Search

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic., The importance of cytokine storms in COVID-19 continues to be widely debated. This Perspective article discusses the challenges in using cytokine measurement in COVID-19 and other disease states as we strive to improve our understanding and treatment of COVID-19.

Background Heart failure (HF) poses a major public health burden in the United States. We examined the burden of out‐of‐pocket healthcare costs on patients with HF and their families. Methods and Results In the Medical Expenditure Panel Survey, we identified all families with ≥1 adult member with HF during 2014 to 2018. Total out‐of‐pocket healthcare expenditures included yearly care‐specific costs and insurance premiums. We evaluated 2 outcomes of financial toxicity: (1) high financial burden—total out‐of‐pocket healthcare expense to postsubsistence income ratio of >20%, and (2) catastrophic financial burden with the ratio of >40%—a bankrupting expense defined by the World Health Organization. There were 788 families in the Medical Expenditure Panel Survey with a member with HF representing 0.54% (95% CI, 0.48%–0.60%) of all families nationally. The overall mean annual out‐of‐pocket healthcare expenses were $4423 (95% CI, $3908–$4939), with medications and health insurance premiums representing the largest categories of cost. Overall, 14% (95% CI, 11%–18%) of families experienced a high burden and 5% (95% CI, 3%–6%) experienced a catastrophic burden. Among the two‐fifths of families considered low income, 24% (95% CI, 18%–30%) experienced a high financial burden, whereas 10% (95% CI, 6%–14%) experienced a catastrophic burden. Low‐income families had 4‐fold greater risk‐adjusted odds of high financial burden (odds ratio [OR] , 3.9; 95% CI, 2.3–6.6), and 14‐fold greater risk‐adjusted odds of catastrophic financial burden (OR, 14.2; 95% CI, 5.1–39.5) compared with middle/high‐income families. Conclusions Patients with HF and their families experience large out‐of‐pocket healthcare expenses. A large proportion encounter financial toxicity, with a disproportionate effect on low‐income families.

Introduction Although both obesity and coronavirus disease 2019 (COVID-19) independently induce inflammation and thrombosis, the association between obesity class and risk of thrombosis in patients with COVID-19 remains unclear. Methods This retrospective cohort study included consecutive patients hospitalized with COVID-19 at a single institution. Patients were categorized based on obesity class. The main outcomes were venous thromboembolism (VTE) and myocardial injury, a marker of microvascular thrombosis in COVID-19. Adjustments were made for sociodemographic variables, cardiovascular disease risk factors and comorbidities. Results 609 patients with COVID-19 were included. 351 (58%) patients were without obesity, 110 (18%) were patients with class I obesity, 76 (12%) were patients with class II obesity, and 72 (12%) were patients with class III obesity. Patients with class I and III obesity had significantly higher risk-adjusted odds of VTE compared to patients without obesity (OR = 2.54, 95% CI: 1.05–6.14 for class I obesity; and OR = 3.95, 95% CI: 1.40–11.14 for class III obesity). Patients with class III obesity had significantly higher risk-adjusted odds of myocardial injury compared to patients without obesity (OR = 2.15, 95% CI: 1.12–4.12). Both VTE and myocardial injury were significantly associated with greater risk-adjusted odds of mortality. Conclusion This study demonstrates that both macrovascular and microvascular thromboses may contribute to the elevated morbidity and mortality in patients with obesity and COVID-19.

As the global community strives to discover effective therapies for COVID-19, immunomodulatory strategies have emerged as a leading contender to combat the cytokine storm and improve clinical outcomes in patients with severe disease. Systemic corticosteroids and selective cytokine inhibitory agents have been utilized both as empiric therapies and in clinical trials. While multiple randomized, placebo controlled trials have now demonstrated that corticosteroids improve survival in patients with COVID-19,1, 2 IL-6 inhibition, which gained significant early interest based on observational studies, has not demonstrated reliable efficacy in randomized, placebo controlled trials.3, 4 To better understand the mechanistic basis of immunomodulatory therapies being implemented for treatment of COVID-19, we assessed longitudinal biochemical changes in response to such approaches in hospitalized patients with COVID-19. We demonstrate broad suppression of multiple immunomodulatory factors associated with adverse clinical outcomes in COVID-19 in patients who received corticosteroids, but no such response was seen in patients who either received tocilizumab or no immunomodulatory therapy. Our findings provide early insights into molecular signatures that correlate with immunomodulatory therapies in COVID-19 which may be useful in understanding clinical outcomes in future studies of larger patient cohorts.

Introduction: Prior analyses suggest a link between food insecurity and cardiovascular (CV) health but are limited by cross-sectional designs. We investigated whether longitudinal changes in food insecurity are independently associated with CV mortality. Methods: Using National Center for Health Statistics data, we determined annual U.S. county-level age-adjusted CV mortality rates for non-elderly (20-64 years old) and elderly (65 years and older) adults. County-level food insecurity rates were obtained from the Map the Meal Gap project. We examined CV mortality trends by quartiles of average annual percent change (APC) in food insecurity. Using a Poisson fixed effects estimator, we assessed the association between longitudinal changes in food insecurity and CV mortality rates after accounting for time-varying demographic (proportion of residents who were male, black, Hispanic), economic (median household income, unemployment, poverty, education attainment, and housing vacancy rates), and healthcare access (insurance coverage, density of healthcare providers and hospital beds) variables. Results: Between 2011 and 2017, mean food insecurity rates decreased from 14.7% to 13.3%. In counties in the highest quartile of APC for absolute value change in food insecurity, non-elderly CV mortality increased from 82.2(SD=33.9) to 87.4(SD=37.3) per 100,000 individuals (p Conclusion: From 2011 to 2017, an increase in food insecurity was independently associated with an increase in CV mortality rates for non-elderly adults in the U.S. Interventions targeting food insecurity may play a role in improving community CV health.

Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW.

BACKGROUND. COVID-19 is a prothrombotic disease, characterized by endotheliopathy, hypercoagulability, and thromboembolic complications. We hypothesized that the pathogenesis of thromboembolism associated with COVID-19 might differ from thromboembolism in patients without COVID-19. In this study, we sought to evaluate the proteomic signatures of plasma from patients with venous thromboembolism with and without COVID-19. METHODS. Between December 17, 2020 and February 25, 2021 blood was collected from 48 hospitalized patients. Of these 24 had a confirmed diagnosis of COVID-19 infection (COVID+) and radiologic confirmation of arterial or venous thromboembolism (TE+); 17 had COVID-19 infection with absence of arterial thrombosis clinically and absence of venous thromboembolism on lower extremity Doppler ultrasound or chest CT angiography (COVID+/TE-), while 7 were arterial or venous thromboembolism in the absence of COVID-19 (COVID-/TE+). Blood was collected in sodium citrate tubes and centrifuged at 4000 rpm for 20 minutes, with resulting plasma supernatant used for protein profiling performed at Eve Technologies (Calgary, Alberta, Canada). Institutional Review Board approval was obtained for this study. Statistical analysis was performed using GraphPad Prism (v9.1, GraphPad Software, San Diego, CA) and R (v4, R Core Team). P values RESULTS. The median age was 63 years; overall 25 (52%) were men (13 [54%] among COVID+/TE+, 11 [65%] among COVID+/TE-, and 1 [14%] among COVID-/TE+). In COVID-19 patients who developed thromboembolic events, several proteins associated with inflammation, complement activation, and hemostasis were present at higher levels than in non-COVID-19 patients who developed thromboembolic events (Fig. 1). These included complement factors C2 and C5a, pentraxin-3 (PTX-3), lipocalin-2 (LCN2), resistin (RETN), platelet endothelial cell adhesion molecule-1 (Pecam1), serum amyloid A (SAA), and tissue factor (TF). The heatmap indicates relative protein levels detected in each subject (columns) for proteins (rows) that had statistically significant differences between groups (Fig. 2). Heatmap revealed relatively lower levels of all proteins in patients with thromboembolism without COVID-19 and relatively higher levels of proteins in patients with COVID-19, and especially in ICU patients with COVID-19 and thromboembolism. CONCLUSIONS. Thromboembolic complications in patients with COVID-19 are associated with increased levels of various proteins involved in complement activation and immunothrombotic cascades, compared to thrombotic events in the absence of COVID-19. Activation of the classical complement pathway as evidenced by a relative increase in complement factor C2 may lead to increased TF activation, reflecting more substantial endothelial damage in COVID-19 patients. Higher levels of Pecam1, SAA, LCN2, and RETN all point to increased endotheliopathy, inflammation, and tissue damage in COVID-19 compared to non-COVID-19 thrombosis. These findings may offer insights into novel therapeutic strategies to treat immunothrombotic complications of COVID-19. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Four non-vitamin K antagonist oral anticoagulants (NOACs) are approved for use to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). However, data are limited regarding the use of NOACs in the obese population. This manuscript summarizes current concepts regarding obesity in patients with AF and reviews in depth the data on the efficacy and safety of NOACs in obese patients with AF. The Pubmed database was searched for relevant articles. When evaluating obese patients with AF, weight loss is important to reduce disease burden. Recent analyses of the four NOAC versus warfarin trials (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48) stratified by body mass index (BMI) demonstrate preserved efficacy with NOACs versus warfarin in obese patients, with similar risk of major bleeding. Although the data are limited in class III obese patients (body mass index ≥40kg/m2), the efficacy and safety of apixaban or edoxaban appears to be similar to warfarin in patients with BMI 40-50kg/m2. In conclusion, these new data should be considered in updated guidelines, which currently provide limited, and sometimes conflicting recommendations regarding the use of NOACs in obese patients, particularly in severely obese patients.

Background: The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known. Methods and Results: We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome ( P P =0.005) signs, jugular venous distention (odds ratio, 0.60; P =0.01), and edema (odds ratio, 0.74; P =0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4–5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes. Conclusions: In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.

Introduction: There are a small number of reports in the literature describing bladder rupture during cystograms in children. We hypothesized that children undergoing cystograms may have their bladder overfilled during the test. We aimed to evaluate the current practice when performing cystograms in our institution, contrasting actual volume used to fill the bladder to the ageadjusted bladder capacity. Methods: We performed a retrospective review of all voiding cystourethrograms (VCUG) and radionuclide cystograms (RNC) performed at the Children’s Hospital of Eastern Ontario from 2006– 2013. Formulas used to estimate age-adjusted bladder capacity: 1) infants 1 year: capacity (mL) = (2 + age [years]) x 30 (Koff et al, 1983). Results: A total of 2411 cystograms were done (1387 VCUG; 1024 RNC) in 817 infants and 1594 children older than one year — 1113 boys and 1298 girls. Generally, bladders tended to be overfilled with 32% more volume in mL than the expected age-adjusted bladder capacity — VCUG 151 (122) mL vs. 120 (97) mL (p

Spontaneous closure of an atrial septal defect (ASD) is well described in pediatric cardiology but may be less familiar to adult internists and cardiologists. We report a moderately sized 6-mm ASD that closed spontaneously without intervention. A literature review found that a smaller defect size and an early age of diagnosis are the most important predictors of closure. Possible mechanisms of a spontaneous ASD closure include adaptive endothelial migration, limited myocardial proliferation, and fibroblast migration with extracellular matrix deposition.

Crosstalk occurs between dyslipidemia and chronic inflammation, which are both precipitants of atherosclerosis. Sterol regulatory element binding proteins cleavage-activating protein (SCAP) plays a key role in regulating cholesterol homeostasis. The present study investigated the effects of SCAP dysfunction on the expression of inflammatory cytokines and lipid metabolism in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assays. The expression of SCAP, HMGCR, pro-IL-1β and N-SREBP2, p65(N) in the nucleus were examined by real-time quantitative RT-PCR and Western blotting. The level of secretary proteins IL-1β, TNF-α and MCP-1 in the supernatants were determined by ELISA. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. Our results demonstrated that over-expression of SCAP significantly increased the expression of HMGCR, pro-IL-1β in the cytoplasm, and mature IL-1β, TNF-α, MCP-1 in the supernatants, while knocking down SCAP dramatically decreased the expression of these molecules. Betulin effectively suppressed the accumulation of intracellular cholesterol in the SCAP over-expressed THP-1 macrophages, but did not affect the expression of inflammatory cytokines, indicating that the pro-inflammatory effect of SCAP was independent of its routine role in regulating cholesterol homeostasis. Furthermore, we investigated the molecular mechanisms mediating the crosstalk between dyslipidemia and inflammatory responses. Knocking down SCAP attenuated LPS-induced IκB phosphorylation and reduced the nuclear level of p65, while over-expression of SCAP increased the nuclear level of p65. Knocking down p65 abolished the proinflammatory effect represented by elevated expression of the inflammatory mediators in the SCAP over-expressed THP-1 macrophages, suggesting that SCAP dysfunction stimulated inflammatory responses via activating the NF-κB signaling pathway. In conclusion, the cholesterol sensor SCAP plays a role in regulating the expression of inflammatory factors such as IL-1β, TNF-α, and MCP-1 in THP-1 macrophages. SCAP mediates the inflammatory response via activating the NF-κB pathway. This new function of SCAP is independent of its role in lipid metabolism.

Background: Recent studies have shown the efficacy for using spironolactone to treat heart failure with reduced ejection fraction (HFrEF), but the efficacy of spironolactone for heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) is unclear. This meta-analysis investigated the efficacy and safety of spironolactone in patients with HFmrEF and HFpEF. Methods and results: We searched several databases including PubMed and the Cochrane Collaboration, for randomized controlled trials (RCTs) that assessed spironolactone treatment in HFmrEF and HFpEF. Eleven RCTs including 4539 patients were included. Spironolactone reduced hospitalizations (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.73–0.95; P = .006), improved New York Heart Association functional classifications (NYHA-FC) (OR, 0.35; 95% CI, 0.19–0.66; P = .001), decreased the levels of brain natriuretic peptide (BNP) (mean difference [MD], − 44.80 pg/mL; 95% CI, −73.44–−16.17; P = .002), procollagen type I C-terminal propeptide (PICP) (MD, −27.04 ng/mL; 95% CI, −40.77–−13.32, P