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Chemotherapy and radiotherapy have drastically improved cancer survival, but they can result in significant short- and long-term cardiovascular complications, most commonly heart failure from chemotherapy, whilst radiotherapy increases the risk of premature coronary artery disease (CAD), valve, and pericardial diseases. Cardiac computed tomography (CT) with calcium scoring has a role in screening asymptomatic patients for premature CAD, cardiac CT angiography (CTCA) allows the identification of significant CAD, also in the acute settings where concerns exist towards invasive angiography. CTCA integrates the diagnostic work-up and guides surgical/percutaneous management of valvular heart diseases and allows the assessment of pericardial conditions, including detection of effusion and pericardial calcification. It is a widely available and fast imaging modality that allows a one-step evaluation of CAD, myocardial, valvular, and pericardial disease. This review aims to provide an update on its current use and accompanying evidence-base for cardiac CT in the management of cardio-oncology patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Chronic inflammation is associated with premature atherosclerotic cardiovascular disease (ASCVD). We studied the prevalence of cardiovascular risk factors (CRFs) amongst individuals with IBD who have not developed ASCVD., Methods: Our study population was derived from the 2015 - 2016 National Health Interview Survey. Those with ASCVD (defined as myocardial infarction, angina or stroke) were excluded. The prevalence of CRFs among individuals with IBD was compared with those without IBD. The odds CRFs among adults with IBD was assessed using logistic regression models., Results: In our study population of 60,155 individuals, 786 (1.3%) had IBD. IBD was associated with increased odds hypertension (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.39-2.09), diabetes (OR 1.68, 95% CI 1.22-2.32), hypercholesterolemia (OR 1.62, 95% CI 1.32-2.99) and insufficient physical activity (OR 1.38, 95% CI 1.16-1.66)., Conclusion: IBD is associated with higher prevalence of CRFs. Early screening and risk mitigation strategies are warranted., Competing Interests: Dr. Nasir is supported by the Jerold B. Katz Academy of Translational Research. Dr's Abraham and Glassner are supported by the Fondren Inflammatory Bowel Diseases Program. Dr Quigley is supported by the Underwood Center and the Hughes Sterling Foundation. Dr. Virani receives research support from the Department of Veterans Affairs, World Heart Federation and the Tahir and Jooma Family. He also reports honorarium from the American College of Cardiology (Associate Editor for Innovations, aacc.org), serves on the Steering Committee, Patient and Provider Assessment of Lipid Management (PALM) registry at the Duke Clinical Research Institute with no financial remuneration. No other disclosures/conflicts of interest were reported. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (© 2021 The Authors. Published by Elsevier B.V.)

Background: Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar 18 Fluorodeoxyglucose ( 18 FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Methods: Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including 18 FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. Results: AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, p = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, p = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (β = 0.41, p = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. Conclusions: AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings., Competing Interests: NM 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. 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 © 2021 Powell-Wiley, Dey, Rivers, Chaturvedi, Andrews, Ceasar, Claudel, Mitchell, Ayers, Tamura, Gutierrez-Huerta, Teague, Oeser, Goyal, Joshi, Collins, Baumer, Chung, Sumner, Playford, Tawakol and Mehta.)

Aims: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy., Methods and Results: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001)., Conclusion: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Since the introduction of transcatheter aortic valve replacement (TAVR), there has been a paradigm shift in the management of severe aortic stenosis. While women represent almost half of the patients undergoing TAVR, there are limited data on sex-based comparisons in hospital outcomes and predictors of mortality in women and men. The National Inpatient Sample database from 2012 to 2015 was used to identify TAVR using international classification of diseases-9 clinical modification procedure codes 35.05 and 35.06. We identified 61,239 patients who underwent TAVR between 2012 and 2015. After adjusting for potential confounders, women had higher odds of all-cause mortality as compared to men [odds ratio (OR) 1.25, 95% confidence interval (CI): 1.01-1.54; P = 0.036]. Moreover, women had significantly increased odds of cardiac complications [OR 2.41, 95% CI: 1.67-3.49; P ≤ 0.01], respiratory complications [OR 1.20 95% CI: 1.07-1.34; P = 0.001], major hemorrhage requiring transfusion [OR 1.51, 95% CI: 1.37-1.67; P ≤ 0.001], neurological complications [OR 1.38, 95% CI: 0.95-1.99; P = 0.08], need for vasopressor treatment [OR 1.33, 95% CI: 1.01-1.75; P = 0.04], and vascular complications [OR 1.73, 95% CI: 1.19-2.52; P = 0.004]. On the contrary, the odds of pacemaker requirement [OR 0.85, 95% CI: 0.75-0.97; P = 0.02], and acute kidney injury [OR 0.80, 95% CI: 0.71-0.91; P = 0.001] were significantly lower in women. Among patients undergoing TAVR, women were more likely to have in-hospital complications and mortality as compared with men. Further studies are needed to identify the discrepancy in in-hospital outcomes with sex-specific factors being considered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD), especially ischemic heart disease and stroke, is the major cause of death worldwide, accounting for more than one-third of all deaths annually. Hypertension is the most prevalent and modifiable risk factor of CVD-related deaths. The same is true for obesity, which is currently being recognized as a major global epidemic. The prevalence of obesity in the United States has increased dramatically, from 13.4% in 1960 to 36.5% in 2014, with as much as 70.7% of the American adult population being overweight or obese (CDC). Epidemiological studies have shown that obesity predisposes to hypertension and CVD - with the relationship between markers of obesity and blood pressure being almost linear across different populations. In this review, we discuss systemic and pulmonary hypertension in the context of obesity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The purpose of this review is to provide a framework for the cardiovascular evaluation and management of patients undergoing hematopoietic cell transplantation (HCT). To accomplish this, we have performed an extensive literature review, critically analyzed the available evidence, and developed a set of recommendations to guide best practice. Herein, we discuss the cardiovascular risk profile of patients undergoing HCT along with putative mechanisms of HCT-induced cardiovascular injury. We then present an algorithm for cardiovascular testing and risk mitigation of potential recipients. Last, we address the management of the most prevalent cardiovascular conditions associated with HCT recipients.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo preclinical imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3, that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy. NP3 is composed of a 16 nm core of gadolinium fluoride (GdF3), coated with bisphosphonate polyethylene glycol (PEG) and functionalized with a Lemke-type fluorophore. It has a hydrodynamic diameter of 28 ± 8 nm and a zeta potential of -42 ± 6 mV. The MR relaxivity ratio at 7 T is r1/r2 = 20; therefore, NP3 is well suited as a T2/T2* contrast agent. In vitro cytotoxicity assessments performed on four human cell lines revealed no toxic effects of NP3. In addition, NP3 is internalized by macrophages in vitro without inducing inflammation or cytotoxicity. In vivo, uptake of NP3 has been observed in the spleen and the liver. NP3 has a prolonged vascular remanence, which is an advantage for macrophage uptake in vivo. The proof-of-concept that NP3 may be used as a contrast agent targeting phagocytic cells is provided in an animal model of ischemic stroke in transgenic CX3CR1-GFP/+ mice using three complementary imaging modalities: MRI, intravital two-photon microscopy and phase contrast imaging with synchrotron X-rays. In summary, NP3 is a promising preclinical tool for the multiscale and multimodal investigation of neuroinflammation.

Biological processes are incredibly complex-integrating molecular signaling networks involved in multicellular communication and function, thus maintaining homeostasis. Dysfunction of these processes can result in the disruption of homeostasis, leading to the development of several disease processes including atherosclerosis. We have significantly advanced our understanding of bioprocesses in atherosclerosis, and in doing so, we are beginning to appreciate the complexities, intricacies, and heterogeneity atherosclerosi. We are also now better equipped to acquire, store, and process the vast amount of biological data needed to shed light on the biological circuitry involved. Such data can be analyzed within machine learning frameworks to better tease out such complex relationships. Indeed, there has been an increasing number of studies applying machine learning methods for patient risk stratification based on comorbidities, multi-modality image processing, and biomarker discovery pertaining to atherosclerotic plaque formation. Here, we focus on current applications of machine learning to provide insight into atherosclerotic plaque formation and better understand atherosclerotic plaque progression in patients with cardiovascular disease., (© 2021 Author(s).)

Cancer patients face a higher risk of future myocardial infarction (MI), even after completion of anticancer therapies. MI is a critical source of physical and financial stress in noncancer patients, but its impacts associated with cancer patients also saddled with the worry (stress) of potential reoccurrence is unknown. Therefore, we aimed to quantify MI's stress and financial burden after surviving cancer and compare to those never diagnosed with cancer. Utilizing cross-sectional national survey data from 2013 to 2018 derived from publicly available United States datasets, the National Health Interview Survey , and economic data from the National Inpatient Sample , we compared the socio-economic outcomes in those with MI by cancer-status. We adjusted for social, demographic, and clinical factors. Overall, 19,504 (10.2%) of the 189,836 National Health Interview Survey responders reported having cancer for more than 1 year. There was an increased prevalence of MI in cancer survivors compared with noncancer patients (8.8% vs 3.2%, p <0.001). MI was associated with increased financial worry, food insecurity, and financial burden of medical bills (p <0.001, respectively); however, concurrent cancer did not seem to be an effect modifier (p >0.05). There was no difference in annual residual family income by cancer status; however, 3 lowest deciles of residual income representing 21.1% cancer-survivor with MI had a residual income of <$9,000. MI continues to represent an immense source of financial and perceived stress. In conclusion, although cancer patients face a higher risk of subsequent MI, this does not appear to advance their reported stress significantly., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stabilized HIV-1 envelope (Env) trimers elicit tier 2 autologous neutralizing antibody (nAb) responses in immunized animals. We previously demonstrated that BG505 SOSIP.664.T332N gp140 (BG505 SOSIP) immunization of rhesus macaques (RM) provided robust protection against autologous intra-vaginal simian-human immunodeficiency virus (SHIV) challenge that was predicted by high serum nAb titers. Here, we show that nAb in these protected RM targeted a glycan hole proximal to residue 465 in gp120 in all cases. nAb also targeted another glycan hole at residues 241/289 and an epitope in V1 at varying frequencies. Non-neutralizing antibodies directed at N611-shielded epitopes in gp41 were also present but were more prevalent in RM with low nAb titers. Longitudinal analysis demonstrated that nAb broadened in some RM during sequential immunization but remained focused in others, the latter being associated with increases in nAb titer. Thirty-eight monoclonal antibodies (mAbs) isolated from a protected RM with an exceptionally high serum neutralization titer bound to the trimer in ELISA, and four of the mAbs potently neutralized the BG505 Env pseudovirus (PV) and SHIV. The four neutralizing mAbs were clonally related and targeted the 465 glycan hole to varying degrees, mimicking the serum. The data demonstrate that the C3/465 glycan hole cluster was the dominant neutralization target in high titer protected RM, despite other co-circulating neutralizing and non-neutralizing specificities. The isolation of a neutralizing mAb family argues that clonotype expansion occurred during BG505 SOSIP immunization, leading to high titer, protective nAb and setting a desirable benchmark for HIV vaccines., Competing Interests: The authors have declared that no competing interests exist.

Pregnancy is characterized by intense physiological and structural alterations in the vagina, cervix, and overlying fetal membranes. High vaginal fluid (HVF) is a proximal fluid that covers the lower part of the female reproductive system and the severity of vaginal pathology often adversely affects pregnancy outcomes. To identify the correlation of vaginal fluid proteome dynamics and physiological changes during the progression of pregnancy, a longitudinal study was performed on 20 pregnant women who delivered a baby in >37 weeks without any complications. SWATH-MS-based label-free quantitative proteomics was performed to profile the HVF proteome at three time points defined as V1 (7-12 weeks), V2 (18-20 weeks), and V3 (26-28 weeks). Linear mixed-effect models were used to estimate protein abundance as a function of the period of gestational age. In this study, we identified 1015 HVF proteins and 61 of them were significantly altered until late second trimester. Our result demonstrates that the HVF proteins reveal gestational age-specific expression patterns and the function of these proteins is associated with tissue remodeling, organ development, and microbial defense. Our study provides an opportunity to monitor the underlying physiology of pregnancy that may be further probed for the biomarker identification in pregnancy-related adverse outcomes. Data are available via ProteomeXchange with identifiers PXD014846 and PXD021811.

Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12 -/+ murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12 -/+ mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Thrombolytic therapy significantly improves outcomes among patients with acute ischemic stroke. While cancer outcomes have dramatically improved, the utilization, safety, and mortality outcomes of patients with cancer who receive thrombolytic therapy for acute ischemic stroke are unknown., Methods: Using a national database, we identified all hospitalizations for acute ischemic stroke requiring thrombolytic therapy between 2003 and 2015. Patients with contraindications to thrombolytic therapy were excluded. Following propensity score matching for comorbidity burden, trends in thrombolytic therapy use and its effect on in-hospital mortality, intracranial or all-cause bleeding, and the combined endpoint of mortality and all-cause bleeding, by presence/absence of cancer were evaluated. We also evaluated 30- and 90-day readmission rates post-thrombolytic therapy administration., Results: We identified 237,687 acute ischemic stroke hospitalizations requiring thrombolytic therapy, of which 26,328 (11%) had an underlying cancer. Over the study period, thrombolytic therapy use increased across all acute ischemic stroke admissions, irrespective of cancer presence (12.4/1000 in 2003 to 81.1/1000 in 2015, P  < 0.0001). However, thrombolytic therapy utilization differed by cancer presence (4.8% cancer vs.·5.1% non-cancer, P  = 0.001). There was no difference in intracranial bleeding (9.6% vs. 9.7%), all-cause bleeding (13.2% vs. 13.2%), or in-hospital mortality (7.6% vs. 7.2%). While there was no difference in 30-day readmission rates by cancer presence (24% vs. 29%, P  = 0.40), at 90-days, cancer patients saw higher readmission rates (17.2% vs. 13.3%, P  = 0.02)., Conclusions: Contemporary thrombolytic therapy use for acute ischemic stroke has risen, irrespective of presence of cancer. Yet, patients with comorbid cancer appear to see lower rates of thrombolytic therapy use for acute ischemic stroke, despite no difference in the rate of intracranial bleeding or mortality after adjustment for comorbidities.

Enrichment of angiomotin (AMOT) in the ectoplacental cone of E7.5 murine placenta prompted our investigation on the role of AMOT in trophoblast differentiation. We show here that AMOT levels increased in mouse placenta during gestation and also upon induction of differentiation in trophoblast stem cell ex vivo. Proteomic data unravelling AMOT-interactome in trophoblast cells indicated a majority of AMOT interactors to be involved in protein translation. In-depth analysis of AMOT-interactome led to identification of eukaryotic translation initiation factor 4A (eIF4A) as the most plausible AMOT interactor. Loss of function of AMOT enhanced, whereas, gain in function resulted in decline of global protein synthesis in trophoblast cells. Bioinformatics analysis evaluating the potential energy of AMOT-eIF4A binding suggested a strong AMOT-eIF4A interaction using a distinct groove encompassing amino acid residue positions 238 to 255 of AMOT. Co-immunoprecipitation of AMOT with eIF4A reaffirmed AMOT-eIF4A association in trophoblast cells. Deletion of 238 to 255 amino acids of AMOT resulted in abrogation of AMOT-eIF4A interaction. In addition, 238 to 255 amino acid deletion of AMOT was ineffective in eliciting AMOT's function in reducing global protein synthesis. Interestingly, AMOT-dependent sequestration of eIF4A dampened its loading to the m 7 -GTP cap and hindered its interaction with eIF4G. Furthermore, enhanced AMOT expression in placenta was associated with intrauterine growth restriction in both rats and humans. These results not only highlight a hitherto unknown novel function of AMOT in trophoblast cells but also have broad biological implications as AMOT might be an inbuilt switch to check protein synthesis in developmentally indispensable trophoblast cells., (©AlphaMed Press 2020.)

Gold nanoparticles (AuNPs) have demonstrated outstanding performance in many biomedical applications. Their safety is recognised; however, their effects on the immune system remain ill defined. Antigen-presenting cells (APCs) are immune cells specialised in sensing external stimulus and in capturing exogenous materials then delivering signals for the immune responses. We used primary macrophages (Ms) and dendritic cells (DCs) of mice as an APC model. Whereas AuNPs did not alter significantly Ms and DCs functions, the exposure to AuNPs affected differently Ms and DCs in their responses to subsequent stimulations. The secretion of inflammatory molecules like cytokines (IL-6, TNF-α), chemokine (MCP-1), and reactive oxygen species (ROS) were altered differently in Ms and DCs. Furthermore, the metabolic activity of Ms was affected with the increase of mitochondrial respiration and glycolysis, while only a minor effect was seen on DCs. Antigen presentation to T cells increased when DCs were exposed to AuNPs leading to stronger Th1, Th2, and Th17 responses. In conclusion, our data provide new insights into the complexity of the effects of AuNPs on the immune system. Although AuNPs may be considered as devoid of significant effect, they may induce discrete modifications on some functions that can differ among the immune cells.

Using siRNAs to genetically manipulate immune cells is important to both basic immunological studies and therapeutic applications. However, siRNA delivery is challenging because primary immune cells are often sensitive to the delivery materials and generate immune responses. We have recently developed an amphiphilic dendrimer that is able to deliver siRNA to a variety of cells, including primary immune cells. We provide here a protocol for the synthesis of this dendrimer, as well as siRNA delivery to immune cells such as primary T and B cells, natural killer cells, macrophages, and primary microglia. The dendrimer synthesis entails straightforward click coupling followed by an amidation reaction, and the siRNA delivery protocol requires simple mixing of the siRNA and dendrimer in buffer, with subsequent application to the primary immune cells to achieve effective and functional siRNA delivery. This dendrimer-mediated siRNA delivery largely outperforms the standard electroporation technique, opening a new avenue for functional and therapeutic studies of the immune system. The whole protocol encompasses the dendrimer synthesis, which takes 10 days; the primary immune cell preparation, which takes 3-10 d, depending on the tissue source and cell type; the dendrimer-mediated siRNA delivery; and subsequent functional assays, which take an additional 3-6 d.

Controlled and efficient activation is the crucial aspect of designing an effective prodrug. Herein we demonstrate a proof of concept for a light activatable prodrug with desired organelle specificity. Mertansine, a benzoansamacrolide, is an efficient microtubule-targeting compound that binds at or near the vinblastine-binding site in the mitochondrial region to induce mitotic arrest and cell death through apoptosis. Despite its efficacy even in the nanomolar level, this has failed in stage 2 of human clinical trials owing to the lack of drug specificity and the deleterious systemic toxicity. To get around this problem, a recent trend is to develop an antibody-conjugatable maytansinoid with improved tumor/organelle-specificity and lesser systematic toxicity. Endogenous CO is recognized as a regulator of cellular function and for its obligatory role in cell apoptosis. CO blocks the proliferation of cancer cells and effector T cells, and the primary target is reported to be the mitochondria. We report herein a new mitochondria-specific prodrug conjugate ( Pro-DC ) that undergoes a photocleavage reaction on irradiation with a 400 nm source (1.0 mW cm -2 ) to induce a simultaneous release of the therapeutic components mertansine and CO along with a BODIPY derivative ( BODIPY(PPH3)2 ) as a luminescent marker in the mitochondrial matrix. The efficacy of the process is demonstrated using MCF-7 cells and could effectively be visualized by probing the intracellular luminescence of BODIPY(PPH3)2 . This provides a proof-of-concept for designing a prodrug for image-guided combination therapy for mainstream treatment of cancer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Chronic inflammatory diseases including human immunodeficiency virus infection, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus predispose to atherosclerotic cardiovascular disease (ASCVD). Inflammatory bowel disease (IBD) is a common chronic inflammatory condition, and the United States has the highest prevalence worldwide. IBD has so far been overlooked as a contributor to the burden of ASCVD among young and middle-age adults, but meta-analyses of cohort studies suggest that IBD is an independent risk factor for ASCVD. This review discusses the epidemiological links between IBD and ASCVD and potential mechanisms underlying these associations. ASCVD risk management of patients with IBD is challenging because of their young age and the inability of current risk scores to fully capture their increased risk. The role of IBD in current primary prevention guidelines is evaluated, and strategies for enhanced ASCVD risk reduction in patients with IBD are outlined. Finally, the authors discuss knowledge gaps and future research directions in this innovative field., Competing Interests: Author Disclosures Dr. Nasir is on the Advisory Boards of Amgen, Novartis, The Medicines Company; and his research is partly supported by the Jerold B. Katz Academy of Translational Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

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., (Published by Elsevier Inc.)

BACKGROUNDPsoriasis is a chronic inflammatory skin disease associated with increased obesity, noncalcified coronary artery burden (NCB), and incident myocardial infarction. Here, we sought to assess the relationship among inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis.METHODSConsecutive psoriasis patients underwent coronary CT angiography to quantify NCB and abdominal CT to calculate VAT at baseline (n = 237), 1 year (n = 176), and 4 years (n = 50).RESULTSPatients with high levels of high-sensitivity C-reactive protein (hs-CRP) had significantly greater visceral adiposity (17,952.9 ± 849.2 cc3 vs. 13370.7 ± 806.8 cc3, P < 0.001) and noncalcified coronary burden (1.26 ± 0.03 vs. 1.07 ± 0.02 mm2) than those with low levels of hs-CRP. Those with higher levels of VAT had more systemic inflammation (hs-CRP, median [IQR], 2.5 mg/L [1.0-5.3 mg/L] vs. 1.2 mg/L [0.6-2.9 mg/L]), with approximately 50% higher NCB (1.42 ± 0.6 mm2 vs. 0.91 ± 0.2 mm2, P < 0.001). VAT associated with NCB in fully adjusted models (β = 0.47, P < 0.001). At 1-year follow-up, patients who had worsening hs-CRP had an increase in VAT (14,748.7 ± 878.1 cc3 to 15,158.7 ± 881.5 cc3; P = 0.03), whereas those who had improved hs-CRP improved their VAT (16,876.1 ± 915.2 cc3 to 16310.4 ± 889.6 cc3; P = 0.04). At 1 year, there was 10.3% reduction in NCB in those who had decreased VAT (β = 0.26, P < 0.0001), which persisted in a subset of patients at 4 years (β = 0.39, P = 0.003).CONCLUSIONSInflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its effect on early atherogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778569.FUNDINGThis study was supported by the National Heart, Lung, and Blood Institute Intramural Research Program (HL006193-05), the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and Elsevier as well as private donors.

Background Myocardial infarction and premature death have been observed in patients with psoriasis. Although inflammation-driven accelerated atherosclerosis has been proposed as a mechanism, the relationship between subclinical noncalcified coronary burden (NCB), functional coronary flow impairment, and myocardial injury is unclear. Methods and Results In an ongoing longitudinal cohort study, 202 consecutive patients with psoriasis (168 at 1 year) underwent coronary computed tomography angiography to identify coronary plaque, quantify NCB, and calculate coronary fractional flow reserve by computed tomography. Serum high-sensitivity troponin-T (hs-cTn-T) was measured using a fifth-generation assay. Overall, patients were middle-aged, predominantly male, and low cardiovascular risk. A higher than median NCB associated with a positive hs-cTn-T (fully adjusted model [odds ratio (OR), 1.72; 95% CI, 1.10-2.69, P =0.018]) at baseline. Additionally, patients with a higher than median baseline NCB had higher odds of positive hs-cTn-T at 1 year in fully adjusted analyses (adjusted OR, 2.36; 95% CI, 1.47-3.79, P <0.001). Higher NCB was associated with a higher frequency of fractional flow reserve by computed tomography ≤0.80 (36.11% versus 25.11%, Pearson χ 2 =6.84, P =0.009, unadjusted OR, 2.09; 95% CI, 1.36-3.22, P <0.001) and higher frequency of a positive hs-cTn-T (54.36% versus 27.54%, Pearson χ 2 =32.23, P <0.001) in adjusted models (OR, 2.63; 95% CI, 1.56-4.42, P <0.001). Conclusions NCB was associated with hs-cTn-T at baseline as well as at 1 year. Furthermore, patients with high NCB had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a >2- fold higher odds of positive hs-cTn-T. These findings underscore the importance of early vascular disease in driving myocardial injury, and support conduct of myocardial perfusion studies to better understand these findings.

GlycA is a biomarker of systemic inflammation, quantifying both the protein concentrations and glycosylation states of several acute phase proteins. GlycA has been shown to be associated with both subclinical atherosclerosis and with cardiovascular disease (CVD). GlycA levels are higher in acute and chronic inflammation. During ongoing systemic inflammatory processes, GlycA specific acute phase reactants and proteins undergo circulating concentration and glycosylation pattern changes, and these alterations are reflected in the GlycA NMR signal. Additionally, levels associate with ongoing disease severity in individuals with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis thus capturing active inflammation. Furthermore, in these disease states, GlycA is associated with cardiovascular disease (CVD) independent of traditional risk factors including C-reactive protein (CRP). Finally, GlycA levels decrease with exercise, weight loss, and systemic anti-inflammatory agents. Therefore, GlycA appears to be a promising new composite biomarker of active systemic inflammation including assessing CVD risk in patients with inflammatory diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Juvenile dermatomyositis (JDM) is an auto-immune inflammatory condition associated with cardiac disorders including conduction abnormalities and myocardial dysfunction. The time of presentation of cardiac abnormalities can range from disease onset to after long-term follow-up, emphasising the importance of screening for cardiac involvement in JDM. A previously healthy 10-year-old girl presented with syncope, fatigue and weakness associated with a heliotrope rash. JDM was diagnosed based on the clinical, laboratory and imaging findings. An ECG demonstrated complete heart block (CHB). All symptoms resolved following treatment with parenteral corticosteroids. In JDM, it is important to investigate for cardiac manifestations and in CHB to consider administering corticosteroids.

Chronic inflammation in humans is associated with accelerated development of cardiometabolic diseases such as myocardial infarction, stroke, and diabetes. Strong evidence from animal models and human interventional trials including CANTOS (The Canakinumab Anti-inflammatory Thrombosis Outcome Study) suggests that targeting residual systemic inflammation in humans may impart a benefit in reducing cardiometabolic diseases. Diseases associated with heightened immune-activation and systemic inflammation including psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus infection are associated with upwards of two to seven-fold risk of future adverse cardiac events even when adjusted for traditional risk factors. Over the past decade, psoriasis has been utilized as a human model to study inflammatory-induced cardiometabolic dysfunction and to better understand residual risk due to inflammation. The high prevalence and early onset of cardiovascular disease in psoriasis enhances the likelihood of discovering novel pathways in vascular disease progression when followed over time. Furthermore, the United States Food and Drug Administration approved treatments for psoriasis include cytokine inhibitors (anti-tumor necrosis factor, anti-interleukin 17, anti-interleukin 12/23) which while treating the skin disease provide a unique opportunity to characterize how treating the inflammatory pathways may impact atherosclerosis. Herein, we provide a review of chronic inflammation, cardiometabolic disease associations, and treatment effects with a focus on psoriasis as a human model of study., (Published by Elsevier Inc.)

Intimate partner violence (IPV) and reproductive coercion (RC)-largely in the form of pressuring pregnancy-appear to contribute to low use of contraceptives in India; however, little is known about the extent to which these experiences differentially affect use of specific contraceptive methods. The current study assessed the association of IPV and RC with specific contraceptive methods (Intrauterine Devices [IUDs], pills, condoms) among a large population-based sample of currently married women (15-49 years, n = 1424) living in Uttar Pradesh. Outcomes variables included past year modern contraceptive use and type of contraceptive used. Primary independent variables included lifetime experience of RC by current husband or in-laws, and lifetime experiences of physical IPV and sexual IPV by current husband. Multivariate logistic regression models were developed to determine the effect of each form of abuse on women's contraceptive use. Approximately 1 in 7 women (15.1%) reported experiencing RC from their current husband or in-laws ever in their lifetime, 37.4% reported experience of physical IPV and 8.3% reported experience of sexual IPV by their current husband ever in their lifetime. Women experiencing RC were less likely to use any modern contraceptive (AOR: 0.18; 95% CI: 0.9-0.36). Such women also less likely to report pill and condom use but were more likely to report IUD use. Neither form of IPV were associated with either overall or method specific contraceptive use. Study findings highlight that RC may influence contraceptive use differently based on type of contraceptive, with less detectable, female-controlled contraceptives such as IUD preferred in the context of women facing RC. Unfortunately, IUD uptake remains low in India. Increased access and support for use, particularly for women contending with RC, may be important for improving women's control over contraceptive use and reducing unintended pregnancy., Competing Interests: The authors have declared that no competing interests exist. The commercial affiliation of author does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Aims: Amygdalar 18F-fluorodeoxyglucose (FDG) uptake represents chronic stress-related neural activity and associates with coronary artery disease by coronary computed tomography angiography (CCTA). Allostatic load score is a multidimensional measure related to chronic physiological stress which incorporates cardiovascular, metabolic and inflammatory indices. To better understand the relationship between chronic stress-related neural activity, physiological dysregulation and coronary artery disease, we studied the association between amygdalar FDG uptake, allostatic load score and subclinical non-calcified coronary artery burden (NCB) in psoriasis., Methods: Consecutive psoriasis patients (n = 275 at baseline and n = 205 at one-year follow-up) underwent CCTA for assessment of NCB (QAngio, Medis). Amygdalar FDG uptake and allostatic load score were determined using established methods., Results: Psoriasis patients were middle-aged, predominantly male and white, with low cardiovascular risk by Framingham risk score and moderate-severe psoriasis severity. Allostatic load score associated with psoriasis severity (β = 0.17, p = 0.01), GlycA (a systemic marker of inflammation, β = 0.49, p < 0.001), amygdalar activity (β = 0.30, p < 0.001), and NCB (β = 0.39; p < 0.001). Moreover, NCB associated with amygdalar activity in participants with high allostatic load score (β = 0.27; p < 0.001) but not in those with low allostatic load score (β = 0.07; p = 0.34). Finally, in patients with an improvement in allostatic load score at one year, there was an 8% reduction in amygdalar FDG uptake (p < 0.001) and a 6% reduction in NCB (p = 0.02)., Conclusions: In psoriasis, allostatic load score represents physiological dysregulation and may capture pathways by which chronic stress-related neural activity associates with coronary artery disease, emphasizing the need to further study stress-induced physiological dysregulation in inflammatory disease states., (Published by Elsevier B.V.)

Background: Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is unknown., Objectives: Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we assessed the relationship of area under LDL-C versus age curve to incident CVD event risk and modulation of risk by time course of area accumulation-whether risk increase for the same area increment is different at different ages., Methods: This prospective study included 4,958 asymptomatic adults age 18 to 30 years enrolled from 1985 to 1986. The outcome was a composite of nonfatal coronary heart disease, stroke, transient ischemic attack, heart failure hospitalization, cardiac revascularization, peripheral arterial disease intervention, or cardiovascular death., Results: During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio: 1.053; p < 0.0001 per 100 mg/dl × years; hazard ratio: 0.797 per mg/dl/year; p = 0.045, respectively)., Conclusions: Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Evaluation of coronary artery disease (CAD) using coronary computed tomography angiography (CCTA) has seen a paradigm shift in the last decade. Evidence increasingly supports the clinical utility of CCTA across various stages of CAD, from the detection of early subclinical disease to the assessment of acute chest pain. Additionally, CCTA can be used to noninvasively quantify plaque burden and identify high-risk plaque, aiding in diagnosis, prognosis, and treatment. This is especially important in the evaluation of CAD in immune-driven conditions with increased cardiovascular disease prevalence. Emerging applications of CCTA based on hemodynamic indices and plaque characterization may provide personalized risk assessment, affect disease detection, and further guide therapy. This review provides an update on the evidence, clinical applications, and emerging technologies surrounding CCTA as highlighted at the 2019 National Heart, Lung and Blood Institute CCTA Summit., (Published by Elsevier Inc.)

Objective: To characterize the contemporary efficacy and utilization patterns of coronary artery bypass grafting (CABG) in specific cancer types., Methods: We leveraged the data from the National Inpatient Sample and plotted trends of utilization and outcomes of isolated CABG (with no other additional surgeries during the same hospitalization) procedures from January 1, 2003, through September 1, 2015. Propensity score matching was used to assess for potential differences in outcomes by type of cancer status among contemporary (2012-2015) patients., Results: Overall, the utilization of CABG decreased over time (250,677 in 2003 vs 134,534 in 2015, P<.001). However, the proportion of those with comorbid cancer increased (7.0% vs 12.6%, P<.001). Over time, in-hospital mortality associated with CABG use in cancer remained unchanged (.9% vs 1.0%, P=.72); yet, cancer patients saw an increase in associated major bleeding (4.5% vs 15.3%, P<.001) and rate of stroke (.9% vs 1.5%, P<.001) over time. In-hospital cost-of-care associated with CABG-use in cancer also increased over time ($29,963 vs $33,636, P<.001). When stratified by cancer types, in-hospital mortality was not higher in breast, lung, prostate, colon cancer, or lymphoma versus non-cancer CABG patients (all P>.05). However, there was a significantly higher prevalence of major bleeding but not stroke in patients with breast and prostate cancer only compared with non-cancer CABG patients (P<.01). Discharge dispositions were not found to be different between cancer sub-groups and non-cancer patients (P>.05), except for breast cancer patients who had lower home care, but higher skilled care disposition (P<.001)., Conclusion: Among those undergoing CABG, the prevalence of comorbid cancer has steadily increased. Outside of major bleeding, these patients appear to share similar outcomes to those without cancer indicating that CABG utilization should be not be declined in cancer patients when otherwise indicated. Further research into the factors underlying the decision to pursue CABG in specific cancer sub-groups is needed., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation., Methods: We utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo., Findings: We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; β = 0.28, p < 0.001)., Interpretation: Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis., Funding: Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB)., Competing Interests: Declaration of Interest Dr. Mehta has received funding from the National Institutes of Health Intramural Research Program (Z01 HL-06193); and has received research grants from Abbvie, Janssen, Novartis Corp, and Celgene. Dr. Gelfand reports personal fees from BMS, Boehringer Ingelheim, GSK, Lilly, Janssen Biologics, Novartis Corp., UCB (DSMB), Neuroder (DSMB), Dr. Reddy's Labs, Pfizer Inc., and Sun Pharma as well as grants from Abbvie, Boehringer Ingelheim, Janssen, Novartis Corp., Celgene, Ortho Dermatologics, and Pfizer, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier B.V.)

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: Inferior vena cava filter (IVCF) use is common after a venous thromboembolic event (VTE). Cancer is associated with higher rates of VTEs and is also seen in a significant proportion of patients requiring IVCF. As hospital readmissions remain a frequently scrutinized metric, we sought to evaluate the impact of cancer on hospital-readmission rates and in-hospital outcomes among patients with VTEs who received an IVCF., Methods: Leveraging the 2013 to 2014 Nationwide Readmission Database, we identified adult patients presenting with a VTE in the United States and evaluated 30-day readmission rates and readmission in-hospital outcomes postindex-admission. Multivariable logistic regression was used to identify factors associated with readmission after an index-procedure, including traditional and nontraditional cardiovascular risk factors, as well as hospital-level characteristics., Results: Among the 619 241 patients presenting with a VTE at index-admission, 11.2% of patients received IVCF on index-admission, of which 30.9% had cancer. The 30-day readmission rate amongst IVCF recipients was 15.8% (N = 10 927), and 19.9% amongst those with cancer compared to 13.9% in patients without cancer (P < .001). Moreover, cancer patients had longer lengths of stay in the hospital (4.5 ± 0.2 vs 4.0 ± 0.1 days; P = .02), higher cost of care ($10 900 ± 308 vs $9242 ± 206; P = .007), but no difference in mortality (8.3% vs 6.3%; P = .70) during readmission compared to noncancer patients., Conclusion: Readmission after IVCF placement is common. In patients readmitted after an IVCF implantation, those with cancer have longer hospital stays and higher costs of care. However, in-hospital mortality is similar to those without cancer., (© 2020 Wiley Periodicals LLC.)

Psoriasis, a chronic immune-mediated disease, is associated with an increased risk of cardiovascular events and mortality. Secukinumab selectively neutralizes IL-17A and has reported high efficacy with a favorable safety profile in various psoriatic disease manifestations. Subsequent to the 12-week randomized, placebo-controlled, double-blind treatment period, patients with moderate-to-severe psoriasis received secukinumab for 40 weeks. Vascular inflammation using 18 F-2-fluorodeoxyglucose-positron emission tomography/computed tomography imaging and blood-based cardiometabolic was assessed at week 0, 12, and 52. The difference in change in aortic inflammation from baseline to week 12 for secukinumab (n = 46) versus placebo (n = 45) was -0.053 (95% confidence interval = -0.169 to 0.064; P= 0.37). Small increases in total cholesterol, low-density lipoprotein, and low-density lipoprotein particles, but no changes in markers of inflammation, adiposity, insulin resistance, or predictors of diabetes, were observed with secukinumab treatment compared with placebo. At week 52, reductions in TNF-α (P= 0.0063) and ferritin (P= 0.0354), and an increase in fetuin-A (P= 0.0024), were observed with secukinumab treatment compared with baseline. No significant changes in aortic inflammation or markers of advanced lipoprotein characterization, adiposity, or insulin resistance were observed with secukinumab treatment compared with baseline. Secukinumab exhibited a neutral impact on aortic vascular inflammation and biomarkers of cardiometabolic disease after 52 weeks of treatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery.

A vaccine will likely be one of the key tools for ending the HIV-1/AIDS epidemic by preventing HIV-1 spread within uninfected populations and achieving a cure for people living with HIV-1. The currently prevailing view of the vaccine field is to introduce protective antibodies, nevertheless, a vaccine to be effective may need to harness protective T cells. We postulated that focusing a T-cell response on the most vulnerable regions of the HIV-1 proteome while maximizing a perfect match between the vaccine and circulating viruses will control HIV-1 replication. We currently use a combination of replication-deficient simian (chimpanzee) adenovirus and poxvirus modified vaccinia virus Ankara to deliver bivalent conserved-mosaic immunogens to human volunteers. Here, we exploit the mRNA platform by designing tetravalent immunogens designated as HIVconsvM, and demonstrate that mRNA formulated in lipid nanoparticles induces potent, broad and polyfunctional T-cell responses in a pre-clinical model. These results support optimization and further development of this vaccine strategy in experimental medicine trials in humans.

Overcoming pandemics, such as the current Covid-19 outbreak, requires the manufacture of several billion doses of vaccines within months. This is an extremely challenging task given the constraints in small-scale manufacturing for clinical trials, clinical testing timelines involving multiple phases and large-scale drug substance and drug product manufacturing. To tackle these challenges, regulatory processes are fast-tracked, and rapid-response manufacturing platform technologies are used. Here, we evaluate the current progress, challenges ahead and potential solutions for providing vaccines for pandemic response at an unprecedented scale and rate. Emerging rapid-response vaccine platform technologies, especially RNA platforms, offer a high productivity estimated at over 1 billion doses per year with a small manufacturing footprint and low capital cost facilities. The self-amplifying RNA (saRNA) drug product cost is estimated at below 1 USD/dose. These manufacturing processes and facilities can be decentralized to facilitate production, distribution, but also raw material supply. The RNA platform technology can be complemented by an a priori Quality by Design analysis aided by computational modeling in order to assure product quality and further speed up the regulatory approval processes when these platforms are used for epidemic or pandemic response in the future., (© 2020 The Authors. Journal of Advanced Manufacturing and Processing published by Wiley Periodicals LLC. on behalf of American Institute of Chemical Engineers.)

Purpose of Review: The role of oral bacteremia and periodontal inflammation driving atherosclerosis is still under investigation. This review article highlights the role of periodontal inflammation and oral microorganisms in the development and progression of atherosclerosis and cardiovascular diseases., Recent Findings: Association between periodontal and cardiovascular diseases has been well characterized, but causal correlation is yet to be established. For instance, untreated gingivitis can progress to periodontitis. Periodontal disease has been associated with several systemic diseases one of which is atherosclerosis. One possible association that was documented in literature is that poor oral hygiene leads to bacteremia, which in turn can cause bacterial growth over atherosclerotic coronary artery plaques and possibly worsen coronary artery disease. It is crucial that clinicians understand the association between periodontal and cardiovascular disease. A comprehensive treatment for periodontitis and re-establishment of a healthy periodontium can help in reduction of overall inflammation in the body. This may play an important role in prevention of cardiovascular disease, though future research is needed to establish this.

Aims: Takotsubo cardiomyopathy (TC) is characterized by transient ventricular impairment, often preceded by emotional or physical stress. Racial differences affect the outcomes of several cardiovascular conditions; however, the effect of race on TC remains unknown. This investigation aims to assess the effect of race on in-hospital outcomes of TC in a large national sample., Methods and Results: We conducted a US-wide analysis of TC hospitalizations from 2006 to 2014 by querying the National Inpatient Sample database for the International Classification of Diseases-ninth Revision TC code, characteristics, and inpatient outcomes. Patients with a primary diagnosis of acute coronary syndrome were excluded to reduce selection bias. Caucasians were compared with African Americans (AA) for differences in baseline characteristics and in-hospital outcomes. Multivariate regression models were created to adjust for potential confounders. Of 97 650 TC patients, 83 807 (86.9%) were women, 89 624 (91.8%) identified as Caucasians, and 8026 (8.2%) as AA. The annual number of TC hospitalizations increased significantly from 2006 to 2014 in both races (from 335 to 21 265 annual cases, P < 0.001). In-hospital mortality initially increased (1-2% in 2006 to 5-6% in 2009, P < 0.001) and subsequently remained relatively stable around 5-7% with no significant difference between races. In unadjusted analysis, AA had more cardiac arrests [304 (3.8%) vs. 2569 (2.9%), P = 0.04], invasive mechanical ventilation [1671 (20.8%) vs. 15 897 (17.7%), P = 0.002], tracheostomies [242 (3%) vs. 1600 (1.8%), P = 0.001], acute kidney injuries [1765 (22%) vs. 14 608 (16.3%), P < 0.0001], and longer hospital stays [4.5 (3.2-4.8) vs. 3.8 (3.7-3.9) days, P < 0.0001] compared with Caucasians. After the adjustment for differences in age, gender, comorbidities (using the enhanced Charlson comorbidity index), hospital location/teaching status, and socio-economic factors, all differences were significantly attenuated or eliminated. Additionally, the adjusted risk was lower in AA compared with Caucasians, for cardiogenic shock [odds ratio (OR) 0.61 (0.47-0.78), P < 0.0001], mechanical ventilation [OR 0.8 (0.70-0.92), P = 0.002] and intraaortic balloon pump insertion [OR 0.63 (0.41-0.99), P = 0.04]., Conclusions: Our investigation is the first large US-wide analysis studying racial variations in TC outcomes. AA overall have more in-hospital complications; however, the differences are driven by racial disparities in demographics, comorbidities, and socio-economic factors., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The establishment and maintenance of pregnancy in humans proceed through a continuous change of biochemical and biophysical processes. It requires a constant interaction between the fetus and the maternal system. The present prospective study aims to elucidate changes in salivary proteome from the early to middle stages of term pregnancy, and establishing an expressional trajectory for modulated proteins. To date, a comprehensive characterization of the longitudinal salivary proteome in pregnancy has not been performed and it is our immediate interest. In the discovery phase, maternal saliva (N = 20) at 6-13, 18-21, and 26-29 weeks of gestation was analyzed using level-free proteomics (SWATH-MS) approach. The expression levels of 65 proteins were found to change significantly with gestational age and distributed into two distinct clusters with a unique expression trajectory. The results revealed that altered proteins are involved in maternal immune modulation, metabolism, and host defense mechanism. Further, verification of 12 proteins was employed using targeted mass spectrometry (MRM-MS) in a separate subset of saliva (N = 14). The MRM results of 12 selected proteins confirmed a similar expression pattern as in SWATH-MS analysis. Overall, the results not only demonstrate the longitudinal maternal saliva proteome for the first time but also set the groundwork for comparative analysis between term birth and adverse pregnancy outcomes.

In the era of emerging options for mitral valvular intervention, we sought to characterize the relative utilization, outcomes, and posthospital dispositions of patients referred for transcatheter mitral valve repair (TMVRepair) and surgical mitral valve procedures (SMVP), by cancer-status. Leveraging the National Inpatient Sample, a representative national dataset, ICD-9 codes for all adults >18 years with co-morbid mitral regurgitation, and cancer without metastatic disease admitted from 2003 to 2015 were queried. TMVRepair was performed in 700 hospitalizations from 2012 to 2015, whereas SMVP was utilized during 12,863 hospitalizations from 2003 to 2015. During follow-up, we observed a proportional increase in TMVRepair utilization among cancer patients (vs noncancer), particularly in 2015 (14.2% vs 8.2%, p <0.0001). There was no difference in in-hospital mortality (1.4% vs 1.8%, p = 0.71), ischemic stroke (0.7% vs 0.6%, p = 0.97), major bleeding (8.6% vs 10.9%, p = 0.36), and home discharge (62.1% vs 65.7%, p = 0.45) by cancer-status among patients who underwent TMVRepair; but, cost of care was increased ($52,325 vs $48,832, p <0.0001). Similarly, there was no difference in in-hospital mortality (3.1% vs 3.4%, p = 0.36), ischemic stroke (2.6% vs 3.1%, p = 0.16) as well as the cost-of-care ($58,106 vs $58,844, p = 0.49) among those who underwent SMVP across the same period; but, cancer was associated with increased major bleeding (34.9% vs 30.5%, p <0.0001), and lower likelihood of home discharge (32.8% vs 38.6%, p <0.0001). In conclusion, TMVRepair and SMVP were associated with comparable in-hospital mortality and outcomes in cancer versus noncancer patients. However, cancer patients treated with SMVP experienced more frequent bleeding related complications compared with noncancer patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fluorodeoxyglucose-PET/computed tomography combines the high sensitivity of PET with the excellent spatial resolution provided by computed tomography, making it a potentially powerful tool for capturing and quantifying early vascular diseases. Patients with chronic inflammatory states have an increased risk of cardiovascular events; there is also increased vascular fluorodeoxyglucose uptake seen compared with healthy controls. This review examines the use of fluorodeoxyglucose-PET/computed tomography in assessing low-grade vascular inflammation in chronic inflammation and then reviews fluorodeoxyglucose-PET/computed tomography as a tool in monitoring the efficacy of various treatments known to modulate cardiovascular disease., Competing Interests: Disclosures NNM 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, and Novartis, receiving grants and/or research funding; and as a principal investigator for the National Institutes of Health, receiving grants and/or research funding. DEU is funded by the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (DDCF Grant # 2014194), Genentech, Elsevier, and other private donors. All other authors have no conflict of interest., (Published by Elsevier Inc.)

Background: Sedentary behavior (SB) is common after cancer surgery and may negatively affect recovery and quality of life, but postoperative symptoms such as pain can be a significant barrier to patients achieving recommended physical activity levels. We conducted a single-arm pilot trial evaluating the usability and acceptability of a real-time mobile intervention that detects prolonged SB in the perioperative period and delivers prompts to walk that are tailored to daily self-reported symptom burden., Objective: The aim of this study is to develop and test a mobile technology-supported intervention to reduce SB before and after cancer surgery, and to evaluate the usability and feasibility of the intervention., Methods: A total of 15 patients scheduled for abdominal cancer surgery consented to the study, which involved using a Fitbit smartwatch with a companion smartphone app across the perioperative period (from a minimum of 2 weeks before surgery to 30 days postdischarge). Participants received prompts to walk after any SB that exceeded a prespecified threshold, which varied from day to day based on patient-reported symptom severity. Participants also completed weekly semistructured interviews to collect information on usability, acceptability, and experience using the app and smartphone; in addition, smartwatch logs were examined to assess participant study compliance., Results: Of eligible patients approached, 79% (15/19) agreed to participate. Attrition was low (1/15, 7%) and due to poor health and prolonged hospitalization. Participants rated (0-100) the smartphone and smartwatch apps as very easy (mean 92.3 and 93.2, respectively) and pleasant to use (mean 93.0 and 93.2, respectively). Overall satisfaction with the whole system was 89.9, and the mean System Usability Scale score was 83.8 out of 100. Overall compliance with symptom reporting was 51% (469/927 days), decreasing significantly from before surgery (264/364, 73%) to inpatient recovery (32/143, 22%) and postdischarge (173/420, 41%). Overall Fitbit compliance was 70% (653/927 days) but also declined from before surgery (330/364, 91%) to inpatient (51/143, 36%) and postdischarge (272/420, 65%)., Conclusions: Perioperative patients with cancer were willing to use a smartwatch- and smartphone-based real-time intervention to reduce SB, and they rated the apps as very easy and pleasant to use. Compliance with the intervention declined significantly after surgery. The effects of the intervention on postoperative activity patterns, recovery, and quality of life will be evaluated in an ongoing randomized trial., (©Carissa A Ann Low, Michaela Danko, Krina C Durica, Abhineeth Reddy Kunta, Raghu Mulukutla, Yiyi Ren, David L Bartlett, Dana H Bovbjerg, Anind K Dey, John M Jakicic. Originally published in JMIR Perioperative Medicine (http://periop.jmir.org), 23.03.2020.)

Background: Mobile assessment of the effects of acute marijuana on cognitive functioning in the natural environment would provide an ecologically valid measure of the impacts of marijuana use on daily functioning., Objective: This study aimed to examine the association of reported acute subjective marijuana high (rated 0-10) with performance on 3 mobile cognitive tasks measuring visuospatial working memory (Flowers task), attentional bias to marijuana-related cues (marijuana Stroop), and information processing and psychomotor speed (digit symbol substitution task [DSST]). The effect of distraction as a moderator of the association between the rating of subjective marijuana high and task performance (ie, reaction time and number of correct responses) was explored., Methods: Young adults (aged 18-25 years; 37/60, 62% female) who reported marijuana use at least twice per week were recruited through advertisements and a participant registry in Pittsburgh, Pennsylvania. Phone surveys and mobile cognitive tasks were delivered 3 times per day and were self-initiated when starting marijuana use. Completion of phone surveys triggered the delivery of cognitive tasks. Participants completed up to 30 days of daily data collection. Multilevel models examined associations between ratings of subjective marijuana high (rated 0-10) and performance on each cognitive task (reaction time and number of correct responses) and tested the number of distractions (rated 0-4) during the mobile task session as a moderator of the association between ratings of subjective marijuana high and task performance., Results: Participants provided 2703 data points, representing 451 reports (451/2703, 16.7%) of marijuana use. Consistent with slight impairing effects of acute marijuana use, an increase in the average rating of subjective marijuana high was associated with slower average reaction time on all 3 tasks-Flowers (B=2.29; SE 0.86; P=.008), marijuana Stroop (B=2.74; SE 1.09; P=.01), and DSST (B=3.08; SE 1.41; P=.03)-and with fewer correct responses for Flowers (B=-0.03; SE 0.01; P=.01) and DSST (B=-0.18; SE 0.07; P=.01), but not marijuana Stroop (P=.45). Results for distraction as a moderator were statistically significant only for certain cognitive tasks and outcomes. Specifically, as hypothesized, a person's average number of reported distractions moderated the association of the average rating of subjective marijuana high (over and above a session's rating) with the reaction time for marijuana Stroop (B=-52.93; SE 19.38; P=.006) and DSST (B=-109.72; SE 42.50; P=.01) and the number of correct responses for marijuana Stroop (B=-0.22; SE 0.10; P=.02) and DSST (B=4.62; SE 1.81; P=.01)., Conclusions: Young adults' performance on mobile cognitive tasks in the natural environment was associated with ratings of acute subjective marijuana high, consistent with slight decreases in cognitive functioning. Monitoring cognitive functioning in real time in the natural environment holds promise for providing immediate feedback to guide personal decision making., (©Tammy Chung, Sang Won Bae, Eun-Young Mun, Brian Suffoletto, Yuuki Nishiyama, Serim Jang, Anind K Dey. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 10.03.2020.)

Background: Cancer inducing a hypercoagulable state, venous thromboembolism (VTE) remains a leading cause of morbidity and mortality globally. We assessed the impacts of cancer on the likelihood for readmission after a VTE-targeted procedure., Methods: We created a new cohort using discharge-level data from all hospitalizations from State Inpatient Databases of geographically dispersed participating states (18-27 states)., Results: In those presenting with VTE during index-admission (619 241), 2.4% patients underwent catheter directed thrombolytic therapy (CDL) on index admission and among those 20.3% had cancer. Moreover, the 30-day readmission rate amongst CDL recipients (10 776 overall) was 14.3% in those with cancer compared to 8.8% in those with no cancer history (P < .0001). Additionally, in-hospital mortality (5.7% vs 1.1%; P = 0.009) and cost-of-care ($11 014 ± 914 vs $10 520 ± 534; P = .04) was significantly higher in cancer compared to noncancer., Conclusion: The use of CDL does not appear to reduce the risk of returning for a VTE-related admission in cancer., (© 2020 Wiley Periodicals, Inc.)

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 < .001), and were associated with Psoriasis Area Severity Index (PASI) score (β = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (β = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (β = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >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.