Search

Lay Abstract: Autistic youth participate less in physical education classes and organised sport than their neurotypical peers. We conducted a review of existing studies to investigate what is known about what motivates (and does not motivate) autistic youth to take part in structured physical activities. We systematically searched electronic databases and found 18 publications that met the criteria to be included in this review. Data from these studies were extracted and mapped to the self-determination theory to identify factors that support (or undermine) motivation for autistic youth. We also discussed the findings with autistic individuals and other relevant stakeholders to discover how the review related to their experiences. Our results found competence (youth feeling competent in their athletic and social skills and abilities) to be the most reported psychological need impacting motivation for autistic youth. Intrinsic motivation (participating for enjoyment and satisfaction) was the most common facilitator of motivation. Autism-specific themes outside of the self-determination theory were mapped inductively, and we found that the sensory environment was a prominent theme reported to influence the motivation of autistic youth not covered by the self-determination theory. The findings of this review suggest that supporting the psychological needs of autistic youth can foster motivation to engage in physical activity, although how these needs are met can differ from their neurotypical peers. Future research should examine motivational factors that support engagement in structured physical activities through the lens of autistic youth and their experiences., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To conduct the first revision of the World Health Organization International Classification of Functioning, Disability and Health (ICF) Core Sets for attention-deficit/hyperactivity disorder (ADHD)., Method: A Delphi-like method was used, integrating evidence from stakeholder feedback and developing and piloting the ADHD ICF Core Set platform to inform revisions to the ADHD Core Sets., Results: A total of 27 second-level ICF codes were added to the comprehensive ADHD Core Set: body functions of temperament and personality, and basic sensory functions; activities and participation in terms of learning to read and write, spoken communication, community life, religion and spirituality, education, economy, and human rights; environmental factors for domestic animals; and several societal services. The revised comprehensive Core Set contains 98 ICF codes: 18 body function codes; 47 activities and participation codes; and 33 environmental factor codes. Extensive changes were also made to the age-appropriate brief Core Sets to allow their independent use in research and clinical practice., Interpretation: Although substantially expanded, the revised ICF Core Sets better reflect the lived experience of individuals with ADHD and clinical implementation preferences than the initial sets. We recommend further feasibility and validation studies of these Core Sets with the goal of optimizing their acceptance and practicability, and strengthening their evidence base., (© 2024 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Lay Abstract: Autistic people experience individual strengths and challenges as well as barriers and facilitators in their environment. All of these factors contribute to how well autistic people can cope in everyday life, fulfill the roles they choose, and meet their needs. The World Health Organization has developed a system aiming to capture the many factors within people (like how someone thinks and feels) and outside of people (things around a person) that influence their daily living, called the International Classification of Functioning, Disability and Health. The International Classification of Functioning, Disability and Health can be used for different purposes in research and practice to assess people's situations and plan support measures. Previously in 2019, the International Classification of Functioning, Disability and Health was adapted to autism by developing so-called Core Sets, which are shorter International Classification of Functioning, Disability and Health versions for use in specific conditions. Here, we present the first revisions of the International Classification of Functioning, Disability and Health Core Sets for autism, based on research, development results, and community feedback. Some factors influencing daily life for autistic people were added to the Core Sets, and other factors deemed less relevant were removed. Changes were also made in Core Sets designed for different age groups (0-5, 6-16, and ⩾17 years). Particularly, contents for sensory processing (like smell, touch, seeing, hearing) were added. We recommend these updated Core Sets for future use in autism research and practice. These changes to the Core Sets after 4 years indicate that there should be ongoing updates based on research and experience from practice and involvement of stakeholders., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.B. discloses that he has in the last 3 years acted as an author, consultant, or lecturer for Medice and Linus Bio. He receives royalties for textbooks and diagnostic tools from Hogrefe, Liber, Ernst Reinhardt, Kohlhammer, and UTB. He is a partner in NeuroSupportSolutions. P.B.M. receives royalties for textbooks from Elsevier, Springer, Mac Keith Press, and Thieme. The other authors have no conflicts of interest to report.

Lay Abstract: The International Classification of Functioning, Disability, and Health (ICF) is a framework designed by the World Health Organization (WHO) to help different sectors, such as healthcare, social services, education, and policy, understand how people with health-related issues function (do the things they want to and need to do) in their daily lives. This framework has also been used to guide clinical practice and research in autism and attention-deficit hyperactivity disorder (ADHD). To make it more practical, shorter versions of the ICF called Core Sets have been developed. We wanted to explore how the ICF and the ICF Core Sets have been used in research relating to autism and ADHD. We looked at the research that had been previously published on this topic by conducting a systematic search and review. Seventy-eight studies meeting our criteria were included in our review. Results show that the ICF has been applied in many ways across various contexts. However, most of the research has focused on autism, mainly involving children. The review highlights that although the ICF was used in some studies, the underlying philosophies of the framework were not always followed. The medical perspective still influenced the way research was done and interpreted. Nevertheless, using the ICF in the right way can help shift research on neurodevelopmental conditions like autism and ADHD toward a more holistic approach, moving away from solely focusing on medical aspects., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors report no conflict of interest related to the work presented. Sven Bölte discloses that he has in the last 3 years acted as an author, consultant, or lecturer for Medice and LinusBio. He receives royalties from Hogrefe, UTB, Ernst Reinhardt, Kohlhammer, and Liber. Bölte is a partner in NeuroSupportSolutions International.

Neurodivergent individuals, including a range of conditions impacting neurological function, are at an increased likelihood of poor life outcomes, such as in functional adaptation, mental health, and well-being. Yet, many live meaningful and fulfilling lives. Resilience may provide some explanation for the heterogeneity in outcomes observed in neurodivergent populations. We conducted a scoping review embedded in a neurodiversity-affirmative approach to provide an understanding of resilience in neurodivergent populations. A total of 176 articles were included in this review and were synthesized using a two-phased process. First, findings were synthesized narratively to examine how resilience has been conceptualized and explored in neurodivergent populations. Second, to identify the bio-psycho-social factors important for resilience in neurodivergent individuals, we converted concepts identified in articles to the nomenclature of the World Health Organizations' International Classification of Functioning, Disability and Health (ICF) using a standardized linking process. We find considerable variability in how resilience is conceptualized and measured in neurodivergent populations. We identified 83 unique ICF categories representing resilience factors, of which only 20 appeared in more than 5% of the articles. Identified ICF categories highlight the importance of support systems such as families and friends, community participation and acceptance, and individual capabilities for resilience., Competing Interests: Declaration of competing interest Sven Bölte discloses that he has in the last 3 years acted as an author, consultant or lecturer for Medice and LinusBio. He receives royalties for textbooks, diagnostic and intervention tools from Hogrefe, Kohlhammer, Ernst Reinhardt and Liber and UTB. Bölte is a partner in NeuroSupportSolutions International. Vincent Grimaldi discloses that he is a partner in Nextperience, a consulting firm., (Copyright © 2024. Published by Elsevier Ltd.)

Recent studies have reported that strengths-based programs, leveraging autistic adolescents' abilities and interests, could improve their skills and facilitate social engagement. However, little is known about the long-term impact of strengths-based approaches. This study aimed to explore the long-term outcomes of community strengths-based programs designed to support autistic adolescents in developing interests and skills in Science, Technology, Engineering, Arts, and Mathematics (STEAM) and the factors influencing their participation in these programs. A repeated cross-sectional survey study over three years recruited 52 parents in 2018, 52 parents in 2019, and 38 parents in 2020. Results highlighted the positive impact of these programs on autistic adolescents' health and well-being, social relationships and interactions, self-confidence and self-esteem, sense of belonging, and activities and participation. Five key elements influencing participation included the enthusiasm of the participants, their self-perception, the approach of the programs, the learning environment, and the attitudes of the mentors. This study implies that strengths-based approaches to intervention and support for autistic adolescents in a supported environment are a social model solution that could potentially have positive participant outcomes. Findings from this study could provide a framework underpinning future strengths-based interventions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autistic adults commonly experience anxiety and worry, although knowledge on how worry presents and the content, extent, and experiences among autistic adults is limited. A convergent parallel mixed-methods approach was used to explore the presentation and experiences of worry in autistic and non-autistic adults. Quantitative surveys were used to compare the content and extent of worry in autistic adults to non-autistic adults, with semi-structured interviews also conducted with autistic adults to gain a deeper understanding of the experiences, impacts and content of worry in autistic adults. Findings indicated that autistic adults demonstrated clinically significant levels of worry which were substantially higher than non-autistic adults. Autistic adults described worry as a cycle of negative thoughts impacting their daily life. Findings indicate that autistic adults may worry more than non-autistic adults, impacting on participation in activities of daily living, sleep, and mental health., (© 2023. The Author(s).)

A systematic review and meta-analysis were utilised to explore the methodological quality, program fidelity, and efficacy of social skills group programs (SSGPs) aiming to support autistic adolescents in navigating their everyday social worlds. The study evaluated the methodological quality and theoretical fidelity of studies, with a random effect meta-analysis conducted to summarise the overall efficacy of SSGP and its effect on social communication and interaction, behavioural/emotional challenges, adaptive functioning, and autism characteristics. Although findings from the 18 identified studies indicated an adjusted medium overall effect with these programs successfully supporting autistic adolescents' socialisation needs (g = 0. 60, p < 0.001), most studies demonstrated medium to low program fidelity despite their good methodological quality. Given the significant heterogeneity of SSGPs and variations in the design and measurement frameworks of efficacy studies, understanding the generalisability of the findings of this research is unclear., (© 2023. The Author(s).)

Purpose: A considerable number of screening and diagnostic tools for autism exist, but variability in these measures presents challenges to data harmonization and the comparability and generalizability of findings. At the same time, there is a movement away from autism symptomatology to stances that capture heterogeneity and appreciate diversity. The International Classification of Functioning, Disability and Health (ICF) provides a classification system that can support content harmonization of different screening and diagnostic tools for autism while enabling the translation of diagnostic information into functioning., Method: Here we linked commonly used screening and diagnostic measures within the field of autism to the ICF to facilitate the unification of data obtained from these measures., Results: As expected, screening and diagnostic measures primarily focus on body functions and activities and participation domains of the ICF, and much less on environmental factors, reflecting biomedical and adaptive behavior operationalizations of autism derived from diagnostic manuals., Conclusion: By translating symptomology-based information to the continuous and diagnostically neutral view of functioning, the ICF linking presented here may provide a means to harmonize measures of autism characteristics while enabling diagnostic information to be re-examined through a more neurodiversity-affirmative lens., (© 2023. The Author(s).)

Despite suicide ideation being one of the most frequently reported health issues impacting tertiary students, there is a paucity of research evaluating the efficacy of preventive interventions aimed at improving mental health outcomes for students studying at two tertiary institutes. The current study evaluated the efficacy of the "Talk-to-Me" Mass Open Online Course (MOOC) in improving tertiary students' abilities to support the mental health of themselves and their peers via a randomised controlled trial design, comparing them to a waitlist control group. Overall, 129 tertiary students (M = 25.22 years, SD = 7.43; 80% female) undertaking a health science or education course at two Western Australian universities were randomly allocated to either "Talk-to-Me" (n = 66) or waitlist control (n = 63) groups. The participants' responses to suicidal statements (primary outcome), knowledge of mental health, generalised self-efficacy, coping skills, and overall utility of the program (secondary outcomes) were collected at three timepoints (baseline 10-weeks and 24-weeks from baseline). Assessment time and group interaction were explored using a random-effects regression model, examining changes in the primary and secondary outcomes. Intention-to-treat analysis (N = 129) at 10-weeks demonstrated a significant improvement in generalised self-efficacy for "Talk-to-Me" compared to the control group (ES = 0.36, p = .04), with only the "Talk-to-Me" participants reporting increased knowledge in responding to suicidal ideation (primary outcome). This change was sustained for 24 weeks. Findings provide preliminary evidence suggesting that the "Talk-to-Me" MOOC can effectively improve tertiary students' mental health and knowledge of how to support themselves and others in distress. ACTRN12619000630112, registered 18-03-2019, anzctr.org.au., (© 2022. The Author(s).)

Large-scale longitudinal biobank data can be leveraged to identify genetic variation contributing to human diseases progression and traits trajectories. While methods for genome-wide association studies (GWAS) of multiple correlated traits have been proposed, an efficient multiple-trait approach to model longitudinal phenotypes is not currently available. We developed GAMUT, a genome-wide association approach for multiple longitudinal traits. GAMUT employs a mixed-effects model to fit longitudinal outcomes where a fast algorithm for inversion by recursive partitioning of the random effects submatrix is introduced. To evaluate performance of the algorithms introduced and assess their statistical power and type I error, stochastic simulation was conducted. Consistent with our expectation, power was greater for cross-sectional (CS) than longitudinal (LT) effects, particularly with a diminishing LT/CS ratio. With a minimum minor allele count of 3 within genotype by time categories, observed type I error was roughly equal to theoretical genome-wide significance. Additionally, 28 blood-based biomarkers measured at 2 time points on participants of the UK Biobank were used to compare GAMUT against single-trait standard and longitudinal GWAS (including rate of change). Across all biomarkers, we observed 539 (CS) and 248 (LT) significant independent variants for the GAMUT method, and 513 (CS) and 30 (LT) for single-trait longitudinal GWAS, respectively. Only 37 variants were identified by modeling rates of change using standard GWAS., (© 2023. The Author(s).)

Background: Road vehicle transportation is essential to support community access and participation for all children. However, little is known about the transport patterns of children with disabilities and medical conditions and their caregivers' experiences supporting them to be transported safely in road vehicles in Australia., Aim: To understand the transport needs of children with disabilities and medical conditions and the transport needs of their caregivers., Materials and Methods: A large-scale national survey was undertaken online to explore the experiences and perspectives of 193 caregivers, identifying the challenges and needs associated with providing and supporting safe road transportation for their children., Results: Caregivers believed their child was missing out on participating in everyday life due to their transportation needs, with caregivers experiencing multiple challenges and barriers to transporting their child safely., Conclusions and Significance: There is a need to provide knowledge and support to caregivers who are primarily responsible for the safe transportation of their children with disabilities and medical conditions.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics 1 ., (© 2023. The Author(s).)

Aim: This study explored caregiver-reported first signs of autism and caregiver experiences of reporting these signs to health professionals using a multiple methods approach., Background: Within the Australian context, children who have been diagnosed with autism represent a significant proportion of individuals requiring access to disability services. Due to the importance of accessing early intervention services to support future outcomes, it is vital that first signs are noticed, reported, and the diagnosis process begun as soon as possible., Method: Phase 1 of the study included a secondary analysis of a survey of caregivers, while phase 2 consisted of focus groups of caregivers of children on the autism spectrum., Results: Survey data indicated that most children were aged 12-18 months when first signs were noticed, with first signs noticed earlier in females than males. Children were age 2-6 years when caregivers sought advice and received a diagnosis. Uncertainty and a lack of information often left caregivers feeling frustrated and under-supported when seeking advice and diagnosis. Despite first signs being recognised early by caregivers, barriers to information and seeking help and support resulted in significant delays in receiving a diagnosis., Conclusions: The study provides valuable consideration of the caregiver perspective regarding reported first signs of autism and the additional challenges faced by caregivers living in regional and rural areas. By being more informed of what caregivers first notice, health professionals may also be able to provide better support and advice to caregivers in regard to access to diagnosis and early intervention services., (© 2023 The Authors. Child: Care, Health and Development published by John Wiley & Sons Ltd.)

Lay Abstract: Mealtimes and eating can be difficult for autistic children. A service where different professions work together is required to address the varied and complex mealtime difficulties of autistic children. Little is known about what is needed for such services to be effective. We interviewed six caregivers of autistic children who were engaged in a mealtime service and 10 therapists who are involved in delivering the service to understand their perspectives on the factors that were driving the effectiveness of the mealtime service. We found that different health professionals from different disciplines working together, focusing on adapting intervention to the child and family and managing expectations of the caregiver were important in contributing to outcomes of the mealtime service. The findings of this study can be used to inform the development of more effective interventions and services to support the well-being and development of autistic children.

Suicide among students enrolled in post-secondary education, including university or college, is a major public health concern. Previous research has examined the effectiveness of suicide prevention programs for this population. However, the effective elements of these interventions remain unknown. This study reviewed the literature on suicide prevention programs for post-secondary students, exploring and identifying those elements likely contributing to their effectiveness. A scoping review process was undertaken exploring suicide prevention programs for post-secondary students. Methodological quality of the articles was assessed, and content analysis was used to explore the programs and their effective elements. Twenty seven articles were included in this review, covering a variety of approaches. Gatekeeper training programs were the most common type of suicide prevention program. Programs for post-secondary students may be effective in improving student rates of engagement with mental health services and were associated with greater knowledge, and help-seeking attitudes and behaviors, and gatekeeper-related outcomes. While evidence was found supporting the effectiveness of some interventions such as gatekeeper programs to influence suicide-related knowledge, attitudes and behaviour, further and more rigorous research surrounding suicide prevention programs for post-secondary students is required, with a particular emphasis on student outcomes., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14 + monocytes and CD4 + and CD8 + T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1 , and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets., Competing Interests: J.M., T.H., D.T., S.L., and M.H.B. are full-time employees of Janssen R&D and own shares of stock in Johnson & Johnson. K.S.E. and A.C.B. are supported by Janssen Oxford Translational Fellowships., (© 2023 The Author(s).)

Introduction: Facial emotion recognition (FER) requires the integration of multi-dimensional information across various brain regions. Autistic individuals commonly experience difficulties in FER, a phenomenon often attributed to differences in brain connectivity. The nature of task-induced functional brain networks could provide insight into the neuromechanisms underlying FER difficulties in autism, however, to date, these mechanisms remain poorly understood., Methods: In this study, the task induced functional brain networks of 19 autistic and 19 gender, age, and IQ matched non-autistic individuals were examined during a complex FER task. Electroencephalogram (EEG)-based functional brain networks were examined, including the investigation of differences in the time-varying whole-brain functional networks and the exploration of the task induced small-world properties., Results: The results showed statistically significant differences in the task-induced functional networks between autistic and non-autistic adults. Autistic adults compared to non-autistic adults showed a significant shift in the connectivity-based FER processing from the lower to the higher EEG frequency bands., Discussion: These findings may provide evidence at a neural level for the notion that autistic individuals have a preference for bottom-up lower-level processing, or alterations in top-down global processing, potentially contributing to the FER difficulties observed in this population. Results also suggest that functional brain networks in autism show significantly altered task-induced whole-brain small-world properties as compared to non-autistic individuals during complex FER. This study motivates further investigation of the underlying networks-basis of altered emotion processing in autism., Competing Interests: SB discloses that he has in the last 3 years acted as an author, consultant or lecturer for Medice and Roche. He receives royalties for textbooks and diagnostic tools from Hogrefe, Kohlhammer, and UTB. SB was partner in SB Education/Psychological Consulting AB and Neuro Support Solutions International AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author SB., (Copyright © 2023 Chouhan, Black, Girdler, Bölte, Tan and Guan.)

Lay Abstract: Factors related to the interiors of buildings, including the layout of rooms, colours, smells, noises, temperature, ventilation, colour and clutter, among other things, can change the way we interact with our environment and the people around us. Autistic individuals can have differences in processing sensory information and may find aspects of the built environment (BE) over-whelming and difficult to navigate. We reviewed the existing literature exploring the BE and autism. This study found that it is possible to make changes to the BE to create more inclusive and friendly environments for everyone, including autistic individuals. Findings from this study provide clear recommendations that can be used by interior designers, architects, builders, and clinical practitioners to make a positive difference. Key recommendations include using simple spatial layouts, compartmentalising and zoning spaces into specific activity sections and providing retreat spaces. The thoughtful placement of windows and blinds and the installation of dimmable lights, for example, will allow users to manage or reduce sensory over-stimulation caused by lights. Similarly, we recommend creating soundproofing and sound absorbent materials to reduce background noise and sound levels. We also recommend using neutral or simple colour palettes and restrained use of patterns. Finally, and most importantly, the BE needs to be flexible and adaptable to meet the unique needs of each person. This study provides a starting point for design guidelines and recommendations towards making a difference to the everyday experiences of the interiors of buildings.

While there is a large body of evidence drawn from randomised controlled trials supporting the efficacy of SSGT in autistic adolescents, the control arms of these studies are almost exclusively treated either as usual or waitlist. Addressing this limitation, 90 verbal autistic adolescents (70% male) aged 12-17 years (M = 13.77, SD = 1.6) with IQ > 70 participated in this pragmatic two-armed randomised controlled trial design study evaluating the efficacy of sixteen 90-min sessions of SSGT KONTAKT® (n = 46) in comparison to a manualised interactive group cooking programme (n = 44) of equal dosage controlling for the potentially confounding effects of exposure to a social group context. The primary outcome was the adolescents' progress towards achieving their personally meaningful social goals at follow-up. Secondary outcomes were changes in autistic traits, quality of life, facial emotion recognition skills, social anxiety, and loneliness. Assessments were conducted at baseline, post intervention and 12-week follow-up. The interaction between time point and group allocation was investigated through a random-effects regression model (linear mixed model) to examine changes in the dependent outcomes. While intention-to-treat analysis (N = 90) demonstrated that both SSGT (ES = 1.36, p < .001) and active control (ES = 1.10, p < .001) groups made progress towards their personally meaningful social goals at follow-up, KONTAKT® participants demonstrated greater progress in social goal attainment than their peers in the active control group (ES = 0.35, p = .04). Findings suggest that KONTAKT® is efficacious in supporting autistic adolescents to achieve their personally meaningful social goals compared to other prosocial group activities.Trial registration: (1) Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617001117303, registered 31 July 2017, anzctr.org.au; (2) ClinicalTrials.gov: NCT03294668 registered 22 September 2017, https://clinicaltrials.gov ., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Intersections are over-represented in crash statistics internationally, suggesting that treatments targeting intersections could substantially improve road safety. Aligning with a Safe Systems approach, several innovative intersection configurations have been proposed. We evaluated the effectiveness of five designs on reducing speed and modifying conflict angles using a driving simulator. The designs were 1) cut-through, 2) modified restricted squircle, 3) unrestricted squircle, 4) raised approach, and 5) raised intersection. For the higher speed green light condition, speed reductions for vehicles travelling straight through the intersection were seen for all five innovative designs on approach to the intersection and at critical conflict points within the intersection. Within the intersection specifically, speed reductions ranged from 1) 7-8 km/h for the modified restricted squircle, 2) 12.5-16.5 km/h for the unrestricted squircle, raised approach, and raised intersection, and 3) 15-19 km/h for the cut-through. In contrast, speeds for drivers turning right were either not substantially reduced (modified restricted squircle, unrestricted squircle, and raised intersection) or were increased (raised approach and cut-through). Beneficial modification of conflict angles were also observed at conflict points for three of the five designs: cut-through, and two variations of the squircle design. Innovative intersection designs may be effective in reducing intersection crash risk by reducing speeds and conflict angles., Competing Interests: Declaration of Competing Interest Melissa Black and Matthew Albrecht report that financial support was provided by Main Roads Western Australia. Adrian Bonner reports a relationship with Main Roads Western Australia that includes: employment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study captured the experiences of 35 autistic adolescents and their parents after completing a 16-session variant of social skills group training KONTAKT® (ACTRN12617001117303). Semi-structured interviews explored participants' and relatives' perceptions of KONTAKT® and associated social outcomes. Adolescents were classified as either high (HR, n = 23) or low (LR, n = 12) responders based on the primary outcome effects during the previous trial. Thematic analysis revealed that both HR and LR participants their parents were satisfied with KONTAKT®, noting consistent patterns of improvement in adolescents' social understanding, communication, relationships, and empowerment, although positive reports were more frequent among HR than LR groups. This study enhances the understanding of the impact of SSGT, which is key in improving their content, principles, and administration., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Multigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined., Methods: Clinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants ("pathogenic variants") were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk., Results: Of 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone., Conclusions: A high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under-recognized component of cancer predisposition syndromes., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Pseudoenzymes resemble active enzymes, but lack key catalytic residues believed to be required for activity. Many pseudoenzymes appear to be inactive in conventional enzyme assays. However, an alternative explanation for their apparent lack of activity is that pseudoenzymes are being assayed for the wrong reaction. We have discovered several new protein kinase-like families which have revealed how different binding orientations of adenosine triphosphate (ATP) and active site residue migration can generate a novel reaction from a common kinase scaffold. These results have exposed the catalytic versatility of the protein kinase fold and suggest that atypical kinases and pseudokinases should be analyzed for alternative transferase activities. In this chapter, we discuss a general approach for bioinformatically identifying divergent or atypical members of an enzyme superfamily, then present an experimental approach to characterize their catalytic activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Mental health problems are common among tertiary education students, with concerning levels of suicide ideation frequently observed in this population. There is a need for evidence-based mental health education and suicide prevention programs designed to meet the specific needs of these students. The "Talk-to-Me" Mass Open Online Course (MOOC) is a strengths-based mental health education program underpinned by a six-phase model for managing a suicidal crisis., Methods: To evaluate the efficacy of the "Talk-to-Me" MOOC in improving student knowledge of appropriate responses to suicide crisis via a randomised control trial (RCT) comparing tertiary education health science and education students attending the program to a waitlist control group. Overall, 170 will be screened and randomly allocated to either the "Talk-to-Me" MOOC or a waitlist control group, with data collection occurring at three-time points (baseline, 10-weeks and 24-weeks from baseline) over one year. The primary outcome will be participants' knowledge and responses to suicidal statements as measured by the Suicide Intervention Response Inventory. Secondary outcomes will be knowledge of mental health and coping skills as well as the overall utility of the program., Conclusions: This pragmatic RCT will demonstrate the efficacy of the "Talk-to-Me" MOOC in improving the students' ability to respond to suicidal and mental health concerns compared to the waitlist group. This design will enable rigorous evaluation of the "Talk-to-Me" MOOC, contributing to a greater understanding of the online-delivered safe-paced suicide prevention programs for tertiary students. Australian New Zealand Clinical Trials Registry (ANZCTR): #12619000630112., (Copyright © 2021. Published by Elsevier Inc.)

The kinase domain transfers phosphate from ATP to substrates. However, the Legionella effector SidJ adopts a kinase fold, yet catalyzes calmodulin (CaM)-dependent glutamylation to inactivate the SidE ubiquitin ligases. The structural and mechanistic basis in which the kinase domain catalyzes protein glutamylation is unknown. Here we present cryo-EM reconstructions of SidJ:CaM:SidE reaction intermediate complexes. We show that the kinase-like active site of SidJ adenylates an active-site Glu in SidE, resulting in the formation of a stable reaction intermediate complex. An insertion in the catalytic loop of the kinase domain positions the donor Glu near the acyl-adenylate for peptide bond formation. Our structural analysis led us to discover that the SidJ paralog SdjA is a glutamylase that differentially regulates the SidE ligases during Legionella infection. Our results uncover the structural and mechanistic basis in which the kinase fold catalyzes non-ribosomal amino acid ligations and reveal an unappreciated level of SidE-family regulation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

During infection, intracellular bacterial pathogens translocate a variety of effectors into host cells that modify host membrane trafficking for their benefit. We found a self-organizing system consisting of a bacterial phosphoinositide kinase and its opposing phosphatase that formed spatiotemporal patterns, including traveling waves, to remodel host cellular membranes. The Legionella effector MavQ, a phosphatidylinositol (PI) 3-kinase, was targeted to the endoplasmic reticulum (ER). MavQ and the Legionella PI 3-phosphatase SidP, even in the absence of other bacterial components, drove rapid PI 3-phosphate turnover on the ER and spontaneously formed traveling waves that spread along ER subdomains inducing vesicle and tubule budding. Thus, bacteria can exploit a self-organizing membrane-targeting mechanism to hijack host cellular structures for survival., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component-clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 ( P = 3.2 × 10 -8 ; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 ( P = 8.0 × 10 -20 ; OR 1.58), rs72982988 near MC4R ( P = 4.4 × 10 -14 ; OR 1.53), rs200893788 in CDC123 ( P = 1.1 × 10 -12 ; OR 1.32), rs2237892 in KCNQ1 ( P = 4.8 × 10 -11 ; OR 1.59), rs937589119 in IGF2BP2 ( P = 3.1 × 10 -9 ; OR 1.34), and rs113748381 in SLC16A11 ( P = 4.1 × 10 -8 ; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 ( P = 3.2 × 10 -8 ; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes., (© 2021 by the American Diabetes Association.)

ADP-ribosyltransferases (ARTs) are a widespread superfamily of enzymes frequently employed in pathogenic strategies of bacteria. Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaire's disease, has acquired over 330 translocated effectors that showcase remarkable biochemical and structural diversity. However, the ART effectors that influence L. pneumophila have not been well defined. Here, we took a bioinformatic approach to search the Legionella effector repertoire for additional divergent members of the ART superfamily and identified an ART domain in Legionella pneumophila gene0181, which we hereafter refer to as Legionella ADP-Ribosyltransferase 1 (Lart1) (Legionella ART 1). We show that L. pneumophila Lart1 targets a specific class of 120-kDa NAD+-dependent glutamate dehydrogenase (GDH) enzymes found in fungi and protists, including many natural hosts of Legionella. Lart1 targets a conserved arginine residue in the NAD+-binding pocket of GDH, thereby blocking oxidative deamination of glutamate. Therefore, Lart1 could be the first example of a Legionella effector which directly targets a host metabolic enzyme during infection., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This study investigated the feasibility and cultural validity of KONTAKT©, a manualised social skills group training, in improving the social functioning of adolescents with autism spectrum disorder (ASD). KONTAKT© was delivered to 17 adolescents (m age  = 14.09, SD age  = 1.43; 70% male) with ASD over sixteen 90 min sessions. A pre-test post-test design evaluated changes in personally meaningful social goals, symptom severity, quality of life, interpersonal efficacy, social anxiety, loneliness, and facial emotion recognition at pre, post and 3 months follow-up. Focus groups were conducted post intervention. Findings indicate that KONTAKT© may support Australian adolescents with ASD in achieving their personally meaningful social goals. This study resulted in finalisation of KONTAKT© in preparation for evaluation of its efficacy in a randomised controlled trial (Australian New Zealand Clinical Registry (ANZCTR): ACTRN12617001117303, ClinicalTrials.gov: NCT03294668).

Background: Genome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study., Methods: The sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa., Results: The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66)., Conclusions: These data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment., (© 2020 Ambry Genetics. The Prostate published by Wiley Periodicals LLC.)

Background: Few studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC)., Methods: The frequency of pathogenic and likely pathogenic (P/LP) variants in clinically actionable genes ( BRCA1 , BRCA2 , PTEN , TP53 , CHEK2 , CDH1 , ATM , PALB2 , NBN , and NF1 ) was compared between women with a primary breast cancer (PBC) and SBC who underwent multigene panel testing at a single diagnostic testing laboratory. Race- and ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes were used to test for associations with SBC. All statistical tests were 2-sided., Results: The study was comprised of 75 550 women with PBC and 7728 with SBC. Median time between breast cancers for SBC was 11 (interquartile range = 6-17) years. Restricting to women tested for all actionable genes (n = 60 310), there were 4231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared with 652 (11.1%) women with SBC ( P < .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% confidence interval [CI] = 1.30 to 1.60) times as likely to have SBC than noncarriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (95% CI = 1.36 to 2.56) and 1.66 (9% CI = 1.02 to 2.58) times as likely to be associated with SBC, respectively ( P < .001 and P = .03)., Conclusion: Women with P/LP variants in breast cancer predisposition genes are more likely to have SBC than noncarriers. Prospective studies are needed confirm these findings., (© The Author(s) 2020. Published by Oxford University Press.)

Autistic individuals often possess strengths and abilities. Despite these strengths, employment outcomes for this population remain low. Strengths-based programs, focusing on developing skills in a supportive environment, may enable autistic adolescents to more effectively prepare for the workforce. This study explores the principal components and associated outcomes of a strengths-based program designed to support autistic children and adolescents to develop interests and skills in Science, Technology, Engineering, Arts, and Mathematics. The baseline results of 52 parents of autistic youth participating in a 3-year longitudinal survey study were explored, with results showing that according to parents the program positively impacted participants' sense of belonging, confidence and self-esteem, health and well-being, social relationships and interactions, and activities and participation.

Backgroud: To determine patient factors that lead to treatment of meniscal tears with osteoarthritis (OA) with knee arthroscopy (KA) or physical therapy only (PT-only); and to assess differences in clinical outcomes including the time to knee arthroplasty., Methods: Patients aged ≥ 45 years with OA at meniscal tear diagnosis were followed up from the date of surgery (KA) or first PT visit (PT-only) until partial/total knee replacement surgery, death, disenrollment, or end of study. Demographic and clinical characteristics were compared and used to derive propensity scores. A Cox proportional hazards model was used to estimate the risk of knee replacement surgery and greater healthcare utilization associated with KA vs. PT-only., Results: Among 7,026 patients (KA, 69%; PT-only, 31%), 27% had partial or total knee replacement surgery during follow-up. PT-only patients were older and more likely to be women and had more comorbidities. After accounting for differences between groups, the cumulative incidence of knee replacement was modestly but significantly higher for those who received KA than those who underwent PT-only (hazard ratio, 1.30; 95% confidence interval, 1.17-1.44; p < 0.001), although there was no significant difference in health service utilization, narcotic medication dispenses, or knee injections after initiating treatment., Conclusions: For patients with meniscal damage complicated by OA, those who underwent KA were 30% more likely to have partial or total knee replacement surgery at any given time than those who had PT alone., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 by The Korean Orthopaedic Association.)

Purpose: We describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer., Methods: One thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms., Results: A yield of 9.4-12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97-1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37-9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48-3.65); and family history of Lynch syndrome-associated cancers (OR 1.97; 95% CI 1.23-3.15) were predictors of positive results., Conclusion: These results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.

Background: The transition to primary school is often a complex and uncertain time for autistic children and their families. Understanding how best to develop school readiness and support transition to primary school for autistic children is essential. School readiness and transition planning are influenced by a range of personal and contextual factors, and it is important to understand the perspectives of the various stakeholders involved in the transition process., Methods: A qualitative exploration employing focus groups and interviews was undertaken with early intervention (EI) staff (n = 45) and parents (n = 18) across Australia to understand their perspectives on school readiness and the transition to primary school., Results: Thematic analysis identified four emerging themes facilitating transition including: 1) building the child; 2) building the parents; 3) building the receiving school; and, 4) connecting the system., Conclusion: Findings highlight the need to consider school readiness and transition planning from a holistic perspective, ensuring clear, collaborative and ongoing communication between parents, teachers and EI staff, using a strength-based approach, and individualizing transition planning., Competing Interests: Conflicts of interest The authors received grants from Australian Government, Department of Social Services and Cooperative Research Centre for Living with Autism., (© 2020 Authors.)

Background: Wearable technology (WT) to measure and support social and non-social functioning in Autism Spectrum Disorder (ASD) has been a growing interest of researchers over the past decade. There is however limited understanding of the WTs currently available for autistic individuals, and how they measure functioning in this population., Objective: This scoping review explored the use of WTs for measuring and supporting abilities, disabilities and functional skills in autistic youth., Method: Four electronic databases were searched to identify literature investigating the use of WT in autistic youth, resulting in a total of 33 studies being reviewed. Descriptive and content analysis was conducted, with studies subsequently mapped to the ASD International Classification of Functioning, Disability and Health Core-sets and the ICF Child and Youth Version (ICF-CY)., Results: Studies were predominately pilot studies for novel devices. WTs measured a range of physiological and behavioural functions to objectively measure stereotypical motor movements, social function, communication, and emotion regulation in autistic youth in the context of a range of environments and activities., Conclusions: While this review raises promising prospects for the use of WTs for autistic youth, the current evidence is limited and requires further investigation., Competing Interests: Conflicts of interest Dr. Bölte reports personal fees from Medice, Roche, Prima Psychiatry, Hogrefe, grants from Swedish Research Council, ALF, Hjärnfonden, Clas Groschinsky, Promobilia, Region Stockholm, FORTE, outside this work. All other authors report no conflicts of interest., (© 2020 Authors.)

Employment rates for autistic individuals are poor, even compared to those from other disability groups. Internationally, there remains limited understanding of the factors influencing employment across the stages of preparing for, gaining, and maintaining employment. This is the third in a series of studies conducted as part of an International Society for Autism Research (INSAR) policy brief intended to improve employment outcomes for autistic individuals. A multi-informant international survey with five key stakeholder groups, including autistic individuals, their families, employers, service providers, and researchers, was undertaken in Australia, Sweden, and the United States to understand the facilitators and barriers to employment for autistic adults. A total of 687 individuals participated, including autistic individuals (n = 246), family members (n = 233), employers (n = 35), clinicians/service providers (n = 123), and researchers (n = 50). Perceptions of the facilitators and barriers to employment differed significantly across both key stakeholder groups and countries, however, ensuring a good job match and focusing on strengths were identified by all groups as important for success. Key barriers to employment included stigma, a lack of understanding of autism spectrum disorder (ASD) and communication difficulties. Results suggest that a holistic approach to employment for autistic individuals is required, aimed at facilitating communication between key stakeholders, addressing attitudes and understanding of ASD in the workplace, using strength-based approaches and providing early work experience. Autism Res 2020, 13: 1195-1214. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autistic individuals experience significant difficulty getting and keeping a job. This article presents a survey study involving autistic individuals, their families, employers, service providers and researchers in Australia, Sweden, and the United States to understand their perspectives on the factors that support or act as barriers to employment. While perspectives varied across key stakeholders, strategies such as using a holistic approach, targeting workplace attitudes and understanding, focusing on strengths, and providing early work experience are important for success., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Employment outcomes for individuals with autism spectrum disorder (ASD) are poor and there is limited understanding on how best to support individuals with ASD in the workplace. Stakeholders involved in the employment of adults with ASD, including employers and employment service providers have unique insights into the factors influencing employment for this population. Organisational and individual factors facilitating successful employment for adults with ASD across Australia and Sweden were explored, including the supports and strategies underpinning employment success from an employers' perspective. Three themes including Knowledge and Understanding of ASD, Work Environment and Job Match emerged, suggesting that a holistic approach was key to supporting success, with employer knowledge and understanding of ASD underpinning their ability to facilitate employment.

Background: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa)., Objective: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease., Design, Setting, and Participants: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics., Outcome Measurements and Statistical Analysis: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test., Results and Limitations: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10 -6 ). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10 -5 ), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10 -6 ), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10 -9 ); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10 -13 ); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02)., Conclusions: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment., Patient Summary: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Pathogenic variants in mismatch repair (MMR) genes ( MLH1, MSH2 , MSH6 and PMS2 ) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes., Methods: Among 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed., Results: Compared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLR alone. Models leveraging in silico scores as prior probabilities accurately classified >76.7% variants. Adding TCLR as quantitative evidence in an MVP model (MVP + TCLR Pred ) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP + TCLR Pred resulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines., Conclusion: Our study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management., Competing Interests: Competing interests: All other authors are employed by and receive a salary from Ambry Genetics., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)