Developing Brain Vital Signs: Initial Framework for Monitoring Brain Function Changes over Time

Clinical assessment of brain function relies heavily on indirect behavior-based tests. Unfortunately, behavior-based assessments are subjective and therefore susceptible to several confounding factors. Event-related brain potentials (ERPs), derived from electroencephalography (EEG), are often used to provide objective, physiological measures of brain function. Historically, ERPs have been characterized extensively within research settings, with limited but growing clinical applications. Over the past 20 years, we have developed clinical ERP applications for the evaluation of functional status following serious injury and/or disease. This work has identified an important gap: the need for a clinically accessible framework to evaluate ERP measures. Crucially, this enables baseline measures before brain dysfunction occurs, and might enable the routine collection of brain function metrics in the future much like blood pressure measures today. Here, we propose such a framework for extracting specific ERPs as potential “brain vital signs.” This framework enabled the translation/transformation of complex ERP data into accessible metrics of brain function for wider clinical utilization. To formalize the framework, three essential ERPs were selected as initial indicators: (1) the auditory N100 (Auditory sensation); (2) the auditory oddball P300 (Basic attention); and (3) the auditory speech processing N400 (Cognitive processing). First step validation was conducted on healthy younger and older adults (age range: 22–82 years). Results confirmed specific ERPs at the individual level (86.81–98.96%), verified predictable age-related differences (P300 latency delays in older adults, p < 0.05), and demonstrated successful linear transformation into the proposed brain vital sign (BVS) framework (basic attention latency sub-component of BVS framework reflects delays in older adults, p < 0.05). The findings represent an initial critical step in developing, extracting, and characterizing ERPs as vital signs, critical for subsequent evaluation of dysfunction in conditions like concussion and/or dementia

Proceedings from the Ice Hockey Summit III: Action on Concussion

The Ice Hockey Summit III provided updated scientific evidence on concussions in hockey to inform these five objectives: 1) describe sport-related concussion (SRC) epidemiology, 2) classify prevention strategies, 3) define objective, diagnostic tests, 4) identify treatment, and 5) integrate science and clinical care into prioritized action plans and policy. Our action plan evolved from 40 scientific presentations. The 155 attendees (physicians, athletic trainers, physical therapists, nurses, neuropsychologists, scientists, engineers, coaches, and officials) voted to prioritize these action items in the final Summit session. 1) Establish a national and international hockey data base for SRC at all levels, 2) eliminate body checking in Bantam youth hockey games, 3) expand a behavior modification program (Fair Play) to all youth hockey levels, 4) enforce game ejection penalties for fighting in Junior A and professional hockey leagues, 5) establish objective tests to diagnose concussion at point of care (POC), and 6) mandate baseline testing to improve concussion diagnosis for all age groups. Expedient implementation of the Summit III prioritized action items is necessary to reduce the risk, severity, and consequences of concussion in the sport of ice hockey

Molecular architecture of the antiophidic protein DM64 and its binding specificity to myotoxin II from Bothrops aasper venom

Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesDM64 is a toxin-neutralizing serum glycoprotein isolated from Didelphis aurita, an ophiophagous marsupial naturally resistant to snake envenomation. This 64 kDa antitoxin targets myotoxic phospholipases A2, which account for most local tissue damage of viperid snakebites. We investigated the noncovalent complex formed between native DM64 and myotoxin II, a myotoxic phospholipase-like protein from Bothrops asper venom. Analytical ultracentrifugation (AUC) and size exclusion chromatography indicated that DM64 is monomeric in solution and binds equimolar amounts of the toxin. Attempts to crystallize native DM64 for X-ray diffraction were unsuccessful. Obtaining recombinant protein to pursue structural studies was also challenging. Classical molecular modeling techniques were impaired by the lack of templates with more than 25% sequence identity with DM64. An integrative structural biology approach was then applied to generate a three-dimensional model of the inhibitor bound to myotoxin II. I-TASSER individually modeled the five immunoglobulin-like domains of DM64. Distance constraints generated by cross-linking mass spectrometry of the complex guided the docking of DM64 domains to the crystal structure of myotoxin II, using Rosetta. AUC, small-angle X-ray scattering (SAXS), molecular modeling, and molecular dynamics simulations indicated that the DM64-myotoxin II complex is structured, shows flexibility, and has an anisotropic shape. Inter-protein cross-links and limited hydrolysis analyses shed light on the inhibitor’s regions involved with toxin interaction, revealing the critical participation of the first, third, and fifth domains of DM64. Our data showed that the fifth domain of DM64 binds to myotoxin II amino-terminal and beta-wing regions. The third domain of the inhibitor acts in a complementary way to the fifth domain. Their binding to these toxin regions presumably precludes dimerization, thus interfering with toxicity, which is related to the quaternary structure of the toxin. The first domain of DM64 interacts with the functional site of the toxin putatively associated with membrane anchorage. We propose that both mechanisms concur to inhibit myotoxin II toxicity by DM64 binding. The present topological characterization of this toxin-antitoxin complex constitutes an essential step toward the rational design of novel peptide-based antivenom therapies targeting snake venom myotoxins.Ye

Phenylephrine infusion impact on surgical site infections after lower extremity bypass surgery.

OBJECTIVE: Lower extremity bypass (LEB) operations have high rates of surgical site infections (SSI). Phenylephrine is a commonly used vasoconstrictor which may reduce skin blood flow and increase the likelihood of SSI in these patients. We studied the potential effect of phenylephrine infusion during LEB surgery on SSI. METHODS: LEB cases and their demographic data were identified through the Vascular Quality Initiative registry. SSI in this population was identified using the hospital epidemiology surveillance database. Phenylephrine use in this population was identified through chart review. RESULTS: We identified 699 patients who underwent LEB; 82 (11.7%) developed an SSI, and 244 of 698 (35.0%) were treated with phenylephrine infusion. In bivariate analysis, higher body mass index (28.8 kg/m CONCLUSIONS: Phenylephrine infusion did not increase the risk of SSI in patients who underwent LEB

Developing brain vital signs: Initial framework for monitoring brain function changes over time

Clinical assessment of brain function relies heavily on indirect behavior-based tests. Unfortunately, behavior-based assessments are subjective and therefore susceptible to several confounding factors. Event-related brain potentials (ERPs), derived from electroencephalography (EEG), are often used to provide objective, physiological measures of brain function. Historically, ERPs have been characterized extensively within research settings, with limited but growing clinical applications. Over the past 20 years, we have developed clinical ERP applications for the evaluation of functional status following serious injury and/or disease. This work has identified an important gap: the need for a clinically accessible framework to evaluate ERP measures. Crucially, this enables baseline measures before brain dysfunction occurs, and might enable the routine collection of brain function metrics in the future much like blood pressure measures today. Here, we propose such a framework for extracting specific ERPs as potential brain vital signs. This framework enabled the translation/transformation of complex ERP data into accessible metrics of brain function for wider clinical utilization. To formalize the framework, three essential ERPs were selected as initial indicators: 1) the auditory N100 (Auditory sensation); 2) the auditory oddball P300 (Basic attention); and 3) the auditory speech processing N400 (Cognitive processing). First step validation was conducted on healthy younger and older adults (age range: 22-82 years). Results confirmed specific ERPs at the individual level (86.81%-98.96%), verified predictable age-related differences (P300 latency delays in older adults, p<0.05), and demonstrated successful linear transformation into the proposed brain vital sign (BVS) framework (basic attention latency sub-component of BVS framework reflects delays in older adults, p<0.05). The findings represent an initial critical step in developing, extracting, and characterizing ERPs as vital signs, critical for subsequent evaluation of dysfunction in conditions like concussion and/or dementia

Phosphorylation of the Conserved Transcription Factor ATF-7 by PMK-1 p38 MAPK Regulates Innate Immunity in Caenorhabditis elegans

Innate immunity in Caenorhabditis elegans requires a conserved PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway that regulates the basal and pathogen-induced expression of immune effectors. The mechanisms by which PMK-1 p38 MAPK regulates the transcriptional activation of the C. elegans immune response have not been identified. Furthermore, in mammalian systems the genetic analysis of physiological targets of p38 MAPK in immunity has been limited. Here, we show that C. elegans ATF-7, a member of the conserved cyclic AMP–responsive element binding (CREB)/activating transcription factor (ATF) family of basic-region leucine zipper (bZIP) transcription factors and an ortholog of mammalian ATF2/ATF7, has a pivotal role in the regulation of PMK-1–mediated innate immunity. Genetic analysis of loss-of-function alleles and a gain-of-function allele of atf-7, combined with expression analysis of PMK-1–regulated genes and biochemical characterization of the interaction between ATF-7 and PMK-1, suggest that ATF-7 functions as a repressor of PMK-1–regulated genes that undergoes a switch to an activator upon phosphorylation by PMK-1. Whereas loss-of-function mutations in atf-7 can restore basal expression of PMK-1–regulated genes observed in the pmk-1 null mutant, the induction of PMK-1–regulated genes by pathogenic Pseudomonas aeruginosa PA14 is abrogated. The switching modes of ATF-7 activity, from repressor to activator in response to activated PMK-1 p38 MAPK, are reminiscent of the mechanism of regulation mediated by the corresponding ancestral Sko1p and Hog1p proteins in the yeast response to osmotic stress. Our data point to the regulation of the ATF2/ATF7/CREB5 family of transcriptional regulators by p38 MAPK as an ancient conserved mechanism for the control of innate immunity in metazoans, and suggest that ATF2/ATF7 may function in a similar manner in the regulation of mammalian innate immunity.National Institutes of Health (U.S.) (Grant GM084477)Ministry of Education, Culture, Sports, Science and Technology of Japa