From bench to bedside: Tracing the payback forwards from basic or early clinical research – A preliminary exercise and proposals for a future study

EXECUTIVE SUMMARY Chapter 1 : Introduction • The members of the research team from HERG and the Wellcome Trust have conducted previous studies showing that it is possible both to assess the payback from applied health research, and to use bibliometrics to trace the links between generations of research and clinical guidelines. In another of the team’s studies, however, it proved difficult to replicate the major study by Comroe and Dripps (1976) that had identified clinical advances and then worked backwards to show that they had relied on earlier basic research. Therefore, the study reported here sets out to use the methods developed in our previous studies of payback to undertake analysis that starts with more basic or early clinical research and traces the research lines forwards to clinical applications. Whilst this preliminary study involved preparation for a future large-scale study, it was hoped that it would also provide an interesting case study. • Starting with the research outputs of one team 20 years ago, called the 1st generation papers, the preliminary study has three main elements: standard bibliometric analysis through several generations of papers; categorisation of the citations; and qualitative analysis using questionnaires, critical pathway analysis and interviews to trace the impact of the 1st generation of research. • Diabetes and cardiology were suggested as possible topics on which to base the study. Initial reviews identified two bodies of research in diabetes as being potentially suitable for reasons such as the continuing activity of key members of the team. • The research into diabetes conducted in 1981 by George Alberti and his team at Newcastle, and collaborators elsewhere, was selected to provide the case study for this preliminary stage for several reasons. It was thought to have been important science and there was a belief that some of it had made a contribution to clinical practice. Chapter 2 : Bibliometric analysis • An original plan to look at publications produced over a three year period was changed to looking at the output of just one year, 1981, because in that year alone Alberti and colleagues published 29 articles. These form the 1st generation papers and the average number of citations they received is high. Identifying the citations given to these 29 papers resulted in 799 2nd generation papers and 12,891 3rd generation papers. The numbers involved meant that it was impractical to go beyond the 3rd generation. Within the high overall average, the variation in the number of citations per paper was iii considerable going from 76 to just one. Similarly, the half-lives of the 29 papers, ie the time taken for an article to receive 50% of its citations, ranged from two years to 11. • Articles can be given a Research Level (ie one of four levels from clinical observation to basic) based on the journals in which they appear. Such analysis demonstrates the breadth of Alberti’s work because the 29 articles are spread across all four Research Levels. Crucially, there was not a shift from basic to more clinical levels across the generations. The higher than average number of authors and addresses per paper is testimony to Alberti’s extensive collaborations. • The funding acknowledgements reveal the high proportion of papers supported, at least partially, by one funder: the British Diabetic Association, now Diabetes UK, which provided core support for Alberti’s Newcastle team. Chapter 3 : Categorisation of citations • Traditional citation analysis does not allow identification of the importance of the cited article to the citing article, and therefore limits the ability to use citation analysis to trace the impact of basic or early research on later research. We conducted a review of the literature of the meaning of citations. • From this review, a template was devised that allowed the location, nature and importance of citations to be recorded as well as the type of research (basic or clinical) described in the paper. This was used by six assessors on a sample of papers and inter-rater reliability was tested. Further work is required to refine the template and its definitions, and to improve its consistency in application. • Nevertheless, for initial analysis, it was applied to 623 out of the 799 2nd generation papers. A four point scale was used for the importance of the cited paper to the citing paper. In just 9% of cases was the cited 1st generation paper thought to be in one of the top two categories, ie of Considerable or Essential importance to the citing paper. • Statistical analysis revealed no relationship between the number of citations a paper received and the proportion of citations where the cited paper was classified as being of high (ie. Considerable or Essential) importance to the citing paper. Self-citations, however, were shown to be significantly more likely to be in this category. • The classification of the type of research (basic or clinical) by our analysis of each paper broadly agreed with the classification of the journals by Research Level. • The time constraints involved in applying the template, plus the lack of any overall pattern in terms of correlations between number and importance of citations, might point to the desirability of adopting a more selective approach, guided by qualitative analysis. In any selective approach, however, it is likely that self-citations should feature. iv Chapter 4 : Qualitative analysis • Given the number of co-authors, it seemed appropriate to send them a questionnaire rather than attempt to interview them. Therefore the interviewing was rather more concentrated than originally intended. Only one formal critical pathway was created, but it was undertaken by an expert in the field who worked with Alberti at Newcastle. • Some problems emerged in taking 1981 as the starting point for the study. Alberti identified 10 selected papers from the 1970s and 1980s that he felt had had most impact on clinical practice. These helped to give us both a better understanding of the payback from our 1st generation, or 1981, papers, and provided further material for analysis. • Attempting to describe the impact from the 1981 body of work, and from the 10 selected papers, underlines the complex reality of how science advances and influences clinical practice. If they make a contribution at all, most studies make a small, incremental one. • A few papers, however, have been shown to have a considerably greater impact. A possible key to the level of payback indicated is the enormous breadth of Alberti’s contacts, and fields and methods of working, to which various references were made. This is well illustrated in the account of how the idea for subcutaneous pumps came about. Similarly, the ability to produce the very important guidelines on treating diabetics during surgery, and diabetic coma, partly resulted from the application to clinical problems of the understandings gained from some of the basic/early clinical studies. It is significant that the key papers on these issues, all of which come from the list of 10 selected papers from the 1970s and 1980s, were having an impact on the 1981 work. • How far the collection of papers from 1981 have been drawn upon in similar ways is less clear. Nevertheless, papers on treating diabetics during open heart surgery, and on bolus delivery of insulin at meal times, were key parts of these wider streams, despite variable citation levels. Furthermore, various papers, including on acarbose, on portal infusion of insulin, and on semi-human insulin, were important steps in bodies of work in their respective areas. The complexity was illustrated by a paper that helped debunk the Chlorpropamide alcohol flushing hypothesis, and thus end a line of scientific enquiry: there was payback in stopping an incorrect line of inquiry, but nothing on which to build. • Each technique in the qualitative study produced information about the successful subsequent careers followed by many researchers trained through working with Alberti. • Historical perspectives, and insider expert opinions, were important in the qualitative analysis. Overall, the qualitative methods highlighted some limitations in the bibliometric approach but also showed how aspects of the citation analysis can complement the opinions expressed, for example about the importance of the breadth of Alberti’s work. v Chapter 5 : Lessons learnt and the way forward • Lessons learnt: a variety of methods can be used successfully to gather considerable data about the payback from a body of research undertaken 20 years ago. Traditional citation analysis alone, however, is not sufficient: the importance of the surgery papers despite their relatively low citation rates illustrates this. The qualitative methods are important and much of the analysis is strengthened by drawing on multiple approaches. Several problems remain, including: identifying a coherent starting point for the analysis; coping with the enormous number of papers involved in later generations; and refining the template for categorising citations and developing ways of fully utilising the results from applying it. • Preparing for the large-scale study: this preliminary study provides a basis on which to attempt to undertake the larger study we envisaged. Issues now being addressed include identification of the level of bibliometric/citation analysis necessary to complement any qualitative studies. To provide confidence in the findings from an eventual large-scale study, we will need to expand the focus. The study will need to cover at least four sets of case studies. Ideally, each set should focus on a number of research groups working in a country in the same field. We hope there will be sets of case studies in two or three fields and in at least two countries. The issues to be explored will include ones highlighted by this study such as breadth of work, level of collaboration, and the role of core funding. • Methods for the large-scale study: for each case study we now propose to employ two methodological elements based on the qualitative and quantitative techniques adopted in the preliminary study. They will work in parallel but the quantitative bibliometric analysis would be applied selectively to parts of ‘research lines’ (ie discrete themes of research) identified in the qualitative studies as being important in influencing clinical practice. • Presenting the findings: each research line could be written-up in a standardised document that would use the HERG payback model and categories to describe the impact of that research. We shall use the qualitative and quantitative data to compare and contrast the ‘payback’ of research lines by country and disease, and then identify common factors that correlate with the translation of basic or early clinical research. • Concluding comments: in the era of ‘evidence based policy’, research funders are looking for value for money in the research they support and for evidence on the effectiveness of different research strategies. In this study we have begun developing a methodology that will allow us to understand the complexity of research development over a series of generations. The utility of the policy research we propose here will only be realised when it is scaled up to cover a number of different fields in different settings.NHS Executive, London Regio

Coulomb correlation in presence of spin-orbit coupling: application to plutonium

Attempts to go beyond the local density approximation (LDA) of Density Functional Theory (DFT) have been increasingly based on the incorporation of more realistic Coulomb interactions. In their earliest implementations, methods like LDA+$U$, LDA + DMFT (Dynamical Mean Field Theory), and LDA+Gutzwiller used a simple model interaction $U$. In this article we generalize the solution of the full Coulomb matrix involving $F^{(0)}$ to $F^{(6)}$ parameters, which is usually presented in terms of an $\ell m_\ell$ basis, into a $jm_{j}$ basis of the total angular momentum, where we also include spin-orbit coupling; this type of theory is needed for a reliable description of $f$-state elements like plutonium, which we use as an example of our theory. Close attention will be paid to spin-flip terms, which are important in multiplet theory but that have been usually neglected in these kinds of studies. We find that, in a density-density approximation, the $jm_j$ basis results provide a very good approximation to the full Coulomb matrix result, in contrast to the much less accurate results for the more conventional $\ell m_\ell$ basis

ENV-654: NUMERICAL MODELLING OF SMOULDERING COMBUSTION TO OPTIMIZE EX SITU SOIL TREATMENT SYSTEM DESIGN

There is widespread soil contamination at thousands of cites in Canada resulting from the historical improper storage and disposal of industrial liquids (Story et al., 2014). Large financial resources are allocated to remediation efforts due to the human and environmental health risks associated with exposure to such contamination, with over $582 million CAN spent on remediation in 2014-15 by the Canadian government alone (Treasury Board of Canada, 2016). Our scientific understanding of site remediation has evolved greatly over the past decades and it is now widely accepted that remediation of the contaminant source zone is necessary to achieve a high level of long-term remediation (Kueper et al., 2014). Non-aqueous phase liquids, or NAPLS, are one of the most prevalent contaminants at contaminated sites and are challenging to remediate due to their highly recalcitrant nature (Kueper et al., 2003). Although many remediation technologies have been developed over the past decades, the challenge in source zone remediation of NAPLs persists. The application of smouldering combustion to treat NAPL contaminated soils has been proven as an effective technology with both the laboratory experiments and applied in situ at a field site (Switzer et al., 2009, Pironi et al., 2011, Switzer et al, 2014, Salman et al., 2015, Scholes et al., 2015). This technology, titled “Self-sustaining treatment for active remediation”, or STAR, utilizes the high calorific value of NAPLs to ignite and sustain a smouldering oxidation reaction, effectively destroying the contaminant in the process. A phenomenological model developed by MacPhee et al. (2012) uniquely combined a multiphase flow model, perimeter expansion model, and analytical expression for the forward smouldering front velocity. This model is able to predict the propagation of the reaction front in response to the interplay between a heterogeneous distribution of permeability and the time-dependent distribution of air flux. After subsequent calibration by Hasan et al. (2014), the model was shown to correctly predict the ultimate extent and time of remediation during treatment for 2D lab scale experiments

Dual kinetic balance approach to basis set expansions for the Dirac equation

A new approach to finite basis sets for the Dirac equation is developed. It solves the problem of spurious states and, as a result, improves the convergence properties of basis set calculations. The efficiency of the method is demonstrated for finite basis sets constructed from B splines by calculating the one-loop self-energy correction for a hydrogenlike ion.Comment: 14 pages, 1 tabl

ENV-601: A NEW METHOD FOR CONVERTING SEWAGE TO ENERGY USING SELF-SUSTAINING SMOULDERING

A major challenge in designing resilient infrastructure is to meet the needs of sustainable development (Kennedy & Corfee-Morlot, 2013). Sustainable development requires a high degree of energy efficiency. Municipal wastewater treatment plants (WWTPs), in particular, have the potential to be much more sustainable. In the U.S., 3 – 4% of the total energy consumed is dedicated to WWTPs and drinking water services, accounting for 30 – 40% of energy consumed by municipalities (U.S. EPA, 2014). In Canada, 25% of the $123 billion municipal deficit in 2006 was tied to water supply systems (i.e., drinking water, wastewater, and storm water) (Mirza, 2006). This problem becomes further complicated as much of North America’s WWTP infrastructure approaches the end of its design life. An estimated$298 billion and $39 billion is required in the U.S. and Canada, respectively, to satisfactorily refurbish WWTP infrastructure (ASCE, 2013; Félio et al., 2012). Within WWTPs, around 50% of the operating and capital costs are dedicated to managing the solid by-product, biosolids, making it the most expensive system component (Khiari et al., 2004). In Canada, 90% of biosolids are either incinerated or land applied for agricultural purposes (Apedaile, 2001). These methods are expensive, requiring high energy inputs in various forms (e.g., fuel, labour, transportation) (Wang et al., 2008). Land application is also subject to limitations and uncertain risks due to the potential for introducing synthetic contaminants into the environment (Hale et al., 2001; U.S. EPA, 1995). In general, managing biosolids persists as a major energy intensive challenge within WWTPs and there is a strong need to provide novel solutions (Tyagi & Lo, 2013). Self-sustaining smouldering combustion of organic wastes was originally developed as a chemical waste management and soil-clean up technology (Pironi et al., 2011; Scholes et al., 2015; Switzer et al., 2009). Smouldering is a flameless form of combustion for solid and liquid fuels, where a common example is glowing red charcoal in a traditional barbeque (Ohlemiller, 1985). The fuel (e.g. oil sludge) is mixed with sand to form a fixed-bed; this increases the surface area for reaction, provides porosity for the oxidant (air), and efficiently transfers, stores, and recycles the released reaction energy (Switzer et al., 2009). The smouldering reaction typically reaches temperatures between 500-800°C for many minutes in one location resulting in upwards of 99% conversion of organic waste to heat (Pironi et al., 2011). Smouldering in this configuration is unique as it supports an extremely energy efficient, self-sustaining reaction; therefore, following ignition, no external energy is required to sustain the reaction indefinitely. As a result, the process can smoulder fuels containing little energy or significant water contents that would otherwise not burn (e.g., via incineration) (Switzer et al., 2009; Yermán et al., 2015). Proof-of-concept experiments demonstrated for the first time that biosolids, obtained from Greenway Pollution Control Centre (London, ON) could be successfully destroyed via self-sustained smouldering. Thirty experiments in 40 cm tall, 15 cm diameter fixed-bed columns mapped the parameter space of self-sustained smouldering as a function of sand dilution, biosolids water content, and injected air flow rate. The results demonstrate that a self-sustaining reaction was achieved using biosolids with water contents as high as 80% (1.6 MJ/kg, effective calorific value). With little input of energy, the biosolids were converted to heat, steam, and emissions dominated by carbon dioxide. These ENV-601-2 results suggest that smouldering presents strong potential as a cost and energy effective waste management alternative for WWTP biosolids, achieving on-site destruction with minimal energy input and limited preliminary processing (Rashwan et al., 2016). This underscores the beneficial application of smouldering as a novel waste management technique that may be useful in designing resilient infrastructure

Calculation of the two-photon decay rates of hydrogen-like ions by using B-polynomials

A new approach is laid out to investigate the two photon atomic transitions. It is based on application of the finite basis solutions constructed from the Bernstein Polynomial (B-Polynomial) sets. We show that such an approach provides a very promising route for the relativistic second- (and even higher-order) calculations since it allows for analytical evaluation of the involved matrices elements. In order to illustrate possible applications of the method and to verify its accuracy, detailed calculations are performed for the 2s_{1/2}-1s_{1/2} transition in neutral hydrogen and hydrogen-like ions, and are compared with the theoretical predictions based on the well-established B-spline-basis-set approach

QED effects on individual atomic orbital energies

Several issues, concerning QED corrections, that are important in precise atomic calculations are presented. The leading QED corrections, self-energy and vacuum polarization, to the orbital energy for selected atoms with 30 ≤ Z ≤ 118 have been calculated. The sum of QED and Breit contributions to the orbital energy is analyzed. It has been found that for ns subshells the Breit and QED contributions are of comparative size, but for np and nd subshells the Breit contribution takes a major part of the QED+Breit sum. It has also, been found that the Breit to leading QED contributions ratio for ns subshells is almost independent of Z. The Z-dependence of QED and Breit+QED contributions per subshell is shown. The fitting coefficients may be used to estimate QED effects on inner molecular orbitals. We present results of our calculations for QED contributions to orbital energy of valence ns-subshell for group 1 and 11 atoms and discuss about the reliability of these numbers by comparing them with experimental first ionization potential data.Fil: Koziol, Karol. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; ArgentinaFil: Aucar, Gustavo Adolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Modelado e Innovación Tecnológica. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Modelado e Innovación Tecnológica; Argentin

Bubbles on Manifolds with a U(1) Isometry

We investigate the construction of five-dimensional, three-charge supergravity solutions that only have a rotational U(1) isometry. We show that such solutions can be obtained as warped compactifications with a singular ambi-polar hyper-Kahler base space and singular warp factors. We show that the complete solution is regular around the critical surface of the ambi-polar base. We illustrate this by presenting the explicit form of the most general supersymmetric solutions that can be obtained from an Atiyah-Hitchin base space and its ambi-polar generalizations. We make a parallel analysis using an ambi-polar generalization of the Eguchi-Hanson base space metric. We also show how the bubbling procedure applied to the ambi-polar Eguchi-Hanson metric can convert it to a global AdS_2xS^3 compactification.Comment: 33 pages, 5 figures, LaTeX; references adde

Elevated systemic antibodies towards commensal gut microbiota in autoinflammatory condition

Article No. e3172Non peer reviewedPublisher PD

Simulated ecology-driven sympatric speciation

We introduce a multi-locus genetically acquired phenotype, submitted to mutations and with selective value, in an age-structured model for biological aging. This phenotype describes a single-trait effect of the environment on an individual, and we study the resulting distribution of this trait among the population. In particular, our simulations show that the appearance of a double phenotypic attractor in the ecology induces the emergence of a stable polymorphism, as observed in the Galapagos finches. In the presence of this polymorphism, the simulations generate short-term speciation, when mating preferences are also allowed to suffer mutations and acquire selective value.Comment: 11 pages, 5 figures, 1 table, uses package RevTe