Development of the CHARIOT Research Register for the Prevention of Alzheimer’s Dementia and Other Late Onset Neurodegenerative Diseases

Identifying cognitively healthy people at high risk of developing dementia is an ever-increasing focus. These individuals are essential for inclusion in observational studies into the natural history of the prodromal and early disease stages and for interventional studies aimed at prevention or disease modification. The success of this research is dependent on having access to a well characterised, representative and sufficiently large population of individuals. Access to such a population remains challenging as clinical research has, historically, focussed on patients with dementia referred to secondary and tertiary services. The primary care system in the United Kingdom allows access to a true prodromal population prior to symptoms emerging and specialist referral. We report the development and recruitment rates of the CHARIOT register, a primary care-based recruitment register for research into the prevention of dementia. The CHARIOT register was designed specifically to support recruitment into observational natural history studies of pre-symptomatic or prodromal dementia stages, and primary or secondary prevention pharmaceutical trials or other prevention strategies for dementia and other cognitive problems associated with ageing.Participants were recruited through searches of general practice lists across the west and central London regions. Invitations were posted to individuals aged between 60 and 85 years, without a diagnosis of dementia. Upon consent, a minimum data set of demographic and contact details was extracted from the patient's electronic health record.To date, 123 surgeries participated in the register, recruiting a total of 24,509 participants-a response rate of 22.3%. The age, gender and ethnicity profiles of participants closely match that of the overall eligible population. Higher response rates tended to be associated with larger practices (r = 0.34), practices with a larger older population (r = 0.27), less socioeconomically disadvantaged practices (r = 0.68), and practices with a higher proportion of White patients (r = 0.82).Response rates are comparable to other registers reported in the literature, and indicate good interest and support for a research register and for participation in research for the prevention of age-related neurodegenerative diseases and dementia. We consider that the simplicity of the approach means that this system is easily scalable and replicable across the UK and internationally

Acceleration Schemes for Ab-Initio Molecular Dynamics and Electronic Structure Calculations

We study the convergence and the stability of fictitious dynamical methods for electrons. First, we show that a particular damped second-order dynamics has a much faster rate of convergence to the ground-state than first-order steepest descent algorithms while retaining their numerical cost per time step. Our damped dynamics has efficiency comparable to that of conjugate gradient methods in typical electronic minimization problems. Then, we analyse the factors that limit the size of the integration time step in approaches based on plane-wave expansions. The maximum allowed time step is dictated by the highest frequency components of the fictitious electronic dynamics. These can result either from the large wavevector components of the kinetic energy or from the small wavevector components of the Coulomb potential giving rise to the so called {\it charge sloshing} problem. We show how to eliminate large wavevector instabilities by adopting a preconditioning scheme that is implemented here for the first-time in the context of Car-Parrinello ab-initio molecular dynamics simulations of the ionic motion. We also show how to solve the charge-sloshing problem when this is present. We substantiate our theoretical analysis with numerical tests on a number of different silicon and carbon systems having both insulating and metallic character.Comment: RevTex, 9 figures available upon request, to appear in Phys. Rev.

Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis

The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor-host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor. Soluble exTEK secreted by transfected tumor cells inhibited HUVECs from forming tubes in Matrigel. ExTEK-transfected C26 colon carcinoma and TS/A mammary tumor cells displayed reduced growth rate when injected subcutaneously, and reduced ability to form experimental metastases when injected intravenously. Immunohistochemical analysis of tumors and metastases showed increased leukocytes infiltration and signs of inflammation in exTEK-secreting compared to parental tumor, as well as impairment in neo-vessel growth and organization. However, while neoangiogenesis eventually rescued in the subcutis, it failed to organize in the experimental metastases of exTEK-secreting tumor, contributing to the hampering of metastatic growth and to increased mice survival. The reactive infiltrate of C26TEK contained a different percentage of leukocytes and was responsible for the tumor inhibition. In fact, leukopenia induced by gamma-irradiation of recipient mice or injection into interferon gamma (IFN-gamma) gene knockout (GKO) mice resulted in reduced mouse survival and an increased number of lung metastases. On the other hand, interleukin (IL)-12 treatment prolonged the survival of mice bearing subcutaneous C26TEK but not of those bearing lung metastases, suggesting that IL-12 could exert further antiangiogenic effects at the site where the tumor can restore neoangiogenesis. These results show in vivo that reduced angiopoietin availability at the tumor site induces a local inflammatory response and impairment of neoangiogenesis which act synergistically to limit tumor growth and metastasis

Extending Hybrid CSP with Probability and Stochasticity

Probabilistic and stochastic behavior are omnipresent in computer controlled systems, in particular, so-called safety-critical hybrid systems, because of fundamental properties of nature, uncertain environments, or simplifications to overcome complexity. Tightly intertwining discrete, continuous and stochastic dynamics complicates modelling, analysis and verification of stochastic hybrid systems (SHSs). In the literature, this issue has been extensively investigated, but unfortunately it still remains challenging as no promising general solutions are available yet. In this paper, we give our effort by proposing a general compositional approach for modelling and verification of SHSs. First, we extend Hybrid CSP (HCSP), a very expressive and process algebra-like formal modeling language for hybrid systems, by introducing probability and stochasticity to model SHSs, which is called stochastic HCSP (SHCSP). To this end, ordinary differential equations (ODEs) are generalized by stochastic differential equations (SDEs) and non-deterministic choice is replaced by probabilistic choice. Then, we extend Hybrid Hoare Logic (HHL) to specify and reason about SHCSP processes. We demonstrate our approach by an example from real-world.Comment: The conference version of this paper is accepted by SETTA 201

Ab initio theory and modeling of water

Water is of the utmost importance for life and technology. However, a genuinely predictive ab initio model of water has eluded scientists. We demonstrate that a fully ab initio approach, relying on the strongly constrained and appropriately normed (SCAN) density functional, provides such a description of water. SCAN accurately describes the balance among covalent bonds, hydrogen bonds, and van der Waals interactions that dictates the structure and dynamics of liquid water. Notably, SCAN captures the density difference between water and ice I{\it h} at ambient conditions, as well as many important structural, electronic, and dynamic properties of liquid water. These successful predictions of the versatile SCAN functional open the gates to study complex processes in aqueous phase chemistry and the interactions of water with other materials in an efficient, accurate, and predictive, ab initio manner

Certainly Unsupervisable States

This paper proposes an abstraction method for compositional synthesis. Synthesis is a method to automatically compute a control program or supervisor that restricts the behaviour of a given system to ensure safety and liveness. Compositional synthesis uses repeated abstraction and simplification to combat the state-space explosion problem for large systems. The abstraction method proposed in this paper finds and removes the so-called certainly unsupervisable states. By removing these states at an early stage, the final state space can be reduced substantially. The paper describes an algorithm with cubic time complexity to compute the largest possible set of removable states. A practical example demonstrates the feasibility of the method to solve real-world problems

Supergravity Higgs Inflation and Shift Symmetry in Electroweak Theory

We present a model of inflation in a supergravity framework in the Einstein frame where the Higgs field of the next to minimal supersymmetric standard model (NMSSM) plays the role of the inflaton. Previous attempts which assumed non-minimal coupling to gravity failed due to a tachyonic instability of the singlet field during inflation. A canonical K\"{a}hler potential with \textit{minimal coupling} to gravity can resolve the tachyonic instability but runs into the $\eta$-problem. We suggest a model which is free of the $\eta$-problem due to an additional coupling in the K\"{a}hler potential which is allowed by the Standard Model gauge group. This induces directions in the potential which we call K-flat. For a certain value of the new coupling in the (N)MSSM, the K\"{a}hler potential is special, because it can be associated with a certain shift symmetry for the Higgs doublets, a generalization of the shift symmetry for singlets in earlier models. We find that K-flat direction has $H_u^0=-H_d^{0*}.$ This shift symmetry is broken by interactions coming from the superpotential and gauge fields. This direction fails to produce successful inflation in the MSSM but produces a viable model in the NMSSM. The model is specifically interesting in the Peccei-Quinn (PQ) limit of the NMSSM. In this limit the model can be confirmed or ruled-out not just by cosmic microwave background observations but also by axion searches.Comment: matches the published version at JCA

Comparison of self-administered survey questionnaire responses collected using mobile apps versus other methods

Background: Self-administered survey questionnaires are an important data collection tool in clinical practice, public health research and epidemiology. They are ideal for achieving a wide geographic coverage of the target population, dealing with sensitive topics and are less resource intensive than other data collection methods. These survey questionnaires can be delivered electronically, which can maximise the scalability and speed of data collection while reducing cost. In recent years, the use of apps running on consumer smart devices (i.e., smartphones and tablets) for this purpose has received considerable attention. However, variation in the mode of delivering a survey questionnaire could affect the quality of the responses collected. Objectives: To assess the impact that smartphone and tablet apps as a delivery mode have on the quality of survey questionnaire responses compared to any other alternative delivery mode: paper, laptop computer, tablet computer (manufactured before 2007), short message service (SMS) and plastic objects. Search methods: We searched MEDLINE, EMBASE, PsycINFO, IEEEXplore, Web of Science, CABI: CAB Abstracts, Current Contents Connect, ACM Digital, ERIC, Sociological Abstracts, Health Management Information Consortium, the Campbell Library and CENTRAL. We also searched registers of current and ongoing clinical trials such as ClinicalTrials.gov and the World Health Organization (WHO)International Clinical Trials Registry Platform. We also searched the grey literature in OpenGrey, Mobile Active and ProQuest Dissertation & Theses. Lastly, we searched Google Scholar and the reference lists of included studies and relevant systematic reviews. We performed all searches up to 12 and 13 April 2015. Selection criteria: We included parallel randomised controlled trials (RCTs), crossover trials and paired repeated measures studies that compared the electronic delivery of self-administered survey questionnaires via a smartphone or tablet app with any other delivery mode. We included data obtained from participants completing health-related self-administered survey questionnaire, both validated and non-validated. We also included data offered by both healthy volunteers and by those with any clinical diagnosis. We included studies that reported any of the following outcomes: data equivalence; data accuracy; data completeness; response rates; differences in the time taken to complete a survey questionnaire; differences in respondent’s adherence to the original sampling protocol; and acceptability to respondents of the delivery mode. We included studies that were published in 2007 or after, as devices that became available during this time are compatible with the mobile operating system (OS) framework that focuses on apps. Data collection and analysis: Two review authors independently extracted data from the included studies using a standardised form created for this systematic review in REDCap. They then compared their forms to reach consensus. Through an initial systematic mapping on the included studies, we identified two settings in which survey completion took place: controlled and uncontrolled. These settings differed in terms of (i) the location where surveys were completed, (ii) the frequency and intensity of sampling protocols, and (iii) the level of control over potential confounders (e.g., type of technology, level of help offered to respondents).We conducted a narrative synthesis of the evidence because a meta-analysis was not appropriate due to high levels of clinical and methodological diversity. We reported our findings for each outcome according to the setting in which the studies were conducted. Main results: We included 14 studies (15 records) with a total of 2275 participants; although we included only 2272 participants in the final analyses as there were missing data for three participants from one included study. Regarding data equivalence, in both controlled and uncontrolled settings, the included studies found no significant differences in the mean overall scores between apps and other delivery modes, and that all correlation coefficients exceeded the recommended thresholds for data equivalence. Concerning the time taken to complete a survey questionnaire in a controlled setting, one study found that an app was faster than paper, whereas the other study did not find a significant difference between the two delivery modes. In an uncontrolled setting, one study found that an app was faster than SMS. Data completeness and adherence to sampling protocols were only reported in uncontrolled settings. Regarding the former, an app was found to result in more complete records than paper, and in significantly more data entries than an SMS-based survey questionnaire. Regarding adherence to the sampling protocol, apps may be better than paper but no different from SMS. We identified multiple definitions of acceptability to respondents, with inconclusive results: preference; ease of use; willingness to use a delivery mode; satisfaction; effectiveness of the system informativeness; perceived time taken to complete the survey questionnaire; perceived benefit of a delivery mode; perceived usefulness of a delivery mode; perceived ability to complete a survey questionnaire; maximum length of time that participants would be willing to use a delivery mode; and reactivity to the delivery mode and its successful integration into respondents’ daily routine. Finally, regardless of the study setting, none of the included studies reported data accuracy or response rates. Authors’ conclusions: Our results, based on a narrative synthesis of the evidence, suggest that apps might not affect data equivalence as long as the intended clinical application of the survey questionnaire, its intended frequency of administration and the setting in which it was validated remain unchanged. There were no data on data accuracy or response rates, and findings on the time taken to complete a self-administered survey questionnaire were contradictory. Furthermore, although apps might improve data completeness, there is not enough evidence to assess their impact on adherence to sampling protocols. None of the included studies assessed how elements of user interaction design, survey questionnaire design and intervention design might influence mode effects. Those conducting research in public health and epidemiology should not assume that mode effects relevant to other delivery modes apply to apps running on consumer smart devices. Those conducting methodological research might wish to explore the issues highlighted by this systematic review