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Endogenous metabolite levels describe the molecular phenotype that is most downstream from chemical exposure. Consequently, quantitative changes in metabolite levels have the potential to predict mode-of-action and adversity, with regulatory toxicology predicated on the latter. However, toxicity-related metabolic biomarker resources remain highly fragmented and incomplete. Although development of the S1500+ gene biomarker panel has accelerated the application of transcriptomics to toxicology, a similar initiative for metabolic biomarkers is lacking. Our aim was to define a publicly available metabolic biomarker panel, equivalent to S1500+, capable of predicting pathway perturbations and/or adverse outcomes. We conducted a systematic review of multiple toxicological resources, yielding 189 proposed metabolic biomarkers from existing assays (BASF, Bowes-44, and Tox21), 342 biomarkers from databases (Adverse Outcome Pathway Wiki, Comparative Toxicogenomics Database, QIAGEN Ingenuity Pathway Analysis, and Toxin and Toxin-Target Database), and 435 biomarkers from the literature. Evidence mapping across all 8 resources generated a panel of 722 metabolic biomarkers for toxicology (MTox700+), of which 462 (64%) are associated with molecular pathways and 575 (80%) with adverse outcomes. Comparing MTox700+ and S1500+ revealed that 418 (58%) metabolic biomarkers associate with pathways shared across both panels, with further metabolites mapping to unique pathways. Metabolite reference standards are commercially available for 646 (90%) of the panel metabolites, and assays exist for 578 (80%) of these biomarkers. This study has generated a publicly available metabolic biomarker panel for toxicology, which through its future laboratory deployment, is intended to help build foundational knowledge to support the generation of molecular mechanistic data for chemical hazard assessment.

Protein coronas on nanoparticles (NPs) affect their physicochemical properties, cellular uptake, and toxicity, and have been described extensively. To date, studies of the occurrence of small molecule (metabolite) coronas are limited. We sought to determine whether a metabolite corona forms on NPs, using high-sensitivity metabolomics combined with a model system for freshwater ecotoxicology (Daphnia magna feeding on Chlorella vulgaris). Using amino-functionalized polystyrene NPs (NH2-pNPs), we showed the impact of this material on Daphnia feeding to provide a rationale for the detailed molecular investigations. We then employed a targeted LC-MS/MS approach for sodium dodecyl sulfate (SDS) as an analog to signaling molecules known to occur in our freshwater model system and optimized a corona extraction method for this representative metabolite. Next, we performed an untargeted discovery-based metabolomics study – using high-sensitivity nanoelectrospray direct infusion mass spectrometry (DIMS) – to enable an unbiased assessment of the metabolite corona of NH2-pNPs in the freshwater model system. Our results demonstrate that SDS was successfully recovered from NH2-pNPs, confirming that the extraction protocol was fit-for-purpose. Untargeted DIMS metabolomics reproducibly detected 100 s of small molecule peaks extracted from NH2-pNPs exposed to conditioned media from the D. magna–C. vulgaris model system. Attempts to annotate these extracted metabolites, including by using van Krevelen and Kendrick Mass Defect plots, indicate a diverse range of metabolites that were not clustered into any particular class. Overall we demonstrate the existence of an ecologically relevant metabolite corona on the surface of NPs through application of a high-sensitivity, untargeted mass spectrometry metabolomics workflow.

BackgroundThe Investigation/Study/Assay (ISA) Metadata Framework is an established and widely used set of open-source community specifications and software tools for enabling discovery, exchange and publication of metadata from experiments in the life sciences. The original ISA software suite provided a set of user-facing Java tools for creating and manipulating the information structured in ISA-Tab – a now widely used tabular format. To make the ISA framework more accessible to machines and enable programmatic manipulation of experiment metadata, a JSON serialization ISA-JSON was developed.ResultsIn this work, we present the ISA API, a Python library for the creation, editing, parsing, and validating of ISA-Tab and ISA-JSON formats by using a common data model engineered as Python object classes. We describe the ISA API feature set, early adopters and its growing user community.ConclusionsThe ISA API provides users with rich programmatic metadata handling functionality to support automation, a common interface and an interoperable medium between the two ISA formats, as well as with other life science data formats required for depositing data in public databases.

Background The Investigation/Study/Assay (ISA) Metadata Framework is an established and widely used set of open source community specifications and software tools for enabling discovery, exchange, and publication of metadata from experiments in the life sciences. The original ISA software suite provided a set of user-facing Java tools for creating and manipulating the information structured in ISA-Tab—a now widely used tabular format. To make the ISA framework more accessible to machines and enable programmatic manipulation of experiment metadata, the JSON serialization ISA-JSON was developed. Results In this work, we present the ISA API, a Python library for the creation, editing, parsing, and validating of ISA-Tab and ISA-JSON formats by using a common data model engineered as Python object classes. We describe the ISA API feature set, early adopters, and its growing user community. Conclusions The ISA API provides users with rich programmatic metadata-handling functionality to support automation, a common interface, and an interoperable medium between the 2 ISA formats, as well as with other life science data formats required for depositing data in public databases.

Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.54.

Background Physical restraints are frequently used for intensive care patients and are associated with substantial morbidity. The effects of common evidence-based critical care interventions on use of physical restraints remain unclear. Objective To identify independent predictors of new-onset use of physical restraints in critically ill adults. Methods Secondary analysis of a prospective cohort study involving 5 adult intensive care units in a tertiary care medical center in the United States. Use of physical restraints was determined via daily in-person assessments and medical record review. Mixed-effects logistic regression analysis was used to examine factors associated with new-onset use of physical restraints, adjusting for covariates and within-subject correlation among intensive care unit days. Results Of 145 patients who were free of physical restraints within 48 hours of intensive care unit admission, 24 (16.6%) had restraints newly applied during their stay. In adjusted models, delirium (odds ratio [OR], 5.09; 95% CI, 1.83-14.14), endotracheal tube presence (OR, 3.47; 95% CI, 1.22-9.86), and benzodiazepine administration (OR, 3.17; 95% CI, 1.28-7.81) significantly increased the odds of next-day use of physical restraints. Tracheostomy was associated with significantly lowered odds of next-day restraint use (OR, 0.13; 95% CI, 0.02-0.73). Compared with patients with a target sedation level, patients who were in a coma (OR, 2.56; 95% CI, 0.80-8.18) or deeply sedated (OR, 2.53; 95% CI, 0.91-7.08) had higher odds of next-day use of physical restraints, and agitated patients (OR, 0.08; 95% CI, 0.00-2.07) were less likely to experience restraint use. Conclusion Several potentially modifiable risk factors are associated with next-day use of physical restraints.

Protein corona formation on nanoparticles (NPs), affect NP physicochemical properties, cellular uptake and toxicity, and has been reported extensively. To date, studies of the occurrence and potential importance of small molecule (metabolite) coronas are limited. We sought to determine such a corona using high-sensitivity metabolomics combined with a well-established model system for freshwater ecotoxicology (Daphnia magna feeding on Chlorella vulgaris) and amino functionalised polystyrene NPs (NH2-pNPs). Initially, we optimised our method using a targeted LC-MS/MS approach for sodium dodecylsulphate (SDS) as an analogue to signalling molecules that are known to occur in our freshwater model system. Following, we performed an untargeted discovery metabolomics study – using high-sensitivity nanoelectrospray direct infusion mass spectrometry (DIMS) for the unbiased assessment of the metabolite corona of NH2-pNPs in the freshwater model system. Untargeted DIMS metabolomics reproducibly detected 100s of small molecule peaks extracted from the NH2-pNPs when exposed to conditioned media from the D. magna-C. vulgaris model system. Attempts to annotate these extracted metabolites, including through the application of van Krevelen and Kendrick Mass Defect plots, indicate a diverse range of metabolites that were not clustered into any particular class. Overall, we demonstrate the existence of an ecologically relevant metabolite corona on the surface of NPs through application of a high-sensitivity, untargeted mass spectrometry metabolomics workflow.

The International Mouse Phenotyping Consortium (IMPC) is providing the world's first functional catalogue of a mammalian genome by characterising a knockout mouse strain for every gene. A robust and highly structured informatics platform has been developed to systematically collate, analyse and disseminate the data produced by the IMPC. As the first phase of the project, in which 5000 new knockout strains are being broadly phenotyped, nears completion, the informatics platform is extending and adapting to support the increasing volume and complexity of the data produced as well as addressing a large volume of users and emerging user groups. An intuitive interface helps researchers explore IMPC data by giving overviews and the ability to find and visualise data that support a phenotype assertion. Dedicated disease pages allow researchers to find new mouse models of human diseases, and novel viewers provide high-resolution images of embryonic and adult dysmorphologies. With each monthly release, the informatics platform will continue to evolve to support the increased data volume and to maintain its position as the primary route of access to IMPC data and as an invaluable resource for clinical and non-clinical researchers.

Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts.

Background: Diagnostic reasoning is often used colloquially to describe the process by which nurse practitioners and physicians come to the correct diagnosis, but a rich definition and description of this process has been lacking in the nursing literature. Method: A literature review was conducted with theoretical sampling seeking conceptual insight into diagnostic reasoning. Results: Four common themes emerged: Cognitive Biases and Debiasing Strategies, the Dual Process Theory, Diagnostic Error, and Patient Harm. Relevant cognitive biases are discussed, followed by debiasing strategies and application of the dual process theory to reduce diagnostic error and harm. Conclusion: The accuracy of diagnostic reasoning of nurse practitioners may be improved by incorporating these items into nurse practitioner education and practice. [ J Nurs Educ. 2018;57(4):203–208.]

Tandem mass spectrometry (MS/MS or MS

Summary Submission to the MetaboLights repository for metabolomics data currently places the burden of reporting instrument and acquisition parameters in ISA-Tab format on users, who have to do it manually, a process that is time consuming and prone to user input error. Since the large majority of these parameters are embedded in instrument raw data files, an opportunity exists to capture this metadata more accurately. Here we report a set of Python packages that can automatically generate ISA-Tab metadata file stubs from raw XML metabolomics data files. The parsing packages are separated into mzML2ISA (encompassing mzML and imzML formats) and nmrML2ISA (nmrML format only). Overall, the use of mzML2ISA & nmrML2ISA reduces the time needed to capture metadata substantially (capturing 90% of metadata on assay and sample levels), is much less prone to user input errors, improves compliance with minimum information reporting guidelines and facilitates more finely grained data exploration and querying of datasets. Availability and Implementation mzML2ISA & nmrML2ISA are available under version 3 of the GNU General Public Licence at https://github.com/ISA-tools. Documentation is available from http://2isa.readthedocs.io/en/latest/. Supplementary information Supplementary data are available at Bioinformatics online.

This work was completed through funding provided by the BBSRC [BB/L005077/1 and BB/M019985/1] and Wellcome Trust [202952/Z/16/Z].

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Part of the responsibility of a professional society is to establish the expectations for appropriate behavior for its members. Some codes are so essential to a society that the code itself becomes the central document defining the organization and its tenets, as we see with the Hippocratic Oath. In that tradition, we have revised the code of professional conduct for the Neurocritical Care Society into its current version, which emphasizes guidelines for personal behavior, relationships with fellow members, relationships with patients, and our interactions with society as a whole. This will be a living document and updated as the needs of our society change in time.Available online: http://www.neurocriticalcare.org/about-us/bylaws-procedures-and-code-professional-conduct (1) Code of professional conduct (this document) (2) Leadership code of conduct (3) Disciplinary policy.

Studies have shown that individuals influence their health outcomes, both positively and negatively, through their illness representation. To date, no studies describe the illness representation of persons with systolic heart failure, a significant contributor of morbidity and mortality in older adults. The purpose of this study was to describe illness representation in heart failure. Twenty-two subjects with New York Heart Association class II or III systolic heart failure were recruited at a university-based heart failure clinic. Illness representation was measured using the revised Illness Perception Questionnaire. The means on each of the 9 subscales were found to be significantly different from the neutral point of 3. The results suggest that participants believed that their heart failure was a chronic, cyclic disease with serious consequences that they could control through treatment. In addition, participants believed that they understood their heart failure and did not have a negative affective response to their heart failure.

Nature 537, 508–514 (2016); doi:10.1038/nature19356 In this Article, the author Wolfgang Wurst was erroneously omitted from the author list. They are associated with the affiliations: HelmholtzZentrum Munich, Institute of Developmental Genetics, 85764 Munich-Neuherberg, Germany; Technical Universityof Munich, Chair of Developmental Genetics, 85764 Munich-Neuherberg, Germany; German Center for Neurodegenerative Diseases (DZNE) Site Munich, 81377 Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.