Clinical validation of a novel web-application for remote assessment of distance visual acuity.

BACKGROUND/OBJECTIVES: Ophthalmic disorders cause 8% of hospital clinic attendances, the highest of any specialty. The fundamental need for a distance visual acuity (VA) measurement constrains remote consultation. A web-application, DigiVis, facilitates self-assessment of VA using two internet-connected devices. This prospective validation study aimed to establish its accuracy, reliability, usability and acceptability. SUBJECTS/METHODS: In total, 120 patients aged 5-87 years (median = 27) self-tested their vision twice using DigiVis in addition to their standard clinical assessment. Eyes with VA worse than +0.80 logMAR were excluded. Accuracy and test-retest (TRT) variability were compared using Bland-Altman analysis and intraclass correlation coefficients (ICC). Patient feedback was analysed. RESULTS: Bias between VA tests was insignificant at -0.001 (95% CI -0.017 to 0.015) logMAR. The upper limit of agreement (LOA) was 0.173 (95% CI 0.146 to 0.201) and the lower LOA -0.175 (95% CI -0.202 to -0.147) logMAR. The ICC was 0.818 (95% CI 0.748 to 0.869). DigiVis TRT mean bias was similarly insignificant, at 0.001 (95% CI -0.011 to 0.013) logMAR, the upper LOA was 0.124 (95% CI 0.103 to 0.144) and the lower LOA -0.121 (95% CI -0.142 to -0.101) logMAR. The ICC was 0.922 (95% CI 0.887 to 0.946). 95% of subjects were willing to use DigiVis to monitor vision at home. CONCLUSIONS: Self-tested distance VA using DigiVis is accurate, reliable and well accepted by patients. The app has potential to facilitate home monitoring, triage and remote consultation but widescale implementation will require integration with NHS databases and secure patient data storage.

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.

Retinopathy of prematurity treatment in the UK: trends in neonatal anaesthetic support and location of treatment from a national surveillance study.

The aim of this study is to evaluate current anaesthetic practice for retinopathy of prematurity (ROP) interventions in the UK. We collected the data from the 12-month prospective British Ophthalmic Surveillance Unit study carried out in 2013/2014 that were analysed with regard to type of anaesthesia used for primary ROP procedures and the hospital department in which treatment took place. A total of 327 cases of treated ROP from 55 different UK units were reported in the study. Type of anaesthesia used during treatment was available for 324 (99.1%) cases and the treatment location in 316 (96.6%). Overall, 266 (89.3%) laser treatments and 13 (50.0%) of primary intravitreal injections were performed with the neonate intubated, using intravenous sedation (IVS) in 158 (59.4%) and the remainder, under general anaesthesia (GA). Two hundred thirteen (67.4%) of all ROP procedures took place in the neonatal unit. GA was used in 98 (95.1%) of theatre cases compared with 19 (8.9%) of cases treated in the neonatal unit. Three (0.9%) neonates suffered significant respiratory distress during or immediately after laser treatment.Conclusion: This survey suggests that the preference in UK units is to undertake ROP laser treatment in the neonatal unit with the neonate intubated and sedated intravenously. Those babies treated in the operating theatre are more likely to receive GA. In the surveyed year, half of the neonates receiving intravitreal injections as sole primary therapy was intubated; the reason for this could not be elucidated from the responses. Adverse respiratory reactions during or after laser treatment affected fewer than 1% of the neonates in this study. What is Known: • Prior to the introduction of intravitreal anti-VEGF, almost all ROP treatments in the UK were performed under general anaesthetic (GA). • The technique of intravitreal injection is described using topical anaesthesia and was thought to be changing anaesthesia preferences for ROP treatment. What is New: • Half of the neonates receiving primary anti-VEGF injection in the UK were treated under intravenous sedation or GA. • The increasing use of primary anti-VEGF treatment has not influenced trends in anaesthetic practice in the UK since the last review 10 years ago.

The infrared reflex: a potential new method for congenital cataract screening.

OBJECTIVE: To compare the accuracy of infrared (IR)-reflex assessment using a prototype imaging device to standard non-mydriatic red-reflex screening with direct ophthalmoscope (DO) in the diagnosis of neonatal and childhood cataract. METHODS: The comparison of the techniques was made in two distinct cohorts: in the first, newborns underwent IR and red-reflex testing by a medical student, with results compared to a reference red-reflex examination by an experienced midwife. In the second, an enriched cohort of children attending a specialist paediatric ophthalmology clinic had IR and red-reflex testing by a medical student to reference examination by a paediatric ophthalmologist. The medical students were considered inexperienced screeners due to their limited exposure to ophthalmology. The sensitivity and specificity of the IR and red-reflex assessments in respect to reference examination were calculated. Diagnostic accuracy was compared in Caucasian and non-Caucasian eyes. RESULTS: IR and red-reflex imaging were possible in all 180 neonatal eyes examined. A total of 5% of newborn eyes were found to have embryological remnants in the anterior segment of the eye with IR-reflex imaging which were not detected on reference red-reflex examination. IR-reflex assessment had significantly better sensitivity (100 vs 71%, p < 0.05) and specificity (100 vs 63%, p < 0.01) than red-reflex assessment in the diagnosis of childhood cataract. Red-reflex specificity was particularly poor in non-Caucasian eyes compared to Caucasian eyes (32 vs 72%, p < 0.05). CONCLUSION: This pilot study indicates that IR-reflex imaging has the potential to improve the diagnostic accuracy of eye screening for cataract by inexperienced healthcare staff, particularly in non-Caucasian children.

A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3 causing distal Renal Tubular Acidosis: case report.

BACKGROUND: Distal Renal Tubular Acidosis is a disorder of acid-base regulation caused by functional failure of α-intercalated cells in the distal nephron. The recessive form of the disease (which is usually associated with sensorineural deafness) is attributable to mutations in ATP6V1B1 or ATP6V0A4, which encode the tissue-restricted B1 and a4 subunits of the renal apical H(+)-ATPase. ATP6V1B1 lies adjacent to the gene encoding the homeobox domain protein VAX2, at 2p13.3. To date, no human phenotype has been associated with VAX2 mutations. CASE PRESENTATION: The male Caucasian proband, born of a first cousin marriage, presented at 2 months with failure to thrive, vomiting and poor urine output. No anatomical problems were identified, but investigation revealed hyperchloremic metabolic acidosis with inappropriately alkaline urine and bilateral nephrocalcinosis. Distal Renal Tubular Acidosis was diagnosed and audiometry confirmed hearing loss at 2 years. ATP6V0A4 was excluded from genetic causation by intragenic SNP linkage analysis, but ATP6V1B1 completely failed to PCR-amplify in the patient, suggesting a genomic deletion. Successful amplification of DNA flanking ATP6V1B1 facilitated systematic chromosome walking to ascertain that the proband harbored a homozygous deletion at 2p13.3 encompassing all of ATP6V1B1 and part of VAX2; gene dosage was halved in the parents. This results in the complete deletion of ATP6V1B1 and disruption of the VAX2 open reading frame. Later ocular examinations revealed bilateral rod / cone photoreceptor dystrophy and mild optic atrophy. Similar changes were not detected in an adult harbouring a disruptive mutation in ATP6V1B1. CONCLUSIONS: The genomic deletion reported here is firstly, the only reported example of a whole gene deletion to underlie Distal Renal Tubular Acidosis, where the clinical phenotype is indistinguishable from that of other patients with ATP6V1B1 mutations; secondly, this is the first reported example of a human VAX2 mutation and associated ocular phenotype, supporting speculation in the literature that VAX2 is important for correct retinal functioning.

Different paths to sexual size dimorphism in two praying mantids, Pseudomantis albofimbriata and Hierodula majuscula.

Sexual size dimorphism (SSD) is widespread among diverse animal taxa and has attracted the attention of evolutionary biologists for over a century. SSD is likely to be adaptive and the result of divergent selection on different size optima for males and females, given their different roles in reproduction. The developmental trajectory leading to SSD may help us to understand how selection acts on male and female size. Here, we describe the growth and development of two Australian praying mantids, Pseudomantis albofimbriata and Hierodula majuscula including the number of moults, time to adulthood, size at each moult, and the degree of SSD. While both species exhibit the common pattern of female-biased SSD, the number of moults required for individuals to reach adulthood differed between males and females and between species. Despite their larger adult size, P. albofimbriata females require fewer moults and less time than males to reach adulthood, but are significantly larger than males from the second instar onwards. In contrast, H. majuscula males reached adulthood in fewer moults, and less time than females, however males and females did not differ in size until females went through their final moult into adulthood. H. majuscula also required more time and more moults to reach adulthood than P. albofimbriata. We discuss these different developmental pathways in light of the existing knowledge of reproductive biology for each species. We also suggest that these differences may relate to the different phenologies that occur in strongly seasonal temperate environments compared with those in the tropics. This study provides evidence that SSD can result from two different patterns of growth and development in closely related species.

A new perimeter using the preferential looking response to assess peripheral visual fields in young and developmentally delayed children.

PURPOSE: To compare the sensitivity, specificity, and interpretability of a newly developed semiautomated static perimeter based on the preferential looking response to the results of confrontation visual field testing in a group of young and/or developmentally delayed children with and without visual field deficit. METHODS: The preferential looking perimeter (PLP) uses observation of the child's natural eye movement response to an appearing target to determine the peripheral visual field. We compared preferential looking perimetry to confrontation testing in 74 children 3-10 years of age (mean, 6.6 years; median, 7 years), including 32 controls and 42 children with neurological and ocular disorders that could cause significant visual field deficit. RESULTS: Using confrontation testing as the gold standard, the PLP was 100% sensitive and 100% specific (95% CI, 90%-100%), with excellent interobserver agreement. An interpretable result could be achieved in 15 (71%) of the 21 children in whom confrontation testing was unhelpful. CONCLUSIONS: PLP is a useful new technique for assessing significant visual field loss in young or developmentally delayed children, with many advantages over confrontation testing.

Congenital unilateral corneal anaesthesia with microphthalmos: a case report.

Congenital corneal anaesthesia (CCA) is an uncommon condition difficult to diagnose. We report the case of a 20-month-old boy who presented with unilateral congenital corneal anaesthesia. The child was referred with a persistent corneal epithelial defect, unresponsive to symptomatic local treatment for over 10 months. Intensive topical treatment and strict corneal protection led to quick corneal healing. Congenital corneal anaesthesia occurs either alone or in association with neurological diseases or systemic congenital abnormalities. It is important to search for corneal anaesthesia in children with chronic ulcerations of the cornea and self-inflicted injuries. Early diagnosis and treatment are important due to the risk of poor visual prognosis. Management of CCA should aim for the prevention of epithelial defects and is a life-long process.

Mutations in the CACNA1F and NYX genes in British CSNBX families.

X-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX.