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Floods are the largest natural disaster currently facing the UK, whilst the incidents of droughts have increased in recent years. Floods and droughts can have devastating consequences on society, resulting in significant financial damage to the economy. Climate models suggest that precipitation and temperature changes will exacerbate future hydrological extremes (i.e., floods and droughts). Such events are likely to become more frequent and intense in the future; thus to develop adaptation plans climate model projections feed hydrological models to provide future water resource projections. ‘eFLaG’ is one set of future river flow projections produced for the UK driven by UKCP18 climate projections from the UK Met Office. The UKCP18-derived eFLaG dataset provides state-of-the-art projections for a single GCM driven by RCP 8.5 across the entire UK. A QE-ANOVA approach has been used to partition contributing sources of uncertainty for two flow quantiles (Q5 high flows and Q95 low flows), at near and far future time scales, for each of the 186 GB catchments in the eFLaG dataset. Results suggest a larger hydrological model uncertainty associated with low flows and greater regional climate model uncertainty for high flows which remains stationary between flow indicators. Total uncertainty increases from near to far future and highly uncertain catchments have been identified with a high concentration in South-East England. [ABSTRACT FROM AUTHOR]

Purpose: Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants.Methods: Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1-3000 mcg given by nebulisation.Results: A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100-3000 mcg). Dose normalised geometric mean Cmax increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety.Conclusions: In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300-3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF. [ABSTRACT FROM AUTHOR]

During the winter of 2013/14, much of the UK experienced repeated intense rainfall events and flooding. This had a considerable impact on property and transport infrastructure. A key question is whether the burning of fossil fuels is changing the frequency of extremes, and if so to what extent. We assess the scale of the winter flooding before reviewing a broad range of Earth system drivers affecting UK rainfall. Some drivers can be potentially disregarded for these specific storms whereas others are likely to have increased their risk of occurrence. We discuss the requirements of hydrological models to transform rainfall into river flows and flooding. To determine any general changing flood risk, we argue that accurate modelling needs to capture evolving understanding of UK rainfall interactions with a broad set of factors. This includes changes to multiscale atmospheric, oceanic, solar and sea-ice features, and land-use and demographics. Ensembles of such model simulations may be needed to build probability distributions of extremes for both pre-industrial and contemporary concentration levels of atmospheric greenhouse gases. [ABSTRACT FROM AUTHOR]

The O-glycans that decorate mucin glycoproteins contribute to the biophysical and biochemical properties of these molecules and hence their function as a barrier and lubricant on epithelial surfaces. Alterations in mucin O-glycosylation in certain diseases may contribute to pathology. It is known that both the host cell type and the amino acid sequence of the mucin tandem repeat contribute to the O-glycosylation of a mucin molecule. We expressed an epitope-tagged MUC1 mucin cDNA construct in the airway cell line 16HBE14o- and the colon carcinoma cell line Caco2 and used Fast Atom Bombardment Mass Spectrometry to evaluate the contribution of the host cell to differences in O-glycosylation of a single mucin. Many of the glycans detected on the MUC1 mucin were common to both cell types, as would be predicted from biosynthetic constraints. However, MUC1 synthesized in the airway cell line showed comparatively low levels of sialylation but carried a range of oligo- N-acetyllactosamine structures that were not seen in the colon carcinoma cell line. Published in 2003. [ABSTRACT FROM AUTHOR]

A reply by the authors to a letter to the editor about their article "Drivers of the 2013-2014 winter floods in the UK" is presented.