STXBP1 -associated neurodevelopmental disorder: a comparative study of behavioural characteristics

Abstract: Background: De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. Methods: To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). Results: The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. Conclusions: De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families

Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study

Funder: Baily Thomas Charitable Fund; doi: http://dx.doi.org/10.13039/501100001262Abstract: Background: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. Methods: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. Results: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. Limitations: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. Conclusion: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful

Tangible Data Souvenirs as a Bridge between a Physical Museum Visit and Online Digital Experience

This paper presents the design, implementation, use and evaluation of a tangible data souvenir for an interactive museum exhibition. We define a data souvenir as the materialisation of the personal visiting experience: a data souvenir is dynamically created on the basis of data recorded throughout the visit and therefore captures and represents the experience as lived. The souvenir provides visitors with a memento of their visit and acts as a gateway to further online content. A step further is to enable visitors to contribute, in other words the data souvenir can become a means to collect visitor-generated content. We discuss the rationale behind the use of a data souvenir, the design process and resulting artefacts, and the implementation of both the data souvenir and online content system. Finally we examine the installation of the data souvenirs as part of a long-lasting exhibition: the use of this souvenir by visitors has been logged over seven months and issues around the gathering of user-generated content in such a way are discussed. Keywords: Tangible interaction; data souvenir; museums; user-generated content

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Social and emotional characteristics of girls and young women with DDX3X-associated intellectual disability: a descriptive and comparative study

Acknowledgements: We sincerely thank the study participants, their families, and carers for their dedication and time in contributing to this study. We are grateful to the DDX3X Support UK group, the Deciphering Developmental Disorders (DDD) study, the IMAGINE-ID study, UK regional genetic centres, diagnostic laboratories, and referring clinicians for enabling us to publicise this study to the families who have taken part.DDX3X variants are a common cause of intellectual disability (ID) in females, and have been associated with autism spectrum disorder and emotional-behavioural difficulties. In this study, we compared phenotypic data for 23 females with DDX3X variants, to 23 females with ID and other genetic diagnoses. We found a wide range of adaptive, social and emotional function within the DDX3X group. Autism characteristics did not differ between DDX3X and comparison groups, while levels of anxiety and self-injurious behaviour (SIB) were significantly higher in the DDX3X group. Within the DDX3X group, adaptive function, autism characteristics, anxiety and SIB scores were positively correlated, with evidence for group-specific associations with SIB. Future work is warranted to explore the multilevel mechanisms contributing to social and emotional development in individuals with DDX3X variants

Cost-Efficient and Easy to Perform PCR-Based Assay to Identify Met Exon 14 Skipping in Formalin-Fixed Paraffin-Embedded (FFPE) Non-Small Cell Lung Cancer (NSCLC) Samples

MET is a receptor tyrosine kinase (RTK) that plays important roles in carcinogenesis. Despite being frequently overexpressed in cancer, clinical responses to targeting this receptor have been limited. Recently novel splicing mutations involving the loss of exon 14 (called METex14 skipping) have emerged as potential biomarkers to predict for responsiveness to targeted therapies with Met inhibitors in non-small cell lung cancer (NSCLC). Currently, the diverse genomic alterations responsible for METex14 skipping pose a challenge for routine clinical diagnostic testing. In this report, we examine three different methodologies to detect METex14 and assess their potential utility for use as a diagnostic assay for both the identification of METex14 and intra-tumoural distribution in NSCLC

Mortality rates and proximal causes of death in patients with Lewy body dementia versus Alzheimer's disease: A longitudinal study using secondary care mental health records

Funder: Cambridge Centre for Parkinson’s Plus disordersFunder: NIHR Cambridge Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100018956Funder: UK Alzheimer’s SocietyFunder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265Background: Previous studies have shown reduced survival in Lewy body dementia (LBD) compared to Alzheimer’s disease (AD), but the reasons for this are not known. We identified cause of death categories accounting for the reduced survival in LBD. Methods: We linked cohorts of patients with dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD) and AD, with proximal cause of death data. We examined mortality by dementia group and hazard ratios for each death category by dementia group in males and females separately. In a specific focus on the dementia group with the highest mortality rate versus reference, we examined cumulative incidence to identify the main causes of death accounting for the excess deaths. Results: Hazard ratios for death were higher in PDD and DLB compared to AD, for both males and females. PDD males had the highest hazard ratio for death across the dementia comparison groups (HR 2.7, 95% CI 2.2–3.3). Compared with AD, hazard ratios for “nervous system” causes of death were significantly elevated in all LBD groups. Additional significant cause‐of‐death categories included aspiration pneumonia, genitourinary causes, other respiratory causes, circulatory and a “symptoms and signs” category in PDD males; other respiratory causes in DLB males; mental disorders in PDD females; and aspiration pneumonia, genitourinary and other respiratory causes in DLB females. Conclusion: Further research and cohort development is required to investigate differences by age group, to extend cohort follow‐up to the whole population and to investigate the risk‐balance of interventions which may differ by dementia group

STROBE diagram showing construction of the cohorts.

DLB, dementia with Lewy bodies; AChEIs, acetylcholinesterase inhibitors; LBD, Lewy body disease; DLB, dementia with Lewy body; CPFT, Cambridgeshire and Peterborough NHS Foundation Trust; ICD-10, World Health Organization International Statistical Classification of Diseases and Related Health Problems, 10th revision.</p

Strengthening the reporting of observational studies in epidemiology (STROBE) checklist.

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Patient characteristics at baseline.

Patient characteristics at baseline.</p