Development of a patient decision aid for children and adolescents following anterior cruciate ligament rupture: an international mixed-methods study

AIM: To develop and user test an evidence-based patient decision aid for children and adolescents who are considering anterior cruciate ligament (ACL) reconstruction.DESIGN: Mixed-methods study describing the development of a patient decision aid.SETTING: A draft decision aid was developed by a multidisciplinary steering group (including various types of health professionals and researchers, and consumers) informed by the best available evidence and existing patient decision aids.PARTICIPANTS: People who ruptured their ACL when they were under 18 years old (ie, adolescents), their parents, and health professionals who manage these patients. Participants were recruited through social media and the network outreach of the steering group.PRIMARY AND SECONDARY OUTCOMES: Semistructured interviews and questionnaires were used to gather feedback on the decision aid. The feedback was used to refine the decision aid and assess acceptability. An iterative cycle of interviews, refining the aid according to feedback and further interviews, was used. Interviews were analysed using reflexive thematic analysis.RESULTS: We conducted 32 interviews; 16 health professionals (12 physiotherapists, 4 orthopaedic surgeons) and 16 people who ruptured their ACL when they were under 18 years old (7 were adolescents and 9 were adults at the time of the interview). Parents participated in 8 interviews. Most health professionals, patients and parents rated the aid's acceptability as good-to-excellent. Health professionals and patients agreed on most aspects of the decision aid, but some health professionals had differing views on non-surgical management, risk of harms, treatment protocols and evidence on benefits and harms.CONCLUSION: Our patient decision aid is an acceptable tool to help children and adolescents choose an appropriate management option following ACL rupture with their parents and health professionals. A clinical trial evaluating the potential benefit of this tool for children and adolescents considering ACL reconstruction is warranted.</p

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine‐glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin‐1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss‐of‐function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.We describe nine unrelated individuals who carry partial deletions or putatively deleterious sequence variants in RERE. An analysis of clinical and molecular data from individuals with mutations affecting RERE suggests the existence of novel genotype‐phenotype correlations and demonstrates that a high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/1/humu23400_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/2/humu23400.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/3/humu23400-sup-0001-SuppMat.pd

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of superenhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods: An international collaboration, exome sequencing, molecular modeling, yeast twohybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability

The secret life of α-catenin: Moonlighting in morphogenesis

Cadherin-based intercellular adhesions are important determinants of proper tissue architecture. These adhesions must be both stable and dynamic to maintain tissue integrity as cells undergo morphogenetic movements during development. The role of α-catenin in this process has been vigorously debated due to conflicting in vitro and in vivo evidence regarding its molecular mechanism of action. Recent data supports the classical view that α-catenin facilitates actin attachments at adherens junctions, but also suggests that α-catenin may act as a force transducer, and may have additional roles in the cytoplasm. These multiple functions for α-catenin converge on the regulation of adhesion and may help to explain its stable yet dynamic nature

Rhinovirus illnesses during infancy predict subsequent childhood wheezing

Background: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/ or allergic diseases in early childhood is not established. Objective: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. Methods: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. Results: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR] 5 2.1), older siblings (OR 5 2.5), allergic sensitization to foods at age 1 year (OR 5 2.0), any moderate to severe respiratory illness without wheezing during infancy (OR 5 3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR 5 3.0), rhinovirus (OR 5 10) and/or non-rhinovirus/RSV pathogens (OR 5 3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR 5 6.6; P &lt; .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR 5 6.6; P &lt; .0001). Conclusion: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature. (J Allergy Clin Immunol 2005;116:571-7.

Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder

Scholarly, Academic, Credible: New Terms for Research Instruction

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