Chris Winkelman

Background: Detection of brain-specific miRNAs in the peripheral blood could serve as a surrogate marker of traumatic brain injury (TBI). Here, we systematically identified brain-enriched miRNAs, and tested their utility for use as TBI biomarkers in the acute phase of care. Methods: Publically-available microarray data generated from 31 postmortem human tissues was used to rank 1,364 miRNAs in terms of their degree of brain-specific expression. Levels of the top five ranked miRNAs were then prospectively measured in serum samples collected from 10 TBI patients at hospital admission, as well as from 10 controls. Results: The top five miRNAs identified in our analysis (miR-137, miR-219a-5p, miR-128-3p, miR-124-3p, and miR-138-5p) exhibited 31 to 74-fold higher expression in brain relative to other tissues. Furthermore, their levels were elevated in serum from TBI patients compared to controls, and were collectively able to discriminate between groups with 90% sensitivity and 80% specificity. Subsequent informatic pathway analysis revealed that their target transcripts were significantly enriched for components of signaling pathways which are active in peripheral organs such as the heart. Conclusions: The five candidate miRNAs identified in this study have promise as blood biomarkers of TBI, and could also be molecular contributors to systemic physiologic changes commonly observed post-injury. A FINAL PEER REVIEWED VERSION OF THIS ARTICLE HAS BEEN PUBLISHED IN BRAIN INJURY AT THE FOLLOWING DOI: 10.1080/02699052.2020.1764102 There are some notable differences between the analysis presented in this preprint and our final peer-reviewed article. There was a single tissue sample originating from spinal cord that we had classified as a non-brain tissue in our original analysis outlined in this preprint. Because the composition of spinal cord and brain are highly similar in terms of gene expression, classifying this sample as a non-brain tissue dramatically reduced the levels of brain enrichment observed in the analysis. Because brain and spinal cord are molecularly highly similar, but technically distinct anatomical structures, we simply decided to exclude this sample from our final analysis published in Brain Injury to avoid confounds. The top 5 miRNAs identified in our original analysis still fell within the top 7 of this final analysis. In addition, the final analysis identified two additional miRNAs which could be candidate biomarkers based on levels of brain enrichment. The final article published in Brain Injury also reports an additional confirmatory tissue specificity analysis performed in a second independent dataset, as well as additional analysis examining the brain specificity of several notable previously proposed miRNA TBI biomarkers, which is not described in this preprint.

This report is a secondary analysis of data from a larger study of a nurse-led early therapeutic mobility intervention among patients receiving mechanical ventilation. This analysis evaluated whether intervention frequency or intensity was associated with pain or fatigue. Frequency was defined as once-daily versus twice-daily interventions. Intensity was defined as low (in-bed activities) or moderate (out-of-bed activities). Thirty-nine patients self-reported pain and fatigue immediately before and after the intervention. Neither pain nor fatigue increased significantly (mean increase, <1 [scale of 0-10] for 95% of interventions). Four patients reported decrements in pain; 1 reported a decrease in fatigue. Less than 5% of enrolled patients indicated a score change of +4 to +6 for pain or fatigue, typically with the first intervention that included sitting at the edge of the bed. Future research could examine the distress associated with these symptoms in critically ill adults receiving early therapeutic mobility interventions.

Background Standards for interfacility transport in the United States recommend that each transport request be triaged to ensure that each patient is transported by an appropriate mechanism and by the appropriate clinicians in order to meet the patient’s intratransport needs. No instrument currently exists to meet that need. The Transport Triage Tool, a novel instrument, has been designed to determine the clinician (paramedic, registered nurse, or advanced practice registered nurse) who will best meet the patient’s needs during transport. Objective To assess psychometric elements—that is, validity and reliability—of the Transport Triage Tool when used by health care professionals in determining which clinician is appropriate for interfacility transport. Methods A 3-step process was used to initially evaluate the reliability and validity of this tool when assigning a lead clinician during transport. Content and predictive validity were evaluated. Both intrarater and interrater agreement were used to examine reliability. Results Predictive validity was supported by an area under the receiver operating characteristic curve of 0.847 and a Youden index of 0.31. Percentage agreement and Cohen κ were reasonable across all periods of testing. Conclusions The Transport Triage Tool has acceptable predictive validity and reliability; however, this preliminary evaluation indicates that further refinement is needed. Large tertiary centers that offer variations in transport team composition may be able to use the Tool in its present form to train and evaluate individuals who make decisions regarding interfacility transport, although additional testing and evaluation are recommended.

Objective: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. Design: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines’ development. A general content review was completed face-to-face by all panel members in January 2017. Methods: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as “strong,” “conditional,” or “good” practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. Results: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. Conclusions: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.