Study of fault-tolerant software technology

Presented is an overview of the current state of the art of fault-tolerant software and an analysis of quantitative techniques and models developed to assess its impact. It examines research efforts as well as experience gained from commercial application of these techniques. The paper also addresses the computer architecture and design implications on hardware, operating systems and programming languages (including Ada) of using fault-tolerant software in real-time aerospace applications. It concludes that fault-tolerant software has progressed beyond the pure research state. The paper also finds that, although not perfectly matched, newer architectural and language capabilities provide many of the notations and functions needed to effectively and efficiently implement software fault-tolerance

The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial: an adaptive trial design case study

Background: The \u27Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT)\u27 project is a collaborative effort supported by the National Institutes of Health (NIH) and United States Food & Drug Administration (FDA) to explore how adaptive clinical trial design might improve the evaluation of drugs and medical devices. ADAPT-IT uses the National Institute of Neurologic Disorders & Stroke-supported Neurological Emergencies Treatment Trials (NETT) network as a \u27laboratory\u27 in which to study the development of adaptive clinical trial designs in the confirmatory setting. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial was selected for funding by the NIH-NINDS at the start of ADAPT-IT and is currently an ongoing phase III trial of tight glucose control in hyperglycemic acute ischemic stroke patients. Within ADAPT-IT, a Bayesian adaptive Goldilocks trial design alternative was developed. Methods: The SHINE design includes response adaptive randomization, a sample size re-estimation, and monitoring for early efficacy and futility according to a group sequential design. The Goldilocks design includes more frequent monitoring for predicted success or futility and a longitudinal model of the primary endpoint. Both trial designs were simulated and compared in terms of their mean sample size and power across a range of treatment effects and success rates for the control group. Results: As simulated, the SHINE design tends to have slightly higher power and the Goldilocks design has a lower mean sample size. Both designs were tuned to have approximately 80% power to detect a difference of 25% versus 32% between control and treatment, respectively. In this scenario, mean sample sizes are 1,114 and 979 for the SHINE and Goldilocks designs, respectively. Conclusions: Two designs were brought forward, and both were evaluated, revised, and improved based on the input of all parties involved in the ADAPT-IT process. However, the SHINE investigators were tasked with choosing only a single design to implement and ultimately elected not to implement the Goldilocks design. The Goldilocks design will be retrospectively executed upon completion of SHINE to later compare the designs based on their use of patient resources, time, and conclusions in a real world setting

Descriptive Analysis of a Baseline Concussion Battery Among U.S. Service Academy Members: Results from the Concussion Assessment, Research, and Education (CARE) Consortium

Introduction The prevalence and possible long-term consequences of concussion remain an increasing concern to the U.S. military, particularly as it pertains to maintaining a medically ready force. Baseline testing is being used both in the civilian and military domains to assess concussion injury and recovery. Accurate interpretation of these baseline assessments requires one to consider other influencing factors not related to concussion. To date, there is limited understanding, especially within the military, of what factors influence normative test performance. Given the significant physical and mental demands placed on service academy members (SAM), and their relatively high risk for concussion, it is important to describe demographics and normative profile of SAMs. Furthermore, the absence of available baseline normative data on female and non-varsity SAMs makes interpretation of post-injury assessments challenging. Understanding how individuals perform at baseline, given their unique individual characteristics (e.g., concussion history, sex, competition level), will inform post-concussion assessment and management. Thus, the primary aim of this manuscript is to characterize the SAM population and determine normative values on a concussion baseline testing battery. Materials and Methods All data were collected as part of the Concussion Assessment, Research and Education (CARE) Consortium. The baseline test battery included a post-concussion symptom checklist (Sport Concussion Assessment Tool (SCAT), psychological health screening inventory (Brief Symptom Inventory (BSI-18) and neurocognitive evaluation (ImPACT), Balance Error Scoring System (BESS), and Standardized Assessment of Concussion (SAC). Linear regression models were used to examine differences across sexes, competition levels, and varsity contact levels while controlling for academy, freshman status, race, and previous concussion. Zero inflated negative binomial models estimated symptom scores due to the high frequency of zero scores. Results Significant, but small, sex effects were observed on the ImPACT visual memory task. While, females performed worse than males (p < 0.0001, pη2 = 0.01), these differences were small and not larger than the effects of the covariates. A similar pattern was observed for competition level on the SAC. There was a small, but significant difference across competition level. SAMs participating in varsity athletics did significantly worse on the SAC compared to SAMs participating in club or intramural athletics (all p’s < 0.001, η2 = 0.01). When examining symptom reporting, males were more than two times as likely to report zero symptoms on the SCAT or BSI-18. Intramural SAMs had the highest number of symptoms and severity compared to varsity SAMs (p < 0.0001, Cohen’s d < 0.2). Contact level was not associated with SCAT or BSI-18 symptoms among varsity SAMs. Notably, the significant differences across competition level on SCAT and BSI-18 were sub-clinical and had small effect sizes. Conclusion The current analyses provide the first baseline concussion battery normative data among SAMs. While statistically significant differences may be observed on baseline tests, the effect sizes for competition and contact levels are very small, indicating that differences are likely not clinically meaningful at baseline. Identifying baseline differences and significant covariates is important for future concussion-related analyses to inform concussion evaluations for all athlete levels

The Association Between Persistent White-Matter Abnormalities and Repeat Injury After Sport-Related Concussion

Objective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion. Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (<48 h), at an asymptomatic time point, 7 days post-return to play (RTP), and 6 months relative to controls (n = 69). The relationship between MD in the identified ROI and likelihood of sustaining a subsequent concussion over a 1-year period was examined with a binary logistic regression (re-injured, yes/no). Results: Eleven of 82 concussed athletes (13.4%) sustained a second concussion within 12 months of initial injury. Mean MD at 7 days post-RTP was significantly higher in those athletes who went on to sustain a repeat concussion within 1 year of initial injury than those who did not (p = 0.048; d = 0.75). In this underpowered sample, the relationship between MD at 7 days post-RTP and likelihood of sustaining a secondary injury approached significance [χ2 (1) = 4.17, p = 0.057; B = 0.03, SE = 0.017; OR = 1.03, CI = 0.99, 1.07]. Conclusions: These preliminary findings raise the hypothesis that persistent signal abnormalities in diffusion imaging metrics at RTP following concussion may be predictive of a repeat concussion. This may reflect a window of cerebral vulnerability or increased susceptibility following concussion, though understanding the clinical significance of these findings requires further study

Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium

Importance: There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective: To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants: This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures: Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. Results: A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non-contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001). Conclusions and Relevance: The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC

Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans.

Cortistatin (CST)-14, a neuropeptide with high homology with somatostatin (SS)-14, binds all sst subtypes but, unlike SS, also ghrelin's receptor. In six normal adults, we studied the effects of CST-14 or SS-14 administration (2.0 micro g/kg/h iv) on: 1) GH and insulin secretion; 2) the GH response to GHRH (1.0 microg/kg i.v.); and 3) the GH, prolactin (PRL), ACTH, cortisol, insulin, and glucose responses to ghrelin (1.0 microg/kg i.v.). CST-14 inhibited GH and insulin secretion (P < 0.01) to the same extent of SS-14. The GH response to GHRH was similarly inhibited (P < 0.01) by either CST-14 or SS-14. Ghrelin released more GH than GHRH (P < 0.01); these responses were similarly inhibited (P < 0.05) by either CST-14 or SS-14, that made ghrelin-induced GH rise similar to that after GHRH alone. Neither CST-14 nor SS-14 modified PRL, ACTH, or cortisol responses to ghrelin. The inhibitory effect of CST-14 and SS-14 on insulin was unaffected by ghrelin that, in turn, reduced insulin secretion per se (P < 0.01). Ghrelin increased glucose levels (P < 0.05); CST-14 and SS-14 did not modify this effect. Thus, CST-14 inhibits both basal and stimulated GH secretion in humans to the same extent of SS-14. The GH-releasing activity of ghrelin seems partially resistant to CST-14 as well as SS-14. CST-14 and SS-14 do not affect PRL and ACTH secretion but, like ghrelin, inhibit insulin secretion; the ghrelin-induced inhibition is not additive with that of CST-14 or SS-14, suggesting a common mechanism of action on beta cell secretion