Publications by authors named "Roly Megaw"

Aims: Early in the COVID-19 pandemic, evidence emerged suggesting that people with diabetic retinopathy (DR) or other microvascular diseases had greater risk of severe short-term outcomes. This study evaluated longer-term outcomes, providing more generalisable evidence.

Methods: We identified a cohort of UKBiobank participants with diabetes and retrieved their diagnostic codes for a variety of microvascular diseases, complications of diabetes and systemic comorbidities.

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Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis.

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As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily.

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Article Synopsis
  • Tubulin is a key component of the cytoskeleton and has various isotypes in animals, but it's unclear how these isotypes influence microtubule structures in different cell types.
  • Research on 12 patients with primary ciliary dyskinesia and mouse models uncovered variants in the tubulin isotype that disrupted the formation of centrioles and cilia, impacting microtubule dynamics.
  • The study identified different variants causing distinct effects on tubulin interactions, allowing for the classification of patients into three types of ciliopathic diseases, highlighting the unique roles of specific tubulin isotypes in cellular functions.
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Ultraviolet Radiation (UVR) has a well-established causative influence within the aetiology of conditions of the skin and the anterior segment of the eye. However, a grounded assessment of the role of UVR within conditions of the retina has been hampered by a historical lack of quantitative, and spectrally resolved, assessment of how UVR impacts upon the retina in terms congruent with contemporary theories of ageing. In this review, we sought to summarise the key findings of research investigating the connection between UVR exposure in retinal cytopathology while identifying necessary avenues for future research which can deliver a deeper understanding of UVR's place within the retinal risk landscape.

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Article Synopsis
  • Genome editing might help treat a serious eye disease called late-onset retinal degeneration (L-ORD).
  • Scientists studied 25 patients with this disease to find the best times and places in the eye to test new treatments.
  • They discovered that changes in the eye's structure start before serious problems occur, meaning treatments could work at different stages of the disease.
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Purpose: Late-onset retinal degeneration (L-ORD) is a rare retinal dystrophy with anterior segment (AS) abnormalities, including long anterior zonules (LAZ) and iris atrophy. This investigation evaluates AS changes in a L-ORD cohort.

Methods: Prospective, longitudinal study including L-ORD individuals (Ser163Arg) with ocular exam and standard slit-lamp photographs between 2011 and 2022.

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Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis.

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Genetic eye diseases, representing a wide spectrum of simple and complex conditions, are one of the leading causes of visual loss in children and working adults, and progress in the field has led to changes in disease investigation, diagnosis, and management. The past 15 years have seen the emergence of novel therapies for these previously untreatable conditions to the extent that we now have a licensed therapy for one form of genetic eye disease and many more in clinical trial. This is a systematic review of published and ongoing clinical trials of gene therapies for monogenic eye diseases.

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Aims: Certain patients with Diabetes Mellitus (DM) have high risk for complications from COVID-19. We aimed to test the hypothesis that pre-existing diabetic retinopathy (DR), a microvascular disease, is a prognostic indicator for poor COVID-19 outcome in this heterogeneous population.

Methods: Seven databases (including MEDLINE) and grey literature were searched, identifying eligible studies using predetermined selection criteria.

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IRDs are one of the leading causes of visual loss in children and young adults. Mutations in over 271 genes lead to retinal dysfunction, degeneration and sight loss. Though no cure exists, gene augmentation therapy has brought hope to the field.

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Background: Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 () gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in and assessed its pathogenicity by in vitro functional analysis.

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Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments.

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The rising prevalence of age-related eye diseases, particularly age-related macular degeneration, places an ever-increasing burden on health care providers. As new treatments emerge, it is necessary to develop methods for reliably assessing patients' disease status and stratifying risk of progression. The presence of drusen in the retina represents a key early feature in which size, number, and morphology are thought to correlate significantly with the risk of progression to sight-threatening age-related macular degeneration.

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Retinitis pigmentosa (RP) is the leading cause of inherited blindness. RP is a genetically heterogeneous disorder, with more than 100 different causal genes identified in patients. Central to disease pathogenesis is the progressive loss of retinal photoreceptors.

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Importance: The ability of patients to measure their own intraocular pressure (IOP) would allow more frequent measurements and better appreciation of peak IOP and IOP fluctuation.

Objective: To examine whether patients with glaucoma can perform self-tonometry using a rebound tonometer and examine patient acceptability.

Design, Setting, And Participants: An observational study in which IOP was assessed using Goldmann applanation tonometry and a rebound tonometer.

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Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments.

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No biological system or structure is likely to be perfectly symmetrical, or have identical right and left forms. This review explores the evidence for eye and visual pathway asymmetry, in health and in disease, and attempts to provide guidance for those studying the structure and function of the visual system, where recognition of symmetry or asymmetry may be essential. The principal question with regards to asymmetry is not 'are the eyes the same?', for some degree of asymmetry is pervasive, but 'when are they importantly different?'.

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Purpose: To determine the relationship between the rate of glaucomatous visual field loss and the amplitude of a 24-h intraocular pressure (IOP)-related profile measured using a contact lens sensor (CLS).

Methods: This observational study included 22 patients with glaucoma and an IOP of consistently ≤21 mm Hg during office hours. All subjects underwent Goldmann tonometry, standard automated perimetry (SAP), dilated fundus examination, and had a CLS recording.

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Age-related macular degeneration (AMD) is one of the leading causes of visual impairment. The development of cataract in AMD patients poses challenges in assessing timing of surgery, predicting potential benefit to the patient of surgery, and predicting short- and long-term effects of surgery on progression of their AMD. Although traditional cataract surgery remains the mainstay of treatment, recently several devices have been developed to address the specific needs of AMD patients with cataract.

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Posner-Schlossman syndrome, or glaucomatocyclitic crisis, is a unilateral ocular condition characterized by recurrent attacks of nongranulomatous anterior uveitis and raised intraocular pressure that can result in chronic secondary glaucoma. This relatively rare disease is most likely the result of recurrent cytomegalovirus infection and affects predominantly middle-aged males. Diagnosis is largely clinical, with aqueous and blood sampling aiding the identification of any underlying infectious cause.

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Photoreceptor degeneration is the prominent characteristic of retinitis pigmentosa (RP), a heterogeneous group of inherited retinal dystrophies resulting in blindness. Although abnormalities in many pathways can cause photoreceptor degeneration, one of the most important causes is defective protein transport through the connecting cilium, the structure that connects the biosynthetic inner segment with the photosensitive outer segment of the photoreceptors. The majority of patients with X-linked RP have mutations in the retinitis pigmentosa GTPase regulator (RPGR) or RP2 genes, the protein products of which are both components of the connecting cilium and associated with distinct mechanisms of protein delivery to the outer segment.

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Background: Retinitis pigmentosa, which affects one in 3000 people, causes blindness and has no treatment. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause 20% of all cases. Recent work suggests that RPGR, localised to the photoreceptor connecting cilium, regulates rhodopsin transport to the outer segment through its effect on the turnover of actin.

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Article Synopsis
  • Mammalian photoreceptors have special parts called connecting cilia that link inner and outer segments, and problems with these cilia can lead to a vision disease called retinitis pigmentosa (RP).
  • A protein called RPGR is linked to many cases of RP, especially in boys, but scientists are still figuring out exactly what RPGR does.
  • Recent research shows that improving our understanding of RPGR and using therapies like gene therapy could help treat this condition, while options like replacing damaged cells are still being developed.
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