A national evaluation of QbTest to support ADHD assessment: a real-world, mixed methods approach.

BACKGROUND: QbTest is a commercially available, computerised test of attention, impulsivity, and activity designed to assist with the diagnosis of attention deficit hyperactivity disorder (ADHD). Health Innovation East Midlands (formerly East Midlands AHSN), led the implementation of the QbTest on behalf of the 15 Health Innovation Networks across Child and Adolescent Mental Health services (CAMHS) and Paediatric sites in England between April 2020 and March 2023. We evaluate the impact of this programme on diagnostic assessment at participating sites. METHODS: A mixed-methods approach was used including: case-note data collected on 10-30 cases per site pre and post QbTest implementation; interviews with healthcare staff working with QbTest; and surveys to explore perspectives of healthcare staff and patients/carers. Case-note data was descriptively analysed to compare time to diagnosis (number of appointments and days) pre/post QbTest implementation. Survey data was analysed descriptively. Qualitative interview data was explored using thematic analysis. RESULTS: Case-note data was provided by 20 sites across England. Comparison of mean values pre- and post-QbTest implementation identified a decrease of 0.37 (11.5%) in number of appointments to reach a diagnostic decision, a 55-day (12.5%) increase in days from initial referral to diagnosis, and a 12-day (10.3%) increase in days to reach a diagnostic decision. Exploratory analyses indicated greater benefit for Paediatric services over CAMHS, in terms of a decrease in days from referral to diagnosis and number of appointments to diagnosis. Interviews with healthcare staff (n=21) revealed that the QbTest was perceived to support a faster, more efficient diagnostic process. Survey data (n=65 healthcare staff, n=22 patients/carers) identified that the QbTest helped patients understand their symptoms and the diagnostic decision.  Although some logistical issues (e.g., room requirements) and patient issues (e.g., sensory sensitivity) were identified, healthcare staff considered that QbTest was easily incorporated into the ADHD assessment pathway. CONCLUSION: The national implementation of QbTest in ADHD clinics resulted in a small reduction in the number of clinical appointments needed to reach a diagnostic decision, with greatest benefit demonstrated in Paediatric sites. Data were impacted by COVID-19 therefore, further evaluation is warranted.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Patients' experience of accessing support for tics from primary care in the UK: an online mixed-methods survey.

BACKGROUND: Tics are common in children and young people and may persist into adulthood. Tics can cause challenges with social, occupational, physical, and academic functioning. The current study explores the perceptions of adults with tics and parents/carers of young people with tics regarding their experience of accessing support from professionals in primary care in the UK. METHODS: Two online cross-sectional surveys were completed by 33 adults with tics and 94 parents/carers of children with tics. Participants were recruited across three online tic support groups. Tic specialist psychologists, academic researchers, and people with lived experience of tics provided feedback on the surveys before they were made available online. Mixed-method analyses were conducted on the surveys. Qualitative data from the free-text responses were analysed using thematic analysis and triangulated with quantitative findings where appropriate. RESULTS: While some participants felt supported by general practitioners (GPs), many felt dismissed. The impact of tics was not always explored, nor information on tics provided, during the consultation. Although 78.7% of participants were referred to secondary care for their tics, some struggled to get the referral. Within secondary care, most adult respondents were assessed by neurologists whilst young people were typically assessed by paediatricians or psychiatrists. Most of these secondary care clinicians did not specialise in tic disorders, with only 27.9% of participants being assessed by tic specialists. Mode waitlist time was 3-6 months for young people and longer for adult respondents. Some participants were referred to multiple secondary care services, spanning neurology, paediatrics, and psychiatry, with each stating that they do not provide support for tics. 21% of participants mentioned being discharged from secondary care with no ongoing support. Almost one-third of respondents accessed support within private healthcare. CONCLUSIONS: Generally, more negative than positive experiences were reported. Possible contributing factors included a lack of clear tic referral pathways, long waitlists, a lack of information about tics provided in primary care appointments and a lack of support offered following diagnosis by secondary care services, together with poor access to tic specialist clinicians. This study highlights areas where improvements to UK services for tics can be made.

Reporting of Factorial Randomized Trials: Extension of the CONSORT 2010 Statement.

Importance: Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal. Objective: To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials. Design: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist. Findings: This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported. Conclusions and Relevance: This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.

Refining Anger: Summarizing the Self-Report Measurement of Anger.

The current paper presents a five-factor measurement model of anger summarizing scores on public-domain self-report measures of anger. Exploratory and confirmatory factor analyses of self-report measures of anger (UK, n = 500; USA, n = 625) suggest five replicable latent anger factors: anger-arousal, anger-rumination, frustration-discomfort, anger-regulation, and socially constituted anger. Findings suggested a 5-factor interpretation provided the best fit of the data. We also report evidence of measurement invariance for this 5-factor model of anger across gender, age, and ethnicity. The findings suggest a useful and parsimonious account of anger, summarizing over 50 years of research around the self-report measurement of anger.

Using the candidacy framework to conceptualize systems and gaps when developing infant mental health (IMH) services: A qualitative study.

The development of infant mental health (IMH) services globally is still in its early stages. This qualitative study aims to understand the challenges of setting up IMH services and explores the views and experiences of 14 multi-disciplinary stakeholders who are part of the IMH implementation group in a large Scottish health board. Six major themes were identified through thematic analysis. This paper examines the most prominent theme "Systems" alongside the theme "Gaps in Current Service". The theoretical framework of "candidacy" is found to be a valuable way to conceptualize the complex systemic layers of micro, meso, and macro factors that contribute to the challenges of setting up services. At the micro level, key themes included the view that services must be accessible, individualized, and involve families. At the meso level, in line with the aims of the service, multiagency integration, aspects of early intervention, and clear operating conditions were all seen as important. Finally, at the macro level, perhaps the biggest challenge perceived by stakeholders is delivering a service that is entirely infant-focused. These findings will help inform policy makers about factors considered by professionals to be vital in the establishment of IMH services in Scotland and across the globe.

El desarrollo de los servicios de salud mental infantil (IMH) globalmente está aún en sus niveles básicos. Este estudio cualitativo se propone comprender los retos de establecer los servicios IMH y explora los puntos de vista y experiencias de 14 personas interesadas de múltiples disciplinas que son parte de un grupo de implementación de IMH dentro de una extensa junta de salud escocesa. A través de análisis temáticos se identificaron seis temas de mayor importancia. Este estudio examina el tema más prominente según la mayor percepción, "Sistemas," junto con el tema "Vacíos en la Actual Prestación de Servicio." Se estima que el marco teorético de trabajo de "candidatura," es una manera valiosa de conceptualizar los complejos niveles sistémicos de micro, medio y macro factores que contribuyen a los retos de establecer los servicios. Al nivel micro, los temas claves incluyen el punto de vista de que los servicios deben ser accesibles, individualizados y deben involucrar a las familias. Al nivel medio, alineados con las metas del servicio, la integración de agencias múltiples, aspectos de temprana intervención y claras condiciones operativas fueron todas estimadas como importantes. Finalmente, al nivel macro, quizás el mayor reto percibido por las personas interesadas es cumplir con el ofrecimiento de un servicio que esté enteramente enfocado en el infante. Estos resultados ayudarán a informar a quienes determinan las políticas a seguir acerca de los factores que los profesionales consideran vitales en el establecimiento de servicios IMH en Escocia y alrededor del globo.

Au niveau global, le développement de service de santé mentale du nourrisson et de la petite enfance en est encore à ses débuts. Cette étude qualitative s'est donnée pour but de comprendre les défis que pose l'installation de services IMH. Elle explore les vues et les perspectives de 14 parties prenantes de diverses disciplines qui font partie d'un groupe de mise en place IMH dans un grand conseil de santé en Ecosse. Six thèmes principaux ont été identifiés au travers une analyse thématique. Cet article examine le thème ayant été perçu comme le plus grand et proéminent, Systèmes, ainsi que le thème « Brèches dans les services actuels ¼. La structure théorique de la 'candidature' a été utilisée pour trouver une manière utile de conceptualiser les couches systémiques complexes de facteurs micro, méso, et macro qui contribuent aux défis qu'il y a dans l'installation de services. Au niveau micro, les thèmes clés ont inclus l'idée que les services doivent être accessibles, individualisés et engager les familles. Au niveau méso, s'alignant avec les buts du service, l'intégration de plusieurs agences, les aspects d'une intervention précoce et des conditions d'opération claires ont tous été estimé être importants. Enfin, au niveau macro, le défi étant peut-être le plus grand selon les parties prenantes est d'offrir un service qui est entièrement focalisé sur le nourrisson. Ces résultats aideront les décideurs pour ce qui s'agit des facteurs considérés comme étant vitaux par les professionnels pour ce qui concerne l'établissement de services IMH en Ecosse et au travers du globe.

Australasian Pediatric Gastroenterologists' Perspectives and Practices of Celiac Disease Diagnosis and Management.

BACKGROUND: The application of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) celiac disease (CeD) guidelines by pediatric gastroenterologists in Australia and New Zealand (Australasia) is unknown. Similarly, long-term management practices for patients with CeD are also unknown in this region. AIMS: This study aimed to explore the perceptions and practices of Australasian pediatric gastroenterologists in diagnosing and managing patients with CeD. METHODS: Australasian pediatric gastroenterologists and trainees were invited to complete an anonymous online survey over a 3-week period. RESULTS: The survey was completed by 28 respondents, 24 from Australia and four from New Zealand. Tissue transglutaminase antibody IgA was the most frequently ordered initial serologic test. Fifteen (54%) respondents relied on duodenal biopsies for the confirmation of CeD, six (21%) followed the ESPGHAN guidelines and the remaining seven offered either biopsy confirmation or no-biopsy diagnosis according to the parents' wishes. Following diagnosis, five (18%) respondents discharged patients from care, three (11%) discharged patients after one follow-up visit, one (4%) reviewed patients for 12 months, six (21%) reviewed patients until celiac antibodies normalized and children were clinically asymptomatic, and 13 (46%) reviewed patients until transition to adult care. CONCLUSION: Tissue transglutaminase antibody IgA was the most common initial serologic test ordered by this group of Australasian pediatric gastroenterologists. Half of these physicians rely solely on duodenal biopsy for the confirmation of CeD diagnosis: a minority routinely use the ESPGHAN guidelines. Physicians reported a wide range of CeD follow-up practices.

Implementation of Telehealth Services to Assess, Monitor, and Treat Neurodevelopmental Disorders: Systematic Review.

BACKGROUND: In response to COVID-19, there has been increasing momentum in telehealth development and delivery. To assess the anticipated exponential growth in telehealth, it is important to accurately capture how telehealth has been used in specific mental health fields prior to the pandemic. OBJECTIVE: This systematic review aimed to highlight how telehealth has been used with clinical samples in the neurodevelopmental field, including patients with neurodevelopmental disorders (NDDs), their families, and health care professionals. To identify which technologies show the greatest potential for implementation into health services, we evaluated technologies for effectiveness, economic impact, and readiness for clinical adoption. METHODS: A systematic search of literature was undertaken in April 2018 and updated until December 2019, by using the Medline, Web of Science, Scopus, CINAHL Plus, EMBASE, and PsycInfo databases. Extracted data included the type of technology, how the technology was used (ie, assessment, treatment, and monitoring), participant characteristics, reported outcomes and authors' views on clinical effectiveness, user impact (ie, feasibility and acceptability), economic impact, and readiness for clinic adoption. A quality review of the research was performed in accordance with the Oxford Centre for Evidence-Based Medicine Levels of Evidence. RESULTS: A total of 42 studies met the inclusion criteria. These studies included participants and family members with autism spectrum disorders (21/42, 50%), attention deficit hyperactivity disorders (8/42, 19%), attention deficit hyperactivity or autism spectrum disorders (3/42, 7%), communication disorders (7/42, 17%), and tic disorders (2/42, 5%). The focus of most studies (33/42, 79%) was on treatment, rather than assessment (4/42, 10%) or monitoring (5/42, 12%). Telehealth services demonstrated promise for being clinically effective, predominantly in relation to diagnosing and monitoring NDDs. In terms of NDD treatment, telehealth services were usually equivalent to control groups. There was some evidence of positive user and economic impacts, including increased service delivery efficiency (eg, increased treatment availability and decreased waiting times). However, these factors were not widely recorded across the studies. Telehealth was demonstrated to be cost-effective in the few studies that considered cost-effectiveness. Study quality varied, as many studies had small sample sizes and inadequate control groups. Of the 42 studies, only 11 (26%) were randomized controlled trials, 12 (29%) were case studies or case series, 6 (14%) were qualitative studies, and 5 (12%) were noncomparative trials. CONCLUSIONS: Telehealth has the potential to increase treatment availability, decrease diagnosis waiting times, and aid in NDD monitoring. Further research with more robust and adequately powered study designs that consider cost-effectiveness and increased efficiency is needed. This systematic review highlights the extent of telehealth technology use prior to the COVID-19 pandemic and the movement for investing in remote access to treatments. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42018091156; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018091156.

A survey of the impact of owning a service dog on quality of life for individuals with physical and hearing disability: a pilot study.

BACKGROUND: Quality of life refers to a person's experienced standard of health, comfort and happiness and is typically measured using subjective self-report scales. Despite increasing scientific interest in the value of dogs to human health and the growing demand for trained service dogs, to date no research has reported how service dogs may affect client perceptions of quality of life. METHOD: We compared quality of life scores on the 16 item Flanagan quality of life scale from individuals who owned a trained service dog with those who were eligible to receive a dog, but did not yet have one (waiting list control). Data were analysed separately from two groups; those with a service dog trained for individuals with physical disabilities (with physical service dog: n = 72; waiting for a service dog: n = 24; recruited from Dogs for Good database) and those with a hearing service dog (with hearing service dog = 111; waiting for a service dog = 30; recruited from Hearing Dogs for Deaf People database). RESULTS: When controlling for age and gender individuals scored higher on total quality of life scores if they owned a service dog or a hearing service dog, but this was only statistically significant for those with a service dog. Both groups (physical service dog and hearing service dog) scored significantly higher on items relating to health, working, learning and independence if they owned a service dog, in comparison to those on the waiting list. Those with a physical service dog also scored significantly higher on items relating to recreational activities (including items relating to reading/listening to music, socialising, creative expression), and those involving social interactions (including items relating to participating in organisations, socialising, relationship with relatives). Additionally, those with a physical service dog scored higher on understanding yourself and material comforts than those on the waiting list control. In contrast, those with a hearing service dog appeared to receive fewer benefits on items relating to social activities. CONCLUSIONS: Owning a service dog can bring significant specific and potentially general benefits to the quality of life of individuals with physical disabilities and hearing impairments. These benefits may have considerable implications for individuals with disabilities, society and the economy by promoting independence, learning and working abilities.

A Systematic Review of Tools to Assess Coeliac Disease-Related Knowledge.

Background: Coeliac disease (CD) is an immune-mediated disorder, with dietary exclusion of gluten the only current treatment. A good knowledge of CD and gluten-free diet (GFD) is essential for those with CD to support effective self-management. Knowledge assessment with a validated tool helps evaluate understanding and knowledge gaps to better tailor educational resources. This study's aim was to perform a systematic review to identify validated CD knowledge assessment tools. Methods: PRISMA guidelines were followed, and searches were carried out in five literature databases. Papers were reviewed for tool development and testing process and assessed against pre-defined criteria for feasibility, validity, and reliability. Results: Twenty-five papers were included in the final analysis. Studies were from 16 countries, with a range of target populations, study designs, and development processes. Eleven reported pilot testing, and five assessed readability. Content validity was assessed in ten papers and formal content validity testing in one. Many tools contained items affecting generalisability outside the region developed. Conclusions: For a CD knowledge assessment tool to be suitable for use, it needs to be well designed, tested, and generalisable. No papers identified satisfied all requirements, thus highlighting a need to develop an appropriate tool.

Waiting-list interventions for children and young people using child and adolescent mental health services: a systematic review.

QUESTION: Children and young people experience delays in assessment and/or treatment within mental health services. The objective of this systematic review, funded by the Emerging Minds Network, was to explore the current evidence base for mental health waiting list interventions to support children and young people. STUDY SELECTION AND ANALYSIS: A literature search was conducted in MEDLINE, PsycINFO, Web of Science and the Cochrane databases from 2000 to 2023 (last searched October 2023). Included studies described interventions to support children and young people and/or their family while on a waiting list for child and adolescent mental health services. Titles and abstracts were screened independently by two reviewers, data were extracted by one reviewer, confirmed by a second and a narrative synthesis was provided. FINDINGS: Eighteen studies including 1253 children and young people were identified. Studies described waiting list interventions for autism spectrum disorders, eating disorders, generic conditions, transgender health, anxiety/depression, self-harm and suicide and behavioural issues. Many interventions were multicomponent; 94% involved psychoeducation, other components included parental support, bibliotherapy and coaching. Duration of the interventions ranged from a single session to over a year; 66% involved face-to-face contact. All studies demonstrated benefits in terms of improved clinical outcomes and/or feasibility/acceptability. Evidence for service outcomes/efficiency was largely unexplored. Limitations of the underpinning research, such as sample size and low-quality papers, limit the findings. CONCLUSIONS: There is limited research exploring waiting list interventions, however, the findings from small-scale studies are promising. Further research using robust study designs and real-world implementation studies are warranted.

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

'Breaking the cycle': a qualitative study exploring general practitioners' views of infant mental health.

BACKGROUND: Infants living in areas of socioeconomic deprivation are more likely to have adverse childhood experiences (ACEs), which are associated with infant mental health (IMH) problems and poor physical and mental health outcomes throughout the life course. As part of the development of IMH services in Scotland, studies are being conducted to explore various stakeholders' perspectives. AIM: To understand the views and experiences of GPs working in socioeconomically deprived areas in relation to IMH. DESIGN & SETTING: Qualitative study with GPs working in deprived urban communities in Scotland, UK. METHOD: Semi-structured interviews were conducted with 12 GPs from 11 practices. Transcribed interviews were thematically analysed, following the Braun and Clarke framework, using NVivo (version 12) software. RESULTS: The following three overarching themes are presented: (1) Deep End GPs' inherent understanding of IMH, owing to their placement in deprived communities and their under-recognised role in current IMH provision; (2) Factors influencing how communities might perceive IMH, including the potential associations of IMH with parental blame or judgement in areas of socioeconomic deprivation; and (3) Using previous experience to visualise future IMH service delivery, particularly improving on current shortcomings of connectivity and accessibility of services, to develop successful new services. CONCLUSION: GPs in areas of socioeconomic deprivation have a deep understanding of the issues affecting IMH, although do not necessarily relate to the term 'IMH'. New community-based IMH services are much needed, particularly in deprived areas. However, the pre-existing role of primary care must be recognised, supported, and integrated into new services, alongside training to increase IMH awareness among GPs and other primary healthcare professionals (HCPs).

Dog owner mental health is associated with dog behavioural problems, dog care and dog-facilitated social interaction: a prospective cohort study.

Despite numerous qualitative and cross-sectional studies investigating how dog-related factors may impact owners' well-being, empirical studies to test these causal effects are lacking. This prospective cohort study examined the correlation and potential causal effect of 17 dog-related factors with six well-being outcomes (depression, anxiety, loneliness, suicidal ideation, hedonic well-being and eudaimonic well-being) in dog owners. Over a four-week period, 709 adult dog owners reported their weekly well-being and occurrence of each dog-related factor (e.g. how many times they ran with their dogs). A random intercept cross-lagged panel model (RI-CLPM) with significance threshold set at 0.001 was used. Six factors correlated with poorer owner well-being (i.e. aggressive dog behaviour, fearful dog behaviour, poor dog health, failure to provide for the dog, lack of control over the dog, and dog presence). Only 'friendly conversation with others due to the dog' correlated with better well-being. Purposeful reductions in the frequency of dog behavioural and health-related issues are likely to improve owner well-being, as well as greater consistency in dog care (i.e. provide for the dog) and more engagement in friendly dog-facilitated social interactions. No potential causal effects were significant. Further studies investigating causal relationships are essential to improve people's well-being through dog ownership.

Rates of Status Epilepticus and Sudden Unexplained Death in Epilepsy in People With Genetic Developmental and Epileptic Encephalopathies.

BACKGROUND AND OBJECTIVES: The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management. METHODS: In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes SCN1A, SCN2A, SCN8A, SYNGAP1, NEXMIF, CHD2, PCDH19, STXBP1, GRIN2A, KCNT1, and KCNQ2 and with Angelman syndrome (AS). RESULTS: The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with SCN1A-associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet SCN1A-DEEs. CSE was also notable in patients with pathogenic variants in KCNT1 (6/10; 60%; 95% CI 26-88) and SCN2A (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet SCN1A-DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with CHD2-DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: SCN1A, SCN2A, SCN8A, and STXBP1. The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3). DISCUSSION: We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.

Consensus Statement for Protocols of Factorial Randomized Trials: Extension of the SPIRIT 2013 Statement.

Importance: Trial protocols outline a trial's objectives as well as the methods (design, conduct, and analysis) that will be used to meet those objectives, and transparent reporting of trial protocols ensures objectives are clear and facilitates appraisal regarding the suitability of study methods. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, no extension of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement, which provides guidance on reporting of trial protocols, for factorial trials is available. Objective: To develop a consensus-based extension to the SPIRIT 2013 Statement for factorial trials. Evidence Review: The SPIRIT extension for factorial trials was developed using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework. First, a list of reporting recommendations was generated using a scoping review of methodological articles identified using a MEDLINE search (inception to May 2019), which was supplemented with relevant articles from the personal collections of the authors. Second, a 3-round Delphi survey (January to June 2022, completed by 104 panelists from 14 countries) was conducted to assess the importance of items and identify additional recommendations. Third, a hybrid consensus meeting was held, attended by 15 panelists to finalize selection and wording of the checklist. Findings: This SPIRIT extension for factorial trials modified 9 of the 33 items in the SPIRIT 2013 checklist. Key reporting recommendations were that the rationale for using a factorial design should be provided, including whether an interaction is hypothesized; the treatment groups that will form the main comparisons should be identified; and statistical methods for each main comparison should be provided, including how interactions will be assessed. Conclusions and Relevance: In this consensus statement, 9 factorial-specific items were provided that should be addressed in all protocols of factorial trials to increase the trial's utility and transparency.

ADDovenom: Thermostable Protein-Based ADDomer Nanoparticles as New Therapeutics for Snakebite Envenoming.

Snakebite envenoming can be a life-threatening medical emergency that requires prompt medical intervention to neutralise the effects of venom toxins. Each year up to 138,000 people die from snakebites and threefold more victims suffer life-altering disabilities. The current treatment of snakebite relies solely on antivenom-polyclonal antibodies isolated from the plasma of hyperimmunised animals-which is associated with numerous deficiencies. The ADDovenom project seeks to deliver a novel snakebite therapy, through the use of an innovative protein-based scaffold as a next-generation antivenom. The ADDomer is a megadalton-sized, thermostable synthetic nanoparticle derived from the adenovirus penton base protein; it has 60 high-avidity binding sites to neutralise venom toxins. Here, we outline our experimental strategies to achieve this goal using state-of-the-art protein engineering, expression technology and mass spectrometry, as well as in vitro and in vivo venom neutralisation assays. We anticipate that the approaches described here will produce antivenom with unparalleled efficacy, safety and affordability.

Complications of Influenza A or B Virus Infection in Individuals With SCN1A-Positive Dravet Syndrome.

BACKGROUND AND OBJECTIVES: To determine the frequency and spectrum of complications of influenza infection in individuals with SCN1A-positive Dravet syndrome (SCN1A-DS). METHODS: Individuals with SCN1A-DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify individuals who had an influenza infection; reported infections were confirmed by pathology report. For these individuals, we obtained baseline clinical characteristics and clinical details of the influenza infection. RESULTS: Twenty-one of 82 individuals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5-25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These individuals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment. DISCUSSION: Our data show that patients with SCN1A-DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population.

Cation leak: a common functional defect causing HCN1 developmental and epileptic encephalopathy.

Pathogenic variants in HCN1 are an established cause of developmental and epileptic encephalopathy (DEE). To date, the stratification of patients with HCN1-DEE based on the biophysical consequence on channel function of a given variant has not been possible. Here, we analysed data from eleven patients carrying seven different de novo HCN1 pathogenic variants located in the transmembrane domains of the protein. All patients were diagnosed with severe disease including epilepsy and intellectual disability. The functional properties of the seven HCN1 pathogenic variants were assessed using two-electrode voltage-clamp recordings in Xenopus oocytes. All seven variants showed a significantly larger instantaneous current consistent with cation leak. The impact of each variant on other biophysical properties was variable, including changes in the half activation voltage and activation and deactivation kinetics. These data suggest that cation leak is an important pathogenic mechanism in HCN1-DEE. Furthermore, published mouse model and clinical case reports suggest that seizures are exacerbated by sodium channel blockers in patients with HCN1 variants that cause cation leak. Stratification of patients based on their 'cation leak' biophysical phenotype may therefore provide key information to guide clinical management of individuals with HCN1-DEE.