Aiming at rapid decrease of disease activity, there has been a trend to start with higher doses of methotrexate (MTX) in newly diagnosed rheumatoid arthritis (RA) patients, both as monotherapy and in combination with other antirheumatic drugs (DMARDs). We hypothesized that in combination with other very effective medication, there might be no additional benefit of high over low doses of MTX.
Objectives
To compare early clinical response to high versus low doses of MTX in mono- and combination therapy in DMARD naive early RA patients.
Methods
RA patients included in the observational international METEOR cohort with symptom duration ≤5 years, time between diagnosis and first visit ≤2 months, MTX prescribed as (part of) first treatment, no medication change within 3 to 6 months after treatment start and available outcome data on disease activity, were selected. Patients were divided into 4 medication groups: MTX monotherapy, MTX + synthetic (cs)DMARDs, MTX + oral glucocorticoid (+ possibly csDMARDs) or MTX + biologic (b)DMARDs (+ possibly csDMARDs). Missing data were imputed using multivariate normal imputation. MTX dose was dichotomized: low dose ≤10 mg/week; high dose ≥15 mg/week. A propensity score (PS) was calculated to adjust the relationship between MTX dose and outcome for potential confounding by indication. Linear mixed model analyses for DAS, DAS28, and HAQ were performed for each medication group, with MTX-dose and time (days between assessment visit and baseline assessment) as co-variates. Associations were adjusted for the PS. Random intercept and slope were used to account for irregular time intervals between visits.
Results
Patients who started on MTX monotherapy had lower baseline disease activity and fewer were erosive and autoantibody positive; other baseline characteristics were comparable between medication groups. The number of patients on combination therapy with bDMARDs was too small to perform analyses (26 visits in 11 patients). For patients starting on MTX monotherapy, MTX+csDMARDs or MTX+glucocorticoids, the PS-adjusted effects of MTX-dose (high vs low) on DAS, DAS28 and HAQ were small and not clinically meaningful. The unadjusted main associations between MTX-dose and outcomes were often in opposite direction and/or much larger than the PS adjusted associations, suggesting that confounding by indication indeed plays a role and that (at least some) correction was achieved by adjusting for the PS (table 1).
Conclusions
In a daily practice derived database in DMARD-naive early RA patients, we found no early clinical benefit of high over low initial MTX doses, neither for MTX monotherapy nor for combination therapy with MTX and csDMARDs or glucocorticoids. This seems to contradict a general trend over time to start higher MTX-doses.
To adapt to an uncertain world, humans must learn event probabilities. These probabilities may be stationary, such as that of rolling a 6 on a die, or changing over time, like the probability of rainfall over the year. Research on how people estimate and track changing probabilities has recently reopened an old epistemological issue. A small, mostly recent literature finds that people accurately track the probability and change their estimates only occasionally, resulting in staircase-shaped response patterns. This has been taken as evidence that people entertain beliefs about unknown, distal states of the world, which are tested against observations to produce discrete shifts between hypotheses. That idea stands in contrast to the claim that people learn by continuously updating associations between observed events. The purpose of this article is to investigate the generality and robustness of the accurate, staircase-shaped pattern. In two experiments, we find that the response pattern is contingent on the response mode and prior information about the generative process. Participants exist on continua of accuracy and staircase-ness and we only reproduce previous results when changing estimates is effortful and prior information is provided-the specific conditions of previous experiments. We conclude that explaining this solely through either hypotheses or associations is untenable. A complete theory of probability estimation requires the interaction of three components: (i) online tracking of observed data, (ii) beliefs about the unobserved "generative process," and (iii) a response updating process. Participants' overt estimates depend on how the specific task conditions jointly determine all three.
The economics of offshore wind energy may probably be improved by application of very large wind turbines in large wind farms. However a gradual upscale of an existing wind turbine design towards 5 or 6 MW is not as straightforward as it may seem. The goal of the Dutch Offshore Wind Energy Converter (DOWEC) Concept Study is to make an inventory of all wind turbine concepts in order to select the most optimal concept for a 5 to 6 MW offshore wind turbine. In the first phase the DOWEC Concept Study aims at the choice of the optimal wind turbine concept. The wind turbine will not be treated as an isolated system. Designs of different wind turbine concepts will be evaluated as an integral part of the complete large-scale offshore wind farm. All significant properties like the structural loads, the power performance, the system reliability, the costs of the electric infrastructure, maintenance costs and installation costs will be determined for the optimised designs. A quantitative ranking will then be made based on the cost of generated energy. Furthermore qualitative criteria like development risk and market potential will be taken into consideration when finalising the choice of concept. The DOWEC concept study serves as a first design phase. The overall DOWEC development comprises of the design, the construction and the prototype testing. Marine testing of the 5 to 6 MW turbine is planned in 2008. Onshore testing of a 3 MW research and development prototype is scheduled for the end of 2001. This paper describes the approach and the current achievements of the project.
A common approach for visualizing data sets is to map them to images in which distinct data dimensions are mapped to distinct visual features, such as color, size and orientation. Here, we consider visualizations in which different data dimensions should receive equal weight and attention. Many of the end-user tasks performed on these images involve a form of visual search. Often, it is simply assumed that features can be judged independently of each other in such tasks. However, there is evidence for perceptual dependencies when simultaneously presenting multiple features. Such dependencies could potentially affect information visualizations that contain combinations of features for encoding information and, thereby, bias subjects into unequally weighting the relevance of different data dimensions. We experimentally assess (1) the presence of judgment dependencies in a visualization task (searching for a target node in a node-link diagram) and (2) how feature contrast relates to salience. From a visualization point of view, our most relevant findings are that (a) to equalize saliency (and thus bottom-up weighting) of size and color, color contrasts have to become very low. Moreover, orientation is less suitable for representing information that consists of a large range of data values, because it does not show a clear relationship between contrast and salience; (b) color and size are features that can be used independently to represent information, at least as far as the range of colors that were used in our study are concerned; (c) the concept of (static) feature salience hierarchies is wrong; how salient a feature is compared to another is not fixed, but a function of feature contrasts; (d) final decisions appear to be as good an indicator of perceptual performance as indicators based on measures obtained from individual fixations. Eye tracking, therefore, does not necessarily present a benefit for user studies that aim at evaluating performance in search tasks.
