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To determine any factors that predict how an individual will adapt to post-stroke hemianopic visual field loss, with close monitoring of the adaptation process from an early stage.The Hemianopia Adaptation Study (HAST) is a prospective observational longitudinal cohort clinical study. Adult stroke survivors (Several baseline variables were found to be good predictors of adaptation. Three variables were associated with adaptation status at 12-weeks post-stroke: inferior % visual field, % total MAC omissions, and MAC completion time (seconds). Baseline measurements of these variables can predict the adaptation at 12 weeks with moderate to high accuracy (area under ROC curve, 0.82, 95% CI 0.74-0.90). A cut-off score of ≤25% target omissions is suggested to predict which individuals are likely to adapt by 12-weeks post-stroke following gold standard care.Adaptation to hemianopia is a personal journey with several factors being important for prediction of its presence, including MAC outcomes and extent of inferior visual field loss. A clinical recommendation is made for inclusion of the MAC as part of a functional assessment for hemianopia.Implications for rehabilitationThe mobility assessment course (MAC) should be considered as an assessment of mobility/scanning in the rehabilitation of patients with homonymous hemianopia.A cut-off score of ≤25% omissions on MAC could be employed to determine those likely to adapt to hemianopia long-term.Targeted support and therapy for patients with significant visual loss in the inferior visual field area should be considered.

Background Falls are the second leading cause of accidental deaths worldwide mainly in older people. Older people have poor vision and published evidence suggests that it is a risk factor for falls. Less than half of falls clinics assess vision as part of the multi-factorial assessment of older adults at risk of falls despite vision being an essential input for postural stability. The aim of our study was to investigate the relationship between all clinically assessed visual functions and falls amongst older adults in a prospective observational individually age-matched case control study. Methods Visual acuity (VA), contrast sensitivity (CS), depth perception, binocular vision and binocular visual field were measured using routinely used clinical methods in falls participants (N = 83) and non-falls participants (N = 83). Data were also collected on socio-demographic factors, general health, number of medications, health quality, fear of falling and physical activity. Logistic regression analysis was carried out to determine key visual and non-visual risk factors for falls whilst adjusting for confounding covariates. Results Older adults have an increased risk of experiencing a fall if they have reduced visual function (odds ratio (OR): 3.49, 1.64-7.45, p = 0.001), specifically impaired stereoacuity worse than 85” of arc (OR: 3.4, 1.20-9.69, p = 0.02) and reduced (by 0.15 log unit) high spatial frequency CS (18 cpd) (OR:1.40, 1.12-1.80, p = 0.003). Older adults with a hearing impairment are also at higher risk of falls (OR: 3.18, 95% CI: 1.36-7.40, p = 0.007). The risk decreases with living in a less deprived area (OR: 0.74, 0.64-0.86, Conclusions The combination of social, behavioural and biological determinants are significant predictors of a fall. The non-visual risk factors include older adults, living in deprived neighbourhoods, socialising less outside of the home and those who have a hearing impairment. Impaired functional visual measures; depth perception and contrast are significant visual risk factors for falls above visual acuity.

BackgroundAtrial fibrillation affects an estimated 33 million individuals worldwide and is a major cause of stroke, heart failure, and death. Anticoagulants substantially reduces risk of stroke but are also associated with an increased risk of bleeding and especially intracranial hemorrhages which are the most feared complication. Because of this many patients are not offered anticoagulants, particularly patients at risk of falls or with history of falls. It is unclear what anticoagulant treatment these patients should be offered, and the Liverpool AF-Falls project aims to investigate this area. This protocol for a systematic review and meta-analysis aims to define what is the most appropriate anticoagulant treatment option for the for the management of atrial fibrillation patients at risk of falls or with a history of falls. MethodsThis systematic review and meta-analysis will include randomized and non-randomized studies evaluating safety and efficacy of different anticoagulant treatments (vitamin K antagonist, non-vitamin K antagonist oral anti-coagulant, anti-platelet agent and no treatment). Bibliographic databases (Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Scopus, CINAHL, Web of Science and ClinicalTrials.gov) will be searched according to a pre-specified search strategy. Titles, abstracts, and full texts will be assessed by two independent reviewers and disagreement resolved with a third independent reviewer. The Cochrane Risk of Bias tool 2 will be used to assess risk of bias in randomized trials and the Newcastle-Ottawa-Scale tool will be used for non-randomized studies. Pairwise meta-analysis based on the fixed and random-effects models will be conducted. Publication bias will be evaluated with a funnel plot and the Egger’s test. Heterogeneity will be assessed with the I2 statistic. If conditions for indirect comparison are met and sufficient data are available, a network meta-analysis will be conducted using frequentist and Bayesian methodologies. DiscussionThis review will be the first to summarize direct and indirect evidence on safety and efficacy of anticoagulant treatments in atrial fibrillation patients at risk of falls or with history of falls. The findings will be important to patients, clinicians, and health policy-makers to inform best practice in the use of these treatments. Systematic review registrationPROSPERO registry number: CRD42020201086

Current research in automated disease detection focuses on making algorithms “slimmer” reducing the need for large training datasets and accelerating recalibration for new data while achieving high accuracy. The development of slimmer models has become a hot research topic in medical imaging. In this work, we develop a two-phase model for glaucoma detection, identifying and exploiting a redundancy in fundus image data relating particularly to the geometry. We propose a novel algorithm for the cup and disc segmentation “EffUnet” with an efficient convolution block and combine this with an extended spatial generative approach for geometry modelling and classification, termed “SpaGen” We demonstrate the high accuracy achievable by EffUnet in detecting the optic disc and cup boundaries and show how our algorithm can be quickly trained with new data by recalibrating the EffUnet layer only. Our resulting glaucoma detection algorithm, “EffUnet-SpaGen”, is optimized to significantly reduce the computational burden while at the same time surpassing the current state-of-art in glaucoma detection algorithms with AUROC 0.997 and 0.969 in the benchmark online datasets ORIGA and DRISHTI, respectively. Our algorithm also allows deformed areas of the optic rim to be displayed and investigated, providing explainability, which is crucial to successful adoption and implementation in clinical settings.

The utility of diffusion kurtosis imaging (DKI) for assessing intra-tumor heterogeneity was evaluated in a rat model of glioblastoma multiforme. Longitudinal MRI including T2 -weighted and diffusion-weighted MRI (DWI) was performed on six female Fischer rats 8, 11 and 14 days after intracranial transplantation of F98 cells. T2 -weighted images were used to measure the tumor volumes and DWI images were used to compute diffusion tensor imaging (DTI) and DWI based parametric maps including mean diffusivity (MD), mean kurtosis (MK), axial diffusivity (AD), axial kurtosis, radial diffusivity, radial kurtosis, fractional anisotropy (FA) and kurtosis fractional anisotropy (KFA). Median values from the segmented normal contralateral cortex, tumor and edema from the diffusion parameters were compared at the three imaging time points to assess any changes in tumor heterogeneity over time. ex vivo DKI was also performed in a representative sample and compared with histology. Significant differences were observed between normal cortex, tumor and edema in both the DTI and DKI parameters. Notably, at the earliest time point MK and KFA were significantly different between normal cortex and tumor in comparison with MD or FA. Although a decreasing trend in MD, AD and FA values of the tumor were observed as the tumor grew, no significant changes in any of the DTI or DKI parameters were observed longitudinally. While DKI was equally sensitive to DTI in differentiating tumor from edema and normal brain, it was unable to detect longitudinal increases in intra-tumoral heterogeneity in the F98 model of glioblastoma multiforme.

Type I collagen is the major structural component of bone where it exists as an (α1)2(α2)1 heterotrimer in all vertebrates. The osteogenesis imperfecta (oim) mouse model comprising solely homotrimeric (α1)3 type I collagen, due to a dysfunctional α2 chain, has a brittle bone phenotype implying that the heterotrimeric form is required for physiological bone function. However, humans with rare null alleles preventing synthesis of the α2 chain have connective tissue and cardiovascular abnormalities (cardiac valvular Ehlers Danlos Syndrome), without evident bone fragility. Conversely a prevalent human single nucleotide polymorphism leading to increased homotrimer synthesis is associated with osteoporosis. Whilst the oim line is well-studied, whether homotrimeric type I collagen is functionally equivalent to the heterotrimeric form in bone has not been demonstrated. Col1a2 null and oim mouse lines were used in this study and bones analysed by microCT and 3-point bending. RNA was also extracted from heterozygote tissues and allelic discrimination analyses performed using qRT-PCR. Here we comprehensively show for the first time that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However Mendelian inheritance was affected in male mice of both lines and male mice null for the α2 chain exhibited age-related loss of condition. The brittle bone phenotype of oim homozygotes could result from detrimental effects of the oim mutant allele, however, the phenotype of oim heterozygotes is known to be less severe. We used allelic discrimination to show that the oim mutant allele is not downregulated in heterozygotes. We then tested whether gene dosage was responsible for the less severe phenotype of oim heterozygotes by generating compound heterozygotes. Data showed that compound heterozygotes had impaired bone structural properties as compared to oim heterozygotes, albeit to a lesser extent than oim homozygotes. Hence, we concluded that the presence of heterotrimeric collagen-1 in oim heterozygotes alleviates the effect of the oim mutant allele but a genetic interaction between homotrimeric collagen-1 and the oim mutant allele leads to bone fragility.

Background In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. Methods We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. Results Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21–33.78 and OR = 8.58, 95% CI = 2.56–29.08, respectively) and brain swelling (P Conclusions Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

Our previous note outlined why method agreement studies are so important in ophthalmology.1 Technology moves at a relentless pace and clinicians are keen to adopt innovative techniques that may offer benefits to their patients, such as shorter or less invasive testing, in addition to creating richer data sets that may increase the research potential of the data captured. Researchers and clinicians must, however, use caution to ensure that any differences observed between measurements made on a patient with different methods of measurement are truly due to changes in pathology rather than the method of measurement, the observer making the measurement or other variables that might influence the measurement. Even if two machines appear to report the same characteristic it is possible that one machine is measuring a different anatomical feature than another machine but using the same name. An example is in studies of keratometry and topography where the term Kmax is used to describe both the steepest meridian of the cornea in the central 3 mm (also called K2) and the power of the steepest point of the cornea.2 3 This is of particular importance in trials investigating treatments for keratoconus where Kmax may be the primary outcome measure or used to determine subject eligibility.4 We commented also in our previous note on the differences between the regulation of devices as compared with that of medicines.1 There is a tension between innovation and safety and while measurement reproducibility may not immediately be seen as relevant to harm, measurements are used to make decisions about diagnosis, progression and treatment. For example, a large change in intraocular pressure (IOP) between two visits in a child with glaucoma may indicate the need for examination under anaesthesia, while a large change in K2 readings in an individual with keratoconus might …

Purpose To investigate whether early detection and treatment of uveal melanoma by screening was associated with a lower mortality rate. Methods Retrospective assessment of prospectively collected data comparing 132 patients with uveal melanoma referred by the National Diabetic Screening Service with 608 control patients referred through other means. Results Mean tumor diameter was smaller in the diabetic screening group (11.1 mm vs. 12.5 mm) as was tumor thickness (3.4 mm vs. 5.4 mm). The prevalence of high-risk monosomy 3 was also lower (17/40, 43% vs. 62/110, 56%). Despite a higher rate of systemic comorbidities in the patients diagnosed through screening and despite older age at diagnosis, the 5-year all-cause mortality was similar in both groups (17% vs. 20%); however, the metastatic mortality was lower in the diabetic screening group (11/132, 8% vs. 95/608, 16%). Conclusion Despite higher rates of comorbidities, the patients detected at diabetic screening had a lower 5-year mortality rate. The diabetic screening programme enabled detection and treatment of posterior uveal melanomas at an earlier stage. However, the confounding factors of lead and length time bias are not to be ignored.

For the diagnosis and monitoring of retinal diseases, the spatial context of retinal thickness is highly relevant but often under-utilised. Despite the data being spatially collected, current approaches are not spatial: they involve analysing each location separately, or they analyse all image sectors together but they ignore the possible spatial correlations such as linear models, and multivariate analysis of variance (MANOVA). We propose spatial statistical inference framework for retinal images, which is based on a linear mixed effect model and which models the spatial topography via fixed effect and spatial error structures. We compare our method with MANOVA in analysis of spatial retinal thickness data from a prospective observational study, the Early Detection of Diabetic Macular Oedema (EDDMO) study involving 89 eyes with maculopathy and 168 eyes without maculopathy from 149 diabetic participants. Heidelberg Optical Coherence Tomography (OCT) is used to measure retinal thickness. MANOVA analysis suggests that the overall retinal thickness of eyes with maculopathy are not significantly different from the eyes with no maculopathy (p = 0.11), while our spatial framework can detect the difference between the two disease groups (p = 0.02). We also evaluated our spatial statistical model framework on simulated data whereby we illustrate how spatial correlations can affect the inferences about fixed effects. Our model addresses the need of correct adjustment for spatial correlations in ophthalmic images and to improve the precision of association in clinical studies. This model can be potentially extended into disease monitoring and prognosis in other diseases or imaging technologies.

Purpose: The presence of central visual field loss does not infer the extent of peripheral visual field loss. In advanced stage glaucoma, we evaluated whether automated kinetic perimetry provided additional visual field information to that of central static perimetry. Materials and Methods: We undertook a prospective cross-sectional study of advanced-stage glaucoma defined as stages 3–4. Visual field assessment for right and left eyes was undertaken within one clinic visit using the Octopus 900 G programme and kinetic strategy. Results: We recruited 126 patients (170 eyes). Mean patient age at assessment was 55.86 years (SD 15.15). Mean kinetic reaction time was 1503.96 ms (SD 801.68). Kinetic I4e was plotted in 71% of eyes with an unadjusted area of 2513.68 degrees2 (SD 2397.91) and mean isopter radius of 23.16 degrees (SD 13.07). Kinetic I2e was plotted in 53.5% of eyes with an unadjusted area of 627.07 degrees2 (SD 1291.94) and mean isopter radius of 7.47 degrees (SD 10.59). Increased reaction time was associated with a poorer visual field (p = .001). Mean sensitivity, mean deviation and standard loss variance values on static perimetry were higher in patients who had a defined kinetic field boundary than in patients with no kinetic response to I4e stimulus (p = .0001). However, this corresponded to only small-to-medium correlation between static fields and existent kinetic fields: the presence of poor static fields did not always infer a poor kinetic visual field as poor static fields could also have good kinetic visual fields. Conclusions: Although we confirmed a lack of agreement and only a small to medium correlation between the extents of central versus peripheral visual field loss, automated kinetic perimetry did provide additional peripheral (outside the static 30-degree central field) visual field information which was clinically useful in the presence of non-informative severely defected central visual fields.

BackgroundRenal Ischaemia Reperfusion Injury (R-IRI) can cause Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD), resulting in significant morbidity and mortality. To understand the underlying mechanisms, reproducible small-animal models of AKI and CKD are needed. We describe how innovative technologies for measuring kidney function non-invasively in small rodents allow successful refinement of the R-IRI models, and offer the unique opportunity to monitor longitudinally in individual animals the transition from AKI to CKD.MethodsMale BALB/c mice underwent bilateral renal pedicle clamping (AKI) or unilateral renal pedicle clamping with delayed contralateral nephrectomy (CKD) under isoflurane anaesthetic. Transdermal GFR monitoring and multi-spectral optoacoustic tomography in combination with statistical analysis were used to identify and standardise variables within these models.ResultsPre-clamping anaesthetic time was one of the most important predictors of AKI severity after R-IRI. Standardising pre-clamping time resulted in a more predictably severe AKI model. In the CKD model, initial improvement in renal function was followed by significant progressive reduction in function between weeks 2 and 4. Performing contralateral nephrectomy on day 14 enabled the development of CKD in a survivable way.ConclusionsNon-invasive monitoring of global and individual renal function after R-IRI is feasible, reproducible and correlates well with classical markers of injury. This facilitates refinement of kidney injury models and enables the degree of injury seen in pre-clinical models to be translated to those seen in the clinical setting. Thus, future therapies can be tested in a clinically relevant, non-invasive manner.What is already knownThe severity of Renal Ischaemia Reperfusion injury (R-IRI) varies between animal strain, gender and age. Experimental variables including temperature and clamping time are usually tightly controlled but significant variability still exists. Classically, small rodent experiments depend on endpoint evaluation of serum and histological features of disease. However, new technologies including transdermal glomerular filtration rate (GFR) monitoring and Multispectral Optoacoustic Tomography (MSOT) may enable renal function to be accurately monitored longitudinally, enabling better refinement of these models.What this study addsThis study shows that transdermal GFR measurements have reliably enabled refinement of the R-IRI model by standardisation of the duration of isoflurane prior to commencing surgery. Individual kidney function can be assessed in-vivo after unilateral R-IRI using MSOT imaging. The excretion tmax of IRDye-800 reliably represents the relative function of the injured kidney, permitting longitudinal in-vivo assessment of differential kidney function.What impact this may have on practiceThis study demonstrates the utility of two minimally-invasive in-vivo methods of monitoring kidney function which have advantages over classical methods and potentially enable fewer animals to be used in future studies. The study demonstrates refinement of bilateral and unilateral R-IRI models which will also enable a reduction in the number of animals needed for experimentation.

It has become increasingly clear that epigenetic deregulation plays a fundamental role in cancer. Although the understanding of molecular, genetic and transcriptional alterations involved in the initiation and progression of uveal melanoma (UM) has grown significantly in recent years, little attention has been paid to the role of epigenetic changes. In cancer, epithelial-to-mesenchymal transition (EMT) enables trans-differentiation of epithelial tumor cells, endowing them with migratory and invasive properties. EMT-inducing transcription factors have been shown to interact with multiple epigenetic modifiers, thus reflecting the reversible nature of EMT. Therefore, the epigenetic therapy targeting these interactions may provide a promising therapeutic option, especially since no improvement in survival of patients with metastatic UM has been achieved using traditional approaches. This review summarizes current knowledge of epigenetic regulation of EMT in UM and emphasizes the need for deeper understanding of these highly dynamic and reversible processes. The potential for targeting individual members of the epigenetic machinery is also addressed.

Good clinical care depends on accurate and precise measurement and is essential throughout medicine. Many decisions about patient care in ophthalmology are based on changes in the measurement of characteristics over time (intraocular pressure in glaucoma, central retinal thickness in medical retina studies, Kmax readings in keratoconus) or differences between the measurements for an individual and the ‘normal’ population (or more strictly speaking those without the condition of interest). We want to know the true value of the characteristic, but this is obtained with measurement error. Measurement error is the difference between the known measured quantity and its unknown true value. It has two main components: random error due to chance and systematic error (sometimes known as systematic bias) not due to chance. Precision is related to random error while accuracy is related to systematic error. Measurement error may cause inappropriate patient management or harm.1 No method of measurement is completely without measurement error. Often less invasive and cheaper methods of measurement have more measurement error. One has to balance the desire for an accurate measurement, against being overly invasive to the patient or too time-consuming to incorporate in a routine clinical setting. Medicine moves at a rapid rate and new measurement technologies frequently arrive in the marketplace. While once there was a single method to measure intraocular pressure (Goldmann Applanation Tonometry), now there are many different methods and different machines on the market for example, non-contact tonometers, hand-held devices, etc. Newer methods may be more accurate and precise than older methods or may be cheaper or quicker to use. Some methods may be more convenient to use, but can have greater measurement error. The regulatory framework for devices within the UK is very different to that of medicines and while safety of the new instrument must be demonstrated, …

ObjectivesIn this study, we sought to evaluate the extent of further visual field that could be assessed when using stimulus size V in standard automated perimetry compared with size III in advanced stage glaucoma and whether cut-off values could be determined for when to switch from size III to size V.DesignProspective cross-sectional study.SettingSingle-centre outpatient eye clinic in India (New Delhi).ParticipantsAdvanced stage glaucoma defined as stages 3–4.InterventionCentral static perimetry with Octopus 900 G programme (size III stimulus dynamic strategy) and low vision central programme (size V stimulus dynamic strategy).Primary and secondary outcome measuresVisual field assessment for right and left eyes with both sizes III and V were undertaken within one clinic visit.ResultsWe recruited 126 patients (170 eyes). Mean patient age at assessment was 55.86 years (SD 15.15). Means (SD) for size III versus size V, respectively, were 6.94 dB (5.58) and 12.98 dB (7.77) for mean sensitivity, 20.02 dB (5.67) and 19.22 dB (7.74) for mean deviation, 5.89 dB (2.29) and 7.69 dB (2.78) for standard loss variance and 3.32 min (1.07) and 6.40 min (1.43) for test duration. All except mean deviation were significantly different between size III and V tests.ConclusionUseful visual field information was obtained with size V stimuli which allowed continued monitoring of these patients that was not possible with size III. Increased test duration, standard loss variance and mean sensitivity were found with size V, as expected, given that more visual responses were obtained with the increased target size. A switch from size III to V may be considered when mean sensitivity reaches 10 dB and/or mean deviation reaches 18 dB.

A lesion specific to Ebola virus disease showed an anatomical distribution suggesting neuronal transmission., We conducted a case–control study in Freetown, Sierra Leone, to investigate ocular signs in Ebola virus disease (EVD) survivors. A total of 82 EVD survivors with ocular symptoms and 105 controls from asymptomatic civilian and military personnel and symptomatic eye clinic attendees underwent ophthalmic examination, including widefield retinal imaging. Snellen visual acuity was

Purpose: To compare hydroxyapatite with acrylic implants after enucleation for uveal melanoma with respect to eyelid position, ocular motility, implant complications, and patient satisfaction. Methods: Patients undergoing primary enucleation for uveal melanoma between May 2005 and November 2012 at the Liverpool Ocular Oncology Centre, United Kingdom, were randomized between hydroxyapatite and acrylic implants. Questionnaires were sent to patients and ocularists to comment on the main outcomes. Results: A total of 416 patients were recruited in the study, of whom 281 were included, with 49.5% (139/281) and 50.5% (142/281) receiving a hydroxyapatite (HA) or acrylic (AC) implant. Mailed questionnaires completed at ≥18 months by patients showed no significant differences between the groups in eyelid position, prosthetic motility, socket complications, and patient satisfaction. Complications included implant extrusion (1% vs 4%), enophthalmos (26% vs 26%), and superior sulcus deformity (24% vs 24%) with HA and AC implants, respectively, (Fisher exact test p > 0.0125 in all, Bonferroni correction). Questionnaires completed by ocularists indicated no significant differences in eyelid opening, prosthetic motility, and other complications at 6 months (Fisher exact test, p > 0.05 in all); there was a higher prevalence of ptosis with AC than HA implants (46% vs 25%, p = 0.03) and a greater need for ocularists’ treatment with HA than AC (50% vs 28%, p = 0.03). Conclusions: Patient-reported outcomes after enucleation for uveal melanoma indicate no major differences between hydroxyapatite and acrylic implants in surgical outcomes and patient satisfaction. There was a higher prevalence of ptosis with AC and a greater need of ocularists’ visits with HA at around 6 months observed by ocularists.

BackgroundGlaucoma is the leading cause of irreversible blindness worldwide. It is a heterogeneous group of conditions with a common optic neuropathy and associated loss of peripheral vision. Both over and under-diagnosis carry high costs in terms of healthcare spending and preventable blindness. The characteristic clinical feature of glaucoma is asymmetrical optic nerve rim narrowing, which is difficult for humans to quantify reliably. Strategies to improve and automate optic disc assessment are therefore needed to prevent sight loss.MethodsWe developed a novel glaucoma detection algorithm that segments and analyses colour photographs to quantify optic nerve rim consistency around the whole disc at 15-degree intervals. This provides a profile of the cup/disc ratio, in contrast to the vertical cup/disc ratio in common use. We introduce a spatial probabilistic model, to account for the optic nerve shape, we then use this model to derive a disc deformation index and a decision rule for glaucoma. We tested our algorithm on two separate image datasets (ORIGA and RIM-ONE).ResultsThe spatial algorithm accurately distinguished glaucomatous and healthy discs on internal and external validation (AUROC 99.6% and 91.0% respectively). It achieves this using a dataset 100-times smaller than that required for deep learning algorithms, is flexible to the type of cup and disc segmentation (automated or semi-automated), utilises images with missing data, and is correlated with the disc size (p = 0.02) and the rim-to-disc at the narrowest rim (pDiscussionThe spatial probabilistic algorithm is highly accurate, highly data efficient and it extends to any imaging hardware in which the boundaries of cup and disc can be segmented, thus making the algorithm particularly applicable to research into disease mechanisms, and also glaucoma screening in low resource settings.

PURPOSE: To report on the utility of a computer tablet-based method for automated testing of visual acuity in children based on the principles of game design. We describe the testing procedure and present repeatability as well as agreement of the score with accepted visual acuity measures.DESIGN: Reliability and validity study.METHODS: Setting: Manchester Royal Eye Hospital Pediatric Ophthalmology Outpatients Department.PATIENT POPULATION: Total of 112 sequentially recruited patients.INTERVENTION: For each patient 1 eye was tested with the Mobile Assessment of Vision by intERactIve Computer for Children (MAVERIC-C) system, consisting of a software application running on a computer tablet, housed in a bespoke viewing chamber. The application elicited touch screen responses using a game design to encourage compliance and automatically acquire visual acuity scores of participating patients. Acuity was then assessed by an examiner with a standard chart-based near ETDRS acuity test before the MAVERIC-C assessment was repeated.MAIN OUTCOME MEASURE: Reliability of MAVERIC-C near visual acuity score and agreement of MAVERIC-C score with near ETDRS chart for visual acuity.RESULTS: Altogether, 106 children (95%) completed the MAVERIC-C system without assistance. The vision scores demonstrated satisfactory reliability, with test-retest VA scores having a mean difference of 0.001 (SD ±0.136) and limits of agreement of 2 SD (LOA) of ±0.267. Comparison with the near EDTRS chart showed agreement with a mean difference of -0.0879 (±0.106) with LOA of ±0.208.CONCLUSIONS: This study demonstrates promising utility for software using a game design to enable automated testing of acuity in children with ophthalmic disease in an objective and accurate manner.

PurposeTo report near-infrared reflectance (NIR-R), near-infrared autofluorescence (NIR-AF) and blue wave autofluorescence (BW-AF) appearance of choroidal nevi using a confocal scanning laser ophthalmoscope (cSLO).Patients and methodsNIR-R, NIR-AF and BW-AF images of choroidal nevi were compared with color fundus photos (CF). Images were graded as hyperreflective if reflectance was much greater than background, hyporeflective if less than background, and isoreflective if the same as the background.ResultsForty-two nevi of 39 patients were imaged. When compared with CF, nevi could be identified on 95% (40/42) NIR-R images (95% CI: 83.5-99.3). On NIR-R 71% (30/42) demonstrated hyperreflectance and 24% (10/42) were hyporeflective. Hyperreflectivity was demonstrated in 96% (23/24) of NIR-AF images (95% CI: 79.1-99.9) and 34% (14/41) of BW-AF images (95% CI: 20.0-50.5). On NIR-R, 29/40 (73%) were apparently smaller in comparison with CF and 11/40 (28%) had the same area. A correlation was found between NIR-R and NIR-AF (P=0.02) but not with BW-AF (P=0.15).ConclusionsNevi can be visualized well using NIR-R and NIR-AF imaging modalities, but are less frequently visible using BW-AF. These changes may be related to melanin within the choroid or chronic changes of the overlying retinal pigment epithelium.

Many eye diseases require on-going assessment for optimal management, creating an ever-increasing burden on patients and hospitals that could potentially be reduced through home vision monitoring. However, there is limited evidence for the utility of current applications and devices for this. To address this, we present a new automated, computer tablet-based method for self-testing near visual acuity (VA) for both high and low contrast targets. We report on its reliability and agreement with gold standard measures. The Mobile Assessment of Vision by intERactIve Computer (MAVERIC) system consists of a calibrated computer tablet housed in a bespoke viewing chamber. Purpose-built software automatically elicits touch-screen responses from subjects to measure their near VA for either low or high contrast acuity. Near high contrast acuity was measured using both the MAVERIC system and a near Landolt C chart in one eye for 81 patients and low contrast acuity using the MAVERIC system and a 25 % contrast near EDTRS chart in one eye of a separate 95 patients. The MAVERIC near acuity was also retested after 20 min to evaluate repeatability. Repeatability of both high and low contrast MAVERIC acuity measures, and their agreement with the chart tests, was assessed using the Bland-Altman comparison method. One hundred and seventy-three patients (96 %) completed the self- testing MAVERIC system without formal assistance. The resulting MAVERIC vision demonstrated good repeatability and good agreement with the gold-standard near chart measures. This study demonstrates the potential utility of the MAVERIC system for patients with ophthalmic disease to self-test their high and low contrast VA. The technique has a high degree of reliability and agreement with gold standard chart based measurements.

Medical research is conducted to answer uncertainties and to identify effective treatments for patients. Different questions are best addressed by different types of study design—but the randomised, controlled clinical trial is typically viewed as the gold standard, providing a very high level of evidence, when examining efficacy.1 While clinical trial methodology has advanced considerably with clear guidance provided as to how to avoid sources of bias, even the most robustly designed study can succumb to missing data.2 ,3 In this statistics note, we discuss strategies for dealing with missing data but what we hope emerges is a very clear message that there is no ideal solution to missing data and prevention is the best strategy. A senior colleague asks me to critique a publication of a randomised, controlled clinical trial comparing two drugs which aim to reduce intraocular pressure (IOP) in patients with primary open angle glaucoma. One eye per patient has been analysed and results are provided for IOP at 6 months. The study presents data on 147 subjects treated with drug A and 145 subjects with drug B. The mean pressure in patients on drug A is lower than in those on drug B, with an estimated treatment difference of 3.1 mm Hg, 95% CI (2.5, 3.8). A p value of

Purpose Computer-assisted assessment of vessel tortuosity is clinically useful in retinopathy of prematurity (ROP). However, poor image quality is often prohibitive for accurate segmentation by fully automated systems and semi-automated systems are prone to unreliability. In the present work, we describe a method of retinal vessel tortuosity measurement by means of purpose-built image analysis software that does not require high image quality yet is also reliable. Methods Images were obtained from neonates at risk of ROP with Retcam Shuttle®. Individual vessels were assessed with the semi-automated Novel Evidenced Assessment of Tortuosity (NEAT) system by two masked experimenters. Scores were compared to assess reliability. They were also compared against clinical scoring of individual vessels by two ROP screeners to assess relationship with clinical assessment. In a second image cohort, the mean of the most tortuous vessel in each of four quadrants in each eye (NEAT-O) was compared against the documented gold standard clinical grading of plus disease. Results Reliability of the NEAT system for 50 individual vessels using Bland–Altman plots was excellent. NEAT tortuosity scores for 50 individual vessels compared to clinical scoring showed strong correlation (0.706). Correlation between the NEAT-O score for average tortuosity and gold standard for 167 eyes was modest (0.578). Conclusions The NEAT system is intuitive, user-friendly and robust enough to be clinically useful in poor-quality images. It allows for a rapid, valid and reliable assessment of tortuosity of individual vessels and produces a tortuosity score that correlates well with severity of plus disease.

A senior colleague asks me to critique a paper which reports to have used multivariate statistical methods to suggest an inhibitory effect of maternal smoking on the development of severe retinopathy of prematurity (ROP).1 S/he is concerned by the paper because the abstract suggests a positive effect of maternal smoking which flies very much against public health messages in general regarding smoking but is reassured by the fact that complex statistical methods, namely multivariate techniques, have been employed. I access the internet and find that the paper has been published in a peer-reviewed journal of high repute and that it reports an analysis conducted using data from 86 premature (

Osteoporosis is the most common age-related bone disease worldwide and is usually clinically asymptomatic until the first fracture happens. MicroRNAs are critical molecular regulators in bone remodelling processes and are stabilised in the blood. The aim of this project was to identify circulatory microRNAs associated with osteoporosis using advanced PCR arrays initially and the identified differentially-expressed microRNAs were validated in clinical samples using RT-qPCR. A total of 161 participants were recruited and 139 participants were included in this study with local ethical approvals prior to recruitment. RNAs were extracted, purified, quantified and analysed from all serum and plasma samples. Differentially-expressed miRNAs were identified using miRNA PCR arrays initially and validated in 139 serum and 134 plasma clinical samples using RT-qPCR. Following validation of identified miRNAs in individual clinical samples using RT-qPCR, circulating miRNAs, hsa-miR-122-5p and hsa-miR-4516 were statistically significantly differentially-expressed between non-osteoporotic controls, osteopaenia and osteoporosis patients. Further analysis showed that the levels of these microRNAs were associated with fragility fracture and correlated with the low bone mineral density in osteoporosis patients. The results show that circulating hsa-miR-122-5p and hsa-miR-4516 could be potential diagnostic biomarkers for osteoporosis in the future.

Purpose: The purpose of this study was to compare optical coherence tomography angiography (OCTA) and indocyanine green angiography (ICGA) for the assessment of corneal neovascularization (CoNV).\ud Methods: Patients with CoNV extending at least 3 mm into the cornea were included. All patients underwent corneal imaging at the same visit. Images were recorded using the AngioVue OCTA system (Optovue, Inc.) with the long corneal adaptor module (CAM-L). ICGA images were recorded with fluorescent filters using the Heidelberg system (HRA2 Scanning Laser Ophthalmoscope; Heidelberg Engineering). Images were graded for quality by two independent observers. Vessel parameters: area, number, diameter, branch and end points, and tortuosity, were compared between devices. Bland-Altman plots were used to assess differences between parameters.\ud Results: Fifteen patients with CoNV predominantly associated with microbial keratitis were included. Mean subjective image quality score was better for ICGA (3.3 ± 0.9) than for OCTA (2.1 ± 1.2, P = 0.002), with almost perfect interobserver agreement for ICGA images (κ = 0.83) and substantial agreement for OCTA images (κ = 0.69). Agreement of grading of all investigated vessel parameters between ICGA and OCT images was slight to moderate, with significant differences found for vessel diameter (−8.98 μm, P = 0.01, 95% limits of agreement [LOA]: −15.89 to −2.07), number of branch (25.93, P = 0.09, 95% LOA: −4.31 to 56.17), and terminal points (49, P = 0.05, 95% LOA: 0.78 to 97.22).\ud Conclusion: Compared with ICGA, current OCTA systems are less precise in capturing small vessels in CoNV complexes, and validation studies are needed for OCTA segmentation software. OCTA, however, complements ICGA by providing evidence of red blood cell flow, which together with depth information, may be helpful when planning treatment of CoNV.

Manual grading of lesions in retinal images is relevant to clinical management and clinical trials, but it is time-consuming and expensive. Furthermore, it collects only limited information - such as lesion size or frequency. The spatial distribution of lesions is ignored, even though it may contribute to the overall clinical assessment of disease severity, and correspond to microvascular and physiological topography. Capillary non-perfusion (CNP) lesions are central to the pathogenesis of major causes of vision loss. Here we propose a novel method to analyse CNP using spatial statistical modelling. This quantifies the percentage of CNP-pixels in each of 48 sectors and then characterises the spatial distribution with goniometric functions. We applied our spatial approach to a set of images from patients with malarial retinopathy, and found it compares favourably with the raw percentage of CNP-pixels and also with manual grading. Furthermore, we were able to quantify a biological characteristic of macular CNP in malaria that had previously only been described subjectively: clustering at the temporal raphe. Microvascular location is likely to be biologically relevant to many diseases, and so our spatial approach may be applicable to a diverse range of pathological features in the retina and other organs.

The study objective is to evaluate a scoring system to assess the quality of anesthesia used in ophthalmic surgery.This is an observational prospective study.The setting is at an operating theater.Patients are all patients undergoing ophthalmic surgery, October 2012.Quality of ophthalmic anesthesia was measured using an interval scale by the operating surgeon. Parameters were graded depending on the type and route of anesthetic: central eye position, anesthesia, akinesia of the eye and or body, soft tissue or orbital hemorrhage, and absence of vitreous bulge.The measurements are quality score and proportion of optimal and suboptimal cases of anesthesia and number of surgical complications.Data were collected on 349 consecutive cases including cataract (55%), retinal (14%), corneal transplant (6%), and strabismus surgery (6%). Sub-Tenon was the most commonly performed (31%) followed by peribulbar (PB) (26%), general anesthesia (GA) (20%), topical (17%), and retrobulbar (RB) (6%) anesthesia. There were 11 surgical complications: posterior capsule rupture (7), dislocated lens (2), and orbital hemorrhage (2). Sub-Tenon had lower quality scores than PB (P = .006), RB (P = .028), and GA (P.001); and PB and RB had lower scores than GA (P.01). There was a significant association between suboptimal anesthesia and surgical complications (P.001), odds ratio = 3.94 (95% confidence interval, 1.03-15.12; P = .046).The quality of ophthalmic anesthesia is an important component of the surgical procedure and should be considered in any risk stratification. Suboptimal anesthesia is associated with an increased rate of surgical complications.

Purpose The purpose of the study was to study the effect of an organic light-emitting diode sleep mask on daytime alertness, wellbeing, and retinal structure/function in healthy volunteers and in diabetic macular oedema (DMO). Patients and methods Healthy volunteers in two groups, 18–30 yrs (A), 50–70 yrs (B) and people with DMO (C) wore masks (504 nm wavelength; 80 cd/m2 luminance; ≤8 h) nightly for 3 months followed by a 1-month recovery period. Changes from baseline were measured for (means): psychomotor vigilance task (PVT) (number of lapses (NL), response time (RT)), sleep, depression, psychological wellbeing (PW), visual acuity, contrast sensitivity, colour, electrophysiology, microperimetry, and retinal thickness on OCT. Results Of 60 participants, 16 (27%) withdrew, 8 (13%) before month 1, due to sleep disturbances and mask intolerance. About 36/55 (65%) who continued beyond month 1 reported ≥1 adverse event. At month 3 mean PVT worsened in Group A (RT (7.65%, P

Perfluorocarbon liquid (PFCL) can migrate into subretinal space in detached and stiffened retina with open holes during vitreoretinal surgery. An innovative 'soft shell' technique was introduced to reduce the complication using hyaluronate (HA) to 'cover' the retinal hole. This study aims to study the effectiveness of this technique in vitro.Ex vivo porcine retina was mounted on a transwell insert. Beneath the retina was an aqueous solution. Two retinal holes were made using needle punctures. One of the two retinal holes was covered with HA. Perfluoro-n-octane (PFO) was added above the retina incrementally using a syringe pump. The height of PFO required to cause the migration of PFO through the retinal holes was measured. The 'pendant drop' method was carried out to measure the interfacial tensions between the PFO and aqueous, and between PFO and four different concentrations of HA solution.A statistically higher PFO level was required to cause the migration of PFO through the retinal hole with HA coating than without HA coating (Tobit regression with p0.05). The use of HA was associated with 2.39-fold increase in hydrostatic pressure before the collapse of the PFO interface at the retinal holes. The interfacial tension between PFO and HA solution with concentrations of 0.05%, 0.25%, 0.5% and 1% were 54.2±0.6, 55.3±0.6, 59.5±1.5 and 68.3±1.3 mN/m, respectively (mean±SD). The interfacial tension between PFO and aqueous with 1% HA coating (68.3±1.3 mN/m) was significantly higher than that without (37.4±3.4 mN/m) (p0.05).The interfacial tension between HA and PFO is higher than that between aqueous and PFO. This is a plausible physical explanation of how the 'soft shell' technique might work to prevent subretinal migration of PFCL.

Objective: To examine the hypothesis that risk of oesophageal, but not of gastric or colorectal, cancer is increased in users of oral bisphosphonates.Design: Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates.Setting: UK General Practice Research Database cohort. Participants: Men and women aged 40 years or over - 2954 with oesophageal cancer, 2018 with gastric cancer, and 10641 with colorectal cancer, diagnosed in 1995-2005; five controls per case matched for age, sex, general practice, and observation time.Main outcome measures: Relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index.Results: The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to 1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity = 0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly to bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.Conclusions: The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five year period. In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years' use of oral bisphosphonates.

Purpose To determine the effect of changing illuminance on visual and stereo acuity. Methods Twenty-eight subjects aged 21 to 60 years were assessed. Monocular visual acuity (ETDRS) of emmetropic subjects was assessed under 15 different illuminance levels (50–8000 lux), provided by a computer controlled halogen lighting rig. Three levels of myopia (−0.50DS, −1.00DS & 1.50DS) were induced in each subject using lenses and visual acuity (VA) was retested under the same illuminance conditions. Stereoacuity (TNO) was assessed under the same levels of illuminance. Results A one log unit change in illuminance level (lx) results in a significant change of 0.060 LogMAR (p

IntroductionDiagnosis of endoleaks is imperative to prevent failure of endovascular aneurysm repairs (EVARs). The gold standard for diagnosis of endoleaks is catheter-directed subtraction angiography, which is not a practicable choice for surveillance. CT angiography (CTA) is the historical surveillance modality of choice. Concerns over cost, potential nephrotoxicity of contrast agents and repeated radiation exposure led to colour duplex ultrasound scan (CDUS) becoming an established alternative. CDUS has a lower sensitivity and specificity for endoleaks detection compared to CTA. Contrast-enhanced ultrasound scan (CEUS) represents an improvement of ultrasound imaging but comparisons against CTA report widely varying results, likely due to technical factors of CEUS and limitations of single-phase CTA.The development of time-resolved CTA (tCTA) offers timing information that much more closely mirrors the dynamic information available from CEUS. Theoretically, these two imaging modalities have the best potential for diagnostic accuracy. The aim of this study will be to compare CEUS to tCTA and investigate the utility of other measurements available from tCTA.Methods and analysisThis is a prospective, single UK centre, comparative study of paired binary diagnostic imaging modalities. Patients identified in routine post-EVAR surveillance as at risk of having a graft-related endoleak will undergo a CEUS and tCTA on the same day. This will allow the first comparison of CEUS to a semidynamic form of CTA. CEUS sensitivity and specificity to endoleak detection will be calculated.Ethics and disseminationThe study has achieved ethical approval. We hope the results will define the diagnostic accuracy of CEUS in comparison to a semidynamic form of CTA, representing a methodological improvement from previous studies. Results will be submitted for presentation at national and international vascular surgeryandradiology meetings. The full results are planned to be published in a medical journal.Trial registration numberNCT02688751