The Aha! experience is associated with a drop in the perceived difficulty of the problem.

The study investigated the correlation between the intensity of the Aha! experience and participants' subjective difficulty ratings of problems before and after finding their solutions. We assumed that the Aha! experience arises from a shift in processing fluency triggered by changing from an initially incoherent problem representation to a coherent one, which ultimately leads to the retrieval of a solution with unexpected ease and speed. First, we hypothesized that higher Aha! experience ratings would indicate more sudden solutions, manifesting in a reduced correlation between the initial difficulty ratings and solution times. Second, we hypothesized that higher Aha! experience ratings would correspond to a greater shift in the subjective difficulty ratings between the initial and retrospective assessments. To test our hypotheses, we developed a novel set of rebus puzzles. A total of 160 participants solved rebuses and provided initial (within 5 s of problem presentation) and retrospective difficulty ratings (following the generation or presentation of a correct solution). They also rated their Aha! experience (after solution generation or presentation), confidence in solutions, and the likability of each rebus. Our findings revealed that the initial ratings of the problem's subjective difficulty were positively correlated with the solution time and that this correlation decreased in the case of a stronger Aha! experience. Aha! experience ratings were positively correlated with the differences between initial and retrospective difficulty ratings, confidence, solution accuracy, and rebus likability. We interpreted our results to be in line with the processing fluency and metacognitive prediction error accounts.

How Difficult Was It? Metacognitive Judgments About Problems and Their Solutions After the Aha Moment.

The insight phenomenon is thought to comprise two components: cognitive and affective (the Aha! experience). The exact nature of the Aha! experience remains unclear; however, several explanations have been put forward. Based on the processing fluency account, the source of the Aha! experience is a sudden increase in processing fluency, associated with emerging of a solution. We hypothesized that in a situation which the Aha! experience accompanies the solution in, the problem would be judged as less difficult, regardless of the objective difficulty. We also planned to confirm previously discovered associations between the Aha! experience and accuracy, confidence, and pleasure. To test the proposed hypothesis, during the preliminary stage of the study, we developed a set of 100 remote associate problems in Russian (RAT-RUS) and asked 125 participants to solve problems and indicate the Aha! moment (after solution generation or solution presentation), confidence, difficulty, and likability of each problem. As expected, the Aha! experience often accompanied correct solutions and correlated with confidence judgments. We also found a positive correlation between the Aha! experience and problem likability. As for the main hypothesis, we confirmed that the Aha! experience after the presentation of the solution was associated with a decrease in subjective difficulty. When participants could not solve a problem but experienced the Aha! moment after the solution was presented to them, the problem was perceived as easier than one without the Aha! experience. We didn't find the same effect for the Aha! after solution generation. Thus, our study partially supports the processing fluency account and demonstrates the association between the Aha! experience and metacognitive judgments about the accuracy and difficulty of problems.

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia.

In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.

LPDs - «Linked to penumbra¼ discharges or EEG correlate of excitotoxicity: A review based hypothesis.

Periodic lateralized epileptiform discharges (PLEDs) or lateralized periodic discharges (LPDs) are a well-known variant of pathological EEG activity. However, the mechanisms underpinning the appearance of this pattern are not completely understood. The heterogeneity of the features derived from LPDs patterns, and the wide range of pathological conditions in which they occur, raise a question about the unifying mechanisms underlying these phenomena. This paper reassesses the current opinion surrounding LPDs which considers glutamate excitotoxicity to be the primary pathophysiological basis, and the penumbral region to be the main morphological substrate. Arguments in favour of this hypothesis are presented, with interpretations supported by evidence from recent literature involving clinical and experimental data. Presently, no single hypothesis places considerable emphasis on the pathochemical properties of LPDs, which are implicitly meaningful towards better understanding of the clinical significance of this pattern.

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development.