Influence of anticardiolipin and anti-β2 glycoprotein I antibody cutoff values on antiphospholipid syndrome classification

Background: Anticardiolipin (aCL) and anti-beta 2 glycoprotein I (a beta 2GPI) immunoglobulin (Ig) G/IgM antibodies are 2 of the 3 laboratory criteria for classification of antiphospholipid syndrome (APS). The threshold for clinically relevant levels of antiphospholipid antibodies (aPL) for the diagnosis of APS remains a matter of debate. The aim of this study was to evaluate the variation in cutoffs as determined in different clinical laboratories based on the results of a questionnaire as well as to determine the optimal method for cutoff establishment based on a clinical approach.Methods: The study included samples from 114 patients with thrombotic APS, 138 patients with non-APS thrombosis, 138 patients with autoimmune disease, and 183 healthy controls. aCL and a beta 2GPI IgG/IgM antibodies were measured at 1 laboratory using 4 commercial assays. Assay-specific cutoff values for aPL were obtained by determining 95th and 99th percentiles of 120 compared to 200 normal controls by different statistical methods.Results: Normal reference value data showed a nonparametric distribution. Higher cutoff values were found when calculated as 99th rather than 95th percentiles. These values also showed a stronger association with thrombosis. The use of 99th percentile cutoffs reduced the chance of false positivity but at the same time reduced sensitivity. The decrease in sensitivity was higher than the gain in specificity when 99th percentiles were calculated by methods wherein no outliers were eliminated.Conclusions: We present cutoff values for aPL determined by different statistical methods. The 99th percentile cutoff value seemed more specific. However, our findings indicate the need for standardized statistical criteria to calculate 99th percentile cutoff reference values.Background: Anticardiolipin (aCL) and anti-beta 2 glycoprotein I (a beta 2GPI) immunoglobulin (Ig) G/IgM antibodies are 2 of the 3 laboratory criteria for classification of antiphospholipid syndrome (APS). The threshold for clinically relevant levels of antiphospholipid antibodies (aPL) for the diagnosis of APS remains a matter of debate. The aim of this study was to evaluate the variation in cutoffs as determined in different clinical laboratories based on the results of a questionnaire as well as to determine the optimal method for cutoff establishment based on a clinical approach.Methods: The study included samples from 114 patients with thrombotic APS, 138 patients with non-APS thrombosis, 138 patients with autoimmune disease, and 183 healthy controls. aCL and a beta 2GPI IgG/IgM antibodies were measured at 1 laboratory using 4 commercial assays. Assay-specific cutoff values for aPL were obtained by determining 95th and 99th percentiles of 120 compared to 200 normal controls by different statistical methods.Results: Normal reference value data showed a nonparametric distribution. Higher cutoff values were found when calculated as 99th rather than 95th percentiles. These values also showed a stronger association with thrombosis. The use of 99th percentile cutoffs reduced the chance of false positivity but at the same time reduced sensitivity. The decrease in sensitivity was higher than the gain in specificity when 99th percentiles were calculated by methods wherein no outliers were eliminated.Conclusions: We present cutoff values for aPL determined by different statistical methods. The 99th percentile cutoff value seemed more specific. However, our findings indicate the need for standardized statistical criteria to calculate 99th percentile cutoff reference values.A

Recommendations for enterovirus diagnostics and characterisation within and beyond Europe.

Enteroviruses (EV) can cause severe neurological and respiratory infections, and occasionally lead to devastating outbreaks as previously demonstrated with EV-A71 and EV-D68 in Europe. However, these infections are still often underdiagnosed and EV typing data is not currently collected at European level. In order to improve EV diagnostics, collate data on severe EV infections and monitor the circulation of EV types, we have established European non-polio enterovirus network (ENPEN). First task of this cross-border network has been to ensure prompt and adequate diagnosis of these infections in Europe, and hence we present recommendations for non-polio EV detection and typing based on the consensus view of this multidisciplinary team including experts from over 20 European countries. We recommend that respiratory and stool samples in addition to cerebrospinal fluid (CSF) and blood samples are submitted for EV testing from patients with suspected neurological infections. This is vital since viruses like EV-D68 are rarely detectable in CSF or stool samples. Furthermore, reverse transcriptase PCR (RT-PCR) targeting the 5'noncoding regions (5'NCR) should be used for diagnosis of EVs due to their sensitivity, specificity and short turnaround time. Sequencing of the VP1 capsid protein gene is recommended for EV typing; EV typing cannot be based on the 5'NCR sequences due to frequent recombination events and should not rely on virus isolation. Effective and standardized laboratory diagnostics and characterisation of circulating virus strains are the first step towards effective and continuous surveillance activities, which in turn will be used to provide better estimation on EV disease burden

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

How to solve the underestimated problem of overestimated sodium results in the hypoproteinemic patient

Objectives: The availability of a fast and reliable sodium result is a prerequisite for the appropriate correction of a patient's fluid balance. Blood gas analyzers and core laboratory chemistry analyzers measure electrolytes via different ion-selective electrode methodology, that is, direct and indirect ion-selective electrodes, respectively. Sodium concentrations obtained via both methods are not always concordant. A comparison of results between both methods was performed, and the impact of the total protein concentration on the sodium concentration was investigated. Furthermore, we sought to develop an adjustment equation to correct between both ion-selective electrode methods. Design: A model was developed using a pilot study cohort (n = 290) and a retrospective patient cohort (n = 690), which was validated using a prospective patient cohort (4,006 samples). Setting: ICU and emergency department at Ghent University Hospital. Patients: Patient selection was based on the concurrent availability of routine blood gas Na-direct(+) as well as core laboratory Na-indirect(+) results. Interventions: In the pilot study, left-over blood gas syringes were collected for further laboratory analysis. Measurement and Main Results: There was a significant negative linear correlation between Na-indirect(+) and Na-direct(+) relative to changes in total protein concentration (Pearson r = -0.69; p < 0.0001). In our setting, for each change of 10 g/L in total protein concentration, a deviation of similar to 1.3 mmol/L is observed with the Na-indirect(+) result. Validity of our adjustment equation protein-corrected Na-indirect(+) = Na-indirect(+) - 10.53 + (0.1316 x total protein) was demonstrated on a prospective patient cohort. Conclusions: As Na-direct(+) measurements on a blood gas analyzer are not influenced by the total protein concentration in the sample, they should be preferentially used in patients with abnormal protein concentrations. However, as blood gas analyzers are not available at all clinical wards, the implementation of a protein-corrected sodium result might provide an acceptable alternative

Test-retest reliability of left and right ventricular systolic function by new and conventional echocardiographic and cardiac magnetic resonance parameters.

Reproducible evaluation of left (LV) and right ventricular (RV) function is crucial for clinical decision-making and risk stratification. We evaluated whether speckle-tracking echocardiography (STE) and cardiac magnetic resonance feature-tracking (cMR-FT) global longitudinal (GLS) and circumferential strains allow better test-retest reproducibility of LV and RV systolic function than conventional cMR and echocardiographic parameters. Thirty healthy volunteers and 20 chronic heart failure patients underwent cMR and STE twice on separate days to evaluate test-retest coefficient of variation (CV), intraclass correlation coefficient (ICC) and estimated sample sizes for significant changes in LV and RV function. Among LV parameters, cMR-left ventricular ejection fraction (LVEF) had the highest reproducibility (CV = 6.7%, ICC = 0.98), significantly better than cMR-FT-GLS (CV = 15.1%, ICC = 0.84), global circumferential strains (CV = 11.5%, ICC = 0.94) and echocardiographic LVEF (CV = 11.3%, ICC = 0.93). STE-LV-GLS (CV = 8.9%, ICC = 0.94) had significantly better reproducibility than cMR-FT-LV-GLS. Among RV parameters, STE-RV-GLS (CV = 7.3%, ICC = 0.93) had significantly better CV than cMR-right ventricular ejection fraction (RVEF) (CV = 13%, ICC = 0.82). cMR-FT-RV-GLS (CV = 43%, ICC = 0.39) performed poorly with significantly lower reproducibility than all other RV parameters. Owing to their superior interstudy reproducibility, cMR-LVEF (n = 12), cMR-RVEF (n = 41), STE-LV-GLS and STE-RV-GLS (both n = 14) were the parameters allowing the lowest calculated sample sizes to detect 10% change in LV or RV systolic function. STE-LV-GLS and STE-RV-GLS showed higher test-retest reliability than other echocardiographic measurements of LV and RV function. They also allowed smaller calculated sample sizes, supporting the use of STE-LV and RV-GLS for longitudinal follow-up of LV and RV function

Prognostic Value of Pulmonary Transit Time by Cardiac Magnetic Resonance on Mortality and Heart Failure Hospitalization in Patients With Advanced Heart Failure and Reduced Ejection Fraction.

Background Pulmonary transit time (PTT) from first-pass perfusion imaging is a novel parameter to evaluate hemodynamic congestion by cardiac magnetic resonance (cMR). We sought to evaluate the additional prognostic value of PTT in heart failure with reduced ejection fraction over other well-validated predictors of risk including the Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. Methods We prospectively followed 410 patients with chronic heart failure with reduced ejection fraction (61±13 years, left ventricular (LV) ejection fraction 24±7%) who underwent a clinical cMR to assess the prognostic value of PTT for a primary endpoint of overall mortality and secondary composite endpoint of cardiovascular death and heart failure hospitalization. Normal reference values of PTT were evaluated in a population of 40 asymptomatic volunteers free of cardiovascular disease. Results PTT was significantly increased in patients with heart failure with reduced ejection fraction as compared to controls (9±6 beats and 7±2 beats, respectively, <0.001), and correlated not only with New York Heart Association class, cMR-LV and cMR-right ventricular (RV) volumes, cMR-RV and cMR-LV ejection fraction, and feature tracking global longitudinal strain, but also with cardiac output. Over 6-year median follow-up, 182 patients died and 200 reached the secondary endpoint. By multivariate Cox analysis, PTT was an independent and significant predictor of both endpoints after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. Importantly in multivariable analysis, PTT in beats had significantly higher additional prognostic value to predict not only overall mortality (χ to improve, 12.3; hazard ratio, 1.35 [95% CI, 1.16-1.58]; <0.001) but also the secondary composite endpoints (χ to improve=20.1; hazard ratio, 1.23 [95% CI, 1.21-1.60]; <0.001) than cMR-LV ejection fraction, cMR-RV ejection fraction, LV-feature tracking global longitudinal strain, or RV-feature tracking global longitudinal strain. Importantly, PTT was independent and complementary to both pulmonary artery pressure and reduced RV ejection fraction<42% to predict overall mortality and secondary combined endpoints. Conclusions Despite limitations in temporal resolution, PTT derived from first-pass perfusion imaging provides higher and independent prognostic information in heart failure with reduced ejection fraction than clinical and other cMR parameters, including LV and RV ejection fraction or feature tracking global longitudinal strain. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03969394

Validation of Semiautomated Quantification of Mitral Valve Regurgitation by Three-Dimensional Color Doppler Transesophageal Echocardiography

Background: The aim of this study was to evaluate the accuracy of mitral regurgitation (MR) volume quantified on three-dimensional (3D) color Doppler transesophageal echocardiography (TEE) using new semiautomated software compared with conventional two-dimensional (2D) proximal isovelocity surface area (PISA) transthoracic echocardiography (TTE) and TEE and cardiac magnetic resonance imaging (CMR). Methods: Fifty-one patients (mean age, 63 ± 16 years; 35 men) prospectively underwent TTE, TEE, and CMR for MR evaluation. Regurgitant volume (RVol) by 3D MR flow quantification was compared with 2D TTE, TEE, and CMR, and the accuracy of evaluation of severe MR by 3D MR flow quantification was compared against guideline criteria by TEE. Results: Twenty-nine patients had severe MR, 16 had moderate MR, and six had mild MR. Three-dimensional MR flow quantification was feasible in all patients, including prolapse (n = 37), restriction (n = 9), functional MR (n = 5), and eccentric or multiple jects (n = 41). RVol on 3D MR flow quantification correlated well with RVol on 2D PISA TTE (interclass correlation coefficient [ICC] = 0.75, P < .001), quantitatively estimated RVol (ICC = 0.74, P < .001), and 2D PISA TEE (ICC = 0.79, P < .001). Three-dimensional MR flow quantification agreed better with CMR (ICC = 0.86, P < .001) than did RVol on 2D PISA TTE (ICC = 0.66, P < .001) and 2D PISA TEE (ICC = 0.69, P < .001), with narrower limits of agreement on Bland-Altman analysis. Three-dimensional MR flow quantification had high accuracy for diagnosing severe MR using TEE (area under the curve = 0.85, 95% CI 0.74-0.96, P < .001) or CMR (area under the curve = 0.95; 95% CI, 0.89–1.00; P < .001) as the criterion. Conclusions: The new software enabled semiautomated 3D MR flow quantification in complex MR with multiple and eccentric jets and showed better agreement with CMR than 2D PISA TTE or TEE, suggesting that this method is more accurate than conventional 2D PISA TTE and TEE. © 2019 American Society of Echocardiograph

Additional Prognostic Value of 2D Right Ventricular Speckle-Tracking Strain for Prediction of Survival in Heart Failure and Reduced Ejection Fraction: A Comparative Study With Cardiac Magnetic Resonance.

OBJECTIVES: This study sought to compare the prognostic value of 2-dimensional (2D) right ventricular (RV) speckle tracking (STE) against cardiac magnetic resonance (CMR) RV ejection fraction (EF) and feature tracking (FT) and conventional echocardiographic parameters on overall and cardiovascular (CV) survival in patients with heart failure with reduced EF (HFrEF). BACKGROUND: Prior works showed that RV systolic function predicts prognosis in HFrEF. 2D RVSTE had recently been proposed as new echocardiographic method to evaluate RV dysfunction. METHODS: A total of 266 patients with HFrEF (mean LVEF 23 ± 7%, 60 ± 14 years of age; 29% women) underwent RV function assessment using CMR and 2D echocardiography and were followed for a primary endpoint of overall death and secondary endpoint of CV death. RESULTS: Average CMR-RVEF was 42 ± 15%, average STE RV global longitudinal strain (STE-RVGLS) was -18.0 ± 4.9%, and average CMR-FT-RVGLS was -11.8 ± 4.3%. After a median follow-up of 4.7 years, 102 patients died, 84 of a CV cause. RVEF, FT-RVGLS, tricuspid annulus plane systolic excursion (TAPSE), fractional area change (FAC), and STE-RVGLS were significant univariate predictors of overall and cardiac death. In multivariate Cox regression, age, ischemic etiology, diabetes, New York Heart Association functional class III to IV, and beta-blocker treatment were independent clinical predictors of overall mortality. CMR-RVEF (chi-square to enter = 3.9; p 15 mm, 1.6 (95% CI: 1.02 to 2.49) for FAC >39%, 1.93 (95% CI: 1.25 to 2.99) for RVEF >41%, and 1.87 (95% CI: 1.10 to 3.19) for CMR-FT-RVGLS <-15%. CONCLUSIONS: 2D RVGLS provides strong additional prognostic value to predict overall and CV mortality in HFrEF, with higher predictive value than CMR-RVEF, CMR-FT-RVGLS, TAPSE, or FAC. This supports use of STE-RVGLS to identify higher-risk HFrEF patients

Sodium-myoinositol cotransporter-1, SMIT1, mediates the production of reactive oxygen species induced by hyperglycemia in the heart

Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy