An observational cohort study to produce and evaluate an improved tool to screen older women with back pain for osteoporotic vertebral fractures (Vfrac): study protocol.

The aim of this study is to produce an easy to use checklist for general practitioners to complete whenever a woman aged over 65 years with back pain seeks healthcare. This checklist will produce a binary output to determine if the patient should have a radiograph to diagnose vertebral fracture. PURPOSE: People with osteoporotic vertebral fractures are important to be identified as they are at relatively high risk of further fractures. Despite this, less than a third of people with osteoporotic vertebral fractures come to clinical attention due to various reasons including lack of clear triggers to identify who should have diagnostic spinal radiographs. This study aims to produce and evaluate a novel screening tool (Vfrac) for use in older women presenting with back pain in primary care based on clinical triggers and predictors identified previously. This tool will generate a binary output to determine if a radiograph is required. METHODS: The Vfrac study is a two-site, pragmatic, observational cohort study recruiting 1633 women aged over 65 years with self-reported back pain. Participants will be recruited from primary care in two sites. The Vfrac study will use data from two self-completed questionnaires, a simple physical examination, a lateral thoracic and lateral lumbar radiograph and information contained in medical records. RESULTS: The primary objective is to develop an easy-to-use clinical screening tool for identifying older women who are likely to have vertebral fractures. CONCLUSIONS: This article describes the protocol of the Vfrac study; ISRCTN16550671.

Tumour necrosis factor-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis.

Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b(+) macrophages and CD4(+) T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage.