Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. ...Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.
Abstract Objective Concept mapping is a method for developing a conceptual framework of a complex topic for use as a guide to evaluation or planning. In concept mapping, thoughts and ideas are ...represented in the form of a picture or map, the content of which is determined by a group of stakeholders. This study aimed to explore the suitability of this method as a tool to integrate practical knowledge with scientific knowledge in order to improve theory development as a sound basis for practical decision-making. Method Following a short introduction to the method of concept mapping, five Dutch studies, serving different purposes and fields in public health, will be described. The aim of these studies was: to construct a theoretical framework for good regional public health reporting; to design an implementation strategy for a guideline for integral local health policy; to guide the evaluation of a local integral approach of overweight and obesity in youth; to guide the construction of a questionnaire to measure the quality of postdisaster psychosocial care; and to conceptualize an integral base for formulation of ambitions and targets for the new youth healthcare programme of a regional health service. Results The studies showed that concept mapping is a way to integrate practical and scientific knowledge with careful selection of participants that represent the different perspectives. Theory development can be improved through concept mapping; not by formulating new theories, but by highlighting the key issues and defining perceived relationships between topics. In four of the five studies, the resulting concept map was received as a sound basis for practical decision-making. Conclusions Concept mapping is a valuable method for evidence-based public health policy, and a powerful instrument for facilitating dialogue, coherence and collaboration between researchers, practitioners, policy makers and the public. Development of public health theory was realized by a step-by-step approach, considering both scientific and practical knowledge. However, the external validity of the concept maps in place and time is of importance.
The need for accessible and motivating treatment approaches within mental health has led to the development of an Internet-based serious game intervention (called "Plan-It Commander") as an adjunct ...to treatment as usual for children with attention-deficit/hyperactivity disorder (ADHD).
The aim was to determine the effects of Plan-It Commander on daily life skills of children with ADHD in a multisite randomized controlled crossover open-label trial.
Participants (N=170) in this 20-week trial had a diagnosis of ADHD and ranged in age from 8 to 12 years (male: 80.6%, 137/170; female: 19.4%, 33/170). They were randomized to a serious game intervention group (group 1; n=88) or a treatment-as-usual crossover group (group 2; n=82). Participants randomized to group 1 received a serious game intervention in addition to treatment as usual for the first 10 weeks and then received treatment as usual for the next 10 weeks. Participants randomized to group 2 received treatment as usual for the first 10 weeks and crossed over to the serious game intervention in addition to treatment as usual for the subsequent 10 weeks. Primary (parent report) and secondary (parent, teacher, and child self-report) outcome measures were administered at baseline, 10 weeks, and 10-week follow-up.
After 10 weeks, participants in group 1 compared to group 2 achieved significantly greater improvements on the primary outcome of time management skills (parent-reported; P=.004) and on secondary outcomes of the social skill of responsibility (parent-reported; P=.04), and working memory (parent-reported; P=.02). Parents and teachers reported that total social skills improved over time within groups, whereas effects on total social skills and teacher-reported planning/organizing skills were nonsignificant between groups. Within group 1, positive effects were maintained or further improved in the last 10 weeks of the study. Participants in group 2, who played the serious game during the second period of the study (weeks 10 to 20), improved on comparable domains of daily life functioning over time.
Plan-It Commander offers an effective therapeutic approach as an adjunct intervention to traditional therapeutic ADHD approaches that improve functional outcomes in daily life.
International Standard Randomized Controlled Trial Number (ISRCTN): 62056259; http://www.controlled-trials.com/ISRCTN62056259 (Archived by WebCite at http://www.webcitation.org/6eNsiTDJV).
Objective
Previous studies demonstrated that mequitazine produces mild sedation after single doses.
Its enantiomer, l-mequitazine, has a stronger potency for the H1 receptor. The aim of the current ...study was to assess the effects of l-mequitazine and mequitazine, alone and with alcohol, on driving.
Methods
Twenty-five healthy volunteers were treated with l-mequitazine 2.5, 5.0 and 10 mg, mequitazine 10 mg and placebo, alone and in combination with alcohol in a double-blind crossover design. Driving performance was assessed using the standardized highway driving test in normal traffic. Its primary measure is the Standard Deviation of the Lateral Position (SDLP). Secondary measures consisted of an auditory word learning test during driving, and subjective measures of driving performance.
Results
L-mequitazine 2.5 and 5.0 mg showed no effect on SDLP in the highway driving test, while SDLP significantly increased after l-mequitazine 10 mg (alone +1.59 cm; with alcohol +1.41 cm) and mequitazine 10 mg (with alcohol +1.17 cm). Alcohol significantly impaired all performance measures (SDLP +2.63 cm) but did not interact with the effects of treatment. Subjective measures indicated that participants were aware of the impairing effects of alcohol, but not of l-mequitazine and mequitazine.
Conclusion
L-mequitazine can be considered safe to drive in dosages of 2.5 and 5.0 mg. L-mequitazine 10 mg led to mild driving impairment. Alcohol impaired all performance measures and added to the effects of l-mequitazine and mequitazine.
Small lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking.
We ...randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization.
We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P<0.001). The primary outcome occurred in 27.1% of the women in the intervention group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99).
In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.).
In an experimental cross between Meishan and Dutch Large White and Landrace lines, 619 F(2) animals and their parents were typed for molecular markers covering the entire porcine genome. Associations ...were studied between these markers and two fatness traits: intramuscular fat content and backfat thickness. Association analyses were performed using interval mapping by regression under two genetic models: (1) an outbred line-cross model where the founder lines were assumed to be fixed for different QTL alleles; and (2) a half-sib model where a unique allele substitution effect was fitted within each of the 19 half-sib families. Both approaches revealed for backfat thickness a highly significant QTL on chromosome 7 and suggestive evidence for a QTL at chromosome 2. Furthermore, suggestive QTL affecting backfat thickness were detected on chromosomes 1 and 6 under the line-cross model. For intramuscular fat content the line-cross approach showed suggestive evidence for QTL on chromosomes 2, 4, and 6, whereas the half-sib analysis showed suggestive linkage for chromosomes 4 and 7. The nature of the QTL effects and assumptions underlying both models could explain discrepancies between the findings under the two models. It is concluded that both approaches can complement each other in the analysis of data from outbred line crosses.
Background One of the key elements to enhance the uptake of evidence in public health policies is stimulating cross-sector collaboration. An intervention stimulating collaboration is a policy game. ...The aim of this study was to describe the design and methods of the development process of the policy game ‘In2Action’ within a real-life setting of public health policymaking networks in the Netherlands, Denmark and Romania. Methods The development of the policy game intervention consisted of three phases, pre intervention, designing the game intervention and tailoring the intervention. Results In2Action was developed as a role-play game of one day, with main focus to develop in collaboration a cross-sector implementation plan based on the approved strategic local public health policy. Conclusions This study introduced an innovative intervention for public health policymaking. It described the design and development of the generic frame of the In2Action game focusing on enhancing collaboration in local public health policymaking networks. By keeping the game generic, it became suitable for each of the three country cases with only minor changes. The generic frame of the game is expected to be generalizable for other European countries to stimulate interaction and collaboration in the policy process.
Previous evaluation showed insufficient use of a national guideline for integrated local health policy by Regional Health Services (RHS) in the Netherlands. The guideline focuses on five health ...topics and includes five checklists to support integrated municipal health policies. This study explores the determinants of guideline use by regional Dutch health professionals.
A web survey was send to 304 RHS health professionals. The questionnaire was based on a theory- and research-based framework of determinants of public health innovations. Main outcomes were guideline use and completeness of use, defined as the number of health topics and checklists used. Associations between determinants and (completeness of) guideline use were explored by multivariate regression models.
The survey was started by 120 professionals (39%). Finally, results from 73 respondents (24%) were eligible for analyses. All 28 Dutch RHS organizations were represented in the final dataset. About half of the respondents (48%) used the guideline. The average score for completeness of use (potential range 1-10) was 2.37 (sd = 1.78; range 1-7). Knowledge, perceived task responsibility and usability were significantly related to guideline use in univariate analyses. Only usability remained significant in the multivariate model on guideline use. Only self-efficacy accounted for significant proportions of variance in completeness of use.
The results imply that strategies to improve guideline use by RHSs should primarily target perceived usability. Self-efficacy appeared the primary target for improving completeness of guideline use. Methods for targeting these determinants in RHSs are discussed.
The aim of this study was to assess the effects of a novel antidepressant, vortioxetine 10 mg, on driving, cognitive, and psychomotor performance in 24 healthy subjects in a double‐blind, ...placebo‐controlled, three‐way crossover design. Mirtazapine 30 mg was included as an active comparator. Drugs were administered in the evening of 15 consecutive days. Performance was measured in the morning of days 2 and 16, using standardized tests measuring on‐the‐road driving, memory, tracking, divided attention, and vigilance. The statistical analysis on the primary measure of driving, i.e., SD of lateral position showed noninferiority of vortioxetine on days 2 and 16, and inferiority for mirtazapine on day 2. Vortioxetine did not cause cognitive or psychomotor impairment. Mirtazapine, however, impaired cognitive and psychomotor performance on day 2. Most of these effects disappeared after multiple doses of mirtazapine. To conclude, vortioxetine did not impair driving, cognitive, or psychomotor performance after single or multiple doses.
Clinical Pharmacology & Therapeutics (2013); 93 6, 493–501. doi:10.1038/clpt.2013.39
High‐density SNP microarrays (“SNP chips”) are a rapid, accurate and efficient method for genotyping several hundred thousand polymorphisms in large numbers of individuals. While SNP chips are ...routinely used in human genetics and in animal and plant breeding, they are less widely used in evolutionary and ecological research. In this article, we describe the development and application of a high‐density Affymetrix Axiom chip with around 500,000 SNPs, designed to perform genomics studies of great tit (Parus major) populations. We demonstrate that the per‐SNP genotype error rate is well below 1% and that the chip can also be used to identify structural or copy number variation. The chip is used to explore the genetic architecture of exploration behaviour (EB), a personality trait that has been widely studied in great tits and other species. No SNPs reached genomewide significance, including at DRD4, a candidate gene. However, EB is heritable and appears to have a polygenic architecture. Researchers developing similar SNP chips may note: (i) SNPs previously typed on alternative platforms are more likely to be converted to working assays; (ii) detecting SNPs by more than one pipeline, and in independent data sets, ensures a high proportion of working assays; (iii) allele frequency ascertainment bias is minimized by performing SNP discovery in individuals from multiple populations; and (iv) samples with the lowest call rates tend to also have the greatest genotyping error rates.
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