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SUMMARY: OBJECTIVE To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure ≥70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period.DESIGN Multicentered, randomized, placebo-controlled, safety and efficacy study.SETTING Forty-eight intensive care units in Europe, North America, and Australia.PATIENTS A total of 312 patients with septic shock diagnosed within 24 hr before randomization.INTERVENTIONS Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s).MEASUREMENTS AND MAIN RESULTS Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p = .004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups.CONCLUSIONS In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile. [ABSTRACT FROM AUTHOR]

We introduce the database of European vascular plant red lists, a compilation of red list categories designated to taxa during in-country conservation assessments. Version 1.0 of the database is a standalone static dataset with open access in an end-user friendly format. Its aim is to fulfil the objectives of European Cooperation in Science and Technology (COST) Action 18201, ConservePlants. The database synthesizes data across 42 red lists from 41 countries, with participation of 39 out of a total of 44 European countries and two additional Mediterranean countries. The database contains 51,109 records representing 21,481 original taxonomic names with 37 different red list categories. During data harmonisation, 20,312 of the original taxonomic names were assigned to 17,873 unique accepted taxonomic names with scientific authorships across 184 families, 1650 genera and 15,593 species; and red list categories were standardised to 13 unique categories. We see this database as a source of information in diverse plant conservation activities and suitable for various stakeholders., (© 2024. The Author(s).)

Preprints provide an indispensable tool for rapid and open communication of early research findings. Preprints can also be revised and improved based on scientific commentary uncoupled from journal-organised peer review. The uptake of preprints in the life sciences has increased significantly in recent years, especially during the COVID-19 pandemic, when immediate access to research findings became crucial to address the global health emergency. With ongoing expansion of new preprint servers, improving discoverability of preprints is a necessary step to facilitate wider sharing of the science reported in preprints. To address the challenges of preprint visibility and reuse, Europe PMC, an open database of life science literature, began indexing preprint abstracts and metadata from several platforms in July 2018. Since then, Europe PMC has continued to increase coverage through addition of new servers, and expanded its preprint initiative to include the full text of preprints related to COVID-19 in July 2020 and then the full text of preprints supported by the Europe PMC funder consortium in April 2022. The preprint collection can be searched via the website and programmatically, with abstracts and the open access full text of COVID-19 and Europe PMC funder preprint subsets available for bulk download in a standard machine-readable JATS XML format. This enables automated information extraction for large-scale analyses of the preprint corpus, accelerating scientific research of the preprint literature itself. This publication describes steps taken to build trust, improve discoverability, and support reuse of life science preprints in Europe PMC. Here we discuss the benefits of indexing preprints alongside peer-reviewed publications, and challenges associated with this process., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Levchenko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Urinary Chemokine (C-C motif) ligand 14 (CCL14) is a biomarker associated with persistent severe acute kidney injury (AKI). There is limited data to support the implementation of this AKI biomarker to guide therapeutic actions., Methods: Sixteen AKI experts with clinical CCL14 experience participated in a Delphi-based method to reach consensus on when and how to potentially use CCL14. Consensus was defined as ≥ 80% agreement (participants answered with 'Yes', or three to four points on a five-point Likert Scale)., Results: Key consensus areas for CCL14 test implementation were: identifying challenges and mitigations, developing a comprehensive protocol and pairing it with a treatment plan, and defining the target population. The majority agreed that CCL14 results can help to prioritize AKI management decisions. CCL14 levels above the high cutoff (> 13 ng/mL) significantly changed the level of concern for modifying the AKI treatment plan ( p  < 0.001). The highest level of concern to modify the treatment plan was for discussions on renal replacement therapy (RRT) initiation for CCL14 levels > 13 ng/mL. The level of concern for discussion on RRT initiation between High and Low, and between Medium and Low CCL14 levels, showed significant differences., Conclusion: Real world urinary CCL14 use appears to provide improved care options to patients at risk for persistent severe AKI. Experts believe there is a role for CCL14 in AKI management and it may potentially reduce AKI-disease burden. There is, however, an urgent need for evidence on treatment decisions and adjustments based on CCL14 results.

In 2004 the first annual BioMalPar meeting was held at EMBL Heidelberg, bringing together researchers from around the world with the goal of building connections between malaria research groups in Europe. Twenty years on it is time to reflect on what was achieved and to look ahead to the future., Competing Interests: Declaration of interests Julian C. Rayner is a member of the journal's advisory board. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis., Methods: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA 1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years., Results: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA 1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001)., Conclusions/interpretation: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline., (© 2024. The Author(s).)

Anthropogenically forced changes in global freshwater biodiversity demand more efficient monitoring approaches. Consequently, environmental DNA (eDNA) analysis is enabling ecosystem-scale biodiversity assessment, yet the appropriate spatio-temporal resolution of robust biodiversity assessment remains ambiguous. Here, using intensive, spatio-temporal eDNA sampling across space (five rivers in Europe and North America, with an upper range of 20-35 km between samples), time (19 timepoints between 2017 and 2018) and environmental conditions (river flow, pH, conductivity, temperature and rainfall), we characterise the resolution at which information on diversity across the animal kingdom can be gathered from rivers using eDNA. In space, beta diversity was mainly dictated by turnover, on a scale of tens of kilometres, highlighting that diversity measures are not confounded by eDNA from upstream. Fish communities showed nested assemblages along some rivers, coinciding with habitat use. Across time, seasonal life history events, including salmon and eel migration, were detected. Finally, effects of environmental conditions were taxon-specific, reflecting habitat filtering of communities rather than effects on DNA molecules. We conclude that riverine eDNA metabarcoding can measure biodiversity at spatio-temporal scales relevant to species and community ecology, demonstrating its utility in delivering insights into river community ecology during a time of environmental change., (© 2024. The Author(s).)

Background and Aims: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition., Approach and Results: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed., Results: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation., Conclusions: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections., Methods: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022., Results: The response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials., Conclusions: The inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens., Competing Interests: Declaration of competing interest Callum Sloan - PhD project funded by Chiesi and received an ECFS Travel Grant. Laura Sherrard - received PhD fellowship support to institution from Chiesi. Gisli Einarsson and Lieven Dupont - no interests to declare. Silke van Koningsbruggen-Rietschel - received consulting fees from German center for Infection Research, Antabio, and Boehringer. Nicholas Simmonds - received honoraria from Vertex, Chiesi, and Gilead, on the consulting fees for Vertex, Chiesi, Gilead, and Menarini, received support for attending conference from Vertex and has roles on the ECFS-Clinical Trials Network Executive Committee, ECFS Diagnostic Network Working Group as Co-coordinator, and the UK CF Registry Research Committee. Damian Downey - received PhD fellowship support to institution from Chiesi, grants from Chiesi and Gilead, honoraria from Vertex, Gilead, Chiesi, and Insmed, and is Director of the ECFS-Clinical Trials Network. Preliminary data from the study was presented as an abstract and poster presentation entitled ‘P150 Antimicrobial prescribing in people with cystic fibrosis: exploring inhaled antimicrobial use for Pseudomonas aeruginosa infections across the ECFS-CTN” Journal of Cystic Fibrosis 2022: 21: S107 at the 45th European Cystic Fibrosis Society Conference in Rotterdam (8th-11th June 2022)., (Copyright © 2023. Published by Elsevier B.V.)

Background: Epidemiological evidence suggests that a potential association between dietary protein intake and cardiovascular disease (CVD) may depend on the protein source, that is, plant- or animal-derived, but past research was limited and inconclusive., Objectives: To evaluate the association of dietary plant- or animal-derived protein consumption with risk of CVD, and its components ischemic heart disease (IHD) and stroke., Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study included 16,244 incident CVD cases (10,784 IHD and 6423 stroke cases) and 15,141 subcohort members from 7 European countries. We investigated the association of estimated dietary protein intake with CVD, IHD, and stroke (total, fatal, and nonfatal) using multivariable-adjusted Prentice-weighted Cox regression. We estimated isocaloric substitutions of replacing fats and carbohydrates with plant- or animal-derived protein and replacing food-specific animal protein with plant protein. Multiplicative interactions between dietary protein and prespecified variables were tested., Results: Neither plant- nor animal-derived protein intake was associated with incident CVD, IHD, or stroke in adjusted analyses without or with macronutrient-specified substitution analyses. Higher plant-derived protein intake was associated with 22% lower total stroke incidence among never smokers [HR 0.78, 95% confidence intervals (CI): 0.62, 0.99], but not among current smokers (HR 1.08, 95% CI: 0.83, 1.40, P-interaction = 0.004). Moreover, higher plant-derived protein (per 3% total energy) when replacing red meat protein (HR 0.52, 95% CI: 0.31, 0.88), processed meat protein (HR 0.39, 95% CI: 0.17, 0.90), and dairy protein (HR 0.54, 95% CI: 0.30, 0.98) was associated with lower incidence of fatal stroke., Conclusion: Plant- or animal-derived protein intake was not associated with overall CVD. However, the association of plant-derived protein consumption with lower total stroke incidence among nonsmokers, and with lower incidence of fatal stroke highlights the importance of investigating CVD subtypes and potential interactions. These observations warrant further investigation in diverse populations with varying macronutrient intakes and dietary patterns., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

West Nile virus (WNV) is an emerging mosquito-borne pathogen in Europe where it represents a new public health threat. While climate change has been cited as a potential driver of its spatial expansion on the continent, a formal evaluation of this causal relationship is lacking. Here, we investigate the extent to which WNV spatial expansion in Europe can be attributed to climate change while accounting for other direct human influences such as land-use and human population changes. To this end, we trained ecological niche models to predict the risk of local WNV circulation leading to human cases to then unravel the isolated effect of climate change by comparing factual simulations to a counterfactual based on the same environmental changes but a counterfactual climate where long-term trends have been removed. Our findings demonstrate a notable increase in the area ecologically suitable for WNV circulation during the period 1901-2019, whereas this area remains largely unchanged in a no-climate-change counterfactual. We show that the drastic increase in the human population at risk of exposure is partly due to historical changes in population density, but that climate change has also been a critical driver behind the heightened risk of WNV circulation in Europe., (© 2024. The Author(s).)

Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case-cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw. We analyzed 817 proteins and 1,025 metabolites in biobanked blood and 16 clinical variables. Forty-eight proteins, 43 metabolites, age, sex and systolic blood pressure were associated with the risk of an imminent first myocardial infarction. Brain natriuretic peptide was most consistently associated with the risk of imminent myocardial infarction. Using clinically readily available variables, we devised a prediction model for an imminent first myocardial infarction for clinical use in the general population, with good discriminatory performance and potential for motivating primary prevention efforts., (© 2024. The Author(s).)

The European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) is one of the world's leading sources of public biomolecular data. Based at the Wellcome Genome Campus in Hinxton, UK, EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe's only intergovernmental life sciences organisation. This overview summarises the latest developments in the services provided by EMBL-EBI data resources to scientific communities globally. These developments aim to ensure EMBL-EBI resources meet the current and future needs of these scientific communities, accelerating the impact of open biological data for all., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The European Nucleotide Archive (ENA; https://www.ebi.ac.uk/ena) is maintained by the European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI). The ENA is one of the three members of the International Nucleotide Sequence Database Collaboration (INSDC). It serves the bioinformatics community worldwide via the submission, processing, archiving and dissemination of sequence data. The ENA supports data types ranging from raw reads, through alignments and assemblies to functional annotation. The data is enriched with contextual information relating to samples and experimental configurations. In this article, we describe recent progress and improvements to ENA services. In particular, we focus upon three areas of work in 2023: FAIRness of ENA data, pandemic preparedness and foundational technology. For FAIRness, we have introduced minimal requirements for spatiotemporal annotation, created a metadata-based classification system, incorporated third party metadata curations with archived records, and developed a new rapid visualisation platform, the ENA Notebooks. For foundational enhancements, we have improved the INSDC data exchange and synchronisation pipelines, and invested in site reliability engineering for ENA infrastructure. In order to support genomic surveillance efforts, we have continued to provide ENA services in support of SARS-CoV-2 data mobilisation and have adapted these for broader pathogen surveillance efforts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Europe PMC (https://europepmc.org/) is an open access database of life science journal articles and preprints, which contains over 42 million abstracts and over 9 million full text articles accessible via the website, APIs and bulk download. This publication outlines new developments to the Europe PMC platform since the last database update in 2020 (1) and focuses on five main areas. (i) Improving discoverability, reproducibility and trust in preprints by indexing new preprint content, enriching preprint metadata and identifying withdrawn and removed preprints. (ii) Enhancing support for text and data mining by expanding the types of annotations provided and developing the Europe PMC Annotations Corpus, which can be used to train machine learning models to increase their accuracy and precision. (iii) Developing the Article Status Monitor tool and email alerts, to notify users about new articles and updates to existing records. (iv) Positioning Europe PMC as an open scholarly infrastructure through increasing the portion of open source core software, improving sustainability and accessibility of the service., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes 1 , we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans., (© 2024. The Author(s).)

Western Eurasia witnessed several large-scale human migrations during the Holocene 1-5 . Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations., (© 2024. The Author(s).)

Domestic cats were derived from the Near Eastern wildcat (Felis lybica), after which they dispersed with people into Europe. As they did so, it is possible that they interbred with the indigenous population of European wildcats (Felis silvestris). Gene flow between incoming domestic animals and closely related indigenous wild species has been previously demonstrated in other taxa, including pigs, sheep, goats, bees, chickens, and cattle. In the case of cats, a lack of nuclear, genome-wide data, particularly from Near Eastern wildcats, has made it difficult to either detect or quantify this possibility. To address these issues, we generated 75 ancient mitochondrial genomes, 14 ancient nuclear genomes, and 31 modern nuclear genomes from European and Near Eastern wildcats. Our results demonstrate that despite cohabitating for at least 2,000 years on the European mainland and in Britain, most modern domestic cats possessed less than 10% of their ancestry from European wildcats, and ancient European wildcats possessed little to no ancestry from domestic cats. The antiquity and strength of this reproductive isolation between introduced domestic cats and local wildcats was likely the result of behavioral and ecological differences. Intriguingly, this long-lasting reproductive isolation is currently being eroded in parts of the species' distribution as a result of anthropogenic activities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Named entity recognition (NER) is a widely used text-mining and natural language processing (NLP) subtask. In recent years, deep learning methods have superseded traditional dictionary- and rule-based NER approaches. A high-quality dataset is essential to fully leverage recent deep learning advancements. While several gold-standard corpora for biomedical entities in abstracts exist, only a few are based on full-text research articles. The Europe PMC literature database routinely annotates Gene/Proteins, Diseases, and Organisms entities. To transition this pipeline from a dictionary-based to a machine learning-based approach, we have developed a human-annotated full-text corpus for these entities, comprising 300 full-text open-access research articles. Over 72,000 mentions of biomedical concepts have been identified within approximately 114,000 sentences. This article describes the corpus and details how to access and reuse this open community resource., (© 2023. Springer Nature Limited.)

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., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Martens M et al.)

The systematic identification of tumour vulnerabilities through perturbational experiments on cancer models, including genome editing and drug screens, is playing a crucial role in combating cancer. This collective effort is known as the Cancer Dependency Map (DepMap). The 1st European Cancer Dependency Map Symposium (EuroDepMap), held in Milan last May, featured talks, a roundtable discussion, and a poster session, showcasing the latest discoveries and future challenges related to the DepMap. The symposium aimed to facilitate interactions among participants across Europe, encourage idea exchange with leading experts, and present their work and future projects. Importantly, it sparked discussions on future endeavours, such as screening more complex cancer models and accounting for tumour evolution., (© 2023 Federation of European Biochemical Societies.)

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject's right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws., (© 2023. The Author(s).)

In the field of life sciences there is a growing need for literature analysis tools that help scientists tackle information overload. Europe PubMed Central (Europe PMC), a partner of PubMed Central (PMC; National Library of Medicine, 2022), is an open access database of over 41 million life science publications and preprints, enriched with supporting data, reviews, protocols, and other relevant resources. Europe PMC is a trusted repository of choice for many life science funders (Europe PMC, 2022a), offering a suite of innovative search tools that allow users to search and evaluate the literature, including finding highly cited articles, preprints with community peer reviews, or papers referencing a proteomics dataset in the figure legend. In addition, Europe PMC utilizes text-mining to help researchers identify key terms and find data and evidence in the literature. First-time users often do not utilize the wealth of tools Europe PMC offers and can feel overwhelmed about how to perform the most effective search. This protocol, describing how to search and evaluate publications and preprints using Europe PMC, demonstrates how to carry out more efficient and effective literature searches using the tools provided by Europe PMC. This includes discovering the latest findings on a research topic, following research from a specific author, journal, or preprint server, exploring literature on a new method, expanding your reading list with relevant articles, as well as accessing and evaluating publications and preprints of interest. © 2023 EMBL-EBI. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Finding articles and preprints on a topic of interest Basic Protocol 2: Accessing an article Basic Protocol 3: Browsing the article Basic Protocol 4: Evaluating the article Basic Protocol 5: Refining search results Basic Protocol 6: Finding research by author Basic Protocol 7: Finding a specific article Basic Protocol 8: Finding information about a methodology Basic Protocol 9: Finding evidence of biological interactions, relations, and modifications Basic Protocol 10: Finding data behind a publication Basic Protocol 11: Expanding a reading list and building a bibliography Basic Protocol 12: Staying on top of the current literature., (© 2023 EMBL-EBI. Current Protocols published by Wiley Periodicals LLC.)

Background: The current study investigated physicians' understanding of the impact of transfusion status (TS) on clinical and economic outcomes in patients with myelodysplastic syndromes (MDS)., Materials & Methods: 378 physicians primarily specializing in hematology/oncology across five European countries completed the survey. The survey asked physicians for their perspectives on the impact of TS on risk of death, risk of progression to acute myeloid leukemia (AML), chance of leukemia-free survival, and number of significant bleeding events, infection events, hospitalizations, and emergency room (ER) visits., Results: Physicians estimated that compared to transfusion-dependent (TD) patients, transfusion-independent (TI) patients had a 37.6% reduced risk of death, lower risk of progression to AML, and lower risk of non-leukemic death, for all MDS risk levels. TD patients who became TI after treatment were estimated to have 40.6% reduced risk of death and 34% reduced risk of progression to AML, compared to TD patients who remained TD., Conclusions: Compared with TD patients, physicians estimated that TI patients have fewer events of infection and significant bleeding, and experience fewer hospitalizations and ER visits per person per year. Overall, physicians reported better outcomes for TI patients. New treatment options for patients with MDS to reduce or eliminate transfusion burden are warranted., (© 2022 Bristol Myers Squibb. Cancer Reports published by Wiley Periodicals LLC.)

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)

The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe and the Americas. However, SARS-CoV-2 sero-prevalence data has demonstrated that there has been more widespread transmission than can be deduced from reported cases. This could be attributed to under reporting due to low testing capacity or high numbers of asymptomatic SARS-CoV-2 infection in communities. Recent data indicates that prior SARS-CoV-2 exposure is protective against reinfection and that vaccination of previously SARS-CoV-2 infected individuals induces robust cross-reactive antibody responses. Considering these data, calls for a need for a re-think of the COVID-19 vaccination strategy in sub-Saharan African settings with high SARSCoV-2 population exposure but limited available vaccine doses. A potential recommendation would be to prioritize rapid and widespread vaccination of the first dose, while waiting for more vaccines to become available., Competing Interests: Potential conflicts of interest. B. K. participates in a DSMB for a COVID-19 vaccine and has advised the COVAX group on use of COVID vaccines in pregnant women. She also directs the vaccine center at LSHTM and the IMPRINT network. She also holds several grants for vaccine research studies outside of COVID-19 vaccines. E. U. claims participation in a PaTs COVID drug trial and held a position on the National Immunisation Technical Advisory Group, The Gambia. I. A. received an African Research Leader Fellowship grant (MR/S005293/1) and NIHR-MPRU at UCL grant (2268427 LSHTM) and has also participated in the WHO Programme Advisory Group, Malaria Vaccine Implementation Programme, the WHO Technical Advisory Group, Respiratory Syncytial Virus, and WHO Africa Region, Regional Immunisation Technical Advisory Group. O. T. I. is currently an employee of Sanofi Pasteur. All views expressed are those of the author and do not reflect those of her employer. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine., Methods: 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambaréné, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP; 3 × 10 5 to 1 × 10 8 plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity., Findings: Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (≥9 × 10 6 pfu) of rVSVΔG-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis)., Interpretation: Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSVΔG-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines., Funding: Innovative Medicines Initiative 2 Joint Undertaking., Competing Interests: Declaration of interests TPM is an employee of NewLink Genetics Corporation. SD and ME are employees of Merck Sharp & Dohme. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics 1 . Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development., (© 2022. The Author(s).)

The aim of the study is the analysis of educational needs of European intensive care nurses (ICNs) with regard to multicultural care. A mixed-method multinational study was performed among 591 ICNs coming from 15 European countries. An online survey was utilised with three research tools: participants' sociodemographic details, Healthcare Provider Cultural Competence Instrument, and a tool to assess the educational needs of ICU nurses with respect to multicultural care. The highest mean values in self-assessment of preparation of ICU nurses to provide multicultural nursing care and their educational needs in this regard were detected in the case of nurses coming from Southern Europe (M = 4.09; SD = 0.43). With higher age, nurses recorded higher educational needs in the scope of multicultural care ( r = 0.138; p = 0.001). In addition, speaking other languages significantly correlated with higher educational needs related to care of patients coming from different cultures (Z = -4.346; p < 0.001) as well as previous education on multicultural nursing care (Z = -2.530; p = 0.011). Experiences of difficult situations when caring for culturally diverse patients in ICU were classified into categories: 'treatment procedures and general nursing care', 'family visiting', 'gender issues', 'communication challenges', and 'consequences of difficult experiences'. The educational needs of intensive care nurses in caring for culturally diverse patients are closely related to experiencing difficult situations when working with such patients and their families.

The European Bioinformatics Institute (EMBL-EBI) maintains a comprehensive range of freely available and up-to-date molecular data resources, which includes over 40 resources covering every major data type in the life sciences. This year's service update for EMBL-EBI includes new resources, PGS Catalog and AlphaFold DB, and updates on existing resources, including the COVID-19 Data Platform, trRosetta and RoseTTAfold models introduced in Pfam and InterPro, and the launch of Genome Integrations with Function and Sequence by UniProt and Ensembl. Furthermore, we highlight projects through which EMBL-EBI has contributed to the development of community-driven data standards and guidelines, including the Recommended Metadata for Biological Images (REMBI), and the BioModels Reproducibility Scorecard. Training is one of EMBL-EBI's core missions and a key component of the provision of bioinformatics services to users: this year's update includes many of the improvements that have been developed to EMBL-EBI's online training offering., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Linking nucleotide sequence data (NSD) to scientific publication citations can enhance understanding of NSD provenance, scientific use, and reuse in the community. By connecting publications with NSD records, NSD geographical provenance information, and author geographical information, it becomes possible to assess the contribution of NSD to infer trends in scientific knowledge gain at the global level., Findings: We extracted and linked records from the European Nucleotide Archive to citations in open-access publications aggregated at Europe PubMed Central. A total of 8,464,292 ENA accessions with geographical provenance information were associated with publications. We conducted a data quality review to uncover potential issues in publication citation information extraction and author affiliation tagging and developed and implemented best-practice recommendations for citation extraction. We constructed flat data tables and a data warehouse with an interactive web application to enable ad hoc exploration of NSD use and summary statistics., Conclusions: The extraction and linking of NSD with associated publication citations enables transparency. The quality review contributes to enhanced text mining methods for identifier extraction and use. Furthermore, the global provision and use of NSD enable scientists worldwide to join literature and sequence databases in a multidimensional fashion. As a concrete use case, we visualized statistics of country clusters concerning NSD access in the context of discussions around digital sequence information under the United Nations Convention on Biological Diversity., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Schistosomes cause schistosomiasis, the world's second most important parasitic disease after malaria in terms of public health and social-economic impacts. A peculiar feature of these dioecious parasites is their ability to produce viable and fertile hybrid offspring. Originally only present in the tropics, schistosomiasis is now also endemic in southern Europe. Based on the analysis of two genetic markers the European schistosomes had previously been identified as hybrids between the livestock- and the human-infective species Schistosoma bovis and Schistosoma haematobium, respectively. Here, using PacBio long-read sequencing technology we performed genome assembly improvement and annotation of S. bovis, one of the parental species for which no satisfactory genome assembly was available. We then describe the whole genome introgression levels of the hybrid schistosomes, their morphometric parameters (eggs and adult worms) and their compatibility with two European snail strains used as vectors (Bulinus truncatus and Planorbarius metidjensis). Schistosome-snail compatibility is a key parameter for the parasites life cycle progression, and thus the capability of the parasite to establish in a given area. Our results show that this Schistosoma hybrid is strongly introgressed genetically, composed of 77% S. haematobium and 23% S. bovis origin. This genomic admixture suggests an ancient hybridization event and subsequent backcrosses with the human-specific species, S. haematobium, before its introduction in Corsica. We also show that egg morphology (commonly used as a species diagnostic) does not allow for accurate hybrid identification while genetic tests do., Competing Interests: The authors have declared that no competing interests exist.

Background There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. Methods and Results We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88-0.99]), cheese (HR, 0.98 [95% CI, 0.96-1.00]), and fish (HR, 0.87 [95% CI, 0.75-1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02-1.12]) and butter (HR, 1.02 [95% CI, 1.00-1.04]). Conclusions This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.

Threats to global biodiversity are increasingly recognised by scientists and the public as a critical challenge. Molecular sequencing technologies offer means to catalogue, explore, and monitor the richness and biogeography of life on Earth. However, exploiting their full potential requires tools that connect biodiversity infrastructures and resources. As a research infrastructure developing services and technical solutions that help integrate and coordinate life science resources across Europe, ELIXIR is a key player. To identify opportunities, highlight priorities, and aid strategic thinking, here we survey approaches by which molecular technologies help inform understanding of biodiversity. We detail example use cases to highlight how DNA sequencing is: resolving taxonomic issues; Increasing knowledge of marine biodiversity; helping understand how agriculture and biodiversity are critically linked; and playing an essential role in ecological studies. Together with examples of national biodiversity programmes, the use cases show where progress is being made but also highlight common challenges and opportunities for future enhancement of underlying technologies and services that connect molecular and wider biodiversity domains. Based on emerging themes, we propose key recommendations to guide future funding for biodiversity research: biodiversity and bioinformatic infrastructures need to collaborate closely and strategically; taxonomic efforts need to be aligned and harmonised across domains; metadata needs to be standardised and common data management approaches widely adopted; current approaches need to be scaled up dramatically to address the anticipated explosion of molecular data; bioinformatics support for biodiversity research needs to be enabled and sustained; training for end users of biodiversity research infrastructures needs to be prioritised; and community initiatives need to be proactive and focused on enabling solutions. For sequencing data to deliver their full potential they must be connected to knowledge: together, molecular sequence data collection initiatives and biodiversity research infrastructures can advance global efforts to prevent further decline of Earth's biodiversity., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Waterhouse RM et al.)

The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management., Competing Interests: Declaration of Interests GRT received research funding from Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Cidara Therapeutics, F2G, IMMY, Mayne Pharma, and Scynexis, and served as a consultant for Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Cidara Therapeutics, F2G, IMMY, Mayne Pharma, Scynexis, and Pfizer. MJB is a founding partner and holds shares of Micología Molecular SL, she has received grant support from the Instituto de Salud Carlos III and has been paid for talks on behalf of United Medical LTDA. AA-I has received research grants to their institution from F2G and honoraria as a speaker from Gilead Sciences and Pfizer. DA-J holds share options in Pulmocide and has received grant support from Pulmocide, Astellas Pharma, Pfizer, and Gilead Sciences. He has received lecture honoraria from Astellas Pharma, Pfizer, Gilead Sciences, and AstraZeneca. JWB has served as a consultant for Pfizer. JFWC has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong, and was an invited speaker for Gilead Sciences Hong Kong and Luminex Corporation. OAC is funded by the German Federal Ministry of Education and Research, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy (CECAD, EXC 2030—390661388), and has received research grants from Actelion, Amplyx Pharmaceuticals, Astellas Pharma, Basilea Pharmaceutica, Cidara Therapeutics, Da Volterra, F2G, Gilead Sciences, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, and, Scynexis. OAC is also a consultant to Actelion, Allecra Therapeutics, Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Biosys UK, Cidara Therapeutics, Da Volterra, Entasis, F2G, Gilead Sciences, Matinas BioPharma, MedPace, Menarini Ricerche, Roche Diagnostics, Merck/MSD, Nabriva Therapeutics, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, and Vical, and received lecture honoraria from Astellas, Basilea Pharmaceutica, Gilead Sciences, Grupo Biotoscana, Merck/MSD, and Pfizer. NK received honoraria from Astellas, Gilead Sciences, Merck/MSD, and Pfizer, and received grants from Merck/MSD and Pfizer. NK was a speaker for Astellas, Gilead Sciences, Merck/MSD, and Pfizer and an adviser for Gilead Sciences, Merck/MSD, and Pfizer. DCMK has sat on advisory boards for Becton Dickinson and Merck/MSD, and received financial and travel support unrelated to the current work from Merck/MSD. MHM has received research support and served as a consultant for Astellas and Scynexis. ISS has served as an adviser to Avir Pharma. AS has received grant funding from Astellas and has consulted for Scynexis, Minnetronix Medical, Mayne Pharma, and Viamet Pharmaceuticals. J-PG has received research grant support from Pfizer. FQ-T has received research grants from Astellas, Merck/MSD, and Pfizer, and also received payments for presentations and continued medical education from Merck/MSD, Pfizer, United Medical, and Teva Brazil. PEV reported grants from Gilead Sciences, Merck/MSD, Pfizer, F2G, and Thermo Fisher Scientific, and travel support from OLM Systems and IMMY, outside of the submitted work. ACP has received research grant support on behalf of Pfizer, Gilead Sciences, Merck/MSD, and IMMY. He has also given paid talks for Pfizer, United Medical, Gilead Sciences, Merck/MSD, Astellas, and IMMY, and participated on the medical board of Pfizer, United Medical, Gilead Sciences, and Merck/MSD. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool., Methods: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R)., Results: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers., Conclusions: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies., Competing Interests: Declaration of Competing Interest RC, AC, VBontemps, EL, EB, VB, MK, FC, MB, HdeK, PdeC, KH and IH have no conflicts of interest. ISG has received grants and personal fees from Vertex Pharmaceuticals, personal fees from Eloxx, and non-financial support from PTC Therapeutics; P-RB has received personal fees from Astra Zeneca, Boehringer-Ingelheim, Chiesi, GSK, Insmed, Novartis and Pfizer and grant from GSK; DH has received personal fees from Vertex; CM personal fees from Chiesi and Zambon., (Copyright © 2021. Published by Elsevier B.V.)

Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D., Competing Interests: Declaration of interests A.L.G.’s spouse is an employee of Genentech and holds stock options in Roche., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI)., Methods and Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds., Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CL is an Academic Editor on PLOS Medicine’s editorial board; ASB reports institutional grants outside of this work from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi; during the course of this project, PS became a full-time employee of GSK. No other conflicts of interest have been declared by the authors.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe., (© 2021. The Author(s).)

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior., Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ)., Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total ( r = - 0.50, p <.05) and subscale scores ( r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior ( r = - 0.45, p = .05) and positively with child age and diabetes duration ( r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c., Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention., Competing Interests: MT reports having received speaker honoraria from Minimed Medtronic and Novo Nordisk. MFr has received speaker honoraria from Minimed Medtronic and has served on advisory boards for Eli Lilly. JM is a member in the advisory board of Becton-Dickinson, Boehringer Ingelheim, Eli Lilly, Medtronic and Sanofi, and has received speaker honoraria from ABBOTT Diabetes Care, Astra Zeneca, Eli Lilly, Nintamed, Novo Nordisk, Roche Diabetes Care, Sanofi, Servier and Takeda. MW has received license fees from Becton Dickinson and has served as a consultant to Beckton Dickinson. SH declares speaker honoraria from Eli Lilly and Sanofi. EF-R reports having received speaker honoraria from Minimed Medtronic and Eli Lilly, serving on advisory boards for Eli Lilly. TK has received speaker honoraria from Minimed Medtronic, Roche and Eli Lilly and is member of an advisory board for ABBOTTt Diabetes Care. CdB has received speaker honoraria from Minimed Medtronic and is member of their European Psychology Advisory Board. FC does attend Advisory Boards and obtain speaking fees for ABBOTTt, Medtronic, Lilly, and NovoNordisk. BR-M reports having received speaker honoraria from Minimed Medtronic, Eli Lilly, Roche, Menarini and Novo Nordisk, serving on advisory boards for Eli Lilly. RH reports having received speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license fees from Medtronic, and being director at CamDiab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Beaufort, Pit-ten Cate, Schierloh, Cohen, Boughton, Tauschmann, Allen, Nagl, Fritsch, Yong, Metcalfe, Schaeffer, Fichelle, Thiele, Abt, Faninger, Mader, Slegtenhorst, Ashcroft, Wilinska, Sibayan, Kollman, Hofer, Fröhlich-Reiterer, Kapellen, Acerini, Campbell, Rami-Merhar and Hovorka.)

Reproductive longevity is essential for fertility and influences healthy ageing in women 1,2 , but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations 3 . The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Biomacromolecular structural data outgrew the legacy Protein Data Bank (PDB) format which the scientific community relied on for decades, yet the use of its successor PDBx/Macromolecular Crystallographic Information File format (PDBx/mmCIF) is still not widespread. Perhaps one of the reasons is the availability of easy to use tools that only support the legacy format, but also the inherent difficulties of processing mmCIF files correctly, given the number of edge cases that make efficient parsing problematic. Nevertheless, to fully exploit macromolecular structure data and their associated annotations such as multiscale structures from integrative/hybrid methods or large macromolecular complexes determined using traditional methods, it is necessary to fully adopt the new format as soon as possible., Results: To this end, we developed PDBeCIF, an open-source Python project for manipulating mmCIF and CIF files. It is part of the official list of mmCIF parsers recorded by the wwPDB and is heavily employed in the processes of the Protein Data Bank in Europe. The package is freely available both from the PyPI repository ( http://pypi.org/project/pdbecif ) and from GitHub ( https://github.com/pdbeurope/pdbecif ) along with rich documentation and many ready-to-use examples., Conclusions: PDBeCIF is an efficient and lightweight Python 2.6+/3+ package with no external dependencies. It can be readily integrated with 3rd party libraries as well as adopted for broad scientific analyses., (© 2021. The Author(s).)

The source of the COVID-19 pandemic is unknown, but the natural host of the progenitor sarbecovirus is thought to be Asian horseshoe (rhinolophid) bats. We identified and sequenced a novel sarbecovirus (RhGB01) from a British horseshoe bat, at the western extreme of the rhinolophid range. Our results extend both the geographic and species ranges of sarbecoviruses and suggest their presence throughout the horseshoe bat distribution. Within the spike protein receptor binding domain, but excluding the receptor binding motif, RhGB01 has a 77% (SARS-CoV-2) and 81% (SARS-CoV) amino acid homology. While apparently lacking hACE2 binding ability, and hence unlikely to be zoonotic without mutation, RhGB01 presents opportunity for SARS-CoV-2 and other sarbecovirus homologous recombination. Our findings highlight that the natural distribution of sarbecoviruses and opportunities for recombination through intermediate host co-infection are underestimated. Preventing transmission of SARS-CoV-2 to bats is critical with the current global mass vaccination campaign against this virus., (© 2021. The Author(s).)

Background: Understanding the processes that lead to hybridization of wolves and dogs is of scientific and management importance, particularly over large geographical scales, as wolves can disperse great distances. However, a method to efficiently detect hybrids in routine wolf monitoring is lacking. Microsatellites offer only limited resolution due to the low number of markers showing distinctive allele frequencies between wolves and dogs. Moreover, calibration across laboratories is time-consuming and costly. In this study, we selected a panel of 96 ancestry informative markers for wolves and dogs, derived from the Illumina CanineHD Whole-Genome BeadChip (174 K). We designed very short amplicons for genotyping on a microfluidic array, thus making the method suitable also for non-invasively collected samples., Results: Genotypes based on 93 SNPs from wolves sampled throughout Europe, purebred and non-pedigree dogs, and suspected hybrids showed that the new panel accurately identifies parental individuals, first-generation hybrids and first-generation backcrosses to wolves, while second- and third-generation backcrosses to wolves were identified as advanced hybrids in almost all cases. Our results support the hybrid identity of suspect individuals and the non-hybrid status of individuals regarded as wolves. We also show the adequacy of these markers to assess hybridization at a European-wide scale and the importance of including samples from reference populations., Conclusions: We showed that the proposed SNP panel is an efficient tool for detecting hybrids up to the third-generation backcrosses to wolves across Europe. Notably, the proposed genotyping method is suitable for a variety of samples, including non-invasive and museum samples, making this panel useful for wolf-dog hybrid assessments and wolf monitoring at both continental and different temporal scales.

Lymphogranuloma venereum (LGV), the invasive infection of the sexually transmissible infection (STI) Chlamydia trachomatis , is caused by strains from the LGV biovar, most commonly represented by ompA -genotypes L2b and L2. We investigated the diversity in LGV samples across an international collection over seven years using typing and genome sequencing. LGV-positive samples ( n =321) from eight countries collected between 2011 and 2017 (Spain n =97, Netherlands n =67, Switzerland n =64, Australia n =53, Sweden n =37, Hungary n =31, Czechia n =30, Slovenia n =10) were genotyped for pmpH and ompA variants. All were found to contain the 9 bp insertion in the pmpH gene, previously associated with ompA -genotype L2b. However, analysis of the ompA gene shows ompA -genotype L2b ( n =83), ompA -genotype L2 ( n =180) and several variants of these ( n =52; 12 variant types), as well as other/mixed ompA -genotypes ( n =6). To elucidate the genomic diversity, whole genome sequencing (WGS) was performed from selected samples using SureSelect target enrichment, resulting in 42 genomes, covering a diversity of ompA -genotypes and representing most of the countries sampled. A phylogeny of these data clearly shows that these ompA -genotypes derive from an ompA -genotype L2b ancestor, carrying up to eight SNPs per isolate. SNPs within ompA are overrepresented among genomic changes in these samples, each of which results in an amino acid change in the variable domains of OmpA (major outer membrane protein, MOMP). A reversion to ompA -genotype L2 with the L2b genomic backbone is commonly seen. The wide diversity of ompA -genotypes found in these recent LGV samples indicates that this gene is under immunological selection. Our results suggest that the ompA -genotype L2b genomic backbone is the dominant strain circulating and evolving particularly in men who have sex with men (MSM) populations.