Brain computer tomography (brain CT) is an important imaging tool in patients with intracranial disorders. In ICU patients, a brain CT implies an intrahospital transport which has inherent risks. The ...proceeds and consequences of a brain CT in a critically ill patient should outweigh these risks. The aim of this study was to critically evaluate the diagnostic and therapeutic yield of brain CT in ICU patients.
In a prospective observational study data were collected during one year on the reasons to request a brain CT, expected abnormalities, abnormalities found by the radiologist and consequences for treatment. An "expected abnormality" was any finding that had been predicted by the physician requesting the brain CT. A brain CT was "diagnostically positive", if the abnormality found was new or if an already known abnormality was increased. It was "diagnostically negative" if an already known abnormality was unchanged or if an expected abnormality was not found. The treatment consequences of the brain CT, were registered as "treatment as planned", "treatment changed, not as planned", "treatment unchanged".
Data of 225 brain CT in 175 patients were analyzed. In 115 (51%) brain CT the abnormalities found were new or increased known abnormalities. 115 (51%) brain CT were found to be diagnostically positive. In the medical group 29 (39%) of brain CT were positive, in the surgical group 86 (57%), p 0.01. After a positive brain CT, in which the expected abnormalities were found, treatment was changed as planned in 33%, and in 19% treatment was changed otherwise than planned.
The results of this study show that the diagnostic and therapeutic yield of brain CT in critically ill patients is moderate. The development of guidelines regarding the decision rules for performing a brain CT in ICU patients is needed.
Making Messy Data Work for Conservation Dobson, A.D.M.; Milner-Gulland, E.J.; Aebischer, Nicholas J. ...
One earth (Cambridge, Mass.),
05/2020, Volume:
2, Issue:
5
Journal Article
Peer reviewed
Open access
Conservationists increasingly use unstructured observational data, such as citizen science records or ranger patrol observations, to guide decision making. These datasets are often large and ...relatively cheap to collect, and they have enormous potential. However, the resulting data are generally “messy,” and their use can incur considerable costs, some of which are hidden. We present an overview of the opportunities and limitations associated with messy data by explaining how the preferences, skills, and incentives of data collectors affect the quality of the information they contain and the investment required to unlock their potential. Drawing widely from across the sciences, we break down elements of the observation process in order to highlight likely sources of bias and error while emphasizing the importance of cross-disciplinary collaboration. We propose a framework for appraising messy data to guide those engaging with these types of dataset and make them work for conservation and broader sustainability applications.
Conservationists increasingly use unstructured observational data to guide decision making. These datasets have enormous potential, but the resulting data are generally "messy," and their use can incur considerable costs, some of which are hidden. We present an overview of these opportunities and limitations and propose a framework for appraising messy data to guide those wishing to make these datasets work for conservation and broader sustainability applications.
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Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (Ca V 2.2) is a well-validated ...pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of N -sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of N -sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both Ca V 2.2 and Ca V 3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in Ca V 2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood–brain barrier. Representative N -sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported N -acyl analogues. These compounds were also found to be relatively stable in an in vitro liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the Ca V 2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational changes required to open and allow calcium ions to pass through.
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Shorthorn sculpins, Myoxocephalus scorpius, are protected from freezing in icy seawater by alanine‐rich, α‐helical antifreeze proteins (AFPs). The major serum isoform (SS‐8) has been reisolated and ...analyzed to establish its correct sequence. Over most of its length, this 42 amino acid protein is predicted to be an amphipathic α‐helix with one face entirely composed of Ala residues. The other side of the helix, which is more heterogeneous and hydrophilic, contains several Lys. Computer simulations had suggested previously that these Lys residues were involved in binding of the peptide to the {11–20} plane of ice in the <−1102> direction. To test this hypothesis, a series of SS‐8 variants were generated with single Ala to Lys substitutions at various points around the helix. All of the peptides retained significant α‐helicity and remained as monomers in solution. Substitutions on the hydrophilic helix face at position 16, 19, or 22 had no obvious effect, but those on the adjacent Ala‐rich surface at positions 17, 21, and 25 abolished antifreeze activity. These results, with support from our own modeling and docking studies, show that the helix interacts with the ice surface via the conserved alanine face, and lend support to the emerging idea that the interaction of fish AFPs with ice involves appreciable hydrophobic interactions. Furthermore, our modeling suggests a new N terminus cap structure, which helps to stabilize the helix, whereas the role of the lysines on the hydrophilic face may be to enhance solubility of the protein.
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The cholesterol-dependent cytolysins (CDCs) attack cells by punching large holes in their membranes. Lectinolysin from Streptococcus mitis is unique among CDCs due to the presence of an N-terminal ...lectin domain that enhances the pore-forming activity of the toxin. We recently determined the crystal structures of the lectin domain in complex with various glycans. These structures revealed the molecular basis for the Lewis antigen specificity of the toxin. Based on this information we have used in silico molecular modeling to design a mutant toxin, which we predicted would increase its specificity for Lewis y, an antigen found on the surface of cancer cells. Surprisingly, we found by surface plasmon resonance binding experiments that the resultant mutant lectin domain exhibited higher specificity for Lewis b antigens instead. We then undertook comparative crystallographic and molecular dynamics simulation studies of the wild-type and mutant lectin domains to understand the molecular basis for the disparity between the theoretical and experimental results. The crystallographic results revealed that the net number of interactions between Lewis y and wild-type versus mutant was unchanged whereas there was a loss of a hydrogen bond between mutant and Lewis b compared to wild-type. In contrast, the molecular dynamics studies revealed that the Lewis b antigen spent more time in the binding pocket of the mutant compared to wild-type and the reverse was true for Lewis y. The results of these simulation studies are consistent with the conclusions drawn from the surface plasmon resonance studies. This work is part of a program to engineer lectinolysin so that it will target and kill specific cells in human diseases.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced five variants of concern (VOC) to date. The important spike mutation ‘N501Y’ is common to Alpha, Beta, Gamma, and Omicron ...VOC, while the ‘P681R’ is key to Delta’s spread. We have analysed circa 10 million SARS-CoV-2 genome sequences from the world’s largest repository, ‘Global Initiative on Sharing All Influenza Data (GISAID)’, and demonstrated that these two mutations have co-occurred on the spike ‘D614G’ mutation background at least 5767 times from 12 May 2020 to 28 April 2022. In contrast, the Y501-H681 combination, which is common to Alpha and Omicron VOC, is present in circa 1.1 million entries. Over half of the 5767 co-occurrences were in France, Turkey, or US (East Coast), and the rest across 88 other countries; 36.1%, 3.9%, and 4.1% of the co-occurrences were Alpha’s Q.4, Gamma’s P.1.8, and Omicron’s BA.1.1 sub-lineages acquiring the P681R; 4.6% and 3.0% were Delta’s AY.5.7 sub-lineage and B.1.617.2 lineage acquiring the N501Y; the remaining 8.2% were in other variants. Despite the selective advantages individually conferred by N501Y and P681R, the Y501-R681 combination counterintuitively did not outcompete other variants in every instance we have examined. While this is a relief to worldwide public health efforts, in vitro and in vivo studies are urgently required in the absence of a strong in silico explanation for this phenomenon. This study demonstrates a pipeline to analyse combinations of key mutations from public domain information in a systematic manner and provide early warnings of spread. The study here demonstrates the usage of the pipeline using the key mutations N501Y, P681R, and D614G of SARS-CoV-2.
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•Nature Futures Framework is a heiristic tool for creating positive futures for nature and people.•Nature Futures scenarios explore a mix of policies that progresses the world towards ...positive futures.•Reflecting diverse values and worldviews helps identify context-relevant interventions.•Mutually reinforcing positive social-ecological feedbacks can accelerate transformation pathways.•Indicators representing diverse values of nature build comprehensive evidence bases for policy.
The Nature Futures Framework (NFF) is a heuristic tool for co-creating positive futures for nature and people. It seeks to open up a diversity of futures through mainly three value perspectives on nature – Nature for Nature, Nature for Society, and Nature as Culture. This paper describes how the NFF can be applied in modelling to support decision-making. First, we describe key considerations for the NFF in developing qualitative and quantitative scenarios: i) multiple value perspectives on nature as a state space where pathways improving nature toward a frontier can be represented, ii) mutually reinforcing key feedbacks of social-ecological systems that are important for nature conservation and human wellbeing, iii) indicators of multiple knowledge systems describing the evolution of complex social-ecological dynamics. We then present three approaches to modelling Nature Futures scenarios in the review, screening, and design phases of policy processes. This paper seeks to facilitate the integration of relational values of nature in models and strengthen modelled linkages across biodiversity, nature’s contributions to people, and quality of life.
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Antifreeze proteins (AFPs) inhibit the growth of ice by binding to the surface of ice crystals, preventing the addition of water molecules to cause a local depression of the freezing point. AFPs from ...insects are much more effective at depressing the freezing point than fish AFPs. Here, we have investigated the possibility that insect AFPs bind more avidly to ice than fish AFPs. Because it is not possible to directly measure the affinity of an AFP for ice, we have assessed binding indirectly by examining the partitioning of proteins into a slowly growing ice hemisphere. AFP molecules adsorbed to the surface and became incorporated into the ice as they were overgrown. Solutes, including non-AFPs, were very efficiently excluded from ice, whereas AFPs became incorporated into ice at a concentration roughly equal to that of the original solution, and this was independent of the AFP concentration in the range (submillimolar) tested. Despite their >10-fold difference in antifreeze activity, fish and insect AFPs partitioned into ice to a similar degree, suggesting that insect AFPs do not bind to ice with appreciably higher affinity. Additionally, we have demonstrated that steric mutations on the ice binding surface that decrease the antifreeze activity of an AFP also reduce its inclusion into ice, supporting the validity of using partitioning measurements to assess a protein's affinity for ice.
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