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ObjeCtiveTo examine changes in colorectal cancer mortality in 34 European countries between 1970 and 2011.Design Retrospective trend analysis. Data sOurCeWorld Health Organization mortality database. POPulatiOnDeaths from colorectal cancer between 1970 and 2011. Profound changes in screening and treatment efficiency took place after 1988; therefore, particular attention was paid to the evolution of colorectal cancer mortality in the subsequent period. Main OutCOMes MeasuresTime trends in rates of colorectal cancer mortality, using joinpoint regression analysis. Rates were age adjusted using the standard European population.results From 1989 to 2011, colorectal cancer mortality increased by a median of 6.0% for men and decreased by a median of 14.7% for women in the 34 European countries. Reductions in colorectal cancer mortality of more than 25% in men and 30% in women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech Republic, Luxembourg, and Ireland. By contrast, mortality rates fell by less than 17% in the Netherlands and Sweden for both sexes. Over the same period, smaller or no declines occurred in most central European countries. Substantial mortality increases occurred in Croatia, the former Yugoslav republic of Macedonia, and Romania for both sexes and in most eastern European countries for men. In countries with decreasing mortality, reductions were more important for women of all ages and men younger than 65 years. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women, compared with corresponding reductions of 39.8% and 38.8% in the United States. COnClusiOnOver the past 40 years, there has been considerable disparity in the level of colorectal cancer mortality between European countries, as well as between men and women and age categories. Countries with the largest reductions in colorectal cancer mortality are characterised by better accessibility to screening services, especially endoscopic screening, and specialised care.

ObjectiveTo analyse stage specific incidence of breast cancer in the Netherlands where women have been invited to biennial mammography screening since 1989 (ages 50-69) and 1997 (ages 70-75), and to assess changes in breast cancer mortality and quantified overdiagnosis.DesignPopulation based study.SettingMammography screening programme, the Netherlands.ParticipantsDutch women of all ages, 1989 to 2012.Main outcome measuresStage specific age adjusted incidence of breast cancer from 1989 to 2012. The extra numbers of in situ and stage 1 breast tumours associated with screening were estimated by comparing rates in women aged 50-74 with those in age groups not invited to screening. Overdiagnosis was estimated after subtraction of the lead time cancers. Breast cancer mortality reductions during 2010-12 and overdiagnosis during 2009-11 were computed without (scenario 1) and with (scenario 2) a cohort effect on mortality secular trends.ResultsThe incidence of stage 2-4 breast cancers in women aged 50 or more was 168 per 100 000 in 1989 and 166 per 100 000 in 2012. Screening would be associated with a 5% mortality reduction in scenario 1 and with no influence on mortality in scenario 2. In both scenarios, improved treatments would be associated with 28% reductions in mortality. Overdiagnosis has steadily increased over time with the extension of screening to women aged 70-75 and with the introduction of digital mammography. After deduction of clinical lead time cancers, 32% of cancers found in women invited to screening in 2010-12 and 52% of screen detected cancers would be overdiagnosed.ConclusionsThe Dutch mammography screening programme seems to have little impact on the burden of advanced breast cancers, which suggests a marginal effect on breast cancer mortality. About half of screen detected breast cancers would represent overdiagnosis.

Increasing physical activity is associated with meaningful reductions in the risk of breast cancer, but in women who ever used HRT, the preventative effect of physical activity seems to be cancelled out.

Inherited neuromuscular disorders (NMD) are chronic genetic diseases posing a significant burden on patients and the health care system. Despite tremendous research and clinical efforts, the molecular causes remain unknown for nearly half of the patients, due to genetic heterogeneity and conventional molecular diagnosis based on a gene-by-gene approach. We aimed to test next generation sequencing (NGS) as an efficient and cost-effective strategy to accelerate patient diagnosis. We designed a capture library to target the coding and splice site sequences of all known NMD genes and used NGS and DNA multiplexing to retrieve the pathogenic mutations in patients with heterogeneous NMD with or without known mutations. We retrieved all known mutations, including point mutations and small indels, intronic and exonic mutations, and a large deletion in a patient with Duchenne muscular dystrophy, validating the sensitivity and reproducibility of this strategy on a heterogeneous subset of NMD with different genetic inheritance. Most pathogenic mutations were ranked on top in our blind bioinformatic pipeline. Following the same strategy, we characterized probable TTN, RYR1 and COL6A3 mutations in several patients without previous molecular diagnosis. The cost was less than conventional testing for a single large gene. With appropriate adaptations, this strategy could be implemented into a routine genetic diagnosis set-up as a first screening approach to detect most kind of mutations, potentially before the need of more invasive and specific clinical investigations. An earlier genetic diagnosis should provide improved disease management and higher quality genetic counseling, and ease access to therapy or inclusion into therapeutic trials.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0982-8) contains supplementary material, which is available to authorized users.

Background. Most genetic disorders are caused by single nucleotide variations (SNVs) or small insertion/deletions (indels). High throughput sequencing has broadened the catalogue of human variation, including common polymorphisms, rare variations or disease causing mutations. However, identifying one variation among hundreds or thousands of others is still a complex task for biologists, geneticists and clinicians.Results. We have developed VaRank, a command-line tool for the ranking of genetic variants detected by high-throughput sequencing. VaRank scores and prioritizes variants annotated either by Alamut Batch or SnpEff. A barcode allows users to quickly view the presence/absence of variants (with homozygote/heterozygote status) in analyzed samples. VaRank supports the commonly used VCF input format for variants analysis thus allowing it to be easily integrated into NGS bioinformatics analysis pipelines. VaRank has been successfully applied to disease-gene identification as well as to molecular diagnostics setup for several hundred patients.Conclusions. VaRank is implemented in Tcl/Tk, a scripting language which is platform-independent but has been tested only on Unix environment. The source code is available under the GNU GPL, and together with sample data and detailed documentation can be downloaded from .

BackgroundObservational studies and meta-analyses relating milk consumption by adults to all-cause mortality, coronary heart disease and stroke have obtained contradictory results. Some studies found a protective effect of milk consumption, whilst other found an increased risk.MethodsWe performed a systematic literature search until June 2015 on prospective studies that looked at milk consumption, all-cause mortality, coronary heart disease and stroke. Random-effect meta-analyses were performed with dose-response.ResultsTwenty-one studies involving 19 cohorts were included in this meta-analysis, 11 on all-cause mortality, 9 on coronary heart disease, and 10 on stroke. Milk intake ranged from 0 to 850 mL/d. The summary relative risk (SRR) for 200 mL/d milk consumption was 1.01 (95% CI: 0.96–1.06) for all-cause mortality, 1.01 (95% CI: 0.98–1.05) for fatal and non fatal coronary heart disease, and 0.91 (95% CI: 0.82–1.02) for fatal and non fatal stroke. Stratified analyses by age, Body Mass Index, total energy intake and physical acitivity did not alter the SRR estimates. The possibility of publication bias was found for all cause mortality and for stroke, indicating a gap in data that could have suggested a higher risk of these conditions with increased milk consumption.ConclusionsWe found no evidence for a decreased or increased risk of all-cause mortality, coronary heart disease, and stroke associated with adult milk consumption. However, the possibility cannot be dismissed that risks associated with milk consumption could be underestimated because of publication bias.Electronic supplementary materialThe online version of this article (doi:10.1186/s12889-016-3889-9) contains supplementary material, which is available to authorized users.