One such questionnaire is the Inflammatory Bowel Disease Questionnaire (IBDQ), a validated and reliable tool used to measure health-related quality of life (HRQoL) in adult patients with IBD, ulcerative colitis and Crohn's disease . Whether the IBDQ can also be used to assess HRQoL in the general population still needs to be tested. One advantage of this questionnaire is that it has been adapted and validated in several languages and cultural milieus. A more general tool is the Bowel Disease Questionnaire (BDQ), which aims to distinguish patients with functional GI disease from those with other conditions such as IBD or CRC . Logistic regression and discriminant analyses have shown that the BDQ is a valid measure of symptoms of functional GI disease. Probably the most suitable HRQoL assessment tool is the Irritable Bowel Syndrome-Quality of Life questionnaire, because IBS is the disease entity closest to the borderline between gut health and GI disease . The Health Status Questionnaire-12 (HSQ-12) is another reliable, valid, low-cost measure of health status that was created to assess the general population . The HSQ-12, in contrast to the also validated 12-item Short Form Health Survey (SF-12), can distinguish between people with and without dementia . On the other hand, both the HSQ-12 and the SF-12 assess general health status, but not specifically gut health. Therefore, a short general questionnaire could be combined with a gut-related one, although this combination has yet to be evaluated.
Bowel functions are extremely complex and variable; therefore, objective assessment is a difficult task. Nevertheless, multiple approaches have been used to assess a range of bowel functions. For example, glucose challenge with a subsequent hydrogen breath test was believed to identify individuals with so-called 'abnormal bacterial colonisation' of the intestine as a possible cause of deterioration of gut health. Over the past few years, there have been impressive developments in techniques for analysing the human microbiome, such as using metagenomic-metabonomic linkage analyses or small subunit ribosomal RNA hypervariable tag sequencing [7, 30, 43, 44, 85]. Microbiome analysis, however, is still considered inappropriate for routine diagnosis of gut function or gut health. However, even modern molecular techniques do not yet allow the definition of what can be considered a 'normal' or 'optimal' microbiome composition. On the other hand, an increasing number of immunological parameters have become available, among which cell counts and cell phenotyping by flow cytometry and immunohistology and quantification of cytokines, antibodies and mediators are the most well-known tools (Table 3).
Previous meta-analyses focused only on comparing the efficacy and tolerability of drugs with placebo, which gave the clinical application directions [6, 11, 12]. Those findings showed modest benefits for improving the symptoms related to cognition, function, behavior, and clinical global changes [13, 14]. But considering the lack of direct comparative evidence among available drugs, the results of those studies were inconclusive on how to choose the optimal therapeutic regimens to achieve the maximum efficiency . The network meta-analysis combines evidence from a network of all included trials to rank all available treatments in terms of efficacy and tolerability, providing estimates for interventions even if they have not been directly compared . Here, we therefore conducted a network meta-analysis to comprehensively compare and rank different types and dosages of cognitive enhancers at different clinical stages for guiding treatment decisions.
Secondly, we performed a random-effects model Bayesian network meta-analysis using WinBUGS software (version 1.4.3; MRC Biostatistics Unit, Cambridge, UK) and drew relevant diagrams with STATA . We summarized the results of the network meta-analysis by choosing the SMD or OR with corresponding credible intervals (CrIs) as effect sizes. We adopted noninformative priors and changed the precision of the prior distribution in sensitivity analyses. Details about the WinBUGS codes are presented in Additional file 1: Supplementary 1. The global heterogeneity of network meta-analyses was assessed by the I2 statistic with the gemtc R package (version 3.2.2). Inconsistency was statistically examined by calculating the significant discrepancies between direct and indirect evidence in each closed loop with the loop-specific method and the node splitting method [21,22,23]. The intervention hierarchy was estimated and expressed by rankograms, the surface under the cumulative ranking curve (SUCRA), and mean ranks . The comparison-adjusted funnel plot could be drawn to detect publication bias in the network meta-analysis .
In this network meta-analysis, we did not involve a cost-effectiveness analysis. Medication cost accounts for a large proportion of the total dementia healthcare cost. It is indicated by most economic evaluations that pharmacological treatments for AD are reasonable in terms of clinical effects and costs. The probabilistic sensitivity analyses suggested that donepezil and memantine were cost-effective with slightly greater quality-adjusted life years (QALYs) [38, 39]. Treatment with donepezil plus memantine was cost-effective within the willingness-to-pay threshold in moderate-to-severe AD [40, 41]. Nevertheless, the results generally are associated with a degree of uncertainty, which is related to country-specific data. In England, the use of prescription drugs doubled after introducing the national dementia strategies . The proportion of people who receive the concomitant use of AChEI and memantine has increased in Europe . Indeed, drug costs are very high in some countries (China, Indonesia, South Africa) because some drugs remain on patent and these countries are reluctant to use generic medicines. 2b1af7f3a8