Measuring the Autistic Women's Experience (AWE).

We developed a Dutch questionnaire called the Autistic Women's Experience (AWE) and compared its psychometric properties to the Autism Spectrum Quotient (AQ). Whilst attenuated gender differences on the AQ have been widely replicated, this instrument may not fully capture the unique experience of autistic women. The AWE was co-developed with autistic women to include items that reflect autistic women's experience. We investigated the AWE (49 items) and compared it with the AQ (50 items) in Dutch autistic individuals (N = 153, n = 85 women) and in the general population (N = 489, n = 246 women) aged 16+. Both the AQ and AWE had excellent internal consistency and were highly and equally predictive of autism in both women and men. Whilst there was a gender difference on the AQ among non-autistic people (men > women), there was no gender difference among autistic people, confirming all earlier studies. No gender differences were detected on the AWE overall scale, yet subtle gender differences were observed on the subscales. We conclude that the AQ is valid for both genders, but the AWE provides an additional useful perspective on the characteristics of autistic women. The AWE needs further validation in independent samples using techniques that allow for testing gender biases, as well as a confirmatory factor analysis in a larger sample.

Perspectives on Autism Spectrum Disorder Diagnosis, Symptoms, Treatment and Gender Roles: A Qualitative Study of Similarities and Differences between Sexes.

This study aims to compare the experiences of women and men of different age groups with regard to their first autism spectrum disorder (ASD) diagnosis, symptoms, treatment, and gender roles to inform our understanding in clinical practice of differences as well as similarities. Semi-structured interviews were conducted amongst 22 women (n = 12) and men (n = 10) in three adult age groups regarding their diagnostic process, symptoms, treatment, and gender roles. Participants also filled out questionnaires on gender traits, social support, coping, and quality of life. Framework analysis guidelines were followed to identify subthemes within the three pre-defined key themes of the semi-structured interviews, and quantitative analyses were performed on the questionnaire results. Women often had caregiver roles and were more focused on social and family-oriented life aspects than men. Family and societal expectations may have been different for women from an early age onward and were considered burdensome by some, but not all. Views on ASD diagnosis, symptoms, and treatment were largely individually determined. The questionnaire results mostly showed no significant sex differences. Perceived gender roles differed between participants. In diagnosis and treatment, awareness of general gender differences and gender roles is important, but inter-individual differences and similar experiences in men should not be overlooked.

Clinical stance on response initiation in autistic adults: co-creating an integrative approach based on theory and lived experiences to act from language, via motor movement to wellbeing.

Getting 'stuck', literally and figuratively, is a common experience for autistic people. Literally 'stuck' means exhibiting limited response initiation due to immobility with tense muscles and inability to move. Figuratively 'stuck' means loneliness, passivity or captivity in activities that do not offer long-term satisfaction. To further conceptualize this complex phenomenon of limited response initiation in autistic individuals, we performed qualitative interviews and focus groups with autistic people and their family members, followed by brainstorm sessions and a Delphi study with input from a larger panel of experts from multiple backgrounds. We aimed to co-create the outline of an integrative approach to support autistic people in moving away from this 'stuck state' to more flexible, limber 'supple states' in order to live freer, more meaningful, satisfying and peaceful lives. Over time, in interaction with all participants, our shared insight grew. Based on this, we here stipulate a conceptual framework, in which the described 'stuck state' at the micro-level of the muscles/behavior of one individual, probably is caused by feeling/being 'stuck' or 'cramped' at several overarching (i.e., meso and macro) levels. For instance, stuck in relationships with unhealthy dynamics, stuck at home creating short-term calm, trance-like states (e.g., gaming), stuck at an educational level that might fit the individuals' current social-emotional state rather than their potential cognitive level, stuck in a job that pays the bills but does not feel meaningful, nor contributes to a satisfying life with opportunities for personal development. Stuck in a mental/public health care system where ever ongoing changes in policies hinder sustained support to suit care-needs. Stuck in a regulated societal system making it likely to repeatedly get stuck. Is this phenomenon specific to autism? Formally we have only conducted interviews with this population, but in another smaller, related project we also spoke to people from the general population with careers that are considered successful in the general society. These people actually voiced similar experiences. Therefore, we hypothesize that this numbing state of being or feeling 'stuck' may be a prevalent phenomenon that needs to be addressed. In this article, we discuss several types of interventive approaches (i.e., language-based talking therapies, affective experiential expressive therapies, physical therapies and systemic therapies), prevention as well as intervention programs, directed at different primary stakeholders, that can complement and enrich each other in an integrative policy, that leads to tailor-made, personalized trajectories of interdisciplinary support to enable people to live satisfying, meaningful, dignified and peaceful lives.

Development, behaviour and autism in individuals with SMC1A variants.

INTRODUCTION: Development and behaviour in Cornelia de Lange Syndrome (CdLS), including autism characteristics, have been described infrequently stratified to genetic cause and only a few studies have considered behavioural characteristics in relation to developmental level. Here, we describe the behavioural phenotype in individuals with CdLS with SMC1A variants. METHODS: We performed an international, interdisciplinary study on 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome and with Autism Spectrum Disorder. Results on cognition and self-injurious behaviour (SIB) are compared to those in individuals with CdLS caused by NIPBL variants. For Dutch participants with SMC1A variants we performed direct in-person assessments of cognition, autism, and added an interview and questionnaire on adaptive behaviour and sensory processing. RESULTS: Individuals with SMC1A variants show a higher cognitive level and less SIB than individuals with NIPBL variants. Individuals with SMC1A variants without classic CdLS phenotype but with a Rett-like phenotype show more severe intellectual disability and more SIB compared to those with a CdLS phenotype. Autism is less present if outcomes in direct in-person assessments are evaluated taking developmental level into account compared to results based on a questionnaire. CONCLUSIONS: Behaviour in individuals with CdLS should be evaluated taking genetic cause into account. Detailed interdisciplinary approaches are of clinical importance to inform tailored care and may eventually improve quality of life of patients and families.

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Self-injurious behavior.

Self-injurious behavior (SIB) is a relatively common behavior in individuals with intellectual disabilities (ID). Severe SIB can be devastating and potentially life-threatening. There is increasing attention for somatic substrates of behavior in genetic syndromes, and growing evidence of an association between pain and discomfort with SIB in people with ID and genetic syndromes. In this review on SIB phenomenology in people with ID in general and in twelve genetic syndromes, we summarize different SIB characteristics across these etiologically distinct entities and identify influencing factors. We demonstrate that the prevalence of SIB in several well-known genetic intellectual disability syndromes is noticeably higher than in individuals with ID in general, and that characteristics such as age of onset and topographies differ widely across syndromes. Each syndrome is caused by a mutation in a different gene, and this allows detection of several pathways that lead to SIB. Studying these with the behavioral consequences as specific aim will be an important step toward targeted early interventions and prevention.

Phenotypes and genotypes in individuals with SMC1A variants.

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

Behaviour in Cornelia de Lange syndrome: a systematic review.

AIM: Careful study and accurate description of behaviour are important to understand developmental challenges for individuals with Cornelia de Lange syndrome (CdLS). Here we present a systematic review of current understanding of behaviour in CdLS. METHOD: A systematic search was performed for articles published between January 1946 and December 2015 evaluating autism, self-injury, and/or cognition in CdLS. After study-selection, 43 papers were included. The Cochrane quality criteria were adjusted to assign quality scores to the included studies. RESULTS: Participants were mostly categorized in the severe/profound developmental level. Methodology and quality were very heterogeneous, as well as reporting occurrence of autism. Self-injurious behaviour was reported in 15 papers. Physical conditions were reported in 21 studies, mostly related to hearing and vision. Only nine studies mentioned details about medication. INTERPRETATION: Comparison of presented results was hindered by heterogeneous assessment methods. Improving our understanding of behavioural characteristics in CdLS requires more uniform methodology. We propose a criterion standard of instruments that can ideally be used in assessment of behaviour and development. This will improve understanding of behaviour in the context of developmental level and daily functioning.

The Additional Value of an E-Mail to Inform Healthcare Professionals of a Drug Safety Issue: A Randomized Controlled Trial in the Netherlands.

BACKGROUND: The usefulness and the impact of Direct Healthcare Professional Communications (DHPCs, or 'Dear Doctor letters') in changing the clinical behaviour of physicians have been debated. Changes in the current risk communication methods should preferably be based on the preferences of the healthcare professionals, to optimize the uptake of the message. OBJECTIVE: The aim of this study was to assess whether safety issues are communicated more effectively with an additional e-mail sent by the Dutch Medicines Evaluation Board (MEB) than with the DHPC only. METHODS: A randomized controlled trial was conducted amongst ophthalmologists and hospital pharmacists in the Netherlands, who were the target group of a DHPC that was issued for pegaptanib, a drug that is administered intra-ocularly in patients with macular degeneration. The intervention group (N = 110) received the pegaptanib DHPC, as well as the MEB e-mail. The control group (N = 105) received the traditional paper-based DHPC only. Two weeks later, the study population received an invitation to fill out an online questionnaire. Questions were asked about the respondents' knowledge and attitude regarding the pegaptanib issue, and any action they had consequently taken. Additional questions were asked about their satisfaction with the DHPC and the e-mail, and their preferred source of such information. RESULTS: Forty respondents (18.6%) completed the questionnaire. Eighty-one percent of the respondents in the intervention group (N = 21) and 47% of the control group (N = 19) correctly indicated that a serious increase in intra-ocular pressure could be caused by pegaptanib injections (Fishers' exact test, p = 0.046). Nine respondents in the intervention group versus none of the control group respondents indicated that they had taken action in response to the pegaptanib safety issue (Fishers' exact test, p = 0.01). The majority of both the intervention group and the control group confirmed that they would like to receive an MEB e-mail with safety information about drugs in the future (90 and 95 %, respectively). CONCLUSION: The results of this study indicate that an additional e-mail might strengthen the uptake of the safety information provided to healthcare professionals, who prefer to receive an e-mail from the MEB as a source of such information, as well as the DHPC. This study may serve as a starting point for new strategies to improve risk communication regarding safety issues associated with drugs and its impact on prescribing.

Healthcare professionals' self-reported experiences and preferences related to direct healthcare professional communications: a survey conducted in the Netherlands.

BACKGROUND: In Europe, Direct Healthcare Professional Communications (DHPCs) are important tools to inform healthcare professionals of serious, new drug safety issues. However, this tool has not always been successful in effectively communicating the desired actions to healthcare professionals. OBJECTIVE: The aim of this study was to explore healthcare providers' experiences and their preferences for improvement of risk communication, comparing views of general practitioners (GPs), internists, community pharmacists and hospital pharmacists. METHODS: A questionnaire was developed and pilot tested to assess experiences and preferences of Dutch healthcare professionals with DHPCs. The questionnaire and two reminders were sent to a random sample of 3488 GPs, internists and community and hospital pharmacists in the Netherlands. Descriptive statistics were used to describe demographic characteristics of the respondents. Chi squares, ANOVAs and the Wilcoxon signed rank test were used, when appropriate, to compare healthcare professional groups. RESULTS: The overall response rate was 34% (N = 1141, ranging from 24% for internists to 46% for community pharmacists). Healthcare providers trusted safety information more when provided by the Dutch Medicines Evaluation Board (MEB) than by the pharmaceutical industry. This was more the case for GPs than for the other healthcare professionals. Respondents preferred safety information to be issued by the MEB, the Dutch Pharmacovigilance Center or their own professional associations. The preferred alternative channels of drug safety information were e-mail, medical journals and electronic prescribing systems. CONCLUSIONS: Safety information of drugs does not always reach healthcare professionals through DHPCs. To improve current risk communication of drug safety issues, alternative and/or additional methods of risk communication should be developed using electronic methods and medical journals. Moreover, (additional) risk communication coming from an independent source such as the MEB should be considered. Special effort is needed to reach GPs.

Impact of safety-related regulatory action on clinical practice: a systematic review.

BACKGROUND: After market approval, new serious safety issues are regularly identified for drugs that lead to regulatory action to inform healthcare professionals. However, the effectiveness of these safety-related regulatory actions is under question. We currently lack a comprehensive overview of the effects of these drug safety warnings on clinical practice to resolve the debate about their effectiveness. OBJECTIVE: The aim of this systematic review is to provide an overview of studies that assessed the impact of safety warnings. STUDY SELECTION: A systematic search was performed for articles assessing the impact of Direct Healthcare Professional Communications or 'Dear Doctor' letters, Black Box Warnings and Public Health Advisories on clinical behaviour published between January 1996 and January 2010. The following variables were extracted: publication year, country, name of the drug, safety issue, specific safety warning (Direct Healthcare Professional Communication/Black Box Warning/Public Health Advisory), effect (intended/unintended) of the safety warning, outcome measure and study design. Papers were checked for several quality aspects. Study data were summarized using descriptive analyses. RESULTS: A total of 50 articles were identified. Two articles assessed two different drugs and were therefore counted twice (n = 52). Thirty-three articles described the impact of safety warnings issued for three drugs and drug groups, i.e. third-generation oral contraceptives, cisapride and selective serotonin reuptake inhibitors. The remaining 19 articles described a broad variety of 14 drugs and drug groups. Twenty-five studies applied an interrupted time series design, 23 a controlled or uncontrolled before/after design, and four articles applied both. None of the articles could rule out the influence of confounding factors. The intended effects were reported in 18 (72%) of the 25 before/after analyses, whereas only 11 (41%) of the 27 interrupted time series analyses reported an impact. Only two (8%) of the before/after analyses against 11 (41%) of the interrupted time series analyses reported mixed impacts. When unintended effects were assessed in case of selective serotonin reuptake inhibitors and third-generation oral contraceptives, these were almost always present: in 19 of 22 and 4 of 5 articles, respectively. Our review shows that safety-related regulatory action can have some impact on clinical practice but firm conclusions are difficult to draw. Evidence is primarily based on three drugs and drug groups. Almost half of the studies had inadequate before/after designs and the heterogeneity in analyses and outcome measures hampered the reporting of overall effect sizes. Studies with adequate interrupted time series design reported a more mixed impact of safety warnings than before/after studies. Furthermore, this review shows the relevance of considering not only the intended but also the unintended effects of safety warnings. CONCLUSIONS: There is a clear need for further research with appropriate study designs and statistical analyses, with more attention to confounding factors such as media coverage, to understand the impact of safety-related regulatory action.

A decade of safety-related regulatory action in the Netherlands: a retrospective analysis of direct healthcare professional communications from 1999 to 2009.

BACKGROUND: As pre-approval trials are inherently limited in assessing the complete benefit-risk profile of a new drug, serious safety issues may emerge once a drug gains widespread use after approval. Regulators face the dilemma of balancing timely market access with the need for complete data on risks. This challenge has led to a life-cycle approach but, so far, few data are available on post-approval safety issues requiring regulatory action. OBJECTIVE: The aim of this study is to determine the frequency, timing and nature of safety issues that necessitated safety-related regulatory action in the form of a Direct Healthcare Professional Communication (DHPC) issued by pharmaceutical companies in collaboration with the Dutch Medicines Evaluation Board during the past decade. METHODS: All DHPCs issued in the Netherlands from 1 January 1999 to 1 January 2009 were retrospectively collected from the national regulatory authorities. Elapsed time between the approval date and the issue of the DHPC was determined. Characteristics of the action including the nature of the safety issue (according to Medical Dictionary for Regulatory Activities [MedDRA] terminology), type of drug and procedural aspects of the regulatory action taken were reviewed. DHPC characteristics were tabulated and explorative non-parametric tests were performed to study the effect of safety issue, drug class, drug type, orphan drug and first-in-class status on elapsed time from approval to the DHPC. RESULTS: 157 DHPCs were issued concerning 112 different active substances, approximately 9% (112/1200) of active substances available in the Netherlands in 2007. The number of DHPCs issued increased by 2.1 (95% CI 1.2, 3.1; p < 0.001) DHPCs per year over the past decade, reaching a total of 25 in 2008. The median time between approval and DHPC was 5.3 years (range 0.13-48 years). No significant trend in elapsed time to DHPC was observed in relation to the studied years (p = 0.06). One-third of all DHPCs were issued in the first 3 years after approval, but 27% (n = 43/157) of the DHPCs were issued 10 or more years after approval. Timing of DHPCs differed depending on safety issue, drug class, drug type and orphan drug status. DHPCs mostly concerned adverse events in the system organ class of 'cardiac disorders' (15%), 'injury, poisoning and procedural complications' (13%) and 'general disorders and administration site conditions' (10%). In ten cases the drug was eventually withdrawn. Withdrawal occurred a median duration of 2.4 years after registration (range of 1.5-48 years) and was most frequently due to cardiac disorders (including QT interval prolongation; four occasions) and hepatobiliary disorders (two occasions). CONCLUSIONS: In the past decade, the number of DHPCs has increased over time. This is likely caused by a multitude of factors: increased risk awareness by the public, media, regulators and other stakeholders; the type of drugs approved, such as orphan drugs and biologicals; and the regulatory process, including conditional approvals. The number of DHPCs may in the future increase further with the possibility of screening large epidemiological databases proactively for adverse drug events. Nine percent of all marketed drugs required a safety-related action. Regulatory action is taken shortly (<3 years) after market approval nearly as often as after intermediate (3-10 years) and long-term (>10 years) market exposure. These findings underline the need for risk management during the whole life cycle of a drug.