End-to-End Formal Verification of Ethereum 2.0 Deposit Smart Contract

We report our experience in the formal verification of the deposit smart contract, whose correctness is critical for the security of Ethereum 2.0, a new Proof-of-Stake protocol for the Ethereum blockchain. The deposit contract implements an incremental Merkle tree algorithm whose correctness is highly nontrivial, and had not been proved before. We have verified the correctness of the compiled bytecode of the deposit contract to avoid the need to trust the underlying compiler. We found several critical issues of the deposit contract during the verification process, some of which were due to subtle hidden bugs of the compiler.Ope

Protective Efficacy of Centralized and Polyvalent Envelope Immunogens in an Attenuated Equine Lentivirus Vaccine

Lentiviral Envelope (Env) antigenic variation and related immune evasion present major hurdles to effective vaccine development. Centralized Env immunogens that minimize the genetic distance between vaccine proteins and circulating viral isolates are an area of increasing study in HIV vaccinology. To date, the efficacy of centralized immunogens has not been evaluated in the context of an animal model that could provide both immunogenicity and protective efficacy data. We previously reported on a live-attenuated (attenuated) equine infectious anemia (EIAV) virus vaccine, which provides 100% protection from disease after virulent, homologous, virus challenge. Further, protective efficacy demonstrated a significant, inverse, linear relationship between EIAV Env divergence and protection from disease when vaccinates were challenged with viral strains of increasing Env divergence from the vaccine strain Env. Here, we sought to comprehensively examine the protective efficacy of centralized immunogens in our attenuated vaccine platform. We developed, constructed, and extensively tested a consensus Env, which in a virulent proviral backbone generated a fully replication-competent pathogenic virus, and compared this consensus Env to an ancestral Env in our attenuated proviral backbone. A polyvalent attenuated vaccine was established for comparison to the centralized vaccines. Additionally, an engineered quasispecies challenge model was created for rigorous assessment of protective efficacy. Twenty-four EIAV-naïve animals were vaccinated and challenged along with six-control animals six months post-second inoculation. Pre-challenge data indicated the consensus Env was more broadly immunogenic than the Env of the other attenuated vaccines. However, challenge data demonstrated a significant increase in protective efficacy of the polyvalent vaccine. These findings reveal, for the first time, a consensus Env immunogen that generated a fully-functional, replication-competent lentivirus, which when experimentally evaluated, demonstrated broader immunogenicity that does not equate to higher protective efficacy

Measuring Metacognition in Cancer: Validation of the Metacognitions Questionnaire 30 (MCQ-30)

Objective The Metacognitions Questionnaire 30 assesses metacognitive beliefs and processes which are central to the metacognitive model of emotional disorder. As recent studies have begun to explore the utility of this model for understanding emotional distress after cancer diagnosis, it is important also to assess the validity of the Metacognitions Questionnaire 30 for use in cancer populations. Methods 229 patients with primary breast or prostate cancer completed the Metacognitions Questionnaire 30 and the Hospital Anxiety and Depression Scale pre-treatment and again 12 months later. The structure and validity of the Metacognitions Questionnaire 30 were assessed using factor analyses and structural equation modelling. Results Confirmatory and exploratory factor analyses provided evidence supporting the validity of the previously published 5-factor structure of the Metacognitions Questionnaire 30. Specifically, both pre-treatment and 12 months later, this solution provided the best fit to the data and all items loaded on their expected factors. Structural equation modelling indicated that two dimensions of metacognition (positive and negative beliefs about worry) were significantly associated with anxiety and depression as predicted, providing further evidence of validity. Conclusions These findings provide initial evidence that the Metacognitions Questionnaire 30 is a valid measure for use in cancer populations

E-learning interventions are comparable to user's manual in a randomized trial of training strategies for the AGREE II

<p>Abstract</p> <p>Background</p> <p>Practice guidelines (PGs) are systematically developed statements intended to assist in patient and practitioner decisions. The AGREE II is the revised tool for PG development, reporting, and evaluation, comprised of 23 items, two global rating scores, and a new User's Manual. In this study, we sought to develop, execute, and evaluate the impact of two internet interventions designed to accelerate the capacity of stakeholders to use the AGREE II.</p> <p>Methods</p> <p>Participants were randomized to one of three training conditions. 'Tutorial'--participants proceeded through the online tutorial with a virtual coach and reviewed a PDF copy of the AGREE II. 'Tutorial + Practice Exercise'--in addition to the Tutorial, participants also appraised a 'practice' PG. For the practice PG appraisal, participants received feedback on how their scores compared to expert norms and formative feedback if scores fell outside the predefined range. <it>'</it>AGREE II User's Manual PDF (control condition)'<it>--</it>participants reviewed a PDF copy of the AGREE II only. All participants evaluated a test PG using the AGREE II. Outcomes of interest were learners' performance, satisfaction, self-efficacy, mental effort, time-on-task, and perceptions of AGREE II.</p> <p>Results</p> <p>No differences emerged between training conditions on any of the outcome measures.</p> <p>Conclusions</p> <p>We believe these results can be explained by better than anticipated performance of the AGREE II PDF materials (control condition) or the participants' level of health methodology and PG experience rather than the failure of the online training interventions. Some data suggest the online tools may be useful for trainees new to this field; however, this requires further study.</p

fMRI evidence of ‘mirror’ responses to geometric shapes

Mirror neurons may be a genetic adaptation for social interaction [1]. Alternatively, the associative hypothesis [2], [3] proposes that the development of mirror neurons is driven by sensorimotor learning, and that, given suitable experience, mirror neurons will respond to any stimulus. This hypothesis was tested using fMRI adaptation to index populations of cells with mirror properties. After sensorimotor training, where geometric shapes were paired with hand actions, BOLD response was measured while human participants experienced runs of events in which shape observation alternated with action execution or observation. Adaptation from shapes to action execution, and critically, observation, occurred in ventral premotor cortex (PMv) and inferior parietal lobule (IPL). Adaptation from shapes to execution indicates that neuronal populations responding to the shapes had motor properties, while adaptation to observation demonstrates that these populations had mirror properties. These results indicate that sensorimotor training induced populations of cells with mirror properties in PMv and IPL to respond to the observation of arbitrary shapes. They suggest that the mirror system has not been shaped by evolution to respond in a mirror fashion to biological actions; instead, its development is mediated by stimulus-general processes of learning within a system adapted for visuomotor control

Teaching Open Science:Published Data and Digital Literacy in Archaeology Classrooms

Digital literacy has been cited as one of the primary challenges to ensuring data reuse and increasing the value placed on open science. Incorporating published data into classrooms and training is at the core of tackling this issue. This article presents case studies in teaching with different published data platforms, in three different countries (the Netherlands, Canada, and the United States), to students at different levels and with differing skill levels. In outlining their approaches, successes, and failures in teaching with open data, it is argued that collaboration with data publishers is critical to improving data reuse and education. Moreover, increased opportunities for digital skills training and scaffolding across program curriculum are necessary for managing the learning curve and teaching students the values of open science

A randomized trial to evaluate e-learning interventions designed to improve learner's performance, satisfaction, and self-efficacy with the AGREE II

<p>Abstract</p> <p>Background</p> <p>Practice guidelines (PGs) are systematically developed statements intended to assist in patient, practitioner, and policy decisions. The AGREE II is the revised and updated standard tool for guideline development, reporting and evaluation. It is comprised of 23 items and a user's Manual. The AGREE II is ready for use.</p> <p>Objectives</p> <p>To develop, execute, and evaluate the impact of two internet-based educational interventions designed to accelerate the capacity of stakeholders to use the AGREE II: a multimedia didactic tutorial with a virtual coach, and a higher intensity training program including both the didactic tutorial and an interactive practice exercise component.</p> <p>Methods</p> <p>Participants (clinicians, developers, and policy makers) will be randomly assigned to one of three conditions. <it>Condition one, didactic tutorial </it>-- participants will go through the on-line AGREE II tutorial supported by a virtual coach and review of the AGREE II prior to appraising the test PG. <it>Condition two, tutorial + practice </it>-- following the multimedia didactic tutorial with a virtual coach, participants will review the on-line AGREE II independently and use it to appraise a practice PG. Upon entering their AGREE II score for the practice PG, participants will be given immediate feedback on how their score compares to expert norms. If their score falls outside a predefined range, the participant will receive a series of hints to guide the appraisal process. Participants will receive an overall summary of their performance appraising the PG compared to expert norms. <it>Condition three, control arm </it>-- participants will receive a PDF copy of the AGREE II for review and to appraise the test PG on-line. All participants will then rate one of ten test PGs with the AGREE II. The outcomes of interest are learners' performance, satisfaction, self-efficacy, mental effort, and time-on-task; comparisons will be made across each of the test groups.</p> <p>Discussion</p> <p>Our research will test innovative educational interventions of various intensities and instructional design to promote the adoption of AGREE II and to identify those strategies that are most effective for training. The results will facilitate international capacity to apply the AGREE II accurately and with confidence and to enhance the overall guideline enterprise.</p

A pilot telephone intervention to increase uptake of breast cancer screening in socially deprived areas in Scotland (TELBRECS):study protocol for a randomised controlled trial

BACKGROUND Breast cancer accounts for almost 30% of all cancers and is the second leading cause of cancer deaths in women in Scotland. Screening is key to early detection. The Scottish Breast Screening Programme is a nationwide, free at point of delivery screening service, to which all women aged between 50 and 70 years are invited to attend every 3 years. Currently over three-quarters of invited women regularly attend screening. However, women from more deprived areas are much less likely to attend: for example in the 3 years from 2010-2012 only 63% of women in the most deprived area attended the East of Scotland Breast Screening programme versus 81% in the least deprived. Research has suggested that reminders (telephone or letter) and brief, personalised interventions addressing barriers to attendance may be helpful in increasing uptake in low-income women. METHODS/DESIGN We will employ a brief telephone reminder and support intervention, whose purpose is to elicit and address any mistaken beliefs women have about breast screening, with the aim that the perceived benefits of screening come to outweigh any perceived barriers for individuals. We will test whether this intervention, plus a simple anticipated regret manipulation, will lead to an increase in the uptake of breast cancer screening amongst low-income women who have failed to attend a first appointment, in a randomised controlled trial with 600 women. Participants will be randomly allocated to one of four treatment arms i.e. 1) Letter reminder (i.e. Treatment as usual: CONTROL); 2) Telephone reminder (TEL), 3) Telephone reminder plus telephone support (TEL-SUPP) and 4) Telephone reminder plus support plus AR (TEL-SUPP-AR). The primary outcome will be attendance at breast screening within 3 months of the reminder letter. DISCUSSION If this simple telephone support intervention (with or without AR intervention) leads to a significant increase in breast screening attendance, this would represent a rare example of a theoretically-driven, relatively simple psychological intervention that could result in earlier detection of breast cancer amongst an under-served group of lower socio-economic women. TRIAL REGISTRATION Current Controlled trials: ISRCTN06039270. Registered 16th January 2014

Direct glia-to-neuron transdifferentiation gives rise to a pair of male-specific neurons that ensure nimble male mating

Sexually dimorphic behaviours require underlying differences in the nervous system between males and females. The extent to which nervous systems are sexually dimorphic and the cellular and molecular mechanisms that regulate these differences are only beginning to be understood. We reveal here a novel mechanism by which male-specific neurons are generated in Caenorhabditis elegans through the direct transdifferentiation of sex-shared glial cells. This glia-to-neuron cell fate switch occurs during male sexual maturation under the cell-autonomous control of the sex-determination pathway. We show that the neurons generated are cholinergic, peptidergic, and ciliated putative proprioceptors which integrate into male-specific circuits for copulation. These neurons ensure coordinated backward movement along the mate’s body during mating. One step of the mating sequence regulated by these neurons is an alternative readjustment movement performed when intromission becomes difficult to achieve. Our findings reveal programmed transdifferentiation as a developmental mechanism underlying flexibility in innate behaviour