OBJECTIVES: Cognitive and other biases can influence the quality of healthcare decision making. While substantial research has explored how biases can lead to diagnostic or other errors in medicine, fewer studies have examined how they impact the decision making of other healthcare professionals. This scoping review aimed to identify and synthesise a broad range of research investigating whether decisions made by allied health professionals are influenced by cognitive, affective or other biases. MATERIALS AND METHODS: A systematic literature search was conducted in five electronic databases. Title, abstract and full text screening was undertaken in duplicate, using prespecified eligibility criteria designed to identify studies attempting to demonstrate the presence of bias when allied healthcare professionals make decisions. A narrative synthesis was undertaken, focussing on the type of allied health profession, type of decision, and type of bias reported within the included studies. RESULTS: The search strategy identified 149 studies. Of these, 119 studies came from the field of psychology, with substantially fewer from social work, physical and occupational therapy, speech pathology, audiology and genetic counselling. Diagnostic and assessment decisions were the most common decision types, with fewer studies assessing treatment, prognostic or other clinical decisions. Studies investigated the presence of over 30 cognitive, affective and other decision making biases, including stereotyping biases, anchoring, and confirmation bias. Overall, 77% of the studies reported at least one outcome that represented the presence of a bias. CONCLUSION: This scoping review provides an overview of studies investigating whether decisions made by allied health professionals are influenced by cognitive, affective or other biases. Biases have the potential to seriously impact the quality, consistency and accuracy of decision making in allied health practice. The findings highlight a need for further research particularly in professional disciplines outside of psychology, using methods that reflect real life healthcare decision making.

PURPOSE: We used systematic review and meta-analysis to identify and assimilate evidence quantifying blindness and visual impairment (VI) associated with myopic macular degeneration (MMD), then derived models to predict global patterns. The models were used to estimate the global prevalence of blindness and VI associated with MMD from 2000 to 2050. METHODS: The systematic review identified 17 papers with prevalence data for MMD VI fitting our inclusion criteria. Data from six papers with age-specific data were scaled to relative age-dependent risk and meta-analysed at VI and blindness levels. We analysed variance in all MMD VI and blindness data as a proportion of high myopia against variables from the place and year of data collection, with a model based on health expenditure providing the best correlation. We used this model to estimate the prevalence and number of people with MMD VI in each country in each decade. RESULTS: We included data from 17 studies comprising 137 514 participants. We estimated 10.0 million people had VI from MMD in 2015 (prevalence 0.13%, 95% CI 5.5 to 23.7 million, 0.07% to 0.34%), 3.3 million of whom were blind (0.04%, 1.8 to 7.8 million, 0.03% to 0.10%). We estimate that by 2050, without changing current interventions, VI from MMD will grow to 55.7 million people (0.57%, 29.0 to 119.7 million, 0.33% to 1.11%), 18.5 million of whom will be blind (0.19%, 9.6 to 39.7 million, 0.11% to 0.37%). CONCLUSION: The burden of MMD blindness and VI will rise significantly without efforts to reduce the development and progression of myopia and improve the management of MMD.

Age-related macular degeneration (AMD) is a leading cause of vision loss, the treatment of which may require monthly intravitreal injections. This is a burden on patients and health services, and new delivery modalities that reduce injection frequency are required. To that end, we investigated the suitability of a novel reverse thermoresponsive polymer (RTP) as an ocular drug-delivery vehicle. In this work, we detail the structure and synthesis of a novel RTP, and determine drug release curves for two drugs commonly used in the treatment of AMD, bevacizumab and aflibercept. Biocompatibility of the RTP was assessed in vitro in human and rat cell lines and in vivo following intravitreal injection in rats. Bevacizumab demonstrated a more appropriate release profile than aflibercept, with 67% released within 14 days and 78% released in total over a 183-day period. No toxic effects of RTP were seen in human or rat cells in up to 14 days of co-culture with RTP. Following intravitreal injection, intraocular pressure was unaffected by the presence of RTP and no changes in retinal function or structure were observed at 1 week or 1 month post-injection. RTP injection did not cause inflammation, gliosis or apoptosis in the retina. This work demonstrates the potential suitability of the novel RTP as a sustained-release vehicle for ocular drug delivery for anti-neovascular therapies. Optimization of polymer chemistry for optimal drug loading and release is needed.

AIMS/HYPOTHESIS: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. METHODS: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. RESULTS: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. CONCLUSIONS/INTERPRETATION: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Purpose: To examine whether a microperimetry testing strategy based on quantifying the spatial extent of functional abnormalities (termed "defect-mapping" strategy) could improve the detection of progressive changes in deep scotomas compared to the conventional thresholding strategy. Methods: A total of 30 healthy participants underwent two microperimetry examinations, each using the defect-mapping and thresholding strategies at the first visit to examine the test-retest variability of each method. Testing was performed using an isotropic stimulus pattern centered on the optic nerve head (ONH), which acted as a model of a deep scotoma. These tests were repeated at a second visit, except using a smaller stimulus pattern and thereby increasing the proportion of test locations falling within the ONH (to simulate the progressive enlargement of a deep scotoma). The extent of change detected between visits relative to measurement variability was compared between the two strategies. Results: Relative to their effective dynamic ranges, the test-retest variability of the defect-mapping strategy (1.8%) was significantly lower compared to the thresholding strategy (3.3%; P < 0.001). The defect-mapping strategy also captured a significantly greater extent of change between visits relative to variability (-4.70 t-1) compared to the thresholding strategy (2.74 t-1; P < 0.001). Conclusions: A defect-mapping microperimetry testing strategy shows promise for capturing the progressive enlargement of deep scotomas more effectively than the conventional thresholding strategy. Translational Relevance: Microperimetry testing with the defect-mapping strategy could provide a more accurate clinical trial outcome measure for capturing progressive changes in deep scotomas in eyes with atrophic retinal diseases, warranting further investigations.

Purpose: To test if relaxin deficiency affects ocular structure and function we investigated expression of relaxin (Rln) and RXFP receptors (Rxfp1, Rxfp2), and compared ocular phenotypes in relaxin gene knockout (Rln-/- ) and wild type (Rln+/+ ) mice. Materials and Methods: Rln, Rxfp1 and Rxfp2 mRNA expression was detected in ocular tissues of Rln+/+ mice using RT-PCR. The eyes of 11 Rln-/- and 5 Rln+/+ male mice were investigated. Corneal and retinal thickness was assessed using optical coherence tomography. Intraocular pressure was measured using a rebound tonometer. Retinal, choroidal and sclera morphology and thickness were evaluated histologically. Eyes were collected and fixed for immunofluorescence staining or used for RNA extraction to evaluate mRNA expression using real-time PCR. Results: Rln mRNA was expressed only in the retina, whereas Rxfp1 transcripts were detected in the retina, cornea and sclera/choroid. Rxfp2 was only present in the cornea. None of these genes were expressed in the lacrimal gland, eyelid or lens. Intraocular pressure was higher and central cornea of Rln-/- mice was significantly thicker and had significantly larger endothelial cells and a lower endothelial cell density than Rln+/+ mice. Immunohistochemistry demonstrated no significant difference in AQP3 and AQP5 staining in the cornea or other regions between wildtype and Rln-/- mice. mRNA expression of Aqp4 was significantly higher in Rln-/- than in Rln+/+ corneas, whereas Col1a2, Mmp9, Timp1 and Timp2 were significantly decreased. Expression of Aqp1, Aqp4, Aqp5, Vim and Tjp1 was significantly decreased in Rln-/- compared to Rln+/+ uvea. No significant differences in these genes were detected in the retina. Retinal, choroidal and scleral thicknesses were not different and morphology appeared normal. Conclusion: The findings indicate that loss of Rln affects expression of several genes in the uvea and cornea and results in thicker corneas with altered endothelial cells. Many of the gene changes suggest alterations in extracellular matrix and fluid transport between cells.

Certain perceptual measures have been proposed as indirect assays of brain neurochemical status in people with migraine. One such measure is binocular rivalry, however, previous studies have not measured rivalry characteristics and brain neurochemistry together in people with migraine. This study compared spectroscopy-measured levels of GABA and Glx (glutamine and glutamate complex) in visual cortex between 16 people with migraine and 16 non-headache controls, and assessed whether the concentration of these neurochemicals explains, at least partially, inter-individual variability in binocular rivalry perceptual measures. Mean Glx level was significantly reduced in migraineurs relative to controls, whereas mean occipital GABA levels were similar between groups. Neither GABA levels, nor Glx levels correlated with rivalry percept duration. Our results thus suggest that the previously suggested relationship between rivalry percept duration and GABAergic inhibitory neurotransmitter concentration in visual cortex is not strong enough to enable rivalry percept duration to be reliably assumed to be a surrogate for GABA concentration, at least in the context of healthy individuals and those that experience migraine.

BACKGROUND: The role of the alternative complement pathway and its mediation by retinal microglia and macrophages, is well-established in the pathogenesis of Age-Related Macular Degeneration (AMD). However, the contribution of the classical complement pathway towards the progression of retinal degenerations is not fully understood, including the role of complement component 1q (C1q) as a critical activator molecule of the classical pathway. Here, we investigated the contribution of C1q to progressive photoreceptor loss and neuroinflammation in retinal degenerations. METHODS: Wild-type (WT), C1qa knockout (C1qa-/-) and mice treated with a C1q inhibitor (ANX-M1; Annexon Biosciences), were exposed to photo-oxidative damage (PD) and were observed for progressive lesion development. Retinal function was assessed by electroretinography, followed by histological analyses to assess photoreceptor degeneration. Retinal inflammation was investigated through complement activation, macrophage recruitment and inflammasome expression using western blotting, qPCR and immunofluorescence. C1q was localised in human AMD donor retinas using immunohistochemistry. RESULTS: PD mice had increased levels of C1qa which correlated with increasing photoreceptor cell death and macrophage recruitment. C1qa-/- mice did not show any differences in photoreceptor loss or inflammation at 7 days compared to WT, however at 14 days after the onset of damage, C1qa-/- retinas displayed less photoreceptor cell death, reduced microglia/macrophage recruitment to the photoreceptor lesion, and higher visual function. C1qa-/- mice displayed reduced inflammasome and IL-1β expression in microglia and macrophages in the degenerating retina. Retinal neutralisation of C1q, using an intravitreally-delivered anti-C1q antibody, reduced the progression of retinal degeneration following PD, while systemic delivery had no effect. Finally, retinal C1q was found to be expressed by subretinal microglia/macrophages located in the outer retina of early AMD donor eyes, and in mouse PD retinas. CONCLUSIONS: Our data implicate subretinal macrophages, C1q and the classical pathway in progressive retinal degeneration. We demonstrate a role of local C1q produced by microglia/macrophages as an instigator of inflammasome activation and inflammation. Crucially, we have shown that retinal C1q neutralisation during disease progression may slow retinal atrophy, providing a novel strategy for the treatment of complement-mediated retinal degenerations including AMD.

Retinal ganglion cells (RGCs) are the only output neurons of the vertebrate retina, integrating signals from other retinal neurons and transmitting information to the visual centers of the brain. The death of RGCs is a common outcome in many optic neuropathies, such as glaucoma, demyelinating optic neuritis and ischemic optic neuropathy, resulting in visual defects and blindness. There are currently no therapies in clinical use which can prevent RGC death in optic neuropathies; therefore, the identification of new targets for supporting RGC survival is crucial in the development of novel treatments for eye diseases. In this study we identify that the receptor tyrosine kinase, Tyro3, is critical for normal neuronal function in the adult mouse retina. The loss of Tyro3 results in a reduction in photoreceptor and RGC function as measured using electroretinography. The reduction in RGC function was associated with a thinner retinal nerve fiber layer and fewer RGCs. In the central retina, independent of the loss of RGCs, Tyro3 deficiency resulted in a dramatic reduction in the number of RGC dendrites in the inner plexiform layer. Our results show that Tyro3 has a novel, previously unidentified role in retinal function, RGC survival and RGC morphology. The Tyro3 pathway could therefore provide an alternative, targetable pathway for RGC protective therapeutics.

The perception of motion is considered critical for performing everyday tasks, such as locomotion and driving, and relies on different levels of visual processing. However, it is unclear whether healthy aging differentially affects motion processing at specific levels of processing, or whether performance at central and peripheral spatial eccentricities is altered to the same extent. The aim of this study was to explore the effects of aging on hierarchically different components of motion processing: the minimum displacement of dots to perceive motion (Dmin), the minimum contrast and speed to determine the direction of motion, spatial surround suppression of motion, global motion coherence (translational and radial), and biological motion. We measured motion perception in both central vision and at 15° eccentricity, comparing performance in 20 older (60-79 years) and 20 younger (19-34 years) adults. Older adults had significantly elevated thresholds, relative to younger adults, for motion contrast, speed, Dmin, and biological motion. The differences between younger and older participants were of similar magnitude in central and peripheral vision, except for surround suppression of motion, which was weaker in central vision for the older group, but stronger in the periphery. Our findings demonstrate that the effects of aging are not uniform across all motion tasks. Whereas the performance of some tasks in the periphery can be predicted from the results in central vision, the effects of age on surround suppression of motion shows markedly different characteristics between central and peripheral vision.

BACKGROUND: The cornea is innervated with a rich supply of sensory nerves that play important roles in ocular surface health. Any injury or pathology of the corneal nerves increases the risk of dry eye disease and infection. This study aims to evaluate the therapeutic potential of topical decorin to improve corneal nerve regeneration in a mouse model of sterile epithelial abrasion injury. METHODS: Bilateral central corneal epithelial abrasions (2-mm, Alger Brush) were performed on young C57BL/6 J mice to remove the corneal sensory nerves. Decorin, or vehicle, was applied topically, three times per day for 1 week or every 2 h for 6 h. Spectral-domain optical coherence tomography was performed to measure the abrasion area and corneal thickness. Wholemount immunofluorescence staining was used to assess sensory nerve regeneration (β-tubulin III) and immune cell density (CD45, Iba1, CD11c). To investigate the specific role of dendritic cells (DCs), Cx3cr1gfp/gfp mice, which spontaneously lack resident corneal epithelial DCs, were also investigated. The effect of prophylactic topical administration of recombinant human decorin (applied prior to the abrasion) was also investigated. Nerve tracing (NeuronJ software) was performed to compare recovery of basal nerve axons and superficial nerve terminals in the central and peripheral cornea. RESULTS: At 6 h after injury, topical decorin application was associated with greater intraepithelial DC recruitment but no change in re-epithelialisation or corneal thickness, compared to the vehicle control. One week after injury, sub-basal nerve plexus and superficial nerve terminal density were significantly higher in the central cornea in the decorin-treated eyes. The density of corneal stromal macrophages in the decorin-treated eyes and their contralateral eyes was significantly lower compared to saline-treated corneas. No significant improvement in corneal nerve regeneration was observed in Cx3cr1gfp/gfp mice treated with decorin. CONCLUSIONS: Decorin promotes corneal epithelial nerve regeneration after injury. The neuroregenerative effect of topical decorin was associated with a higher corneal DC density during the acute phase, and fewer macrophages at the study endpoint. The corneal neuroregenerative effects of decorin were absent in mice lacking intraepithelial DCs. Together, these findings support a role for decorin in DC-mediated neuroregeneration following corneal abrasion injury.

Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying vessel regression and allowing ECs to persist in clusters throughout the ischemic zone. In response to hypoxia, these preserved ECs underwent a vessel sprouting response and rapidly reassembled into a functional vascular network. This alleviated retinal hypoxia, preventing subsequent pathogenic neovascularization. Vessel reassembly was not limited by VEGFA neutralization, suggesting it was not dependent on the excess VEGFA produced by the ischemic retina. Neutralization of ANG2 did not prevent vessel reassembly, but did impair subsequent angiogenic expansion of the reassembled vessels. Blockade of EC apoptosis may promote ischemic tissue revascularization by preserving ECs within ischemic tissue that retain the capacity to reassemble a functional network and rapidly restore blood supply.