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The introduction of the Act on Quality, Complaints and Disputes in Health care (WKKGZ) on 1 January 2016, brings changes for physicians in the Netherlands. Even though not all the implications of the Act are yet known, it is clear that the new provisions on quality entail a substantial increase in the administrative workload. With respect to the right of complaint a great deal will change for physicians and other care providers. Independent complaints committees are no longer mandatory. They are to be replaced by dispute settlement authorities that are able to make binding decisions with the possibility of awarding damages for patient claims. The legal position of physicians is not satisfactorily regulated in a well-balanced way in all areas, and deserves further attention.

This book explores the contemporary cultural significance and understandings of self-help books and the narratives they contain. In the following, we introduce a considerable shift of perspective into our argument. In earlier chapters, we have explored the transnational popularisation of self-help books, and we have examined self-help’s narratives of self, personal development and social relationships in various national contexts. In contrast, here we consider how readers engage with self-help texts. Who reads self-help books? Why and how do they read them? What do self-help readers say about the books they read? How do they feel about them? What do they want from them? Why do they use them? How do self-help books inform their readers’ beliefs and actions in everyday life? How do divisions of class and gender impact the consumption of self-help literature? In the context of the overall objectives of this book, these questions are significant in so far as they draw attention to the roles which self-help narratives may come to play within the lived realities of individuals’ everyday lives.

Paul McKenna is a popular British self-help entrepreneur. Since the early 1990s, he has published self-help books on a wide range of topics, from weight loss in I Can Make You Thin (McKenna, 2009) to happiness in I Can Make You Happy (McKenna, 2011) and enhanced intelligence in I Can Make You Smarter (McKenna, 2012). Alongside his books, McKenna has gained public attention as a hypnotist and personal development expert. He promotes therapies to cope with trauma (Moore, 2013) or to achieve greater success through mental reprogramming (McKenna, 2014), and newspapers write of his successful work with celebrities (Lampert, 2008). As with many self-help entrepreneurs, his success seems to rest on a mixture of claims to scientific expertise, stories of past success and high visibility across a wide range of media platforms. His personal website, for instance, highlights his doctorate before pointing out that ‘Paul McKenna is the UK’s most successful non-fiction author’ and listing a succession of bestsellers (McKenna, 2013). This is followed by a set of testimonials by former patients, who attest that McKenna’s advice enabled them to lose weight and improve their lives dramatically. Likewise, he promotes his work through Twitter and Facebook, and Apple’s online shop iTunes sells various apps allowing users to track their success applying McKenna’s self-help techniques. Over the years, he has also been the host of various TV series, and channels on video platforms such as YouTube and Hulu allow viewers to watch him in action anytime.

A Survival Guide for Life was published in 2012 by Bantam Press in London. Bear Grylls, the book’s author, is a well-known British media personality. On his website, Grylls portrays himself as an outdoorsman, adventurer and survivalist: Bear Grylls has become known around the world as one of the most recognized faces of survival and outdoor adventure. His journey to this acclaim started in the UK on the Isle of Wight, where his late father taught him to climb and sail. Trained from a young age in martial arts, Bear went on to spend three years as a soldier in the British Special Forces, serving with 21 SAS. It was here that he perfected many of the skills that his fans all over the world enjoy watching him pit against mother-nature. (Grylls, no date-c) Along these lines, the story continues. A biographical sketch tells readers of free-fall parachuting accidents in Africa, journeys to remote regions — from Antarctica to the Arctic — and mountaineering expeditions to Mount Everest. It also highlights his high-profile media work for Channel 4 and Discovery Channel, claiming that the ‘Discovery Channel’s Emmy nominated TV show Man Vs. Wild and Born Survivor […] has become one of the most watched shows on the planet, reaching an estimated 1.2 billion viewers’ (Grylls, no date-c).

Susan Jeffers’ Feel the Fear … and Do it Anyway (1987/2007) is a typical self-help book. It seeks to enable its readers to overcome situations, experiences and practices of which they are afraid: What is it for you? Fear of … public speaking, asserting yourself, making decisions, intimacy, changing jobs, being alone, aging, driving, losing a loved one, ending a relationship? […] Never mind … join the crowd! Fear seems to be an epidemic in our society. […] Whatever the fear, this book will give you the insight and tools to vastly improve your ability to handle any given situation. (Jeffers, 1987/2007: Introduction; emphasis in original) Here, right at the outset of her argument, Jeffers makes several moves that are typical of many self-help authors. First, she sets up a problem — fear — as endemic and requiring an urgent response. Then she goes on to direct her readers to ‘insights and tools’ that will ‘vastly improve’ their ability to manage any situation they might face. By highlighting a source of crisis and simultaneously offering guidance that will empower her readers to fundamentally improve their lives, Jeffers in fact spells out the promise of the self-help genre as a whole.

In this book, we have offered two new insights into self-help and, by extension, therapeutic culture that to date have been significant omissions in the research literature. These are, first, the transnationalisation of self-help culture, and by implication its glocal hybridisation; and, second, the tension between self-help’s discursive heterogeneity and its relative political-ideological (neoliberal) homogeneity. In developing these insights across the various chapters we have illustrated how self-help operates as a multidirectional transnational network with a dominant nodal centre in the US and UK whose reach extends far beyond the Global Northwest.

Most epidemiological studies have been conducted based on relations between pollution concentrations measured at fixed ambient air quality monitoring sites, or modelled values using land-use regression models, and various health indicators. However, such simplistic modelling ignores several crucial factors, such as, (i) the activity patterns of individuals, i.e. people’s day-to-day movements, and (ii) the differences between indoor and outdoor air. We have developed a mathematical model for the determination of human exposure to ambient air pollution in an urban area, called EXPAND (EXposure model for Particulate matter And Nitrogen oxiDes). The model combines (i) predicted concentrations, and (ii) information on people’s activities and location of the population, to evaluate the spatial and temporal variation of average exposure of the urban population to ambient air pollution in different microenvironments. In particular, the model takes into account the movements of the population and the infiltration from outdoor to indoor air. We present fine-resolution numerical results on annual spatial concentration, time activity and population exposures to PM2.5 in London and in the Helsinki Metropolitan Area, for 2008 and 2009. We have shown that the effect of neglecting the movements of the population, which is the currently commonly applied procedure, can result in an underprediction of exposure by several tens of per cent.

In Latin America over the past two decades self-help texts have grown in both production and circulation, making self-help one of the most popular book genres across the region. Self-help texts amount to between 13 and 20 per cent of the books sold in the bigger Latin American countries such as Mexico, Brazil, Argentina, Colombia, Venezuela and Peru (Souroujon, 2009). Self-help books are notably popular in the region. As indicated in Chapter 3, the national publisher’s chamber of commerce in Mexico has found that between 3.5 and 4.5 million self-help books were sold annually in Mexico between 2005 and 2011; similar trends pointing to an increased circulation of self-help books have also been identified in other nations in the region1 (Camara Nacional de la Industria Editorial Mexicana, 2013; Papalini, 2010).

The preceding chapter situated the sociological analysis of self-help books in broader academic debates about therapeutic culture. In turn, this chapter argues for approaching these debates from a transnational perspective. Research about the role which psychotherapeutic narratives about self and social relationships play in contemporary popular cultures has tended to focus on specific societies. The titles of key studies in this field alone already suggest this. Take Barbara Ehrenreich’s Bright-Sided: How the Relentless Promotion of Positive Thinking Has Undermined America (Ehrenreich, 2009), Micki McGee’s Self-Help, Inc.: Makeover Culture in American Life (McGee, 2005), or Eva Moskowitz’s In Therapy We Trust: America’s Obsession with Self-Fulfilment (Moskowitz, 2001). These all trace how cultural and socio-economic shifts in the contemporary United States promoted the growing prominence of psychotherapeutic narratives in public and private life. These books have little or nothing to say about the roles of American therapeutic narratives and products in therapeutic cultures in other parts of the world, or about the ways American therapeutic culture was itself shaped by influences from elsewhere.

Self-help today is a global phenomenon. While the previous chapter mentioned examples of self-help in the Americas, Western Europe and South Asia, we now focus on the rise of self-help in the People’s Republic of China. Self-help enjoys considerable popularity in East and Southeast Asia; reports indicate that self-help books have a broad readership in countries such as South Korea (Choon, 2008), Japan (Helwig, 2015; Tan, 2014) and Vietnam (Viet Nam News, 2011). In the post-socialist People’s Republic of China of the late 20th and early 21st century, self-help and self-help entrepreneurs have likewise experienced a remarkable prominence, enjoying a considerable presence in mass media and public life. Though the exact size of the market for self-help is unknown, ‘supplementary educational books’, of which self-help forms the bulk, accounted in 2010 for 34 per cent of the total annual revenue of the market for print books in China, equalling 18.2 billion RMB or approximately 1.9 billion pounds (Open Books, 2011).

Agonist exposure can cause internalisation of G-protein coupled receptors (GPCRs), which may be a part of desensitisation but also of cellular signaling. Previous methods to study internalisation have been tedious or only poorly quantitative. Therefore, we have developed and validated a quantitative method using a sphingosine-1-phosphate (S1P) receptor as a model. Because of a lack of suitable binding studies, it has been difficult to study S1P receptor internalisation. Using a N-terminal HisG-tag, S1P(1) receptors on the cell membrane can be visualised via immunocytochemistry with a specific anti-HisG antibody. S1P-induced internalisation was concentration dependent and was quantified using a microplate reader, detecting either absorbance, a fluorescent or luminescent signal, depending on the antibodies used. Among those, the fluorescence detection method was the most convenient to use. The relative ease of this method makes it suitable to measure a large number of data points, e.g. to compare the potency and efficacy of receptor ligands.

De gezondheidsrechtelijke wet- en regelgeving is de afgelopen jaren op een aantal (deel)terreinen ingrijpend veranderd. Alle pogingen tot deregulering ten spijt zijn de regels met betrekking tot de zorg daarnaast eerder toe- dan afgenomen. Bundels die belangstellenden wegwijs proberen te maken in het woud aan regelingen aangaande de gezondheidszorg dreigen daardoor snel te verouderen.

Many people in developing countries lack access to basic surgical care. This lack of access leads to preventable mortality and disability. Mortality due to surgically treatable conditions currently exceeds that due to HIV, TB and malaria combined. However, efforts by global healthcare organisations to address this problem remain limited. Essential surgery consist of basic surgical interventions that can save lives and prevent disability. It involves a limited number of interventions, is cost-effective and can be implemented sustainably in national healthcare systems. Essential surgery should therefore be accessible to everyone worldwide. In this article we discuss why it has received insufficient attention as a component of global healthcare. We also look at initiatives that aim to change this status quo.

Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome.We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14.Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been excluded.

BACKGROUND: The impact of physical inactivity and unhealthy diet on health is increasingly profound. Lifestyle interventions targeting both behaviors simultaneously might decrease the prevalence of overweight and comorbidities. The Dutch 'BeweegKuur' is a combined lifestyle intervention (CLI) in primary care, to improve physical activity and dietary behavior in overweight people. In a cluster randomized controlled trial, the (cost-) effectiveness of an intensively guided program has been compared to a less intensively guided program. This process evaluation aimed to assess protocol adherence and potential differences between clusters. In addition, sustainability (i.e. continuation of the CLI in practice after study termination) was evaluated. METHODS: Existing frameworks were combined to design the process evaluation for our intervention and setting specifically. We assessed reach, fidelity, dose delivered and received, context and implementation strategy. Both qualitative and quantitative data were used for a comprehensive evaluation. Data were collected in semi-structured interviews with health care providers (HCPs, n = 25), drop-out registration by HCPs, regular questionnaires among participants (n = 411) and logbooks kept by researchers during the trial. RESULTS: Protocol adherence by professionals and participants varied between the programs and clusters. In both programs the number of meetings with all HCPs was lower than planned in the protocol. Participants of the supervised program attended, compared to participants of the start-up program, more meetings with physiotherapists, but fewer with lifestyle advisors and dieticians. The 'BeweegKuur' was not sustained, but intervention aspects, networks and experiences were still utilized after finalization of the project. Whether clusters continued to offer a CLI seemed dependent on funding opportunities and collaborations. CONCLUSIONS: Protocol adherence in a CLI was problematic in both HCPs and participants. Mainly the amount of dietary guidance was lower than planned, and decreased with increasing guidance by PT. Thus, feasibility of changing physical activity and dietary habits simultaneously by one intervention in one year was not as high as expected. Also the sustainability of CLI was poor. When a CLI program is started, re-invention should be allowed and maximum effort should be taken to guarantee long term continuation, by planning both implementation and sustainability carefully. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46574304 . Registered 23 December 2010.

Background and purpose: The thiazolidine carboxylic acid, BML-241, has been proposed as a lead compound in development of selective antagonists at the sphingosine-1-phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML-241 for the S1P3 receptor in more detail. Experimental approach: Chinese hamster ovary (CHO) cells stably transfected with the S1P3, S1P2 or α1A-adrenoceptors were used to investigate the effect of BML-241 on increases in [Ca2+]i mediated via different receptors. CHO-K1 cells were used to study ATP-induced [Ca2+]i elevations. Effects on S1P3-mediated inhibition of forskolin-induced cAMP accumulation and on binding to α1A-adrenoceptors were also investigated. In addition, the effect of BML-241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. Key results: High concentrations of BML-241 (10 μM) inhibited the rise in [Ca2+]i induced by S1P3 and S1P2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML-241 also inhibited [Ca2+]i increases via P2 (nucleotide) receptor or α1A-adrenoceptor stimulation. Moreover, BML-241 (10 μM) inhibited α1-adrenoceptor-mediated contraction of rat mesenteric artery but did not displace [3H]-prazosin from α1A-adrenoceptors in concentrations up to 100 μM. BML-241 (10 μM) did not affect the S1P3-mediated decrease of forskolin-induced cAMP accumulation. Conclusions and Implications: We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor. British Journal of Pharmacology (2006) 149, 277–282. doi:10.1038/sj.bjp.0706872

The Dutch government funds health research in several ways. One component of public funding consists of funding programmes issued by the Netherlands Organisation for Health Research and Development (ZonMw). The majority of ZonMw's programmes provide funding for research in specific health research areas. Such targeted funding plays an important role in addressing knowledge gaps and in generating products for which there is a need. Good governance of the allocation of targeted funding for health research requires three elements: a research agenda, an overview of the health research currently being conducted, and a transparent decision-making process regarding the distribution of funds. In this article, we describe how public funding for health research is organized in the Netherlands and how the allocation of targeted funds is governed. By describing the questions that the current model of governance raises, we take a first step towards a debate about the governance of targeted public funding for health research in the Netherlands.

Administrative information in accordance with SPIRIT 2013 guidelines. (PDF 85Â kb)

SPIRIT 2013 checklist. (PDF 118Â kb)

Overview of literature search. (PDF 11Â kb)

Contains fulltext : 155052.pdf (Publisher’s version ) (Open Access) The aim of this study was to determine the similarities and differences in social network characteristics, satisfaction and wishes with respect to the social network between people with mild or borderline intellectual disabilities (ID), people with autism spectrum disorders (ASD) and a reference group. Data were gathered from 105 young adults living independently in the community. The social networks of people with ID and ASD are more restricted than those of the reference group. Compared with the other groups, people with ASD are less often satisfied with their networks. Each group has its own characteristics, issues and wishes with respect to their social network. Practical measures to enable professionals to adapt to these issues are discussed. 13 p.

BACKGROUND: although proactive primary care, including early detection and treatment of community-dwelling frail older people, is a part of the national healthcare policy in several countries, little is known about its cost-effectiveness. OBJECTIVE: to evaluate the cost-effectiveness of a proactive primary care approach in community-dwelling frail older people. DESIGN AND SETTING: embedded in a cluster randomised trial among 12 Dutch general practitioner practices, an economic evaluation was performed from a societal perspective with a time horizon of 24 months. METHOD: frail older people in the intervention group received an in-home assessment and interdisciplinary care based on a tailor-made treatment plan and regular evaluation and follow-up. Practices in the control group delivered usual care. The primary outcome for the cost-effectiveness and cost-utility analysis was disability and health-related quality of life, respectively. RESULTS: multilevel analyses among 346 frail older people showed no significant differences between the groups regarding disability and health-related quality of life at 24 months. People in the intervention group used, as expected, more primary care services, but there was no decline in more expensive hospital and long-term care. Total costs over 24 months tended to be higher in the intervention group than in the control group (euro26,503 versus euro20,550, P = 0.08). CONCLUSIONS: the intervention under study led to an increase in healthcare utilisation and related costs without providing any beneficial effects. This study adds to the scarce amount of evidence of the cost-effectiveness of proactive primary care in community-dwelling frail older people. Trial registration: Current Controlled Trials, ISRCTN 31954692.

BackgroundCombined lifestyle interventions (CLIs) have been advocated as an effective instrument in efforts to reduce overweight and obesity. The odds of maintaining higher levels of physical activity (PA) and healthier dietary behaviour improve when people are more intrinsically motivated to change their behaviour. To promote the shift towards more autonomous types of motivation, facilitator led CLIs have been developed including lifestyle coaching as key element. The present study examined the shift in types of motivation to increase PA and healthy dieting among participants of a primary care CLI, and the contribution of lifestyle coaching to potential changes in motivational quality.MethodsThis prospective cohort study included participants of 29 general practices in the Netherlands that implemented a CLI named `BeweegKuur inverted question mark. Questionnaires including items on demographics, lifestyle coaching and motivation were sent at baseline and after 4 months. Aspects of motivation were assessed with the Behavioural Regulation and Exercise Questionnaire (BREQ-2) and the Regulation of Eating Behaviour Questionnaire (REBS). We performed a drop out analysis to identify selective drop-out. Changes in motivation were analysed with t-tests and effect size interpretations (Cohen inverted question marks d), and multivariate regression analysis was used to identify predictors of motivational change.ResultsFor physical activity, changes in motivational regulation were fully in line with the tenets of Self Determination Theory and Motivational Interviewing: participants made a shift towards a more autonomous type of motivation (i.e. controlled types of motivation decreased and autonomous types increased). Moreover, an autonomy supportive coaching style was generally found to predict a larger shift in autonomous types of motivation. For healthy dietary behaviour, however, except for a small decrease in external motivation, no favourable changes in different types of motivation were observed. The relation between coaching and motivation appeared to be influenced by the presence of physical activity guidance in the programme.ConclusionsMotivation of participants of a real life primary care CLI had changed towards a more autonomous motivation after 4 months of intervention. Autonomy-supportive lifestyle coaching contributed to this change with respect to physical activity. Lifestyle coaching for healthy diet requires thorough knowledge about the problem of unhealthy dieting and solid coaching skills.

BACKGROUND: Health is associated with amount of daily physical activity. Recently, the identification of sedentary time as an independent factor, has gained interest. A valid and easy to use activity monitor is needed to objectively investigate the relationship between physical activity, sedentary time and health. We compared validity and reproducibility of physical activity measurement and posture identification of three activity monitors, as well as user friendliness. METHODS: Healthy volunteers wore three activity monitors simultaneously: ActivPAL3, ActiGraphGT3X and CAM. Data were acquired under both controlled (n = 5) and free-living conditions (n = 9). The controlled laboratory measurement, that included standardized walking intensity and posture allocation, was performed twice. User friendliness was evaluated with a questionnaire. Posture classification was compared with direct observation (controlled measurement) and with diaries (free living). Accelerometer intensity accuracy was tested by correlations with walking speed. User friendliness was compared between activity monitors. RESULTS: Reproducibility was at least substantial in all monitors. The difference between the two CAM measurements increased with walking intensity. Amount of correct posture classification by ActivPAL3 was 100.0% (kappa 0.98), 33.9% by ActiGraphGT3X (kappa 0.29) and 100.0% by CAM (kappa 0.99). Correlations between accelerometer intensity and walking speed were 0.98 for ActivPAL3, 1.00 for ActiGraphGT3X and 0.98 for CAM. ICCs between activity monitors and diary were 0.98 in ActivPAL3, 0.59 and 0.96 in ActiGraphGT3X and 0.98 in CAM. ActivPAL3 and ActiGraphGT3X had higher user friendliness scores than the CAM. CONCLUSIONS: The ActivPAL3 is valid, reproducible and user friendly. The posture classification by the ActiGraphGT3X is not valid, but reflection of walking intensity and user friendliness are good. The CAM is valid; however, reproducibility at higher walking intensity and user friendliness might cause problems. Further validity studies in free living are recommended.

Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality.We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor.We found a heterozygous WT1 whole-gene deletion but no other gene defects.This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.

Item does not contain fulltext This study describes the implementation of the main phases of the rehabilitation process of children with motor disabilities who visit Dutch therapeutic toddler classes. Parent involvement, as well as parents' and professionals' satisfaction were also investigated. It was found that in about half of the cases there was no initial assessment of the child, nor a jointly formulated intervention plan. When there was an assessment, several quality standards were not met. In most cases parents were involved in the evaluation phase of the rehabilitation process. However, the proportion of parents involved in the phases of assessment and intervention planning were much lower. The results are discussed within the context of current developments in The Netherlands with respect to team communication and recent research findings. 8 p.

The effects of multiple-dose telmisartan on the steady-state pharmacodynamics and pharmacokinetics of warfarin were assessed in 12 healthy young males in an open-label, single-period study conducted over 30 days. Subjects received loading doses of oral once-daily warfarin on days 1 to 5, which were individually adjusted at days 6 and/or 9 to attain stable predose prothrombin time values (INRpre) of between 1.2 and 1.8 by the end of medication phase 1 (day 14). From days 15 to 24 (medication phase 2), subjects received oral once-daily telmisartan 120 mg in addition to individualized oral doses of once-daily warfarin. On days 25 to 31 (medication phase 3), oral once-daily warfarin was again administered alone at individualized doses. Under steady-state conditions, INRpre remained unchanged during medication phases 1, 2, and 3. The difference between phases 1 and 3 was -0.04 (95% confidence interval [CI]: -0.7 to 0.10) and between phases 2 and 1 was 0.03 (95% CI: -0.11 to 0.10). Mean trough plasma warfarin concentrations (Cpre) were stable during medication with warfarin alone but showed a small, although statistically significant, decrease during the combined-medication phase. The point estimate of the ratio of phase 2/phase 1 was 0.89 (95% CI: 0.84 to 0.95). The decrease in Cpre did not result in decreased anticoagulation. This suggests that the extent of pharmacokinetic interaction between telmisartan and warfarin is limited, and since telmisartan had no effect on INRpre and the concomitant medication was well tolerated, there is no evidence for a clinically relevant interaction between telmisartan and warfarin.

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Objective: To determine parents' service needs at the start of therapeutic toddler class treatment, to analyse determinants and to investigate received help after a period of 10 months. Subjects: Parents with motor or multiply disabled children in therapeutic toddler classes. Setting: Sixteen out of 17 Dutch rehabilitation centres. Design: A sample of 84 parents, stratified according to toddler class size. Main outcome measures: A questionnaire of 33 items, divided into five categories, was designed to assess parents' needs and to evaluate the amount of received help. Several measures were used to assess child, parent and family characteristics. Results: Based on factor analysis, five need subscales were distinguished which only partially corresponded to the initial categories. The initial category concerning needs for help in family functioning did not come out as a factor. Needs expressed most frequently belonged to the three subscales of needs for information concerning the child. The average level of needs generally did not differ for mothers and fathers across the subscales. However, we found large variation in needs for both mothers and fathers on each subscale. The most important, positively correlated determinant of parents' needs was social isolation of the family. After 10 months a considerable level of unmet needs was found. Conclusions: A systematic and periodic assessment of individual needs of parents as well as the services offered is recommended. Professionals of the therapeutic toddler classes should especially focus on providing parents with information on their child's disability and therapy, community services and parenting.

The combination of calcium channel blockers and beta blockers is more effective for the treatment of exercise-induced angina pectoris than beta blocker monotherapy. Since ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 and 10 mg, diltiazem XR 200 and 300 mg, and mibefradil 50 and 100 mg treatment added to baseline beta blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. Although none of the calcium channel blockers improved duration of exercise or amount of workload, all of them significantly delayed onset of 1 mm ST segment depres sion on ETT (p The authors conclude that calcium channel blockers with negative chronotropic property provide better delay of ischemia in patients with exercise-induced angina but that the concomitant risk of intolerable dizziness largely reduces this benefit.

Air pollution is associated with adverse effects on human health through exposure to PM and ozone. To design effective air pollution mitigation strategies it is essential to quantify the effect of pollutant emission reductions on their concentrations as well as health and ecosystem impacts. Within integrated assessment modeling source-receptor relationships (SRRs) are used that are based on chemistry transport modelling. Currently, these SRRs are made using invariant emission time profiles. The LOTOS-EUROS model equipped with a source attribution module was used to test this assumptions for renewable energy scenarios. Renewable energy availability and thereby fossil fuel back up are strongly dependent on meteorological conditions. We have used the spatially and temporally explicit energy model REMix to derive time profiles for backup power generation. These time profiles were used in LOTOS-EUROS to investigate the effect of emission timing on air pollutant concentrations and SRRs. It is found that the effectiveness of emission reduction in the power sector is significantly lower when accounting for the shift in the way emissions are divided over the year and the correlation of emissions with synoptic situations. The source receptor relationships also changed significantly. This effect was found for both primary and secondary pollutants. Our results indicate that emission timing deserves explicit attention when assessing the impacts of system changes on air quality.

Contains fulltext : 134594.pdf (Publisher’s version ) (Closed access) This study investigates the delivered care in a multidisciplinary lifestyle intervention by dieticians and physiotherapists compared to the protocol of this intervention. Participants with a body mass index (BMI) between 25 and 40 kg m-2 were divided over three different programs depending on their BMI and comorbidities. All these programs consisted of individual and group sessions with the dietician, while care by the physiotherapist differed by program. The dieticians and physiotherapists of 30 locations were contacted to provide data about health care use within the intervention from their health records. Data of 379 participants were available and showed that group sessions by dieticians were often not attended. Care by the physiotherapist was delivered according to the protocol to a larger extent. An average of 43-93% of the sessions was attended. The level of attendance is comparable to other interventions, but especially attendance at group sessions with dieticians should be improved. 7 p.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 × 10-7) in SOX2OT and rs17030795 (P = 5.84 × 10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 × 10-6) between CUL3 and FAM124B and rs1886797 (P = 8.05 × 10-6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P = 4 × 10-6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. © 2014 Macmillan Publishers Limited All rights reserved.

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia. © 2014 Macmillan Publishers Limited All rights reserved.

In this study we investigate the ability of the Chemistry Transport Model (CTM) LOTOS-EUROS to explain the observed decrease in secondary inorganic aerosol (SIA) and its precursors between 1990 and 2009 over Europe. The model explicitly accounts for cloud chemistry and aerosol thermodynamics. The results have shown that the model largely captures the observed trends in SIA and its precursors’ concentrations while it underestimates the interannual variability. Using a source-apportionment module the amount of SIA formed per unit emission was traced for a number of regions. The results show 20–50 % more efficient SO4 2− formation in 2009 compared to 1990, whereas the change in NO3 − formation per unit NOx emission is lower (−10 % to +20 %) for the same time period.

There is a lack of real-time continuous beam-diagnostic tools for medical cyclotrons due to high power deposition during proton irradiation. To overcome this limitation, we have developed a profile monitor that is capable of providing continuous feedback about beam shape and current in real time while it is inserted in the beam path. This enables users to optimize the beam profile and observe fluctuations in the beam over time with periodic insertion of the monitor.

In this study the sensitivity of the model performance of the chemistry transport model (CTM) LOTOS-EUROS to the description of the temporal variability of emissions was investigated. Currently the temporal release of anthropogenic emissions is described by European average diurnal, weekly and seasonal time profiles per sector. These default time profiles largely neglect the variation of emission strength with activity patterns, region, species, emission process and meteorology. The three sources dealt with in this study are combustion in energy and transformation industries (SNAP1), non-industrial combustion (SNAP2) and road transport (SNAP7). First the impact of neglecting the temporal emission profiles for these SNAP categories on simulated concentrations was explored. In a~second step, we constructed more detailed emission time profiles for the three categories and quantified their impact on the model performance separately as well as combined. The performance in comparison to observations for Germany was quantified for the pollutants NO2, SO2 and PM10 and compared to a simulation using the default LOTOS-EUROS emission time profiles. In general the largest impact on the model performance was found when neglecting the default time profiles for the three categories. The daily average correlation coefficient for instance decreased by 0.04 (NO2), 0.11 (SO2) and 0.01 (PM10) at German urban background stations compared to the default simulation. A systematic increase of the correlation coefficient is found when using the new time profiles. The size of the increase depends on the source category, the component and station. Using national profiles for road transport showed important improvements of the explained variability over the weekdays as well as the diurnal cycle for NO2. The largest impact of the SNAP1 and 2 profiles were found for SO2. When using all new time profiles simultaneously in one simulation the daily average correlation coefficient increased by 0.05 (NO2), 0.07 (SO2) and 0.03 (PM10) at urban background stations in Germany. This exercise showed that to improve the performance of a CTM a better representation of the distribution of anthropogenic emission in time is recommendable. This can be done by developing a dynamical emission model which takes into account regional specific factors and meteorology.

Background Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. Conclusions This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Relationships between support staff and clients with intellectual disability (ID) are important for quality of care, especially when dealing with challenging behaviour. Building upon an interpersonal model, this study investigates the influence of client challenging behaviour, staff attitude and staff emotional intelligence on interactive behaviour of one of these relationship partners, being support staff.A total of 158 support staff members completed a questionnaire on staff interactive behaviour for 158 clients with ID and challenging behaviour, as well as two questionnaires on staff interpersonal attitude and emotional intelligence.Confronted with challenging behaviour as opposed to no challenging behaviour, staff reported less friendly, more assertive control and less support-seeking interpersonal behaviour. Also, staff used more proactive thinking and more self-reflection in dealing with challenging behaviour. Staff interpersonal attitude in general, mainly a harsh-dominant-resentful attitude, had a significant influence on most staff interactive behaviours towards an individual client with challenging behaviour. The influence of staff emotional intelligence, specifically intrapersonal abilities, on staff interactive behaviour towards an individual client with challenging behaviour was somewhat limited.This research supports the necessity for training staff in general interpersonal attitudes towards clients as well as training in intrapersonal emotional intelligence, when confronted with challenging behaviour. Future research should focus more on the bidirectional dynamics of staff and client interactions.

Item does not contain fulltext Sexually offensive behavior is prevalent among individuals with intellectual disabilities (ID) and many sex offenders also commit other offenses such as vandalism or assault. We examined the differences between sex offenders with ID and a history of combined sex and other types of offenses (mixed sex offenders) versus offenders with no history of sexual offenses (non-sex offenders). Dynamic client and environmental factors were measured using the Adult Behaviour Checklist (ABCL) and the Risk Inventarization Scale on Sexually Offensive Behavior of Clients with intellectual disabilities (RISC-V). Item, subscale, and total scores were then compared for the two groups. Most of the comparisons did not reveal significant differences between the two groups. The findings call for a general theory of offending behavior to explain the absence of differences between the mixed sex offenders and non-sex offenders with ID. 9 p.