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The recent trial Pediatric Neuro-Oncology Consortium 003 (PNOC003) utilized a molecular tumor board to recommend personalized treatment regimens based on tumor sequencing results in children with DIPG. We separately developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which numerically scores targeted anticancer agents using preclinical, clinical, and patient-specific data. We hypothesized that highly scored agents from CNS-TAP would overlap with the PNOC003 tumor boards recommendations. For each of the 28 participants, actionable genetic alterations were derived from PNOC003 genomic reports and input to CNS-TAP to identify the highest scoring agents. These agents were then compared with PNOC003 recommendations, with a resultant concordance percentage calculated. Overall, 38% of the total agents recommended by the tumor board were also selected by CNS-TAP, with higher concordance (63%) in a subanalysis including only targeted anticancer agents. Furthermore, nearly all patients (93%) had at least 1 drug chosen by both methods. We demonstrate overlap between agents recommended by CNS-TAP and PNOC003 tumor board, though this does not appear to improve survival. We do observe some discordance, highlighting strengths and limitations of each method. We propose that a combination of expert opinion and data-driven tools may improve targeted treatment recommendations for children with DIPG.

Trauma-informed frameworks are needed in metropolitan and urban university settings because many who enter higher education have experienced trauma or will experience trauma while at the university. This paper addresses the neurobiological and psychological underpinnings of trauma and addresses how these experiences can pose academic challenges, leading to misinterpretations of students' behaviors by faculty. This paper provides faculty with the knowledge to recognize, empathize, and respond effectively to students with trauma experiences and all students. The authors share four practical strategies for implementation (address feeling overwhelmed, address planning for assignments, provide ways to remember content and incorporate a focus on learning content) in the metropolitan and urban university classroom to create an inclusive educational environment that facilitates learning and growth for students who have experienced trauma and all students.

We demonstrate the utility of block polyelectrolyte (bPE) additives to enhance viscosity and resolve challenges with the three-dimensional (3D) printability of extrusion-based biopolymer inks. The addition of oppositely charged bPEs to solutions of photocurable gelatin methacryloyl (GelMA) results in complexation-driven self-assembly of the bPEs, leading to GelMA/bPE inks that are printable at physiological temperatures, representing stark improvements over GelMA inks that suffer from low viscosity at 37 °C, leading to low printability and poor structural stability. The hierarchical microstructure of the self-assemblies (either jammed micelles or 3D networks) formed by the oppositely charged bPEs, confirmed by small-angle X-ray scattering, is attributed to the enhancements in the shear strength and printability of the GelMA/bPE inks. Varying bPE concentration in the inks is shown to enable tunability of the rheological properties to meet the criteria of pre- and postextrusion flow characteristics for 3D printing, including prominent yielding behavior, strong shear thinning, and rapid recovery upon flow cessation. Moreover, the bPE self-assemblies also contribute to the robustness of the photo-cross-linked hydrogels; photo-cross-linked GelMA/bPE hydrogels are shown to exhibit higher shear strength than photo-cross-linked GelMA hydrogels. Last, the assessment of the printability of GelMA/bPE inks indicates excellent printing performance, including minimal swelling postextrusion, satisfactory retention of the filament shape upon deposition, and satisfactory shape fidelity of the various printed constructs. We envision this study to serve as a practical guide for the printing of bespoke extrusion inks where bPEs are used as scaffolds and viscosity enhancers that can be emulated in a range of photocurable precursors.

Abstract Translation of mRNA into protein is a fundamental process and tightly controlled during development. Several mechanisms acting on the mRNA level regulate when and where an mRNA is expressed. To explore the effects of conditional and transient gene expression in a developing organism, it is vital to experimentally enable abrogation and restoration of translation. We recently developed the FlashCaps technology allowing preparation of translationally muted mRNAs and their controlled activation by light. Here, we validate its functionality in vivo. We demonstrate that translation of FlashCap-eGFP-mRNA can be triggered in zebrafish embryos with spatiotemporal control. The injected FlashCap-mRNA is stable for hours and remains muted. Light-mediated activation up to 24 h post fertilization produces visible amounts of eGFP and can be restricted to distinct parts of the embryo. This methodology extends the toolbox for vertebrate models by enabling researchers to locally activate mRNA translation at different timepoints during development.

With the continued interest in trauma-informed practice (TIP) knowledge at the P-12 level, it has become imperative to consider the role of teacher preparation programs in providing this crucial knowledge to preservice educators. The TIP program at Mountain U (pseudonym) School of Education (SOE) is working to increase the current TIP knowledge of preservice teachers so that they are ready to implement TIP from the beginning of their careers. This paper adds to the trauma-informed literature in teacher preparation by describing the TIP initiative at Mountain U. It provides a roadmap for schools and departments that want to undertake this endeavor and explains each step in the roadmap. This roadmap is a three-pronged approach that includes capacity building, individual course integration, and departmental integration through creative, flexible, and patient TIP support.

Chronic limb-threatening ischemia (CLTI) is a critical end-stage disease that leads to high amputation rates. Over the past few decades, therapeutic angiogenesis has attracted a lot of attention as a means to reduce the necessity for amputations. Especially gene- and cell therapy are regarded to as possible treatment modalities to restore the hampered blood flow. So far, early-phase clinical trials often fail to prove a significant clinical improvement in mortality, amputation rate, and ulcer healing but still conclude that therapeutic angiogenesis might be promising as therapy. The subsequent phase III clinical trials based on these indecisive early trials fail consistently to demonstrate clinical benefits leaving the promising early results unvalidated. In this review we will illustrate that designing good trials for CLTI patients is challenging, not in the last place since patients are often not eligible due to strict inclusion criteria. Moreover, in this review, we advocate that clinical trials should be conducted with a low risk of bias and that it is of utmost importance to publish results, regardless of the outcome. It is definitely very concerning that many studies of a lower quality (due to small group size or high chance for bias) reporting positive outcomes are published while good quality trials (often with larger group sizes) are stopped prematurely due to lack of effects and remain unpublished. This keeps the ‘promising but not yet proven’ image of these therapeutic neovascularization studies alive, with still new groups starting similar trials.

The nature and timing of the transition to farming north of the Linearbandkeramik zone in Europe is the subject of much debate, but our understanding of this fundamental shift in lifeways is hampered by the low resolution of available data. This article presents new multi-proxy evidence from Swifterbant (4240-4050 BC), in the Dutch wetlands, for morphologically domestic cattle with two different dietary regimes. The authors argue that the results indicate early animal management, alongside arable farming and the continuance of foraging practices, prompting the reconsideration away from broad statements about the Neolithic north of the Linearbandkeramik zone towards more local trajectories. Keywords: Northern Europe, Neolithic, Linearbandkeramik, dietary stable isotopes, zooarchaeology, archaeobotany, human-animal interactions, Introduction The transition from hunting and gathering to farming represents a fundamental shift in human lifeways and in the relationship between humans and non-humans. North of the Linearbandkeramik (LBK) zone […]

Introduction Foot ulcers are one of the most serious complications of diabetes, leading to significant risks on amputation and mortality. Peripheral arterial disease (PAD) is an important factor for the development and the outcome of diabetic foot ulcers (DFU). Although prompt and accurate detection of PAD is critical to reduce complications, its diagnosis can be challenging with currently used bedside tests (such as ankle–brachial index and toe pressure) due to medial arterial calcification. A new and promising bedside test for the detection of PAD is the maximal systolic acceleration (ACCmax), measured by duplex ultrasonography (DUS). The primary aim of this study is to assess the diagnostic performance of the ACCmax to detect PAD in patients with DFU, in comparison with commonly used bedside tests. Secondary aims include the correlation between diagnostic test accuracy and patient comorbidities. Tertiary objectives focus on collecting (follow-up) data for prognostic evaluation, such as ulcer healing, revascularisation feasibility, amputation risk, cardiovascular events and mortality.Methods and analysis A multicentre prospective diagnostic accuracy study with 198 patients will be conducted to assess the diagnostic performance of multiple index tests to detect PAD in patients with DFU, with special emphasis on ACCmax. A full lower limb arterial DUS will serve as reference test.Ethics and dissemination Study protocol approval was gained from the Medical Ethical Committee Leiden/Den Haag/Delft and registered at ClinicalTrials.gov. The findings of this study will be reported through peer-reviewed publications and (inter)national conferences.Trial registration number NCT05646147.

IntroductionAdolescence is a dynamic developmental phase in which contact with peers is crucial for socio-emotional development and wellbeing. Depression and social anxiety show patterns of high onset during this period, and more for girls than boys. Here we examine this development among Dutch adolescents, as well as how desire for more peer contact as a result of social distancing measures during the COVID-19 pandemic contributed to this increase.MethodsWe used a longitudinal three-wave design to examine 406 typically developing Dutch adolescents across two consecutive cohorts; Cohort 1: 2016–2019 (N = 138, 53.6% girls, age at T0 M = 13.00, SD = 0.42), Cohort 2: 2017–2020 (N = 268, 63.1% girls, age at T0 M = 13.05, SD = 0.39), final wave during spring 2020 during the first COVID-19 lockdown. Self-report questionnaires were used to measure depression and social anxiety symptoms, desire for change in the amount of peer contact during lockdowns, and emotion regulation. Parallel process dual latent growth models and autoregressive cross-lagged models were used to test the hypotheses.ResultsResults showed that symptoms of both depression and social anxiety increase during adolescence. Gender analysis reveal a higher initial level and increase in depression symptoms for girls, while levels for boys decreased. Adolescents exposed to the pandemic showed a steeper increase in depression but not in social anxiety. Desire for more peer contact was related to an increase in depression and social anxiety, though only in girls. No evidence was found for moderation of emotion regulation skills concerning COVID evoked emotions on the association between desire for peer contact and anxiety and depression symptom development.DiscussionSymptoms of social anxiety increased during adolescence in boys and girls. Symptoms of depression increased for girls, but decreased for boys. The increase in depression was greater in a cohort who experienced the COVID-19 pandemic. For girls, a desire for more peer contact was associated with an increase of depression and social anxiety symptoms in times of social restrictions.

Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.