A retrospective cross-sectional study analyzed 2D vascular en-face OCTA images from Heidelberg Spectralis (1478 samples: 1102 training, 276 validation, 100 testing) and Optovue Solix (1003 samples: 754 training, 189 validation, 60 testing). OCTA scans were labeled based on clinical diagnoses and adjacent B-scan OCT fluid information, categorizing activity into normal, dry AMD, active wet AMD, and wet AMD in remission. Experiments explored cross-instrument disease classification using separate and combined datasets for training the DNN. Testing involved 100 Heidelberg and 60 Optovue samples. Training on Heidelberg data alone yielded 73% accuracy on Heidelberg images and 60% on Optovue images. Training on Optovue data alone resulted in 34% accuracy on Heidelberg and 85% on Optovue images. Combined training data from both instruments achieved 78% accuracy on Heidelberg and 76% on Optovue test sets. Results indicate that cross-instrument classifier training demonstrates high classification prediction accuracy, making cross-instrument training viable for future clinical applications. This implies that vascular morphology in OCTA can predict disease progression., (© 2024. The Author(s).)

Systemic inflammation or insulin resistance drive atherosclerosis. However, they are difficult to capture for assessing cardiovascular risk in clinical settings. The monocyte-to-high-density lipoprotein ratio (MHR) is an accessible biomarker that integrates inflammatory and metabolic information and has been associated with poorer cardiovascular outcomes. Our aim was to evaluate the association of MHR with the presence of subclinical atherosclerosis in patients with psoriasis. The study involved a European and an American cohort including 405 patients with the disease. Subclinical atherosclerosis was assessed by coronary computed tomography angiography. First, MHR correlated with insulin resistance through homeostatic model assessment for insulin resistance, with high-sensitivity CRP and with 18 F-fluorodeoxyglucose uptake in spleen, liver, and bone marrow by positron emission tomography/computed tomography. MHR was associated with both the presence of coronary plaques >50% of the artery lumen and noncalcified coronary burden, beyond traditional cardiovascular risk factors (P < .05). In a noncalcified coronary burden prediction model accounting for cardiovascular risk factors, statins, and biologic treatment, MHR added value (area under the curve base model = 0.72 vs area under the curve base model plus MHR = 0.76, P = .04) within the American cohort. These results suggests that MHR may detect patients with psoriasis who have subclinical burden of cardiovascular disease and warrant more aggressive measures to reduce lifetime adverse cardiovascular outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease., Methods: We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF., Results: TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF., Conclusions: In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans., Competing Interests: S. Panda is the author of the book “The Circadian Code and The Circadian Diabetes Code” and serves on the scientific advisory board of Hooke London. J.L. Witztum received consulting fees from Ionis Pharmaceuticals Inc; royalties/patent beneficiary from the University of California San Diego; and ownership interest from Kleanthi, and Oxitope.

Background: A post-operative pancreatic fistula is a major cause of morbidity and mortality in patients undergoing pancreaticoduodenectomy. We compared two methods of reconstruction of pancreaticojejunal anastomosis, an isolated loop with a single loop, to assess their effects on the incidence and severity of fistula., Methods: The data was collected in an ambispective manner. The drain fluid was sent for amylase measurement on post-operative day 3 and a fistula was defined and classified according to the 2016 modification of the International Study Group for Pancreatic Surgery definition. The patients were divided into the isolated (Group I) and single (Group II) loop groups and compared for the incidence and severity of clinically relevant fistula along with other parameters., Results: A total of 349 (Group I: 201, Group II: 148) patients were included in the study. The incidence of clinically relevant fistula was comparable (p = 0.206). Grade C fistula was found to be lower in the group I (7 % vs 11.6 %, p = 0.137), in patients with a soft pancreas (8.5 % vs 18.3 %, p = 0.049) and pancreatic duct diameter less than 5 mm (9.8 % vs 17.2 %, p = 0.036). The operative time was lower in Group I than in Group II (438 min vs 478, p < 0.001)., Conclusion: We found that the incidence of clinically relevant fistula was similar in both the groups but the isolated reconstruction method reduced the incidence of severe fistula. In patients with a smaller pancreatic duct, soft pancreas echotexture and obesity, it provides a safer alternative and can be performed in less time than a single loop reconstruction., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Psoriasis is a chronic and inflammatory disease that affects the skin and joints and is associated with multiple comorbidities and cardiovascular risk factors. Consequently, patients with psoriasis have an increased risk of cardiovascular diseases such as atherosclerosis, a chronic pathology that shares common inflammatory and immune-response mechanisms with psoriasis, including vascular inflammation and complement activation. To better understand the relationship between atherosclerosis and psoriasis, a proteomics study followed by a bioinformatics analysis was carried out, with a subsequent validation step using ELISA and western blotting. When the plasma from patients with psoriasis alone was compared with that from patients with psoriasis and atherosclerosis, 31 proteins of interest related to the complement system and oxygen transport were identified. After the validation phase, 11 proteins appeared to define the presence of subclinical atherosclerosis in patients with psoriasis, indicating the importance of complement cascades in the development of atherosclerotic plaques in individuals with psoriasis. These results are a step forward in understanding the pathological pathways implicated in the cardiovascular risk associated with this population, which may represent an interesting starting point for developing predictive tools that improve the follow-up of these patients and design more effective therapies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Beta-defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defense and prime the adaptive immune system in the body. Psoriasis, a chronic immune-mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation., Objectives: We aimed to investigate the circulating expression of beta-defensin-2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at one-year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signaling mechanisms linking inflammation with BD2 expression., Methods: Multimodality imaging as well inflammatory biomarker assays were performed in biologic naïve psoriasis (n=71) and non-psoriasis (n=53) subjects. A subset of psoriasis patients were followed for one-year after biological intervention (anti-Tumor Necrosis Factor-α (TNFα), n=30; anti-Interleukin17A (IL17A), n=21). Measurements of circulating BD2 were completed by Enzyme-Linked Immunosorbent Assay (ELISA). Using HaCaT transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction (qPCR) and ELISA., Results: Herein, we confirm that human circulating BD2 levels associate with psoriasis, which attenuate upon biologic interventions (anti-TNFα, anti-IL-17A). A link between circulating BD2 and sub-clinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL-17A-driven BD2 expression occurs in a Phosphatidylinositol 3-kinase (PI3-kinase) and Rac1 GTPase-dependent manner., Conclusions: Our findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describes the role of an IL-17A-PI3-kinase/Rac signaling axis in regulating BD2 levels in keratinocytes., Competing Interests: Conflicts of Interest Disclosures Nehal Mehta has received research grants from Abbvie, Janssen, Novartis Corp, and Celgene, outside the submitted work. All other authors report no conflicts of interest.

Background: Psoriasis is a chronic inflammatory condition associated with coronary artery disease risk. Uptake of oxidized low-density lipoprotein by the lectin-like low-density lipoprotein receptor-1 triggers release of the soluble extracellular domain of the receptor (sLOX-1). We sought to characterize the relationship between sLOX-1, inflammation, and coronary plaque progression in psoriasis., Methods and Results: A total of 327 patients with psoriasis had serum sLOX-1 levels measured at baseline by an ELISA-based assay. Stratification by high-sensitivity C-reactive protein ≥4.0 mg/L (quartile 4), identified 81 participants who had coronary plaque phenotyping at baseline and were followed longitudinally by coronary computed tomography angiography. Subjects within high-sensitivity C-reactive protein quartile 4 were middle-aged (51.47±12.62 years), predominantly men (54.3%) with moderate psoriasis disease severity (6.60 [interquartile range, 3.30-13.40]). In the study cohort, participants with sLOX-1 above the median displayed increased vulnerable coronary plaque features. At baseline, sLOX-1 was associated with total burden (rho=0.296; P =0.01), noncalcified burden (rho=0.286; P =0.02), fibro-fatty burden (rho=0.346; P =0.004), and necrotic burden (rho=0.394; P =0.002). A strong relationship between sLOX-1, noncalcified burden ( β =0.19; P =0.03), and fibro-fatty burden ( β =0.29; P =0.003) was found in fully adjusted models at baseline and 1- and 4-year follow-up. Finally, coronary plaque features progressed over 1 year regardless of biologic or systemic treatment in subjects with high sLOX-1., Conclusions: Patients with psoriasis with both high sLOX-1 and high-sensitivity C-reactive protein levels have increased coronary plaque burden associated with atherosclerotic plaque progression independent of biologic and systemic treatment. Thus, sLOX-1 might be considered as a promising marker in coronary artery disease risk estimation beyond traditional risk factors., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01778569.

Psoriasis (PSO) is a chronic and systemic inflammatory autoimmune disease associated with atherosclerosis and myocardial infarction. Given that atherosclerosis is both inflammation and immune driven, we sought to expand on known immune and inflammatory biomarkers in a PSO cohort. In this study, we focus on oxidized mtDNA (ox-mtDNA), a product of cells undergoing pyroptosis, including keratinocytes, which was quantified in patients with PSO and individuals without PSO by ELISA. Patients with PSO had significantly higher ox-mtDNA levels than healthy subjects (mean ± SD = 9246 ± 2518 pg/ml for patients with PSO vs 7382 ± 2506 pg/ml for those without; P  = .006). Importantly, ox-mtDNA was positively associated with IL-17a (β = 0.25; P  = .03) and low-density granulocytes (β = 0.37; P  = .005) but negatively associated with high-density lipoprotein-cholesterol (β = -0.29; P = .006). After adjusting for traditional cardiovascular risk factors, we found that ox-mtDNA was associated with noncalcified coronary burden, which was measured by coronary computed tomography angiography (β = 0.19; P  = .003). Biologic-naïve patients with PSO receiving anti-IL-17a therapy had a 14% decrease in ox-mtDNA (mean ± SD: 10540 ± 614 pg/ml at baseline to 9016 ± 477 pg/ml at 1 year; P  = .016) and a 10% reduction in noncalcified coronary artery burden (mean ± SD: 1.06 ± 0.45 at baseline, reducing to 0.95 ± 0.35 at 1 year; P  = .0037). In summary, levels of ox-mtDNA in PSO are associated with measures of coronary plaque formation, indicating that this biomarker may be an autoimmune-driven early atherosclerotic feature., (© 2023 The Authors. Published by Elsevier Inc. on behalf of the Society for Investigative Dermatology.)

Background: s: Psoriasis is a disease of systemic inflammation associated with increased cardiometabolic risk. Epicardial adipose tissue (EAT) and thoracic adipose tissue (TAT) are contributing factors for atherosclerosis and cardiac dysfunction. We strove to assess the longitudinal impact of the EAT and TAT on coronary and cardiac characteristics in psoriasis., Methods: The study consisted of 301 patients with baseline coronary computed tomography angiography (CTA), of which 139 had four-year follow up scans. EAT and TAT volumes from non-contrast computed tomography scans were quantified by an automated segmentation framework. Coronary plaque characteristics and left ventricular (LV) mass were quantified by CTA., Results: When stratified by baseline EAT and TAT volume quartiles, a stepwise significant increase in cardiometabolic parameters was observed. EAT and TAT volumes associated with fibro-fatty burden (FFB) (TAT: ρ = 0.394, P < 0.001; EAT: ρ = 0.459, P < 0.001) in adjusted models. Only EAT had a significant four-year time-dependent association with FFB in fully adjusted models (β = 0.307 P = 0.003), whereas only TAT volume associated with myocardial injury in fully adjusted models (TAT: OR = 1.57 95 % CI = (1.00-2.60); EAT: OR = 1.46 95 % CI = (0.91-2.45). Higher quartiles of EAT and TAT had increased LV mass and developed strong correlation (TAT: ρ = 0.370, P < 0.001; EAT: ρ = 0.512, P < 0.001)., Conclusions: Our study is the first to explore how both EAT and TAT volumes associate with increased cardiometabolic risk profile in an inflamed psoriasis cohorts and highlight the need for further studies on its use as a potential prognostic tool for high-risk coronary plaques and cardiac dysfunction., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Dr. Sorokin is a full-time US government employee., (© 2023 The Authors. Published by Elsevier Ltd.)

APOA-1 is central to the high-density lipoprotein function of reverse cholesterol transport measured by cholesterol efflux capacity. Psoriasis is a systemic inflammatory disease associated with poor cholesterol efflux capacity and accelerated noncalcified coronary burden (NCB) as measured by coronary computed tomographic angiography. In this study, we characterized the relationship between APOA-1, cholesterol efflux capacity, and progression of NCB over 4 years. Consecutively recruited participants with psoriasis underwent coronary computed tomographic angiography for NCB quantification (Medis QAngio, Leiden, The Netherlands) at baseline (n = 310) and at four years (n = 124). Blood was assessed for cardiometabolic biomarkers. The lowest quartile of APOA-1 was associated with cardiometabolic blood markers (insulin, homeostatic model assessment for insulin resistance, and cholesterol efflux capacity) and higher NCB (P < 0.001). The low APOA-1 quartile had higher NCB at 4 years (β = -0.36, P = 0.02) in fully adjusted models. Finally, a 10-unit decrease of APOA-1 was associated with a 16% increase in NCB progression over 4 years (OR = 0.83, 95% confidence interval = 0.70-0.99, P = 0.04). In addition to being associated with cardiometabolic disease, low APOA-1 was associated with more NCB over time. These findings show that low APOA-1 is correlated with initiation and progression of coronary artery disease and may have clinical utility in identifying high-risk populations for development of cardiovascular disease., (Published by Elsevier Inc.)

To evaluate whether nicotinamide adenine dinucleotide-positive (NAD + ) boosting modulates adaptive immunity, primary CD4 + T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts interferon γ (IFNγ) and interleukin (IL)-17 secretion with greater effects on T helper (Th) 17 polarization. RNA sequencing (RNA-seq) analysis implicates NR blunting of sequestosome 1 (sqstm1/p62)-coupled oxidative stress. NR administration increases sqstm1 and reduces reactive oxygen species (ROS) levels. Furthermore, NR activates nuclear factor erythroid 2-related factor 2 (Nrf2), and genetic knockdown of nrf2 and the Nrf2-dependent gene, sqstm1, diminishes NR amelioratory effects. Metabolomics analysis identifies that NAD + boosting increases arginine and fumarate biosynthesis, and genetic knockdown of argininosuccinate lyase ameliorates NR effects on IL-17 production. Hence NR via amino acid metabolites orchestrates Nrf2 activation, augments CD4 + T cell antioxidant defenses, and attenuates Th17 responsiveness. Oral NR supplementation in healthy volunteers similarly increases serum arginine, sqstm1, and antioxidant enzyme gene expression and blunts Th17 immune responsiveness, supporting evaluation of NAD + boosting in CD4 + T cell-linked inflammation., Competing Interests: Declaration of interests The NR and matching placebo were supplied by Chromadex Inc. (Los Angeles, CA, USA) under a Cooperative and Development Research Agreement (CRADA)., (Published by Elsevier Inc.)

BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).

Hilar cholangiocarcinomas are highly aggressive malignancies. They are usually at an advanced stage at initial presentation. Surgical resection with negative margins is the standard of management. It provides the only chance of cure. Liver transplantation has increased the number of 'curative' procedures for cases previously considered to be unresectable. Meticulous and thorough preoperative planning is required to prevent fatal post-operative complications. Extended resection procedures, including hepatic trisectionectomy for Bismuth type IV tumors, hepatopancreaticoduodenectomy for tumors with extensive longitudinal spread, and combined vascular resection with reconstruction for tumors involving hepatic vascular structures, are challenging procedures with surgical indications expanded. Liver transplantation after the standardization of a neoadjuvant protocol described by the Mayo Clinic has increased the number of patients who can undergo operation.

Persistent skin inflammation and impaired resolution are the main contributors to psoriasis and associated cardiometabolic complications. Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are known to exert beneficial effects on inflammatory response and lipid function. However, a specific role of omega-3 PUFAs in psoriasis and accompanied pathologies are still a matter of debate. Here, we carried out a direct comparison between EPA and DHA 12 weeks diet intervention treatment of psoriasis-like skin inflammation in the K14-Rac1V12 mouse model. By utilizing sensitive techniques, we targeted EPA- and DHA-derived specialized pro-resolving lipid mediators and identified tightly connected signaling pathways by RNA sequencing. Treatment with experimental diets significantly decreased circulating pro-inflammatory cytokines and bioactive lipid mediators, altered psoriasis macrophage phenotypes and genes of lipid oxidation. The superficial role of these changes was related to DHA treatment and included increased levels of resolvin D5, protectin DX and maresin 2 in the skin. EPA treated mice had less pronounced effects but demonstrated a decreased skin accumulation of prostaglandin E 2 and thromboxane B 2 . These results indicate that modulating psoriasis skin inflammation with the omega-3 PUFAs may have clinical significance and DHA treatment might be considered over EPA in this specific disease., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented., Objectives: This study sought to develop a deep-learning network for automated quantification of EAT volume from CCTA, test it in patients who are technically challenging, and validate its prognostic value in routine clinical care., Methods: The deep-learning network was trained and validated to autosegment EAT volume in 3,720 CCTA scans from the ORFAN (Oxford Risk Factors and Noninvasive Imaging Study) cohort. The model was tested in patients with challenging anatomy and scan artifacts and applied to a longitudinal cohort of 253 patients post-cardiac surgery and 1,558 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) Trial, to investigate its prognostic value., Results: External validation of the deep-learning network yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT volume was associated with coronary artery disease (odds ratio [OR] per SD increase in EAT volume: 1.13 [95% CI: 1.04-1.30]; P = 0.01), and atrial fibrillation (OR: 1.25 [95% CI: 1.08-1.40]; P = 0.03), after correction for risk factors (including body mass index). EAT volume predicted all-cause mortality (HR per SD: 1.28 [95% CI: 1.10-1.37]; P = 0.02), myocardial infarction (HR: 1.26 [95% CI:1.09-1.38]; P = 0.001), and stroke (HR: 1.20 [95% CI: 1.09-1.38]; P = 0.02) independently of risk factors in SCOT-HEART (5-year follow-up). It also predicted in-hospital (HR: 2.67 [95% CI: 1.26-3.73]; P ≤ 0.01) and long-term post-cardiac surgery atrial fibrillation (7-year follow-up; HR: 2.14 [95% CI: 1.19-2.97]; P ≤ 0.01)., Conclusions: Automated assessment of EAT volume is possible in CCTA, including in patients who are technically challenging; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification., Competing Interests: Funding Support and Author Disclosures This study received support from the British Heart Foundation (grant TG/19/2/34831) and the European Union Commission Horizon 2020 program via the Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation (MAESTRIA) Consortium (grant 965286). Drs Siddique, Tomlins, and Shirodaria are employees of Caristo Diagnostics Ltd. Dr Williams has received support from the British Heart Foundation (grant FS/ICRF/20/26002); and has served on the Speakers Bureau for Canon Medical Systems. Dr Adlam has received support from the Leicester National Institute of Health Research Biomedical Research Centre; has received research funding and in-kind support for unrelated research from AstraZeneca Inc; has received an educational grant from Abbott Vascular Inc to support a clinical research fellow for unrelated research; and has also conducted consultancy for GE Inc to support research funds for unrelated research. Drs Shirodaria, Neubauer, Channon, and Antoniades are founders, shareholders, and directors of Caristo Diagnostics Ltd, a CT-image analysis company. Dr Antoniades has received support from the British Heart Foundation (grants CH/F/21/90009, TG/19/2/34831, and RG/F/21/110040), Innovate UK (grant 104472), and the National Consortium of Intelligent Medical Imaging through the Industry Strategy Challenge Fund (Innovate UK grant 104688); and is also the inventor of patents US10,695,023B2, PCT/GB2017/053262, GB2018/1818049.7, GR20180100490, and GR20180100510, which are licensed through exclusive license to Caristo Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cystic lesions of the adrenal glands are relatively uncommon and most of them are clinically silent. Though rarely associated with malignant changes, they may carry clinically detrimental consequences if misdiagnosed. Cystic adrenal lesions exhibit a broad histomorphological spectrum, ranging from pseudocysts, endothelial cysts, epithelial cysts and parasitic cysts. Here we present the case of a young woman with left-sided abdominal pain and contrast-enhanced CT showing a 10.4×7.7×7.8 cm fluid-filled left suprarenal lesion. The patient underwent exploratory laparotomy with cyst excision, and the histopathological examination of the specimen revealed a pseudocyst of the left adrenal gland. Despite being rare, usually benign and asymptomatic, the diagnosis and management of these cystic lesions of the adrenal glands are often unclear. Any functional lesion, potentially malignant lesion or lesion more than 5 cm deserves surgical management, whereas others can be managed conservatively., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflicts of interest Dr Mehta is a full-time US government employee and has served as a consultant for Amgen, Eli Lilly, and Leo Pharma, receiving grants/other payments; as a principal investigator and/or investigator for AbbVie, Celgene, Janssen Pharmaceuticals, Inc, and Novartis receiving grants and/or research funding; and as a principal investigator for the National Institute of Health receiving grants and/or research funding. Dr González- Cantero has served as a consultant for AbbVie, Janssen, Novartis, Almirall, Celgene, and Leo Pharma receiving grants/other payments. All other authors have no disclosures to report.

Background: Psoriasis (PSO) is a skin disorder with systemic inflammation and high coronary artery disease risk. A distinct lipid phenotype occurs in psoriasis, which is characterized by high plasma triglycerides (TGs) with typically normal or even low LDL-C. The extent to which cholesterol on LDL subfractions, such as small dense LDL-C (sdLDL-C), are associated with vulnerable coronary plaque characteristics in PSO remains elusive., Methods: A recently developed equation for estimating sdLDL-C from the standard lipid panel was utilized in a PSO cohort (n = 200) with 4-year follow-up of 75 subjects. Coronary plaque burden was assessed by quantitative coronary computed tomography angiography (CCTA). Multivariate regression analyses were used for establishing associations and prognostic value of estimated sdLDL-C., Results: Estimated sdLDL-C was positively associated with non-calcified burden (NCB) and fibro-fatty burden (FFB), which remained significant after multivariate adjustment for NCB (β = 0.37; P = 0.050) and LDL-C adjustment for FFB (β = 0.29; P < 0.0001). Of note, total LDL-C calculated by the Friedewald equation was not able to capture these associations in the study cohort. Moreover, in the regression modelling estimated sdLDL-C was significantly predicting necrotic burden progression over 4 years follow-up (P = 0.015), whereas LDL-C did not. Finally, small LDL particles (S-LDLP) and small HDL particles (S-HDLP), along with large and medium TG-rich lipoproteins (TRLPs) had the most significant positive correlation with estimated sdLDL-C., Conclusions: Estimated sdLDL-C has a stronger association than LDL-C with high-risk features of coronary atherosclerotic plaques in psoriasis patients., Clinical Trial Registration: URL: https://www., Clinicaltrials: gov . Unique identifiers: NCT01778569., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI., Methods: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18 F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 μm, PM 2.5 ) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM 2.5 ≥ sample median., Results: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized β [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05)., Conclusion: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Patients with psoriasis have a higher prevalence of cardiovascular risk factors. This study evaluated cardiovascular screening practices and statin prescribing habits among dermatologists, rheumatologists and primary care physicians (PCPs) through an online questionnaire, which was distributed through the Spanish scientific societies of the above-mentioned specialties. A total of 299 physicians (103 dermatologists, 94 rheumatologists and 102 PCPs) responded to the questionnaire. Of these, 74.6% reported screening for smoking, 37.8% for hypertension, 80.3% for dyslipidaemia, and 79.6% for diabetes mellitus. Notably, only 28.4% performed global screening, defined as screening for smoking, hypertension, dyslipidaemia, and diabetes mellitus by the same physician, and 24.4% reported calculating 10-year cardiovascular disease (CVD) risk, probably reflecting a lack of comprehensive cardiovascular risk assessment in these patients. This study also identified unmet needs for awareness of cardiovascular comorbidities in psoriasis and corresponding screening and treatment recommendations among PCPs. Of PCPs, 61.2% reported not being aware of the association between psoriasis and CVD and/or not being aware of its screening recommendations, and 67.6% did not consider psoriasis as a risk-enhancing factor when deciding on statin prescription. Thirteen dermatologists (12.6%) and 35 rheumatologists (37.2%) reported prescribing statins. Among those who do not prescribe, 49.7% would be willing to start their prescription.

Background and Objective: Psoriasis is a systemic inflammatory condition with poor cholesterol transport measured by cholesterol efflux capacity (CEC) that is associated with a heightened risk of cardiovascular disease (CVD). In psoriasis patients, we sought to characterize the lipoprotein profile by size using a novel nuclear magnetic resonance algorithm in patients with low CEC compared to normal CEC., Methods: Lipoprotein profile was assessed using the novel nuclear magnetic resonance LipoProfile-4 deconvolution algorithm. Aortic vascular inflammation (VI) and non-calcified burden (NCB) were characterized via positron emission tomography-computed tomography and coronary computed tomography angiography. To understand the relationship between lipoprotein size and markers of subclinical atherosclerosis, linear regression models controlling for confounders were constructed., Results: Psoriasis patients with low CEC had higher more severe psoriasis ( p = 0.04), VI ( p = 0.04) and NCB ( p = 0.001), concomitant with smaller high-density lipoprotein (HDL) ( p < 0.001) and low-density lipoprotein (LDL) particles ( p < 0.001). In adjusted models HDL size ( β = -0.19; p = 0.02) and LDL size ( β = -0.31; p < 0.001) associated with VI and NCB. Lastly, HDL size strongly associated with LDL size in fully adjusted models ( β = -0.27; p < 0.001)., Conclusion: These findings demonstrate that in psoriasis, low CEC associates with a lipoprotein profile comprised of smaller HDL and LDL particles which correlates with vascular health and may be driving early onset atherogenesis. Further, these results demonstrate a relationship between HDL and LDL size and provide novel insights into the complexities of HDL and LDL as biomarkers of vascular health., Competing Interests: NM has served as a consultant for Amgen, Eli Lilly, and Leo Pharma receiving grants/other payments; as a principal investigator and/or investigator for AbbVie, Celgene, Janssen Pharmaceuticals, Inc., and Novartis receiving grants and/or research funding. AG-C has served as a consultant for Abbie, Janssen, Novartis, Almirall, Celgene and Leo Pharma receiving grants/other payments. TThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berg, Petrole, Li, Sorokin, Gonzalez-Cantero, Playford, Mehta and Teague.)

For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R 2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution., (© 2023. The Author(s).)

Importance: Psoriasis is an inflammatory condition associated with metabolic and cardiovascular disease. Apremilast, a phosphodiesterase 4 inhibitor, is commonly used for psoriasis and can cause weight loss., Objective: To determine the association between apremilast and aortic vascular inflammation as assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), cardiometabolic markers (primary outcomes at week 16), and abdominal fat composition., Design, Setting, and Participants: A single-arm, open-label, interventional, nonrandomized clinical trial in which the imaging and laboratory outcomes were measured by an investigator who was blinded to time was conducted between April 11, 2017, and August 17, 2021, at 7 dermatology sites in the United States. A total of 101 patients with moderate to severe psoriasis were screened, 70 enrolled, 60 completed week 16, and 39 completed week 52., Intervention: Apremilast, 30 mg, twice daily., Main Outcomes and Measures: Aortic vascular inflammation (measured by FDG-PET/CT), 68 cardiometabolic biomarkers, and abdominal fat composition (measured by CT) at week 16 and week 52 compared with baseline., Results: The mean (SD) age of the 70 patients was 47.5 (14.6) years, 54 were male (77.1%), 4 were Black (5.7%), and 58 were White (82.9%). There was no change in aortic vascular inflammation at week 16 (target to background ratio, -0.02; 95% CI, -0.08 to 0.05; P = .61) or week 52 (target to background ratio, -0.07; 95% CI, -0.15 to 0.01; P = .09) compared with baseline. At week 16, potentially beneficial decreases in interleukin 1b, valine, leucine, isoleucine, fetuin A, and branched-chain amino acids were observed. At week 52 compared with baseline, potentially beneficial decreases in ferritin, β-hydroxybutyrate, acetone, and ketone bodies, with an increase in apolipoprotein A-1, were observed, but there was a reduction in cholesterol efflux. There was an approximately 5% to 6% reduction in subcutaneous and visceral adiposity at week 16 that was maintained at week 52., Conclusions and Relevance: The findings of this nonrandomized clinical trial suggest that apremilast has a neutral association with aortic vascular inflammation, variable but generally beneficial associations with a subset of cardiometabolic biomarkers, and associations with reductions in visceral and subcutaneous fat, indicating that the drug may have an overall benefit for patients with cardiometabolic disease and psoriasis., Trial Registration: ClinicalTrials.gov Identifier: NCT03082729.

Competing Interests: Conflicts of interest HBN has received grant support from AbbVie, consulting fees from 23andMe, AbbVie, and DAVA Oncology, and advisory board fees from Boehringer Ingelheim, all related to hidradenitis suppurativa. DMS and HBN have received grant support from the National Psoriasis Foundation. RGM has received grant support from SOBI, Novartis, Regeneron, and Lilly under US Federal Government Cooperative Research and Development Agreements. DCP, MO, MM, JT, HNS, SMS, SM, AADJ, THM, AD, RKR, ZD, NNM and EWC have no conflicts of interest to report.

Cardiac computed tomography angiography (CTA) is an emerging imaging modality for assessing coronary artery as well as various cardiovascular structures. Recently, deep learning (DL) methods have been successfully applied to many applications of medical image analysis including cardiac CTA structure segmentation. However, DL requires a large amounts of data and high-quality labels for training which can be burdensome to obtain due to its labor-intensive nature. In this study, we aim to develop a fully automatic artificial intelligence (AI) system, named DeepHeartCT, for accurate and rapid cardiac CTA segmentation based on DL. The proposed system was trained using a large clinical dataset with computer-generated labels to segment various cardiovascular structures including left and right ventricles (LV, RV), left and right atria (LA, RA), and LV myocardium (LVM). This new system was trained directly using high-quality computer labels generated from our previously developed multi-atlas based AI system. In addition, a reverse ranking strategy was proposed to assess the segmentation quality in the absence of manual reference labels. This strategy allowed the new framework to assemble optimal computer-generated labels from a large dataset for effective training of a deep convolutional neural network (CNN). A large clinical cardiac CTA studies ( n = 1,064) were used to train and validate our framework. The trained model was then tested on another independent dataset with manual labels ( n = 60). The Dice score, Hausdorff distance and mean surface distance were used to quantify the segmentation accuracy. The proposed DeepHeartCT framework yields a high median Dice score of 0.90 [interquartile range (IQR), 0.90-0.91], a low median Hausdorff distance of 7 mm (IQR, 4-15 mm) and a low mean surface distance of 0.80 mm (IQR, 0.57-1.29 mm) across all segmented structures. An additional experiment was conducted to evaluate the proposed DL-based AI framework trained with a small vs. large dataset. The results show our framework also performed well when trained on a small optimal training dataset ( n = 110) with a significantly reduced training time. These results demonstrated that the proposed DeepHeartCT framework provides accurate and rapid cardiac CTA segmentation that can be readily generalized for handling large-scale medical imaging applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bui, Hsu, Chang, Sun, Tran, Shanbhag, Zhou, Mehta and Chen.)

Psoriasis is a systemic inflammatory disease with an increased risk of atherosclerotic events and premature cardiovascular disease. S100A7, A8/A9, and A12 are protein complexes that are produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. Lipid-rich necrotic core (LRNC) is a high-risk coronary plaque feature previously found to be associated with cardiovascular risk factors and psoriasis severity. LRNC can decrease with biologic therapy, but how this occurs remains unknown. We investigated the relationship between S100 proteins, LRNC, and biologic therapy in psoriasis. S100A8/A9 associated with LRNC in fully adjusted models (β = 0.27, P = 0.009; n = 125 patients with psoriasis with available coronary computed tomography angiography scans; LRNC analyses; and serum S100A7, S100A8, S100A9, S100A12, and S100A8/A9 levels). At 1 year, in patients receiving biologic therapy (36 of 73 patients had 1-year coronary computed tomography angiography scans available), a 79% reduction in S100A8/A9 levels (‒172 [‒291.7 to 26.4] vs. ‒29.9 [‒137.9 to 50.5]; P = 0.04) and a 0.6 mm 2 reduction in average LRNC area (0.04 [‒0.48 to 0.77] vs. ‒0.56 [‒1.8 to 0.13]; P = 0.02) were noted. These results highlight the potential role of S100A8/A9 in the development of high-risk coronary plaque in psoriasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Myriad roles for high-density lipoprotein (HDL) beyond atheroprotection include immunologic functions implicated in the severity of coronavirus disease-2019 (COVID-19) in adults. We explored whether there is an association between HDL and COVID-19 severity in youth., Methods: A pediatric cohort ( N = 102), who tested positive for COVID-19 across a range of disease manifestations from mild or no symptoms, to acute severe symptoms, to the multisystem inflammatory syndrome of children (MIS-C) was identified. Clinical data were collected from the medical record and reserve plasma aliquots were assessed for lipoproteins by NMR spectroscopy and assayed for HDL functional cholesterol efflux capacity (CEC). Findings were compared by COVID-19 status and symptom severity. Lipoprotein, NMR spectroscopy and CEC data were compared with 30 outpatient COVID negative children., Results: Decreasing HDL cholesterol (HDL-c), apolipoprotein AI (ApoA-I), total, large and small HDL particles and HDL CEC showed a strong and direct linear dose-response relationship with increasing severity of COVID-19 symptoms. Youth with mild or no symptoms closely resembled the uninfected. An atypical lipoprotein that arises in the presence of severe hepatic inflammation, lipoprotein Z (LP-Z), was absent in COVID-19 negative controls but identified more often in youth with the most severe infections and the lowest HDL parameters. The relationship between HDL CEC and symptom severity and ApoA-I remained significant in a multiply adjusted model that also incorporated age, race/ethnicity, the presence of LP-Z and of GlycA, a composite biomarker reflecting multiple acute phase proteins., Conclusion: HDL parameters, especially HDL function, may help identify youth at risk of more severe consequences of COVID-19 and other novel infectious pathogens., Competing Interests: Author JO is a consultant, stockholder, and former employee of Labcorp, the commercial provider of the NMR LipoProfile testing system used at the NIH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mietus-Snyder, Suslovic, Delaney, Playford, Ballout, Barber, Otvos, DeBiasi, Mehta and Remaley.)

Background: Psoriasis is an immune-mediated disease associated with excess risk for cardiovascular disease (CVD). Guidelines recognize psoriasis as a CVD risk enhancer; however, psoriasis patients often do not have CVD risk factors identified nor managed., Objective: This study examines strategies to improve CVD prevention care from the perspective of dermatologists and patients with psoriasis., Methods: Qualitative interviews were conducted using the Consolidated Framework for Implementation Research to examine the perspectives of physicians (N = 16) and patients with psoriatic disease (N = 16) on barriers/facilitators to CVD prevention. Interviews were transcribed and coded using an integrated approach designed to enhance reliability and validity using NVivo software., Results: We found three major themes suggesting areas to target for the future: (1) Appropriateness: perceptions of whether CVD care should be deployed in this setting by both clinicians and patients, (2) Feasibility: whether CVD prevention care could be integrated into the current structure of specialist practice, and (3) Care Coordination: an interest by all parties to better integrate a team approach in CVD preventative care to reduce duplicative efforts, work practically in an already existing system rather than reinventing the wheel, and progress with the patients' best interests in mind., Conclusions: These findings will inform the design of a clinical trial comparing the effectiveness of specialist clinician implementation of CVD guideline-based prevention care in patients with psoriasis. Ultimately, this study aims to increase the lifespan and health of patients living with psoriatic disease by decreasing barriers to their receiving appropriate CVD prevention care., Competing Interests: Conflicts of Interest: The authors declare the following competing interests: Dr. Beidas receives royalties from Oxford University Press. She has provided consultation to the Camden Coalition of Healthcare Providers. She currently consults to United Behavioral Health and serves on the Clinical and Scientific Advisory Board for Optum Behavioral Health. She also sits on the advisory board for the AIM Youth Mental Health Foundation and the Klingenstein Third Generation Foundation. Dr. Armstrong has served as a research investigator and/or scientific advisor to AbbVie, ASLAN, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, Pfizer, and Modmed. Dr. Ogdie has received honoraria for consulting for Abbvie, Amgen, BMS, Celgene, CorEvitas, Janssen, Gilead, Lilly, Novartis, Pfizer and UCB. Dr. Ogdie has also received grants to Penn from Abbvie, Novartis and Pfizer and to Forward Databank from Amgen. Dr. Mehta is a full time US government employee. Dr. Gelfand served as a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Novartis Corp, Regeneron, UCB (Data Safety and Monitoring Board), Sanofi, and Pfizer Inc, receiving honoraria; in addition, he receives research grants (to the Trustees of the University of Pennsylvania) from AbbVie, Janssen, Novartis Corp, Sanofi, Celgene, OrthoDermatologics, and Pfizer Inc

Background: Limited data are available on long-term efficacy and safety of biologics in patients with psoriasis and metabolic syndrome (MetS), a common comorbidity., Objectives: This analysis updates tildrakizumab efficacy and safety for up to 5 years in patients with and without MetS., Methods: This was a post hoc analysis of the double-blind, randomized, placebo-controlled, phase 3 reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) trials in adult patients with moderate to severe chronic plaque psoriasis. Analyses included data through Week 244 from patients who continuously received tildrakizumab 100 (TIL100) or 200 mg (TIL200) and entered the extension studies, stratified by baseline MetS status. Efficacy was assessed via Psoriasis Area and Severity Index (PASI) scores. Safety was evaluated from exposure-adjusted incidence rates (EAIRs) of treatment-emergent adverse events (TEAEs)., Results: reSURFACE 1 and reSURFACE 2 analyses included 26 and 44 TIL100-treated patients with MetS, 98 and 167 TIL100-treated patients without MetS, 34 and 30 TIL200-treated patients with MetS, and 111 and 130 TIL200-treated patients without MetS, respectively. There were no clinically relevant differences in PASI 75/90/100 response rates at Week 244 between patients with vs without MetS. The proportion of patients with vs without MetS achieving absolute PASI score <3 at Week 244 was 53.8% vs 69.4% and 77.3% vs 80.8% in reSURFACE 1 and 2, respectively, for TIL100-treated patients and 58.8% vs 72.1% and 63.3% vs 72.3%, respectively, for TIL200-treated patients. In both studies, median reduction from baseline PASI score at all time points in patients with vs without MetS was >83% vs >89% for TIL100 and >85% vs >90% for TIL200. Pooled EAIRs of TEAEs, serious TEAEs, and TEAEs of special interest were similar in patients with and without MetS., Conclusions: Tildrakizumab maintains efficacy and a favorable safety profile over 5 years in patients with psoriasis regardless of MetS status., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)