ABSTRACT:It is unknown what proportion of long-term lung function decline in cystic fibrosis (CF) is explained by pulmonary exacerbations. The aim of this study was to determine how exacerbations requiring hospitalisation contribute to the course of CF lung disease.This was a retrospective cohort study. The primary outcome was the rate of decline of forced expiratory volume in 1 s (FEV1) % predicted.Out of 851 subjects, 415 (48.8%) subjects had o1 exacerbation. After adjustment for confounders, the annual rate of FEV1 decline in those without an exacerbation was 1.2% per yr (95% CI 1.0-1.5), compared with 2.5% per yr (95% CI 2.1-2.8) in those with an exacerbation. The proportion of overall FEV1 decline associated with o1 exacerbation was 52% (95% CI 35.0-68.9). For a given number of exacerbations, the annual rate of FEV1 decline was greatest in subjects with f6 months between exacerbations.Half of FEV1 decline seen in CF patients was associated with pulmonary exacerbations. Time between exacerbations, specifically f6 months between exacerbations, plays an important contribution to overall lung function decline. These findings support using time to next exacerbation as a clinical end-point for CF trials.

Formation of embryonic vasculature involves vasculogenesis as endothelial cells differentiate and aggregate into vascular cords and angiogenesis which includes branching from the existing vessels. In the zebrafish which has emerged as an advantageous model to study vasculogenesis, cranial vasculature is thought to originate by a combination of vasculogenesis and angiogenesis, but how these processes are coordinated is not well understood. To determine how angioblasts assemble into cranial vasculature, we generated an etsrp:GFP transgenic line in which GFP reporter is expressed under the promoter control of an early regulator of vascular and myeloid development, etsrp/etv2. By utilizing time-lapse imaging we show that cranial vessels originate by angiogenesis from angioblast clusters, which themselves form by the mechanism of vasculogenesis. The two major pairs of bilateral clusters include the rostral organizing center (ROC) which gives rise to the most rostral cranial vessels and the midbrain organizing center (MOC) which gives rise to the posterior cranial vessels and to the myeloid and endocardial lineages. In Etsrp knockdown embryos initial cranial vasculogenesis proceeds normally but endothelial and myeloid progenitors fail to initiate differentiation, migration and angiogenesis. Such angioblast cluster-derived angiogenesis is likely to be involved during vasculature formation in other vertebrate systems as well.

Baseline chronic S. maltophilia infection is associated with an almost three-fold increased risk of death or lung transplant in CF patients. It is still unclear, however, whether chronic S. maltophilia infection is simply a marker of severity of disease and ultimate mortality or whether it is causally related to disease progression.