Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry:A randomised controlled trial

Background: Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV₁) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV₁ >90% predicted. Methods: This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV₁ >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352. Findings: Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period. Interpretation: In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV₁ in detecting response to intervention in these patients with mild lung disease. Funding: Vertex Pharmaceuticals Incorporated. © 2013 Elsevier Ltd.

Effect of ultraviolet-B light on lymphocyte activity at doses at which normal bone marrow stem cells are preserved

Ultraviolet B (UVB) light is known to be immunosuppressive, but, probably because of a small UVC component in the emission spectra of some of the UVB lamps used, reports vary on effective dose levels. To prevent potentially lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation, alloreactive donor T-cell activity must be suppressed. In this study, a narrow wavelength UVB lamp (TL01, 312 nm peak emission) was used to determine what doses of UVB were required to abolish rat lymphocyte proliferation while simultaneously preserving rat bone marrow progenitor cell and primitive hematopoietic stem cell viability. Lymphocyte proliferation, as measured by 3H-Thymidine incorporation, in response to lectin stimulation was abolished below detection at doses greater than 3,500 J/m2. When T-cell clonogenicity was measured in a limiting dilution assay, a small fraction (0.6%) was maintained at doses up to 4,000 J/m2. Cytotoxic T-lymphocyte (CTL) activity was reduced after treatment with 4,000 J/m2, but a significant level of cytotoxicity was still maintained. Natural killer cell cytolytic activity was not affected by doses up to 4,000 J/m2. At 4,000 J+m2 there was a 10% survival of colony-forming units-granulocyte-macrophage; a 1% and 4% survival of day-8 and day-12 colony-forming units-spleen, respectively; and 11% survival of marrow repopulating ability cells. Up to 25% of late cobblestone area forming cells (4 to 5 weeks), reflecting the more immature hematopoietic stem cells, were preserved in bone marrow treated with 4,000 J/m2, indicating that early stem cells are less sensitive to UVB damage than are more committed progenitor cells. Thus, a potential therapeutic window was established at approximately 4,000 J/m2 using this light source, whereby the potentially GVHD-inducing T cells were suppressed, but a sufficient proportion of the cells responsible for engraftment was maintained.

Risk of Agricultural Practices and Habitat Change to Farmland Birds

Many common bird species have declined as a result of agricultural intensification and this could be mitigated by organic farming. We paired sites for habitat and geographical location on organic and nonorganic farms in Ontario, Canada to test a priori predictions of effects on birds overall, 9 guilds and 22 species in relation to candidate models for farming practices (13 variables), local habitat features (12 variables), or habitat features that influence susceptibility to predation. We found that: (1) Overall bird abundance, but not richness, was significantly (p < 0.05) higher on organic sites (mean 43.1 individuals per site) than nonorganic sites (35.8 individuals per site). Significantly more species of birds were observed for five guilds, including primary grassland birds, on organic vs. nonorganic sites. No guild had higher richness or abundance on nonorganic farms; (2) Farming practice models were the best (ΔAIC < 4) for abundance of birds overall, primary grassland bird richness, sallier aerial insectivore richness and abundance, and abundance of ground nesters; (3) Habitat models were the best for overall richness, Neotropical migrant abundance, richness and abundance of Ontario-USA-Mexico (short-distance) migrants and resident richness; (4) Predation models were the best for richness of secondary grassland birds and ground feeders; (5) A combination of variables from the model types were best for richness or abundance overall, 13 of 18 guilds (richness and abundance) and 16 of 22 species analyzed. Five of 10 farming practice variables (including herbicide use, organic farm type) and 9 of 13 habitat variables (including hedgerow length, proportion of hay) were significant in best models. Risk modeling indicated that herbicide use could decrease primary grassland birds by one species (35% decline from 3.4 to 2.3 species) per site. Organic farming could benefit species of conservation concern by 49% (an increase from 7.6 to 11.4 grassland birds). An addition of 63 m of hedgerow could increase abundance and richness of short distance migrants by 50% (3.0 to 4.8 and 1.3 to 2.0, respectively). Increasing the proportion of hay on nonorganic farms to 50% could increase abundance of primary grassland bird by 40% (6.7 to 9.4). Our results provide support for alternative farmland designs and agricultural management systems that could enhance select bird species in farmland.

The influence of livestock management on habitat quality for farmland birds

This review covers research linking foraging habitat quality for birds to livestock management in lowland farmland. Based on this research we propose a framework for predicting the value of grazing systems to birds. This predictive framework is needed to guide the development of agri-environment measures to address farmland bird declines in pastoral areas. We show that the exacting requirements of declining granivorous birds pose the greatest challenges, while the needs of soil invertebrate feeding species are more easily met.

Leaving final-cut grass silage in situ overwinter as a seed resource for declining farmland birds

The loss of seed-rich wintering habitats has been a major contributory cause of farmland bird population declines in western Europe. Agricultural grasslands are particularly poor winter foraging habitats for granivorous birds, which have declined most in the pastoral farming regions of western Britain. We describe an experiment to test the utility of fertile ryegrass (Lolium) swards as a potentially rich source of winter seed for declining farmland birds. Four patches of final-cut grass silage were allowed to set seed and were left in situ overwinter. Half of each patch was lightly aftermath grazed in an attempt to increase the accessibility of the seed to foraging birds and reduce the perceived predation risk. Large numbers of yellowhammers (Emberiza citrinella) and reed buntings (E. schoeniclus) foraged on the seeded plots throughout the winter. They preferred to forage on ungrazed seeded plots, where the accumulation of senescent foliage resulted in a 14% average loss in silage yield in the following season. However, seed produced on the plots also led to sward regeneration, increasing subsequent yields on some plots. The technique offers clear benefits as a potential future agri-environment measure for declining granivorous birds, with wide applicability, but requires further development to minimise sward damage and costs to the farmer. Autumn grazing should reduce sward damage, but at the cost of reduced usage by buntings. Using the technique just prior to reseeding would be one way of avoiding any costs of sward damage.

A cross-taxonomic index for quantifying the health of farmland biodiversity

P>1. The development of sustainable, multi-functional agricultural systems involves reconciling the needs of agricultural production with the objectives for environmental protection, including biodiversity conservation. However, the definition of sustainability remains ambiguous and it has proven difficult to identify suitable indicators for monitoring progress towards, and the successful achievement of, sustainability. 2. In this study, we show that a trait-based approach can be used to assess the detrimental impacts of agricultural change to a broad range of taxonomic groupings and derive a standardised index of farmland biodiversity health, built around an objective of achieving stable or increasing populations in all species associated with agricultural landscapes. 3. To demonstrate its application, we assess the health of UK farmland biodiversity relative to this goal. Our results suggest that the populations of two-thirds of 333 plant and animal species assessed are unsustainable under current UK agricultural practices. 4. We then explore the potential benefits of an agri-environment scheme, Entry Level Stewardship (ELS), to farmland biodiversity in the UK under differing levels of risk mitigation delivery. We show that ELS has the potential to make a significant contribution to progress towards sustainability targets but that this potential is severely restricted by current patterns of scheme deployment. 5.Synthesis and applications: We have developed a cross-taxonomic sustainability index which can be used to assess both the current health of farmland biodiversity and the impacts of future agricultural changes relative to quantitative biodiversity targets. Although biodiversity conservation is just one of a number of factors that must be considered when defining sustainability, we believe our cross-taxonomic index has the potential to be a valuable tool for guiding the development of sustainable agricultural systems.

Farmland biodiversity and the footprint of agriculture

Sustainable development requires the reconciliation of demands for biodiversity conservation and increased agricultural production. Assessing the impact of novel farming practices on biodiversity and ecosystem services is fundamental to this process. Using farmland birds as a model system, we present a generic risk assessment framework that accurately predicts each species' current conservation status and population growth rate associated with past changes in agriculture. We demonstrate its value by assessing the potential impact on biodiversity of two controversial land uses, genetically modified herbicide-tolerant crops and agri-environment schemes. This framework can be used to guide policy and land management decisions and to assess progress toward sustainability targets.