From developmental theory to effective training: long-term and transfer effects of promoting the quantity–to–number word linkage in first-graders at risk for mathematical difficulties

IntroductionThe model of quantity–to–number word linkage (QNL model) identifies relevant milestones in the process of early numerical acquisition and describes a developmental sequence that can guide the fostering of foundational mathematical abilities in at-risk children. While there is substantial evidence for the predictive value of the quantity-number competencies (QNC) described by the model, evidence supporting the preventive potential of interventions targeting these QNC is so far largely restricted to short-term effects. Findings regarding their long-term preventive impact, especially in terms of transfer to mathematical school achievement, are still limited. This quasi-experimental study aimed to address this gap by evaluating the long-term transfer effects of an intervention program that is strictly derived from the QNL model of mathematical development [QNL training; in German “Mengen, zählen, Zahlen” (MZZ)].MethodsWe assessed the quantity-number competencies of 575 first-graders and identified 119 of them as being at risk for mathematical learning difficulties, who were then assigned to three experimental conditions. Sixty one children received 12 sessions of the QNL training, while 30 underwent training in inductive reasoning. Another 28 children served as a control group, receiving no specific intervention.Results and DiscussionMulti-level analyses confirmed both significant short-and long-term effects in the specifically trained quantity–number competencies as well as transfer effects on subsequent mathematical school achievement. In accordance with previous findings, transfer effects of the QNL training on mathematical school achievement were not yet evident immediately after the intervention but turned out to be significant after a delay of 6 months and remained stable even 15 months after training. Effect sizes ranged from d = 0.32 to d = 1.12. These findings both underscore the preventive potential of interventions that are strictly driven by developmental theory and, conversely, support the theoretical assumptions of the QNL model

Bitcoin

El presente trabajo de investigación funda su importancia en el análisis de la utilidad y facilidades que permite una nueva moneda digital. Dicha moneda se encuentra en etapa de auge, ya que cada día cuenta con más usuarios o poseedores de la misma; esto conforma una amplia red que va creciendo día a día. La amplitud de dicha red genera que la moneda sea cada día más aceptada y que una alternativa de pago respecto al papel moneda. Cabe mencionar que dicha moneda no sólo posee características que la hacen utilizable desde el punto de vista de las transacciones, sino que toma un segundo plano frente a su utilidad para todo tipo de inversiones la cual aumenta su significatividad constantemente. Principales conceptos teóricos: Bitcoin es la más reciente tecnología digital que viene a ser presentada como una moneda. Es un invento que viene a aprovechar las posibilidades que existen en la era digital para solucionar distintos inconvenientes de la humanidad, como son el transporte de valor económico en el tiempo y en el espacio. La moneda, para ser considerada como tal, debe poseer las siguientes funciones: • MEDIDA DE VALOR. Ya que el valor de las cosas puede ser representado por medio de las unidades que ella representa. • INSTRUMENTO DE ADQUISICIÓN DIRECTA. Puesto que permite adquirir cualquier bien en función de su valor. • INSTRUMENTO DE LIBERACIÓN DE DEUDAS. Debido a que tiene una fuerza cancelatoria de las mismas al constituirse en un medio de pago reconocido legalmente. • MEDIO DE ATESORAMIENTO DE RIQUEZA. Se puede atesorar para necesidades futuras debido a que conserva indefinidamente su valor. Para ser considerado medio de pago, un instrumento debe poseer las siguientes características: • El gran valor que representa con relación a su peso y volumen. • Reconocimiento unánime como medio de pago, que impide juzgar acerca de su calidad. • Su divisibilidad, que permite fraccionar su valor en forma ilimitada. • La dificultad en su falsificación, que impide la circulación de un medio de pago que no se encuentra debidamente controlado, ya que en cada país se aprueba sólo una moneda a la vez. Metodología: Se tuvo en cuenta un enfoque cuantitativo, en donde se plantea un problema de estudio delimitado y concreto. Se revisó la literatura y se constituyó un marco teórico, elaborando la hipótesis y sometiéndola a prueba.Fil: Cacciavillani Magni, Fabrizio Damián. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Casas Sinner, Federico Daniel. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Robledo, Emiliano Nicolás. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Ruiz, Isaías Daniel. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas

Simulation of FRET dyes allows quantitative comparison against experimental data

Fully understanding biomolecular function requires detailed insight into the systems’ structural dynamics. Powerful experimental techniques such as single molecule Förster Resonance Energy Transfer (FRET) provide access to such dynamic information yet have to be carefully interpreted. Molecular simulations can complement these experiments but typically face limits in accessing slow time scales and large or unstructured systems. Here, we introduce a coarse-grained simulation technique that tackles these challenges. While requiring only few parameters, we maintain full protein flexibility and include all heavy atoms of proteins, linkers, and dyes. We are able to sufficiently reduce computational demands to simulate large or heterogeneous structural dynamics and ensembles on slow time scales found in, e.g., protein folding. The simulations allow for calculating FRET efficiencies which quantitatively agree with experimentally determined values. By providing atomically resolved trajectories, this work supports the planning and microscopic interpretation of experiments. Overall, these results highlight how simulations and experiments can complement each other leading to new insights into biomolecular dynamics and function

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

BACKGROUND & AIMS: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. METHODS: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. RESULTS: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. CONCLUSIONS: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. IMPACT AND IMPLICATIONS: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy