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Invention activities and worked solutions are considered to be effective learning tasks. To date, limited research has been conducted regarding these tasks in teacher education and the process of solving these tasks. This study focuses on the solution quality of student teachers' task solutions. 149 students were randomly assigned to one of two experimental conditions: invention activity and worked solution. The latter group were given a set of categories; the former group had to invent their own categories to compare two constructed contrasting auditive cases with a focus on the subject classroom management. To determine whether it is more effective to compare cases with given categories (worked solution) or with self-generated categories (invention activity), we coded the 149 solutions regarding the content-related solution quality using qualitative content analysis. Students in the worked solution condition demonstrated a significantly higher content-related solution quality than those in the invention activity condition. Thus, it may be assumed that students of the worked solution gained a better conceptual understanding of classroom management through working on this task. Implications for the use of this task format in teacher education are discussed.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

BACKGROUND: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood. METHODS: We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline pathogenic or likely pathogenic BARD1 variants, we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via next-generation sequencing and with functional assays measuring the efficiency of DNA repair. RESULTS: Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 loss-of-function variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. CONCLUSIONS: Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications.

Social norms are often characterized as a system of rules that guide behavior. However, social norms also allow for flexibility; not entirely restricting individuals to one possible behavior. Here, we put forward an agent-based cognitive model that captures social norms as processes that are socially constructed through interactions between individuals. In this modelling work, we focus on the role of norm acquisition and conformity bias in both action production and inference-making. This computational cognitive model allows us to think about social norms along three dimensions: individual vs. collective, behavior vs. belief, and subjective vs. objective. Our simulation results show that increased conformity bias can induce misjudgments about the true desires of others and misalignment between different agents' perceptions of the social norm. However, if agents do not assume that others also conform in their behavior, this increased conformity bias does not necessarily lead to excessive misperceptions of the social norm.

Abstract A genomic database of all Earth’s eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

Abstract Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13–0.68) and CN-ST (HR 0.68, CI 0.47–0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26–0.77) and CN-ST (HR 0.9, CI 0.68–1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

Abstract Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.

Abstract The harm-made mind phenomenon implies that witnessing intentional harm towards agents with ambiguous minds, such as robots, leads to augmented mind perception in these agents. We conducted two replications of previous work on this effect and extended it by testing if robots that detect and simulate emotions elicit a stronger harm-made mind effect than robots that do not. Additionally, we explored if someone is perceived as less prosocial when harming a robot compared to treating it kindly. The harm made mind-effect was replicated: participants attributed a higher capacity to experience pain to the robot when it was harmed, compared to when it was not harmed. We did not find evidence that this effect was influenced by the robot’s ability to detect and simulate emotions. There were significant but conflicting direct and indirect effects of harm on the perception of mind in the robot: while harm had a positive indirect effect on mind perception in the robot through the perceived capacity for pain, the direct effect of harm on mind perception was negative. This suggests that robots are both anthropomorphized and dehumanized when harmed intentionally. Additionally, the results showed that someone is perceived as less prosocial when harming a robot compared to treating it kindly.

Abstract Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

O presente trabalho aborda sobre a literatura surda, seu conceito recente, mas que esteve presente no documento de 1999 "A educação que nós surdos queremos" através de aspectos que compreendo como literatura surda. Após 20 anos da passeata, o que percebo é que não houve muitos avanços na educação de surdos no que tange a literatura surda, que possui várias definições, mas destaco aquela que se refere às histórias, identidade e cultura surda presentes nas narrativas em língua de sinais. Desta forma, o que ainda se encontra na escola são bibliotecas fechadas, incentivo apenas ao teatro e à pintura e muito pouco acesso à leitura de textos sinalizados, disponíveis em vídeos. A literatura surda ainda não é bem compreendida pelos alunos, mas isso se deve à falta de compreensão dos próprios professores, que confessam seu frágil conhecimento, e à falta de formação que apresente a possibilidade de trabalhar a literatura surda. O que se percebe diante dos dados e relatos é que a literatura surda continua em processo de execução.

A 26-year-old male with Behçet's disease (BD) presented with recurrent oral and genital ulcers, bilateral pneumonia, and a left lower pulmonary artery aneurysm. Endovascular coil embolization was initially performed, followed by treatment with prednisone, colchicine, and azathioprine. Despite treatment, disease progression occurred, requiring additional embolization, intravenous pulse methylprednisolone, and cyclophosphamide. Ultimately, a combination of medical and endovascular interventions resolved the pulmonary arterial aneurysms. This case highlights BD's systemic inflammatory nature and vascular complications like pulmonary artery aneurysms. It emphasizes the importance of early detection and individualized, multidisciplinary care for such complications.

The present study assessed the effectiveness of the ECRIMO educational application designed to build first-grade level spelling skills. We tested whether using the app to teach spelling would be as effective as providing the same training using traditional paper exercises. The effect of integrating gamification into mobile learning apps, which has been little studied in the context of young children, is also investigated. A pretest/training/posttest design was implemented with 311 first-graders divided in four groups: no training, paper training, the ECRIMO app with gamification features, and the ECRIMO app without gamification. Spelling, reading and phonological awareness abilities was measured at both pretest and posttest. The training was conducted over a 7-week period (4.40 hours in total). The experimental design allowed us to answer three questions: (1) Is spelling training effective regardless of the medium used? (2) Is training through the app as efficient as paper-based training? (3) Does gamification impact students' learning performance? Mixed-model analyses revealed (1) a positive effect on the training outcome depended on the initial spelling ability of participants, (2) a comparable efficiency between autonomous training using the ECRIMO app on tablets and the same training provided by teachers using paper exercises and (3) a marginally positive effect of gamification that is greater for the weakest students. The present study proposes an original and pertinent experimental design to test the relevance of educational applications. The design features of learning apps can impact students' learning differently depending on their initial level. A critical step should be verifying that using online apps for training is at least as effective as the same training using paper exercises.

Research suggests that providing children with activities that involve using their bodies to form the shapes of letters can help them acquire pre-reading skills. Little is known, however, as to the extent to which such embodied learning interventions are superior to more traditional pencil-and-paper activities, which of specific arm or body movements are most effective, and whether this approach compensates or exacerbates the learning gap between high- and low-skilled pre-readers. Using a preregistered randomized-controlled experiment (N = 160 kindergarten students, M = 5.18 years, 54% girls), the present study assessed the educational effects of 6-week-long training sessions with increasing degrees of bodily movement integration (pencil-and-paper training vs. arm training vs. arm-body training) on five measures of letter knowledge and script. Aligning with theories of embodied cognition and cognitive load in instructional designs, results showed that integrating arm movement exercises into handwriting training bore the greatest acquisitions in pre-reading skills overall and were most beneficial to students with initially low pre-reading skills (compensatory effect against learning inequalities). Implications are drawn on the need to consolidate and replicate present findings, while highlighting their potential for supporting educational effectiveness and equity in kindergarten.

BACKGROUND: De novo neuroendocrine prostate cancer (NEPC) and treatment-emergent neuroendocrine prostate cancer (T-NEPC) are rare diseases with a poor prognosis. After first-line platinum chemotherapy, there is no consensus on second-line treatments. PATIENTS AND METHODS: Patients with a pathologic diagnosis of de novo NEPC or T-NEPC between 2000 and 2020 who received first-line platinum and any second-line systemic therapy were selected and standardized clinical data was collected via the electronic health record at each institution. The primary endpoint was overall survival (OS) based on second-line therapy. Secondary endpoints included objective response rate (ORR) to second-line therapy, PSA response, and time on treatment. RESULTS: Fifty-eight patients (32 de novo NEPC, 26 T-NEPC) from 8 institutions were included. At de novo NEPC or T-NEPC diagnosis, the overall cohort had a median age of 65.0 years (IQR 59.2-70.3) and median PSA of 3.0 ng/dL (IQR 0.6-17.9). Following first-line platinum chemotherapy, 21 patients (36.2%) received platinum chemotherapy, 10 (17.2%) taxane monotherapy, 11 (19.0%) immunotherapy, 10 (17.2%) other chemotherapy, and 6 (16.2%) other systemic therapy. Among 41 evaluable patients, the ORR was 23.5%. The mOS after start of second-line therapy was 7.4 months (95% CI 6.1-11.9). CONCLUSIONS: In this retrospective study, patients with de novo NEPC or T-NEPC who received second-line therapy were treated with wide variety of treatment regimens, reflecting the lack of consensus in this setting. Most patients received chemotherapy-based treatments. Overall prognosis was poor and ORR was low in the second line regardless of treatment choice.