Minimal clinically important difference for the 6-min walk test: literature review and application to Morquio A syndrome.

Morquio A syndrome is an ultra-rare, inherited lysosomal storage disorder associated with progressive, multi-systemic clinical impairments, causing gradual loss of functional capacity and endurance, impaired quality of life, and early mortality. Studies in Morquio A patients have used the 6-min walk test (6MWT) to assess functionality and endurance and to evaluate disease progression or efficacy of treatment. The objective of the present study was to review minimal clinically important differences (MCIDs) for the 6MWT reported for disease states that widely use the 6MWT to evaluate clinical benefit and to discuss the results in view of the challenges in estimating MCID for ultra-rare diseases, using the case of elosulfase alfa in Morquio A patients. A systematic literature search was performed using Embase and Medline to identify studies specifically estimating the MCID using either anchor-based or distribution-based methods. A total of 19 publications on 17 studies were identified; none of these included patients with Morquio A syndrome or the wider disease category of lysosomal storage disorders. Therefore, the MCIDs determined by studies in patients with respiratory, cardiovascular, or musculoskeletal disease were compared to changes in the 6MWT seen in Morquio A patients in the pivotal phase 3 clinical trial of elosulfase alfa enzyme replacement therapy. The literature review showed a mean MCID for the 6MWT of 7% change (range 3-15%) in studies using anchor-based methods and a 9% change (range 4-16%) using distribution-based methods. Results of the elosulfase alfa clinical trial and its extension showed a placebo-adjusted 14.9% improvement in the 6MWT from baseline at week 24, which was greater than the mean MCID based on the results of the systematic literature review. After 2 years, 6MWT distance increased by a mean of 20.7% from baseline in a modified per-protocol population, versus a reduction of 6.9% in comparable untreated patients from the MorCAP natural history study over the same period. Although further research is required to establish the MCID of the 6MWT in Morquio A patients, the presented data provide further evidence for the positive effect of elosulfase alfa in this patient population.

A critical overview of model estimates of net primary productivity for the Australian continent.

Net primary production links the biosphere and the climate system through the global cycling of carbon, water and nutrients. Accurate quantification of net primary productivity (NPP) is therefore critical in understanding the response of the world's ecosystems to global climate change, and how changes in ecosystems might themselves feed back to the climate system.

On the direct effect of clouds and atmospheric particles on the productivity and structure of vegetation.

The volume of shade within vegetation canopies is reduced by more than an order of magnitude on cloudy and/or very hazy days compared to clear sunny days because of an increase in the diffuse fraction of the solar radiance. Here we show that vegetation is directly sensitive to changes in the diffuse fraction and we conclude that the productivity and structure of vegetation is strongly influenced by clouds and other atmospheric particles. We also propose that the unexpected decline in atmospheric [CO2] which was observed following the Mt. Pinatubo eruption was in part caused by increased vegetation uptake following an anomalous enhancement of the diffuse fraction by volcanic aerosols that would have reduced the volume of shade within vegetation canopies. These results have important implications for both understanding and modelling the productivity and structure of terrestrial vegetation as well as the global carbon cycle and the climate system.

A Model of the Responses of Ecotones to Climate Change.

It has been suggested that global climatic change may be detected by monitoring the positions of ecotones. I built a model of the dynamics of ecotones similar to those found in altitudinal or latitudinal treelines, where a slow tendency for the ecotone to advance is counterbalanced by disturbances such as fire or landslides. The model showed that the response of such ecotones to a wide range of simulated climate changes was slow and that the ecotone front was dissected. It would appear that such ecotones would not make suitable sites for monitoring climate change.