A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Charter for disabled people using hospitals: a completed access audit cycle.

This completed audit cycle assessed access for disabled people to a district general hospital, in relation to standards laid down in the Royal College of Physicians Charter for Disabled People using Hospitals. The project was effective in demonstrating problems and implementing change to overcome them. It was also useful in raising disability awareness in the young investigators, who easily recognised the shortcomings in facilities for disabled people, and is proposed as a possible model for inclusion in medical undergraduate training programmes to raise disability awareness amongst a new generation of doctors.

The UK FIM+FAM: development and evaluation. Functional Assessment Measure.

BACKGROUND AND AIMS: The aim of this study was to develop and evaluate the UK version of the Functional Assessment Measure (UK FIM+FAM). DESIGN: Before and after evaluation of inter-rater reliability. DEVELOPMENT: Ten 'troublesome' items in the original FIM+FAM were identified as being particularly difficult to score reliably. Revised decision trees were developed and tested for these items over a period of two years to produce the UK FIM+FAM. EVALUATION: A multicentre study was undertaken to test agreement between raters for the UK FIM+FAM, in comparison with the original version, by assessing accuracy of scoring for standard vignettes. METHODS: Baseline testing of the original FIM+FAM was undertaken at the start of the project in 1995. Thirty-seven rehabilitation professionals (11 teams) each rated the same three sets of vignettes - first individually and then as part of a multidisciplinary team. Accuracy was assessed in relation to the agreed 'correct' answers, both for individual and for team scores. Following development of the UK version, the same vignettes (with minimal adaptation to place them in context with the revised version) were rated by 28 individuals (nine teams). RESULTS: Taking all 30 items together, the accuracy for scoring by individuals improved from 74.7% to 77.1% with the UK version, and team scores improved from 83.7% to 86.5%. When the 10 troublesome items were taken together, accuracy of individual raters improved from 69.5% to 74.6% with the UK version (p <0.001), and team scores improved from 78.2% to 84.1% (N/S). For both versions, team ratings were significantly more accurate than individual ratings (p <0.01). Kappa values for team scoring of the troublesome items were all above 0.65 in the UK version. CONCLUSION: The UK FIM+FAM compares favourably with the original version for scoring accuracy and ease of use, and is now sufficiently well-developed for wider dissemination.

The use of standardized outcome measures in rehabilitation centres in the UK.

OBJECTIVE: To ascertain which standardized instruments are currently most commonly used as outcome measures for rehabilitation in routine clinical practice in the UK. DESIGN: The study used a postal questionnaire which was sent out to members of two major societies of rehabilitation professionals in the UK. RESULTS: Of 182 rehabilitation centres represented by respondents, 140 (77%) collected at least one standardized measure and 42 did not. Principal reasons for not recording measures were lack of time and not knowing what to collect. As had been anticipated, a very wide range of different measures were used by different centres, however some clear favourites emerged including the 10 m Walk, the Motricity Index and the Nine-hole Peg Test. One hundred and twenty-three centres used one or more global disability measure of which the commonest were the Barthel index or one of its modifications and the functional Independence Measure (FIM) and/or Functional Assessment Method (FAM). Among units that used handicap or extended activities of daily living (EADL) scales, the Nottingham EADL, the London Handicap Scale and the General Health Questionnaire (GHQ-22 or 12) were most popular. Outside neurorehabilitation, the Harold Wood/Stanmore mobility grades were used by 10/18 amputee rehabilitation centres and the Health Assessment Questionnaire (HAQ) was used by 15/48 units providing musculoskeletal rehabilitation. CONCLUSIONS: It is clear that no one measure is suitable in all settings and services, but the most popular measures from this survey may reasonably form the basis for a 'basket of recommended instruments' that may help to guide units wishing to collect outcome data but not knowing which to choose.