Functional correlates of clinical phenotype and severity in recurrent SCN2A variants

In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the alpha(1) and beta(2) subunits of the Na(v)1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity. A comprehensive biophysical analysis of disease-associated mutations in the voltage-gated sodium channel gene, SCN2A, suggests that dynamic action potential clamp may be a better predictor than voltage clamp of how these mutations alter neuronal excitability, though other approaches are needed to predict severity

International Care programs for Pediatric Post-COVID Condition (Long COVID) and the way forward

Background: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care. // Methods: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care. // Results: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support. // Conclusions: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration

Stakeholder perspectives of immunisation delivery for adolescents with disability in specialist schools in Victoria, Australia: ‘we need a vaccination pathway’

Abstract Background Adolescents with disability have lower vaccination rates than the general population, including HPV vaccination. Understanding the multi-level influences on vaccination in specialist schools is crucial to achieve optimal vaccination coverage and vaccination experiences for adolescents living with disability. Objective To identify and improve understanding of the facilitators and barriers of HPV vaccination among adolescents with intellectual disabilities or autism in Victorian specialist schools to inform strategies to increase vaccination acceptance and uptake. Methods Qualitative interviews with key stakeholders (adolescents with disabilities, parents, school and council immunisation staff) from six specialist schools in Victoria, Australia. Data were analysed thematically. Inductively derived themes were then deductively mapped across the UNICEF ‘Journey to Immunization’ model. Results 32 interviews were conducted with stakeholders (2 adolescents, 7 parents, 13 school staff, 10 council staff). Trust in vaccines was high, but knowledge of the HPV vaccine was limited. Barriers included lack of accessible information for parents, the consent process, behavioural challenges and vaccine-related anxiety among students. The immunisation program in special schools was perceived as convenient, however preparing students for vaccination day and catering to individual student needs were key. Participants expressed a need for more parent information about options and additional support for vaccination outside of the school program. Conclusions Our study identified a range of facilitators and barriers to the school immunisation program for students with disabilities in specialist schools. The next phase of this work will use co-design workshops to build on the suggestions for improvement and opportunities that could be leveraged to improve vaccination uptake

Behavioural and social drivers of COVID-19 vaccination in Vietnam: a scoping review

Background Understanding of the behavioural and social drivers (BeSD) of vaccination is key to addressing vaccine hesitancy and accessibility issues. Vietnam’s national COVID-19 vaccination programme resulted in high uptake of primary doses among adults, but lower booster doses for adults and primary doses for 5–11 years. This scoping review assessed BeSD influencing COVID-19 vaccine uptake in Vietnam to design interventions on reaching the national vaccination targets.Method We conducted a scoping review by searching PubMed, MedRxiv, LitCOVID, COVID-19 LOVE platform, WHO’s COVID-19 research database and seven dominant Vietnamese language medical journals published in English or Vietnamese between 28 December 2019 and 28 November 2022. Data were narratively synthesised and summarised according to the four components of the WHO BeSD framework. The drivers were then mapped along the timeline of COVID-19 vaccine deployment and the evolution of the pandemic in Vietnam.Results We identified 680 records, of which 39 met the inclusion criteria comprising 224 204 participants. Adults’ intention to receive COVID-19 vaccines for themselves (23 studies) ranged from 58.0% to 98.1%. Parental intention to vaccinate their under 11-year-old children (six studies) ranged from 32.8% to 79.6%. Key drivers of vaccination uptake were perceived susceptibility and severity of disease, perceived vaccine benefits and safety, healthcare worker recommendation, and positive societal perception. Commonly reported COVID-19 vaccines’ information sources (six studies) were social and mainstream media (82%–67%), television (72.7%–51.6%) and healthcare workers (47.5%–17.5%). Key drivers of COVID-19 uptake remained consistent for both adults and children despite changes in community transmission and vaccine deployment.Conclusion Key enablers of vaccine uptake for adults and children included perceived disease severity, perceived vaccine benefits and safety and healthcare worker recommendations. Future studies should assess vaccine communication targeted to these drivers, national policies and political determinants to optimise vaccine uptake

A novel anterior nasal swab to detect respiratory viruses: a prospective study of diagnostic accuracy

Abstract Detection of respiratory viruses requires testing of the upper respiratory tract to obtain specimens for analysis. However, nasal and throat swabs can cause discomfort and procedural anxiety in children. Respiratory sampling methods which are accurate and less invasive are needed. We aim to determine the positive and negative percentage agreement of a novel anterior nasal swab (ANS) compared with the combined throat and anterior nasal swab (CTN), the reference standard, for detection of respiratory viruses. Children 5 – 18 years of age presenting to a tertiary paediatric hospital with respiratory symptoms were tested with both swabs in randomised order. Respiratory samples were tested on a multiplex RT-PCR panel. Viral detections, RT-PCR cycle-threshold values and child/parent/clinician experience of the swab were recorded. There were 157 viral detections from 249 participant CTN swabs. In comparison with the CTN, the overall positive and negative percentage agreement of ANS for detection of respiratory viruses was 96.2% (95% CI, 91.8–98.3%) and 99.8% (95% CI, 99.6–99.9%), respectively. The ANS was “extremely comfortable”, or only a “little uncomfortable” for 90% of children compared with 48% for CTN. 202 children (84%) rated the ANS as the preferred swab, and 208 (87%) indicated they would prefer ANS for future testing. The ANS required additional laboratory handling processes compared to the CTN. The ANS has high positive percentage agreement and is comparable to the current standard of care. The high acceptability from the less invasive ANS provides a more comfortable method for respiratory virus testing in children. Trial registration ClinicalTrials.gov ID NCT05043623

International care programs for Pediatric Post-COVID Condition (Long COVID) and the way forward

Background: Pediatric Post-COVID-Condition (PPCC) clinics treat children despite limited scientific substantiation. By exploring real-life management of children diagnosed with PPCC, the International Post-COVID-Condition in Children Collaboration (IP4C) aimed to provide guidance for future PPCC care. Methods: We performed a cross-sectional international, multicenter study on used PPCC definitions; the organization of PPCC care programs and patients characteristics. We compared aggregated data from PPCC cohorts and identified priorities to improve PPCC care. Results: Ten PPCC care programs and six COVID-19 follow-up research cohorts participated. Aggregated data from 584 PPCC patients was analyzed. The most common symptoms included fatigue (71%), headache (55%), concentration difficulties (53%), and brain fog (48%). Severe limitations in daily life were reported in 31% of patients. Most PPCC care programs organized in-person visits with multidisciplinary teams. Diagnostic testing for respiratory and cardiac morbidity was most frequently performed and seldom abnormal. Treatment was often limited to physical therapy and psychological support. Conclusions: We found substantial heterogeneity in both the diagnostics and management of PPCC, possibly explained by scarce scientific evidence and lack of standardized care. We present a list of components which future guidelines should address, and outline priorities concerning PPCC care pathways, research and international collaboration