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Digital skills : unlocking the information society
\"Digital Skills systematically discusses the skills or literacies needed in the use of digital media, primarily computers and the Internet. Following the work of van Dijk's, The Deepening Divide: Inequality in the Information Society, it uses conceptual analysis and empirical observations to show what digital skills are, how they are distributed, how skill inequalities develop, and how these inequalities can be remedied by designers, educators, policymakers, and different types of Internet users\"-- Provided by publisher.
Book
Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial
Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year.
The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A–B] vs seizure recurrence [Engel 1C–4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673.
Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference –23·5%, 90% CI –39·1 to –7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was –25·5%, –45·1 to –6·0, and for the 30 patients with extratemporal lobe epilepsy it was –20·3%, –46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of –7·9% (90% CI –20·7 to 4·9; adjusted risk difference –12·5%, –31·0 to 5·9, for temporal lobe epilepsy and 5·8%, –7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died.
HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy.
UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.
Journal Article
ضد الانتخابات : دفاعا عن الديمقراطية
يثير هذا الكتاب تساؤلات عدة عن ماهية الديمقراطية وإن كانت الإنتخابات وسيلة حقيقية لتحقيق الديمقراطية بالفعل فى العالم بأكمله أم لا ومن بينها تأتى الديكتاتورية دائما عن طريق الانتخابات مثل هتلر وستالين فهل الإنتخابات تؤدي دائما إلى الديمقراطية أم لا ويناقش الكاتب فكرة أن هناك شيئا غير مألوف يرتبط بالديمقراطية دائما فالكل يأمل فى تحقيق الديمقراطية بشكل حقيقي وفى الوقت نفسه لا يؤمن بها أحد على الإطلاق حتى لو أشارت الإحصائيات العالمية إلى أن الغالبية العظمى من الناس يفضلون تحقيق الديمقراطية.
BOOK
Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia
Response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). However, the large MRD-based medium risk group (MRD-M; 50–60% of the patients) harbors many relapses. We analyzed MRD in 131 uniformly treated precursor-B-ALL patients and evaluated whether combined MRD and
IKZF1
(Ikaros zinc finger-1) alteration status can improve risk stratification. We confirmed the strong prognostic significance of MRD classification, which was independent of
IKZF1
alterations. Notably, 8 of the 11 relapsed cases in the large MRD-M group (
n
=81; 62%) harbored an
IKZF1
alteration. Integration of both MRD and
IKZF1
status resulted in a favorable outcome group (
n
=104; 5 relapses) and a poor outcome group (
n
=27; 19 relapses), and showed a stronger prognostic value than each of the established risk factors alone (hazard ratio (95%CI): 24.98 (8.29–75.31)). Importantly, whereas MRD and
IKZF1
status alone identified only 46 and 54% of the relapses, respectively, their integrated use allowed prediction of 79% of all the relapses with 93% specificity. Because of the unprecedented sensitivity in upfront relapse prediction, the combined parameters have high potential for future risk stratification, particularly for patients originally classified as non-high risk, such as the large group of MRD-M patients.
Journal Article
Uh-Oh Octopus!
When a small octopus arrives home one day to find an intruder barricading his entrance, he asks other sea creatures for advice on what to do about the situation.
Book
Prime editing for functional repair in patient-derived disease models
Prime editing is a recent genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority of genetic defects. Here, we develop prime editing for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions in the gene encoding β‐catenin (
CTNNB1
) that result in proliferation independent of Wnt-stimuli, mimicking a mechanism of the development of liver cancer. Moreover, prime editing functionally recovers disease-causing mutations in intestinal organoids from patients with DGAT1-deficiency and liver organoids from a patient with Wilson disease (
ATP7B
). Prime editing is as efficient in 3D grown organoids as in 2D grown cell lines and offers greater precision than Cas9-mediated homology directed repair (HDR). Base editing remains more reliable than prime editing but is restricted to a subgroup of pathogenic mutations. Whole-genome sequencing of four prime-edited clonal organoid lines reveals absence of genome-wide off-target effects underscoring therapeutic potential of this versatile and precise gene editing strategy.
Prime editing uses Cas9 nickase fused to a reverse transcriptase to edit genetic information. Here, the authors prime edit primary adult stem cells in 3D organoid cultures to show functional correction of pathogenic mutations without genome-wide off-target effects.
Journal Article
الأرنب ريكي
يتناول الكتاب ثلاثة قصص متعة للنظر وبديعة الصور ومخصصة للأطفال في مرحلة ما قبل الإبتدائية ويفرحون إذا فرح ريكي ويحزنون إذا حزن ريكي ويكتشفون معان مختلفة للحياة ومع كل مغامرة لغز وأسرار والقصة الأولى \"الأرنب ريكي\" في الغابة أرانب سمينة وأرنب نحيلة وأرانب ذكية وأرانب غبية وأرانب شجاعة وأرانب جبانة وأرانب إناث وأرانب ذكور ولكنها كلها تملك آذانا طويلة والقصة الثانية \"ريكي يلعب مع أصدقائه\" كل مساء يذهب ريكي إلى الغابة ويمضي وقته في الهواء الطلق وكان يحب اللعب مع أصدقائه الأرانب والبيضاء والرمادية والبنية والسوداء والقصة الثالثة \"حفلة ريكي\" هذا اليوم مميز جدا، فاليوم حفلة ريكي لذا نهض ريكي من نومه باكرا، وبدأ بمساعدة أمه في الأعداد لحفلته ولكن عندما وصل أصدقاؤه أخيرا لم تكن \"لالا\" برفقتهم وأين هي يا ترى؟ وهل يخبئ هذا اليوم المزيد من المفاجآت لريكي؟ قصة مصورة وممتعة للأطفال في سن الرابعة وما فوق وتدور حول حفلة ريكي.
Book
Towards Adaptive Grids for Atmospheric Boundary-Layer Simulations
We present a proof-of-concept for the adaptive mesh refinement method applied to atmospheric boundary-layer simulations. Such a method may form an attractive alternative to static grids for studies on atmospheric flows that have a high degree of scale separation in space and/or time. Examples include the diurnal cycle and a convective boundary layer capped by a strong inversion. For such cases, large-eddy simulations using regular grids often have to rely on a subgrid-scale closure for the most challenging regions in the spatial and/or temporal domain. Here we analyze a flow configuration that describes the growth and subsequent decay of a convective boundary layer using direct numerical simulation (DNS). We validate the obtained results and benchmark the performance of the adaptive solver against two runs using fixed regular grids. It appears that the adaptive-mesh algorithm is able to coarsen and refine the grid dynamically whilst maintaining an accurate solution. In particular, during the initial growth of the convective boundary layer a high resolution is required compared to the subsequent stage of decaying turbulence. More specifically, the number of grid cells varies by two orders of magnitude over the course of the simulation. For this specific DNS case, the adaptive solver was not yet more efficient than the more traditional solver that is dedicated to these types of flows. However, the overall analysis shows that the method has a clear potential for numerical investigations of the most challenging atmospheric cases.
Journal Article
Signal signature and transcriptome changes of Arabidopsis during pathogen and insect attack
Plant defenses against pathogens and insects are regulated differentially by cross-communicating signaling pathways in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. To understand how plants integrate pathogen- and insect-induced signals into specific defense responses, we monitored the dynamics of SA, JA, and ET signaling in Arabidopsis after attack by a set of microbial pathogens and herbivorous insects with different modes of attack. Arabidopsis plants were exposed to a pathogenic leaf bacterium (Pseudomonas syringae pv. tomato), a pathogenic leaf fungus (Alternaria brassicicola), tissue-chewing caterpillars (Pieris rapae), cell-content-feeding thrips (Frankliniella occidentalis), or phloem-feeding aphids (Myzus persicae). Monitoring the signal signature in each plant-attacker combination showed that the kinetics of SA, JA, and ET production varies greatly in both quantity and timing. Analysis of global gene expression profiles demonstrated that the signal signature characteristic of each Arabidopsis-attacker combination is orchestrated into a surprisingly complex set of transcriptional alterations in which, in all cases, stress-related genes are overrepresented. Comparison of the transcript profiles revealed that consistent changes induced by pathogens and insects with very different modes of attack can show considerable overlap. Of all consistent changes induced by A. brassicicola, Pieris rapae, and F. occidentalis, more than 50% also were induced consistently by P. syringae. Notably, although these four attackers all stimulated JA biosynthesis, the majority of the changes in JA-responsive gene expression were attacker specific. All together, our study shows that SA, JA, and ET play a primary role in the orchestration of the plant's defense response, but other regulatory mechanisms, such as pathway cross-talk or additional attacker-induced signals, eventually shape the highly complex attacker-specific defense response.
Journal Article