Identification of major hemorrhage in trauma patients in the prehospital setting: diagnostic accuracy and impact on outcome.

BACKGROUND: Hemorrhage is the most common cause of potentially preventable death after injury. Early identification of patients with major hemorrhage (MH) is important as treatments are time-critical. However, diagnosis can be difficult, even for expert clinicians. This study aimed to determine how accurate clinicians are at identifying patients with MH in the prehospital setting. A second aim was to analyze factors associated with missed and overdiagnosis of MH, and the impact on mortality. METHODS: Retrospective evaluation of consecutive adult (≥16 years) patients injured in 2019-2020, assessed by expert trauma clinicians in a mature prehospital trauma system, and admitted to a major trauma center (MTC). Clinicians decided to activate the major hemorrhage protocol (MHPA) or not. This decision was compared with whether patients had MH in hospital, defined as the critical admission threshold (CAT+): administration of ≥3 U of red blood cells during any 60-minute period within 24 hours of injury. Multivariate logistical regression analyses were used to analyze factors associated with diagnostic accuracy and mortality. RESULTS: Of the 947 patients included in this study, 138 (14.6%) had MH. MH was correctly diagnosed in 97 of 138 patients (sensitivity 70%) and correctly excluded in 764 of 809 patients (specificity 94%). Factors associated with missed diagnosis were penetrating mechanism (OR 2.4, 95% CI 1.2 to 4.7) and major abdominal injury (OR 4.0; 95% CI 1.7 to 8.7). Factors associated with overdiagnosis were hypotension (OR 0.99; 95% CI 0.98 to 0.99), polytrauma (OR 1.3, 95% CI 1.1 to 1.6), and diagnostic uncertainty (OR 3.7, 95% CI 1.8 to 7.3). When MH was missed in the prehospital setting, the risk of mortality increased threefold, despite being admitted to an MTC. CONCLUSION: Clinical assessment has only a moderate ability to identify MH in the prehospital setting. A missed diagnosis of MH increased the odds of mortality threefold. Understanding the limitations of clinical assessment and developing solutions to aid identification of MH are warranted. LEVEL OF EVIDENCE: Level III-Retrospective study with up to two negative criteria. STUDY TYPE: Original research; diagnostic accuracy study

Does the biomarker search paradigm need re-booting?

The clinical problem of bladder cancer is its high recurrence and progression, and that the most sensitive and specific means of monitoring is cystoscopy, which is invasive and has poor patient compliance. Biomarkers for recurrence and progression could make a great contribution, but in spite of decades of research, no biomarkers are commercially available with the requisite sensitivity and specificity. In the post-genomic age, the means to search the entire genome for biomarkers has become available, but the conventional approaches to biomarker discovery are entirely inadequate to yield results with the new technology. Finding clinically useful biomarker panels with sensitivity and specificity equal to that of cystoscopy is a problem of systems biology

A Cognitive Architecture Based on a Learning Classifier System with Spiking Classifiers

© 2015, Springer Science+Business Media New York. Learning classifier systems (LCS) are population-based reinforcement learners that were originally designed to model various cognitive phenomena. This paper presents an explicitly cognitive LCS by using spiking neural networks as classifiers, providing each classifier with a measure of temporal dynamism. We employ a constructivist model of growth of both neurons and synaptic connections, which permits a genetic algorithm to automatically evolve sufficiently-complex neural structures. The spiking classifiers are coupled with a temporally-sensitive reinforcement learning algorithm, which allows the system to perform temporal state decomposition by appropriately rewarding “macro-actions”, created by chaining together multiple atomic actions. The combination of temporal reinforcement learning and neural information processing is shown to outperform benchmark neural classifier systems, and successfully solve a robotic navigation task

Somatic Integration of Single Ion Channel Responses of α7 Nicotinic Acetylcholine Receptors Enhanced by PNU-120596

Positive allosteric modulators of highly Ca2+-permeable α7 nicotinic acetylcholine receptors, such as PNU-120596, may become useful therapeutic tools supporting neuronal survival and function. However, despite promising results, the initial optimism has been tempered by the concerns for cytotoxicity. The same concentration of a given nicotinic agent can be neuroprotective, ineffective or neurotoxic due to differences in the expression of α7 receptors and susceptibility to Ca2+ influx among various subtypes of neurons. Resolution of these concerns may require an ability to reliably detect, evaluate and optimize the extent of α7 somatic ionic influx, a key determinant of the likelihood of neuronal survival and function. In the presence of PNU-120596 and physiological choline (∼10 µM), the activity of individual α7 channels can be detected in whole-cell recordings as step-like current/voltage deviations. However, the extent of α7 somatic influx remains elusive because the activity of individual α7 channels may not be integrated across the entire soma, instead affecting only specific subdomains located in the channel vicinity. Such a compartmentalization may obstruct detection and integration of α7 currents, causing an underestimation of α7 activity. By contrast, if step-like α7 currents are integrated across the soma, then a reliable quantification of α7 influx in whole-cell recordings is possible and could provide a rational basis for optimization of conditions that support survival of α7-expressing neurons. This approach can be used to directly correlate α7 single-channel activity to neuronal function. In this study, somatic dual-patch recordings were conducted using large hypothalamic and hippocampal neurons in acute coronal rat brain slices. The results demonstrate that the membrane electrotonic properties do not impede somatic signaling, allowing reliable estimates of somatic ionic and Ca2+ influx through α7 channels, while the somatic space-clamp error is minimal (∼0.01 mV/µm). These research efforts could benefit optimization of potential α7-PAM-based therapies

Wolbachia and DNA barcoding insects: patterns, potential and problems

Wolbachia is a genus of bacterial endosymbionts that impacts the breeding systems of their hosts. Wolbachia can confuse the patterns of mitochondrial variation, including DNA barcodes, because it influences the pathways through which mitochondria are inherited. We examined the extent to which these endosymbionts are detected in routine DNA barcoding, assessed their impact upon the insect sequence divergence and identification accuracy, and considered the variation present in Wolbachia COI. Using both standard PCR assays (Wolbachia surface coding protein – wsp), and bacterial COI fragments we found evidence of Wolbachia in insect total genomic extracts created for DNA barcoding library construction. When >2 million insect COI trace files were examined on the Barcode of Life Datasystem (BOLD) Wolbachia COI was present in 0.16% of the cases. It is possible to generate Wolbachia COI using standard insect primers; however, that amplicon was never confused with the COI of the host. Wolbachia alleles recovered were predominantly Supergroup A and were broadly distributed geographically and phylogenetically. We conclude that the presence of the Wolbachia DNA in total genomic extracts made from insects is unlikely to compromise the accuracy of the DNA barcode library; in fact, the ability to query this DNA library (the database and the extracts) for endosymbionts is one of the ancillary benefits of such a large scale endeavor – for which we provide several examples. It is our conclusion that regular assays for Wolbachia presence and type can, and should, be adopted by large scale insect barcoding initiatives. While COI is one of the five multi-locus sequence typing (MLST) genes used for categorizing Wolbachia, there is limited overlap with the eukaryotic DNA barcode region

Taming of the shrewd: novel eukaryotic genes from RNA viruses

Genomes of several yeast species contain integrated DNA copies of complete genomes or individual genes of non-retroviral double-strand RNA viruses as reported in a recent BMC Biology article by Taylor and Bruenn. The integrated virus-specific sequences are at least partially expressed and seem to evolve under pressure of purifying selection, indicating that these are functional genes. Together with similar reports on integrated copies of some animal RNA viruses, these results suggest that integration of DNA copies of non-reverse-transcribing RNA viruses might be much more common than previously thought. The integrated copies could contribute to acquired immunity to the respective viruses

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

The Occurrence of Photorhabdus-Like Toxin Complexes in Bacillus thuringiensis

Recently, genomic sequencing of a Bacillus thuringiensis (Bt) isolate from our collection revealed the presence of an apparent operon encoding an insecticidal toxin complex (Tca) similar to that first described from the entomopathogen Photorhabdus luminescens. To determine whether these genes are widespread among Bt strains, we screened isolates from the collection for the presence of tccC, one of the genes needed for the expression of fully functional toxin complexes. Among 81 isolates chosen to represent commonly encountered biochemical phenotypes, 17 were found to possess a tccC. Phylogenetic analysis of the 81 isolates by multilocus sequence typing revealed that all the isolates possessing a tccC gene were restricted to two sequence types related to Bt varieties morrisoni, tenebrionis, israelensis and toumanoffi. Sequencing of the ∼17 kb tca operon from two isolates representing each of the two sequence types revealed >99% sequence identity. Optical mapping of DNA from Bt isolates representing each of the sequence types revealed nearly identical plasmids of ca. 333 and 338 kbp, respectively. Selected isolates were found to be toxic to gypsy moth larvae, but were not as effective as a commercial strain of Bt kurstaki. Some isolates were found to inhibit growth of Colorado potato beetle. Custom Taqman® relative quantitative real-time PCR assays for Tc-encoding Bt revealed both tcaA and tcaB genes were expressed within infected gypsy moth larvae

Comparative Analysis of DNA Replication Timing Reveals Conserved Large-Scale Chromosomal Architecture

Recent evidence suggests that the timing of DNA replication is coordinated across megabase-scale domains in metazoan genomes, yet the importance of this aspect of genome organization is unclear. Here we show that replication timing is remarkably conserved between human and mouse, uncovering large regions that may have been governed by similar replication dynamics since these species have diverged. This conservation is both tissue-specific and independent of the genomic G+C content conservation. Moreover, we show that time of replication is globally conserved despite numerous large-scale genome rearrangements. We systematically identify rearrangement fusion points and demonstrate that replication time can be locally diverged at these loci. Conversely, rearrangements are shown to be correlated with early replication and physical chromosomal proximity. These results suggest that large chromosomal domains of coordinated replication are shuffled by evolution while conserving the large-scale nuclear architecture of the genome