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Contains fulltext : 137892.pdf (publisher's version ) (Open Access), PURPOSE: General practitioners are increasingly called upon to deliver genetic services and could play a key role in translating potentially life-saving advancements in oncogenetic technologies to patient care. If general practitioners are to make an effective contribution in this area, their genetics competencies need to be upgraded. The aim of this study was to investigate whether oncogenetics training for general practitioners improves their genetic consultation skills. METHODS: In this pragmatic, blinded, randomized controlled trial, the intervention consisted of a 4-h training (December 2011 and April 2012), covering oncogenetic consultation skills (family history, familial risk assessment, and efficient referral), attitude (medical ethical issues), and clinical knowledge required in primary-care consultations. Outcomes were measured using observation checklists by unannounced standardized patients and self-reported questionnaires. RESULTS: Of 88 randomized general practitioners who initially agreed to participate, 56 completed all measurements. Key consultation skills significantly and substantially improved; regression coefficients after intervention were equivalent to 0.34 and 0.28 at 3-month follow-up, indicating a moderate effect size. Satisfaction and perceived applicability of newly learned skills were highly scored. CONCLUSION: The general practitioner-specific training proved to be a feasible, satisfactory, and clinically applicable method to improve oncogenetics consultation skills and could be used as an educational framework to inform future training activities with the ultimate aim of improving medical care.

Contains fulltext : 136897.pdf (publisher's version ) (Open Access), Medical professionals are increasingly expected to deliver genetic services in daily patient care. However, genetics education is considered to be suboptimal and in urgent need of revision and innovation. We designed a Genetics e-learning Continuing Professional Development (CPD) module aimed at improving general practitioners' (GPs') knowledge about oncogenetics, and we conducted a randomized controlled trial to evaluate the outcomes at the first two levels of the Kirkpatrick framework (satisfaction, learning and behavior). Between September 2011 and March 2012, a parallel-group, pre- and post-retention (6-month follow-up) controlled group intervention trial was conducted, with repeated measurements using validated questionnaires. Eighty Dutch GP volunteers were randomly assigned to the intervention or the control group. Satisfaction with the module was high, with the three item's scores in the range 4.1-4.3 (5-point scale) and a global score of 7.9 (10-point scale). Knowledge gains post test and at retention test were 0.055 (P<0.05) and 0.079 (P<0.01), respectively, with moderate effect sizes (0.27 and 0.31, respectively). The participants appreciated applicability in daily practice of knowledge aspects (item scores 3.3-3.8, five-point scale), but scores on self-reported identification of disease, referral to a specialist and knowledge about the possibilities/limitations of genetic testing were near neutral (2.7-2.8, five-point scale). The Genetics e-learning CPD module proved to be a feasible, satisfactory and clinically applicable method to improve oncogenetics knowledge. The educational effects can inform further development of online genetics modules aimed at improving physicians' genetics knowledge and could potentially be relevant internationally and across a wider range of potential audiences.

Non-invasive prenatal testing (NIPT) and its potential to test for multiple disorders has received much attention. This study explores attitudes of women and men towards NIPT, and their views on widening the scope of prenatal testing in a country with a low uptake of prenatal screening (The Netherlands). Five focus groups with low-risk pregnant women (n=28), three focus groups with men (n=19) and 13 interviews with high- and low-risk pregnant women were conducted. Participants felt that current prenatal screening has great disadvantages such as uncertain results and risk of miscarriage from follow-up diagnostics. Characteristics of NIPT (accurate, safe and early testing) could therefore diminish these disadvantages of prenatal screening and help lower the barrier for participation. This suggests that NIPT might allow couples to decide about prenatal testing based mostly on their will to test or not, rather than largely based on fear of miscarriage risk or the uncertainty of results. The lower barrier for participation was also seen as a downside that could lead to uncritical use or pressure to test. Widening the scope of prenatal testing was seen as beneficial for severe disorders, although it was perceived difficult to determine where to draw the line. Participants argued that there should be a limit to the scope of NIPT, avoiding testing for minor abnormalities. The findings suggest that NIPT could enable more meaningful decision-making for prenatal screening. However, to ensure voluntary participation, especially when testing for multiple disorders, safeguards on the basis of informed decision-making will be of utmost importance.European Journal of Human Genetics advance online publication, 19 March 2014; doi:10.1038/ejhg.2014.32.

Item does not contain fulltext, High-throughput nucleotide sequencing (often referred to as next-generation sequencing; NGS) is increasingly being chosen as a diagnostic tool for cases of expected but unresolved genetic origin. When exploring a higher number of genetic variants, there is a higher chance of detecting unsolicited findings. The consequential increased need for decisions on disclosure of these unsolicited findings poses a challenge for the informed consent procedure. This article discusses the ethical and practical dilemmas encountered when contemplating informed consent for NGS in diagnostics from a multidisciplinary point of view. By exploring recent similar experiences with unsolicited findings in other settings, an attempt is made to describe what can be learned so far for implementing NGS in standard genetic diagnostics. The article concludes with a set of points to consider in order to guide decision-making on the extent of return of results in relation to the mode of informed consent. We hereby aim to provide a sound basis for developing guidelines for optimizing the informed consent procedure.

Contains fulltext : 119058.pdf (publisher's version ) (Open Access), BACKGROUND: The Netherlands does not have a national haemoglobinopathy (HbP)-carrier screening programme aimed at facilitating informed reproductive choice. HbP-carrier testing for those at risk is at best offered on the basis of anaemia. Registration of ethnicity has proved controversial and may complicate the introduction of a screening programme if based on ethnicity. However, other factors may also play a role. OBJECTIVE: To explore perceived barriers and attitudes among GPs and midwives regarding the registration of ethnicity and ethnicity-based HbP-carrier screening. METHODS: Six focus groups in Dutch primary care, with a total of 37 GPs (n = 9) and midwives (n = 28) were conducted, transcribed and content analysed using Atlas-ti. RESULTS: Both GPs and midwives struggled with correctly identifying ethnicities at risk for HbP. Ethical concerns regarding privacy seemed to originate from World War II experiences, when ethnic and religious registration facilitated deportation of Jewish citizens, coupled with the political climate at the time focus groups were held. Some respondents thought the ethnicity question might undermine the relationship with their clients. Software programmes prevented GPs from registering ethnicity of patients at risk. Financial implications for patients were also a concern. Despite this, respondents seemed positive about screening and were familiar with identifying ethnicity and used this for individual patient care. CONCLUSIONS: Although health professionals are generally positive about screening, ethical, financial and practical issues surrounding ethnicity-based HbP-carrier screening need to be clarified before introducing such a programme. Primary care professionals can be targeted through professional organizations but they need national policy support.

Contains fulltext : 110225.pdf (publisher's version ) (Open Access), Haemoglobinopathies (HbP) are severe autosomal recessive disorders with high prevalence among certain ethnic groups. World Health Organisation (WHO) advises implementing screening programmes for risk groups. Research in the Netherlands has shown that general practitioners and midwives do not perceive ethnicity as a risk factor for HbP. Moreover, registration of ethnicity is a controversial societal issue, which may complicate the introduction of a national preconception or antenatal carrier screening programme. This study investigates attitudes, intention and behaviour of general practitioners and midwives towards ethnicity-based HbP-carrier screening in general. A structured questionnaire based on the Theory of Planned Behaviour was sent by mail to a random selection of 2100 general practitioners and 1800 primary care midwives. Response was 35% (midwives 44.2%; GPs 27.6%). Although 45% of respondents thought that offering a carrier test on the basis of ethnicity alone should become national policy, it is currently not carried out. The main factor explaining lack of intention towards ethnicity-based HbP-carrier screening was subjective norm, the perception that their peers do not think they should offer screening (52.2% variance explained). If ethnicity-based HbP-carrier screening would become national policy, most professionals report that they would carry this out. Most respondents favoured ethnicity registration for health purposes. As most practitioners look for role models among peers, debate among general practitioners and midwives should be encouraged when new policy is to be developed, articulating the voices of colleagues who already actively offer HbP-carrier screening. Moreover, primary care professionals and professional organisations need support of policy at national level.

Radboud Universiteit Nijmegen, 14 november 2012, Promotores : Lagro-Janssen, A.L.M., Cornel, M.C Co-promotores : Jonge, A. de, Henneman, L., Contains fulltext : 100609.pdf (publisher's version ) (Open Access)

Background: The prevalence of obesity and overweight is highest among ethnic minority groups in Western countries. The objective of this study is to examine the contribution of ethnicity and beliefs of parents about overweight preventive behaviours to their childs outdoor play and snack intake, and to the parents intention to monitor these behaviours. Methods. A cross-sectional survey was conducted among parents of native Dutch children and children from a large minority population (Turks) at primary schools, sampled from Youth Health Care registers. Results: Native Dutch parents observed more outdoor play and lower snack intake in their child and had stronger intentions to monitor these behaviours than parents of Turkish descent. In the multivariate analyses, the parents attitude and social norm were the main contributing factors to the parental intention to monitor the childs outdoor play and snack intake. Parental perceived behavioural control contributed to the childs outdoor play and, in parents who perceived their child to be overweight, to snacking behaviour. The associations between parents behavioural cognitions and overweight related preventive behaviours were not modified by ethnicity, except for perceived social norm. The relationship between social norm and intention to monitor outdoor play was stronger in Dutch parents than in Turkish parents. Conclusions

Objective: We investigated the accuracy of self-reported family history for diabetes, hypertension, and overweight against two reference standards: family history based on physician-assessed health status of relatives and on self-reported personal health status of relatives. Study Design and Setting: Subjects were participants from the Erasmus Rucphen Family study, an extended family study among descendants of 20 couples who lived between 1850 and 1900 in a southwest region of the Netherlands and their relatives (n = 1,713). Sensitivity and specificity of self-reported family history were calculated. Results: Sensitivity of self-reported family history was 89.2% for diabetes, 92.2% for hypertension, and 78.4% for overweight when family history based on relatives' self-reported personal health status was used as reference and 70.8% for diabetes, 67.4% for hypertension, and 77.3% for overweight when physician-assessed health status of relatives was used. Sensitivity and specificity of self-reported personal health status were 76.8% and 98.8% for diabetes, 38.9% and 98.0% for hypertension, and 80.9% and 75.7% for overweight, respectively. Conclusion: The accuracy of self-reported family history of diabetes and hypertension is strongly influenced by the accuracy of self-reported personal health status of relatives. Raising awareness of personal health status is crucial to ensure the utility of family history for the assessment of risk and disease prevention. © 2012 Elsevier Inc. All rights reserved.

Contains fulltext : 109674.pdf (publisher's version ) (Closed access), TRPM7 encodes a Ca(2+)-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II-based cellular tension, thereby modifying focal adhesion number, cell-cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. Cancer Res; 72(16); 4250-61. (c)2012 AACR.

Recently, a number of commercial companies are offering preconceptional carrier tests directly-to-consumers. This offer raises a number of concerns and issues above and beyond those encountered with preconceptional tests offered within the traditional health care setting. In order to bring some of these issues to light and to initiate dialogue on this topic, this article discusses the following issues: the current offer of preconceptional carrier tests (until the end of 2010) through online commercial companies; the implications for the informed consent procedure and the need for good information; the need for medical supervision and follow-up; and the appropriate use of existing resources. The article concludes with some reflections about the potential sustainability of the offer of preconceptional carrier tests directly-to-consumers., Borry, Pascal Henneman, Lidewij Lakeman, Phillis ten Kate, Leo P Cornel, Martina C Howard, Heidi C eng Research Support, Non-U.S. Gov't England 2011/03/03 06:00 Hum Reprod. 2011 May;26(5):972-7. doi: 10.1093/humrep/der042. Epub 2011 Feb 28.

Contains fulltext : 96953.pdf (publisher's version ) (Open Access), BACKGROUND: Available evidence suggests that improvements in genetics education are needed to prepare primary care providers for the impact of ongoing rapid advances in genomics. Postgraduate (physician training) and master (midwifery training) programmes in primary care and public health are failing to meet these perceived educational needs. The aim of this study was to explore the role of genetics in primary care (i.e. family medicine and midwifery care) and the need for education in this area as perceived by primary care providers, patient advocacy groups and clinical genetics professionals. METHODS: Forty-four participants took part in three types of focus groups: mono-disciplinary groups of general practitioners and midwives, respectively and multidisciplinary groups composed of a diverse set of experts. The focus group sessions were audio-taped, transcribed verbatim and analysed using content analysis. Recurrent themes were identified. RESULTS: Four themes emerged regarding the educational needs and the role of genetics in primary care: (1) genetics knowledge, (2) family history, (3) ethical dilemmas and psychosocial effects in relation to genetics and (4) insight into the organisation and role of clinical genetics services. These themes reflect a shift in the role of genetics in primary care with implications for education. Although all focus group participants acknowledged the importance of genetics education, general practitioners felt this need more urgently than midwives and more strongly emphasized their perceived knowledge deficiencies. CONCLUSION: The responsibilities of primary care providers with regard to genetics require further study. The results of this study will help to develop effective genetics education strategies to improve primary care providers' competencies in this area. More research into the educational priorities in genetics is needed to design courses that are suitable for postgraduate and master programmes for general practitioners

Background. A family history, reflecting genetic susceptibility as well as shared environmental and behavioral factors, is an important risk factor for common chronic multifactorial diseases such as cardiovascular diseases, type 2 diabetes and many cancers. Discussion. The purpose of the present paper is to discuss the evidence for the use of family history as a tool for primary prevention of common chronic diseases, in particular for tailored interventions aimed at promoting healthy lifestyles. The following questions are addressed: (1) What is the value of family history information as a determinant of personal disease risk?; (2)How can family history information be used to motivate at-risk individuals to adopt and maintain healthy lifestyles in order to prevent disease?; and (3) What additional studies are needed to assess the potential value of family history information as a tool to promote a healthy lifestyle?. Summary. In addition to risk assessment, family history information can be used to personalize health messages, which are potentially more effective in promoting healthy lifestyles than standardized health messages. More research is needed on the evidence for the effectiveness of such a tool.

Background: The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only.Methods/Design: This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis.Discussion: This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compa

BACKGROUND: A family history, reflecting genetic susceptibility as well as shared environmental and behavioral factors, is an important risk factor for common chronic multifactorial diseases such as cardiovascular diseases, type 2 diabetes and many cancers. DISCUSSION: The purpose of the present paper is to discuss the evidence for the use of family history as a tool for primary prevention of common chronic diseases, in particular for tailored interventions aimed at promoting healthy lifestyles. The following questions are addressed: (1) What is the value of family history information as a determinant of personal disease risk?; (2)How can family history information be used to motivate at-risk individuals to adopt and maintain healthy lifestyles in order to prevent disease?; and (3) What additional studies are needed to assess the potential value of family history information as a tool to promote a healthy lifestyle? SUMMARY: In addition to risk assessment, family history information can be used to personalize health messages, which are potentially more effective in promoting healthy lifestyles than standardized health messages. More research is needed on the evidence for the effectiveness of such a tool.

Contains fulltext : 57426.pdf (publisher's version ) (Open Access), The aim of this study was to assess the attitudes and intentions of individuals planning a pregnancy with regard to preconceptional cystic fibrosis (CF) carrier screening and to determine factors associated with a positive and negative/neutral intention to have the test. A survey, based on a questionnaire, was conducted among a stratified random sample of 303 recently married couples (606 individuals). Of the eligible individuals, 70% (n = 380) participated. Of the respondents, 73% had a positive attitude toward a routine offer of preconceptional CF carrier screening, and 56% had the intention to participate in a screening program. A positive intention to have the test was associated with high perceived anticipation of regret, intended preconceptional behavior, high perceived pressure from experts, high perceived consequences of the test results, low perceived barriers, and low perceived negative consequences for family members. These results suggest that the offer of routine preconceptional CF carrier screening would lead to substantial acceptance among couples planning a pregnancy. Several variables related with intention were identified.

Item does not contain fulltext, OBJECTIVE: This qualitative study aimed to explore possibilities and barriers in the implementation of a nationwide preconceptional cystic fibrosis (CF) carrier screening programme. METHODS: Sessions were held with two focus groups of CF patients and CF relatives, one focus group of people from the target population (couples planning a pregnancy), and two focus groups of potential providers (general practitioners (GPs) and municipal health service workers). RESULTS: Important barriers in the implementation of a preconceptional CF carrier screening programme included the problem of reaching the target population, the heavy workload of GPs, the limited public knowledge about CF in general, and the absence of a preconceptional consultation setting. In general, there was a positive attitude among the participants towards CF carrier screening. CONCLUSION: This study revealed some important barriers in the implementation of CF carrier screening programmes. More research is needed to specify and quantify the importance of the various barriers. Eventually, different intervention strategies should be included in an implementation plan to overcome the most important barriers in the organization and execution of screening.

Department of Biochemistry, Maastricht University, The Netherlands. jwm.heemskerk@bioch.unimaas.nl In single platelets and in suspensions of platelets, alpha-thrombin evokes dose-dependent, transient increases in cytosolic Ca2+ concentration, [Ca2+]i, which are more prolonged than the [Ca2+]i transients evoked by other platelet agonists such as the thrombin-receptor-activating hexapeptide SFLLRN, thromboxane A2 analog U46619, and ADP. As a quantity taking into account both the magnitude and length of the Ca2+ response, we defined the Ca2+-mobilizing potency (CMP) of an agonist as the integrated rise in [Ca2+]i during the time of the Ca2+ signal. It was observed that: (a) the CMP increased with the agonist concentration in a saturating way, its maximal value being about four-times higher with alpha-thrombin than with SFLLRN; (b) the high CMP of alpha-thrombin was for only a small part due to endogenous production of ADP or thromboxane, and was mainly a consequence of prolonged influx of external Ca2+; (c) the CMP declined when alpha-thrombin was inactivated during the course of the Ca2+ signal; (d) CMP values increased with the agonist concentration upon sequential addition of increasing amounts of alpha-thrombin or SFLLRN; (e) when alpha-thrombin was gradually added to the platelets or formed by an in situ reconstituted prothrombinase system (with factor Xa, factor Va, and prothrombin), integrated Ca2+ responses were a function of the product of the alpha-thrombin concentration and the time of its presence. However, in these cases, the final CMP values were independent of the rate of alpha-thrombin addition or formation. We conclude that alpha-thrombin-induced Ca2+ signals in platelets rely largely upon Ca2+ influx, are not, or only slightly, subjected to homologous desensitization, and reflect the enzymatic capacity of alpha-thrombin to cleave protease-activated receptors. Thus, the high and prolonged Ca2+ signal induced by alpha-thrombin is due to continu