Tailored therapy in type 2 diabetes:unintended effects of glucose-lowering agents

The clinical treatment landscape of type 2 diabetes has rapidly evolved over the last decades. With the arrival of several new treatment options, the possibility of tailored therapy for patients with type 2 diabetes has become an option. This thesis investigated several advantages and disadvantages of the treatment options. Some of the results contradict with the Dutch treatment guideline, e.g. gliclazide does not seem to better than other sulphonylureas with regard to some important outcomes and there might be role for thiazolidinedionen in the treatment of selected patients. This underlines the importance of tailored therapy. However, this thesis also showed that implementation of tailored therapy is difficult and that there is room for improvement in guidelines and among prescribers

Size and Causes of the Occupational Gender Wage-gap in the Netherlands

Research from the United States consistently shows that female-dominated occupations generally yield lower wages than male-dominated occupations. Using detailed occupational data, this study analyses the size andcauses of this occupational genderwage-gap in the Dutch labourmarket using multi-levelmodelling techniques.The analyses showthat bothmen andwomen earn lowerwages if they are employed in female-dominated occupations. This especially indicates the signi¢cance of gender inWestern labour markets, since overall levels of wage inequality are relatively small in the Netherlands compared to, for example, the United Kingdom and the United States. Di¡erences in required responsibility are particularly important in accounting for this occupational wage-gap. Nonetheless, we find large wage penalties for working in a female-dominated instead of a maledominated occupation for occupations that require high levels of education, skills, and responsibility.

Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms

The hippocampal expression profiles of wild-type mice and mice transgenic for δC-doublecortin-like kinase were compared with Solexa/Illumina deep sequencing technology and five different microarray platforms. With Illumina's digital gene expression assay, we obtained ∼2.4 million sequence tags per sample, their abundance spanning four orders of magnitude. Results were highly reproducible, even across laboratories. With a dedicated Bayesian model, we found differential expression of 3179 transcripts with an estimated false-discovery rate of 8.5%. This is a much higher figure than found for microarrays. The overlap in differentially expressed transcripts found with deep sequencing and microarrays was most significant for Affymetrix. The changes in expression observed by deep sequencing were larger than observed by microarrays or quantitative PCR. Relevant processes such as calmodulin-dependent protein kinase activity and vesicle transport along microtubules were found affected by deep sequencing but not by microarrays. While undetectable by microarrays, antisense transcription was found for 51% of all genes and alternative polyadenylation for 47%. We conclude that deep sequencing provides a major advance in robustness, comparability and richness of expression profiling data and is expected to boost collaborative, comparative and integrative genomics studies

Cost Analysis From a Randomized Comparison of Immediate Versus Delayed Angiography After Cardiac Arrest

Background In patients with out‐of‐hospital cardiac arrest without ST‐segment elevation, immediate coronary angiography did not improve clinical outcomes when compared with delayed angiography in the COACT (Coronary Angiography After Cardiac Arrest) trial. Whether 1 of the 2 strategies has benefits in terms of health care resource use and costs is currently unknown. We assess the health care resource use and costs in patients with out‐of‐hospital cardiac arrest. Methods and Results A total of 538 patients were randomly assigned to a strategy of either immediate or delayed coronary angiography. Detailed health care resource use and cost‐prices were collected from the initial hospital episode. A generalized linear model and a gamma distribution were performed. Generic quality of life was measured with the RAND‐36 and collected at 12‐month follow‐up. Overall total mean costs were similar between both groups (EUR 33 575±19 612 versus EUR 33 880±21 044; P=0.86). Generalized linear model: (β, 0.991; 95% CI, 0.894–1.099; P=0.86). Mean procedural costs (coronary angiography and percutaneous coronary intervention, coronary artery bypass graft) were higher in the immediate angiography group (EUR 4384±3447 versus EUR 3028±4220; P<0.001). Costs concerning intensive care unit and ward stay did not show any significant difference. The RAND‐36 questionnaire did not differ between both groups. Conclusions The mean total costs between patients with out‐of‐hospital cardiac arrest randomly assigned to an immediate angiography or a delayed invasive strategy were similar during the initial hospital stay. With respect to the higher invasive procedure costs in the immediate group, a strategy awaiting neurological recovery followed by coronary angiography and planned revascularization may be considered. Registration URL: https://trialregister.nl; Unique identifier: NL4857

Targeting Several CAG Expansion Diseases by a Single Antisense Oligonucleotide

To date there are 9 known diseases caused by an expanded polyglutamine repeat, with the most prevalent being Huntington's disease. Huntington's disease is a progressive autosomal dominant neurodegenerative disorder for which currently no therapy is available. It is caused by a CAG repeat expansion in the HTT gene, which results in an expansion of a glutamine stretch at the N-terminal end of the huntingtin protein. This polyglutamine expansion plays a central role in the disease and results in the accumulation of cytoplasmic and nuclear aggregates. Here, we make use of modified 2′-O-methyl phosphorothioate (CUG)n triplet-repeat antisense oligonucleotides to effectively reduce mutant huntingtin transcript and protein levels in patient-derived Huntington's disease fibroblasts and lymphoblasts. The most effective antisense oligonucleotide, (CUG)7, also reduced mutant ataxin-1 and ataxin-3 mRNA levels in spinocerebellar ataxia 1 and 3, respectively, and atrophin-1 in dentatorubral-pallidoluysian atrophy patient derived fibroblasts. This antisense oligonucleotide is not only a promising therapeutic tool to reduce mutant huntingtin levels in Huntington's disease but our results in spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy cells suggest that this could also be applicable to other polyglutamine expansion disorders as well

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Outsourcing the Gender Factory: Living Arrangements and Service Expenditures on Female and Male Tasks

Using data from the U.S. Consumer Expenditure Survey 1998, this study analyzes how much money different types of households spend for domestic services on “female” and “male” tasks.We test alternative hypotheses based on economic and sociological theories of gender differentiation. Contrary to arguments that marriage lowers the risk to one partner of specializing in housework, we find no differences in service expenditures between cohabiting and married couples. Consistent with gender production arguments that the household context shapes behavior, single women outspend couples across the board. Single men, however, reveal spending behavior more consistent with gender socialization. Comparing single men and single women points to the gendered nature of the tasks as an important aspect of domestic service expenditures.

A generalized approach for automatic 3-D geometry assessment of blood vessels in transverse ultrasound images using convolutional neural networks

Accurate 3-D geometries of arteries and veins are important clinical data for diagnosis of arterial disease and intervention planning. Automatic segmentation of vessels in the transverse view suffers from the low lateral resolution and contrast. Convolutional neural networks are a promising tool for automatic segmentation of medical images, outperforming the traditional segmentation methods with high robustness. In this study, we aim to create a general, robust, and accurate method to segment the lumen-wall boundary of healthy central and peripheral vessels in large field-of-view freehand ultrasound (US) datasets. Data were acquired using freehand US, in combination with a probe tracker. A total of ± 36000 cross-sectional images, acquired in the common, internal, and external carotid artery (N = 37), in the radial, ulnar artery, and cephalic vein (N = 12), and in the femoral artery (N = 5) were included. To create masks (of the lumen) for training data, a conventional automatic segmentation method was used. The neural networks were trained on a) data of all vessels and b) the carotid artery only. The performance was compared and tested using an open access dataset. The Recall, Precision, DICE, and the intersect-over-union (IoU) were calculated. Overall, segmentation was successful in the carotid and peripheral arteries. The Multires U-net architecture performs best overall with DICE = 0.93 when trained on the total dataset. Future studies will focus on the inclusion of vascular pathologies