A study protocol to investigate the relationship between dietary fibre intake and fermentation, colon cell turnover, global protein acetylation and early carcinogenesis: the FACT study

Background: A number of studies, notably EPIC, have shown a descrease in colorectal cancer risk associated with increased fibre consumption. Whilst the underlying mechanisms are likely to be multifactorial, production of the short-chain fatty-acid butyrate fro butyratye is frequently cited as a major potential contributor to the effect. Butyrate inhibits histone deacetylases, which work on a wide range of proteins over and above histones. We therefore hypothesized that alterations in the acetylated proteome may be associated with a cancer risk phenotype in the colorectal mucosa, and that such alterations are candidate biomarkers for effectiveness of fibre interventions in cancer prevention. Methods an design: There are two principal arms to this study: (i) a cross-sectional study (FACT OBS) of 90 subjects recruited from gastroenterology clinics and; (ii) an intervention trial in 40 subjects with an 8 week high fibre intervention. In both studies the principal goal is to investigate a link between fibre intake, SCFA production and global protein acetylation. The primary measure is level of faecal butyrate, which it is hoped will be elevated by moving subjects to a high fibre diet. Fibre intakes will be estimated in the cross-sectional group using the EPIC Food Frequency Questionnaire. Subsidiary measures of the effect of butyrate on colon mucosal function and precancerous phenotype will include measures of apoptosis, apoptotic regulators cell cycle and cell division. Discussion: This study will provide a new level of mechanistic data on alterations in the functional proteome in response to the colon microenvironment which may underwrite the observed cancer preventive effect of fibre. The study may yield novel candidate biomarkers of fibre fermentation and colon mucosal function

European skills framework? - but what are skills? Anglo-Saxon versus German concepts

With the proposed introduction of a common framework for comparing qualifications within the European Union (EU), as a result of the Lisbon agreement of 2000, the question of commonly agreed transnational concepts of skills and qualifications is has become a pressing political and practical issue. The paper argues that there are grounds for doubting that there is a ready translation of the English terms 'skill'and 'qualification' in a way that avoids problems of comparing and calibrating German and English vocational qualifications. Reasons for this difficulty are explored, the most important of which relate to: a) the conceptual structure of skill and its cognates in the two languages; b) the differing socio-political role of qualifications; c) different industrial structures and labour processes; d) differences in institutions regulating vocational education and training (VET). These problems are discussed in relation to examples of similar industries and occupations and apparently similar levels of qualification in England and Germany

Income distribution trends and future food demand

This paper surveys the theoretical literature on the relationship between income distribution and food demand, and identifies main gaps of current food modelling techniques that affect the accuracy of food demand projections. At the heart of the relationship between income distribution and food demand is Engel's law. Engel's law establishes that as income increases, households' demand for food increases less than proportionally. A consequence of this law is that the particular shape of the distribution of income across individuals and countries affects the rate of growth of food demand. Our review of the literature suggests that existing models of food demand fail to incorporate the required Engel flexibility when (i) aggregating different food budget shares among households; and (ii) changing budget shares as income grows. We perform simple simulations to predict growth in food demand under alternative income distribution scenarios taking into account nonlinearity of food demand. Results suggest that (i) distributional effects are to be expected from changes in between-countries inequality, rather than within-country inequality; and (ii) simulations of an optimistic and a pessimistic scenario of income inequality suggest that world food demand in 2050 would be 2.7 per cent higher and 5.4 per cent lower than distributional-neutral growth, respectively

Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor

VX-659-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles

Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659–tezacaftor–ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659–tezacaftor–ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-659–tezacaftor–ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659–tezacaftor–ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del–MF genotypes; in patients with the Phe508del–Phe508del genotype already receiving tezacaftor–ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised improved in both patient populations. Conclusions Robust in vitro activity of VX-659–tezacaftor–ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del–MF or Phe508del–Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455.

Lives on track? Long-term earnings returns to selective school placement in England and Denmark

We explore the influence of between-school ability placement at lower secondary education on earnings across the life course in England and Denmark. We go beyond the mid-career snapshot provided by previous studies by exploiting the availability of four decades worth of earnings data for individuals born in the mid-1950s. Members of this cohort who were judged to be among the most academically able attended grammar schools in England (19 percent) and advanced secondary schools (Realskole) in Denmark (51 percent) prior to the start of comprehensivisation. This key difference makes England and Denmark interesting cases for comparison, not least since pro-selection policies have re-emerged in England based on the claim that grammar schools lead to better educational and labour market outcomes. Our analysis of the influence of selective school placement on earnings finds little support for this contention. We find that those from socioeconomically disadvantaged backgrounds were strikingly under-represented in schools ear-marked for higher ability pupils in both countries, even after taking into account social class differences in measured ability. Our analysis for England finds only modest earnings returns to attending a grammar school, totalling just £39,000 across the life course, while in Denmark the lifetime earnings returns to attending Realskole are somewhat larger (£194,000). Because those from advantaged backgrounds were substantially over-represented at grammar schools and Realskoles, these returns accrue disproportionately to pupils from more advantaged backgrounds. Lower secondary school placement in Denmark accounts for forty percent of the intergenerational reproduction of socioeconomic advantage and disadvantage, more than half of which is due to selection into school types based on socioeconomic background rather than measured ability. Our findings question the wisdom of expanding grammar schools when they appear to do little to improve individuals’ earnings or increase social mobility