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BACKGROUND: The combined experience of autism and bilingualism is poorly understood, leading to poor support for autistic people in multilingual environments or those interested in languages. While most available studies focus on the language and cognitive profiles of autistic bilinguals, or on the experiences of parents, little is known about the lived experiences of autistic multilinguals. METHODS: To address this question, this study examined the impact of autism and multilingualism on the lives of 54 autistic multilingual adults who completed an online survey assessing the profiles of autistic bi- and multilinguals. We conducted a thematic analysis of responses to the survey's open-ended questions to explore motivations for learning languages and the perceived benefits of being both autistic and multilingual. RESULTS: There was a wide range of language profiles in the sample, with various levels of proficiency, ages of acquisition, and learning environments. Respondents felt that being autistic can both positively and negatively influence language learning. They reported various motivating factors for the acquisition of multiple languages, including social aspects and a predisposition for language learning. Respondents reported many benefits of multilingualism, such as educational, employment, or leisure opportunities; social skills and understanding of other people; self-confidence in their own abilities; and relationships with family, friends, and the worldwide autistic community. CONCLUSIONS: Unlike previous work with autistic multilinguals involving case studies, the larger sample involved here offers valuable insight into the profiles and experiences of this overlooked population. Importantly, autistic people can experience numerous benefits from multilingualism. These findings will have implications for language education practices as well as for multilingual families and the practitioners who support them. LAY SUMMARY: WHY WAS THIS STUDY DONE? We wanted to understand what it feels like to be both autistic and multilingual, in a world where it is often assumed that both cannot go together. The combined experience of autism and bilingualism is poorly understood. This leads to poor support for autistic people in bilingual environments or for those interested in languages. Most studies available focus on the language and mental abilities of autistic bilinguals, or on the experiences of parents. However, very few studies focus on the lived experiences of autistic multilinguals themselves. WHAT WAS THE PURPOSE OF THIS STUDY? The purpose of this study was to understand the experiences of autistic multilingual adults. We focused on their learning motivations and the perceived benefits of being autistic and multilingual. WHAT DID THE RESEARCHERS DO? Fifty-four autistic multilingual adults completed an online questionnaire designed for autistic bi- and multilinguals. The questionnaire included questions about the respondents' language history and language profiles. There were also open-ended questions about the respondents' motivations for learning languages, and their general experience of being both autistic and multilingual. We analyzed and summarized the responses to these open-ended questions to understand the experience of autistic multilingual adults. WHAT WERE THE RESULTS OF THE STUDY? Our sample had a diverse range of language profiles and experiences. Respondents thought that autism could be both an advantage and a disadvantage for language learning. They reported a range of motivations for language learning, including a predisposition for language learning. They considered relationships as both a motivation to learn languages and a benefit of multilingualism. Respondents thought that being multilingual had brought them many opportunities for leisure, travels, education, and employment. They considered that being multilingual had improved their self-confidence. They also thought that being multilingual had increased their awareness and understanding of autism, allowing them to connect with the wider autistic population. WHAT DO THESE FINDINGS ADD TO WHAT WAS ALREADY KNOWN? Previous research with autistic multilinguals involved only one or two participants. The larger group of autistic multilinguals involved in this study offers valuable insight into the lived experiences of this overlooked population. WHAT ARE POTENTIAL WEAKNESSES IN THE STUDY? The online questionnaire was not originally designed to collect in-depth data on lived experiences. This means that the questions included very few prompts: respondents were able to discuss the aspects of their experience that were the most important to them. The absence of specific topics in the results does not mean that they are not experienced, but simply that the participants did not spontaneously mention them. Future research should build upon our findings and focus on specific topics, such as learning environments or opportunities. HOW WILL THESE FINDINGS HELP AUTISTIC ADULTS NOW OR IN THE FUTURE? These findings will help autistic adults by highlighting the diversity and richness of their language profiles, abilities, and experiences. This will prompt families, educators, and practitioners to better support and include autistic people in multilingual environments or those interested in languages.

Autism is considered to entail a social impairment whereby autistic people experience difficulty interpreting others' mental states. However, recent research has shown that nonautistic people also have difficulty understanding the mental states of autistic people. This mismatch of understanding may explain lower rapport in interactions between autistic and nonautistic people. As mental states can be expressed externally through socially normed signals, it is important to investigate the role of such signals in autistic, nonautistic, and mixed interactions. This study explores variability in two social signals between autistic, nonautistic, and mixed interactions, and how their use may affect rapport within interactions.Videos from a previous study of autistic, nonautistic, and mixed pair interactions in a diffusion chain context in which participants were aware of others' diagnostic status were video coded for mutual gaze and backchanneling as candidate indicators of interactional rapport.Although use of mutual gaze and backchanneling was lower in mixed pairs than in nonautistic pairs, corresponding to lower ratings of interactional rapport, less backchanneling in autistic pairs of both nonverbal and verbal subtypes corresponded to higher ratings of rapport.We observed differences in the use of candidate rapport markers between autistic, mixed, and nonautistic interactions, which did not map onto patterns of rapport scores, suggesting differences in reliance on these cues between autistic and nonautistic people. These results suggest that visible markers of rapport may vary by neurotype or pairing and give clues to inform future investigations of autistic interaction.When someone is autistic, society generally assumes they have difficulty interacting with others. Social difficulties between autistic and nonautistic people are thought to be due to the autistic person not being able to interact using nonautistic social behaviors. This belief can lead to many autistic people feeling alienated. However, recent research supports what autistic people have been saying for a long time: that autistic people are capable of having successful and rewarding interactions with other autistic people. This suggests that social difficulties between autistic and nonautistic people may be due to a mismatch in social norms leading to difficulty for both people, not just the autistic person.In this study, we wanted to investigate whether certain social signals are used differently between autistic and nonautistic people. We also questioned whether using these signals helped or hurt the interaction depending on who was involved.We recorded people passing a story down a chain of people, like the game telephone, to see how they interacted with each other. Afterward, people wrote down scores for how much they enjoyed their interaction. We focused on two parts of the interaction: how much people were looking at each other and when they made short verbal responses such as “mhm” to show they were listening (backchanneling). We watched the recordings back and analyzed how long or how many times these actions were occurring.We found that when one autistic and one nonautistic person were interacting, they looked at each other and backchanneled less than two nonautistic people. This seemed to be linked with a less enjoyable interaction for them. However, backchanneling seemed to matter less in interactions between two autistic people. They backchanneled less while still having enjoyable interactions.Research has previously suggested that different social norms exist between autistic and nonautistic people. This study shows specific examples of this and how they may affect the interaction in a natural setting.This study has some weaknesses. For example, we measured when people looked at each other's faces rather than eye contact specifically, which can only be done with an eye tracker. Also, the people in the study knew whether the person they were talking to was autistic. This can be similar to normal life, as people do sometimes know this, although we would also be interested to see what the effect of not knowing would be.This line of research has important implications for how autistic people can be supported in society. Not only will understanding of social differences between autistic and nonautistic people help the way autistic people are perceived, but it will also help nonautistic people better understand and support the autistic people in their lives.

The Sensory Totes Programme is a series of COVID-19 adapted sensory-friendly events taking place in a metropolitan area of the south-central United States. It offers experiences for children with a...

Dystrophin plays a crucial role in maintaining sarcolemma stability during muscle contractions, and mutations that prevent the expression of a functional protein cause Duchenne muscular dystrophy (DMD). Antisense oligonucleotide-mediated manipulation of pre-messenger RNA splicing to bypass Duchenne-causing mutations and restore functional dystrophin expression has entered the clinic for the most common DMD mutations. The rationale of “exon skipping” is based upon genotype-phenotype correlations observed in Becker muscular dystrophy, a milder allelic disorder generally characterized by in-frame deletions and internally truncated but semi-functional dystrophin isoforms. However, there is a lack of genotype-phenotype correlations downstream of DMD exon 55, as deletions in this region are rare and most single exon deletions would disrupt the reading frame. Consequently, the amenability of mutations in this region of the DMD gene to exon skipping strategies remains unknown. Here, we induced “Becker muscular dystrophy-like” in-frame dystrophin isoforms in vivo by intraperitoneal injection of peptide-conjugated phosphorodiamidate morpholino oligomers targeting selected exons. The dystrophin isoform encoded by the transcript lacking exons 56+57 appears to be more functional than that encoded by the 58+59-deleted transcript, as determined by higher dystrophin expression, stabilized β-dystroglycan, and less severe dystrophic pathology, indicating some potential for the strategy to address Duchenne-causing mutations affecting these exons., Graphical Abstract, Antisense oligonucleotide-mediated exon skipping is used to induce different dystrophin isoforms, one isoform missing amino acids encoded by DMD exons 56+57 and the other missing exons 58+59. Initial studies indicate that the latter is less functional, suggesting that mutations involving these exons may not respond to an exon skipping therapy.

There is evidence to suggest that certain executive functions are impaired in autistic children, contributing to many daily challenges. Regular use of two languages has the potential to positively influence executive functions, though evidence is mixed. Little is known about the impact of bilingualism on the executive functions of autistic children, with only a handful of studies published worldwide to date. This study investigated the impact of bilingualism on sustained attention, interference control, flexible switching and working memory, in Arabic-English autistic children (n = 27) and their typically developing peers (n = 66), aged 5-12 years old. Groups were matched on age, nonverbal IQ and socioeconomic status, and completed a battery of computerized tests. Results showed an advantage for bilingual autistic children relative to their monolingual peers in sustained attention, and equivalent performance between bilingual and monolingual autistic children on all other executive functions. There were no generalized positive effects of bilingualism, and typically-developing children performed better than autistic children on all measures. The findings indicate that bilingualism does not negatively impact the executive function skills of autistic children, and that it might mitigate difficulties in sustained attention. LAY SUMMARY: Contrary to widespread belief, but in line with previous research, this study showed that speaking two languages did not harm thinking skills in autistic children. The thinking skills evaluated in this study included the ability to focus over a period of time, the ability to resist distractions, the ability to move back and forth between tasks, and the ability to use short-term memory. In fact, speaking two languages might help reduce difficulties that autistic children might face when focusing over a period of time.

Patient need for cancer care services is growing. At the same time, cancer programs face a confluence of dynamics that impact their ability to meet patient demand, including an increasing number of...

Mutations in the splicing factor pre-messenger RNA processing factor 31 (PRPF31) gene cause autosomal dominant retinitis pigmentosa 11 (RP11) through a haplo-insufficiency mechanism. We describe th...

Many long non-coding RNAs (lncRNA) are highly dysregulated in cancer and are emerging as therapeutic targets. One example is NEAT1, which consists of two overlapping lncRNA isoforms, NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb), that are functionally distinct. The longer NEAT1_2 is responsible for scaffolding gene-regulatory nuclear bodies termed paraspeckles, whereas NEAT1_1 is involved in paraspeckle-independent function. The NEAT1 isoform ratio is dependent on the efficient cleavage and polyadenylation of NEAT1_1 at the expense of NEAT1_2. Here, we developed a targeted antisense oligonucleotide (ASO) approach to sterically block NEAT1_1 polyadenylation processing, achieving upregulation of NEAT1_2 and abundant paraspeckles. We have applied these ASOs to cells of the heterogeneous infant cancer, neuroblastoma, as we found higher NEAT1_1:NEAT1_2 ratio and lack of paraspeckles in high-risk neuroblastoma cells. These ASOs decrease NEAT1_1 levels, increase NEAT1_2/paraspeckles and concomitantly reduce cell viability in high-risk neuroblastoma specifically. In contrast, overexpression of NEAT1_1 has the opposite effect, increasing cell proliferation. Transcriptomic analyses of high-risk neuroblastoma cells with altered NEAT1 ratios and increased paraspeckle abundance after ASO treatment showed an upregulation of differentiation pathways, as opposed to the usual aggressive neuroblastic phenotype. Thus, we have developed potential anti-cancer ASO drugs that can transiently increase growth-inhibiting NEAT1_2 RNA at the expense of growth-promoting NEAT1_1 RNA. These ASOs, unlike others that degrade lncRNAs, provide insights into the importance of altering lncRNA polyadenylation events to suppress tumorigenesis as a strategy to combat cancer.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders that manifest various motor and nonmotor symptoms. Although currently available therapies can alleviate some of the symptoms, the disease continues to progress, leading eventually to severe motor and cognitive decline and reduced life expectancy. The past two decades have witnessed rapid progress in our understanding of the molecular and genetic pathogenesis of the disease, paving the way for the development of new therapeutic approaches to arrest or delay the neurodegenerative process. As a result of these advances, biomarker‐driven subtyping is making it possible to stratify PD patients into more homogeneous subgroups that may better respond to potential genetic‐molecular pathway targeted disease‐modifying therapies. Therapeutic nucleic acid oligomers can bind to target gene sequences with very high specificity in a base‐pairing manner and precisely modulate downstream molecular events. Recently, nucleic acid therapeutics have proven effective in the treatment of a number of severe neurological and neuromuscular disorders, drawing increasing attention to the possibility of developing novel molecular therapies for PD. In this review, we update the molecular pathogenesis of PD and discuss progress in the use of antisense oligonucleotides, small interfering RNAs, short hairpin RNAs, aptamers, and microRNA‐based therapeutics to target critical elements in the pathogenesis of PD that could have the potential to modify disease progression. In addition, recent advances in the delivery of nucleic acid compounds across the blood–brain barrier and challenges facing PD clinical trials are also reviewed.

As autistic people get older, they may suffer increasingly with poor health and as a result may transition to residential care. Very little is known about the support needs of older autistic adults...

Effective information transfer requires social communication skills. As autism is clinically defined by social communication deficits, it may be expected that information transfer between autistic people would be particularly deficient. However, the Double Empathy theory would suggest that communication difficulties arise from a mismatch in neurotype; and thus information transfer between autistic people may be more successful than information transfer between an autistic and a non-autistic person. We investigate this by examining information transfer between autistic adults, non-autistic adults and mixed autistic-with-non-autistic pairs. Initial participants were told a story which they recounted to a second participant, who recounted the story to a third participant and so on, along a ‘diffusion chain’ of eight participants ( n = 72). We found a significantly steeper decline in detail retention in the mixed chains, while autistic chains did not significantly differ from non-autistic chains. Participant rapport ratings revealed significantly lower scores for mixed chains. These results challenge the diagnostic criterion that autistic people lack the skills to interact successfully. Rather, autistic people effectively share information with each other. Information transfer selectively degrades more quickly in mixed pairs, in parallel with a reduction in rapport. Lay abstract Sharing information with other people relies on the ability to communicate well. Autism is defined clinically by deficits in social communication. It may therefore be expected that autistic people find it difficult to share information with other people. We wanted to find out whether this was the case, and whether it was different when autistic people were sharing information with other autistic people or with non-autistic people. We recruited nine groups, each with eight people. In three of the groups, everyone was autistic; in three of the groups, everyone was non-autistic; and three of the groups were mixed groups where half the group was autistic and half the group was non-autistic. We told one person in each group a story and asked them to share it with another person, and for that person to share it again and so on, until everyone in the group had heard the story. We then looked at how many details of the story had been shared at each stage. We found that autistic people share information with other autistic people as well as non-autistic people do with other non-autistic people. However, when there are mixed groups of autistic and non-autistic people, much less information is shared. Participants were also asked how they felt they had got on with the other person in the interaction. The people in the mixed groups also experienced lower rapport with the person they were sharing the story with. This finding is important as it shows that autistic people have the skills to share information well with one another and experience good rapport, and that there are selective problems when autistic and non-autistic people are interacting.

As in the general population, autistic adults may need residential care in their old age. Little is known about the needs of older autistic adults in residential care, and how to support them withi...

Bilingualism is a valuable tool that enriches and facilitates cultural, social and lived experiences for autistic and non-autistic people alike. Research consistently finds no negative effects of bilingualism and highlights the potential for positive effects across cognitive and socio-cultural domains for autistic and non-autistic children. Yet parents of autistic children remain concerned that bilingualism will cause delays in both cognitive and language development and are still frequently advised by practitioners to raise their child monolingually. Evidently, findings from research are not reflected in practice or subsequent advice, and it is essential to identify ways to ensure equal access to additional language learning. We briefly summarise the existing literature on bilingualism and autism, considering perspectives from the bilingual autistic community, and experimental research. We identify the most pertinent barriers to participation for autistic bilingual children in terms of familial, clinical and educational perspectives. We propose novel solutions to promote additional language learning and suggest changes to practice that will contribute to an evidence base for families and practitioners. This commentary makes innovative recommendations at both the individual and societal level to ensure that autistic bilingual people have equal rights and opportunities to language learning and are optimally supported in accessing them.

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C&gt, T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

A wide array of digital supports (such as apps) have been developed for the autism community, many of which have little or no evidence to support their effectiveness. A Delphi study methodology was used to develop a consensus on what constitutes good evidence for digital supports among the broader autism community, including autistic people and their families, as well as autism-related professionals and researchers. A four-phase Delphi study consultation with 27 panel members resulted in agreement on three categories for which evidence is required: reliability, engagement and effectiveness of the technology. Consensus was also reached on four key sources of evidence for these three categories: hands-on experience, academic sources, expert views and online reviews. These were differentially weighted as sources of evidence within these three categories. Lay abstract Digital supports are any type of technologies that have been intentionally developed to improve daily living in some way. A wide array of digital supports (such as apps) have been developed for the autism community specifically, but there is little or no evidence of whether they work or not. This study sought to identify what types of evidence the autistic community valued and wanted to see provided to enable an informed choice to be made regarding digital supports. A consensus was developed between autistic people and their families, practitioners (such as therapists and teachers) as well as researchers, to identify the core aspects of evidence that everyone agreed were useful. In all, 27 people reached agreement on three categories for which evidence is required: reliability, engagement and the effectiveness of the technology. Consensus was also reached on four key sources of evidence for these three categories: hands-on experience, academic sources, expert views and online reviews. The resulting framework allows for any technology to be evaluated for the level of evidence identifying how effective it is. The framework can be used by autistic people, their families, practitioners and researchers to ensure that decisions concerning the provision of support for autistic people is informed by evidence, that is, ‘evidence-based practice’.

This month’s editorial continues an occasional theme of myth-busting in the journal, this time focusing on associations between autism and empathy. We argue that this is a fraught area of research where flawed terminology, measurement and theory have all contributed to the mis-characterisation of autistic people as lacking empathy, to severely negative effect.

A distinct feature of autism is difficulties in several aspects of executive functioning. One factor that may influence how executive functions develop is exposure to more than one language in childhood. This study explored the impact of bilingualism on inhibitory control in autistic (n = 38) and non-autistic children (n = 51). Bilingualism was measured on a continuum of exposure in order to investigate the effects of language environment on two facets of inhibitory control. Results did not show meaningful effects of bilingual exposure on inhibition involving visual attention, but behavioural control of motor impulses was modulated positively through increased bilingual exposure, irrespective of diagnostic status. However, bilingual exposure was not related to parental reports of everyday executive functioning, and there was no correlation between these parent-report data and performance on experimental tasks. The results partially support the hypothesis that bilingual exposure differentially affects components of inhibitory control and provides important evidence for families raising autistic children that bilingualism is not detrimental to their development.

Mutations in ABCA4 gene are causative for autosomal recessive Stargardt disease (STGD1), the most common inherited retinal dystrophy. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a STGD1 patient carrying biallelic c.[5461-10T>C;5603A>T];[6077T>C] mutations in the ABCA4 gene. Episomes carrying OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed for the reprogramming of patient-derived fibroblasts. This iPSC line expressed comparable pluripotency markers as in a commercially available human iPSC line, displayed normal karyotype and potential for trilineage differentiation, and were negative for both reprogramming episomes and mycoplasma test.

Stargardt disease (STGD1) is the most common inherited retinal dystrophy and ABCA4 c.546-–10 T>C is the most commonly reported splice mutation. Here, we generated and characterized two induced pluripotent stem cell (iPSC) lines from a STGD1 patient with compound heterozygous mutations in ABCA4 (c.[5461-10 T > C;5603A > T];[4163 T > C;455G > A]). Episomal vectors containing OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed to conduct the reprogramming of patient-derived fibroblasts. Both lines had a normal karyotype, displayed iPSC morphology, expressed pluripotency markers and showed trilineage differentiation potential. These lines can provide a powerful platform for further investigating the pathophysiological consequences of mutations in ABCA4.

There is evidence that autistic children may have reduced executive function skills, contributing to day-to-day difficulties, but much remains unknown regarding the influence of bilingualism. We investigated its influence on sustained attention, interference control, flexible switching and working memory, in Arabic-English autistic (n = 27) and typically developing peers (n = 53) children, aged 5 to 12 years old. Parents and teachers completed rating measures assessing children’s daily EF abilities. Results showed generalized positive effects for bilingual autistic children relative to their monolingual peers across all EF domains, but using parent ratings only. The findings indicate that bilingualism does not negatively impact the executive function skills of autistic children, and that it might mitigate difficulties faced on a day-to-day basis.

ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

BackgroundRoutinely-collected mental health data could deliver novel insights for mental health research. However, patients’ willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with experience of mental illness.MethodsWe collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data.ResultsThere was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the effect of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness.ConclusionsThese findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research.

BackgroundMental health research is commonly affected by difficulties in recruiting and retaining participants, resulting in findings which are based on a sub-sample of those actually living with mental illness. Increasing the use of Big Data for mental health research, especially routinely-collected data, could improve this situation. However, steps to facilitate this must be enacted in collaboration with those who would provide the data - people with mental health conditions.MethodsWe used the Delphi method to create a best practice checklist for mental health data science. Twenty participants with both expertise in data science and personal experience of mental illness worked together over three phases. In the Phase 1, participants rated a list of 63 statements and added any statements or topics that were missing. Statements receiving a mean score of 5 or more (out of 7) were retained. These were then combined with the results of a rapid thematic analysis of participants’ comments to produce a 14-item draft checklist, with each item split into two components: best practice now and best practice in the future. In Phase 2, participants indicated whether or not each item should remain in the checklist, and items that scored more than 50% endorsement were retained. In Phase 3 participants rated their satisfaction with the final checklist.ResultsThe final checklist was made up of 14 “best practice” items, with each item covering best practice now and best practice in the future. At the end of the three phases, 85% of participants were (very) satisfied with the two best practice checklists, with no participants expressing dissatisfaction.ConclusionsIncreased stakeholder involvement is essential at every stage of mental health data science. The checklist produced through this work represents the views of people with experience of mental illness, and it is hoped that it will be used to facilitate trustworthy and innovative research which is inclusive of a wider range of individuals.

The Double Empathy Problem suggests that communicative difficulties between autistic and non-autistic people are due to bi-directional differences in communicative style and a reciprocal lack of understanding. If true, there should be increased similarity in interaction style, resulting in higher rapport during interactions between pairs of the same neurotype. Here, we provide two empirical tests of rapport, with data revealing whether self- and observer- rated rapport varies depending on the match or mismatch in autism status within a pair. An additional opportunity afforded by these data is to examine the effect of the autism status of the rater on the perceived rapport between matched and mismatched pairs. In Study 1 72 participants were allocated to one of three dyad conditions: autistic pairs (n = 24), non-autistic pairs (n = 24) and mixed pairs (n = 12 autistic; n = 12 non-autistic). Each participant completed three semi-structured interactions with their partner, rating rapport after each interaction. Non-autistic pairs experienced higher self-rated rapport than mixed and autistic pairs, and autistic pairs experienced higher rapport than mixed pairs. In Study 2 (n = 80) autistic and non-autistic observers rated interactional rapport while watching videoed interactions between autistic pairs, non-autistic pairs, and mixed pairs (n = 18, a subset of participants in Study 1). Mixed pairs were rated significantly lower on rapport than autistic and non-autistic pairs, and autistic pairs were rated more highly for rapport than non-autistic pairs. Both autistic and non-autistic observers show similar patterns in how they rate the rapport of autistic, non-autistic, and mixed pairs. In summary, autistic people experience high interactional rapport when interacting with other autistic people, and this is also detected by external observers. Rather than autistic people experiencing low rapport in all contexts, their rapport ratings are influenced by a mismatch of diagnosis. These findings suggest that autistic people possess a distinct mode of social interaction style, rather than demonstrating social skills deficits. These data are considered in terms of their implications for psychological theories of autism, as well as practical impact on educational and clinical practice.

Background Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child’s challenging restricted repetitive behaviours. Methods The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3–9 years 11 months with a diagnosis of autism. All analyses will be done under intention-to-treat principle. The primary outcome at 24 weeks will use generalised estimating equation (GEE) to compare proportion of children with improved RRB between the MRB group and the LAA group. The GEE model will account for the clustering of children by parent groups using exchangeable working correlation. All secondary outcomes will be analysed in a similar way using appropriate distribution and link function. The economic evaluation will be conducted from the perspective of both NHS costs and family access to local community services. A ‘within trial’ cost-effectiveness analysis with results reported as the incremental cost per additional child achieving at least the target improvement in CGI-I scale at 24 weeks. Discussion This is an efficacy trial to investigate the clinical and cost-effectiveness of a parent group based intervention designed to help parents understand and manage their child’s challenging RRB. If found to be effective, this intervention has the potential to improve the well-being of children and their families, reduce parental stress, greatly enhance community participation and potential for learning, and improve longer-term outcomes. Trial registration Trial ID: ISRCTN15550611 Date registered: 07/08/2018. Sponsor and Monitor: Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust R&D Manager Lyndsey Dixon, Address: St Nicholas Hospital, Jubliee Road, Gosforth, Newcastle upon Tyne NE3 3XT, lyndsey.dixon@cntw.nhs.uk, Tel: 0191 246 7222

Introduction:2000 different mutations have been reported in patients with Cystic Fibrosis (CF) and occur in all CFTR exons and introns. Some mutations are not amenable to current therapies, and new drugs must be developed. Antisense oligonucleotides (AO) are synthetic nucleic acid analogues whose binding to pre-mRNA modulates exon selection. We hypothesise that skipping in frame CFTR exon 15 in patients with intra-exonic mutations such as p.Phe861Leufsx3 studied here, the induced isoform may retain residual function. Methods: AO sequences were initially optimised using 2’-O-Methyl modified bases on a phosphorothioate backbone (2OMe) and transfected into monolayer primary non-CF and p.Phe861Leufsx3/p.Phe508del CF airway epithelial cells. The most effective 2OMe AO sequence was re-synthesised as the clinically validated phosphorodiamidate morpholino (PMO) chemistry. Monolayer transfections were repeated and modification of protein was detected by western blot analysis. Residual CFTR function was measured using Ussing Chamber. Results: The 2OMe sequence produced 50% skipping in p.Phe861Leufsx3/p.Phe508del CF airway epithelial cells The PMO induced skipping of exon 15 from non-CF (49%) and p.Phe861Leufsx3/p.Phe508del CF (88%) cells after 7 days in culture. Western blot was then used to determine the effect on the induced CFTR protein. In addition, airway epithelial cells from children with CF prior to and following AO treatment were mucocillary differentiated at the air-liquid interface for 28 days and CFTR function assessed using Ussing chamber. Conclusion: Exon 15 can be skipped from CFTR in airway epithelial cells. We propose that exon skipping to remove disease-causing mutations in selected in-frame exons can improve CFTR function.

Many autistic people are motivated to have friends, relationships and close family bonds, despite the clinical characterisation of autism as a condition negatively affecting social interaction. Many first-hand accounts of autistic people describe feelings of comfort and ease specifically with other autistic people. This qualitative research explored and contrasted autistic experiences of spending social time with neurotypical and autistic friends and family. In total, 12 autistic adults (10 females, aged 21–51) completed semi-structured interviews focused on time spent with friends and family; positive and negative aspects of time spent with neurotypical and autistic friends and family; and feelings during and after spending time together. Three themes were identified: cross-neurotype understanding, minority status and belonging. Investigation of these themes reveals the benefits of autistic people creating and maintaining social relationships with other autistic people, in a more systematic way than previous individual reports. They highlight the need for autistic-led social opportunities and indicate benefits of informal peer support for autistic adults. Lay abstract Although autistic people may struggle to interact with others, many autistic people have said they find interacting with other autistic people more comfortable. To find out whether this was a common experience, we did hour-long interviews with 12 autistic adults. We asked them questions about how it feels when spending time with their friends and family, and whether it felt different depending on whether the friends and family were autistic or neurotypical. We analysed the interviews and found three common themes in what our participants said. First, they found spending with other autistic people easier and more comfortable than spending time with neurotypical people, and felt they were better understood by other autistic people. Second, autistic people often felt they were in a social minority, and in order to spend time with neurotypical friends and family, they had to conform with what the neurotypical people wanted and were used to. Third, autistic people felt like they belonged with other autistic people and that they could be themselves around them. These findings show that having time with autistic friends and family can be very beneficial for autistic people and played an important role in a happy social life.

BACKGROUND: The presence, types, disclosure rates, and effects of conflicts of interest (COIs) on autism early intervention research have not previously been studied. The purpose of this study was to examine these issues. METHODS: This study is a secondary analysis of a comprehensive meta-analysis of all group-design, non-pharmacological early intervention autism research conducted between 1970 and 2018. We coded reports for the presence/absence of COI statements, the types of COIs that were disclosed, and for 8 types of COIs, including: (a) the author developed the intervention, (b) the author is affiliated with a clinical provider, (c) the author is employed by a clinical provider, (d) the author is affiliated with an institution that trains others to use the intervention, (e) the author receives payment or royalties related to the intervention, (f) the study was funded by an intervention provider, (g) the study used a commercially available measure developed by the author, and (h) proceeds of the intervention fund the author’s research. Frequencies and proportions were calculated to determine prevalence of COIs and COI disclosures. Meta-analysis was used to estimate summary effects by COI type, and to determine if they were larger than for reports with no coded COIs. RESULTS: Seventy percent of reports were coded for ≥ 1 COI, but only ~6% of reports contained COI statements fully accounting for all coded COIs. Meta-regressions did not detect significant influences of any COI type on summary effects, however point estimates for each COI type were larger than for reports with no coded COIs. CONCLUSIONS: COIs are prevalent but under-reported in autism early intervention research. Improved reporting practices are necessary for researcher transparency, and would enable more robust examination of the effects of COIs on research outcomes.

Background Deletion–insertion (delins) variants in the retina‐specific ATP‐binding cassette transporter gene, subfamily A, member 4 (ABCA4) accounts for, This work epitomizes the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and illustrates the use of patient‐derived fibroblasts to evaluate the effect on splicing of a novel ABCA4 indel variant, and as a method for pathogenicity assessment of other novel ABCA4 variants.

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of DMD lesion, however, whole exon duplications account for between 10&ndash, 15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the DMD gene. Phosphorodiamidate morpholino oligomers and phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide were evaluated in a Duchenne muscular dystrophy patient cell strain carrying an exon 14&ndash, 17 duplication. Two strategies were employed, the conventional approach was to remove both copies of exon 17 in addition to exon 18, and the second strategy was to remove only the first copy of exon 17. Both approaches result in a larger than normal but in-frame DMD transcript, but surprisingly, the removal of only the first exon 17 appeared to be more efficient in restoring dystrophin, as determined using western blotting. The emergence of a normal sized DMD mRNA transcript that was not apparent in untreated samples may have arisen from back splicing and could also account for some of the dystrophin protein being produced.

Many long non-coding RNAs (lncRNA) are highly dysregulated in cancer and are emerging as therapeutic targets. One example is NEAT1, which consists of two overlapping lncRNA isoforms, NEAT1_1 (3.7kb) and NEAT1_2 (23kb), that are functionally distinct. The longer NEAT1_2 is responsible for scaffolding gene-regulatory nuclear bodies termed paraspeckles, whereas NEAT1_1 is involved in paraspeckle-independent function. The NEAT1 isoform ratio is dependent on the efficient cleavage and polyadenylation of NEAT1_1 at the expense of NEAT1_2. Here we developed a targeted antisense oligonucleotide (ASO) approach to sterically block NEAT1_1 polyadenylation processing, achieving upregulation of NEAT1_2 and abundant paraspeckles. We have applied these ASOs to cells of the heterogeneous infant cancer, neuroblastoma, as we found higher NEAT1_1:NEAT1_2 ratio and lack of paraspeckles in high-risk neuroblastoma cells. These ASOs decrease NEAT1_1 levels, increase NEAT1_2/paraspeckles and concomitantly reduce cell viability in high-risk neuroblastoma specifically. In contrast, overexpression of NEAT1_1 has the opposite effect, increasing cell-proliferation. Transcriptomic analyses of high-risk neuroblastoma cells with altered NEAT1 ratios and increased paraspeckle abundance after ASO treatment showed an upregulation of differentiation pathways, as opposed to the usual aggressive neuroblastic phenotype. Thus, we have developed potential anti-cancer ASO drugs that can transiently increase growth-inhibiting NEAT1_2 RNA at the expense of growth-promoting NEAT1_1 RNA. These ASOs, unlike others that degrade lncRNAs, provide insights into the importance of altering lncRNA polyadenylation events to suppress tumorigenesis as a strategy to combat cancer.

Capturing variability in use of commercial technologies by autistic children can inform future learning and support technology design. Survey data were collected from parents (n = 388) in the UK, Spain, and Belgium, and includes information about individuals with a range of ages and ability levels. We found a comparable pattern of access and usage across age groups, though higher reading and language ability was linked to use of more devices and interfaces. Reported worries about technology correlated with longer time spent using technology. Autistic children use mainstream technologies for a broad range of recreational uses. The data suggest that technologies developed with therapeutic goals in mind may need to achieve a high standard of design to engage users.

Cancer is one of the leading causes of death worldwide, and conventional cancer therapies such as surgery, chemotherapy, and radiotherapy do not address the underlying molecular pathologies, leading to inadequate treatment and tumor recurrence. Angiogenic factors, such as EGF, PDGF, bFGF, TGF-β, TGF-α, VEGF, endoglin, and angiopoietins, play important roles in regulating tumor development and metastasis, and they serve as potential targets for developing cancer therapeutics. Nucleic acid-based therapeutic strategies have received significant attention in the last two decades, and antisense oligonucleotide-mediated intervention is a prominent therapeutic approach for targeted manipulation of gene expression. Clinical benefits of antisense oligonucleotides have been recognized by the U.S. Food and Drug Administration, with full or conditional approval of Vitravene, Kynamro, Exondys51, and Spinraza. Herein we review the scope of antisense oligonucleotides that target angiogenic factors toward tackling solid cancers. Keywords: antisense oligonucleotides, nucleic acids, angiogenesis, antisense, modified oligonucleotides, cancer

Current clinical trials demonstrate Duchenne muscular dystrophy (DMD) patients receiving phosphorodiamidate morpholino oligomer (PMO) therapy exhibit improved ambulation and stable pulmonary function; however, cardiac abnormalities remain. Utilizing the same PMO chemistry as current clinical trials, we have identified a non-toxic PMO treatment regimen that restores metabolic activity and prevents DMD cardiomyopathy. We propose that a treatment regimen of this nature may have the potential to significantly improve morbidity and mortality from DMD by improving ambulation, stabilizing pulmonary function, and preventing the development of cardiomyopathy.

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these ‘independent’ registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease.

The influence of the broader autism phenotype (BAP) on the adjustment of siblings of children with autism has previously been researched mainly in Western cultures. The present research evaluated a diathesis-stress model of sibling adjustment using a questionnaire study including 80 and 75 mother-typically developing sibling dyads in Taiwan and the United Kingdom (UK). UK siblings reported elevated adjustment difficulties compared to the Taiwanese sample and to normative data. Whilst higher BAP levels were generally associated with greater adjustment difficulties, differences were found across cultures and respondents. Although significant diathesis-stress interactions were found, these were in the opposite direction from those predicted by the model, and differed across cultural settings. Implications for culturally-sensitive sibling support are considered.

The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and diversity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2&prime, O-methyl modified bases on a phosphorothioate backbone.

The scientific landscape surrounding amyotrophic lateral sclerosis (ALS) continues to shift as the number of genes associated with the disease risk and pathogenesis, and the cellular processes involved, continues to grow. Despite decades of intense research and over 50 potentially causative or disease-modifying genes identified, etiology remains unexplained and treatment options remain limited for the majority of ALS patients. Various factors have contributed to the slow progress in understanding and developing therapeutics for this disease. Here, we review the genetic basis of ALS, highlighting factors that have contributed to the elusiveness of genetic heritability. The most commonly mutated ALS-linked genes are reviewed with an emphasis on disease-causing mechanisms. The cellular processes involved in ALS pathogenesis are discussed, with evidence implicating their involvement in ALS summarized. Past and present therapeutic strategies and the benefits and limitations of the model systems available to ALS researchers are discussed with future directions for research that may lead to effective treatment strategies outlined.

The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

Key Points Question What are the associations of socioeconomic deprivation and gestational age with preschool language ability? Findings In this cohort study of 26 341 children in Scotland, neighborhood deprivation and lower gestational age were associated with additive risks for speech, language, and communication concerns at age 27 to 30 months. Meaning Policies designed to lessen deprivation could be an important strategy for reducing preschool language impairment, including for children born preterm., This cohort study investigates the associations of neighborhood disadvantage, gestational age, and English as a first language with speech, language, and communication concerns at age 27 to 30 months among children in Scotland., Importance Successful acquisition of language is foundational for health and well-being across the life course and is patterned by medical and social determinants that operate in early life. Objective To investigate the associations of neighborhood disadvantage, gestational age, and English as first language with speech, language, and communication concerns among children aged 27 to 30 months. Design, Setting, and Participants This cohort study used birth data from the National Health Service maternity electronic medical record linked to the Child Health Surveillance Programme for preschool children. The cohort included 28 634 children in the United Kingdom (NHS Lothian, Scotland) born between January 2011 and December 2014 who were eligible for a health review at age 27 to 30 months between April 2013 and April 2016. Data analysis was conducted between January 2018 and February 2019. Exposures The associations of neighborhood deprivation (using the Scottish Index of Multiple Deprivation 2016 quintiles), gestational age, and whether English was the first language spoken in the home with preschool language function were investigated using mutually adjusted logistic regression models. Main Outcomes and Measures Speech, language, and communication (SLC) concern ascertained at age 27 to 30 months. Results Records of 28 634 children (14 695 [51.3%] boys) with a mean (SD) age of 27.7 (2.2) months were matched. After excluding records with missing data, there were 26 341 records. The prevalence of SLC concern was 13.0% (3501 of 26 963 children with SLC data). In fully adjusted analyses, each 1-week increase in gestational age from 23 to 36 weeks was associated with an 8.8% decrease in the odds of a child having an SLC concern reported at 27 months (odds ratio, 0.92; 95% CI, 0.90-0.93). The odds of a child for whom English is not the first language of having SLC concern at age 27 to 30 months were 2.1-fold higher than those for a child whose first language is English (OR, 2.09; 95% CI, 1.66-2.64). The odds ratio for having an SLC concern among children living in the most deprived neighborhoods, compared with the least deprived neighborhoods, was 3.15 (95% CI, 2.79-3.56). The estimated probabilities for preterm children having an SLC concern were highest for those living in the most deprived areas. Conclusions and Relevance This study found that SLC concerns at age 27 to 30 months are common and independently associated with increasing levels of neighborhood deprivation and lower gestational age. Policies that reduce childhood deprivation could be associated with improved preschool language ability and potentially avoid propagation of disadvantage across the life course, including for children born preterm.

With recent approvals of antisense oligonucleotides as therapeutics, there is an increasing interest in expanding the application of these compounds to many other diseases. Our laboratory focuses on developing therapeutic splice modulating antisense oligonucleotides to treat diseases potentially amendable to intervention during pre-mRNA processing, and here we report the use of oligomers to down-regulate integrin alpha 4 protein levels. Over one hundred antisense oligonucleotides were designed to induce skipping of individual exons of the ITGA4 transcript and thereby reducing protein expression. Integrin alpha 4-mediated activities were evaluated in human dermal fibroblasts and Jurkat cells, an immortalised human T lymphocyte cell line. Peptide conjugated phosphorodiamidate morpholino antisense oligomers targeting ITGA4 were also assessed for their effect in delaying disease progression in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. With the promising results in ameliorating disease progression, we are optimistic that the candidate oligomer may also be applicable to many other diseases associated with integrin alpha 4 mediated inflammation. This highly specific strategy to down-regulate protein expression through interfering with normal exon selection during pre-mRNA processing should be applicable to many other gene targets that undergo splicing during expression.

Duchenne muscular dystrophy is an inherited muscle wasting disease with severe symptoms and onset in early childhood. Duchenne muscular dystrophy is caused by loss-of-function mutations, most commonly deletions, within the DMD gene. Characterizing the junction points of large genomic deletions facilitates a more detailed model of the origins of these mutations and allows for a greater understanding of phenotypic variations associated with particular genotypes, potentially providing insights into the deletion mechanism. Here, we report sequencing of breakpoint junctions for seven patients with intragenic, whole-exon DMD deletions. Of the seven junction sequences identified, we found one instance of a “clean” break, three instances of microhomology (2–5 bp) at the junction site, and three complex rearrangements involving local sequences. Bioinformatics analysis of the upstream and downstream breakpoint regions revealed a possible role of short inverted repeats in the initiation of some of these deletion events., Duchenne muscular dystrophy: Understanding how the DMD gene breaks Researchers in Australia have identified new examples of the genomic factors and mechanisms that lead to deletions linked with Duchenne muscular dystrophy (DMD). DMD is an inherited neuromuscular disease which causes progressive deterioration of muscles and, in some cases, intellectual impairment. Using samples from seven DMD patients, Niall Keegan of Murdoch University in Perth and colleagues sequenced the DNA left behind around the deletions in the DMD gene which cause the disease. They found one clean break, three sections with short repeated sequences, and three with more complex rearrangements. The diversity of these findings led them to suggest that the deletions resulted from a diversity of genomic factors and repair mechanisms. Future work could incorporate these findings into a model to predict where deletions will occur, expanding our understanding of DMD and its causes.

A key question is how technologies can influence social interaction in autistic children, and how opportunities for interaction can embedded into design. Here, we present observations from video recordings of autistic children playing with different technological interfaces and use cognitive event analysis (CEA) to identify instances of child-led interactions. Artefacts which fostered interaction include i) visual prompts for collaboration, ii) multi-media feedback, and iii) expansion of opportunities through tangible interactions.

SummaryAn increasing body of genetic and imaging research shows that it is becoming possible to forecast the onset of major psychiatric disorders such as depression and schizophrenia before people become ill with ever improving accuracy. Practical issues such as the optimal combination of clinical and biological variables are being addressed, but the application of predictive algorithms to individuals or in routine clinical settings have yet to be tested. The development of predictive methods in mental health comes with substantial ethical questions, including whether people wish to know their level of risk, as well as individual and societal attitudes to the potential adverse effects of data sharing, early diagnosis and treatment, which so far have been largely ignored. Preliminary data suggests that at least some people think predictive research is valuable and would take part in such studies, and some would welcome knowing the results. Future initiatives should systematically assess opinions and attitudes in conjunction with scientific and technical advances.Declaration of interestIn the past 3 years, S.M.L. has received personal fees from Otsuaka, Sunovion and Janssen, and research grant support from Janssen and Lundbeck. A.M.M. has received research support from the Sackler Trust, Eli Lilly and Janssen. S.M.L. is part of the PSYSCAN consortium.

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation., Supported in part by grants from the Health Institute Carlos III and FEDER a way to achieve Europe (PI16–01843 to CP, JR15/00042 to MC-S), the Fundación Progreso y Salud, Junta de Andalucía (PI-0085-2016 to JLN-G), and Australian National Health and Medical Research Council (NHMRC) Fellowships (APP1122952 and APP1117510 to GR and NGL).

Adjustment of siblings of children with ASD must be viewed within cultural context.•UK siblings reported greater difficulties than Taiwanese siblings.•Difficulties in peer relationships were a concern for UK siblings.•Different coping styles related to siblings’ adjustment in Taiwan and the UK.•The broader autism phenotype influenced outcome, but only in the UK siblings. Background The present paper examined the psychosocial adjustment of typically developing (TD) siblings of children with ASD and the extent to which this is impacted by key demographic and psychosocial variables. A cross-cultural perspective was adopted to compare influences on coping and adjustment in Taiwan and the United Kingdom (UK). Method155 mother-TD sibling dyads participated, 80 in Taiwan and 75 in the UK. Participants reported by questionnaire on family demographics, symptom severity of the child with ASD, TD siblings’ life events, subjective well-being, social support, coping strategies, parent and sibling Broader Autism Phenotype (BAP) level and adjustment outcome. Results According to their self-report, TD siblings’ in Taiwan were fairly well adjusted, while slightly elevated difficulties were found in the UK sample, with peer problems the biggest concern. Impact of life experience, sibling coping, and social support were related to adjustment in both countries, but with different coping styles important in the two countries. In the UK, parents’ coping style and siblings’ own BAP level also contributed to outcome. Some differences between Taiwan and the UK samples may result from culturally-specific patterns in evaluation of child behaviours. Conclusions The findings from this large-scale questionnaire study have implications for clinical practice. UK siblings’ adjustment might be enhanced via intervention on parent coping style, while Taiwanese siblings may be better supported through promotion of their own coping. Health professionals should be aware of the influence of BAP levels in parents and TD siblings, which might change the way they experience stress and respond under pressure.

Evidence is accumulating that early intervention can be effective in improving the skills of young children with autism spectrum disorder. However, the science is hampered by the lack of agreed “gold standard” tools for the measurement of progress and outcome. What is required is a reliable, valid, and sensitive measure of change in the core domains of autism, which can be undertaken blind to group and time. This article explores the use of a promising measure of change, for which reliability, validity, and sensitivity to change over a lengthy period have been previously demonstrated. Pilot data indicate that, despite some sensitivity to change over a short period of time, it does not capture treatment effects more effectively than an existing diagnostic tool. Future directions for the ongoing search are suggested, including consideration of how to achieve sensitivity to differential change as well as to change over time.