Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup

Tofacitinib for ulcerative colitis:results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry

Background: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). Aim: To evaluate effectiveness, safety and use of tofacitinib in daily practice. Methods: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation. Results: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively. Conclusion: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients

Neighbourhood spatial order and firm mobility in disadvantaged urban neighbourhoods of the Netherlands

Contains fulltext : 142210.pdf (publisher's version ) (Open Access)In recent years, urban residential neighbourhoods in the Netherlands have become increasingly known to function as incubation zones for small-scale businesses. Despite this development, little is known about whether and how the local production environment in these neighbourhoods shapes firm development prospects. In this paper we remedy this shortcoming by studying how two aspects of the local production environment, namely the neighbourhood built environment and spatial regulations, affect firm mobility of small-scale businesses in urban residential neighbourhoods. Towards this aim, we contrast two sets of urban neighbourhoods, namely pre-WWII and post-WWII neighbourhoods, with comparable, low socio-economic profile, but with distinct built environment and spatial regulations. We combine quantitative and qualitative methods analysing available trade register data from Dutch regional Chambers of Commerce, studying neighbourhood development plans, and conducting focus group and individual interviews with neighbourhood experts and entrepreneurs. The local built environment and its spatial regulations do indeed appear to affect firm mobility choices of entrepreneurs in the studied neighbourhoods, although overall mobility rates do not significantly differ between pre-war and post-war neighbourhoods. Further analysis, however, reveals that these two sets of neighbourhoods offer distinct local production environments, since the nature of commercial activities and entrepreneurs' neighbourhood experiences differ notably.32 p

Woonvoorkeuren van kennismigranten

Europese steden en regio’s beconcurreren elkaar om internationale kenniswerkers aan te trekken. Het is voor overheden daarom belangrijk om te weten waarom deze ‘kennismigranten’ voor een bepaalde stad kiezen en hoe zij daar willen wonen. Hun woonvoorkeuren zijn echter aanzienlijk minder uniform dan vaak verondersteld wordt in het beleid. Vooral verschillen tussen beroepsgroepen vallen op