Spectrum of Mutations in NDP Resulting in Ocular Disease; a Systematic Review

Aims and Rationale: The inner retina is supplied by three intraretinal capillary plexi whereas the outer retina is supplied by the choroidal circulation: NDP is essential for normal intraretinal vascularisation. Pathogenic variants in NDP (Xp11.3) may result in either a severe retinal phenotype associated with hearing loss (Norrie Disease) or a moderate retinal phenotype (Familial Exudative Vitreoretinopathy, FEVR). However, little is known about whether the nature or location of the NDP variant is predictive of severity. In this systematic review we summarise all reported NDP variants and draw conclusions about whether the nature of the NDP variant is predictive of the severity of the resulting ocular pathology and associated hearing loss and intellectual disability. Findings: 201 different variants in the NDP gene have been reported as disease-causing. The pathological phenotype that may result from a disease-causing NDP variant is quite diverse but generally comprises a consistent cluster of features (retinal hypovascularisation, exudation, persistent foetal vasculature, tractional/exudative retinal detachment, intellectual disability and hearing loss) that vary predictably with severity. Previous reviews have found no clear pattern in the nature of NDP mutations that cause either FEVR or Norrie disease, with the exception that mutations affecting cysteine residues have been associated with Norrie Disease and that visual loss amongst patients with Norrie disease tends to be more severe if the NDP mutation results in an early termination of translation as opposed to a missense related amino acid change. A key limitation of previous reviews has been variability in the case definition of Norrie disease and FEVR amongst authors. We thus reclassified patients into two groups based only on the severity of their retinal disease. Of the reported pathogenic variants that have been described in more than one patient, we found that any given variant caused an equivalent severity of retinopathy each time it was reported with very few exceptions. We therefore conclude that specific NDP mutations generally result in a consistent retinal phenotype each time they arise. Reports by different authors of the same variant causing either FEVR or Norrie disease conflict primarily due to variability in the authors' respective case definitions rather than true differences in disease severity

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndp$^{tm1Wbrg}$), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease

Evidence Based Prediction and Progression Monitoring on Retinal Images from Three Nations.

Purpose: The aim of this work is to demonstrate how a retinal image analysis system, DAPHNE, supports the optimization of diabetic retinopathy (DR) screening programs for grading color fundus photography. Method: Retinal image sets, graded by trained and certified human graders, were acquired from Saudi Arabia, China, and Kenya. Each image was subsequently analyzed by the DAPHNE automated software. The sensitivity, specificity, and positive and negative predictive values for the detection of referable DR or diabetic macular edema were evaluated, taking human grading or clinical assessment outcomes to be the gold standard. The automated software's ability to identify co-pathology and to correctly label DR lesions was also assessed. Results: In all three datasets the agreement between the automated software and human grading was between 0.84 to 0.88. Sensitivity did not vary significantly between populations (94.28%-97.1%) with specificity ranging between 90.33% to 92.12%. There were excellent negative predictive values above 93% in all image sets. The software was able to monitor DR progression between baseline and follow-up images with the changes visualized. No cases of proliferative DR or DME were missed in the referable recommendations. Conclusions: The DAPHNE automated software demonstrated its ability not only to grade images but also to reliably monitor and visualize progression. Therefore it has the potential to assist timely image analysis in patients with diabetes in varied populations and also help to discover subtle signs of sight-threatening disease onset. Translational Relevance: This article takes research on machine vision and evaluates its readiness for clinical use

Man versus Machine: Software Training for Surgeons-An Objective Evaluation of Human and Computer-Based Training Tools for Cataract Surgical Performance

This study aimed to address two queries: firstly, the relationship between two cataract surgical feedback tools for training, one human and one software based, and, secondly, evaluating microscope control during phacoemulsification using the software. Videos of surgeons with varying experience were enrolled and independently scored with the validated PhacoTrack motion capture software and the Objective Structured Assessment of Cataract Surgical Skill (OSACCS) human scoring tool. Microscope centration and path length travelled were also evaluated with the PhacoTrack software. Twenty-two videos correlated PhacoTrack motion capture with OSACCS. The PhacoTrack path length, number of movements, and total procedure time were found to have high levels of Spearman's rank correlation of −0.6792619 ( = 0.001), −0.6652021 ( = 0.002), and −0.771529 ( = 0001), respectively, with OSACCS. Sixty-two videos evaluated microscope camera control. Novice surgeons had their camera off the pupil centre at a far greater mean distance (SD) of 6.9 (3.3) mm, compared with experts of 3.6 (1.6) mm ( ≪ 0.05). The expert surgeons maintained good microscope camera control and limited total pupil path length travelled 2512 (1031) mm compared with novices of 4049 (2709) mm ( ≪ 0.05). Good agreement between human and machine quantified measurements of surgical skill exists. Our results demonstrate that surrogate markers for camera control are predictors of surgical skills

Writing, directing and translating poetic film

International audienceIn this paper I examine the possibility of a holistic approach to audiovisual translation which puts the emphasis on people, context(s) and interpretation(s). I consider the relation between image, sound, and the spoken and/or written word in the audiovisual medium, and then explore some of the issues involved in creating poetic films, in particular the choice of language or silence. Th e translator’s mediating voice is not always easy to observe in subtitles. For they are governed by a complex set of constraints and conventions, to such an extent that it may appear there are no significant choices to be made, choices which, if noticed, might reflect competing interpretations. I endeavour to trace the translators’ voice in a small collection of poetic films translated into English and French, and explain that it manifests through more or less felicitous subtitling choices, and sometimes through failure

Automated feature-based grading and progression analysis of diabetic retinopathy

BACKGROUND: In diabetic retinopathy (DR) screening programmes feature-based grading guidelines are used by human graders. However, recent deep learning approaches have focused on end to end learning, based on labelled data at the whole image level. Most predictions from such software offer a direct grading output without information about the retinal features responsible for the grade. In this work, we demonstrate a feature based retinal image analysis system, which aims to support flexible grading and monitor progression. METHODS: The system was evaluated against images that had been graded according to two different grading systems; The International Clinical Diabetic Retinopathy and Diabetic Macular Oedema Severity Scale and the UK's National Screening Committee guidelines. RESULTS: External evaluation on large datasets collected from three nations (Kenya, Saudi Arabia and China) was carried out. On a DR referable level, sensitivity did not vary significantly between different DR grading schemes (91.2-94.2.0%) and there were excellent specificity values above 93% in all image sets. More importantly, no cases of severe non-proliferative DR, proliferative DR or DMO were missed. CONCLUSIONS: We demonstrate the potential of an AI feature-based DR grading system that is not constrained to any specific grading scheme

Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Abstract Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease