Interrater Agreement between Bedside and Video Raters Using the CPOT-Neuro for Pain Assessment in Critically Ill Patients with a Brain Injury.

This study aimed to examine the interrater agreement of Critical-Care Pain Observation Tool-Neuro (CPOT-Neuro) scores as a newly developed tool for pain assessment in patients with critical illness and brain injury between raters using two methods of rating (bedside versus video) during standard care procedures (i.e., non-invasive blood pressure and turning). The bedside raters were research staff, and the two video raters had different backgrounds (health and non-health disciplines). Raters received standardized 45 min training by the principal investigator. Video recordings of 56 patient participants with a brain injury at different levels of consciousness were included. Interrater agreement was supported with an Intraclass Correlation Coefficient (ICC) > 0.65 for all pairs of raters and for each procedure. Interrater agreement was highest during turning in the conscious group, with ICCs ranging from 0.79 to 0.90. The use of video recordings was challenging for the observation of some behaviors (i.e., tearing, face flushing), which were influenced by factors such as lighting and the angle of the camera. Ventilator alarms were also challenging to distinguish from other sources for the video rater from a non-health discipline. Following standardized training, video technology was useful in achieving an acceptable interrater agreement of CPOT-Neuro scores between bedside and video raters for research purposes.

4E-BP1-dependent translation in nociceptors controls mechanical hypersensitivity via TRIM32/type I interferon signaling.

Activation of the mechanistic target of rapamycin complex 1 (mTORC1) contributes to the development of chronic pain. However, the specific mechanisms by which mTORC1 causes hypersensitivity remain elusive. The eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is a key mTORC1 downstream effector that represses translation initiation. Here, we show that nociceptor-specific deletion of 4E-BP1, mimicking activation of mTORC1-dependent translation, is sufficient to cause mechanical hypersensitivity. Using translating ribosome affinity purification in nociceptors lacking 4E-BP1, we identified a pronounced translational up-regulation of tripartite motif-containing protein 32 (TRIM32), an E3 ubiquitin ligase that promotes interferon signaling. Down-regulation of TRIM32 in nociceptors or blocking type I interferon signaling reversed the mechanical hypersensitivity in mice lacking 4E-BP1. Furthermore, nociceptor-specific ablation of TRIM32 alleviated mechanical hypersensitivity caused by tissue inflammation. These results show that mTORC1 in nociceptors promotes hypersensitivity via 4E-BP1-dependent up-regulation of TRIM32/interferon signaling and identify TRIM32 as a therapeutic target in inflammatory pain.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus.

OBJECTIVES: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. METHODS: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. RESULTS: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. DISCUSSION: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Destined for Greatness: A Family-Based Stress Management Intervention for African-American Mothers and their Children.

RATIONALE: African-American mothers in the U.S. experience high rates of stress, placing them at risk for depression, anxiety, and preterm births, and their children at risk for poor social-emotional development later in childhood. Yet, few studies have developed and tested family-based interventions that target optimal management of stress in this population. OBJECTIVE: The current mixed methods study examined whether a six-week family-based intervention (e.g., cognitive behavioral stress management intervention component for mothers and mindfulness-based kindness curriculum for their children) was effective in improving psychosocial outcomes among low-income African-American mothers and increasing prosocial behaviors in their children. METHOD: Seventy-two mothers (28% pregnant, 72% postpartum) completed pre- and post-intervention assessments of stress, depression, anxiety, and self-efficacy for stress management. Prosocial behaviors for 38 of their children (3-10 years of age) were also assessed via mother's self-report and two observational child assessments of sharing and helping behaviors. Qualitative interviews at post-intervention and reunion focus groups (up to two years later) were also conducted. RESULTS: Mothers showed significant reductions in perceived stress, depressive symptoms, and anxiety, as well as improved self-efficacy for stress management at post-intervention. Although observational assessments of children's sharing and helping behaviors did not change, mothers' qualitative responses indicated improvements in their child's prosocial behaviors at home. Qualitative responses also revealed unique stressors that mothers experienced, the short- and long-term impact of these interventions on mothers and their children, and program recommendations. CONCLUSIONS: These results support the efficacy of family-based stress management interventions in this at-risk population.