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Recent studies have suggested a bacterial role in the development of autoimmune disorders including type 1 diabetes (T1D). Over 30 billion nucleotide bases of Illumina shotgun metagenomic data were analyzed from stool samples collected from four pairs of matched T1D case-control subjects collected at the time of the development of T1D associated autoimmunity (i.e., autoantibodies). From these, approximately one million open reading frames were predicted and compared to the SEED protein database. Of the 3,849 functions identified in these samples, 144 and 797 were statistically more prevalent in cases and controls, respectively. Genes involved in carbohydrate metabolism, adhesions, motility, phages, prophages, sulfur metabolism, and stress responses were more abundant in cases while genes with roles in DNA and protein metabolism, aerobic respiration, and amino acid synthesis were more common in controls. These data suggest that increased adhesion and flagella synthesis in autoimmune subjects may be involved in triggering a T1D associated autoimmune response. Extensive differences in metabolic potential indicate that autoimmune subjects have a functionally aberrant microbiome. Mining 16S rRNA data from these datasets showed a higher proportion of butyrate-producing and mucin-degrading bacteria in controls compared to cases, while those bacteria that produce short chain fatty acids other than butyrate were higher in cases. Thus, a key rate-limiting step in butyrate synthesis is more abundant in controls. These data suggest that a consortium of lactate- and butyrate-producing bacteria in a healthy gut induce a sufficient amount of mucin synthesis to maintain gut integrity. In contrast, non-butyrate-producing lactate-utilizing bacteria prevent optimal mucin synthesis, as identified in autoimmune subjects.

ObjectivesTo review systematically the evidence of age-related macular degeneration (AMD) affecting real-world visual ability and quality of life (QoL). To explore trends in specific topics within this body of the literature.DesignSystematic review.MethodsA systematic literature search was carried out using MEDLINE, EMBASE, CINAHL, PsycINFO, PsychARTICLES and Health and Psychosocial Instruments for articles published up to January 2015 for studies including people diagnosed with AMD, assessing real-world visual ability or QoL as an outcome. Two researchers screened studies for eligibility. Details of eligible studies including study design, characteristics of study population and outcomes measured were recorded in a data extraction table. All included studies underwent quality appraisal using the Mixed Methods Appraisal Tool 2011 Version (MMAT).ResultsFrom 5284 studies, 123 were eligible for inclusion. A range of approaches were identified, including performance-based methods, quantitative and qualitative patient-reported outcome measures (PROMs). AMD negatively affects tasks including mobility, face recognition, perception of scenes, computer use, meal preparation, shopping, cleaning, watching TV, reading, driving and, in some cases, self-care. There is evidence for higher rates of depression among people with AMD than among community dwelling elderly. A number of adaptation strategies have been associated with AMD of varying duration. Much of the research fails to report the type of AMD studied (59% of included studies) or the duration of disease in participants (74%). Of those that do report type studied, the breakdown is as follows: wet AMD 20%, dry AMD 4% and both types 17%.ConclusionsThere are many publications highlighting the negative effects of AMD in various domains of life. Future research should focus on delivering some of this research knowledge into patient management and clinical trials and differentiating between the types of AMD.

Background/ObjectivesTo examine the association between multiple deprivation with late diagnosis and rapid worsening of glaucoma in patients in English hospital eye services (HES).Methods602,439 visual fields (VFs) were extracted from five regionally different glaucoma clinics in England. Mean Deviation (MD) worse than −12 dB was used as a surrogate definition for advanced VF loss at diagnosis in patients with ≥2 reliable VF records. MD loss worse than -1 dB per year was used to define rapid VF progression in patients with ≥6 VFs. Patient data were stratified into deciles of the Index of Multiple Deprivation (IMD) from residential postcodes.ResultsThere was an association between IMD and advanced VF loss at diagnosis in 44,956 patients with 18% (293/1608) and 11% (771/6929) in the most and least deprived IMD decile, respectively. Age-corrected odds ratio (OR) for having advanced VF loss at entry into HES was 1.42 (95% confidence interval [CI] 1.21–1.67) and 0.75 (95% CI: 0.66–0.85) in the most and least deprived IMD decile respectively (reference = fifth decile). In 15,094 patients with follow up data (median [interquartile range] of 6.9 [4.5, 10.0] years), the proportion having rapid VF progression did not differ across the IMD spectrum.ConclusionLarge-scale VF data from clinics indicates that glaucoma severity at presentation to English HES is associated with levels of multiple deprivation. We found no evidence to suggest likelihood of having rapid VF progression during follow-up is associated with IMD; this hints at equity of glaucoma care and outcomes once patients are in English HES.

BackgroundGlaucoma services are under unprecedented strain. The UK Healthcare Safety Investigation Branch recently called for new ways to identify glaucoma patients most at risk of developing sight loss, and of filtering-out false-positive referrals. Here, we evaluate the feasibility of one such technology, Eyecatcher: a free, tablet-based ‘triage’ perimeter, designed to be used unsupervised in clinic waiting areas. Eyecatcher does not require a button or headrest: patients are simply required to look at fixed-luminance dots as they appear.MethodsSeventy-seven people were tested twice using Eyecatcher (one eye only) while waiting for a routine appointment in a UK glaucoma clinic. The sample included individuals with an established diagnosis of glaucoma, and false-positive new referrals (no visual field or optic nerve abnormalities). No attempts were made to control the testing environment. Patients wore their own glasses and received minimal task instruction.ResultsEyecatcher was fast (median: 2.5 min), produced results in good agreement with standard automated perimetry (SAP), and was rated as more enjoyable, less tiring and easier to perform than SAP (all p<0.001). It exhibited good separation (area under receiver operating characteristic=0.97) between eyes with advanced field loss (mean deviation (MD) < −6 dB) and those within normal limits (MD > −2 dB). And it was able to flag two thirds of false-positive referrals as functionally normal. However, eight people (10%) failed to complete the test twice, and reasons for this limitation are discussed.ConclusionsTablet-based eye-movement perimetry could potentially provide a pragmatic way of triaging busy glaucoma clinics (ie, flagging high-risk patients and possible false-positive referrals).

Background Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. Methods Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. Results An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. Conclusion Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment.

Visual fields measured with standard automated perimetry are a benchmark test for determining retinal function in ocular pathologies such as glaucoma. Their monitoring over time is crucial in detecting change in disease course and, therefore, in prompting clinical intervention and defining endpoints in clinical trials of new therapies. However, conventional change detection methods do not take into account non-stationary measurement variability or spatial correlation present in these measures. An inferential statistical model, denoted 'Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement' (ANSWERS), was proposed. In contrast to commonly used ordinary linear regression models, which assume normally distributed errors, ANSWERS incorporates non-stationary variability modelled as a mixture of Weibull distributions. Spatial correlation of measurements was also included into the model using a Bayesian framework. It was evaluated using a large dataset of visual field measurements acquired from electronic health records, and was compared with other widely used methods for detecting deterioration in retinal function. ANSWERS was able to detect deterioration significantly earlier than conventional methods, at matched false positive rates. Statistical sensitivity in detecting deterioration was also significantly better, especially in short time series. Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies.

To test the hypothesis that the performance in novel computer-based tasks of everyday visual function worsens with disease severity in people with non-neovascular age-related macular degeneration. Participants with and without non-neovascular age-related macular degeneration (≥60 years, minimum logMAR binocular visual acuity 0.7) performed a series of standard visual function tests and two novel computer-based tasks. In a visual search task, participants had to locate an image of a single real-world object within an array of 49 distractor images. Next, in a series of simulated dynamic driving scenes, participants were asked to identify one or two approaching real-world road signs and then select these road signs from four options. Outcome measures were median response times and total correct responses. Forty-nine participants had no macular disease (n = 11), early/intermediate age-related macular degeneration (n = 16) or geographic atrophy (n = 22). Groups were age-similar with median (interquartile range) logMAR visual acuity of 0.00 (-0.08,0.12), 0.13 (-0.08,0.70) and 0.32 (0.12,0.70) respectively. Median (interquartile range) visual search response times were 1.9 (1.0,2.4), 1.8 (1.1,3.7) and 2.4 (1.2,6.0) seconds respectively. Median (interquartile range) road sign response times (single road signs) were 1.2 (0.4,1.7), 1.5 (0.9,2.8) and 1.8 (1.0,5.5) seconds respectively. Median (interquartile range) road sign response times (double road signs) were 1.7 (0.7,2.4), 2.3 (1.2,3.1) and 2.5 (1.7,6) seconds respectively. Participants with geographic atrophy recorded slower response times in all tasks and over 50% performed outside the normative limit for task performance. There were no significant differences between groups in total correct responses across all tasks. In a novel computer-based assessment, people with increasing severity of age-related macular degeneration take longer to perform visual search of everyday objects and take longer to identify road signs than those with no age-related macular degeneration. These novel assessments could be useful as patient-relevant, secondary outcomes for clinical trials.

Several studies have shown that gut bacteria have a role in diabetes in murine models. Specific bacteria have been correlated with the onset of diabetes in a rat model. However, it is unknown whether human intestinal microbes have a role in the development of autoimmunity that often leads to type 1 diabetes (T1D), an autoimmune disorder in which insulin-secreting pancreatic islet cells are destroyed. High-throughput, culture-independent approaches identified bacteria that correlate with the development of T1D-associated autoimmunity in young children who are at high genetic risk for this disorder. The level of bacterial diversity diminishes overtime in these autoimmune subjects relative to that of age-matched, genotype-matched, nonautoimmune individuals. A single species, Bacteroides ovatus , comprised nearly 24% of the total increase in the phylum Bacteroidetes in cases compared with controls. Conversely, another species in controls, represented by the human firmicute strain CO19, represented nearly 20% of the increase in Firmicutes compared with cases overtime. Three lines of evidence are presented that support the notion that, as healthy infants approach the toddler stage, their microbiomes become healthier and more stable, whereas, children who are destined for autoimmunity develop a microbiome that is less diverse and stable. Hence, the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children.

Background/ObjectivesThe acceptability of emerging intravitreal therapies for patients with Geographic Atrophy (GA) is currently unknown. This study therefore aimed to investigate the extent to which regular intravitreal injections may be acceptable to GA patients.Subjects/MethodsThirty UK-based individuals with GA secondary to age-related macular degeneration (AMD), recruited from two London-based hospitals, were interviewed in April-October 2021 regarding acceptability of new GA treatments. Participants responded to a structured questionnaire, as well as open-ended questions in a semi-structured interview. The Theoretical Framework of Acceptability (TFA) informed framework analysis of the qualitative data.ResultsTwenty participants (67%) were female, and median (interquartile range (IQR)) age was 83 (78, 87) years. 37% of participants had foveal centre-involving GA, and better eye median (IQR) logMAR visual acuity was 0.30 (0.17, 0.58). Data suggested that 18 participants (60% (95% CI: 41–79%)) would accept the treatment, despite awareness of potential drawbacks. Eight participants (27% (95% CI: 10–43%) were ambivalent or undecided about treatment, and four (13%) (95% CI: 0–26%) would be unlikely to accept treatment. Reducing the frequency of injections from monthly to every other month increased the proportion of participants who considered the treatments acceptable. Conversely, factors limiting acceptability clustered around: the limited magnitude of treatment efficacy; concerns about side effects or the increased risk of neovascular AMD; and the logistical burden of regular clinic visits for intravitreal injections. Misunderstandings of potential benefits indicate the need for appropriately-designed patient education tools to support decision-making.ConclusionsOur study suggests a majority of participants would be positive about intravitreal treatment for GA, in spite of potential burdens.

To introduce a novel method to quantitively analyse in three dimensions traction forces in a vast area of the ocular posterior pole. Retrospective analysis of 14 eyes who underwent peeling surgery for idiopathic, symptomatic and progressive epiretinal membrane. The technique measures the shift in position of vascular crossings after surgery from a fixed point, which is the retinal pigmented epithelium. This shift is defined as the relaxation index (RI) and represents a measure of the postoperative movement of the retina due to released traction after surgery. Best-corrected visual acuity was significantly better than baseline at all follow ups while the RI had its maximum value at baseline. Moreover, we found a significant correlation between best-corrected visual acuity at 6 months and RI at baseline. While all previous published methods focused on bi-dimensional changes observed in a small region, this study introduces a three-dimensional assessment of tractional forces. Future integration of RI into built-in processing software will allow systematic three-dimensional measurement of intraretinal traction.