Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 mum RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development

CSF Biomarker Levels of Aß40 and TAU/Aß 42 Correspond to Neuropsychological Outcome in Chronic TBI Participants

Objectives: Traumatic brain injury (TBI) involves axonal injury and accumulation of pathological protein aggregates including amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Biomarker analysis of tau and Aβ concentrations in cerebrospinal fluid (CSF) may be an objective marker of cognitive status after TBI. The goal of the current study was to analyze tau and Aβ 40–42 in a cohort of military and civilian participants with chronic deficits secondary to TBI, and correlate neuropsychological outcome data with concentrations of tau and Aβ42 measured in CSF from the same subjects. Methods: 19 chronic TBI participants ( > 6 months from injury; 16 males, mean age 41yrs, 8 military veterans and 11 civilians) underwent lumbar puncture as well as neuropsychological testing. CSF was analyzed for concentrations of total tau, Aβ1-42 (Aβ42) and Aβ1-40 (Aβ40) by ELISA, and tau/Aβ42 ratio was calculated. The neuropsychological test battery included measures of memory, processing speed and executive function: California Verbal Learning Test-II (CVLT) Short and Long Delay Free Recall (SDFR, LDFR), Wechsler Adult Intelligence Scale Working Memory Index (WAIS IV) and Trail Making Test Part A/B. Nonparametric correlation (Spearman rho, ρ) was used to relate CSF levels to neuropsychological data, controlling for age. Results: CSF tau/Aβ42 ratio was inversely associated with Trails B (Spearman p > −0.49, p  −0.51, p  −0.50, p < 0.034, respectively). There were no significant correlations between CSF biomarker levels and WAIS neuropsychological measures. Conclusions: In chronic TBI, neuropsychological outcome on measures of memory and executive function (CVLT and Trails B) corresponded to CSF biomarkers of tau and Aβ concentrations. Additional studies with a larger cohort of TBI participants are needed to draw meaningful conclusions. The use of CSF biomarkers in ongoing studies will allow us to test more specific hypotheses regarding the link between TBI and chronic neurodegenerative conditions such as chronic traumatic encephalopathy

Recommendations for the use of common outcome measures in pediatric traumatic brain injury research

This article addresses the need for age-relevant outcome measures for traumatic brain injury (TBI) research and summarizes the recommendations by the inter-agency Pediatric TBI Outcomes Workgroup. The Pediatric Workgroup\u27s recommendations address primary clinical research objectives including characterizing course of recovery from TBI, prediction of later outcome, measurement of treatment effects, and comparison of outcomes across studies. Consistent with other Common Data Elements (CDE) Workgroups, the Pediatric TBI Outcomes Workgroup adopted the standard three-tier system in its selection of measures. In the first tier, core measures included valid, robust, and widely applicable outcome measures with proven utility in pediatric TBI from each identified domain including academics, adaptive and daily living skills, family and environment, global outcome, health-related quality of life, infant and toddler measures, language and communication, neuropsychological impairment, physical functioning, psychiatric and psychological functioning, recovery of consciousness, social role participation and social competence, social cognition, and TBI-related symptoms. In the second tier, supplemental measures were recommended for consideration in TBI research focusing on specific topics or populations. In the third tier, emerging measures included important instruments currently under development, in the process of validation, or nearing the point of published findings that have significant potential to be superior to measures in the core and supplemental lists and may eventually replace them as evidence for their utility emerges

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Time to Follow Commands in Severe Traumatic Brain Injury Survivors With Favorable Recovery at 2 Years.

BACKGROUND: The recovery of severe traumatic brain injury (TBI) survivors with long-term favorable outlook is understudied. Time to follow commands varies widely in this patient population but has important clinical implications. OBJECTIVE: To (1) evaluate time to follow commands in severe patients with TBI with favorable outcomes, (2) characterize their trajectory of recovery, and (3) identify predictors associated with delayed cognitive improvement. METHODS: Participants were recruited prospectively at a Level I trauma center through the Brain Trauma Research Center from 2003 to 2018. Inclusion criteria were age 16 to 80 years, Glasgow Coma Scale score ≤8 and motor score &lt;6, and Glasgow Outcome Scale-Extended measure ≥4 at 2 years postinjury. RESULTS: In 580 patients, there were 229 (39.5%) deaths and 140 (24.1%) patients had favorable outcomes at 2 years. The mean age was 33.7 ± 14.5 years, median Glasgow Coma Scale was 7 (IQR 6-7), and median Injury Severity Score was 30 (IQR 26-38). The mean time to follow commands was 12.7 ± 11.8 days. On multivariable linear regression, the presence of diffuse axonal injury (B = 9.2 days [4.8, 13.7], P &lt; .0001) or intraventricular hemorrhage (B = 6.4 days [0.5, 12.3], P &lt; .035) was associated with longer time before following commands and patients who developed nosocomial infections (B = 6.5 days [1.6-11.4], P &lt; .01). CONCLUSION: In severe TBI survivors with favorable outcomes, time to follow commands varied widely. Most patients began to follow commands within 2 weeks. Evidence of diffuse axonal injury, intraventricular hemorrhage, and infections can delay cognitive improvement in the acute period. Patients make considerable recovery up to 2 years after their injury