Translational Medicine - doing it backwards

In recent years the concept of "translational medicine" has been advanced in an attempt to catalyze the medical applications of basic biomedical research. However, there has been little discussion about the readiness of scientists themselves to respond to what we believe is a required new approach to scientific discovery if this new concept is to bear fruit. The present paradigm of hypothesis-driven research poorly suits the needs of biomedical research unless efforts are spent in identifying clinically relevant hypotheses. The dominant funding system favors hypotheses born from model systems and not humans, bypassing the Baconian principle of relevant observations and experimentation before hypotheses. Here, we argue that that this attitude has born two unfortunate results: lack of sufficient rigor in selecting hypotheses relevant to human disease and limitations of most clinical studies to certain outcome parameters rather than expanding knowledge of human pathophysiology; an illogical approach to translational medicine. If we wish to remain true to our responsibility and duty of performing research relevant to human disease, we must begin to think about fundamental new approaches

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system

Abatement costs of alternative tax systems to regulate agricultural nitrogen loss

Nitrogen emissions from agriculture are considered an important environmental problem in Denmark motivating consideration of different tax schemes as regulatory instruments. In this paper, input/output behaviour of Danish pig farmers is estimated with farm level panel data using the dual profit function approach, and emission functions for nitrogen loss are derived. With the estimated model we are able to compare cost-effectiveness of a comprehensive Pigouvian tax on nitrogen loss with simpler tax schemes that focus on nitrogen use. We find that both a fertilizer tax and a feed tax generate substantially higher abatement costs than Pigouvian incentives. A tax on nitrogen in all inputs will, on the other hand, only generate a marginal increase in abatement costs. These results are of interest because a tax on all nitrogen inputs is easier to implement than a comprehensive nitrogen loss tax. Our result implies that even a limited administrative cost advantage may make the input tax preferable to implementing Pigouvian incentives through an nitrogen loss tax

Sustainable Land Use: Methodology and Application

The chapters in this volume are edited versions of papers presented at the NATO Ad- vanced Research Workshop on Environmental Change Adaptation and Security held in Budapest, Hungary, from October 16 - 18, 1997. As is evident in this volume, the papers ranged from descriptions of environmental and health issues in Russia and Eastern Europe to models of sustainable land use. This diversity of perspectives on environ- ment and security is indicative of both the breadth of this new area of research as well as the varied background of the researchers involved. The discussions at the NATO workshop were remarkably animated and exciting, not surprising given the interest in the topic. I think this vitality is reflected in the papers in this volume as well. The main purpose of the NATO ARW is to foster research links among researchers from NATO countries and Central and Eastern European States, Russia, and the Newly Independent States. In editing this volume, a decision was made to keep to the spirit of this purpose and-if at all possible-include all papers prepared for the workshop. This required extensive editing and rewriting of some of the papers (and consequent delays in production). A determination was made early in the process by the workshop steering committee that the value of publishing the entire collection of articles out- weighed the advantages of accepting only a limited number

Regulation of MYCN expression in human neuroblastoma cells

Contains fulltext : 81722.pdf (publisher's version ) (Open Access)BACKGROUND: Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (DeltaMYCN) that was recently identified in fetal tissues. Both MYCNOS and DeltaMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level. METHODS: Expression of MYCN, MYCNOS and DeltaMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR). RESULTS: Both DeltaMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:DeltaMYCN expression was identical in all tested NBs. This indicates that DeltaMYCN and MYCN are co-regulated, which suggests that DeltaMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level. CONCLUSION: The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by DeltaMYCN

Registered nurses' perceptions and experiences of autonomy: a descriptive phenomenological study

Background Professional autonomy is a key concept in understanding nurses’ roles in delivering patient care. Recent research exploring the role of autonomy in the nursing work environment indicated that English and American nurses had differing perceptions of autonomy. This qualitative study aimed to explore the understanding and experiences of autonomy of nurses working in England. Methods A descriptive phenomenological analysis of data from 48 semi-structured interviews with registered nurses from two National Health Service (NHS) hospitals (purposive sample) was used to explore the concept of autonomy. Results Six themes were identified: working independently; working in a team; having professional skills and knowledge; involvement in autonomy; boundaries around autonomy; and developing autonomy requires support. A key finding was that nurses related autonomy to their clinical work and to the immediate work environment of their ward, rather than to a wider professional context. Nurses also perceived that autonomy could be turned off and on rather than comprising an integrated aspect of nursing. Conclusions Findings suggest that nurses in England, as framed by the sample, had a local ward-focused view of autonomy in comparison to nurses in America, who were reported to relate autonomy to a wider involvement in hospital level committees. Findings further indicate that autonomy was practiced occasionally, rather than incorporated into practice. Findings highlight the need for nurses in England to adopt a broader perspective and actively contribute to writing hospital guidelines and policies that recognise the importance of autonomy to nurse training and practice

White Matter Development in Early Puberty: A Longitudinal Volumetric and Diffusion Tensor Imaging Twin Study

White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ∼85%), surface area (∼85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = –0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization

Neck Pain and Disability Scale and the Neck Disability Index: reproducibility of the Dutch Language Versions

The first aim of this study was to translate the Neck Pain and Disability Scale (NPAD) from English into Dutch producing the NPAD–Dutch Language Version (DLV). The second aim was to analyze test–retest reliability and agreement of the NPAD–DLV and the Neck Disability Index (NDI)–DLV. The NPAD was translated according to established guidelines. Thirty-four patients (mean age 37.5 years, 68% female) with chronic neck pain (CNP), within an outpatient rehabilitation setting, participated in this study. The NPAD–DLV and the NDI–DLV were filled out twice with a mean test–retest interval of 18 days. The intraclass correlation coefficient of the NPAD–DLV was 0.76 (95% confidence interval (CI) 0.57–0.87) and of the NDI–DLV 0.84 (95% CI 0.69–0.92). The limits of agreement of the NPAD–DLV and the NDI–DLV were, respectively, ±20.9 (scale 0–100) and ±6.5 (scale 0–50). The reliability of the NPAD–DLV and the NDI–DLV was acceptable for patients with CNP. The variation (‘instability’) in the NPAD–DLV total scores was relatively large and larger than the variation of the NDI–DLV