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Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling
No full textBACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.Not permittedThis article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site
PROTOCOL: Health and social care interventions in the 80 years old and over population: An evidence and gap map
No full textThis is the protocol for a Campbell systematic review. The objectives are as follows: identify available systematic reviews and randomised controlled trials on interventions targeting health or social needs of the people aged over 80; identify qualitative studies relating to the experiences of people aged over 80 of interventions that target their health or social needs; identify areas where systematic reviews are needed; identify gaps in evidence where further primary research is needed; assess equity considerations (using the PROGRESS plus criteria) in available systematic reviews, randomised trials and qualitative studies of identified interventions; assess gaps and evidence related to health equity.Published version, accepted version, submitted versionSupports Open Acces
Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356)
No full textAs suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.Published version, accepted version, submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Intraoperative cell salvage in revision hip arthroplasty
No full textAIMS: The aim of this study was to perform a systematic review of the evidence for the use of intraoperative cell salvage in patients undergoing revision hip arthroplasty, and specifically to analyze the available data in order to quantify any associated reduction in the use of allogenic blood transfusion, and the volume which is used. METHODS: An electronic search of MEDLINE (PubMed), Embase, Scopus, and the Cochrane Library was completed from the date of their inception to 24 February 2022, using a search strategy and protocol created in conjunction with the PRISMA statement. Inclusion criteria were patients aged > 18 years who underwent revision hip arthroplasty when cell salvage was used. Studies in which pre-donated red blood cells were used were excluded. A meta-analysis was also performed using a random effects model with significance set at p = 0.05. RESULTS: Of the 283 studies which were identified, 11 were included in the systematic review, and nine in the meta-analysis. There was a significant difference (p < 0.001) in the proportion of patients requiring allogenic transfusion between groups, with an odds ratio of 0.331 (95% confidence interval (CI) 0.165 to 0.663) associated with the use of cell salvage. For a total of 561 patients undergoing revision hip arthroplasty who were treated with cell salvage, 247 (44.0%) required allogenic transfusion compared with 418 of 643 patients (65.0%) who were treated without cell salvage. For those treated with cell salvage, the mean volume of allogenic blood which was required was 1.95 units (390 ml) per patient (0.7 to 4.5 units), compared with 3.25 units (650 ml) per patient (1.2 to 7.0 units) in those treated without cell salvage. The mean difference of -1.91 units (95% CI -4.0 to 0.2) in the meta-analysis was also significant (p = 0.003). CONCLUSION: We found a a significant reduction in the need for allogenic blood transfusion when cell salvage was used in patients undergoing revision hip arthroplasty, supporting its routine use in these patients. Further research is required to determine whether this effect is associated with types of revision arthroplasty of differing complexity.Accepted version (12 month embargo)The article is available via Open Access. Click on the 'Additional link' above to access the full-text
NICE guideline review: Epilepsies in children, young people and adults NG217
No full textPublished version, accepted version, submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The effects of open wedge high tibial osteotomy for knee osteoarthritis on the patellofemoral joint. A systematic review
No full textBACKGROUND (INCLUDING AIMS OF THE STUDY): To investigate the impact medial opening wedge high tibial osteotomy (MOWHTO) has on the progression of patellofemoral (PF) OA, patella height, contact pressure within the PF joint and clinical outcomes. METHODS: A systematic review was conducted in January 2022 according to PRISMA guidelines. The ICRS cartilage grade of the PF joint at the initial MOWHTO surgery and at second look surgery was compared and relative risk of progression of PF OA was calculated. Evaluation of patella height was assessed by Caton-Deschamps index, Blackburne-Peel index or Insall-Salvati index pre and post MOWHTO. Cadaveric studies assessing contact pressures in the PF after MOWHTO were included. RESULTS: Forty-two studies comparing 2419 patients were included. The mean age was 53.1 years (16-84), 61.3% female. The risk of progression of PF OA was highest in the uniplanar and biplanar MOWHTO with proximal tubercle osteotomy groups (RR = 1.28-1.51) compared to biplanar MOHWTO with distal tubercle osteotomy (RR = 0.96-1.04). Patella height was not affected after biplanar MOWHTO with distal tubercle osteotomy (p < 0.001). Cadaveric studies demonstrate that PF contact pressures increase with more severe corrections (15°) but suggest biplanar MWOHTO and distal tubercle osteotomy induces lower contact pressures within the PF joint than other MOWHTO techniques. Significant over correction is associated with worse clinical outcomes and anterior knee pain. CONCLUSION: Biplanar MOWHTO and distal tubercle osteotomy has minimal effect on the contact pressures in the PF joint resulting in less severe progression of PF OA and has minimal impact on patella height.Published version, accepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Interstitial Lung Disease and Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Review
No full textInterstitial lung disease is a common complication of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). It is seen most commonly in microscopic polyangiitis owing to the pathogenic effect of myeloperoxidase in the lung. Oxidative stress, neutrophil elastase release, and expression of inflammatory proteins by neutrophil extracellular traps result in fibroblast proliferation and differentiation and therefore fibrosis. Usually, interstitial pneumonia pattern fibrosis is common and associated with poor survival. Treatment for patients with AAV and interstitial lung disease lacks evidence, and those with vasculitis are treated with immunosuppression, whereas those with progressive fibrosis may well benefit from antifibrotic therapy.Published version, accepted version, submitted versionNot hel
SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission
No full textSLC4A10 is a plasma-membrane bound transporter which utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of cerebrospinal fluid. Using next generation sequencing on samples from five unrelated families encompassing ten affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and typically severe intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorders including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioral abnormalities including delayed habituation and alterations in the 2-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggests an important role of SLC4A10 in the production of the cerebrospinal fluid. However, it is notable that despite diverse roles of the cerebrospinal fluid in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel characteristic neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Intermittently scanned continuous glucose monitoring and hypoglycaemia awareness in drivers with diabetes: Insights from the Association of British Clinical Diabetologists Nationwide audit
No full textAIM: Frequent hypoglycaemia results in disruption to usual hypoglycaemic autonomic responses leading to impaired awareness of hypoglycaemia, which is associated with an increased risk of severe hypoglycaemia requiring third-party assistance (SH). The UK Driving and Vehicle Licensing Agency (DVLA) does not permit car driving if they have either a complete loss of hypoglycaemia awareness or more than one SH event a year. METHODS: The FreeStyle Libre (FSL) Association of British Clinical Diabetologists (ABCD) Nationwide Audit consists of data collected by clinicians during routine clinical work, submitted into a secure web-based tool held within the National Health Service (NHS) N3 network. Analysis of paired baseline and follow-up data for people with type 1 diabetes who also held a driving licence was undertaken. RESULTS: The study consisted of 6304 people who had data recorded about driving status from 102 UK specialist diabetes centres, of which 4218 held a driving licence: 4178 a group 1, standard licence, 33 a group 2, large lorries and buses, seven a taxi licence; 1819 did not drive. Paired baseline and follow-up data were available for a sub-cohort of 1606/4218. At a mean follow-up of 6.9 months [95% CI (6.8, 7.1)], the Gold score had improved (2.3 ± 1.5 vs. 2.0 ± 1.3 p < .001), and the number of people who experienced an SH episode was also significantly lower (12.1% vs. 2.7%, p < .001). CONCLUSION: This study suggests that intermittently scanned continuous glucose monitoring may improve impaired awareness of hypoglycaemia and reduce the number of people with type 1 diabetes with a driving licence experiencing a severe hypoglycaemic episode.Published version, accepted version (12 month embargo), submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial
No full textPURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.Published versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text