Capturing the ghost in the machine: a process for development and validation of measures of phenomenal consciousness in delirium.

BACKGROUND: Delirium has conventionally been considered a disorder of consciousness. Alertness and arousal are used as surrogates in clinical practice but are insufficient for the purposes of a more dimensional assessment of consciousness. We present a process of development and validation of candidate measures of phenomenal consciousness that could be applied to the diagnosis of delirium. METHODS: First, a narrative review of available instruments in the fields of phenomenal consciousness, including prereflective consciousness, the phenomenal-sensed experience and reflective thought, was undertaken. Eligibility of tools in the context of applicability to delirium was based upon objectivity in test interpretation and the requirement for tester administration. Second, where there was a gap in suitable cognitive tools, new items were derived using the silent generation technique. A process of face and construct validity using a diverse panel of experts was performed, and readability was evaluated. RESULTS: 814 articles were screened from the literature review. Fourteen candidate tools were reported from the three domains of phenomenal consciousness. One of these met the eligibility criteria for a delirium assessment. Fifty-seven new tests of phenomenal consciousness were identified. After a process of item reduction, a total of 26 individual tests were identified. After content validity, 22 of the 26 items were retained. The scale average content validity index was 0.89. The agreement between raters was between 80% and 97%. 100% of responses for face validity were rated as positive. Flesch Reading Ease Score was 91.6 (very easy to read). CONCLUSIONS: Candidate measures of phenomenal consciousness are described, and early validity studies are promising.

A narrative review of the development and performance characteristics of electronic delirium-screening tools.

BACKGROUND: Electronic delirium-screening tools are an emergent area of research. OBJECTIVE: The objective of this study was to summarise the development and performance characteristics of electronic screening tools in delirium. METHODS: Searches were conducted in Pubmed, Embase, and CINAHL Complete databases to identify electronic delirium-screening tools. RESULTS: Five electronic delirium-screening tools were identified and reviewed. Two were designed for and tested within a medical setting, and three were applied to intensive care. Adaptive design features, such as skip function to reduce test burden, were variably integrated into instrument design. All tools were shown to have acceptable psychometric properties, but validation studies were largely incomplete. CONCLUSIONS: Electronic delirium-screening tools are an exciting area of development and may offer hope for improved uptake of delirium screening.

MATR3 F115C knock-in mice do not exhibit motor defects or neuropathological features of ALS.

The F115C mutation in the MATR3 gene has been linked to amyotrophic lateral sclerosis (ALS). To determine the pathogenicity of the F115C mutation and the mechanism by which this mutation causes ALS, we generated mice that harbor the F115C mutation in the endogenous murine Matr3 locus. Heterozygous or homozygous MATR3 F115C knock-in mice were viable and did not exhibit motor deficits up to 2 years of age. The mutant mice showed no significant differences in the number of Purkinje cells or motor neurons compared to wild-type littermates. Neuropathological examination revealed an absence of MATR3 and TDP-43 pathology in Purkinje cells and motor neurons in the mutant mice. Together, our results suggest that the F115C mutation in MATR3 may not confer pathogenicity.

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.