38 research outputs found
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforløb).Peer reviewe
Posterior mini-incision total hip arthroplasty controls the extent of post-operative formation of heterotopic ossification
Factors predicting the self-evaluated health of hidradenitis suppurativa patients recruited from an outpatient clinic
Self-reported minor infections in patients with hidradenitis suppurativa and healthy controls
Hidradenitis suppurativa and perceived stigmatization in a diverse Canadian clinic population: a pilot study
Partial or full component exchange in hip revision? The relevance of off-label use and mix & match
Off-label use is frequently practiced in hip revision arthroplasty, as there may be indications for the application of implants for purposes outside the one the manufacturers intended (i.e. large bone and soft tissue defects, obesity). Patients may also benefit from selective application of mix & match in hip revision, when the exchange of one component only is necessary and the invasiveness of surgery can be reduced. Currently, there are no formal guidelines for these situations. Therefore, within a recent EFORT initiative, evidence- and consensus-based recommendations have been developed for the safe application of off-label use and mix & match in revision hip and knee arthroplasty.Orthopaedics, Trauma Surgery and Rehabilitatio
Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE–MD (Coordinating Research and Evidence for Medical Devices)
■In the European Union (EU), the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, while authorising the placing on the market of medical devices is decentralised to independent ‘conformity assessment’ organisations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the Medical Device Directive, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details - which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE–MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024. Here, we describe how it may contribute to the development of regulatory science in Europe