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It is a widespread practice among Canadian school districts to assess the French language proficiency of candidates applying for French as a Second Language (FSL) teaching positions. This pan-Canadian study used surveys, interviews, and website data to examine the French language proficiency assessment practices and processes used by Canadian schools when hiring FSL teachers. The findings show that almost 90% of Canadian school districts assess French language proficiency when hiring FSL teachers and that the most common form of assessment is to ask one to three questions in French (with candidates responding in French) during the employment interview. Evaluation of the candidates' responses is rarely informed by a language proficiency framework or rubric; instead, evaluators' decisions are informed by their overall impressions of the candidate's language proficiency. Other promising assessment practices are described, along with suggestions about how districts may improve their French language proficiency assessments when hiring FSL teachers.

Abstract Background Lyme borreliosis is by far the most common vector-borne infection in Western Europe. The most severe manifestation of Lyme borreliosis is Lyme neuroborreliosis (LNB). In LNB symptoms vary from mild to severe and may include late complications that involve both physical and/or neurocognitive constraints. An estimated 25–28% of the LNB population suffers from late complications. This study investigates patient and relative perspectives on everyday life with LNB symptoms, diagnosis, and treatment to identify areas for improvement of healthcare. Methods A focus group was conducted at Odense University Hospital, Denmark. The focus group comprised 16 participants, nine patients diagnosed with LNB who had been treated at the Clinical Center for Emerging and Vector-borne Infections, and seven relatives of the patients’ choice. The focus group lasted 2 ½ hours and was audio recorded as well as documented in field notes. Results Data analysis was grounded in the conceptual framework of critical psychology and resulted in three main themes: (1) Burden of LNB symptoms in everyday life, (2) A break in the conduct of everyday life caused by LNB and (3) Need for transparent pathways to specialist knowledge. Conclusions Before diagnosis and treatment, each patient reported varying degrees of non-treatable pain, and cognitive and/or musculoskeletal symptoms. Visible physical symptoms were rare. All patients had experienced that their bodily symptoms remained unaddressed throughout numerous encounters with the healthcare system. The course of LNB comes with a break in patients’ everyday lives and self-understandings affecting their ability to work and manage everyday activities. Patients and relatives strongly recommend a specialised LNB clinic.

The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount. The NanoSafety Cluster (NSC) delineates key safety and sustainability areas, pinpointing unresolved issues and research gaps to steer the development of safe(r) materials. Leveraging FAIR data management and integration, alongside the alignment of regulatory aspects, fosters informed decision-making and innovation. Integrating circularity and sustainability mandates clear guidance, ensuring responsible innovation at every stage. Collaboration among stakeholders, anticipation of regulatory demands, and a commitment to sustainability are pivotal for translating SSbD into tangible advancements. Harmonizing standards and test guidelines, along with regulatory preparedness through an exchange platform, is imperative for governance and market readiness. By adhering to these principles, the effective and sustainable deployment of innovative materials can be realized, propelling positive transformation and societal acceptance.

Expansion microscopy (ExM) has significantly reformed the field of super-resolution imaging, emerging as a powerful tool for visualizing complex cellular structures with nanoscale precision. Despite its capabilities, the epitope accessibility, labeling density, and precision of individual molecule detection pose challenges. We recently developed an iterative indirect immunofluorescence (IT-IF) method to improve the epitope labeling density, improving the signal and total intensity. In our protocol, we iteratively apply immunostaining steps before the expansion and exploit signal processing through noise estimation, denoising, and deblurring (NEDD) to aid in quantitative image analyses. Herein, we describe the steps of the iterative staining procedure and provide instructions on how to perform NEDD-based signal processing. Overall, IT-IF in ExM–laser scanning confocal microscopy (LSCM) represents a significant advancement in the field of cellular imaging, offering researchers a versatile tool for unraveling the structural complexity of biological systems at the molecular level with an increased signal-to-noise ratio and fluorescence intensity.

Background and purpose: Mortality after major lower extremity amputations is high and may depend on amputation level. We aimed to examine the mortality risk in the first year after major lower extremity amputation divided into transtibial and transfemoral amputations. Methods: This observational cohort study used data from the Danish Nationwide Health registers. 11,205 first-time major lower extremity amputations were included from January 1, 2010, to December 31, 2021, comprising 3,921 transtibial amputations and 7,284 transfemoral amputations. Results: The 30-day mortality after transtibial amputation was overall 11%, 95% confidence interval (CI) 10–12 (440/3,921) during the study period, but declined from 10%, CI 7–13 (37/381) in 2010 to 7%, CI 4–11 (15/220) in 2021. The 1-year mortality was 29% overall, CI 28–30 (1,140 /3,921), with a decline from 31%, CI 21–36 (117/381) to 20%, CI 15–26 (45/220) during the study period. For initial transfemoral amputation, the 30-day mortality was overall 23%, CI 22–23 (1,673/7,284) and declined from 27%, CI 23–31 (138/509) to 22%, CI 19–25 (148/683) during the study period. The 1-year mortality was 48% overall, CI 46–49 (3,466/7,284) and declined from 55%, CI 50–59 (279/509) to 46%, CI 42–50 (315/638). Conclusion: The mortality after major lower extremity amputation declined in the 12-year study period; however, the 1-year mortality remained high after both transtibial and transfemoral amputations (20% and 46% in 2021). Hence, major lower extremity amputation patients constitute one of the most fragile orthopedic patient groups, emphasizing an increased need for attention in the pre-, peri-, and postoperative setting.

The COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.

Abstract The Fiber Pathogenicity Paradigm (FPP) establishes connections between fiber structure, durability, and disease‐causing potential observed in materials like asbestos and synthetic fibers. While emerging nanofibers are anticipated to exhibit pathogenic traits according to the FPP, their nanoscale diameter limits rigidity, leading to tangling and loss of fiber characteristics. The absence of validated rigidity measurement methods complicates nanofiber toxicity assessment. By comprehensively analyzing 89 transcriptomics and 37 proteomics studies, this study aims to enhance carbon material toxicity understanding and proposes an alternative strategy to assess morphology‐driven toxicity. Carbon materials are categorized as non‐fibrous, high aspect ratio with shorter lengths, tangled, and rigid fibers. Mitsui‐7 serves as a benchmark for pathogenic fibers. The meta‐analysis reveals distinct cellular changes for each category, effectively distinguishing rigid fibers from other carbon materials. Subsequently, a robust random forest model is developed to predict morphology, unveiling the pathogenicity of previously deemed non‐pathogenic NM‐400 due to its secondary structures. This study fills a crucial gap in nanosafety by linking toxicological effects to material morphology, in particular regarding fibers. It demonstrates the significant impact of morphology on toxicological behavior and the necessity of integrating morphological considerations into regulatory frameworks.

Lektionsstudier har traditionelt været brugt som en måde at udvikle fagdidaktikken i et bestemt fag på. I denne artikel redegøres for et projekt, hvor arbejdet med lektionsstudier blev afprøvet som ramme for et samarbejde mellem lærere i forskellige fag i et årgangs­team for at undersøge, om lektionsstudiemetoden brugt på denne måde kunne udvikle deres professionelle kapital og derved understøtte dem i at udvikle fælles didaktiske løsninger på udfordringerne i deres klasser. Lektionsstudierne i dette studie kaldes der­for fagoverskridende lektionsstudier. Studiet er et aktionsforskningsstudie, hvor kvalitative data i form af observations- og interviewdata blev indsamlet. Udviklingen af den professionelle kapital analyseres og vurderes ud fra Hargreaves og Fullans begreb professionel kapital og Albrechtsens fem karakteristika for professionelle læringsfællesskaber. Udviklingen af didaktiske tiltag vurderes ud fra viden om elevers læring og deltagelse. Det konkluderes, at fagoverskridende lektionsstudier kan bidrage til udviklingen af læreres professionelle kapital i teams på tværs af fag, og at samarbejdsformen i lektions­studier styrker udviklingen af dels lærernes professionelle kapital, dels udviklingen af fælles didaktikker, der kan løse didaktiske udfordringer i klassen eller udfordringer omkring elever i klassen. Studiet er det første, der undersøger fagoverskridende lektionsstudier i Danmark, og vi anbefaler, at der gennemføres flere undersøgelser af lektionsstudier som metode til udvikling af samarbejdet i årgangsteam.

Abstract Objectives In this study, we propose a diagnostic model for automatic detection of otitis media based on combined input of otoscopy images and wideband tympanometry measurements. Methods We present a neural network‐based model for the joint prediction of otitis media and diagnostic difficulty. We use the subclassifications acute otitis media and otitis media with effusion. The proposed approach is based on deep metric learning, and we compare this with the performance of a standard multi‐task network. Results The proposed deep metric approach shows good performance on both tasks, and we show that the multi‐modal input increases the performance for both classification and difficulty estimation compared to the models trained on the modalities separately. An accuracy of 86.5% is achieved for the classification task, and a Kendall rank correlation coefficient of 0.45 is achieved for difficulty estimation, corresponding to a correct ranking of 72.6% of the cases. Conclusion This study demonstrates the strengths of a multi‐modal diagnostic tool using both otoscopy images and wideband tympanometry measurements for the diagnosis of otitis media. Furthermore, we show that deep metric learning improves the performance of the models.

Background and purpose: Re-amputation after lower extremity amputation is frequent. The primary aim of our study was to investigate cumulative re-amputation risk after transtibial amputation (TTA), knee disarticulation (KD), and transfemoral amputation (TFA) and secondarily to investigate time to re-amputation, and risk factors. Methods: This observational cohort study was based on data from the Danish Nationwide Health registers. The population included first-time major lower extremity amputations (MLEA) performed in patients ≥ 50 years between 2010 and 2021. Both left and right sided MLEA from the same patient were included as index procedures. Results: 11,743 index MLEAs on 10,052 patients were included. The overall cumulative risks for re-amputation were 29% (95% confidence interval [CI] 27–30), 30% (CI 26–35), and 11% (CI 10–12) for TTA, KD, and TFA, respectively. 58% of re-amputations were performed within 30 days after index MLEA. Risk factors for re-amputation within 30 days were dyslipidemia (hazard ratio [HR] 1.2, CI 1.0–1.3), renal insufficiency (HR 1.2, CI 1.1–1.4), and prior vascular surgery (HR 1.3, CI 1.2–1.5). Conclusion: The risk of re-amputation was more than twice as high after TTA (29%) and KD (30%) compared with TFA (11%). Most re-amputations were conducted within 30 days of the index MLEA. Dyslipidemia, renal insufficiency, and prior vascular surgery were associated with higher risk of re-amputation.

Abstract Epithelial cells are in continuous dynamic biochemical and physical interaction with their extracellular environment. Ultimately, this interplay guides fundamental physiological processes. In these interactions, cells generate fast local and global transients of Ca2+ ions, which act as key intracellular messengers. However, the mechanical triggers initiating these responses have remained unclear. Light‐responsive materials offer intriguing possibilities to dynamically modify the physical niche of the cells. Here, a light‐sensitive azobenzene‐based glassy material that can be micropatterned with visible light to undergo spatiotemporally controlled deformations is used. Real‐time monitoring of consequential rapid intracellular Ca2+ signals reveals that the mechanosensitive cation channel Piezo1 has a major role in generating the Ca2+ transients after nanoscale mechanical deformation of the cell culture substrate. Furthermore, the studies indicate that Piezo1 preferably responds to shear deformation at the cell‐material interphase rather than to absolute topographical change of the substrate. Finally, the experimentally verified computational model suggests that Na+ entering alongside Ca2+ through the mechanosensitive cation channels modulates the duration of Ca2+ transients, influencing differently the directly stimulated cells and their neighbors. This highlights the complexity of mechanical signaling in multicellular systems. These results give mechanistic understanding on how cells respond to rapid nanoscale material dynamics and deformations.

Purpose To describe the patient’s experience of participation in their care when admitted for elective surgical procedures. Materials and methods A purposive sample of 14 patients who had undergone elective surgery was included in semi-structured individual interviews at a university hospital. The data was analysed using qualitative content analysis. Results One theme was identified: Creating a meaningful relationship to enable participation in the care, based on three categories; Abilities, willingness, and a lack of experience affect participation, A professional approach with an open communication and individualized information, and The importance of structural factors. Conclusions To meet the patient’s individual needs and wishes regarding participation, meaningful relationships need to be created between patient and healthcare personnel. The results also indicate that the patients have insufficient knowledge about their role regarding participation. To improve patient participation, its meaning needs to be clarified individually to the patient, emphasizing the importance to be active involved in his or her own care.

Abstract Background The non-neuronal retinal pigment epithelium (RPE) functions in intimate association with retinal photoreceptors, performing a multitude of tasks critical for maintaining retinal homeostasis and collaborating with retinal glial cells to provide metabolic support and ionic buffering. Accordingly, the RPE has recently been shown to display dynamic properties mediated by an array of ion channels usually more characteristic of astrocytes and excitable cells. The recent discovery of canonical voltage-activated Na+ channels in the RPE and their importance for phagocytosis of photoreceptor outer segments raises a question about their electrogenic function. Here, we performed a detailed electrophysiological analysis related to the functioning of these channels in human embryonic stem cell (hESC)-derived RPE. Results Our studies examining the electrical properties of the hESC-RPE revealed that its membrane mainly displays passive properties in a broad voltage range, with the exception of depolarization-induced spikes caused by voltage-activated Na+ current (I Na). Spike amplitude depended on the availability of I Na and spike kinetics on the membrane time constant, and the spikes could be largely suppressed by TTX. Membrane resistance fluctuated rapidly and strongly, repeatedly changing over the course of recordings and causing closely correlated fluctuations in resting membrane potential. In a minority of cells, we found delayed secondary I Na-like inward currents characterized by comparatively small amplitudes and slow kinetics, which produced secondary depolarizing spikes. Up to three consecutive delayed inward current waves were detected. These currents could be rapidly and reversibly augmented by applying L-type Ca2+ channel blocker nifedipine to diminish influx of calcium and thus increase gap junctional conductance. Conclusions This work shows, for the first time, that I Na and I Na-mediated voltage spikes can spread laterally through gap junctions in the monolayer of cells that are traditionally considered non-excitable. Our findings support a potential role of the RPE that goes beyond giving homeostatic support to the retina.

Abstract Toxicological evaluation of substances in regulation still often relies on animal experiments. Understanding the substances’ mode-of-action is crucial to develop alternative test strategies. Omics methods are promising tools to achieve this goal. Until now, most attention was focused on transcriptomics, while proteomics is not yet routinely applied in toxicology despite the large number of datasets available in public repositories. Exploiting the full potential of these datasets is hampered by differences in measurement procedures and follow-up data processing. Here we present the tool PROTEOMAS, which allows meta-analysis of proteomic data from public origin. The workflow was designed for analyzing proteomic studies in a harmonized way and to ensure transparency in the analysis of proteomic data for regulatory purposes. It agrees with the Omics Reporting Framework guidelines of the OECD with the intention to integrate proteomics to other omic methods in regulatory toxicology. The overarching aim is to contribute to the development of AOPs and to understand the mode of action of substances. To demonstrate the robustness and reliability of our workflow we compared our results to those of the original studies. As a case study, we performed a meta-analysis of 25 proteomic datasets to investigate the toxicological effects of nanomaterials at the lung level. PROTEOMAS is an important contribution to the development of alternative test strategies enabling robust meta-analysis of proteomic data. This workflow commits to the FAIR principles (Findable, Accessible, Interoperable and Reusable) of computational protocols.

Abstract Background Asbestos has been shown to cause chromosomal damage and DNA aberrations. Exposure to asbestos causes many lung diseases e.g. asbestosis, malignant mesothelioma, and lung cancer, but the disease-related processes are still largely unknown. We exposed the human cell lines A549, Beas-2B and Met5A to crocidolite asbestos and determined time-dependent gene expression profiles by using Affymetrix arrays. The hybridization data was analyzed by using an algorithm specifically designed for clustering of short time series expression data. A canonical correlation analysis was applied to identify correlations between the cell lines, and a Gene Ontology analysis method for the identification of enriched, differentially expressed biological processes. Results We recognized a large number of previously known as well as new potential asbestos-associated genes and biological processes, and identified chromosomal regions enriched with genes potentially contributing to common responses to asbestos in these cell lines. These include genes such as the thioredoxin domain containing gene (TXNDC) and the potential tumor suppressor, BCL2/adenovirus E1B 19kD-interacting protein gene (BNIP3L), GO-terms such as "positive regulation of I-kappaB kinase/NF-kappaB cascade" and "positive regulation of transcription, DNA-dependent", and chromosomal regions such as 2p22, 9p13, and 14q21. We present the complete data sets as Additional files. Conclusion This study identifies several interesting targets for further investigation in relation to asbestos-associated diseases.

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in microalgae is currently not feasible. In fact, rapid conversion into the inactive pigment diadinoxanthin is triggered when cells are removed from a high-intensity light source, which is the case during large-scale harvesting of microalgae biomass. Zeaxanthin epoxidase (ZEP) 2 and/or ZEP3 have been suggested to be responsible for the back-conversion of high-light accumulated diatoxanthin to diadinoxanthin in low-light in diatoms. Using CRISPR/Cas9 gene editing technology, we knocked out the ZEP2 and ZEP3 genes in the marine diatom Phaeodactylum tricornutum to investigate their role in the diadinoxanthin–diatoxanthin cycle and determine if one of the mutant strains could function as a diatoxanthin production line. Light-shift experiments proved that ZEP3 encodes the enzyme converting diatoxanthin to diadinoxanthin in low light. Loss of ZEP3 caused the high-light-accumulated diatoxanthin to be stable for several hours after the cultures had been returned to low light, suggesting that zep3 mutant strains could be suitable as commercial production lines of diatoxanthin.

Large amounts of nanotoxicity data from alternative non-animal (in vitro) test methods have been generated, but there is a lack of harmonized quality evaluation approaches for these types of data. Tools for scientifically sound and structured evaluation of the reliability and relevance of in vitro toxicity data to effectively inform regulatory hazard assessment of nanomaterials (NMs), are needed. Here, we present the development of a pragmatic approach to facilitate such evaluation. The tool was developed based on the Science in Risk Assessment and Policy (SciRAP) tool currently applicable to quality evaluation of chemical toxicity studies. The approach taken to develop the tool, referred to as SciRAPnano, included refinement of the original SciRAP in vitro tool through implementation of identified NM-relevant criteria, and further refined based on a set of case studies involving evaluation of 11 studies investigating in vitro toxicity of nano-sized titanium dioxide. Parameters considered cover key physicochemical properties as well as assay-specific aspects that impact NM toxicity, including NM interference with test methods and NM transformation. The final SciRAPnano tool contains 38 criteria for reporting quality, 19 criteria for methodological quality, and 4 guidance items to evaluate relevance. The approach covers essential parameters for pragmatic and harmonized evaluation of NM in vitro toxicity studies and allows for structured use of in vitro data in regulatory hazard assessment of NMs, including transparency on data quality.

Toxicology has been an active research field for many decades, with academic, industrial and government involvement. Modern omics and computational approaches are changing the field, from merely disease-specific observational models into target-specific predictive models. Traditionally, toxicology has strong links with other fields such as biology, chemistry, pharmacology, and medicine. With the rise of synthetic and new engineered materials, alongside ongoing prioritisation needs in chemical risk assessment for existing chemicals, early predictive evaluations are becoming of utmost importance to both scientific and regulatory purposes. ELIXIR is an intergovernmental organisation that brings together life science resources from across Europe. To coordinate the linkage of various life science efforts around modern predictive toxicology, the establishment of a new ELIXIR Community is seen as instrumental. In the past few years, joint efforts, building on incidental overlap, have been piloted in the context of ELIXIR. For example, the EU-ToxRisk, diXa, HeCaToS, transQST, and the nanotoxicology community have worked with the ELIXIR TeSS, Bioschemas, and Compute Platforms and activities. In 2018, a core group of interested parties wrote a proposal, outlining a sketch of what this new ELIXIR Toxicology Community would look like. A recent workshop (held September 30th to October 1st, 2020) extended this into an ELIXIR Toxicology roadmap and a shortlist of limited investment-high gain collaborations to give body to this new community. This Whitepaper outlines the results of these efforts and defines our vision of the ELIXIR Toxicology Community and how it complements other ELIXIR activities.

Abstract The placenta is crucial to fetal well-being and it plays a significant role in the pathogenesis of hypertensive pregnancy disorders. Moreover, a timely diagnosis of placenta previa may save lives. Ultrasound is the primary imaging modality in pregnancy, but high-quality imaging depends on the access to equipment and staff, which is not possible in all settings. Convolutional neural networks may help standardize the acquisition of images for fetal diagnostics. Our aim was to develop a deep learning based model for classification and segmentation of the placenta in ultrasound images. We trained a model based on manual annotations of 7,500 ultrasound images to identify and segment the placenta. The model's performance was compared to annotations made by 25 clinicians (experts, trainees, midwives). The overall image classification accuracy was 81%. The average intersection over union score (IoU) reached 0.78. The model’s accuracy was lower than experts’ and trainees’, but it outperformed all clinicians at delineating the placenta, IoU = 0.75 vs 0.69, 0.66, 0.59. The model was cross validated on 100 2nd trimester images from Barcelona, yielding an accuracy of 76%, IoU 0.68. In conclusion, we developed a model for automatic classification and segmentation of the placenta with consistent performance across different patient populations. It may be used for automated detection of placenta previa and enable future deep learning research in placental dysfunction.

Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. We first used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that β-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiratory capacity, mediated by an inhibition of mitochondrial complex I. The net result of this action was increased oxidative stress that led to apoptosis. This effect was only seen in tumor cells, and not in normal cells. Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.

Abstract Background Lower extremity amputation patients represent a frail group with extensive comorbidity. Transfemoral amputation is a high-risk procedure with 37–50% risk of mortality in the first year. Substantial blood loss during surgery increases the risk of anemic complications and death for these already weakened patients. The use of tourniquet during surgery may reduce blood loss, the need for blood transfusions, the related complications as well as the length of the surgery. However the use of tourniquet may be related to impaired wound healing and hence the use should be investigated in a randomized controlled trial. The primary aim of this study is to investigate the total blood loss and secondary to investigate differences in complications after transfemoral amputation between patients operated with or without tourniquet. Methods The total blood loss is calculated using Nadlers approach. Based on data from a pilot series, the sample size was calculated to 124, allocated 1:1 in two groups of 62 participants to ensure detection of at least 200 mL difference in the total blood loss. The primary outcome is the total blood loss. Secondary outcomes are blood transfusions, duration of surgery, length of hospital stay and risk of complications within 90 days (re-admissions, re-operations and mortality). Explorative outcomes are 1 year mortality and re-operation risk. Further explorative outcomes are postoperative quality of life (questionnaire EQ-5D-5L) and evaluation of number of prosthesis users including evaluation of prosthesis-specific function measured 3, 6, and 12 months postoperatively. Discussion The possibility to enhance patient safety is highly relevant and this trial will provide data for evidence based recommendations of best practice in amputation surgery. Trial registration The trial is registered on ClinicalTrials.gov with ID: NCT05550623. Initial release: 13/09 2022.

The introduction of sulfur into the phosphate linkage of chemically synthesized oligonucleotides creates the stereocenters on phosphorus atoms. Researchers have valued the nature of backbone stereochemistry and early on investigated drug properties for the individual stereocenters in dimers or short oligomers. Only very recently, it has become possible to synthesize fully stereodefined antisense oligonucleotides in good yield and purity. Non-bridging phosphorodithioate (PS2) introduces second sulfur into the phosphorothioate linkage to remove the chirality of phosphorus atom. Here, we describe the application of symmetrical non-bridging PS2 linkages in the context of stereodefined locked nucleic acids (LNAs) antisense oligonucleotides with the goal of reducing chiral complexity and, ultimately, resulting in single molecules. In addition, we propose a rather simple strategy to rapidly identify stereodefined gapmers, combining PS2 and a preferred stereochemistry motif (RSSR), which supports RNase-H-mediated target knockdown. Pharmacological efficacy and metabolic stability are investigated systematically using ApoB as a target sequence, where in vivo data correlate well to what is observed in vitro.

The family of chloroplast ALBINO3 (ALB3) proteins function in the insertion and assembly of thylakoid membrane protein complexes. Loss of ALB3b in the marine diatom Phaeodactylum tricornutum leads to a striking change of cell color from the normal brown to green. A 75% decrease of the main fucoxanthin-chlorophyll a/c-binding proteins was identified in the alb3b strains as the cause of changes in the spectral properties of the mutant cells. The alb3b lines exhibit a truncated light-harvesting antenna phenotype with reduced amounts of light-harvesting pigments and require a higher light intensity for saturation of photosynthesis. Accumulation of photoprotective pigments and light-harvesting complex stress-related proteins was not negatively affected in the mutant strains, but still the capacity for nonphotochemical quenching was lower compared with the wild type. In plants and green algae, ALB3 proteins interact with members of the chloroplast signal recognition particle pathway through a Lys-rich C-terminal domain. A novel conserved C-terminal domain was identified in diatoms and other stramenopiles, questioning if ALB3b proteins have the same interaction partners as their plant/green algae homologs.

Abstract Management of nanomaterials and nanosafety data needs to operate under the FAIR (findability, accessibility, interoperability, and reusability) principles and this requires a unique, global identifier for each nanomaterial. Existing identifiers may not always be applicable or sufficient to definitively identify the specific nanomaterial used in a particular study, resulting in the use of textual descriptions in research project communications and reporting. To ensure that internal project documentation can later be linked to publicly released data and knowledge for the specific nanomaterials, or even to specific batches and variants of nanomaterials utilised in that project, a new identifier is proposed: the European Registry of Materials Identifier. We here describe the background to this new identifier, including FAIR interoperability as defined by FAIRSharing, identifiers.org, Bioregistry, and the CHEMINF ontology, and show how it complements other identifiers such as CAS numbers and the ongoing efforts to extend the InChI identifier to cover nanomaterials. We provide examples of its use in various H2020-funded nanosafety projects. Graphical Abstract

Adverse Outcome Pathways (AOPs) summarize mechanistic understanding of toxicological effects and have, for example, been highlighted as a promising tool to integrate data from novel in vitro and in silico methods into chemical risk assessments. Networks based on AOPs are considered the functional implementation of AOPs, as they are more representative of complex biology. At the same time, there are currently no harmonized approaches to generate AOP networks (AOPNs). Systematic strategies to identify relevant AOPs, and methods to extract and visualize data from the AOP-Wiki, are needed. The aim of this work was to develop a structured search strategy to identify relevant AOPs in the AOP-Wiki, and an automated data-driven workflow to generate AOPNs. The approach was applied on a case study to generate an AOPN focused on the Estrogen, Androgen, Thyroid, and Steroidogenesis (EATS) modalities. A search strategy was developed a priori with search terms based on effect parameters in the ECHA/EFSA Guidance Document on Identification of Endocrine Disruptors. Furthermore, manual curation of the data was performed by screening the contents of each pathway in the AOP-Wiki, excluding irrelevant AOPs. Data were downloaded from the Wiki, and a computational workflow was utilized to automatically process, filter, and format the data for visualization. This study presents an approach to structured searches of AOPs in the AOP-Wiki coupled to an automated data-driven workflow for generating AOPNs. In addition, the case study presented here provides a map of the contents of the AOP-Wiki related to the EATS-modalities, and a basis for further research, for example, on integrating mechanistic data from novel methods and exploring mechanism-based approaches to identify endocrine disruptors (EDs). The computational approach is freely available as an R-script, and currently allows for the (re)-generation and filtering of new AOP networks based on data from the AOP-Wiki and a list of relevant AOPs used for filtering.

Introduction: Case-based training improves novices pattern recognition and diagnostic accuracy in skin cancer diagnostics. However, it is unclear how pattern recognition is best taught in conjunction with the knowledge needed to justify a diagnosis. Objectives: The aim of this study was to examine whether an explanation of the underlying histopathological reason for dermoscopic criteria improves skill acquisition and retention during case-based training in skin cancer diagnostics. Methods: In this double-blinded randomized controlled trial, medical students underwent eight days of case-based training in skin cancer diagnostics, which included access to written diagnosis modules. The modules dermoscopic subsections differed between the study groups. All participants received a general description of the criteria, but the intervention group additionally received a histopathological explanation. Results: Most participants (78%) passed a reliable test in skin cancer diagnostics, following a mean training time of 217 minutes. Access to histopathological explanations did not affect participants' learning curves or skill retention. Conclusions: The histopathological explanation did not affect the students, but the overall educational approach was efficient and scalable.

The analysis of maritime traffic patterns for safety and security purposes is increasing in importance and, hence, Vessel Traffic Service operators need efficient and contextualized tools for the detection of abnormal maritime behavior. Current models lack interpretability and contextualization of their predictions and are generally not quantitatively evaluated on a large annotated dataset comprising all expected traffic in a Region of Interest. We propose a model for the detection of abnormal maritime behaviors that provides the closest behaviors as context to the predictions. The normalcy model relies on two-step clustering, which is first computed based on the positions of the vessels and then refined based on their kinematics. We design for each step a similarity measure, which combined are able to distinguish boats cruising shipping lanes in different directions, but also vessels with more freedom, such as pilot boats. Our proposed abnormality detection model achieved, on a large annotated dataset extracted from AIS logs that we publish, an ROC-AUC of 0.79, which is on a par with State-of-the-Art deep neural networks, while being more computationally efficient and more interpretable, thanks to the contextualization offered by our two-step clustering.

Abstract Aim To evaluate missed nursing care and patient safety during the first wave of the COVID‐19 pandemic at in‐patient cardiology wards. Design A cross‐sectional design with a comparative approach. Method Registered nurses and nurse assistants at a cardiology department were invited to answer the MISSCARE Survey‐Swedish version, and questions on patient safety and quality of care during the COVID‐19 pandemic. The data were compared with a reference sample. Results A total of 43 registered nurses and nurse assistants in the COVID‐19 sample and 59 in the reference sample participated. The COVID‐19 sample reported significantly more overtime hours and more absence from work due to illness in comparison with the reference sample. The patient safety and quality of care were perceived significantly worse, 76.7% (N = 33) versus 94.7% (N = 54), and 85.7% (N = 36) versus 98.3% (N = 58, respectively. The COVID‐19 sample reported more missed nursing care in wound care and in basic nursing.