Assessing the reach, effectiveness, adoption, implementation, and maintenance of the ProACTIVE SCI physical activity counseling intervention among physiotherapists and SCI peer coaches during the transition from rehabilitation to community

IntroductionPhysical Activity (PA) levels for individuals with spinal cord injury (SCI) peak during rehabilitation and sharply decline post-discharge. The ProACTIVE SCI intervention has previously demonstrated very large-sized effects on PA; however, it has not been adapted for use at this critically understudied timepoint. The objective is to evaluate the reach, effectiveness, adoption, implementation, and maintenance of the ProACTIVE SCI intervention delivered by physiotherapists and SCI peer coaches during the transition from rehabilitation to community.MethodsA single-group, within-subjects, repeated measures design was employed. The implementation intervention consisted of PA counseling training, champion support, prompts and cues, and follow-up training/community of practice sessions. Physiotherapists conducted counseling sessions in hospital, then referred patients to SCI peer coaches to continue counseling for 1-year post-discharge in the community. The RE-AIM Framework was used to guide intervention evaluation.ResultsReach: 82.3% of patients at the rehabilitation hospital were reached by the intervention. Effectiveness: Interventionists (physiotherapists and SCI peer coaches) perceived that PA counseling was beneficial for patients. Adoption: 100% of eligible interventionists attended at least one training session. Implementation: Interventionists demonstrated high fidelity to the intervention. Intervention strategy highlights included a feasible physiotherapist to SCI peer coach referral process, flexibility in timepoint for intervening, and time efficiency. Maintenance: Ongoing training, PA counseling tracking forms, and the ability to refer to SCI peer coaches at discharge are core components needed to sustain this intervention.DiscussionThe ProACTIVE SCI intervention was successfully adapted for use by physiotherapists and SCI peer coaches during the transition from rehabilitation to community. Findings are important for informing intervention sustainability and scale-up

Implementation of the spinal cord injury exercise guidelines in the hospital and community settings : Protocol for a type II hybrid trial

Study design: Type II hybrid effectiveness-implementation trial protocol. Primary objectives: To 1) evaluate the implementation of coordinated physical activity (PA) coaching delivered by physiotherapists and spinal cord injury (SCI) peers during transition from in-hospital care to living in community (implementation objective) and 2) assess the effect of coaching on PA behaviour and psychosocial predictors among people with SCI (effectiveness objective). Setting: Rehabilitation hospital and home/community settings in British Columbia, Canada. Methods: Implementation objective: PA coaches (physiotherapists and SCI peers) receive an implementation intervention including training, monitoring, feedback, and champion support. A Theoretical Domains Framework-based questionnaire is collected at baseline, post-training, 2, and 6 months follow-up and semi-structured interviews conducted at 6 months. Effectiveness objective: Using a quasi-experimental design, 55 adults with SCI are allocated to intervention (PA coaching, n=30) or control (usual care, n=25) groups. Participants in the intervention group are referred by physiotherapists to receive 11 SCI peer-delivered PA coaching sessions in the community. Control participants receive usual care. Questionnaires assessing PA behaviour and psychosocial predictors are administered at baseline, 2-months, 6-months, and 1-year. Semi-structured interviews are conducted to assess intervention satisfaction at 6 months. Analyses include one-way (implementation objective) and two-way (effectiveness objective) repeated measures ANCOVAs for questionnaire-reported outcomes and thematic content analysis for interview data. Data are summarized using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework.Health and Social Development, Faculty of (Okanagan)Medicine, Faculty ofNon UBCHealth and Exercise Sciences, School of (Okanagan)Medicine, Department ofReviewedFacultyResearcherPostdoctoralOthe

“The healing power of that should never be underestimated” : Implementing coordinated physical activity counselling among physiotherapists and spinal cord injury peer coaches

Purpose: A large decrease in physical activity (PA) is typically observed among people with spinal cord injury (SCI) when discharged from inpatient rehabilitation. We aimed to identify implementation factors of coordinated PA counselling among physiotherapists and SCI peer coaches during the transition from inpatient rehabilitation to community. Methods: Semi-structured interviews guided by the Theoretical Domains Framework (TDF) were conducted. Using the TDF, factors affecting PA counselling delivery were coded abductively. A critical friend and member checking were used throughout analysis. Results: Participants included nine physiotherapists and two SCI peer coaches. The most salient TDF domains were social influences (34%), environmental context and resources (31%), and skills (15%). Specifically, participants identified challenges in addressing patient barriers and continual staff onboarding. Intervention delivery was supported by the ability to refer out to peer coaches with lived experience, having champion support, a time-efficient PA counselling form, and training sessions that included motivational interviewing skill development. Conclusion: Successfully implementing coordinated PA counselling during the transition from rehabilitation to community may be strengthened by 1) providing resources/training that guide both content and delivery of PA counselling and 2) a referral system that leverages the strengths of both clinicians and people with lived experience of SCI.Education, Faculty ofHealth and Social Development, Faculty of (Okanagan)Medicine, Faculty ofNon UBCHealth and Exercise Sciences, School of (Okanagan)Kinesiology, School ofMedicine, Department ofUnreviewedFacultyResearcherGraduat

De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects

International audienceCadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects)

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy

Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)–associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings

De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

BackgroundHelios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.MethodsWe performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.ResultsGenome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner.ConclusionThis study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1 beta subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder