Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

The surgical management of dysphagia secondary to diffuse idiopathic skeletal hyperostosis

OBJECTIVE: This study reviews the management pathway and surgical outcomes of patients referred to and operated on at a tertiary neurosurgical centre, for dysphagia associated with anterolateral cervical hyperostosis (ACH) in diffuse idiopathic skeletal hyperostosis (DISH). PATIENTS & METHODS: Electronic patient records for 6 patients who had undergone anterior cervical osteophytectomy for dysphagia secondary to ACH were reviewed. ACH diagnosis was made by an Ear, Nose and Throat (ENT) specialist and patients were referred to a neurosurgical-led multidisciplinary team (MDT) for review. A senior radiologist performed imaging measurements and vertebral level localization was confirmed via barium-swallow video-fluoroscopy. Speech and language therapists (SLTs) determined the suitability of pre-operative conservative management. Patients were followed-up post-operatively with clinical and radiological assessments. RESULTS: 6 patients (Male to female ratio, 6:0; mean age, 59 years) were referred to a tertiary neurosurgical centre with DISH related dysphagia, an average of 25 months after ENT review (range, 14-36 months) between 2005 and 2016. The vertebral levels implicated in dysphagia ranged from C2 to T1 with a median of 4 vertebral levels involved. The most frequently affected vertebral levels were C4-6 (all 6 patients). The average antero-posterior height (as measured on axial images) of the most prominent osteophyte was 15.9 mm (range 12.0-20.0 mm). Patients underwent elective cervical osteophytectomy on average 10.8 months after neurosurgical review (range, 3-36 months). One patient had a post-operative haematoma needing evacuation and prolonged hospital stay. The average duration of follow-up was 42.3 months. All our patients maintained good symptomatic resolution without osteophyte recurrence. CONCLUSIONS: All our patients experienced significant and sustained clinical improvement. Anterior cervical osteophytectomy consistently leads to improvement in symptomatic ACH patients without recurrence. Early referral to a neurosurgical multi-disciplinary team (MDT) is indicated in ACH related dysphagia, once conservative management has failed

Timing of Invasive Mechanical Ventilation and Death in Critically Ill Adults With Covid-19: A Multicenter Cohort Study

PURPOSE: To investigate if the timing of initiation of invasive mechanical ventilation (IMV) for critically ill patients with COVID-19 is associated with mortality. MATERIALS AND METHODS: The data for this study were derived from a multicenter cohort study of critically ill adults with COVID-19 admitted to ICUs at 68 hospitals across the US from March 1 to July 1, 2020. We examined the association between early (ICU days 1-2) versus late (ICU days 3-7) initiation of IMV and time-to-death. Patients were followed until the first of hospital discharge, death, or 90 days. We adjusted for confounding using a multivariable Cox model. RESULTS: Among the 1879 patients included in this analysis (1199 male [63.8%]; median age, 63 [IQR, 53-72] years), 1526 (81.2%) initiated IMV early and 353 (18.8%) initiated IMV late. A total of 644 of the 1526 patients (42.2%) in the early IMV group died, and 180 of the 353 (51.0%) in the late IMV group died (adjusted HR 0.77 [95% CI, 0.65-0.93]). CONCLUSIONS: In critically ill adults with respiratory failure from COVID-19, early compared to late initiation of IMV is associated with reduced mortality

A Preliminary Genome-Wide Association Study of Pain-Related Fear: Implications for Orofacial Pain

Background. Acute and chronic orofacial pain can significantly impact overall health and functioning. Associations between fear of pain and the experience of orofacial pain are well-documented, and environmental, behavioral, and cognitive components of fear of pain have been elucidated. Little is known, however, regarding the specific genes contributing to fear of pain. Methods. A genome-wide association study (GWAS; ) was performed to identify plausible genes that may predispose individuals to various levels of fear of pain. The total score and three subscales (fear of minor, severe, and medical/dental pain) of the Fear of Pain Questionnaire-9 (FPQ-9) were modeled in a variance components modeling framework to test for genetic association with 8.5 M genetic variants across the genome, while adjusting for sex, age, education, and income. Results. Three genetic loci were significantly associated with fear of minor pain (8q24.13, 8p21.2, and 6q26; for all) near the genes TMEM65, NEFM, NEFL, AGPAT4, and PARK2. Other suggestive loci were found for the fear of pain total score and each of the FPQ-9 subscales. Conclusions. Multiple genes were identified as possible candidates contributing to fear of pain. The findings may have implications for understanding and treating chronic orofacial pain

Compendium of Current Single Event Effects for Candidate Spacecraft Electronics for NASA

NASA spacecraft are subjected to a harsh space environment that includes exposure to various types of ionizing radiation. The performance of electronic devices in a space radiation environment are often limited by their susceptibility to single event effects (SEE). Ground-based testing is used to evaluate candidate spacecraft electronics to determine risk to spaceflight applications. Interpreting the results of radiation testing of complex devices is and adequate understanding of the test condition is critical. Studies discussed herein were undertaken to establish the application-specific sensitivities of candidate spacecraft and emerging electronic devices to single-event upset (SEU), single-event latchup (SEL), single-event gate rupture (SEGR), single-event burnout (SEB), and single-event transient (SET). For total ionizing dose (TID) and displacement damage dose (DDD) results, see a companion paper submitted to the 2015 Institute of Electrical and Electronics Engineers (IEEE) Nuclear and Space Radiation Effects Conference (NSREC) Radiation Effects Data Workshop (REDW) entitled "compendium of Current Total Ionizing Dose and Displacement Damage for Candidate Spacecraft Electronics for NASA by M. Campola, et al

Compendium of Current Single Event Effects for Candidate Spacecraft Electronics for NASA

We present the results of single event effects (SEE) testing and analysis investigating the effects of radiation on electronics. This paper is a summary of test results

Dementia risk and dynamic response to exercise: A non-randomized clinical trial

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background Physical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the Apolipoprotein epsilon 4 (APOE4) allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers. Methods Sixty-two older adults (73±5 years old, 41 female [67%]) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF). Results Genotyping failed in one individual (n = 23 APOE4 carriers and n = 38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellum across both groups. Among high inter-individual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise. Conclusions Our findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study provide an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease

Compendium of Current Single Event Effects Results from NASA Goddard Space Flight Center and NASA Electronic Parts and Packaging Program

We present the results of single event effects (SEE) testing and analysis investigating the effects of radiation on electronics. This paper is a summary of test results

Compendium of Single Event Effect Results from NASA Goddard Space Flight Center

We present the results of single event effects (SEE) testing and analysis investigating the effects of radiation on electronics.This paper is a summary of test results