Developmental trajectories in infants and pre-school children with Neurofibromatosis 1.

BACKGROUND: Children with Neurofibromatosis 1 (NF1) show cognitive, behavioural and social differences compared to their peers. However, the age and sequence at which these differences begin to emerge is not fully understood. This prospective cohort study examines the cognitive, behavioural, ADHD trait and autism symptom development in infant and pre-school children with NF1 compared with typically developing (TD) children without a family history of neurodevelopmental conditions. METHODS: Data from standardised tests was gathered at 5, 10, 14, 24 and 36 months of age (NF1 n = 35, TD n = 29). Developmental trajectories of cognitive (Mullen Scales of Early Learning, MSEL) and adaptive behavioural (Vineland Adaptive Behavior Scales, VABS) development from 5 to 36 months were analysed using linear mixed modelling. Measures of ADHD (Child Behavior Checklist) and autism traits (ADOS-2, BOSA-MV and ADI-R) were assessed at 24 and 36 months. RESULTS: The developmental trajectory of cognitive skills (all domains of the MSEL) and behavioural skills (four domains of the VABS) differed significantly between NF1 and TD groups. Post-hoc tests demonstrated that the NF1 participants scored significantly lower than TD participants at 24 months on all MSEL and VABS domains. The NF1 cohort demonstrated higher mean autism and ADHD traits at 24 months and 14% of the NF1 cohort met a research diagnostic classification for autism at 36 months. LIMITATIONS: The study has a relatively small sample size due to variable retention and rolling recruitment. Due to limitations imposed by the COVID-19 pandemic, we utilised the Brief Observation of Symptoms of Autism for Minimally Verbal children (BOSA-MV) for some participants, which was administered online and may not gather as accurate a picture of traits as ADOS-2. The BOSA-MV was utilised for 41% of participants with NF1 at 36 months compared to 11% at 24 months. This may explain the reduction in the percentage of children with NF1 that met autism criteria at 36 months. CONCLUSIONS: By 24 months of age, the NF1 cohort show lower cognitive skills and adaptive behaviour and higher levels of autism and ADHD traits as compared to TD children. This has implications for developmental monitoring and referral for early interventions. TRIAL REGISTRATION: Not applicable.

The ecology of ageing in wild societies: linking age structure and social behaviour.

The age of individuals has consequences not only for their fitness and behaviour but also for the functioning of the groups they form. Because social behaviour often changes with age, population age structure is expected to shape the social organization, the social environments individuals experience and the operation of social processes within populations. Although research has explored changes in individual social behaviour with age, particularly in controlled settings, there is limited understanding of how age structure governs sociality in wild populations. Here, we synthesize previous research into age-related effects on social processes in natural populations, and discuss the links between age structure, sociality and ecology, specifically focusing on how population age structure might influence social structure and functioning. We highlight the potential for using empirical data from natural populations in combination with social network approaches to uncover pathways linking individual social ageing, population age structure and societal functioning. We discuss the broader implications of these insights for understanding the social impacts of anthropogenic effects on animal population demography and for building a deeper understanding of societal ageing in general.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.

Dynamic soaring decouples dynamic body acceleration and energetics in albatrosses.

Estimates of movement costs are essential for understanding energetic and life-history trade-offs. Although overall dynamic body acceleration (ODBA) derived from accelerometer data is widely used as a proxy for energy expenditure (EE) in free-ranging animals, its utility has not been tested in species that predominately use body rotations or exploit environmental energy for movement. We tested a suite of sensor-derived movement metrics as proxies for EE in two species of albatrosses, which routinely use dynamic soaring to extract energy from the wind to reduce movement costs. Birds were fitted with a combined heart-rate, accelerometer, magnetometer and GPS logger, and relationships between movement metrics and heart rate-derived V̇O2, an indirect measure of EE, were analyzed during different flight and activity modes. When birds were exclusively soaring, a metric derived from angular velocity on the yaw axis provided a useful proxy of EE. Thus, body rotations involved in dynamic soaring have clear energetic costs, albeit considerably lower than those of the muscle contractions required for flapping flight. We found that ODBA was not a useful proxy for EE in albatrosses when birds were exclusively soaring. As albatrosses spend much of their foraging trips soaring, ODBA alone was a poor predictor of EE in albatrosses. Despite the lower percentage of time flapping, the number of flaps was a useful metric when comparing EE across foraging trips. Our findings highlight that alternative metrics, beyond ODBA, may be required to estimate energy expenditure from inertial sensors in animals whose movements involve extensive body rotations.

The development, feasibility and acceptability of Empower-Autism: A new psychoeducational and psychotherapeutic programme for caregivers of children recently diagnosed with autism.

LAY ABSTRACT: What is already known about the topic?Parents and carers face many challenges following their child's autism diagnosis. They often look for information, and social and emotional support. There has been relatively little research into how best to provide this support and this means that there is no evidence to guide the delivery of services. Studies have suggested that an approach called Acceptance and Commitment Therapy can help parents and carers with their adjustment and emotional wellbeing.What does this article add?This article describes the development of a new group-based programme to address the diverse needs of caregivers after their child's autism diagnosis. The new programme was developed with caregivers, autistic people and professionals. It was called Empower-Autism and contained lots of information about autism and strategies to support autistic children, alongside therapeutic aspects based on Acceptance and Commitment Therapy. The programme was delivered to 29 parents/carers in three groups. Attendance at the groups was satisfactory. Both parents/carers and facilitators liked and valued the programme and found it accessible. They made suggestions for improvements. After the programme, parents and carers described improved wellbeing. They felt more positive and more connected to other people. They also described parenting their child in a more informed and sensitive way.Implications for practice, research or policyThe new programme is being tested within a large clinical trial. If there are positive results, the programme could be recommended for delivery and this would address an important gap in evidence-based practice.

Amphiphilic shuttle peptide delivers base editor ribonucleoprotein to correct the CFTR R553X mutation in well-differentiated airway epithelial cells.

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery. By isolating and extending the ELD, we created a novel shuttle peptide, termed S237. While S237 achieved lower delivery of green fluorescent protein, it outperformed S10 at Cas9 RNP delivery to cultured human airway epithelial cells and to pig airway epithelia in vivo, possibly due to its lower net charge. In well-differentiated primary human airway epithelial cell cultures, S237 achieved a 4.6-fold increase in base editor RNP delivery, correcting up to 9.4% of the cystic fibrosis transmembrane conductance regulator (CFTR) R553X allele and restoring CFTR channel function close to non-CF levels. These findings deepen the understanding of peptide-mediated delivery and offer a translational approach for base editor RNP delivery for CF airway disease.

Parent-mediated intervention in infants with an elevated likelihood for autism reduces dwell time during a gaze-following task.

Cognitive markers may in theory be more sensitive to the effects of intervention than overt behavioral measures. The current study tests the impact of the Intervention with the British Autism Study of Infant Siblings-Video Interaction for Promoting Positive Parenting (iBASIS-VIPP) on an eye-tracking measure of social attention: dwell time to the referred object in a gaze following task. The original two-site, two-arm, assessor-blinded randomized controlled trial (RCT) of this intervention to increase parental awareness, and responsiveness to their infant, was run with infants who have an elevated familial likelihood for autism (EL). Fifty-four EL infants (28 iBASIS-VIPP intervention, 26 no intervention) were enrolled, and the intervention took place between 9 months (baseline) and 15 months (endpoint), with gaze following behavior measured at 15 months. Secondary intention to treat (ITT) analysis showed that the intervention was associated with significantly reduced dwell time to the referent of another person's gaze (ß = -0.32, SE = 0.14, p = 0.03) at 15-month treatment endpoint. Given the established link between gaze following and language, the results are considered in the context of a previously reported, non-significant and transient trend toward lower language scores at the treatment endpoint (Green et al. (2015) The Lancet Psychiatry, 2(2), 133-140). Future intervention trials should aim to include experimental cognitive measures, alongside behavioral measures, to investigate mechanisms associated with intervention effects.

The Ruminant Telomere-to-Telomere (RT2T) Consortium.

Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock.

Autistic and autism community perspectives on infant and family support in the first two years of life: Findings from a community consultation survey.

LAY ABSTRACT: Most support programmes for Autistic children are available only after they are diagnosed. Research suggests that parenting supports may be helpful for parents and their infants, when provided in the first 2 years of life - before a formal diagnosis is given, but when information suggests an infant is more likely to be Autistic. However, we do not know how acceptable these types of supports might be to the Autistic and autism communities. We asked 238 Autistic and non-autistic people - some of whom were parents, and some of whom were professionals working in research, health and education - about their perspectives on very-early supports. People generally agreed that it could be acceptable to work with parents to help them understand and support their child's specific needs and unique ways of communicating. People suggested a variety of support strategies could be acceptable, including parent education, changing the environment to meet an infant's needs, and creating opportunities for infants' to make choices and exercise control. People preferred respectful and accurate language - including the term 'support' (rather than 'intervention') and 'early-in-life' (rather than 'at-risk' of autism, or 'pre-emptive' when describing developmental stage). Continuing to work with community members will help to make sure autism support programmes are relevant and helpful.

Parent and professional perspectives on implementing the Pediatric Autism Communication Therapy: A mixed-methods analysis.

LAY ABSTRACT: Factors influencing the implementation of parent-mediated intervention are insufficiently studied. This study examines for the first-time factors of implementation into clinical practice across the world of Pediatric Autism Communication Therapy, an internationally disseminated, evidence-based, parent-mediated therapy. From both the parents' and the professionals' perspectives, parents attitudes (e.g. self-reflection abilities and videotaping management) and life-circumstances (e.g. stressed families condition and time) were central factors. In this type of therapy, the target is a child's development; still, this improvement is dependent on the parent's behavior when interacting with their child. What's more, Pediatric Autism Communication Therapy method (video reflection, empowerment of parent, play-based) was enabler according to most of the parents. And more, most professionals report factors linked to the Implementation Process that is planning, execution, reflection and assessment in implementation of a new therapy. Indeed, the professionals underlined barriers related to the population seen in practice, flexibility of schedule, support from colleagues and manager. All these factors could be improved and addressed with a formal implementation plan including factors related to the parents of each country.

An analysis of NHS 111 demand for primary care services: A retrospective cohort study.

The NHS 111 service triages over 16,650,745 calls per year and approximately 48% of callers are triaged to a primary care disposition, such as a telephone appointment with a general practitioner (GP). However, there has been little assessment of the ability of primary care services to meet this demand. If a timely service cannot be provided to patients, it could result in patients calling 999 or attending emergency departments (ED) instead. This study aimed to explore the patient journey for callers who were triaged to a primary care disposition, and the ability of primary care services to meet this demand. We obtained routine, retrospective data from the Connected Yorkshire research database, and identified all 111 calls between the 1st January 2021 and 31st December 2021 for callers registered with a GP in the Bradford or Airedale region of West Yorkshire, who were triaged to a primary care disposition. Subsequent healthcare system access (111, 999, primary and secondary care) in the 72 hours following the index 111 call was identified, and a descriptive analysis of the healthcare trajectory of patients was undertaken. There were 56,102 index 111 calls, and a primary care service was the first interaction in 26,690/56,102 (47.6%) of cases, with 15,470/26,690 (58%) commenced within the specified triage time frame. Calls to 999 were higher in the cohort who had no prior contact with primary care (58% vs 42%) as were ED attendances (58.2% vs 41.8), although the proportion of avoidable ED attendances was similar (10.5% vs 11.8%). Less than half of 111 callers triaged to a primary care disposition make contact with a primary care service, and even when they do, call triage time frames are frequently not met, suggesting that current primary care provision cannot meet the demand from 111.

Parent-infant interaction trajectories in infants with an elevated likelihood for autism in relation to 3-year clinical outcome.

Developmental antecedents of autism may affect parent-infant interactions (PII), altering the context in which core social skills develop. While studies have identified differences in PII between infants with and without elevated likelihood (EL) for autism, samples have been small. Here, we examined whether previously reported differences are replicable. From a longitudinal study of 113 EL and 27 typical likelihood infants (TL), 6-min videotaped unstructured PII was blind rated at 8 and 14 months on eight interactional qualities. Autism outcome was assessed at 36 months. Linear mixed-effects models found higher parent sensitive responsiveness, nondirectiveness, and mutuality ratings in TL than EL infants with and without later autism. PII qualities at 8 (infant positive affect, parent directiveness) and 14 months (infant attentiveness to parent, mutuality) predicted 3-year autism. Attentiveness to parent decreased between 8 and 14 months in EL infants with later autism. This larger study supports previous findings of emerging alterations in PII in this group and extends on this by detecting earlier (8-month) predictive effects of PII for autism outcome and a more marked trajectory of decreased social attentiveness. The findings strengthen the evidence base to support the implementation of early preemptive interventions to support PII in infants with early autism signs.

Identifying priority sites for whale shark ship collision management globally.

The expansion of the world's merchant fleet poses a great threat to the ocean's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark (Rhincodon typus) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation" sites are of significant ecological, socio-economic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world (>50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.

Taking a shortcut: what mechanisms do fish use?

Path integration is a powerful navigational mechanism whereby individuals continuously update their distance and angular vector of movement to calculate their position in relation to their departure location, allowing them to return along the most direct route even across unfamiliar terrain. While path integration has been investigated in several terrestrial animals, it has never been demonstrated in aquatic vertebrates, where movement occurs through volumetric space and sensory cues available for navigation are likely to differ substantially from those in terrestrial environments. By performing displacement experiments with Lamprologus ocellatus, we show evidence consistent with fish using path integration to navigate alongside other mechanisms (allothetic place cues and route recapitulation). These results indicate that the use of path integration is likely to be deeply rooted within the vertebrate phylogeny irrespective of the environment, and suggests that fish may possess a spatial encoding system that parallels that of mammals.

Generalisation of Social Communication Skills by Autistic Children During Play-Based Assessments Across Home, School and an Unfamiliar Research Setting.

We investigated autistic children's generalisation of social communication over time across three settings during a play-based assessment with different adults and explore the potential moderating effects on generalisation of age, nonverbal IQ and level of restricted and repetitive behaviours. The social communication abilities of 248 autistic children (2-11 years, 21% female, 22% single parent, 60% white) from three UK sites were assessed from 1984 video interactions in three contexts with three different interaction partners (parent/home, teaching assistant/school, researcher/clinic) at baseline, midpoint (+ 7m) and endpoint (+ 12m) within the Paediatric Autism Communication Trial-Generalised (PACT-G), a parent-mediated social communication intervention. Children's midpoint social communication at home generalised to school at midpoint and to clinic at endpoint. Generalisation was stronger from home to school and clinic than school to home and clinic. Generalisation was not moderated by age, nonverbal IQ or restricted and repetitive behaviour. Broader child development did not explain the pattern of results. The current study is the largest study to date to explore generalisation with autistic children and provides novel insight into their generalisation of social communication skills. Further research is needed to gain a more comprehensive understanding of facilitators of generalisation across settings and interaction partners in order to develop targeted strategies for interventions to enhance outcomes for young autistic children.

Experiences and concerns of parents of children with a 16p11.2 deletion or duplication diagnosis: a reflexive thematic analysis.

BACKGROUND: 16p11.2 proximal deletion and duplication syndromes (Break points 4-5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known propensity for lifelong psychiatric problems. This study aimed to contribute to a research gap by qualitatively exploring the challenges families with 16p11.2 deletion and duplication face by answering three research questions: (1) What are parents' perceptions of the ongoing support needs of families with children who have 16p11.2 living in the UK?; (2) What are their experiences in trying to access support?; (3) In these regards, do the experiences of parents of children with duplication converge or vary from those of parents of children with 16p11.2 deletion? METHODS: 33 parents with children (aged 7-17 years) with 16p11.2 deletion or duplication participated in structured interviews, including the Autism Diagnostic Interview- Revised (ADI-R). Their answers to the ADI-R question 'what are your current concerns' were transcribed and subsequently analysed using Braun and Clarke's six step reflexive thematic analysis framework. RESULTS: Three themes were identified: (1) Child is Behind Peers (subthemes: developmentally; academically; socially; emotionally); (2) Metabolism and Eating Patterns and; (3) Support (subthemes: insufficient support available; parent has to fight to access support; COVID-19 was a barrier to accessing support; 16p11.2 diagnosis can be a barrier to support, child is well-supported). CONCLUSIONS: Parents of children with either 16p11.2 deletion or duplication shared similar experiences. However, metabolism concerns were specific to parents of children with 16p11.2 deletion. The theme Child is Behind Peers echoed concerns raised in previous Neurodevelopmental Copy Number Variant research. However, there were some key subthemes relating to research question (2) which were specific to this study. This included parents' descriptions of diagnostic overshadowing and the impact of a lack of eponymous name and scant awareness of 16p11.2.

Locked down-locked in: experiences of families of young children with autism spectrum disorders in Delhi, India.

Introduction: The onset of the COVID-19 pandemic and subsequent lockdowns in March 2020 disrupted the lives of families across India. The lockdown related restrictions brought forth a multitude of challenges including loss of employment, social isolation, school closures and financial burdens. Specifically, it also resulted in the restriction of health-care services for children with neurodevelopmental disabilities. Methods: This qualitative study was conducted as a part of a larger trial in India to understand the experiences of families of young children with autism during the pandemic. In-depth interviews were carried out with 14 caregivers residing in New Delhi, India. Results: Our findings identified pandemic and lockdown's universal impacts on family life and financial stability stemming from job loss, business closure, and salary deductions, affecting quality of life of families. Furthermore, COVID-19 pandemic's impact on autistic children was evident through limited access to essential services and financial challenges related service interruptions even after resumption of services. The lockdown's novelty also affected children's behavior, with both challenging behavioral changes and positive impacts. Primary caregivers, predominantly mothers, assumed additional responsibilities in household tasks, schooling, and therapy administration. While some these experiences were universally experienced, a few of these improved outcomes for autistic children. Despite challenges, parents expressed gratitude for their family's safety and well-being during the difficult time. Discussions: These findings inform service provision for vulnerable families and offer implications for designing interventions such as credit schemes for families, guidance and resources for establishing and maintaining routines of children with autism, adopting flexible and adaptable approaches to service delivery, and special provisions for children with autism to be able to maintain their routines outside of home. Furthermore, the study highlights the need for comprehensive support, including educational resources and stress management counselling to empower parents in supporting essential care and routines for their children during such unprecedented times.

Acceptability and feasibility of a parent-mediated social-communication therapy for young autistic children in Brazil: A qualitative implementation study of Paediatric Autism Communication Therapy.

LAY ABSTRACT: Parents of autistic children and health professionals who work with autistic children in Brazil had positive views about introducing Paediatric Autism Communication Therapy as a therapy for autistic children in Brazil. The parents and clinicians also mentioned some difficulties about using Paediatric Autism Communication Therapy in Brazil. We made adaptations to Paediatric Autism Communication Therapy to address these difficulties. Paediatric Autism Communication Therapy is a therapy to support the development of social and communication skills for autistic children aged 2-10 years. The therapy is conducted with the autistic child's parent. Paediatric Autism Communication Therapy has not been used in Brazil before. There are few therapy options available for autistic children in Brazil and we believed that Paediatric Autism Communication Therapy may be useful. We asked three groups of people in Brazil about their views of Paediatric Autism Communication Therapy, after explaining how the therapy works. Group 1 included 18 parents of autistic children aged 2-10 years. Group 2 included 20 health professionals such as psychologists who work with autistic children. Group 3 included 15 parents of autistic children aged 2-7 years who received the Paediatric Autism Communication Therapy. We learned that parents and clinicians felt that Paediatric Autism Communication Therapy would be a beneficial therapy for autistic children in Brazil. We also found out about the challenges of using Paediatric Autism Communication Therapy in Brazil. We used these findings to make small cultural adaptations to Paediatric Autism Communication Therapy to make it more suitable for Brazil.

Induced Pluripotent Stem Cells in the Era of Precise Genome Editing.

Genome editing has enhanced our ability to understand the role of genetics in a number of diseases by facilitating the development of more precise cellular and animal models to study pathophysiological processes. These advances have shown extraordinary promise in a multitude of areas, from basic research to applied bioengineering and biomedical research. Induced pluripotent stem cells (iPSCs) are known for their high replicative capacity and are excellent targets for genetic manipulation as they can be clonally expanded from a single cell without compromising their pluripotency. Clustered, regularly interspaced short palindromic repeats (CRISPR) and CRISPR/Cas RNA-guided nucleases have rapidly become the method of choice for gene editing due to their high specificity, simplicity, low cost, and versatility. Coupling the cellular versatility of iPSCs differentiation with CRISPR/Cas9-mediated genome editing technology can be an effective experimental technique for providing new insights into the therapeutic use of this technology. However, before using these techniques for gene therapy, their therapeutic safety and efficacy following models need to be assessed. In this review, we cover the remarkable progress that has been made in the use of genome editing tools in iPSCs, their applications in disease research and gene therapy as well as the hurdles that remain in the actual implementation of CRISPR/Cas systems.