Model-free and model-based reward prediction errors in EEG

Learning theorists posit two reinforcement learning systems: model-free and model-based. Model-based learning incorporates knowledge about structure and contingencies in the world to assign candidate actions with an expected value. Model-free learning is ignorant of the world’s structure; instead, actions hold a value based on prior reinforcement, with this value updated by expectancy violation in the form of a reward prediction error. Because they use such different learning mechanisms, it has been previously assumed that model-based and model-free learning are computationally dissociated in the brain. However, recent fMRI evidence suggests that the brain may compute reward prediction errors to both model-free and model-based estimates of value, signalling the possibility that these systems interact. Because of its poor temporal resolution, fMRI risks confounding reward prediction errors with other feedback-related neural activity. In the present study, EEG was used to show the presence of both model-based and model-free reward prediction errors and their place in a temporal sequence of events including state prediction errors and action value updates. This demonstration of model-based prediction errors questions a long-held assumption that model-free and model-based learning are dissociated in the brain

Potential regulatory interactions of Escherichia coli RraA protein with DEAD-box helicases.

Members of the DEAD-box family of RNA helicases contribute to virtually every aspect of RNA metabolism, in organisms from all domains of life. Many of these helicases are constituents of multicomponent assemblies, and their interactions with partner proteins within the complexes underpin their activities and biological function. In Escherichia coli the DEAD-box helicase RhlB is a component of the multienzyme RNA degradosome assembly, and its interaction with the core ribonuclease RNase E boosts the ATP-dependent activity of the helicase. Earlier studies have identified the regulator of ribonuclease activity A (RraA) as a potential interaction partner of both RNase E and RhlB. We present structural and biochemical evidence showing how RraA can bind to, and modulate the activity of RhlB and another E. coli DEAD-box enzyme, SrmB. Crystallographic structures are presented of RraA in complex with a portion of the natively unstructured C-terminal tail of RhlB at 2.8-Å resolution, and in complex with the C-terminal RecA-like domain of SrmB at 2.9 Å. The models suggest two distinct mechanisms by which RraA might modulate the activity of these and potentially other helicases

Cloud Computing in Virtual Environments

In this paper we present the basis of a new middleware service that provisions clouds for virtual organizations (VOs).This service makes use of a virtual environment\u27s inherent ability to render objects to represent clouds with real clouds. These clouds are created on demand by avatars and tagged to provide a rudimentary semantic that can be used for searching. Clouds are then loaded with an inventory that contains objects and scripts used to access remote resources. Compute resources, sensor networks, and visualization services can be part of the cloud\u27s inventory. Second Life is used to implement this cloud computing service. The authorization mechanism of Second Life and an external database managed by our cloud service is used to restrict access to clouds based on avatar roles and group membership.We argue that this service can be used effectively by a VO to provide a very interactive experience for its members as well as potential collaboration between multiple VOs. Cloud computing takes a very figurative meaning in our work since we literally create clouds in the environment and manage their ownership, access and capabilities. We believe this innovative work brings together grid computing, social networking and virtual environments in a very attractive and understandable way

Low cost, SPF aluminum cryogenic tank structure for ALS

Past production work has shown that cryogenic tank structure for the Shuttle Booster Rockets and the Titan system have very high life cycle costs for the fuel tank structure. The tanks are machined stiffener-skin combination that are subsequently formed into the required contour after machining. The material scrap rate for these configurations are usually high, and the loss of a tank panel due to forming or heat treatment problems is very costly. The idea of reducing the amount of scrap material and scrapped structural members has prompted the introduction of built-up structure for cryogenic tanks to be explored on the ALS program. A build-up structure approach that has shown improvements in life cycle cost over the conventional built-up approach is the use of superplastically formed (SPF) stiffened panels (reducing the overall part count and weight for the tank) resistance spot welded (RSW) to outer tank skin material. The stiffeners provide for general stability of the tank, while the skin material provides hoop direction continuity for the loads

Crystal structure of Caulobacter crescentus polynucleotide phosphorylase reveals a mechanism of RNA substrate channelling and RNA degradosome assembly

Polynucleotide phosphorylase (PNPase) is an exoribonuclease that cleaves single-stranded RNA substrates with 3′–5′ directionality and processive behaviour. Its ring-like, trimeric architecture creates a central channel where phosphorolytic active sites reside. One face of the ring is decorated with RNA-binding K-homology (KH) and S1 domains, but exactly how these domains help to direct the 3′ end of single-stranded RNA substrates towards the active sites is an unsolved puzzle. Insight into this process is provided by our crystal structures of RNA-bound and apo Caulobacter crescentus PNPase. In the RNA-free form, the S1 domains adopt a ‘splayed’ conformation that may facilitate capture of RNA substrates. In the RNA-bound structure, the three KH domains collectively close upon the RNA and direct the 3′ end towards a constricted aperture at the entrance of the central channel. The KH domains make non-equivalent interactions with the RNA, and there is a marked asymmetry within the catalytic core of the enzyme. On the basis of these data, we propose that structural non-equivalence, induced upon RNA binding, helps to channel substrate to the active sites through mechanical ratcheting. Structural and biochemical analyses also reveal the basis for PNPase association with RNase E in the multi-enzyme RNA degradosome assembly of the α-proteobacteria

Adalimumab in Juvenile Idiopathic Arthritis–Associated Uveitis:5-Year Follow-up of the Bristol Participants of the SYCAMORE Trial

PURPOSE:To determine longer-term outcomes of participants enrolled from a single center in the SYCAMORE trial, a randomized placebo-controlled trial of adalimumab versus placebo in children with juvenile idiopathic arthritis-associated uveitis (JIA-U) uncontrolled on methotrexate. DESIGN:Retrospective interventional case series. METHODS:Medical records of all 28 SYCAMORE participants recruited at the Bristol Eye Hospital were reviewed at approximately 3-monthly intervals up to 5 years from the trial randomization date. Uveitis activity, treatment course, visual outcomes, ocular complications and adverse events were recorded. Data are presented using summary statistics. RESULTS:Following withdrawal of the investigational medicinal product (IMP), 25 of the 28 participants were started on adalimumab for active juvenile idiopathic arthritis-associated uveitis (JIA-U). Of the 12 participants in the active treatment arm of the SYCAMORE study, 11 (92%) were restarted on adalimumab after withdrawal of the IMP for active JIA-U (median time to flare 188 days (range 42-413)). Two participants stopped adalimumab for uncontrolled JIA-U. One participant had a reduction in vision to 0.3 due to cataract. Mean visual acuity for the remaining 27 participants was -0.04 (right eye) and -0.05 (left eye). CONCLUSIONS:Drug-induced remission of JIA-U did not persist when adalimumab was withdrawn after 1-2 years treatment. Adalimumab was well tolerated and visual acuity outcomes were excellent

A phase II trial protocol of Tocilizumab in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial).

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of intraocular inflammation (uveitis). In the initial stages of mild-moderate inflammation uveitis is asymptomatic. Most children with mild-moderate uveitis are managed on topical steroid drops with or without systemic methotrexate (MTX). When children with moderate-severe uveitis are refractory to MTX, monoclonal anti-tumour necrosis factor agents have been trialled, interim analysis data showed positive results. However, several children with severe recalcitrant disease or non-responsive to anti-tumour necrosis factor agents remain and are at greater risk of significant ocular complications and visual loss. Further evidence of alternative therapies is needed with evidence of a potential role of anti-interleukin-6 agents in the management of severe refractory uveitis.MethodsThe trial will be conducted following a two-stage Simon design. The trial will register at least 22 patients aged 2 to 18 years with active JIA-associated uveitis, who have taken MTX for at least 12 weeks and have failed an anti-TNF agent. It will take place in 7 centres across the UK. All participants will be treated for 6 months, with follow up of 9 months from registration. Participants will receive a stable dose of MTX and those weighing ≥30 kg will be dosed with 162 mg of Tocilizumab every 2 weeks and participants weighing DiscussionThis is a novel adaptive design study of subcutaneous IL-6 inhibition in anti-TNF refractory JIA associated uveitis which will be able to determine if further research should be conducted. This is the first trial to look at ophthalmology outcomes in the efficacy of Tocilizumab in uveitis.This is the first paediatric clinical trial to assess the clinical effectiveness and safety of tocilizumab with MTX in JIA associated uveitis.Trials registrationThe Trial is registered on the ISRCTN registry (ISRCTN95363507) on the 10/06/2015 and EU Clinical Trials Register on the 03/07/2015 (EudraCT Number: 2015-001323-23)

Effectiveness and cost-effectiveness of a web-based cardiac rehabilitation programme for people with chronic stable angina:protocol for the ACTIVATE (Angina Controlled Trial Investigating the Value of the 'Activate your heart' Therapeutic E-intervention) randomised controlled trial

INTRODUCTION: Chronic stable angina is common and disabling. Cardiac rehabilitation is routinely offered to people following myocardial infarction or revascularisation procedures and has the potential to help people with chronic stable angina. However, there is insufficient evidence of effectiveness and cost-effectiveness for its routine use in this patient group. The objectives of this study are to compare the effectiveness and cost-effectiveness of the 'Activate Your Heart' cardiac rehabilitation programme for people with chronic stable angina compared with usual care.METHODS AND ANALYSIS: ACTIVATE is a multicentre, parallel-group, two-arm, superiority, pragmatic randomised controlled trial, with recruitment from primary and secondary care centres in England and Wales and a target sample size of 518 (1:1 allocation; allocation sequence by minimisation programme with built-in random element). The study uses secure web-based allocation concealment. The two treatments will be optimal usual care (control) and optimal usual care plus the 'Activate Your Heart' web-based cardiac rehabilitation programme (intervention). Outcome assessment and statistical analysis will be performed blinded; participants will be unblinded. Outcomes will be measured at baseline and at 6 and 12 months' follow-up. Primary outcome will be the UK version of Seattle Angina Questionnaire (SAQ-UK), physical limitations domain at 12 months' follow-up. Secondary outcomes will be the remaining two domains of SAQ-UK, dyspnoea, anxiety and depression, health utility, self-efficacy, physical activity and the incremental shuttle walk test. All safety events will be recorded, and serious adverse events assessed to determine whether they are related to the intervention and expected. Concurrent economic evaluation will be cost-utility analysis from health service perspective. An embedded process evaluation will determine the mechanisms and processes that explain the implementation and impacts of the cardiac rehabilitation programme.ETHICS AND DISSEMINATION: North of Scotland National Health Service Research Ethics Committee approval, reference 21/NS/0115. Participants will provide written informed consent. Results will be disseminated by peer-reviewed publication.TRIAL REGISTRATION NUMBER: ISRCTN10054455.</p

Cost-effectiveness analysis of adalimumab for the treatment of uveitis associated with Juvenile Idiopathic Arthritis

Purpose To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). Design A cost-utility analysis based on a clinical trial and decision analytic model. Participants Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. Methods The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. Main Outcome Measures Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. Results Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. Conclusions Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting