Use of evidence in decision models: an appraisal of health technology assessments in the UK since 1997

OBJECTIVES: To review the sources and quality of evidence used in the development of economic decision models in health technology assessments (HTAs). METHODS: All economic decision models developed as part of the NHS Research and Development HTA Programme between 1997 and 2003 were reviewed. Quality of evidence was assessed using a hierarchy of data sources developed for economic analyses. RESULTS: Decision models are parameterized using diverse sources of evidence (e.g. randomized controlled trials, observational studies, expert opinion). Evidence on the main clinical effect was mostly identified and quality assessed as part of the companion systematic review/meta-analysis of the HTA and therefore reported in a transparent and reproducible way. For the other model inputs (i.e. adverse events, baseline clinical data, resource use and utilities), the search strategies for identifying relevant evidence were rarely made explicit and in a number of reports the sources of specific evidence were unclear due to poor reporting. CONCLUSIONS: A more formal and replicable approach to identification and assessment of quality of model inputs is required to reduce the 'black box' nature of decision models, and lead to less scepticism regarding model outputs.     

Topographic analysis of the innervation of the rat neocortex and hippocampus by the basal forebrain cholinergic system

The basal forebrain-cortex connections of the rat were topographically mapped by retrograde tracer methods; and their contribution to the cholinergic innervation of the cortex was assessed by excitotoxin lesions placed in the rostral and caudal aspects of the complex. Discrete injections of tracer into frontal cortex labeled the prominent multipolar acetylcholinesterase (AchE)-positive cells of the ventromedial globus pallidus. Injections of tracer into the parietal cortex labelled cells in the ventral globus pallidus, the underlying substantia innominata, and the lateral hypothalamus. Separate injections of Fast Blue and Nuclear Yellow in the frontal and in the parietal cortex resulted in double-labeled cells in the ventral globus pallidus, which indicates that at least some of these cells may possess collateralizing axons. The cingulate cortex is innervated predominantly by neurons in the nucleus of the horizontal limb of the diagonal band. The occipital cortex was also shown to receive a projection primarily from the nucleus of the horizontal limb of the diagonal band. The hippocampal formation is innervated primarily by cells located in the vertical limb of the diagonal band and in the medial septum. Consistent with the results of the retrograde tracing studies, excitotoxin lesions affecting the diagonal band and medial septum decreased choline acetyltransferase (CAT) activity up to 40% on the occipital cortex and by 64% in the hippocampus, but did not affect CAT activity in the rostral neocortex. In contrast, ibotenate lesions of the caudal ventral globus pallidus and substantia innominata caused decreases in CAT activity in the frontal cortex of up to 65% without affecting enzyme activity in the hippocampal formation. The results of the present study provide details on the topographic organization of the cortical projections originating in the basal forebrain complex and indicate that these neurons are the predominant source of cortical cholinergic innervation.     

Dopaminergic dsyfunction in Tourette syndrome

A prospective clinical and biochemical study on the effects of treatment with haloperidol has been performed in seven patients with Tourette syndrome. Pretreatment cerebrospinal fluid levels of homovanillic acid (CSF HVA) were significantly reduce in all patients, whereas 5-hydroxyindoleacetic acid was reduced in only two. With haloperidol treatment, symptoms decreased in all cases (21 to 88%) and clinical improvement was associated with an increased level of CSF HVA, often returning to the normal range. Optimal therapeutic response was found with serum levels of haloperidol between 1 and 4 ng/ml; however, disturbing side effects also occurred within this range. These results support the hypothesis that Tourette syndrome may result from a supersensitivity of dopaminergic receptors.     

The role of ICOS and other costimulatory molecules in allergy and asthma

Activation and differentiation of T cells play a critical role in the pathogenesis of allergies and asthma. Upon encounter with specific antigen, naïve T helper precursor (ThP) cells become activated, an event that is regulated not only by engagement of the T cell receptor (TCR) with peptide presented in the context of MHC class II molecules, but also by a number of costimulatory signals. CD28 engagement by B7-1 and B7-2 on resting ThP cells provides a critical signal for initial cell cycle progression, interleukin-2 production and clonal expansion. However, in recent years, other related members of the immunoglobulin (Ig) family, such as inducible costimulatory molecules (ICOS) and the TNF receptor family members which include OX40, have also been demonstrated to play an important role in providing unique and complementary signals that regulate the outcome of immune responses. These positive costimulatory signals are counterbalanced by signals that dampen down immune responses and include CTLA-4, PD-1 and the recently described Ig superfamily members BTLA and TIM-3. This review discusses the role of these costimulatory signals and their potential involvement in the pathogenesis of asthma and allergic responses.