Trends in adult cardiovascular disease risk factors and their socio-economic patterning in the Scottish population 1995–2008: cross-sectional surveys

<p>Objectives To examine secular and socio-economic changes in cardiovascular disease risk factor prevalences in the Scottish population. This could contribute to a better understanding of why the decline in coronary heart disease mortality in Scotland has recently stalled along with a widening of socio-economic inequalities.</p> <p>Design Four Scottish Health Surveys 1995, 1998, 2003 and 2008 (6190, 6656, 5497 and 4202 respondents, respectively, aged 25–64 years) were used to examine gender-stratified, age-standardised prevalences of smoking, alcohol consumption, physical activity, fruit and vegetable consumption, discretionary salt use and self-reported diabetes or hypertension. Prevalences were determined according to education and social class. Inequalities were assessed using the slope index of inequality, and time trends were determined using linear regression.</p> <p>Results There were moderate secular declines in the prevalence of smoking, excess alcohol consumption and physical inactivity. Smoking prevalence declined between 1995 and 2008 from 33.4% (95% CI 31.8% to 35.0%) to 29.9% (27.9% to 31.8%) for men and from 36.1% (34.5% to 37.8%) to 27.4% (25.5% to 29.3%) for women. Adverse trends in prevalence were noted for self-reported diabetes and hypertension. Over the four surveys, the diabetes prevalence increased from 1.9% (1.4% to 2.4%) to 3.6% (2.8% to 4.4%) for men and from 1.7% (1.2% to 2.1%) to 3.0% (2.3% to 3.7%) for women. Socio-economic inequalities were evident for almost all risk factors, irrespective of the measure used. These social gradients appeared to be maintained over the four surveys. An exception was self-reported diabetes where, although inequalities were small, the gradient increased over time. Alcohol consumption was unique in consistently showing an inverse gradient, especially for women.</p> <p>Conclusions There has been only a moderate decline in behavioural cardiovascular risk factor prevalences since 1995, with increases in self-reported diabetes and hypertension. Adverse socio-economic gradients have remained unchanged. These findings could help explain the recent stagnation in coronary heart disease mortalities and persistence of related inequalities.</p&gt

Modelling Future Coronary Heart Disease Mortality to 2030 in the British Isles.

OBJECTIVE: Despite rapid declines over the last two decades, coronary heart disease (CHD) mortality rates in the British Isles are still amongst the highest in Europe. This study uses a modelling approach to compare the potential impact of future risk factor scenarios relating to smoking and physical activity levels, dietary salt and saturated fat intakes on future CHD mortality in three countries: Northern Ireland (NI), Republic of Ireland (RoI) and Scotland. METHODS: CHD mortality models previously developed and validated in each country were extended to predict potential reductions in CHD mortality from 2010 (baseline year) to 2030. Risk factor trends data from recent surveys at baseline were used to model alternative future risk factor scenarios: Absolute decreases in (i) smoking prevalence and (ii) physical inactivity rates of up to 15% by 2030; relative decreases in (iii) dietary salt intake of up to 30% by 2030 and (iv) dietary saturated fat of up to 6% by 2030. Probabilistic sensitivity analyses were then conducted. RESULTS: Projected populations in 2030 were 1.3, 3.4 and 3.9 million in NI, RoI and Scotland respectively (adults aged 25-84). In 2030: assuming recent declining mortality trends continue: 15% absolute reductions in smoking could decrease CHD deaths by 5.8-7.2%. 15% absolute reductions in physical inactivity levels could decrease CHD deaths by 3.1-3.6%. Relative reductions in salt intake of 30% could decrease CHD deaths by 5.2-5.6% and a 6% reduction in saturated fat intake might decrease CHD deaths by some 7.8-9.0%. These projections remained stable under a wide range of sensitivity analyses. CONCLUSIONS: Feasible reductions in four cardiovascular risk factors (already achieved elsewhere) could substantially reduce future coronary deaths. More aggressive polices are therefore needed in the British Isles to control tobacco, promote healthy food and increase physical activity

Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells

ABSTRACT The triple-negative breast cancer (TNBC) subtype is enriched in cancer stem cells (CSCs) and clinically correlated with the highest rate of recurrence. Several studies implicate the RSK pathway as being pivotal for the growth and proliferation of CSCs, which are postulated to drive tumor relapse. We now address the potential for the newly developed RSK inhibitor LJI308 to target the CSC population and repress TNBC growth and dissemination. Overexpression of the Y-box binding protein-1 (YB-1) oncogene in human mammary epithelial cells (HMECs) drove TNBC tumor formation characterized by a multi-drug resistance phenotype, yet these cells were sensitive to LJI308 in addition to the classic RSK inhibitors BI-D1870 and luteolin. Notably, LJI308 specifically targeted transformed cells as it had little effect on the non-tumorigenic parental HMECs. Loss of cell growth, both in 2D and 3D culture, was attributed to LJI308-induced apoptosis. We discovered CD44+/CD49f+ TNBC cells to be less sensitive to chemotherapy compared to the isogenic CD44-/CD49f-cells. However, inhibition of RSK using LJI308, BI-D1870, or luteolin was sufficient to eradicate the CSC population. We conclude that targeting RSK using specific and potent inhibitors, such as LJI308, delivers the promise of inhibiting the growth of TNBC

Trends and inequalities in short-term acute myocardial infarction case fatality in Scotland, 1988-2004

<p>Abstract</p> <p>Background</p> <p>There have been substantial declines in ischemic heart disease in Scotland, partly due to decreases in acute myocardial infarction (AMI) incidence and case fatality (CF). Despite this, Scotland's IHD mortality rates are among the worst in Europe. We examine trends in socioeconomic inequalities in short-term CF after a first AMI event and their associations with age, sex, and geography.</p> <p>Methods</p> <p>We used linked hospital discharge and death records covering the Scottish population (5.1 million). Between 1988 and 2004, 178,781 of 372,349 patients with a first AMI died on the day of the event (Day0 CF) and 34,198 died within 28 days after surviving the day of their AMI (Day1-27 CF).</p> <p>Results</p> <p>Age-standardized Day0 CF at 30+ years decreased from 51% in 1988-90 to 41% in 2003-04. Day1-27 CF decreased from 29% to 18% over that period. Socioeconomic inequalities in Day0 CF existed for both sexes and persisted over time. The odds of case fatality for men aged 30-59 living in the most deprived areas in 2000-04 were 1.7 (95%CI: 1.3-2.2) times as high as in the least deprived areas and 1.9 (1.1-3.2) times as high for women. There was little evidence of socioeconomic inequality in Day1-27 CF in men or women. After adjustment for socioeconomic deprivation, significant geographic variation still remained for both CF definitions.</p> <p>Conclusions</p> <p>A high proportion of AMI incidents in Scotland result in death on the day of the first event; many of these are sudden cardiac deaths. Short-term CF has improved, perhaps reflecting treatment advances and reductions in first AMI severity. However, persistent socioeconomic and geographic inequalities suggest these improvements are not uniform across all population groups, emphasizing the need for population-wide primary prevention.</p

Assessing mathematical problem solving using comparative judgement

There is an increasing demand from employers and universities for school leavers to be able to apply their mathematical knowledge to problem solving in varied and unfamiliar contexts. These aspects are however neglected in most examinations of mathematics and, consequentially, in classroom teaching. One barrier to the inclusion of mathematical problem solving in assessment is that the skills involved are difficult to define and assess objectively. We present two studies that test a method called comparative judgement (CJ) that might be well suited to assessing mathematical problem solving. CJ is an alternative to traditional scoring that is based on collective expert judgements of students’ work rather than item-by-item scoring schemes. In Study 1 we used CJ to assess traditional mathematics tests and found it performed validly and reliably. In Study 2 we used CJ to assess mathematical problem-solving tasks and again found it performed validly and reliably. We discuss the implications of the results for further research and the implications of CJ for the design of mathematical problem-solving tasks

A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may b

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nbt.327