Objective: To identify markers associated with in-hospital death in patients with coronavirus disease 2019 (COVID-19)eassociated pneumonia. Patients and Methods: A retrospective cohort study was conducted of 140 patients with moderate to critical COVID-19eassociated pneumonia requiring oxygen supplementation admitted to the hospital

Background The relation between central obesity and survival in community-dwelling adults with a normal body mass index (BMI) is not well known. Objectives To examine the risk of total and cardiovascular mortality associated with central obesity but normal BMI Design Stratified multistage probability design Setting Third National Health and Nutrition Examination Survey Participants We analyzed data on 15,184 people (52.3% women) aged 18 to 90 years.. Measurements We used multivariable Cox proportional hazards model to evaluate the relation of obesity patterns defined by BMI and WHR and total and cardiovascular mortality risk after adjustment for confounding factors. Results Persons with normal-weight central obesity had the worst long-term survival: a man with a normal BMI (22 kg/m2) and central obesity had greater total mortality risk than one with similar BMI but no central obesity (hazard ratio [HR], 1.87 [95% CI, 1.53–2.29]) and twice the mortality risk of participants who were overweight or obese by BMI only (HR, 2.24 [95% CI,1.52–3.32] and HR, 2.42 [95% CI, 1.30–4.53], respectively). Similarly, women with normal weight and central obesity had higher mortality risk than both women with similar BMI but no central obesity (HR, 1.48 [95% CI, 1.35–1.62]) and women who were obese by BMI only (HR, 1.32 [95% CI, 1.15–1.51]). Expected survival estimates were consistently lower for those with central obesity when controlled for age and BMI. Limitations Body fat distribution was assessed based on anthropometric indicators alone. Information on comorbidities was collected by self-report. Conclusion Normal-weight central obesity defined by WHR is associated with higher mortality than BMI–defined obesity, particularly in the absence of central fat distribution.

Synopsis Inadequate sleep has become increasingly pervasive, and the impact on health and quality of life remains to be fully understood. The cardiovascular consequences alone appear to be substantial and significant. This brief review summarizes epidemiologic evidence regarding the association between extremes of sleep duration and the prevalence and incidence of cardiovascular diseases. The adverse effects of experimental sleep loss on physiological functions are discussed, along with those cardiovascular risk factors that may underlie the association with increased morbidity and mortality. Current data support the concept that inadequate sleep duration confers heightened cardiovascular risk. Thus implementation of preventative strategies may be needed to reduce the potential disease burden associated with this widespread high-risk behavior.

Objective-There is increasing evidence of an association between leptin and increased cardiovascular risk. Higher leptin levels are associated with increased levels of C-reactive protein (CRP), which itself elicits proatherogenic effects in the vascular endothelium. We tested the hypothesis that leptin induces CRP expression in human coronary artery endothelial cells (HCAECs). Methods and Results-We confirmed the presence of both long and short isoforms of the leptin receptor in cultured HCAECs. Leptin but not IFN␣A/D nor tumor necrosis factor (TNF) ␣, induced expression of CRP. A dose dependent increase of CRP mRNA and protein was observed with increasing concentration of leptin (0 to 400 ng/mL). This increased CRP expression was attenuated in the presence of anti-leptin receptor antibodies and also by inhibition of ERK1/2 by PD98059 (20 to 40 mol/L). Time (0 to 60 minutes) and leptin concentration (0 to 200 ng/mL)-dependence of ERK1/2 phosphorylation were evident in response to leptin treatment. Leptin also elicited ROS generation. Inhibition of ROS by catalase (200 g/mL) prevented ERK1/2 phosphorylation and CRP mRNA transcription. Conclusion-Leptin induces CRP expression in HCAECs via activation of the leptin receptor, increased ROS production, and phosphorylation of ERK1/2. These studies suggest a mechanism for the proatherogenic effects of leptin. Key Words: leptin Ⅲ endothelium Ⅲ C-reactive protein Ⅲ obesity Ⅲ atherosclerosis L eptin, a protein encoded by the Ob gene, is produced mainly by adipocytes and is primarily involved in regulation of food intake and energy expenditure. Several studies have shown an independent interaction between high leptin and atherosclerosis, 1,2 myocardial infarction, stroke, and coronary artery intima-media thickness, suggesting that high levels of leptin imply increased cardiovascular risk. 3 Detrimental effects of leptin may include sympathetic activation, pressor responses, insulin resistance, platelet activation and aggregation, inflammation, oxidative stress, and proliferation and migration of vascular smooth muscle cells. 3,4 The molecular mechanisms underlying the association of leptin with poor cardiovascular outcomes are not fully elucidated.C-reactive protein (CRP), an acute phase protein, is also an indicator of cardiovascular (CV) risk. 5 Localization of CRP in atherosclerotic lesions 6 -8 and its role in complement activation, cell adhesion, and thrombosis make it likely an important mediator in the development and progression of the atherosclerotic lesion. 9 We and others have shown positive correlations between CRP and plasma leptin in normal weight and obese subjects. 10,11 Exogenous administration of leptin increases plasma CRP in normal weight and fasting obese subjects. 12,13 Decreases in leptin during weight loss and fasting directly correlate with decreased CRP levels. 14 Induction of CRP by leptin in vascular endothelial cells would have important implications for understanding interactions between leptin and CRP in promoting CV risk. We tested the hypot...

Objective This study sought to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans. Background Endothelial dysfunction has been identified as an independent predictor of cardiovascular events. Whether fat gain impairs endothelial function is unknown. Methods A randomized controlled study to assess the effects of fat gain on endothelial function. We recruited 43 normal weight healthy volunteers (mean age 29 years; 18 women). Subjects were assigned to gain weight (approximately 4 kg) (n=35) or to maintain weight (n=8). Endothelial function (brachial artery flow mediated dilation -FMD) was measured at baseline, after fat gain (8 weeks) and after weight loss (16 weeks) for fat-gainers and at baseline and follow-up (8 weeks) for weight-maintainers. Body composition was measured by DXA and abdominal CT scans. Results After an average weight gain of 4.1 kg, fat-gainers significantly increased their total, visceral and subcutaneous fat. Blood pressure and overnight polysomnography did not change after fat gain or loss. FMD remained unchanged in weight-maintainers. FMD decreased in fat-gainers (9.1 ± 3% vs. 7.8 ± 3.2%, p =0.003), but recovered to baseline when subjects shed the gained weight. There was a significant correlation between the decrease in FMD and the increase in visceral fat gain (rho = −0.42, p=0.004), but not with subcutaneous fat gain (rho = −0.22, p=0.15). Conclusions In normal weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction.

Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC50 values of less than 20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative potency of 24 is supported by demonstration of JAK-STAT and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides new leads for assessment of JAK and HDAC pathway dual inhibiton achieved with a single molecule.

BackgroundObstructive sleep apnea (OSA) is an important risk factor for the development of cardiovascular diseases including myocardial infarction (MI). The aim of this study was to investigate the effects of OSA on prognosis after MI, and to determine which specific measures of OSA severity best predicted outcomes.Methods and ResultsWe performed a prospective study, in which 112 patients without a prior diagnosis of sleep apnea underwent comprehensive polysomnography within a median of 7 days after MI. Patients were followed up at 6‐monthly intervals (±2 weeks) for a total of 48 months. Patients classified with central apnea (n=6) or those using continuous positive airway pressure (n=8) after polysomnography were excluded from analyses. The primary end point was major adverse cardiac events, including death from any cause, recurrent MI, unstable angina, heart failure, stroke, and significant arrhythmic events. Forty of 98 patients (41%) had OSA (apnea‐hypopnea index ≥15 events/h). OSA patients had higher major adverse cardiac event rates when compared to those without OSA (47.5% versus 24.1%; χ2=5.41, P=0.020). In a multivariate model that adjusted for clinically relevant variables including age, left ventricular ejection fraction, diabetes mellitus, oxygen desaturation index, and arousal index, significant hypoxemia, as defined by nocturnal nadir oxygen saturation ≤85%, was an independent risk factor for major adverse cardiac events (hazard ratio=6.05, P=0.004) in follow‐up 15 months after baseline.ConclusionsNocturnal hypoxemia in OSA is an important predictor of poor prognosis for patients after MI. These findings suggest that routine use of low‐cost nocturnal oximetry may be an economical and practical approach to stratify risk in post‐MI patients.

A prothrombotic state in obesity may be partially responsible for the higher incidence of atherosclerotic complications. However the factors responsible for this prothrombotic state, linked with high levels of plasminogen activator inhibitor-1 (PAI-1), are not fully known. Leptin is elevated in obesity and studies have shown a positive correlation between leptin and PAI-1 levels in human subjects, along with a negative correlation with tissue type plasminogen activator (tPA). We tested the hypothesis that leptin induces PAI-1 and inhibits tPA expression using human coronary artery endothelial cells (HCAEC) in culture as these cells play an important role in atherosclerosis. We demonstrate that leptin induces the transcription and translation of PAI-1 in HCAEC. The leptin dependent upregulation of PAI-1 mRNA and protein was comparable to insulin-induced PAI-1 expression. We show leptin concentration (0-150 ng/ml) dependent increases in PAI-1 mRNA and protein after six and twelve hours of leptin administration respectively. Increased intracellular PAI-1 expression correlates with increased PAI-1 activity in conditioned media and inhibition of specific ERK1/2 pathway by treatment with PD98059 (20 to 40 μM) inhibits leptin dependent PAI-1 expression. However no changes in tPA expression were seen with time or increasing concentrations of leptin. Also leptin treatment did not alter total tPA concentration or tPA activity in conditioned media. In conclusion, our study shows that leptin up-regulates the expression of PAI-1 in vascular endothelial cells via activation of ERK1/2 but does not regulate tPA expression. These studies demonstrate a novel mechanism for the prothrombotic role of leptin in development of atherosclerosis.