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

Small business lending in low- and Moderate-income areas: The effects of credit scoring

Credit scoring systems ; Lender liability ; Small business

Short-term and long-term outcomes in 133 429 emergency patients admitted with angina or myocardial infarction in Scotland, 1990-2000: population-based cohort study

Objective: To analyse short- and long-term outcomes and prognostic factors in a large population-based cohort of unselected patients with a first emergency admission for suspected acute coronary syndrome between 1990 and 2000 in Scotland. Methods: All first emergency admissions for acute myocardial infarction (AMI) and all first emergency admissions for angina (the proxy for unstable angina) between 1990 and 2000 in Scotland (population 5.1 million) were identified. Survival to five years was examined by Cox multivariate modelling to examine the independent prognostic effects of diagnosis, age, sex, year of admission, socioeconomic deprivation and co-morbidity. Results: In Scotland between 1990 and 2000, 133 429 individual patients had a first emergency admission for suspected acute coronary syndrome: 96 026 with AMI and 37 403 with angina. After exclusion of deaths within 30 days, crude five-year case fatality was similarly poor for patients with angina and those with AMI (23.9% v 21.6% in men and 23.5% v 26.0% in women). The longer-term risk of a subsequent fatal or non-fatal event in the five years after first hospital admission was high: 54% in men after AMI (53% in women) and 56% after angina (49% in women). Event rates increased threefold with increasing age and 20–60% with different co-morbidities, but were 11–34% lower in women. Conclusions: Longer-term case fatality was similarly high in patients with angina and in survivors of AMI, about 5% a year. Furthermore, half the patients experienced a fatal or non-fatal event within five years. These data may strengthen the case for aggressive secondary prevention in all patients presenting with acute coronary syndrome

Some Combinatorial Properties of Hook Lengths, Contents, and Parts of Partitions

This paper proves a generalization of a conjecture of Guoniu Han, inspired originally by an identity of Nekrasov and Okounkov. The main result states that certain sums over partitions p of n, involving symmetric functions of the squares of the hook lengths of p, are polynomial functions of n. A similar result is obtained for symmetric functions of the contents and shifted parts of n.Comment: 20 pages. Correction of some inaccuracies, and a new Theorem 4.

Flow cytometric evaluation of red blood cells transformed with variable amounts of synthetic A and B glycolipids

Background: According to national guidelines or directives, monoclonal ABO reagents may be required to detect Ax and B weak subgroup red blood cells (RBCs). Many routine laboratories do not have access to naturallyoccurring ABO subgroups that can be used as weak controls for these reagents. Group O RBCs modified with synthetic analogs of blood group A and/or B glycolipids (KODE technology) to mimic weak ABO subgroups could be used for quality control purposes. Aim: Extensive serological testing of KODE RBCs has previously been performed. An extended evaluation of KODE RBCs using flow cytometry was performed to explore the correlation between the concentrations of synthetic glycolipids and A/B site density of the resulting RBCs. The aim of this study was to examine if KODE RBCs mimic the distinct flow cytometric patterns of naturally-occurring ABO subgroups. Material and Methods: KODE RBCs were prepared according to a previously decribed procedure [Frame et al., Transfusion 2007; 47: 876–82]. RBCs were modified with 15 different concentrations of synthetic glycolipids, ranging from 1 mg/mL to 60 ng/mL for KODE-A and 5 mg/mL to 0.3 lg/mL for KODE-B. The concentration was decreased by doubling dilution steps. Sensitive and specific flow cytometry [Hult & Olsson. Transfusion 2006; 9S: 32A] was used to characterize and semiquantify the synthetic A and B antigen levels on RBCs. Relevant control RBCs (A1, A2, Ax, B, Bweak and O) were included in each run. For both KODE-A and KODE-B RBCs, repeat samples were produced for four selected concentrations and all KODE batches were tested in triplicate. Results: Flow cytometric testing of KODE RBCs modified with high concentrations of synthetic glycolipids revealed a uniform and even distribution of antigens in the cell population as shown by a single narrow peak in the FACS histograms. When lower concentrations were used, peaks tended to broaden to a pattern found in Ax and most B subgroups indicating a more variable antigen site density on the cells in the population. The concentrations of synthetic glycolipids that produced KODE cells that resembled the naturally-occurring subgroup control RBCs used in this study are ~2–4 lg/mL for KODE-A and ~10 lg/mL for KODEB. Repeat testing demonstrated good correlation between flow cytometric runs. Discussion and Conclusion: Using very low amounts of synthetic glycolipids, KODE-A and KODE-B RBCs can be made to mimic Ax and Bweak subgroup control RBCs, respectively, according to this flow cytometry method. With higher concentrations of synthetic glycolipids, the KODE RBCs demonstrated a more uniform and even distribution of antigens among the cells. This is in contrast to naturally-occurring subgroups in which some cells express almost no A or B antigen whilst others have close to normal levels. The reason for this is unknown. KODE RBCs obviously lack A carrying glycoproteins but it is not fully understood to what extent glycolipid versus glycoprotein epitopes contribute to the phenotype of weak subgroups. This study indicates that KODE RBCs with weak expression of A and/or B antigen have characteristics compatible with use as quality controls for monoclonal ABO reagents and could be a valuable addition in the serological laboratory

Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy including senscence, necrosis, and autophagy, but not apoptosis

In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer

Wolf Reproduction in Response to Caribou Migration and Industrial Development on the Central Barrens of Mainland Canada

Reproductive success of mammals is greatly influenced by food availability. Where wolves (Canis lupus) prey on migratory barren-ground caribou (Rangifer tarandus), caribou migration patterns strongly influence food availability for wolves. However, industrial development in formerly undeveloped wolf range could also negatively influence wolf reproduction, either directly (by disrupting normal feeding behavior) or indirectly (by impacting caribou migrations). We used a cross-sectional timeseries regression to analyze eight years of wolf reproductive data with respect to spatial and temporal variation in caribou migration and economic development in a 49 900 km2 area of the Northwest Territories, Canada. Reproductive success decreased as the distance from wolf dens to caribou migration routes increased, while the timing of caribou migrations had little effect. There was no measurable effect of current levels of economic development on reproductive success, although evidence suggests the potential for indirect effects. Continued monitoring is required to identify possible thresholds of adverse effects for wolf populations.La réussite de reproduction des mammifères dépend beaucoup de la disponibilité de la nourriture. Là où les loups (Canis lupus) ont comme proie le caribou de la toundra en migration (Rangifer tarandus), le schéma des migrations du caribou joue un grand rôle sur la disponibilité de nourriture des loups. Cela dit, l’expansion industrielle dans d’anciennes aires de répartition non aménagées du loup pourrait aussi avoir une influence négative sur la reproduction du loup, directement (perturbation du comportement d’alimentation habituel) ou indirectement (impact sur la migration du caribou). Nous avons recouru à une régression chronologique transversale pour analyser huit années de données de reproduction du loup par rapport à la variation spatiale et temporelle de la migration du caribou et au développement économique dans une zone de 49 900 km2 des territoires du Nord-Ouest, au Canada. La réussite de reproduction diminuait au fur et à mesure que la distance entre les tanières de loups et les routes de migration du caribou augmentaient, tandis que le moment choisi pour les migrations du caribou avait peu d’effets. Le développement économique actuel n’avait aucun effet mesurable sur la réussite de reproduction, bien que certains indices laissent croire qu’il pourrait avoir des effets indirects. Il y a donc lieu d’effectuer une surveillance continue afin de déterminer les seuils possibles d’effets nuisibles sur les populations de loups

Failure to learn from feedback underlies word learning difficulties in toddlers at risk for autism

Children’s assignment of novel words to nameless objects, over objects whose names they know (mutual exclusivity; ME) has been described as a driving force for vocabulary acquisition. Despite their ability to use ME to fast-map words (Preissler & Carey, 2005), children with autism show impaired language acquisition. We aimed to address this puzzle by building on studies showing that correct referent selection using ME does not lead to word learning unless ostensive feedback is provided on the child’s object choice (Horst & Samuelson, 2008). We found that although toddlers aged 2;0 at risk for autism can use ME to choose the correct referent of a word, they do not benefit from feedback for long-term retention of the word–object mapping. Further, their difficulty using feedback is associated with their smaller receptive vocabularies. We propose that difficulties learning from social feedback, not lexical principles, limits vocabulary building during development in children at risk for autism

Impact of seasonality on the dynamics of native Vitamin D repletion in long-term renal transplant patients

BACKGROUND: Renal transplant recipients (RTRs) are often Vitamin D (VitD) depleted as a result of both chronic kidney disease and mandated sun avoidance behaviours. Repleting VitD may be warranted, but how, and for how long, is unknown, as is the impact of seasonality on the success of repletion. We investigated the impact of seasonality on VitD status following VitD repletion in a large cohort of stable, long-term RTRs. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] concentrations and bone biochemistry parameters were analysed from 102 VitD repletion courses in 98 RTRs that had undergone VitD repletion. Repletion was delivered over 6 months with either 240 000 IU colecalciferol if pre-repletion serum VitD was between 20 and 50 nmol/L, or with 360 000 IU if VitD was <20 nmol/L. Twelve months post-repletion 25(OH)D and parathyroid hormone (PTH) were available for 75 patients. RESULTS: At baseline, 25(OH)D was 20.1 ± 1.0 nmol/L, increasing to 65.4 ± 1.8 nmol/L following repletion (+7.55 nmol/L/month, P < 0.0001). Twelve months post-repletion and after no further VitD administration, 25(OH)D fell to 35.4 ± 1.8 nmol/L (14.2 ± 0.7 ng/mL; −2.50 nmol/L/month, P < 0.0001). PTH followed the opposite trend with baseline, repletion-end and post-repletion values being 144.2 ± 12.0, 109.6 ± 7.5 and 129.2 ± 11.4 ng/L, respectively. VitD repletion during the summer was associated with significantly higher at repletion-end 25(OH)D compared with any other time of year [summer 80.9 ± 4.0, autumn 64.1 ± 3.0 (P = 0.002), winter 48.9 ± 3.0 (P <0.001), spring 63.8 ± 2.5 nmol/L (P <0.001)]. There was no hypercalcaemia during repletion and renal transplant function remained stable without any evidence of allograft rejection. CONCLUSIONS: VitD repletion can safely and effectively be achieved in the majority of chronic stable RTRs using a 6-month bolus intermediate-dose schedule. Winter repletion is associated with an inadequate response in 25(OH)D; however, all patients experience a post-repletion fall towards deficiency in the absence of maintenance supplementation, irrespective of the season of repletion