More Than Just Adolescence: Differences in Fatigue Between Youth With Cerebral Palsy and Typically Developing Peers

Objective To quantify differences in fatigue and disordered sleep between adolescents with cerebral palsy (CP) and their typically developing peers. A secondary aim was to investigate the association between fatigue and disordered sleep in adolescents with CP. Methods A convenience sample of 36 youth with CP aged 10-18 years was matched for age and sex with 36 typically developing peers. The Fatigue Impact and Severity Self-Assessment (FISSA), the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue profile, and the Sleep Disturbance Scale for Children (SDSC) were collected. Results Higher fatigue was reported in participants with CP than in their typically developing peers based on the FISSA total score (mean paired difference=19.06; 99% confidence interval [CI], 6.06-32.1), the FISSA impact subscale (mean paired difference=11.19; 99% CI, 3.96-18.4), and the FISSA Management and Activity Modification subscale (mean paired difference=7.86; 99% CI, 1.1-14.6). There were no differences between groups in the PROMIS fatigue profile (mean paired difference=1.63; 99% CI, -1.57-4.83) or the SDSC total score (mean paired difference=2.71; 99% CI, -2.93-8.35). Conclusion Youth with CP experienced significantly more fatigue than their peers as assessed by a comprehensive measure that considered both general and diagnosis-specific concerns. Sleep did not differ between youth with CP and their typically developing peers. These findings underscore the need to consider the clinical management of fatigue across the lifespan of individuals with CP to prevent the associated deterioration of functional abilities

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Concurrent neuromechanical and functional gains following upper-extremity power training post-stroke

<p>Abstract</p> <p>Background</p> <p>Repetitive task practice is argued to drive neural plasticity following stroke. However, current evidence reveals that hemiparetic weakness impairs the capacity to perform, and practice, movements appropriately. Here we investigated how power training (i.e., high-intensity, dynamic resistance training) affects recovery of upper-extremity motor function post-stroke. We hypothesized that power training, as a component of upper-extremity rehabilitation, would promote greater functional gains than functional task practice without deleterious consequences.</p> <p>Method</p> <p>Nineteen chronic hemiparetic individuals were studied using a crossover design. All participants received both functional task practice (FTP) and HYBRID (combined FTP and power training) in random order. Blinded evaluations performed at baseline, following each intervention block and 6-months post-intervention included: Wolf Motor Function Test (WMFT-FAS, Primary Outcome), upper-extremity Fugl-Meyer Motor Assessment, Ashworth Scale, and Functional Independence Measure. Neuromechanical function was evaluated using isometric and dynamic joint torques and concurrent agonist EMG. Biceps stretch reflex responses were evaluated using passive elbow stretches ranging from 60 to 180º/s and determining: EMG onset position threshold, burst duration, burst intensity and passive torque at each speed.</p> <p>Results</p> <p>Primary outcome: Improvements in WMFT-FAS were significantly greater following HYBRID vs. FTP (<it>p</it> = .049), regardless of treatment order. These functional improvements were retained 6-months post-intervention (<it>p</it> = .03).</p> <p>Secondary outcomes: A greater proportion of participants achieved minimally important differences (MID) following HYBRID vs. FTP (<it>p</it> = .03). MIDs were retained 6-months post-intervention. Ashworth scores were unchanged (<it>p</it> > .05).</p> <p>Increased maximal isometric joint torque, agonist EMG and peak power were significantly greater following HYBRID vs. FTP (<it>p</it> < .05) and effects were retained 6-months post-intervention (<it>p</it>’s < .05). EMG position threshold and burst duration were significantly reduced at fast speeds (≥120º/s) (<it>p</it>’s < 0.05) and passive torque was reduced post-washout (<it>p</it> < .05) following HYBRID.</p> <p>Conclusions</p> <p>Functional and neuromechanical gains were greater following HYBRID vs. FPT. Improved stretch reflex modulation and increased neuromuscular activation indicate potent neural adaptations. Importantly, no deleterious consequences, including exacerbation of spasticity or musculoskeletal complaints, were associated with HYBRID. These results contribute to an evolving body of contemporary evidence regarding the efficacy of high-intensity training in neurorehabilitation and the physiological mechanisms that mediate neural recovery.</p

"We're a lot closer, we talk more": Family experiences and relationships following child's participation in an adapted physical activity camp

Purpose: Children and adolescents with developmental challenges may rely on their parents for assistance with everyday tasks to a greater extent than typically developing children. The objective of this study was to examine family members’ perspectives regarding family relationships related to participation in an adapted summer camp for children and adolescents living with a disability. Materials and Methods: A collective case study was conducted with eleven families who had a child living with a disability who participated in an adapted physical activity (PA) summer camp. A focus group was conducted with each family and thematically analyzed. Results: Families experienced changes in perspectives and pride surrounding adapted PA, more family conversations about disability, less parental worry, more independence of the child living with a disability, and enhanced family bonds through PA. The children who participated in the camp saw impacts on their self-confidence and independence. COVID-19-related program suspension was associated with frustration, worry, and strained family relationships. Conclusions: These findings elucidate how participation in adapted PA for children and youth with disabilities can impact family relationships. Future interventions allow for space for family interactions and create opportunity for children and adolescents with disabilities to be independent.OtherFunding for this study was provided by the Vi Riddell Pediatric Rehabilitation Research Program at the Alberta Children’s Hospital

More than just adolescence: differences in fatigue between youth with cerebral palsy and typically developing peers

Objective To quantify differences in fatigue and disordered sleep between adolescents with cerebral palsy (CP) and their typically developing peers. A secondary aim was to investigate the association between fatigue and disordered sleep in adolescents with CP. Methods A convenience sample of 36 youth with CP aged 10–18 years was matched for age and sex with 36 typically developing peers. The Fatigue Impact and Severity Self-Assessment (FISSA), the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue profile, and the Sleep Disturbance Scale for Children (SDSC) were collected. Results Higher fatigue was reported in participants with CP than in their typically developing peers based on the FISSA total score (mean paired difference=19.06; 99% confidence interval [CI], 6.06–32.1), the FISSA impact subscale (mean paired difference=11.19; 99% CI, 3.96–18.4), and the FISSA Management and Activity Modification subscale (mean paired difference=7.86; 99% CI, 1.1–14.6). There were no differences between groups in the PROMIS fatigue profile (mean paired difference=1.63; 99% CI, -1.57–4.83) or the SDSC total score (mean paired difference=2.71; 99% CI, -2.93–8.35). Conclusion Youth with CP experienced significantly more fatigue than their peers as assessed by a comprehensive measure that considered both general and diagnosis-specific concerns. Sleep did not differ between youth with CP and their typically developing peers. These findings underscore the need to consider the clinical management of fatigue across the lifespan of individuals with CP to prevent the associated deterioration of functional abilities