Establishing a framework for dynamic risk management in 'intelligent' aero-engine control

The behaviour of control functions in safety critical software systems is typically bounded to prevent the occurrence of known system level hazards. These bounds are typically derived through safety analyses and can be implemented through the use of necessary design features. However, the unpredictability of real world problems can result in changes in the operating context that may invalidate the behavioural bounds themselves, for example, unexpected hazardous operating contexts as a result of failures or degradation. For highly complex problems it may be infeasible to determine the precise desired behavioural bounds of a function that addresses or minimises risk for hazardous operation cases prior to deployment. This paper presents an overview of the safety challenges associated with such a problem and how such problems might be addressed. A self-management framework is proposed that performs on-line risk management. The features of the framework are shown in context of employing intelligent adaptive controllers operating within complex and highly dynamic problem domains such as Gas-Turbine Aero Engine control. Safety assurance arguments enabled by the framework necessary for certification are also outlined

Formal Verification of Neural Network Controlled Autonomous Systems

In this paper, we consider the problem of formally verifying the safety of an autonomous robot equipped with a Neural Network (NN) controller that processes LiDAR images to produce control actions. Given a workspace that is characterized by a set of polytopic obstacles, our objective is to compute the set of safe initial conditions such that a robot trajectory starting from these initial conditions is guaranteed to avoid the obstacles. Our approach is to construct a finite state abstraction of the system and use standard reachability analysis over the finite state abstraction to compute the set of the safe initial states. The first technical problem in computing the finite state abstraction is to mathematically model the imaging function that maps the robot position to the LiDAR image. To that end, we introduce the notion of imaging-adapted sets as partitions of the workspace in which the imaging function is guaranteed to be affine. We develop a polynomial-time algorithm to partition the workspace into imaging-adapted sets along with computing the corresponding affine imaging functions. Given this workspace partitioning, a discrete-time linear dynamics of the robot, and a pre-trained NN controller with Rectified Linear Unit (ReLU) nonlinearity, the second technical challenge is to analyze the behavior of the neural network. To that end, we utilize a Satisfiability Modulo Convex (SMC) encoding to enumerate all the possible segments of different ReLUs. SMC solvers then use a Boolean satisfiability solver and a convex programming solver and decompose the problem into smaller subproblems. To accelerate this process, we develop a pre-processing algorithm that could rapidly prune the space feasible ReLU segments. Finally, we demonstrate the efficiency of the proposed algorithms using numerical simulations with increasing complexity of the neural network controller

Application of allogeneic fibroblast cells in cellular therapy of recessive dystrophic epidermolysis bullosa

Context: Connective tissue cells include fibroblasts, chondrocytes, adipocyte, and osteocytes. These cells are specialized for the secretion of collagenous extracellular matrix and are responsible for the architectural framework of the human body. Evidence Acquisition: Connective tissue cells play a central role in supporting as well as repairing tissues and organs. Fibroblast cell therapy could be used for the treatment of burn wounds, scars, diabetic foot ulcers, acne scars and skin aging. This review focused on biology of fibroblasts and their role in cell therapy of recessive dystrophic epidermolysis bullosa (RDEB). Results: Fibroblasts are known to play a pivotal role in skin structure and integrity, and dermal fibroblasts are believed to promote skin regeneration and rejuvenation via collagen production. Conclusions: Fibroblasts can be used in transplantations to ameliorate an immune system response, in order to reduce antigen production. Human fibroblasts suppress ongoing mixed lymphocyte reactions (MLRs) between lymphocyte cells from two individuals, and supernatant materials from fibroblast cultures suppress MLRs. © 2015, Skin and Stem Cell Journal

Predictors of Performance during a 161 km Mountain Footrace

Training volume and cardiovascular dynamics influence endurance performance. However, there is limited information on the interplay between training volume, cardiovascular dynamics, and performance in ultra-marathon athletes. PURPOSE: We aimed to determine predictors of performance in finishers of the 2023 Western States Endurance Run (WSER). METHODS: Sixty participants who finished the race (49 males/11 females; mean age: 44.7 ± 9.6 y, range: 26–66 y; BMI: 22.7 ± 2.2 kg/m2) completed pre-race surveys including average training volume (AV) and peak training volume (PV), as well as resting cardiovascular measures including resting heart rate (RHR) and augmentation index (AIx), a measure of wave reflection characteristics. Based on WSER completion time, we calculated average running velocity (RV). We assessed associations among 22 variables using bivariate correlation analysis (Pearson’s Correlation for normally distributed data and Spearman’s Rank Correlation if normality was not met). Within our listed variables, normality was met in age and AV. Additionally, we completed multiple regression analyses for predictors. We present descriptive data as mean ± SD. RESULTS: Participants had an average RV of 6.33 ± 0.97 km/h (3.93 ± 0.6 mph), and reported an AV of 91.9 ± 24.5 km/wk (57.1 ± 15.2 miles/wk) and a PV of 141.0 ± 47.2 km/wk (87.6 ± 29.3 miles/wk). We observed significant associations between RV and age (r(58) = -0.57, p r(58) = 0.41, p r(58) = 0.34, p R2 = 0.37; F(3,56) = 12.4, pb1 = 0.013; t(56) = 2.57, p = 0.013), resulting in a 0.33 km/h increase in RV for every 25-km increase in AV. Last, significant relations existed between RV and AIx (r(58) = -0.30, p = 0.022); and RHR (r(58) = -0.26, p = 0.046). CONCLUSION: We found that (1) average weekly training volume is a significant predictor of performance in elite ultra-marathon athletes and (2) race performance was inversely associated with resting arterial wave reflection characteristics and heart rate

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority

Cost per responder for ixekizumab and other biologic drugs approved for the treatment of moderate-to-severe plaque psoriasis in Italy

This analysis was aimed at estimating the cost per responder as measured by number needed to treat of ixekizumab as compared with other biologic drugs approved in Italy for the treatment of moderate-to-severe plaque psoriasis. The clinical efficacy was assessed in terms of number needed to treat, based on a network meta-analysis of published efficacy data as measured by Psoriasis Area and Severity Index response (PASI75, PASI90, and PASI100) for relevant biologic comparators. The cost was based on the number of administrations dispensed in the first (induction plus maintenance period) and the second (maintenance period only) year of treatment and the ex-factory price net of discounts of each biologic drug. The cost per responder was adopted as a cost-effectiveness indicator. Independent of the Psoriasis Area and Severity Index response (PASI75, PASI90, and PASI100) used and the year of treatment considered, the cost per number needed to treat for ixekizumab appeared consistently to be the lowest. For example, considering first-year costs and PASI75, the cost per responder for ixekizumab was €16,388, compared to adalimumab (€22,574), etanercept (branded original: €32,420; biosimilar: €21,432), secukinumab (€17,937), and ustekinumab (€20,014). The differences in the cost per responder between ixekizumab and the comparators increased when higher Psoriasis Area and Severity Index response levels were considered. This economic assessment confirmed that ixekizumab is a cost-efficient option from the perspective of the Italian National Health Service for the treatment of moderate-to-severe plaque psoriasis

Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin

<p>Abstract</p> <p>Background</p> <p>Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The pathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine production. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical use. We have previously documented the therapeutic applicability of targeting TNFα mRNA for RNA interference-mediated down-regulation by anti-TNFα small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted psoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and IL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs.</p> <p>Methods</p> <p>Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.</p> <p>Results</p> <p>Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimick the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination.</p> <p>Conclusions</p> <p>Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.</p

International Influences and Drag: Just a Case of Tucking or Binding?

Recently there has been an  internationalisation in the training of UK drag performers. Whilst papers exist focused on drag kings and queens related to their community, few explore how kings/queens train – and fewer still explore international aspects. There are formal courses for drag, but historically this training was informal, present within specific performance communities built around LGBTQ cultures. Tracing dominant figures in such training – the drag mother/father – in order to historicise and contextualise the current explosion in drag performance,the paper argues that the potential globalisation of drag is largely down to the diversification of sources of knowledge available via the internet. Traditionally, performers trained with an established practitioner, where regional variances of drag were passed on. However, current new performers often learn ‘tricks of the trade’ through internet videos posted by people on other continents. In these videos, practitioners pass on their knowledge from the perspective of their locality, as if universal. New kings/queens are not passive in this training and locally infuse their acts, yet historical and local erasures persist. The paper argues that to engage with drag as performance one must be aware of locality and the deep connects drag has with its communities

Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates