Longitudinal Assessment of Retinal Microvasculature in Preclinical Alzheimer's Disease.

Purpose: To investigate if changes in vessel density (VD) and the foveal avascular zone (FAZ) occur in the preclinical phase of Alzheimer's disease (pAD) over time. Methods: Optical coherence tomography angiography (OCTA) was used to image VD and FAZ at baseline and for a follow-up period of 2 years. Positron emission tomography (PET) was used to determine the amyloid beta (Aß) status of participants. Results: The VD and FAZ of 148 participants (54% female) were analyzed at baseline and follow-up (mean time between measurements, 2.24 ± 0.35 years). The mean age of the participants was 68.3 ± 6.0 years at baseline and 70.3 ± 5.9 years at follow-up. Participants were divided into three groups: control group, participants who had negative Aß status at both measurements (Aß-, n = 116); converter group, participants who transitioned from negative to positive between baseline and follow-up (Aß-+, n = 18); and participants who were consistently positive at both visits (Aß++, n = 14). The VD of both Aß+ groups demonstrated non-significant increases over time in both macula and optic nerve head (ONH) regions. The Aß- group was found to be significantly higher in both ONH and macular regions. The VD of the Aß++ group was significantly higher in the macula inner and outer rings compared to the Aß-+ and Aß- groups. No significant change was found in FAZ values over time. Conclusions: Alterations in VD seem to manifest already in pAD, exhibiting distinct variations between the ONH and macula. Further longitudinal studies with a longer follow-up design and known amyloid pathology should be undertaken to validate these observations.

Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases.

The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer's disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer's disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer's disease, primary tauopathies and controls with Alzheimer's disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.

A New Approach to Staging Diabetic Eye Disease: Staging of Diabetic Retinal Neurodegeneration and Diabetic Macular Edema.

Topic: The goal of this review was to summarize the current level of evidence on biomarkers to quantify diabetic retinal neurodegeneration (DRN) and diabetic macular edema (DME). Clinical relevance: With advances in retinal diagnostics, we have more data on patients with diabetes than ever before. However, the staging system for diabetic retinal disease is still based only on color fundus photographs and we do not have clear guidelines on how to incorporate data from the relatively newer modalities into clinical practice. Methods: In this review, we use a Delphi process with experts to identify the most promising modalities to identify DRN and DME. These included microperimetry, full-field flash electroretinogram, spectral-domain OCT, adaptive optics, and OCT angiography. We then used a previously published method of determining the evidence level to complete detailed evidence grids for each modality. Results: Our results showed that among the modalities evaluated, the level of evidence to quantify DRN and DME was highest for OCT (level 1) and lowest for adaptive optics (level 4). Conclusion: For most of the modalities evaluated, prospective studies are needed to elucidate their role in the management and outcomes of diabetic retinal diseases. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tear biomarkers for Alzheimer's disease screening and diagnosis (the TearAD study): design and rationale of an observational longitudinal multicenter study.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, and due to increasing life expectancy the number of patients is expected to grow. The diagnosis of AD involves the use of biomarkers determined by an amyloid PET scan or cerebrospinal fluid analyses that are either invasive or expensive, and not available in each hospital, thus limiting their usage as a front-line screener. The TearAD study aims to use tear fluid as a potential source for AD biomarkers. In previous reports, we demonstrated that AD biomarkers amyloid-beta and tau, are measurable in tear fluid and are associated with disease severity and neurodegeration. This study aims to validate previous results in a larger cohort and evaluate the diagnostic accuracy of tear biomarkers to discriminate between individuals with and without neurodegeneration as determined by hippocampal atrophy. METHODS: The TearAD study is an observational longitudinal multi-center study that will enroll 50 cognitively healthy controls, 50 patients with subjective cognitive decline, 50 patients with mild cognitive impairment and 50 patients with AD dementia from the memory clinic. Participants will be examined at baseline, after one year, and after two years follow-up. Study assessments include neuropsychological tests and ophthalmic examination. All participants will receive a MRI scan, and a subset of the study population will undergo cerebral spinal fluid collection and an amyloid PET scan. Tear fluid will be collected with Schirmer strips and levels of Aß38, Aß40, Aß42, t-tau and p-tau in tear fluid will be determined using multiplex immunoassays. Blood samples will be collected from all participants. Images of the retina will be obtained with a standard, hyperspectral and ultra-wide field fundus camera. Additionally, macular pigment optical density will be measured with the macular pigment reflectometer, and cross-sectional images of the retina will be obtained through optical coherence tomography imaging. DISCUSSION: The TearAD study will provide insight into the potential diagnostic use of tear biomarkers as a minimally invasive and low cost tool for the screening and diagnosis of AD. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov (NCT05655793).

α-Synuclein pathology in post-mortem retina and optic nerve is specific for α-synucleinopathies.

There is increasing interest in studying retinal biomarkers for various neurodegenerative diseases. Specific protein aggregates associated with neurodegenerative diseases are present in the retina and could be visualised in a non-invasive way. This study aims to assess the specificity and sensitivity of retinal α-synuclein aggregates in neuropathologically characterised α-synucleinopathies, other neurodegenerative diseases and non-neurological controls. Post-mortem eyes (N = 99) were collected prospectively through the Netherlands Brain Bank from donors with Parkinson's disease (and dementia), dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, other neurodegenerative diseases and non-neurological controls. Multiple retinal and optic nerve cross-sections were immunostained with anti-α-synuclein antibodies (LB509, KM51, and anti-pSer129) and assessed for aggregates and inclusions. α-Synuclein was observed as Lewy neurites in the retina and oligodendroglial cytoplasmic inclusions in the optic nerve and was highly associated with Lewy body disease (P < 0.001) and multiple system atrophy (P = 0.001). In all multiple system atrophy cases, the optic nerve showed oligodendroglial cytoplasmic inclusions, while retinal Lewy neurites were absent, despite coincidental brain Lewy pathology. With high specificity (97%) and sensitivity (82%), retinal/optic nerve α-synuclein differentiates primary α-synucleinopathies from other cases and controls. α-Synuclein pathology occurs specifically in the retina and optic nerve of primary α-synucleinopathies as opposed to other neurodegenerative diseases-with and without α-synuclein co-pathology-and controls. The absence of retinal Lewy neurites in multiple system atrophy could contribute to the development of an in vivo retinal biomarker that discriminates between Lewy body disease and multiple system atrophy.

Radiation-Induced Retinopathy and Optic Neuropathy after Radiation Therapy for Brain, Head, and Neck Tumors: A Systematic Review.

BACKGROUND: Patients with brain, head, and neck tumors experience a decline in their quality of life due to radiation retinopathy and optic neuropathy. Little is known about the dose-response relationship and patient characteristics. We aimed to systematically review the prevalence of radiation retinopathy and optic neuropathy. METHOD: The primary outcome was the pooled prevalence of radiation retinopathy and optic neuropathy. The secondary outcome included the effect of the total radiation dose prescribed for the tumor according to the patient's characteristics. Furthermore, we aimed to evaluate the radiation dose parameters for organs at risk of radiation retinopathy and optic neuropathy. RESULTS: The pooled prevalence was 3.8%. No retinopathy was reported for the tumor's prescribed dose of <50 Gy. Optic neuropathy was more prevalent for a prescribed dose of >50 Gy than <50 Gy. We observed a higher prevalence rate for retinopathy (6.0%) than optic neuropathy (2.0%). Insufficient data on the dose for organs at risk were reported. CONCLUSION: The prevalence of radiation retinopathy was higher compared to optic neuropathy. This review emphasizes the need for future studies considering retinopathy and optic neuropathy as primary objective parameters.

Development of retinal structure in perinatally HIV-infected children and adolescents: A longitudinal and cross-sectional assessment.

In perinatally HIV-infected (PHIV) children, cross-sectional studies reported on subtle structural retinal differences and found associations between the retina and structural brain changes. Our objective is to investigate whether neuroretinal development in PHIV children is similar to the development in healthy matched controls and to explore associations with the brain structure. We measured RT using optical coherence tomography (OCT) on two occasions in 21 PHIV children or adolescents and 23 matched controls-all with good visual acuity-with a mean interval of 4.6 years (SD 0.3). We also included 22 participants (11 PHIV children and 11 controls) together with the follow-up group for a cross-sectional assessment using a different OCT device. Magnetic resonance imaging (MRI) was used to assess the white matter microstructure. We used linear (mixed) models to assess changes in RT and its determinants (over time), adjusting for age and sex. The development of the retina was similar between the PHIV adolescents and controls. In our cohort, we found that changes in the peripapillary RNFL was significantly associated with changes in WM microstructural makers: fractional anisotropy (coefficient = 0.030, p = 0.022) and radial diffusivity (coefficient = -0.568, p = 0.025). We found comparable RT between groups. A thinner pRNFL was associated with lower WM volume (coefficient = 0.117, p = 0.030). PHIV children or adolescents appear to have a similar development of the retinal structure. In our cohort, the associations between RT and MRI biomarkers underscore the relation between retina and brain.

Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer's disease and primary tauopathies.

The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer's disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.

Optimizing Computer Adaptive Test Performance: A Hybrid Simulation Study to Customize the Administration Rules of the CAT-EyeQ in Macular Edema Patients.

Purpose: In previous research the EyeQ item bank, which measures vision-related quality of life (Vr-QoL), was calibrated for future use as a computer adaptive test (CAT). The aim of the current study was to define optimal administration rules. Methods: CAT simulations were performed using real responses. Patients (N = 704; mean age, 76.2 years), having macular edema completed the EyeQ. Four CAT simulations were performed, which were set with different administration rules regarding length, accuracy level and the association with best health, which means the test was aborted after the first 4 responses of having no complaints. Results: The CATDefault showed a mean test length of 6.9 and 15.1% unreliable estimations. Extending the test length to 15 items (CATAlt1) resulted in a mean test length of 7.3 and slightly decreased the percentage unreliable estimations (11.5%). Under CATAlt2, the percentage unreliable estimations was 15.1% and the mean test length was 9.7. Percentages of floor/ceiling effects for CATDefault, CATAlt1, and CATAlt2 were 3.1, 3.0, and 3.1, respectively. CATBestHealth reduced the mean test length to 5.9 and showed 18.2% unreliably estimated patients, of which 14.2% had floor/ceiling scores. Conclusions: This study shows that the CATBestHealth provided reliably estimated ability scores, with a negligible increase in the number of unreliably estimated patients and ensures that patients having little or no vision-related quality of life problems are minimally burdened with completing items. Translational Relevance: The computer adaptive test EyeQ, set with optimal administration rules, can now be used for the computer adaptive assessment of vision-related quality of life in patients suffering from exudative retinal diseases in ophthalmic clinical practice.

Certolizumab Pegol Treatment in Patients with Axial-Spondyloarthritis-Associated Acute Anterior Uveitis: a Narrative Review.

BACKGROUND: Acute anterior uveitis (AAU) affects up to 40% of patients with axial spondyloarthritis (axSpA). An effective treatment for patients with axSpA that reduces the risk of AAU flares while also targeting axial symptoms is therefore highly desirable. Tumor necrosis factor inhibitors (TNFis) have been shown effective for treatment of axSpA and AAU occurrence, with guidelines conditionally recommending treating patients with axSpA and associated AAU with TNFi monoclonal antibodies. To date, most available data on the impact of TNFis on AAU in axSpA are from observational, open-label studies without parallel comparator arms. However, there is a growing body of evidence describing the impact of the TNFi certolizumab pegol (CZP) on the incidence of axSpA-associated AAU. OBJECTIVE: Our objective was to collate data pertaining to the impact of CZP in axSpA-associated AAU in patients across the full axSpA spectrum. METHODS: Data were obtained from four industry-supported phase 3 and 4 clinical trials (C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA). To supplement these data, a targeted literature review was performed through searches of MEDLINE, Embase, and reference lists. RESULTS: Available data from 1467 patients from the C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA trials show CZP to be effective in AAU in patients across the full axSpA spectrum, reducing AAU flares when compared with placebo or pretreatment period. No differences in AAU outcomes were reported when stratified by axSpA subgroup age or sex. The targeted literature review identified six further studies of CZP in spondyloarthritis-associated AAU, only one of which was specific to axSpA. CONCLUSION: CZP was effective in reducing AAU incidence in clinical trials with patients with axSpA. The targeted literature review, however, highlighted that there remains a paucity of data beyond these trials. Data from comparative studies would further enhance the body of evidence on the effects of CZP in patients with axSpA who develop AAU.

No difference in retinal fluorescence after oral curcumin intake in amyloid-proven AD cases compared to controls.

Introduction: Previous work has showed the in vivo presence of retinal amyloid in Alzheimer's disease (AD) patients using curcumin. We aimed to replicate these findings in an amyloid biomarker-confirmed cohort. Methods: Twenty-six patients with AD (age 66 [+9], Mini-Mental Status Examination [MMSE] ≥17) and 14 controls (age 71 [+12]) used one of three curcumin formulations: Longvida, Theracurmin, and Novasol. Plasma levels were determined and pre- and post-curcumin retinal fluorescence scans were assessed visually in all cases and quantitatively assessed in a subset. Results: Visual assessment showed no difference between AD patients and controls for pre- and post-curcumin images. This was confirmed by quantitative analyses on a subset. Mean conjugated plasma curcumin levels were 198.7 nM (Longvida), 576.6 nM (Theracurmin), and 1605.8 nM (Novasol). Discussion: We found no difference in retinal fluorescence between amyloid-confirmed AD cases and control participants, using Longvida and two additional curcumin formulations. Additional replication studies in amyloid-confirmed cohorts are needed to assess the diagnostic value of retinal fluorescence as an AD biomarker.

Predictors of vision-related quality of life in patients with macular oedema receiving intra-vitreal anti-VEGF treatment.

PURPOSE: To determine which demographic and clinical characteristics are predictive of vision-related quality of life (VrQoL) and quality of life (QoL) in patients with macular oedema receiving intravitreal anti-vascular endothelial growth factor (VEGF) treatment. METHODS: Vision-related quality of life (VrQoL) and quality of life (QoL) were measured in 712 patients with retinal exudative disease receiving anti-VEGF treatment at baseline, 6 and 12 months. VrQoL was measured using an item-response theory based 47-question item bank (EyeQ), whereas QoL was measured using the EuroQol Five Dimensions (EQ-5D) questionnaire. The EQ-5D score was dichotomized into a perfect score of 1 and a suboptimal score of <1. Demographic and clinical patient characteristics were considered as possible predictors of (Vr)QoL. Prediction models for (Vr)QoL were created with linear mixed models and generalised estimating equations, using a forward selection procedure. RESULTS: A worse VrQoL was predicted by poorer LogMAR visual acuity of the better eye, female sex, single civil status, older age, longer length of anti-VEGF treatment at baseline and the presence of non-ocular and ocular comorbidities. Suboptimal EQ-5D scores were predicted by poorer LogMAR visual acuity of the better eye, female sex, single civil status, older age, the presence of non-ocular comorbidities and a lower educational background. CONCLUSIONS: Along with visual acuity of the better eye, which is the main factor used in clinical decision making, other patient characteristics should also be considered for the risk assessment of (Vr)QoL, such as sex, age, civil status, comorbidities and length of anti-VEGF treatment.

High Prevalence of Previously Undiagnosed Axial Spondyloarthritis in Patients Referred With Anterior Uveitis and Chronic Back Pain: The SpEYE Study.

OBJECTIVE: To reduce the diagnostic delay in axial spondyloarthritis (axSpA), guidelines recommend referring patients with acute anterior uveitis (AAU) and chronic back pain (CBP) to a rheumatologist. This observational study in daily practice evaluated the prevalence of previously unrecognized axSpA in patients with AAU who were referred by ophthalmologists because of concurrent CBP. METHODS: All patients with AAU referred with CBP (≥ 3 months, age of onset < 45 yrs) from 5 ophthalmology clinics underwent rheumatologic assessment, including pelvic radiographs. Patients with previously diagnosed rheumatic disease and AAU due to other causes were excluded. The primary endpoint was a clinical axSpA diagnosis by the rheumatologist. RESULTS: Eighty-one patients fulfilled the referral criteria (52% male, 56% HLA-B27 positive, median age 41 yrs, median CBP duration 10 yrs). In total, 58% (n = 47) had recurring AAU, of whom 87% already had CBP during previous AAU attacks. After assessment, 23% (n = 19) of patients were clinically diagnosed with definite axSpA (10/19 radiographic), 40% (n = 32) with suspicion of axSpA, and 37% (n = 30) with no axSpA. AxSpA was diagnosed more often in men (33% of the men vs 13% of the women). CONCLUSION: A high prevalence of axSpA was found in patients with AAU referred because of CBP. There was substantial diagnostic delay in the majority of patients with recurring AAU, as many already had CBP during previous AAU flares. In AAU, screening for CBP and prompt referral has a high diagnostic yield and should consistently be promoted among ophthalmologists.

INTERNATIONAL IMPACT OF THE COVID-19 PANDEMIC LOCKDOWN ON INTRAVITREAL THERAPY OUTCOMES: Fight Retinal Blindness Registry.

PURPOSE: To evaluate the impact of the COVID-19 pandemic lockdowns on the outcomes of eyes treated for neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion in eight countries. METHODS: A multicenter international database study of 5,782 eyes (4,708 patients) receiving intravitreal antivascular endothelial growth factor injections before, during, and after national lockdowns. The baseline visit was defined as the last visit within 3 months before lockdown, and prelockdown and postlockdown periods were defined as 6 months before and after the lockdown date. RESULTS: Eyes with neovascular age-related macular degeneration (n = 4,649) lost vision in all countries in proportion to the reduced number of injections. The mean visual acuity change postlockdown ranged from -0.4 to -3.8 logarithm of the minimum angle of resolution letters, and the median number of injections/visits decreased from 4-5/4-7 to 2-4/2-4 postlockdown. The diabetic macular edema (n = 654) and retinal vein occlusion (n = 479) eyes' mean visual acuity change ranged from -2.8 to +1.7 letters and -1.6 to +0.1 letters, and the median number of injections/visits decreased from 2.5-5/4-6 to 1-3/2-4 and from 3-5.5/4-5 to 1-3.5/2-3.5, respectively. The 6-month dropout rates postlockdown were 20% for neovascular age-related macular degeneration, 27% for diabetic macular edema, and 28% for retinal vein occlusion. CONCLUSION: This international study provides estimates of the impact of COVID-19 pandemic lockdown on intravitreal therapy and suggests that prioritizing neovascular age-related macular degeneration eyes seems appropriate.

Trustworthy AI: Closing the gap between development and integration of AI systems in ophthalmic practice.

An increasing number of artificial intelligence (AI) systems are being proposed in ophthalmology, motivated by the variety and amount of clinical and imaging data, as well as their potential benefits at the different stages of patient care. Despite achieving close or even superior performance to that of experts, there is a critical gap between development and integration of AI systems in ophthalmic practice. This work focuses on the importance of trustworthy AI to close that gap. We identify the main aspects or challenges that need to be considered along the AI design pipeline so as to generate systems that meet the requirements to be deemed trustworthy, including those concerning accuracy, resiliency, reliability, safety, and accountability. We elaborate on mechanisms and considerations to address those aspects or challenges, and define the roles and responsibilities of the different stakeholders involved in AI for ophthalmic care, i.e., AI developers, reading centers, healthcare providers, healthcare institutions, ophthalmological societies and working groups or committees, patients, regulatory bodies, and payers. Generating trustworthy AI is not a responsibility of a sole stakeholder. There is an impending necessity for a collaborative approach where the different stakeholders are represented along the AI design pipeline, from the definition of the intended use to post-market surveillance after regulatory approval. This work contributes to establish such multi-stakeholder interaction and the main action points to be taken so that the potential benefits of AI reach real-world ophthalmic settings.

Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review.

PURPOSE: Osteogenesis imperfecta (OI) is a rare inherited heterogeneous connective tissue disorder characterized by bone fragility, low bone mineral density, skeletal deformity and blue sclera. The dominantly inherited forms of OI are predominantly caused by mutations in either the COL1A1 or COL1A2 gene. Collagen type I is one of the major structural proteins of the eyes and therefore is the eye theoretically prone to alterations in OI. The aim of this systematic review was to provide an overview of the known ocular problems reported in OI. METHODS: A literature search (in PubMed, Embase and Scopus), which included articles from inception to August 2020, was performed in accordance with the PRISMA guidelines. RESULTS: The results of this current review show that almost every component of the eye could be affected in OI. Decreased thickness of the cornea and sclera is an important factor causing eye problems in patients with OI such as blue sclera. Findings that stand out are ruptures, lacerations and other eye problems that occur after minor trauma, as well as complications from standard surgical procedures. DISCUSSION: Alterations in collagen type I affect multiple structural components of the eye. It is recommended that OI patients wear protective glasses against accidental eye trauma. Furthermore, when surgery is required, it should be approached with caution. The prevalence of eye problems in different types of OI is still unknown. Additional research is required to obtain a better understanding of the ocular defects that may occur in OI patients and the underlying pathology.

Anxiety and depression in patients who receive anti-VEGF treatment and the usability and feasibility of e-mental health support: the E-PsEYE pilot study.

PURPOSE: E-PsEYE is an internet-based, guided self-help course, following the principles of cognitive behavioural therapy, to reduce anxiety and depression in patients with retinal exudative diseases who receive anti-vascular endothelial growth factor (anti-VEGF) treatment. The purpose of this study was to determine the prevalence and related factors of anxiety and depression in this population and evaluate the usability and feasibility of E-PsEYE. METHODS: Symptoms of anxiety and depression and related factors were determined in 90 patients (mean age 77 years, 58% female), based on multiple logistic regression analysis. Five patients with mild to moderate depression/anxiety tested the usability of E-PsEYE. They were asked to think aloud while completing two modules of the intervention and freely explore system features. The feasibility of the total E-PsEYE intervention was tested in 14 patients with mild to moderate depression/anxiety, based on a single arm pre-post study with a follow-up of three months: fidelity, acceptability, feasibility of study methods and potential effectiveness were explored. RESULTS: Fifty-three percent of the total study population experienced at least mild anxiety and/or depression symptoms. Especially female patients (odds ratio (OR) 3.89, 95% confidence interval (CI) 1.33-11.40), those who experienced limitations in daily life activities due to vision loss (OR 9.67; 95% CI 3.18-29.45) and those who experienced loneliness (OR 3.53, 95% CI 1.14-10.95) were more likely to have anxiety/depression. The usability study raised several possibilities for improvement, based on which E-PsEYE was improved. The feasibility study showed adequate fidelity and acceptability. Most participants were satisfied with the results (79%). There was a high response rate, no loss to follow-up and mental health problems decreased in more than half of the patients. The Wilcoxon signed rank test indicated lower post-test ranks compared to pre-test ranks (depression Z -1.34, p = 0.18; anxiety Z -1.45, p = 0.15). CONCLUSIONS: Mental health problems are prevalent in patients who receive anti-VEGF treatment. Healthcare providers should recognise these problems and related factors in order to refer patients to appropriate care in a timely manner. Outcomes on the usability and feasibility of E-PsEYE are promising as a prelude to performing a randomised controlled trial, which will shed more light on its (cost-)effectiveness.

Reduction of anterior uveitis flares in patients with axial spondyloarthritis on certolizumab pegol treatment: final 2-year results from the multicenter phase IV C-VIEW study.

INTRODUCTION: Acute anterior uveitis (AAU), affecting up to 40% of patients with axial spondyloarthritis (axSpA), risks permanent visual deficits if not adequately treated. We report 2-year results from C-VIEW, the first study to prospectively investigate certolizumab pegol (CZP) on AAU in patients with active axSpA at high risk of recurrent AAU. PATIENTS AND METHODS: C-VIEW (NCT03020992) was a 104-week (96 weeks plus 8-week safety follow-up), open-label, multicenter study. Eligible patients had active axSpA, human leukocyte antigen-B27 (HLA-B27) positivity and a history of recurrent AAU (⩾2 AAU flares in total; ⩾1 in the year prior to baseline). Patients received CZP 400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks to week 96. The primary efficacy endpoint was the AAU flare event rate during 96 weeks' CZP versus 2 years pre-baseline. RESULTS: Of 115 enrolled patients, 89 initiated CZP (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean disease duration: 9.1 years); 83 completed week 96. There was a significant 82% reduction in AAU flare event rate during CZP versus pre-baseline [rate ratio (95% confidence interval): 0.18 (0.12-0.28), p < 0.001]. One hundred percent and 59.6% of patients experienced ⩾1 and ⩾2 AAU flares pre-baseline, respectively, compared to 20.2% and 11.2% during treatment. Age, sex and axSpA population subgroup analyses were consistent with the primary analysis. There were substantial improvements in axSpA disease activity with no new safety signal identified. CONCLUSION: CZP treatment significantly reduced AAU flare event rate in patients with axSpA and a history of AAU, indicating CZP is a suitable treatment option for patients at risk of recurrent AAU. TRIAL REGISTRATION CLINICALTRIALSGOV: NCT03020992, URL: https://clinicaltrials.gov/ct2/show/NCT03020992.