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Background Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets. Objective In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis. Methods The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models. Results Using the random forest algorithm, we found that the top 10 predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output. Limitation We were unable to provide external validation and did not study cardiovascular events. Conclusion Machine learning methods identified the top predictors of noncalcified coronary burden in psoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing that these are important targets when treating comorbidities in psoriasis.

Background: Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. Given the critical role for autophagy in promoting the cellular degradation of damaged organelles and the negative impact of aging on this protective mechanism, we hypothesized that treatment with an autophagic inducer such as trehalose may be a promising therapeutic strategy for TBI aged animals. Methods: Controlled cortical impact was used to induce moderate TBI in male C57BL/6 mice. Young (10 weeks) or old (18 months) animals were evaluated behaviorally for 12 weeks after injury. Autophagy, inflammation, and neurodegeneration were examined using NanoString analysis, flow cytometry, and immunohistochemistry. Trehalose or sucrose as a control were administered in drinking water beginning day1 post-injury for 8 weeks. Results: Aged mice had a higher mortality rate than young mice at 12 weeks post-injury. At 12 weeks, aged mice showed greater cognitive deficits and depression than younger animals. There were also larger lesion volumes and increased microglial activation in aged TBI mice at 16 weeks post-injury. NanoString analysis identified several age- and TBI-specific genes changes that were differentially expressed in the chronically injured brain, including those involved with the complement, phagocytosis, and autophagy pathways. Flow cytometry demonstrated temporal dysregulation of phagocytosis and autophagy in microglia from injured mice that were exacerbated with age and accompanied by an increased inflammation and lymphocyte infiltration. Old TBI mice treated with trehalose exhibited either more delayed deficits or enhanced recovery in cognitive and motor tasks. In addition, Trehalose treatment modified expression of autophagy markers and attenuated the microglial response to TBI. Conclusions: Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.

Background: Functional mitral regurgitation (MR) grading by echocardiography is often challenging, and cardiac magnetic resonance (CMR) may provide more accurate and reproducible assessment, however optimal CMR thresholds have not been established. We aimed to determine clinically significant thresholds of MR-volume and MR-fraction by CMR in patients with non-ischemic cardiomyopathy (NICM). Methods: All patients having CMR with confirmed NICM between 2001/4/1-2019/3/31 were retrospectively studied. Time to death, heart transplant and/or left ventricular assist device is the primary endpoint, and receiver-operative (ROC) characteristics analyses were used to identify significant cut-points for MR-volume and MR-fraction. Results: Mean MR-volume was 11±12% and MR-fraction 14±13% in 840 NICM patients. C-statistics for the primary endpoint (141 events) were MR-volume 0.629 (95%CI: 0.577-0.691) and MR-fraction 0.594 (95%CI 0.542-0.647). Thresholds of MR-volume≥10mL and MR-fraction≥15% had the highest products of sensitivities and specificities (57.4%, 56.8%; and 54.6%, 63.4% respectively) reflecting elevated risk. MR-volume≥35mL and MR-fraction≥40% were associated the best combination of positive and negative predictive values (40.1%, 84.2%; and 38.4%, 84.6% respectively) representing severe risk. The figure illustrates Kaplan-Meier curves of the primary endpoint, categorized into three subgroups based on aforementioned MR-volume and MR-fraction thresholds. Conclusion: Adverse prognosis are observed when MR-volume≥10mL or MR-fraction≥15%, with increasing risk of adverse outcomes as functional MR severity increased in NICM. The proposed MR thresholds from this study for elevated and severe risk are lower than current valvular regurgitation guidelines, suggesting the need for separate classification schema for functional MR.

Background: Functional mitral regurgitation (MR) is associated with poor outcomes and the prognostic role of cardiac magnetic resonance imaging (CMR) quantification of secondary MR has rarely been studied. We evaluated the associations between CMR-derived MR-fraction and adverse outcomes in non-ischemic cardiomyopathy (NICM) patients. Methods: We retrospectively studied 840 consecutive NICM patients undergoing CMR during 2001/4/1-2019/3/31. Multivariable Cox proportional hazards regression was performed for MR-fraction and two composite endpoints: primary (time to death, heart transplant and/or left ventricular assist device) and secondary (primary endpoint plus heart failure hospitalizations). Results: The cohort had mean age of 53.0±15.9 years, 319 (38.0) were female, and mean MR-fraction of 14±13% by CMR. There were 141 (16.8%) primary and 223 (26.5%) secondary endpoints over a mean follow-up of 3.6±3.0 years. Multivariable analyses results are shown in the Table. MR-fraction was independently associated with the primary and secondary endpoints with hazards ratios of 1.13 (95%CI 1.07-1.20) and 1.13 (95%CI 1.07-1.19) respectively per 5% increase in MR-fraction. MR-fraction provided stronger prognostic power compared to late gadolinium enhancement (LGE) in both models. Older age and diabetes were independently associated with both composite endpoints, while lower LVEF was independently associated with the secondary endpoint only. Conclusion: CMR quantification of functional MR is a powerful predictor of adverse outcomes and demonstrated stronger associations with poor prognosis compared to LGE and left ventricular remodeling in a large cohort of patients with NICM.

Background: Lipid-rich necrotic core (LRNC), a high-risk coronary plaque feature assessed by coronary computed tomography angiography, is associated with increased risk of future cardiovascular events in patients with subclinical, nonobstructive coronary artery disease. Psoriasis is a chronic inflammatory condition that is associated with increased prevalence of high-risk coronary plaque and risk of cardiovascular events. This study characterized LRNC in psoriasis and how LRNC modulates in response to biologic therapy. Methods: Consecutive biologic naïve psoriasis patients (n=209) underwent coronary computed tomography angiography at baseline and 1-year to assess changes in LRNC using a novel histopathologically validated software (vascuCAP Elucid Bioimaging, Boston, MA) before and after biologic therapy over 1 year. Results: Study participants were middle-aged, predominantly male with similar cardiometabolic and psoriasis status between treatment groups. In all participants at baseline, LRNC was associated with Framingham risk score (β [standardized β]=0.12 [95% CI, 0.00–0.15]; P =0.045), and psoriasis severity (β=0.13 [95% CI, 0.01–0.26]; P =0.029). At 1-year, participants receiving biologic therapy had a reduction in LRNC (mm 2 ; 3.12 [1.99–4.66] versus 2.97 [1.84–4.35]; P =0.028), while those who did not receive biologic therapy over 1 year demonstrated no significant change with nominally higher LRNC (3.12 [1.82–4.60] versus 3.34 [2.04–4.74]; P =0.06). The change in LRNC was significant compared with that of the nonbiologic treated group (ΔLRNC, −0.22 mm 2 versus 0.14 mm 2 , P =0.004) and remained significant after adjusting for cardiovascular risk factors and psoriasis severity (β=−0.09 [95% CI, −0.01 to −0.18]; P =0.033). Conclusions: LRNC was associated with psoriasis severity and cardiovascular risk factors in psoriasis. Additionally, there was favorable modification of LRNC in those on biologic therapy. This study provides evidence of potential reduction in LRNC with treatment of systemic inflammation. Larger, longer follow-up prospective studies should be conducted to understand how changes in LRNC may translate into a reduction in future cardiovascular events in psoriasis.

Background: Inflammation plays a major role in the development and progression of cardiovascular disease (CVD) morbidity and mortality. The well-established relationship between periodontal disease (PD) and CVD may be causal. Left untreated, PD can lead to high systemic inflammation, thus contributing to inflammatory CVD, such as atherosclerosis. Multiple mechanisms have been proposed to elucidate the causal relationship between PD and its contribution to CVD. Objective: This review article highlights the current evidence supporting the role of PD in the development and progression of atherosclerosis. Methods: After creating a list of relevant medical subject heading (MeSH) terms, a systematic search within PubMed in English for each MeSH term between 2000 and 2019 was used to generate evidence for this review article. Conclusion: There is overwhelming evidence in the current literature that supports an association between PD and CVD that is independent of known CVD risk factors. However, the supporting evidence that PD directly causes CVD in humans continues to remain elusive. Multiple biologically plausible mechanisms have been proposed and investigated, yet most studies are limited to mouse models and in vitro cell cultures. Additional studies testing the various proposed mechanisms in longitudinal human studies are required to provide deeper insight into the mechanistic link between these 2 related diseases.

Introduction: Psoriasis (PSO) is a chronic inflammatory condition associated with accelerated atherosclerosis and increased risk of myocardial infarction in part mediated through high visceral adipose tissue (VAT) volume. VAT has been shown to be associated with increased coronary burden; however, the relationship with prevalent coronary plaque in PSO has not been explored. Hypothesis: We hypothesized that VAT would associate with coronary plaque in PSO beyond traditional risk factors. Methods: A total of 164 consecutive PSO patients underwent coronary computed tomography angiography (CCTA) as part of a large cohort study to assess presence of coronary plaque. Low-dose CT was utilized to quantify VAT and subcutaneous adipose tissue (SAT) volume from the level of the diaphragm to the pubic symphysis. Logistic regression was used to assess the association between the presence of coronary plaque and the ratio of VAT-to-total adiposity in adjusted models (STATA 12). Results: The cohort was middle-aged, predominantly male, relatively low CV risk by FRS and mild to moderate PSO (Table 1). Patients with increased VAT-to-total adiposity, had significantly increased coronary plaque presence (70% (45 of 65) vs. 31% (31 of 99), p Conclusions: Having higher VAT was associated with higher prevalence of coronary plaque independent of total adiposity and cardiovascular risk factors. These findings suggest VAT contributes to coronary plaque in psoriasis and that weight loss efforts may improve outcomes in this high-risk population.

Neutral lithium (Li) has been used for the mitigation of heat flux to the plasma facing components and for the control of hydrogen of fusion plasmas. Radial and axial variations of densities of Li neutrals and ions are obtained analytically for a cylindrical chamber by assuming the classical diffusion with or without the magnetic field (B). Neutrals and ions without B can be expressed as a linear combination of the modified Bessel functions of order zero (I0 and K0), while ions with B are to be expressed as the square root of them. Analytical solutions of Li neutral densities with Dirichlet and Neumann boundary conditions are compared to those using Monte Carlo simulation and experimental values of the LIGHT-1 (Lithium Injection Gettering of Hydrogen and its Transport experiments) device. Proper combinations of the relaxation length and size of the source would produce well fitted profiles similar to those observed experimentally and those using Monte Carlo codes.

IMPORTANCE: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis. OBJECTIVE: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year. EXPOSURES: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status. RESULTS: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P 50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (β = 0.14; 95% CI, 0.028-0.246; P = .02). CONCLUSIONS AND RELEVANCE: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

Psoriasis is a chronic inflammatory skin disease associated with increased coronary plaque burden and cardiovascular events. Biologic therapy for psoriasis has been found to be favorably associated with luminal coronary plaque, but it is unclear whether these associations are attributable to direct anti-inflammatory effects on the coronary arteries.To investigate the association of biologic therapy with coronary inflammation in patients with psoriasis using the perivascular fat attenuation index (FAI), a novel imaging biomarker that assesses coronary inflammation by mapping spatial changes of perivascular fat composition via coronary computed tomography angiography (CCTA).This prospective cohort study performed from January 1, 2013, through March 31, 2019, analyzed changes in FAI in patients with moderate to severe psoriasis who underwent CCTA at baseline and at 1 year and were not receiving biologic psoriasis therapy at baseline.Biologic therapy for psoriasis.Perivascular FAI mapping was performed based on an established method by a reader blinded to patient demographics, visit, and treatment status.Of the 134 patients (mean [SD] age, 51.1 [12.1] years; 84 [62.5%] male), most had low cardiovascular risk by traditional risk scores (median 10-year Framingham Risk Score, 3% [interquartile range, 1%-7%]) and moderate to severe skin disease. Of these patients, 82 received biologic psoriasis therapy (anti-tumor necrosis factor α, anti-interleukin [IL] 12/23, or anti-IL-17) for 1 year, and 52 did not receive any biologic therapy and were given topical or light therapy (control group). At baseline, 46 patients (27 in the treated group and 19 in the untreated group) had a focal coronary atherosclerotic plaque. Biologic therapy was associated with a significant decrease in FAI at 1 year (median FAI -71.22 HU [interquartile range (IQR), -75.85 to -68.11 HU] at baseline vs -76.09 HU [IQR, -80.08 to -70.37 HU] at 1 year; P .001) concurrent with skin disease improvement (median PASI, 7.7 [IQR, 3.2-12.5] at baseline vs 3.2 [IQR, 1.8-5.7] at 1 year; P .001), whereas no change in FAI was noted in those not receiving biologic therapy (median FAI, -71.98 [IQR, -77.36 to -65.64] at baseline vs -72.66 [IQR, -78.21 to -67.44] at 1 year; P = .39). The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents, including anti-tumor necrosis factor α (median FAI, -71.25 [IQR, -75.86 to -66.89] at baseline vs -75.49 [IQR, -79.12 to -68.58] at 1 year; P .001) and anti-IL-12/23 or anti-IL-17 therapy (median FAI, -71.18 [IQR, -75.85 to -68.80] at baseline vs -76.92 [IQR, -81.16 to -71.67] at 1 year; P .001).In this study, biologic therapy for moderate to severe psoriasis was associated with reduced coronary inflammation assessed by perivascular FAI. This finding suggests that perivascular FAI measured by CCTA may be used to track response to interventions for coronary artery disease.

BACKGROUND: The contribution of inflammation to the incidence of cardiovascular disease (CVD) has been increasingly recognized in recent years. We investigated the relationship of aortic vascular uptake of 18F-FDG by PET/CT and aortic wall thickness (AWT) by MRI in psoriasis, a chronic inflammatory disease with increased incidence of CVD.165 patients with plaque psoriasis participated in an ongoing longitudinal cohort study. Subclinical atherosclerosis was assessed as aortic uptake of 18F-FDG by PET/CT reported as target to background ratio (TBR) and AWT by MRI reported as maximal thickness. RESULTS: Patients with psoriasis were middle-aged, predominantly male and had mild CV risk by traditional risk factors. Psoriasis severity as measured by PASI score was a notable determinant of AWT (ρ=0.20, p=0.01). Moreover, aortic vascular uptake of 18F-FDG associated with AWT by MRI at baseline in unadjusted analysis (β=0.27 p=0.001) and following adjustment for traditional cardiovascular risk factors, waist-to-hip ratio and statin use (β=0.21 p=0.01). Finally, following one year of psoriasis treatment, a decrease in aortic vascular uptake of 18F-FDG was associated with a reduction in AWT in fully adjusted models (β=0.33, p=0.02). CONCLUSION: In conclusion, we demonstrate that psoriasis severity and aortic vascular uptake of 18F-FDG in the aorta were associated with AWT. Following treatment of psoriasis, a decrease in aortic vascular uptake of 18F-FDG was associated with a reduction in AWT at one-year. These findings suggest that aortic vascular uptake of 18F-FDG is associated with early evidence of vascular disease assessed by aortic wall thickness. Prospective studies in larger populations including other inflammatory diseases are warranted.

Background: Psoriasis, a chronic inflammatory disease, is associated with accelerated vascular inflammation (VI) by FDG PET/CT and increased cardiometabolic dysfunction, including adipose tissue dysregulation. Both visceral and subcutaneous adipose volume are associated with sub-clinical aortic VI as well as future cardiovascular events, however, the relationship of adipose inflammation (assessed as adipose FDG uptake) with sub-clinical aortic VI has never been characterized in psoriasis. Methods: 104 consecutive biologic naïve psoriasis patients underwent FDG PET/CT scans to measure VI and adipose FDG uptake, represented as target-to-background ratio (TBR) and standardized uptake value (SUV) respectively. After identification of anatomical location (vertebral level T10), a single 3D-volume region of interest with a fixed volume (4.0 cm 3 ) was placed in the subcutaneous adipose to measure FDG uptake as standardized uptake value (SUV) using a dedicated software (OsiriX MD, Geneva, Switzerland). Results: The cohort was middle-aged, predominantly male, low CV risk by Framingham risk score and mild-moderate psoriasis. Adipose FDG uptake significantly associated with skin disease severity as well as aortic VI even beyond traditional risk factors (β=0.33, p=0.001 and β=0.24, p=0.014 respectively). Additionally, adipose FDG uptake mediated the association between psoriasis skin disease severity and aortic VI accounting for 23% of the total effect (Figure). Conclusions: Our study demonstrated that adipose inflammation is positively associated with psoriasis severity as well as aortic VI. Moreover, adipose inflammation also mediated the relationship between skin disease severity and aortic VI, suggesting that it may contribute to the potential link between psoriasis and CV disease. However, larger studies are needed to confirm our findings.

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.

In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications., Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

Psoriasis, a chronic inflammatory skin disease, is associated with heightened FDG-uptake in the bone marrow (BM) by FDG/PET-CT concomitant with increased non-calcified coronary plaque burden (NCB) by CCTA. Additionally, psoriasis patients have reduced cholesterol efflux capacity (CEC), which in turn

Psoriasis, a chronic systemic inflammatory disease, is associated with elevated non-calcified coronary plaque burden (NCB) and increased cardiovascular (CV) events. In this study, we used machine learning (ML) as a tool to determine the top predictors of NCB, which is prone to rupture and cause

Psoriasis is a chronic inflammatory skin disease associated with accelerated high-risk plaque (HRP). High-sensitivity troponin (hs-cTnT) is highly specific for myocardial injury and therefore may provide information on potential significance of high-risk plaque in psoriasis. We aimed to explore

Psoriasis (PSO), a chronic inflammatory skin disease is associated with increased non-calcified coronary plaque burden (NCB) as well as heightened MI. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a scavenger receptor for oxidized LDL, is critical in the development of NCB. We

Psoriasis, a chronic inflammatory skin disease, contributes to accelerated atherogenesis and increased risk of cardiovascular (CV) events. Aortic distensibility (AD) by magnetic resonance imaging (MRI) and non-calcified coronary burden (NCB) measured by coronary computed tomography angiography (CCTA