Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring

Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across three to five chromosomes. Two mothers did not show any phenotypic abnormalities, although 3-13 protein-coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy-number changes in two children. This resulted in gene-dosage changes, which are probably responsible for the severe congenital phenotypes of these two children. In contrast, the third child, who has a severe congenital disease, harbored all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy-number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein-coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals affects reproduction and is expected to substantially increase the risk of miscarriages, abortions, and severe congenital disease. © 2015 The American Society of Human Genetics

Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

Shared Decision Making in women testing for a BRCA 1/2 mutation.

Women with a BRCA1/2 mutation have a high genetic risk of developing breast and ovarian cancer. They face the difficult choice between screening and prophylactic surgery for the breasts and ovaries. We have developed a shared decision making program to prepare these women for decision making. The shared decision making program consisted of two decision aids. The decision aids have been developed as adjuncts to standard genetic counselling and were evaluated in a randomized trial. The study included both women affected and unaffected with cancer testing for a BRCA1/2 mutation. The first decision aid consisted of a brochure and video providing information on screening and prophylactic surgery and their consequences. It was provided either before or after the DNA-test result. This decision aid had no impact on well-being neither on decision related outcomes. Beneficial effects were found on information related outcomes. These effects occurred irrespective whether the decision aid was presented before or after the DNA-test result. No interaction effect was found between the DA and the personal history of cancer. The second decision aid consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality adjusted) life expectancy derived form a decision model. This decision aid only had an effect on the long term (9 months after the test result). Women reported less intrusive thoughts about cancer, a better general health, and tended to be less depressed. Furthermore, the SDMI strengthened treatment preferences and increased the feeling of having weighed the pros and cons. A differential impact was found in women affected with cancer versus unaffected women. Unaffected women benefited from this decision aid, while affected women tended to experience detrimental effects. The effects of the two decision aids are complementary. Thus, preferably, the complete support package should be offered

Shared Decision Making in women testing for a BRCA 1/2 mutation.

Contains fulltext : 19591_shardemai.pdf (publisher's version ) (Open Access)Women with a BRCA1/2 mutation have a high genetic risk of developing breast and ovarian cancer. They face the difficult choice between screening and prophylactic surgery for the breasts and ovaries. We have developed a shared decision making program to prepare these women for decision making. The shared decision making program consisted of two decision aids. The decision aids have been developed as adjuncts to standard genetic counselling and were evaluated in a randomized trial. The study included both women affected and unaffected with cancer testing for a BRCA1/2 mutation. The first decision aid consisted of a brochure and video providing information on screening and prophylactic surgery and their consequences. It was provided either before or after the DNA-test result. This decision aid had no impact on well-being neither on decision related outcomes. Beneficial effects were found on information related outcomes. These effects occurred irrespective whether the decision aid was presented before or after the DNA-test result. No interaction effect was found between the DA and the personal history of cancer. The second decision aid consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality adjusted) life expectancy derived form a decision model. This decision aid only had an effect on the long term (9 months after the test result). Women reported less intrusive thoughts about cancer, a better general health, and tended to be less depressed. Furthermore, the SDMI strengthened treatment preferences and increased the feeling of having weighed the pros and cons. A differential impact was found in women affected with cancer versus unaffected women. Unaffected women benefited from this decision aid, while affected women tended to experience detrimental effects. The effects of the two decision aids are complementary. Thus, preferably, the complete support package should be offered.KUN Katholieke Universiteit Nijmegen, 21 februari 2005Promotor : Daal, W.A.J. van Co-promotores : Stalmeier, P.F.M., Verhoef, C.G.141 p

Concise evaluation of decision aids.

Contains fulltext : 81420.pdf (publisher's version ) (Closed access)OBJECTIVE: Decision aids purport to help patients make treatment related choices. Several instruments exist to evaluate decision aids. Our aim is to compare the responsiveness of several instruments. METHODS: Two different decision aids were randomized in patients at high risk for breast and ovarian cancer. Treatment choices were between prophylactic surgery and screening. Effect sizes were calculated to compare the responsiveness of the measures. RESULTS: One decision aid was randomized in 390 women, the other in 91 ensuing mutation carriers. Three factors were identified related to Information, Well-being and Decision Making. Within each factor, single item measures were as responsive as multi-item measures. CONCLUSION: Four single items, 'the amount of information received for decision making,' 'strength of preference,' 'I weighed the pros and cons,' and 'General Health,' were adequately responsive to the decision aids. PRACTICE IMPLICATIONS: These items might be considered for inclusion in questionnaires to evaluate decision aids

Decision making regarding prophylactic mastectomy: stability of preferences and the impact of anticipated feelings of regret.

Item does not contain fulltextPURPOSE: Women who test positive for a BRCA1/2 mutation face difficult choices to manage their breast cancer risk; one of these choices is whether to opt for prophylactic mastectomy. Few data are available about this decision-making process. The current study provides data regarding the stability of risk-management preferences over time and the factors that are associated with these preferences. PATIENTS AND METHODS: We analyzed data from 338 women who opted for breast cancer antigen (BRCA) testing. First, we prospectively assessed preferences of 80 BRCA mutation carriers at five different points in time ranging from 1 week after blood sampling up to 9 months after BRCA-test disclosure. Second, we applied univariate and multivariate regression analyses to examine which medical, sociodemographic, and psychological factors are related to a preference for prophylactic mastectomy. RESULTS: Ninety percent of the women already indicated a preference regarding risk management at baseline. Moreover, most women had stable preferences over time. Furthermore, anticipated feelings of regret in case of a hypothetical breast cancer diagnosis in the near future were strongly related to risk-management preference (odds ratio = 8.93; P < .0001). CONCLUSION: Women seem to decide at a relatively early stage about their risk-management preferences. Many of them may be sensitive to the possibility of regret in case of a bad outcome. We discuss whether possible regret in the future is a rational reason for opting for prophylactic mastectomy, or whether it signifies an emotional coping process or strategy in which the future costs are no longer fully considered

De kwaliteit van het medisch handelen in de huisartspraktijk: Een literatuuroverzicht over 1997-2001.

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Randomized trial of a shared decision-making intervention consisting of trade-offs and individualized treatment information for BRCA1/2 mutation carriers.

Contains fulltext : 57884.pdf (publisher's version ) (Open Access)PURPOSE: To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries. PATIENTS AND METHODS: The SDMI consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality-adjusted) life expectancy. After the baseline assessment (2 weeks after a positive DNA test result), women were randomly assigned to the SDMI group (n = 44), receiving the SDMI 2 months after the test result, or to the control group (n = 44). The short- and long-term effects, 3 and 9 months after the test result, were assessed using questionnaires. Data were collected on well-being, treatment choice, and decision-related outcomes. RESULTS: In the short term, the SDMI had no effect. In the long term, with respect to well-being, patients in the SDMI group had less intrusive thoughts (P =.05) and better general health (P =.01) and tended to be less depressed (P =.07). With respect to decision-related outcomes for the breasts, the SDMI group held stronger preferences (P =.02) and agreed more strongly to having weighed the pros and cons (P =.01). No effect was found on treatment choice. In the long term, interaction effects between the SDMI and cancer history were found. The SDMI showed an overall beneficial effect for unaffected women, whereas affected women tended to experience detrimental effects. CONCLUSION: We conclude that the SDMI improved decision making in unaffected BRCA1/2 mutation carriers. Supporting decision making in a systematic way using trade-offs is beneficial for these women

Validity of willingness-to-pay for nondecisional diagnostic information

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Patient participation in discussing palliative radiotherapy.

Item does not contain fulltextCancer patients' participation in doctor-patient interactions has been shown to be an important factor in the emotional processing of their condition, particularly when only palliative treatments can be offered. In this study, we assessed incurable cancer patients' participation in initial consultations with their radiation oncologists (ROs). RO stimulation of patient participation and discussions about treatment decisions were also measured. The entire consultation was videotaped and analyzed using the Roter Interaction Analysis System (RIAS). Patients' participation proved to be low on medical information, but high on discussing their experiences and life circumstances. The ROs stimulated patient participation mainly by providing medical information and giving patients opportunities to tell their stories. Decisions about radiation treatment had previously taken place and were rarely discussed in the consultations studied. The results suggest that patient participation in palliative treatment consultations might be improved for facilitating patients' emotional processing of the incurable nature of their cancer