Few reports have examined the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) or their relationship with mortality in patients with heart failure with mildly reduced ...ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF).
Data from the PARAGON-HF, TOPCAT, I-Preserve, and CHARM-Preserved trials were merged. VT/VF, reported as adverse events, were identified. Patients who experienced VT/VF were compared with patients who did not. The relationship between VT/VF and mortality was examined in time-updated Cox proportional hazard regression models. Variables associated with VT/VF were examined in Cox proportional hazard regression models. The rate of VT/VF in patients with HFmrEF compared with patients with HFpEF was examined in a Cox proportional hazards regression model. Of 13 609 patients, over a median follow-up of 1170 days (interquartile range: 966-1451), 146 (1.1%) experienced an investigator-reported VT/VF (incidence rate 0.3 per 100 person-years). Patients who experienced VT/VF were more likely to be male, have had a myocardial infarction, poorer renal function, more adverse left ventricular remodelling, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) than patients who did not. Occurrence of VT/VF was associated with NT-proBNP, history of atrial fibrillation/flutter, male sex, lower ejection fraction, and history of hypertension. VT/VF was associated with all-cause death adjusted hazard ratio (HR): 3.95, 95% confidence interval (CI): 2.80-5.57; P < 0.001 and cardiovascular death, driven by death from heart failure and not sudden death. Patients with HFmrEF had a higher rate of VT/VF than patients with HFpEF (adjusted HR: 2.19, 95% CI: 1.77-2.71).
VT/VF was uncommon in patients with HFmrEF and HFpEF. However, such events were strongly associated with mortality and appear to be a marker of disease severity rather than risk of sudden death.
ClinicalTrials.gov unique identifier: NCT01920711(PARAGON-HF); NCT00094302 (TOPCAT); NCT00095238 (I-Preserve); NCT00634712 (CHARM-Preserved).
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ...ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairments in social, educational, and occupational functioning, as well as specific strengths. Currently, there is no ...internationally accepted standard to assess the functioning of individuals with ADHD. WHO’s International Classification of Functioning, Disability and Health—child and youth version (ICF) can serve as a conceptual basis for such a standard. The objective of this study is to develop a comprehensive, a common brief, and three age-appropriate brief ICF Core Sets for ADHD. Using a standardised methodology, four international preparatory studies generated 132 second-level ICF candidate categories that served as the basis for developing ADHD Core Sets. Using these categories and following an iterative consensus process, 20 ADHD experts from nine professional disciplines and representing all six WHO regions selected the most relevant categories to constitute the ADHD Core Sets. The consensus process resulted in 72 second-level ICF categories forming the comprehensive ICF Core Set—these represented 8 body functions, 35 activities and participation, and 29 environmental categories. A Common Brief Core Set that included 38 categories was also defined. Age-specific brief Core Sets included a 47 category preschool version for 0–5 years old, a 55 category school-age version for 6–16 years old, and a 52 category version for older adolescents and adults 17 years old and above. The ICF Core Sets for ADHD mark a milestone toward an internationally standardised functional assessment of ADHD across the lifespan, and across educational, administrative, clinical, and research settings.
Aims
Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time‐point. We investigated independent predictors of SCD addressing the impact of integrating ...time‐varying covariates to improve prediction assessment.
Methods and results
We studied 8399 patients enrolled in the PARADIGM‐HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time‐updated multivariable‐adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non‐sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (Pinteraction < 0.001). In multivariable models adjusted for baseline covariates, seven time‐updated variables independently contributed to SCD risk (incremental likelihood chi‐square = 46.2). CART analysis identified that baseline variables (implantable cardioverter‐defibrillator use and N‐terminal prohormone of B‐type natriuretic peptide levels) and time‐updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART‐defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6–16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non‐sudden cardiovascular deaths (P < 0.05).
Conclusions
Beyond single time‐point assessments, distinct changes in multiple cardiac‐specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.
Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death (SCD) in heart failure with reduced ejection fraction (HFrEF): a PARADIGM‐HF analysis.
The cardiovascular safety from azithromycin in the treatment of several infectious diseases has been challenged. In this prespecified pooled analysis of 2 multicenter randomized clinical trials, we ...aimed to assess whether the use of azithromycin might lead to corrected QT (QTc) interval prolongation or clinically relevant ventricular arrhythmias. In the COALITION COVID Brazil I trial, 667 patients admitted with moderate COVID-19 were randomly allocated to hydroxychloroquine, hydroxychloroquine plus azithromycin, or standard of care. In the COALITION COVID Brazil II trial, 447 patients with severe COVID-19 were randomly allocated to hydroxychloroquine alone versus hydroxychloroquine plus azithromycin. The principal end point for the present analysis was the composite of death, resuscitated cardiac arrest, or ventricular arrhythmias. The addition of azithromycin to hydroxychloroquine did not result in any prolongation of the QTc interval (425.8 ± 3.6 ms vs 427.9 ± 3.9 ms, respectively, mean difference −2.1 ms, 95% confidence interval −12.5 to 8.4 ms, p = 0.70). The combination of azithromycin plus hydroxychloroquine compared with hydroxychloroquine alone did not result in increased risk of the primary end point (proportion of patients with events at 15 days 17.2% vs 16.0%, respectively, hazard ratio 1.08, 95% confidence interval 0.78 to 1.49, p = 0.65). In conclusion, in patients hospitalized with COVID-19 already receiving standard-of-care management (including hydroxychloroquine), the addition of azithromycin did not result in the prolongation of the QTc interval or increase in cardiovascular adverse events. Because azithromycin is among the most commonly prescribed antimicrobial agents, our results may inform clinical practice. Clinical Trial Registration: NCT04322123, NCT04321278.
Background
Irritability, a frequent complaint in children with psychiatric disorders, reflects increased predisposition to anger. Preliminary work in pediatric clinical samples links irritability to ...attention bias to threat, and the current study examines this association in a large population‐based sample.
Methods
We studied 1,872 children (ages 6–14) using the Development and Well‐Being Assessment (DAWBA), Childhood Behavior Checklist (CBCL), and dot‐probe tasks. Irritability was defined using CBCL items that assessed temper tantrums and hot temper. The dot‐probe task assessed attention biases for threat‐related (angry face) stimuli. Multiple regression analysis was used to assess specificity of associations to irritability when adjusting for demographic variables and co‐occurring psychiatric traits. Propensity score matching analysis was used to increase causal inference when matching for demographic variables and co‐occurring psychiatric traits.
Results
Irritability was associated with increased attention bias toward threat‐related cues. Multiple regression analysis suggests associations between irritability and threat bias are independent from demographic variables, anxiety, and externalizing traits (attention‐deficit/hyperactivity, conduct, and headstrong/hurtful), but not from broad internalizing symptoms. Propensity score matching analysis indicated that this association was found for irritable versus nonirritable groups matched on demographic and co‐occurring traits including internalizing symptoms.
Conclusions
Irritability in children is associated with biased attention toward threatening information. This finding, if replicated, warrants further investigation to examine the extent to which it contributes to chronic irritability and to explore possible treatment implications.
To explore and validate the best returned latent class solution for reading and writing subtests from the Academic Performance Test (TDE).
A total of 1,945 children (6-14 years of age), who answered ...the TDE, the Development and Well-Being Assessment (DAWBA), and had an estimated intelligence quotient (IQ) higher than 70, came from public schools in São Paulo (35 schools) and Porto Alegre (22 schools) that participated in the 'High Risk Cohort Study for Childhood Psychiatric Disorders' project. They were on average 9.52 years old (standard deviation = 1.856), from the 1st to 9th grades, and 53.3% male. The mean estimated IQ was 102.70 (standard deviation = 16.44).
Via Item Response Theory (IRT), the highest discriminating items ('a'>1.7) were selected from the TDE subtests of reading and writing. A latent class analysis was run based on these subtests. The statistically and empirically best latent class solutions were validated through concurrent (IQ and combined attention deficit hyperactivity disorder ADHD diagnoses) and discriminant (major depression diagnoses) measures.
A three-class solution was found to be the best model solution, revealing classes of children with good, not-so-good, or poor performance on TDE reading and writing tasks. The three-class solution has been shown to be correlated with estimated IQ and to ADHD diagnosis. No association was observed between the latent class and major depression.
The three-class solution showed both concurrent and discriminant validity. This work provides initial evidence of validity for an empirically derived categorical classification of reading, decoding, and writing performance using the TDE. A valid classification encourages further research investing correlates of reading and writing performance using the TDE.
Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non‐genetic factors. ...Phenprocoumon metabolism is mediated by CYP2C9 and CYP3A enzymes. Moreover, VKORC1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP3A4 and CYP3A5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of European ancestry, were investigated. Genotypes were determined by allelic discrimination with TaqMan assays. Polymorphisms −1639G>A and 1173C>T in VKORC1 and the presence of CYP2C9*2 and/or CYP2C9*3 are associated with lower doses. On the other hand, 3730G>A in VKORC1 gene is associated with higher doses. No association was found between CYP3A4*1B, CYP3A5*3 and CYP3A5*6 polymorphisms. Among non‐genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and β‐blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm.
The objectives of this study were to prospectively assess the rectal carriage rate of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) in non-ICU patients on hospital admission ...and to investigate resistance mechanisms and risk factors for carriage.
Adult patients were screened for 3GCREB carriage at six German tertiary care hospitals in 2014 using rectal swabs or stool samples. 3GCREB isolates were characterized by phenotypic and molecular methods. Each patient answered a questionnaire about potential risk factors for colonization with MDR organisms (MDROs). Univariable and multivariable risk factor analyses were performed to identify factors associated with 3GCREB carriage.
Of 4376 patients, 416 (9.5%) were 3GCREB carriers. Escherichia coli was the predominant species (79.1%). ESBLs of the CTX-M-1 group (67.3%) and the CTX-M-9 group (16.8%) were the most frequent β-lactamases. Five patients (0.11%) were colonized with carbapenemase-producing Enterobacteriaceae. The following risk factors were significantly associated with 3GCREB colonization in the multivariable analysis (P < 0.05): centre; previous MDRO colonization (OR = 2.12); antibiotic use within the previous 6 months (OR = 2.09); travel outside Europe (OR = 2.24); stay in a long-term care facility (OR = 1.33); and treatment of gastroesophageal reflux disease (GERD) (OR = 1.22).
To our knowledge, this is the largest admission prevalence study of 3GCREB in Europe. The observed prevalence of 9.5% 3GCREB carriage was higher than previously reported and differed significantly among centres. In addition to previously identified risk factors, the treatment of GERD proved to be an independent risk factor for 3GCREB colonization.
Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) ...dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.
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