How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Cholinergic imbalance in the multiple sclerosis hippocampus

Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls. By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus. In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered. In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this diseas

Confiabilidade do teste da caminhada de seis minutos em pacientes com miastenia gravis generalizada

Este estudo objetivou determinar a confiabilidade do teste da caminhada de seis minutos (TC6M) como um teste de capacidade funcional em pacientes com miastenia gravis generalizada (MG). Foram selecionados 11 pacientes com MG - 5 homens, 6 mulheres - com idade de 55±9 anos, avaliados inicialmente quanto à função fulmonar, que se submeteram a três TC6M em dias diferentes. Durante e/ou após cada teste foram medidas freqüência cardíaca e saturação de oxigênio (por oxímetro portátil), sensação de dispnéia (pela escala de Borg) e distância percorrida. Nos três testes as distâncias percorridas foram 498 m, 517 m e 520 m (respectivamente 99%, 103% e 104% do valor predito). Em média, a freqüência cardíaca, dispnéia e saturação de oxigênio mostraram comportamento constante nos três testes. Foram encontradas alta confiabilidade relativa, com coeficiente de correlação interclasse maior que 0,90 entre os testes (TC6M1-TC6M2, 0,960; TC6M1-TC6M3, 0,945; e TC6M2-TC6M3, 0,970) e confiabilidade absoluta de 4%, 3,5% e 4,8%, com reprodutibilidade de 11%, 9,8% e 13,4%, respectivamente para o primeiro, segundo e terceiro testes. Os limites superiores e inferiores de concordância e o valor médio das médias das diferenças (bias) calculados pelo teste de Bland-Altman mostraram-se clinicamente aceitáveis. Conclui-se que o TC6M se mostrou seguro, confiável e reprodutível, podendo ser aplicado para avaliação e seguimento da tolerância ao exercício em pacientes com MG generalizada.The purpose of this study was to assess the reliability of the six minutes walking test (6MWT) as a functional capacity test for patients with generalized myasthenia gravis (MG). Eleven patients with generalized MG (5 men, six women), aged 55±9 years, were first assessed as to pulmonary function and then submitted to three 6MWT in different days. Heart rate and oxygen saturation were measured (by means of portable oxymeter) during, and dyspnea (by the Borg scale) and distance walked were measured after, each test. At the three tests distances walked were 498 m, 517 m and 520 m (respectively 99%, 103%, and 104% of predicted values). Mean heart rate, oxygen saturation, and dyspnea values showed constant behaviour through the three tests. A high relative reliability was found between the tests, with interclass coefficient correlation over 0.90 (6MWT1-6MWT2, 0.960; 6MWT1-6MWT3, 0.945; and 6MWT2-6MWT3, 0.970); absolute reliability of 4%, 3.5% and 4.8%, as well as good repeatability of 11%, 9.8% and 13.4% were found for respectively the first, second, and third tests. Upper and lower agreement limits, as well as bias mean values by the Bland-Altman test show clinically acceptability. It may hence be said that the 6MWT proved safe, reliable and reproducible, and may be used for exercise tolerance assessment and follow up of patients with generalized myasthenia gravis

E-C Coupling and Contractile Characteristics of Mechanically Skinned Single Fibres from Young Rats During Rapid Growth and Maturation

The postnatal growth of rats involves a developmental phase (0 to ∼3 weeks), a rapid growth phase (∼3 to ∼10 weeks), and a slower maturation phase (∼10 weeks+). In this study, we investigated the age-related changes in excitation–contraction (E–C) coupling characteristics of mammalian skeletal muscle, during rapid growth (4– 10 weeks) and maturation (10–21 weeks) phases, using single, mechanically skinned fibres from rat extensor digitorum longus (EDL) muscle. Fibres from rats aged 4 and 8 weeks produced lower maximum T-system depolarizationinduced force responses and fewer T-system depolarizationinduced force responses to 75% run-down than those produced by fibres from rats aged 10 weeks and older. The sensitivity of the contractile apparatus to Ca2+ in fibres from 4-week rats was significantly higher than that in fibres from 10-week rats; however, the maximum Ca2+-activated force per skinned fibre cross-sectional area (specific force) developed by fibres from 4-week rats was on average ∼44% lower than the values obtained for all the other age groups. In agreement with the age difference in specific force, the MHC content of EDL muscles from 4-week rats was ∼29% lower than that of 10-week rats. Thus, mechanically skinned fibres from rats undergoing rapid growth are less responsive to T-system depolarization and maximal Ca2+ activation than fibres from rats at the later stage of maturation or adult rats. These results suggest that during the rapid growth phase in rats, the structure and function of elements involved in E–C coupling in fast-twitch skeletal muscle continue to undergo significant changes