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Backward Internal Erosion Piping, called piping in the Dutch context, is a dike failure mech­anism caused by a process by which seepage forces gradually erode cohesionless material from the foundation of dikes, thereby forming shallow pipes at the interface of the granular material and a co­hesive cover layer. One new innovative type of reinforcement measure to increase the resistance of a dike to the piping failure mechanism are filter solutions. These solutions work by blocking the soil particles in the seepage paths with an erosion-resistant permeable filter, preventing the formation of a full-grown pipe erosion channel. The purpose of an erosion-resistant filter is to prevent erosion while also enabling the discharge of seepage, unlike anti-piping heave screens, which do not enable seep­age of discharge. HDSR, a water authority with dikes, is implementing a new innovative filter screen solution as part of a pilot project. While HDSR as a water manager with dikes, is experienced with pip­ing as a failure mechanism, with implementing these innovative filter screens, there is no experience. In this research, a measuring & monitoring strategy for innovative anti-piping filter solutions is developed. A measurement and monitoring strategy should be able to provide insight into the continued functionality with regard to piping of the filter screen during the management life cycle. The research is requested by HDSR and is, therefore, the primary stakeholder of this research. The target group, in general, are water managers of dikes (to be) reinforced with an anti-piping filter screen. The research goal is to design a measurement & monitoring strategy to monitor the continued functionality of a filter as an anti-piping measure during the management life cycle phase of a dike.

Het schooljaar loopt stilaan op zijn einde en leerlingen gaan nu op zoek naar een stageplaats voor volgend schooljaar. Wat komt er allemaal bij kijken als je een stagiair op je bedrijf hebt?

The Data availability statement of this article has been modified to add the accession link to the raw data. The old Data availability statement read “Materials and data that support the findings of this research are available within the paper. All data are available from the corresponding author upon request”. This has been replaced by “Materials and data that support the findings of this research are available within the paper.

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Contains fulltext : 253637.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 253637.pdf (Publisher’s version ) (Open Access)

Objectives:Knowledge on long-term outcomes in patients with Hirschsprung disease is progressing. Nevertheless, differences in outcomes according to aganglionic lengths are unclear. We compared long-term bowel function and generic quality of life in Hirschsprung patients with total colonic or long-segment versus rectosigmoid aganglionosis.Methods:In this nationwide, cross-sectional study participants with proven Hirschsprung disease received the Defecation and Fecal Continence questionnaire, and the Child Health Questionnaire Child Form-87, or the WHO Quality of Life-100. We excluded deceased patients, patients who were younger than 8 years, lived abroad, had a permanent enterostomy, or were intellectually impaired.Results:The study population (n = 334) was operated for rectosigmoid (83.9%), long-segment (8.7%), or total colonic aganglionosis (7.5%). Fecal incontinence in general was not significantly different between the three groups, but liquid fecal incontinence was significantly associated with total colonic aganglionosis (odds ratio [OR] = 6.00, 95% confidence interval [CI] 2.07-17.38, P = 0.001). Regarding constipation, patients with total colonic or long-segment aganglionosis were less likely to suffer from constipation than the rectosigmoid group (OR = 0.21, 95% CI, 0.05-0.91, P = 0.038 and OR = 0.11, 95% CI, 0.01-0.83, P = 0.032). Quality of life was comparable between the three groups, except for a lower physical score in children with total colonic aganglionosis (P = 0.016).Conclusions:Over time Hirschsprung patients with total colonic or long-segment aganglionosis do not suffer from worse fecal incontinence in general. A difference in stool consistency may underlie the association between liquid fecal incontinence and total colonic aganglionosis and constipation in patients with rectosigmoid aganglionosis. Despite these differences, generic quality of life is comparable on reaching adulthood.

Introduction: Familial occurrence of Hirschsprung's disease may have a positive effect on patients' ability to cope with the disease. The aim was to compare long-term bowel function and generic quality of life between patients with familial and non-familial Hirschsprung's disease. Methods: This was a nationwide, cross-sectional study in which we included all 830 Hirschsprung patients of 8 years and older who had undergone surgery between 1957 and 2015. We excluded patients with a permanent stoma, intellectual disability, or an unknown or foreign address. We requested patients to complete the validated pediatric or adult Defecation and Fecal Continence questionnaire and the Child Health Questionnaire Child Form-87, or the World Health Organization Quality of Life-100 Assessment Instrument. Results: We analyzed 336 Hirschsprung patients, 15.8% of whom were familial cases and 84.2% were non-familial cases. After adjusting for aganglionic length, sex, and age, patients with familial Hirschsprung's disease were twice more likely to suffer from constipation (OR = 2.47, 95% CI, 1.21–5.05, p = 0.013). The quality of life of the pediatric patients was comparable, but in adult patients the energy/fatigue, thinking/learning/concentration, and work capacity facets showed better scores in the familial patients with Hirschsprung's disease of the rectosigmoid (p = 0.029, p = 0.024, p = 0.036, respectively). Conclusions: Different facets of generic quality of life are better in adult patients with familial Hirschsprung's disease of the rectosigmoid. It seems that familial experience with the disease influences patients' coping abilities positively.

Item does not contain fulltext, The increasing presence of genetic neurodevelopmental disorders (NDDs) results in greater demands for counseling. Many studies focus on the characteristics of patients, but less on family functioning. The aim of this study is to objectify parental stress and to study its relationship with child characteristics and environmental factors across several syndromes. 56 individuals with NDD participated: 24 with Kleefstra Syndrome, 13 with Koolen-de Vries Syndrome, and 19 with other rare (mono) genetic disorders. Parents were asked to complete the General Functioning subscale of the Family Assessment Device (FAD-GF), the Child Behavioral Checklist, and a questionnaire about demographic parental data. 25.5% of the families scored above the cut-off for pathological stress (>2.17). The mean FAD-GF score was 1.84. There was no significant difference between mean FAD-score of the subgroups (p=0,70). (Para)medical counselors should address this high amount of parental stress during counseling and consider these genetic syndromes as complex chronical illnesses.

Contains fulltext : 241691.pdf (Publisher’s version ) (Closed access), The increasing presence of genetic neurodevelopmental disorders (NDDs) results in greater demands for counseling. Many studies focus on the characteristics of patients, but less on family functioning. The aim of this study is to objectify parental stress and to study its relationship with child characteristics and environmental factors across several syndromes. 56 individuals with NDD participated: 24 with Kleefstra Syndrome, 13 with Koolen-de Vries Syndrome, and 19 with other rare (mono) genetic disorders. Parents were asked to complete the General Functioning subscale of the Family Assessment Device (FAD-GF), the Child Behavioral Checklist, and a questionnaire about demographic parental data. 25.5% of the families scored above the cut-off for pathological stress (>2.17). The mean FAD-GF score was 1.84. There was no significant difference between mean FAD-score of the subgroups (p=0,70). (Para)medical counselors should address this high amount of parental stress during counseling and consider these genetic syndromes as complex chronical illnesses.

Contains fulltext : 241691.pdf (Publisher’s version ) (Closed access), The increasing presence of genetic neurodevelopmental disorders (NDDs) results in greater demands for counseling. Many studies focus on the characteristics of patients, but less on family functioning. The aim of this study is to objectify parental stress and to study its relationship with child characteristics and environmental factors across several syndromes. 56 individuals with NDD participated: 24 with Kleefstra Syndrome, 13 with Koolen-de Vries Syndrome, and 19 with other rare (mono) genetic disorders. Parents were asked to complete the General Functioning subscale of the Family Assessment Device (FAD-GF), the Child Behavioral Checklist, and a questionnaire about demographic parental data. 25.5% of the families scored above the cut-off for pathological stress (>2.17). The mean FAD-GF score was 1.84. There was no significant difference between mean FAD-score of the subgroups (p=0,70). (Para)medical counselors should address this high amount of parental stress during counseling and consider these genetic syndromes as complex chronical illnesses.

Contains fulltext : 221392.pdf (publisher's version ) (Open Access), Witteveen-Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch-insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive-compulsive behaviors, as well as Attention-Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10-23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social-emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions.

Strong spin–orbit semiconductor nanowires coupled to a superconductor are predicted to host Majorana zero modes. Exchange (braiding) operations of Majorana modes form the logical gates of a topological quantum computer and require a network of nanowires. Here, we utilize an in-plane selective area growth technique for InSb–Al semiconductor–superconductor nanowire networks. Transport channels, free from extended defects, in InSb nanowire networks are realized on insulating, but heavily mismatched InP (111)B substrates by full relaxation of the lattice mismatch at the nanowire/substrate interface and nucleation of a complete network from a single nucleation site by optimizing the surface diffusion length of the adatoms. Essential quantum transport phenomena for topological quantum computing are demonstrated in these structures including phase-coherence lengths exceeding several micrometers with Aharonov–Bohm oscillations up to five harmonics and a hard superconducting gap accompanied by 2e-periodic Coulomb oscillations with an Al-based Cooper pair island integrated in the nanowire network.

Contains fulltext : 221392.pdf (publisher's version ) (Open Access), Witteveen-Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch-insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive-compulsive behaviors, as well as Attention-Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10-23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social-emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions.

Contains fulltext : 221392.pdf (publisher's version ) (Open Access), Witteveen-Kolk syndrome (WITKOS) is a rare neurodevelopmental disorder characterized by developmental delay/intellectual disability, facial dysmorphisms, and short stature. The syndrome is caused by loss of function of switch-insensitive 3 transcription regulator family member A (SIN3A). Regarding behavioral functioning, Autism Spectrum Disorders (ASD), obsessive-compulsive behaviors, as well as Attention-Deficit/Hyperactivity Disorder symptoms (ADHD) have been suggested. The present study explores various aspects of neurocognitive functioning in five individuals (age range 10-23) with WITKOS. Medical records and results of extensive neuropsychological assessment are used to describe developmental trajectories and neurocognitive profiles. Systematic analysis of medical records displays developmental difficulties described as ASD or ADHD in childhood, sleep problems and internalizing problems during adolescence. Results of cognitive assessments indicate profoundly disabled (n = 1), mildly disabled (n = 2), borderline (n = 1), and average (n = 1) levels of intelligence. Furthermore, results indicate weaknesses in speed of information processing/sustained attention in all participants, and difficulties in planning and maintaining overview in three participants. Furthermore, parent reports of behavioral functioning primarily suggest problems in social functioning. Implications of both cognitive problems and social-emotional vulnerabilities for counseling are discussed and supplemented with suggestions for interventions.

Strong spin–orbit semiconductor nanowires coupled to a superconductor are predicted to host Majorana zero modes. Exchange (braiding) operations of Majorana modes form the logical gates of a topological quantum computer and require a network of nanowires. Here, we utilize an in-plane selective area growth technique for InSb–Al semiconductor–superconductor nanowire networks. Transport channels, free from extended defects, in InSb nanowire networks are realized on insulating, but heavily mismatched InP (111)B substrates by full relaxation of the lattice mismatch at the nanowire/substrate interface and nucleation of a complete network from a single nucleation site by optimizing the surface diffusion length of the adatoms. Essential quantum transport phenomena for topological quantum computing are demonstrated in these structures including phase-coherence lengths exceeding several micrometers with Aharonov–Bohm oscillations up to five harmonics and a hard superconducting gap accompanied by 2e-periodic Coulomb oscillations with an Al-based Cooper pair island integrated in the nanowire network.

Contains fulltext : 202749.pdf (publisher's version ) (Open Access), KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 genetic patients with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen’s d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning, that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.

Molecular diagnostics have an increasing impact on diagnosis, risk stratification and targeted treatment in haemato-oncology. In the framework of a pilot study for the implementation of next-generation sequencing in the Belgian healthcare system, the Commission of Personalised Medicine was founded to give professional and evidence-based advice on the molecular analysis in haemato-oncology. This paper describes its recommendations for NGS analysis in myeloid malignancies. In addition, the minimally required set of genes that must be analysed is defined and algorithms for molecular workflow in myeloid malignancies are proposed.

Contains fulltext : 202749.pdf (publisher's version ) (Open Access), KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 genetic patients with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen’s d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning, that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.

Background Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. Aim: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. Methods: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. Results: The overall theme of this study was found to be Not getting worse. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. Conclusion Not getting worse was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Background Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. Aim: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. Methods: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. Results: The overall theme of this study was found to be Not getting worse. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. Conclusion Not getting worse was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Contains fulltext : 199705.pdf (publisher's version ) (Open Access), Objective: Specific knowledge on neurocognitive functioning in (syndrome based) intellectual disability (ID) is important for the assessment, treatment and support of patients in whom this condition is present. The present study investigates the applicability of computerized neurocognitive testing in patients with rare monogenetic ID disorders by (1) determining the developmental age at which the use is contributive and (2) investigating the specificity of the tests for neurocognitive functions, independent of the ID. Method: A total of 56 patients with monogenetic ID disorders, including Kleefstra Syndrome (KS; n = 24), and a contrast group of various rare disorders (n = 32) participated. Assessments included (a) the Vineland Adaptive Behavior Scale (VABS) interview to calculate developmental age and (b) four simplified subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). A cut-off in developmental age was estimated based on the ability to complete the CANTAB-tasks. A developmental age of 2,5 years and older allows practical application in our cohort. Results: There was no significant correlation between developmental age and results on cognitive tests (range: -0,171 <=rho <= 0,336 with p-values > 0,07). A between-group comparison shows a larger dropout in the KS sub cohort (based on cross tabulation) and longer latencies on the motor screening test. Conclusions: Our results indicate that simplified CANTAB tasks are suitable for application in the ID population to unravel individual neurocognitive characteristics and, hence also, syndrome specific neurocognitive features. Furthermore, successful employment of computerized testing in this complex population may be the only way to avoid the restraints of standard classificatory clinical procedures that aim at categories of patients rather than at the individual patient with its unique cognitive neuropsychiatric complexion.

Radboud University, 05 oktober 2018, Promotores : Egger, J.I.M., Bokhoven, J.H.L.M. van, Staal, W.G. Co-promotor : Kleefstra, T., Contains fulltext : 195502.pdf (publisher's version ) (Open Access)

Contains fulltext : 182339.pdf (publisher's version ) (Open Access), Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism.

Contains fulltext : 199705.pdf (publisher's version ) (Open Access), Objective: Specific knowledge on neurocognitive functioning in (syndrome based) intellectual disability (ID) is important for the assessment, treatment and support of patients in whom this condition is present. The present study investigates the applicability of computerized neurocognitive testing in patients with rare monogenetic ID disorders by (1) determining the developmental age at which the use is contributive and (2) investigating the specificity of the tests for neurocognitive functions, independent of the ID. Method: A total of 56 patients with monogenetic ID disorders, including Kleefstra Syndrome (KS; n = 24), and a contrast group of various rare disorders (n = 32) participated. Assessments included (a) the Vineland Adaptive Behavior Scale (VABS) interview to calculate developmental age and (b) four simplified subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). A cut-off in developmental age was estimated based on the ability to complete the CANTAB-tasks. A developmental age of 2,5 years and older allows practical application in our cohort. Results: There was no significant correlation between developmental age and results on cognitive tests (range: -0,171 <=rho <= 0,336 with p-values > 0,07). A between-group comparison shows a larger dropout in the KS sub cohort (based on cross tabulation) and longer latencies on the motor screening test. Conclusions: Our results indicate that simplified CANTAB tasks are suitable for application in the ID population to unravel individual neurocognitive characteristics and, hence also, syndrome specific neurocognitive features. Furthermore, successful employment of computerized testing in this complex population may be the only way to avoid the restraints of standard classificatory clinical procedures that aim at categories of patients rather than at the individual patient with its unique cognitive neuropsychiatric complexion.

Radboud University, 05 oktober 2018, Promotores : Egger, J.I.M., Bokhoven, J.H.L.M. van, Staal, W.G. Co-promotor : Kleefstra, T., Contains fulltext : 195502.pdf (publisher's version ) (Open Access)

Contains fulltext : 182339.pdf (publisher's version ) (Open Access), Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism.

Contains fulltext : 182339.pdf (publisher's version ) (Open Access), Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism.

Contains fulltext : 199705.pdf (publisher's version ) (Open Access), Objective: Specific knowledge on neurocognitive functioning in (syndrome based) intellectual disability (ID) is important for the assessment, treatment and support of patients in whom this condition is present. The present study investigates the applicability of computerized neurocognitive testing in patients with rare monogenetic ID disorders by (1) determining the developmental age at which the use is contributive and (2) investigating the specificity of the tests for neurocognitive functions, independent of the ID. Method: A total of 56 patients with monogenetic ID disorders, including Kleefstra Syndrome (KS; n = 24), and a contrast group of various rare disorders (n = 32) participated. Assessments included (a) the Vineland Adaptive Behavior Scale (VABS) interview to calculate developmental age and (b) four simplified subtests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). A cut-off in developmental age was estimated based on the ability to complete the CANTAB-tasks. A developmental age of 2,5 years and older allows practical application in our cohort. Results: There was no significant correlation between developmental age and results on cognitive tests (range: -0,171 <=rho <= 0,336 with p-values > 0,07). A between-group comparison shows a larger dropout in the KS sub cohort (based on cross tabulation) and longer latencies on the motor screening test. Conclusions: Our results indicate that simplified CANTAB tasks are suitable for application in the ID population to unravel individual neurocognitive characteristics and, hence also, syndrome specific neurocognitive features. Furthermore, successful employment of computerized testing in this complex population may be the only way to avoid the restraints of standard classificatory clinical procedures that aim at categories of patients rather than at the individual patient with its unique cognitive neuropsychiatric complexion.

Background Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. Aim: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. Methods: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. Results: The overall theme of this study was found to be Not getting worse. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. Conclusion Not getting worse was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Background Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. Aim: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. Methods: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. Results: The overall theme of this study was found to be Not getting worse. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. Conclusion Not getting worse was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Objectives. Health-related quality of life (HR-QoL) of patients with heart failure (HF) is low despite the aim of HF treatment to improve HR-QoL. To date, most studies have focused on medical and physical factors in relation to HR-QoL, few data are available on the role of emotional factors such as dispositional optimism. This study examines the prevalence of optimism and pessimism in HF patients and investigates how optimism and pessimism are associated with different patient characteristics and HR-QoL. Methods. Dispositional optimism was assessed in 86 HF patients (mean age 70 +/- 9 years, 28% female, mean left ventricular ejection fraction 33%) with the Revised Life Orientation Test (LOT-R). HR-QoL was assessed with the Minnesota Living with Heart Failure Questionnaire and the EuroQol. Results. The (mean +/- SD) total score on the LOT-R was 14.6 +/- 2.9 (theoretical range 0-24) and the scores on the subscales optimism and pessimism were 8.1 +/- 1.9 and 5.5 +/- 2.5, respectively. Higher age was related to more optimism (r = 0.22, p amp;lt; 0.05), and optimism was associated with higher generic HR-QoL (B = 0.04, p amp;lt; 0.05). Significance of results. The association found between optimism and generic HR-QoL of HF patients can lead to promising strategies to improve HF patients HR-QoL, particularly because the literature has indicated that optimism is a modifiable condition., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Background Knowledge of patient reported outcomes helps to provide personalized care on a patient level, optimize care on a population level, and identify the most appropriate patient reported outcomes for clinical trials. To be able to provide personalized care to patients with HF, it is important to know which treatment goals patients with HF consider the most important. This is particularly useful for interventions aimed at improving symptoms, functional status, or health-related quality of life. Aim: The aim of this study was (1) to explore which treatment goals patients with heart failure (HF) perceive as important for their treatment and (2) to identify which treatment goals take priority over other treatment goals. Methods: The study had a qualitative design and included one focus group interview with 6 patients with HF. Data were analyzed using qualitative content analysis. Results: The overall theme of this study was found to be Not getting worse. This theme was composed of 4 categories that described how the patients perceived the goals of treatment: to decrease symptoms, to improve physical function, to prevent readmission, and to live a normal life. None of the participants mentioned improved survival or being cured of their HF as a treatment goal. Conclusion Not getting worse was perceived as the treatment goal that matters to patients with HF and is in line with currently used endpoints for the evaluation of a treatment in a clinical trial. More research is necessary to develop endpoints that are consistent with the perception of patients, useful for clinical practice, and measurable., Funding Agencies|Dutch Ministry of Health, Welfare, and Sport

Contains fulltext : 175699.pdf (publisher's version ) (Closed access), Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning.

Contains fulltext : 173921.pdf (publisher's version ) (Closed access), Last December, Dr. Havdahl et al. highlighted the use of autism spectrum disorder (ASD) symptom measurements in specific groups in their article "Multidimensional Influences on Autism Symptom Measures: Implications for Use in Etiological Research". This is an important and timely topic, because public attention is currently tuned to the increasing prevalence of ASD. Dr. Havdahl et al. carefully mapped which of the tested instruments was most sensitive to detect actual ASD symptoms and to distinguish these from other typical comorbid neurodevelopmental disorders, such as intellectual disability (ID) and attention-deficit/hyperactivity disorder.

Contains fulltext : 173890.pdf (publisher's version ) (Closed access), Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.

Contains fulltext : 176488.pdf (publisher's version ) (Open Access)

Contains fulltext : 175699.pdf (publisher's version ) (Closed access), Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning.

Contains fulltext : 173921.pdf (publisher's version ) (Closed access), Last December, Dr. Havdahl et al. highlighted the use of autism spectrum disorder (ASD) symptom measurements in specific groups in their article "Multidimensional Influences on Autism Symptom Measures: Implications for Use in Etiological Research". This is an important and timely topic, because public attention is currently tuned to the increasing prevalence of ASD. Dr. Havdahl et al. carefully mapped which of the tested instruments was most sensitive to detect actual ASD symptoms and to distinguish these from other typical comorbid neurodevelopmental disorders, such as intellectual disability (ID) and attention-deficit/hyperactivity disorder.

Contains fulltext : 173890.pdf (publisher's version ) (Closed access), Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.

Contains fulltext : 176488.pdf (publisher's version ) (Open Access)

Contains fulltext : 173921.pdf (publisher's version ) (Closed access), Last December, Dr. Havdahl et al. highlighted the use of autism spectrum disorder (ASD) symptom measurements in specific groups in their article "Multidimensional Influences on Autism Symptom Measures: Implications for Use in Etiological Research". This is an important and timely topic, because public attention is currently tuned to the increasing prevalence of ASD. Dr. Havdahl et al. carefully mapped which of the tested instruments was most sensitive to detect actual ASD symptoms and to distinguish these from other typical comorbid neurodevelopmental disorders, such as intellectual disability (ID) and attention-deficit/hyperactivity disorder.

Contains fulltext : 173890.pdf (publisher's version ) (Closed access), Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.

Contains fulltext : 176488.pdf (publisher's version ) (Open Access)

Contains fulltext : 175699.pdf (publisher's version ) (Closed access), Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning.