Crowdsourcing critical appraisal of research evidence (CrowdCARE) was found to be a valid approach to assessing clinical research quality.

OBJECTIVES: We developed a free, online tool (CrowdCARE: crowdcare.unimelb.edu.au) to crowdsource research critical appraisal. The aim was to examine the validity of this approach for assessing the methodological quality of systematic reviews. STUDY DESIGN AND SETTING: In this prospective, cross-sectional study, a sample of systematic reviews (N = 71), of heterogeneous quality, was critically appraised using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool, in CrowdCARE, by five trained novice and two expert raters. After performing independent appraisals, experts resolved any disagreements by consensus (to produce an "expert consensus" rating, as the gold-standard approach). RESULTS: The expert consensus rating was within ±1 (on an 11-point scale) of the individual expert ratings for 82% of studies and was within ±1 of the mean novice rating for 79% of studies. There was a strong correlation (r2 = 0.89, P < 0.0001) and very good concordance (κ = 0.67, 95% CI: 0.61-0.73) between the expert consensus rating and mean novice rating. CONCLUSION: Crowdsourcing can be used to assess the quality of systematic reviews. Novices can be trained to appraise systematic reviews and, on average, achieve a high degree of accuracy relative to experts. These proof-of-concept data demonstrate the merit of crowdsourcing, compared with current gold standards of appraisal, and the potential capacity for this approach to transform evidence-based practice worldwide by sharing the appraisal load.

Appraising the Quality of Systematic Reviews for Age-Related Macular Degeneration Interventions: A Systematic Review.

Importance: Age-related macular degeneration (AMD) is a leading cause of vision impairment. It is imperative that AMD care is timely, appropriate, and evidence-based. It is thus essential that AMD systematic reviews are robust; however, little is known about the quality of this literature. Objectives: To investigate the methodological quality of systematic reviews of AMD intervention studies, and to evaluate their use for guiding evidence-based care. Evidence Review: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. All studies that self-identified as a systematic review in their title or abstract or were categorized as a systematic review from a medical subject heading and investigated the safety, efficacy and/or effectiveness of an AMD intervention were included. Comprehensive electronic searches were performed in Ovid MEDLINE, Embase, and the Cochrane Library from inception to March 2017. Two reviewers independently assessed titles and abstracts, then full-texts for eligibility. Quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Study characteristics (publication year, type of intervention, journal, citation rate, and funding source) were extracted. Findings: Of 983 citations retrieved, 71 studies (7.6%) were deemed eligible. The first systematic review relating to an AMD intervention was published in 2003. More than half were published since 2014. Methodological quality was highly variable. The mean (SD) AMSTAR score was 5.8 (3.2) of 11.0, with no significant improvement over time (r = -0.03; 95% CI, -0.26 to 0.21; P = .83). Cochrane systematic reviews were overall of higher quality than reviews in other journals (mean [SD] AMSTAR score, 9.9 [1.2], n = 15 vs 4.7 [2.2], n = 56; P < .001). Overall, there was poor adherence to referring to an a priori design (22 articles [31%]) and reporting conflicts of interest in both the review and included studies (16 articles [23%]). Reviews funded by government grants and/or institutions were generally of higher quality than industry-sponsored reviews or where the funding source was not reported. Conclusions and Relevance: There are gaps in the conduct of systematic reviews in the field of AMD. Enhanced endorsement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement by refereed journals may improve review quality and improve the dissemination of reliable evidence relating to AMD interventions to clinicians.

Older age results in difficulties separating auditory and visual signals in time.

Previous research provides conflicting evidence regarding whether older adults have altered tolerance to timing differences between auditory and visual events. We examine the potential impact of age-related unisensory decline on audiovisual synchrony perception. Fifteen younger (21-32 years) and 13 older (60-72 years) adults participated. To assess unisensory sensitivity, visual Gabor contrast detection thresholds and auditory masked tone pip detection thresholds were measured. Four multisensory conditions were then tested: suprathreshold and near-threshold stimuli (based on individual unisensory psychometric functions), each tested with a masked tone pip stimuli at 0.5 and 4 kHz sound frequencies. Two audiovisual pairs (one synchronous, the other asynchronous) were presented in a two-interval forced-choice procedure, with observers identifying the interval containing the asynchronous stimulus. Older adults required a larger physical asynchrony to perceive the stimuli as asynchronous, particularly for low frequency sounds. Our results demonstrate that the impact of age on audiovisual synchrony perception cannot be explained by decline in unisensory sensitivity alone.

Reduced audiovisual recalibration in the elderly.

Perceived synchrony of visual and auditory signals can be altered by exposure to a stream of temporally offset stimulus pairs. Previous literature suggests that adapting to audiovisual temporal offsets is an important recalibration to correctly combine audiovisual stimuli into a single percept across a range of source distances. Healthy aging results in synchrony perception over a wider range of temporally offset visual and auditory signals, independent of age-related unisensory declines in vision and hearing sensitivities. However, the impact of aging on audiovisual recalibration is unknown. Audiovisual synchrony perception for sound-lead and sound-lag stimuli was measured for 15 younger (22-32 years old) and 15 older (64-74 years old) healthy adults using a method-of-constant-stimuli, after adapting to a stream of visual and auditory pairs. The adaptation pairs were either synchronous or asynchronous (sound-lag of 230 ms). The adaptation effect for each observer was computed as the shift in the mean of the individually fitted psychometric functions after adapting to asynchrony. Post-adaptation to synchrony, the younger and older observers had average window widths (±standard deviation) of 326 (±80) and 448 (±105) ms, respectively. There was no adaptation effect for sound-lead pairs. Both the younger and older observers, however, perceived more sound-lag pairs as synchronous. The magnitude of the adaptation effect in the older observers was not correlated with how often they saw the adapting sound-lag stimuli as asynchronous. Our finding demonstrates that audiovisual synchrony perception adapts less with advancing age.

Human scotopic dark adaptation: Comparison of recoveries of psychophysical threshold and ERG b-wave sensitivity.

We have compared the time course of dark adaptation of the human scotopic visual system, measured psychophysically and from the b-wave of the electroretinogram (ERG), for bleaches ranging from a few percent to near total. We also measured light adaptation, in order to apply a "Crawford transformation" to convert the raw measurements of dark adaptation into equivalent background intensities. For both the "psychophysical threshold equivalent" intensity and the "ERG b-wave sensitivity equivalent" intensity, the equivalent background declined over much of its range with an "S2" component, though with somewhat different slopes of -0.36 (psychophysical) and -0.22 (ERG) log(10) unit min(-1), respectively. In addition, the magnitude of the equivalent background was approximately 1 log(10) unit lower in the psychophysical experiments than in the ERG experiments. Despite these differences, the two approaches extract a common time course for the decline in level of free opsin following moderately large bleaches. We conclude that the recovery of psychophysical scotopic visual threshold over the S2 region reflects events that are present by the stage of the first synapse of rod vision, stemming ultimately from the presence of unregenerated opsin in the rod outer segments.

Retinal thinning in tree shrews with induced high myopia: optical coherence tomography and histological assessment.

This study determined retinal thinning in a mammalian model of high myopia using optical coherence tomography (OCT) and histological sections from the same retinal tissue. High myopia was induced in three tree shrews (Tupaia belangeri) by deprivation of form vision via lid suture of one eye, with the other eye a control. Ocular biometry data was obtained by Ascan ultrasonography, keratometry and retinoscopy. The Zeiss StratusOCT was used to obtain Bscans in vivo across the retina. Subsequently, eyes were enucleated and retinas fixed, dehydrated, embedded and sectioned. Treated eyes developed a high degree of axial myopia (-15.9 ± 2.3D; n = 3). The OCT analysis showed that in myopic eyes the nasal retina thinned more than the temporal retina relative to the disc (p=0.005). Histology showed that the retinas in the myopic eyes comprise all layers but were thinner than the retinas in normal and control eyes. Detailed thickness measurements in corresponding locations of myopic and control eyes in superior nasal retina using longitudinal reflectivity profiles from OCT and semithin vertical histological sections showed the percentage of retinal thinning in the myopic eyes was similar between methods (OCT 15.34 ± 5.69%; histology 17.61 ± 3.02%; p = 0.10). Analysis of retinal layers revealed that the inner plexiform, inner nuclear and outer plexiform layers thin the most. Cell density measurements showed all neuronal cell types are involved in retinal thinning. The results indicate that in vivo OCT measurements can accurately detect retinal thinning in high myopia.

Angiotensin type-1 receptor inhibition is neuroprotective to amacrine cells in a rat model of retinopathy of prematurity.

Retinopathy of prematurity (ROP) is characterized by deficits in the scotopic pathway, although the cellular locus for these deficits is not clear. Here we examined neurochemical and cellular changes that develop during oxygen-induced retinopathy, a model of ROP. In addition, we examined whether treatment with the angiotensin II type-1 receptor inhibitor, valsartan, prevented these changes. Newborn Sprague-Dawley rats were exposed from postnatal day (P) 0 to 11 to 80%:20% O(2) (22:2 hr/day) and then room air until P18. Valsartan (40 mg/kg/day) was administered from P12-P18. Pattern recognition analysis of overlapping amino acid profiles was used to provide a statistically robust and spatially complete classification of neural elements for each experimental condition. Classification yielded 12 neuronal theme classes in controls and nine classes following ROP. ROP was associated with a reduction in the number of amacrine and bipolar cell theme classes. The reduction in theme classes was confirmed as true neuronal loss by quantifying anatomical changes and using an apoptotic marker. ROP was associated with shifts in amino acid levels across all neuronal populations except for horizontal cells. A reduction in the density of glycine-immunoreactive amacrine cells, and particularly parvalbumin-immunoreactive AII amacrine cells, was observed following ROP. Valsartan treatment during ROP prevented loss of theme classes and loss of AII amacrine cells. This study suggests that deficits in scotopic vision during ROP may be associated with loss of AII amacrine cells. In addition, this study highlights the potential of AT(1)R blockade in preventing neuronal anomalies in this condition.

The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy.

Retinopathy of prematurity is a devastating vascular disease of premature infants. A number of studies indicate that retinal function is affected in this disease. Using the rat model of oxygen-induced retinopathy, it is possible to explore more fully the complex relationship between neuronal, glial and vascular pathology in this condition. This review examines the structural and functional changes that occur in the rat retina following oxygen-induced retinopathy. We highlight that vascular pathology in rats is characterized by aberrant growth of blood vessels into the vitreous at the expense of blood vessel growth into the body of the retina. Moreover, amino acid neurochemistry, a tool for examining neuronal changes in a spatially complete manner reveals widespread changes in amacrine and bipolar cells. In addition, neurochemical anomalies within inner retinal neurons are highly correlated with the absence of retinal vessels. The key cell types that link blood flow with neuronal function are macroglia. Macroglia cells, which in the retina include astrocytes and Müller cells, are affected by oxygen-induced retinopathy. Astrocyte loss occurs in the peripheral retina, while Müller cells show signs of reactive gliosis that is highly localized to regions that are devoid of intraretinal blood vessels. Finally, we propose that treatments, such as blockade of the renin-angiotensin system, that not only targets pathological angiogenesis, but that also promotes re-vascularization of the retina are likely to prove important in the treatment of those with retinopathy of prematurity.

The contribution of human cone photoreceptors to the photopic flicker electroretinogram.

We aimed to noninvasively estimate the relative contribution of the cone photoreceptors to the photopic flicker electroretinogram (ERG) in humans. Responses to ganzfeld square-wave flicker (15, 30, and 60 Hz) were recorded in the presence of a rod-saturating background. We used a modified paired flash technique in which a bright probe flash was presented at different times during a flicker cycle and the ERG response was recorded. The cone photoreceptor response was estimated by comparing the relative amplitude of the response during a flicker cycle to the response in the absence of flicker, at early times after the presentation of the probe flash. The normalized responses were then scaled to absolute values based on the assumption that the response to 15-Hz flicker is dominated by the photoreceptor response at early times in a cycle (<15 ms). The postreceptoral contribution was obtained by subtracting the absolute photoreceptor response from the flicker response. The derived cone response showed a peak around 25 ms, from the start of the flicker cycle for 15-Hz and 30-Hz flicker with no clear peak for 60-Hz flicker. In humans, the postreceptoral components dominate the photopic flicker ERG at 15, 30, and 60 Hz. The findings are comparable to those from pharmacological studies in monkeys.

Relationship of the optical coherence tomography signal to underlying retinal histology in the tree shrew (Tupaia belangeri).

PURPOSE: To interpret the retinal origin of the optical coherence tomography (OCT) signal by objectively (i.e., minimal investigator bias) aligning in vivo OCT longitudinal reflectivity profiles (LRPs) with corresponding vertical histologic sections. METHODS: The Zeiss StratusOCT system was used to obtain retinal B-scans in vivo in eyes from adult tree shrews. Subsequently, the retinas were fixed and embedded. Semithin vertical sections through the retina were obtained from the same locations as the LRPs. A statistical correlation procedure that accounted for axial tissue shrinkage determined the best relationship between features in the LRP and sublaminae boundaries in corresponding histology sections. RESULTS: For the optimal relationship, the three regions of high reflectivity in the inner OCT signal corresponded to (1) the nerve fiber and ganglion cell layers, (2) the inner plexiform layer and amacrine cell somas, and (3) the outer plexiform layer. The two regions of low reflectivity in the inner OCT signal corresponded to (1) the somas of Müller, bipolar, and horizontal cells in the inner nuclear layer and (2) the outer nuclear layer. The outer OCT signal had a region of high reflectivity that corresponded to the photoreceptor inner and outer segments, the pigment epithelium, Bruch's membrane, and at least part of the choriocapillaris. CONCLUSIONS: These results provide a clear interpretation for the OCT signal in terms of the underlying retinal anatomy. This interpretation can be used in vivo to identify sublaminae affected by retinal disease and has implications for the origin of the inner OCT signal in human retina.

AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen-induced retinopathy.

We investigated the effect of receptor blockade induced by an angiotensin II type-1 receptor antagonist (AT(1)-RB) on glial and vascular changes in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity (ROP). OIR was induced in Sprague-Dawley rats by exposure to 80% oxygen from postnatal (P) days 0-11, followed by 7 days in room air. Control animals were in room air for the entire duration. One cohort of OIR and control pups received the AT(1)-RB valsartan (40 mg/kg/day intraperitoneal) from P11 to P18. The vascular response was examined immunocytochemically using retinal wholemounts and vertical sections labeled with endothelial (Isolectin-B4) and pericyte (NG2, desmin) markers. Glial cell changes were assessed by measuring cell numbers and immunoreactivity (S100beta, connexin-26, and glial fibrillary acidic protein). OIR resulted in extensive intravitreal neovascularization and under-development of the outer vascular plexus. Pericyte numbers were not significantly affected in OIR, although pericyte-endothelial (desmin-IB4) interactions were impaired. Peripheral astrocyte degeneration occurred between P11 and P13 with prominent Müller cell reactivity at P18. Valsartan imparted a protective effect on glia and blood vessels in OIR. At P18, valsartan-treated OIR retinae showed significantly greater astrocyte survival, improved revascularization of the retina, and reduced preretinal neovascularization and Müller cell reactivity. This study identifies a glio-vascular protective effect with AT(1)-RB in OIR.

Neuronal and glial cell changes are determined by retinal vascularization in retinopathy of prematurity.

We have characterized the vascular, neuronal, and glial changes in oxygen-induced retinopathy, a model of retinopathy of prematurity (ROP). Newborn Sprague-Dawley rats were exposed to either 80% +/- 2% oxygen to postnatal day P11 and then room air until P18 (ROP) or room air for the entire duration (controls). Retinal structure was examined under the light microscope and following postembedding immunocytochemistry in central, midperipheral, and peripheral regions. Müller cells were evaluated immunocytochemically with glial fibrillary acidic protein. The extent of vascularization was established histologically. ROP caused significant thinning of the inner cellular and plexiform layers, which became more pronounced in the peripheral inner nuclear layer of ROP animals (11.3% loss vs. 25.4% loss). Amacrine cell amino acid levels were particularly vulnerable in the peripheral retina; bipolar cells showed similar but less prominent changes. Müller cells had elevated glutamine levels and were most gliotic in the periphery. The vasculature extended to peripheral retinal regions at P18 in controls but not in ROP rats. The most striking pattern of change was evident in the midperipheral "transition zone" of ROP animals. Areas close to blood vessels showed neurochemical properties that were similar to those of the central retina, indicating a local protective effect of the inner retinal blood supply. We find that ROP produces complex vascular, neural, and glial changes that relate to the proximity of inner retinal blood vessels.

The effect of surface placement and surface overlap on stereo slant contrast and enhancement.

Stereoscopic slant contrast is an apparent slant induced in a stereoscopically frontal plane surface (the test) opposite in direction to the specified stereoscopic slant of a neighbouring surface (the inducer). Test surfaces offset from the inducer in a direction collinear with the axis of slant (twist) show more contrast than those offset in a direction orthogonal to the axis of slant (hinge). We attribute this anisotropy to the presence and extent of a gradient of relative disparity in twist configurations and the absence of such a gradient in hinge configurations. This hypothesis was tested by measuring the perceived slant of the test and inducer surfaces for horizontal and vertical axes of inducer slant and collinear and orthogonal surface offsets. For vertical axis slant, the hypothesis was supported; contrast variations with position of the test surface could be explained by variations in relative slant. For horizontal axis slant, variations in contrast could be accounted for by normalisation of the slanted surface, with relative slant remaining constant. Two further experiments showed that the extent of the gradient of relative disparity rather than the area of texture overlap of the two surfaces best predicted the contrast results and that perceived relative slant did not vary with the absolute slants of the two surfaces. The arrangement of stereo surfaces is critical in predicting their relative slant.

Monocular gap stereopsis: manipulation of the outer edge disparity and the shape of the gap.

A binocular stimulus that arises when two black frontal plane surfaces located at different depths have a gap between them for one eye but not for the other eye is interesting since the gap is monocular--it has no matching contours in the other eye--and yet binocular processes resolve a depth step effortlessly (Vision Research, 39, 493). In two experiments we investigate the processes and constraints underlying this depth resolution by varying the width of the solid image (the one without the gap) and the shape of the gap. The results show that the processes underlying monocular gap stereopsis can handle a situation in which the images of two surfaces in depth are effectively overlapping for one eye's view with the other eye seeing between them and that binocular depth is seen even when there is no disparity present. We also show that under ecologically appropriate conditions, depth curvature and warping can result when the monocular gap has a curved or warped edge. Both these experiments imply that the visual system responds to the ambiguity of the stimulus by adopting a minimum slant constraint.

Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination.

Mutations in CRB1, the human homolog of Drosophila Crumbs, cause autosomal recessive blinding disorders of the retina. Whereas Crumbs is implicated in apical-basal epithelial polarity and photoreceptor morphogenesis, the role of CRB1 in normal or diseased retina remains unclear. We characterized the retinal organization in vivo of patients with CRB1 mutations and found that, unlike other inherited retinal degenerations studied to date, the CRB1 mutant retinas are remarkably thick in cross-section and lack the distinct layers of normal adult retina. There are coarse outer and inner zones and a thick surface layer around the optic nerve. The abnormal retinal architecture in CRB1 mutations resembles that of immature normal retina. The results suggest that the CRB1 disease pathway disturbs the development of normal human retinal organization by interrupting naturally occurring apoptosis.

Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis.

PURPOSE: To study the retinal degeneration in an 11 -year-old patient with Leber congenital amaurosis (LCA) caused by mutation in GUCY2D. STUDY DESIGN: Comparative human tissue study. PARTICIPANTS: Two subjects with LCA; postmortem eye from one LCA patient and three normal donors. METHODS: Clinical and visual function studies were performed between the ages of 6 and 10 years in the LCA eye donor and at age 6 in an affected sibling. Genomic DNA was screened for mutations in known LCA genes. The retina of the 11 -year-old subject with LCA was compared with normal retinas from donors age 3 days, 18 years, and 53 years. The tissues were processed for histopathologic studies and immunofluorescence with retinal cell-specific antibodies. RESULTS: Vision in both siblings at the ages examined was limited to severely impaired cone function. Mutation in the GUCY2D gene was identified in both siblings. Histopathologic study revealed rods and cones without outer segments in the macula and far periphery. The cones formed a monolayer of cell bodies, but the rods were clustered and had sprouted neurites in the periphery. Rods and cones were not identified in the midperipheral retina. The inner nuclear layer appeared normal in thickness throughout the retina, but ganglion cells were reduced in number. CONCLUSIONS: An 11-year-old subject with LCA caused by mutant GUCY2D had only light perception but retained substantial numbers of cones and rods in the macula and far periphery. The finding of numerous photoreceptors at this age may portend well for therapies designed to restore vision at the photoreceptor level.

In vivo micropathology of Best macular dystrophy with optical coherence tomography.

Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5-61), representing four families with known VMD2 mutations, were included. OCT scans were recorded in the central retina and longitudinal reflectivity profiles were analysed. The central retina in BMD showed different OCT abnormalities at or near the level of the highly reflective deep retinal band termed the outer retina-choroid complex (ORCC). Two types of ORCC change were noted to occur either separately or together: (1) splitting with or without intervening hyporeflective areas; and (2) elevation. Longitudinal study of a BMD patient indicated that such abnormalities were dynamic and changed in type and degree with time. The pathogenetic sequence in BMD may begin with defective fluid transport across the RPE secondary to the channelopathy in the basolateral membrane. In the macula, this leads to an abnormal interface with adjacent structures at both apical and basal surfaces of the RPE. The disease process results in detachments of the neurosensory retina, such as in central serous chorioretinopathy, and sub-RPE pathology resembling some stages of age-related macular degeneration, with eventual loss of photoreceptors, inner retina and central vision.

Paired and unpaired features can be equally effective in human depth perception.

The horizontal separation of the eyes results in the projection of slightly different images in each eye that are used to recover depth. One source of depth information is disparity, the relative position of paired features in the two eyes. Another source of depth information comes from features that are present in only one eye's view. These unpaired features arise from occlusion and by definition cannot generate a conventional disparity signal. Here we compare the depth signals generated by paired and unpaired features using stimuli that differ only in whether a given feature (a vertical gap) is paired or unpaired. Ecologically, both stimuli are consistent with two panels separated in depth at the gap, but only the paired gap provides a conventional disparity signal. We found strikingly that depth thresholds for the two gap conditions were the same and that there was perfect cross-adaptation of perceived depth from the unpaired to paired condition, strongly suggesting a common mechanism.

Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa.

Rhodopsin is the G protein-coupled receptor that is activated by light and initiates the transduction cascade leading to night (rod) vision. Naturally occurring pathogenic rhodopsin (RHO) mutations have been previously identified only in humans and are a common cause of dominantly inherited blindness from retinal degeneration. We identified English Mastiff dogs with a naturally occurring dominant retinal degeneration and determined the cause to be a point mutation in the RHO gene (Thr4Arg). Dogs with this mutant allele manifest a retinal phenotype that closely mimics that in humans with RHO mutations. The phenotypic features shared by dog and man include a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern to the retinal degeneration. The canine disease offers opportunities to explore the basis of prolonged photoreceptor recovery after light in RHO mutations and determine whether there are links between the dysfunction and apoptotic retinal cell death. The RHO mutant dog also becomes the large animal needed for preclinical trials of therapies for a major subset of human retinopathies.