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Supriya Dabir,1 Mohan Rajan,1 Liji Parasseril,1 Vaidehi Bhatt,2 Preetam Samant,3 CAB Webers,4 TTJM Berendschot4 1Department of Retina, Rajan Eye Care Pvt Ltd, Chennai, India; 2Rajiv Gandhi Medical College, Thane, India; 3Department of Retina, PD Hinduja Hospital and Medical Research Center, Mumbai, India; 4University Eye Clinic, Maastricht, the NetherlandsCorrespondence: Supriya DabirRajan Eye Care Hospital Pvt. Ltd, No. 5, Vidyodaya East 2nd Street, T. Nagar, Chennai, Tamil Nadu 600017, IndiaTel +919900974800Email supriad@gmail.comPurpose: Diabetic macular oedema (DME) is a vision-threatening complication of diabetic retinopathy. Spectral domain optical coherence tomography angiography (OCTA) is useful for assessing DME. We performed serial OCTA measurements before and after 3 monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections to understand its relationship with best corrected visual acuity (BCVA), central macular thickness (CMT) and vascular indices.Methods: OCTA assessment consisting of 6 × 6 mm scans centred on fovea and en-face retinal angiograms were obtained. Scans were done at baseline and at 1 month following each of the 3 intravitreal injections of anti-VEGF (ranibizumab, Lucentis®).Results: Our prospective study included 24 eyes of 24 subjects, aged 63.0 ± 5.0 years. There was a mean gain of 0.07 LogMAR (3 letters) and reduction of CMT, vessel density (VD) and perfusion density (PD) by end of 3rd month. CMT was independently associated with improvement in BCVA. There were significant reductions in FAZ area, VD and PD over 3 months from baseline.Conclusion: At three months, intravitreal anti-VEGF therapy is associated with visual function recovery in DME, with reduction in CMT being the most reliable predictor of response. OCTA shows a reduction in VD and PD respectively suggestive of reduced macular perfusion in the short term. Simultaneous reduction in FAZ size can be due to reversal of manual displacement of the retinal capillaries resulting from resolution of intraretinal oedema.Keywords: diabetic macular oedema, superficial capillary plexus, vascular density, perfusion density, foveal avascular zone, optical coherence tomography angiography, macular ischemia

Background: Epidemiological and toxicological studies indicate that increased exposure to air pollutants can lead to neurodegenerative diseases. To further confirm this relationship, we evaluated the association between exposure to ambient air pollutants and corneal nerve measures as a surrogate for neurodegeneration, using corneal confocal microscopy., Methods: We used population-based observational cross-sectional data from The Maastricht Study including N = 3635 participants (mean age 59.3 years, 51.6% were women, and 19.9% had type 2 diabetes) living in the Maastricht area. Using the Geoscience and hEalth Cohort COnsortium (GECCO) data we linked the yearly average exposure levels of ambient air pollutants at home address-level [particulate matter with diameters of ≤ 2.5 µm (PM2.5), and ≤ 10.0 µm (PM10), nitrogen dioxide (NO2), and elemental carbon (EC)]. We used linear regression analysis to study the associations between Z-score for ambient air pollutants concentrations (PM 2.5 , PM 10 , NO 2 , and EC) and Z-score for individual corneal nerve measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length, and fractal dimension)., Results: After adjustment for potential confounders (age, sex, level of education, glucose metabolism status, corneal confocal microscopy lag time, inclusion year of participants, smoking status, and alcohol consumption), higher Z-scores for PM 2.5 and PM 10 were associated with lower Z-scores for corneal nerve bifurcation density, nerve density, nerve length, and nerve fractal dimension [stβ (95% CI): PM 2.5 -0.10 (-0.14; -0.05), -0.04 (-0.09; 0.01), -0.11 (-0.16; -0.06), -0.20 (-0.24; -0.15); and PM 10 -0.08 (-0.13; -0.03), -0.04 (-0.09; 0.01), -0.08 (-0.13; -0.04), -0.17 (-0.21; -0.12)], respectively. No associations were found between NO 2 and EC and corneal nerve measures., Conclusions: Our population-based study demonstrated that exposure to higher levels of PM 2.5 and PM 10 are associated with higher levels of corneal neurodegeneration, estimated from lower corneal nerve measures. Our results suggest that air pollution may be a determinant for neurodegeneration assessed in the cornea and may impact the ocular surface health as well., (© 2024. The Author(s).)

Purpose: The aim is to analyze automated quantification of choriocapillaris flow deficit (CCFD) on swept-source (SS)-optical coherence tomography angiography (OCTA) in tubercular serpiginous-like choroiditis (TBSLC)., Methods: In this prospective study, automated CCFD calculations were performed on SS-OCTA and compared with CCFD areas on indocyanine green angiography (ICGA). Patients were divided into two groups based on the occurrence of paradoxical worsening (PW)., Results: Twenty-nine eyes (29 subjects; 18 males; mean age: 33±12 years) were included. The mean CCFD at baseline was 34.9 ± 4.3% on OCTA in eyes without PW and 35.4 ± 5.0% on SS-OCTA with PW (p = .77). At 4 and 12 weeks, CCFD on SS-OCTA improved to 30.6 ± 3.9% and 28.0 ± 4.2% (p < .001) without PW, respectively, and increased to 42.9 ± 4.4% and 48.8 ± 4.1% (p < .001) with PW, respectively. The SS-OCTA CCFD correlated well with ICGA (r = 0.48; p < .001)., Conclusions: Automated quantitative serial assessment of CCFD on SS-OCTA can serve as a useful biomarker of disease activity in eyes with TBSLC.

Background: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms., Methods: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%])., Results: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43])., Conclusions: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Purpose: We describe a patient after customized crosslinking (CXL) for progressive keratoconus who developed corneal edema with spontaneous resolution., Observations: A 24-year-old male with progressive keratoconus of the left eye underwent a customized CXL procedure with a total energy of 10 J/cm 2 for 16.4 minutes. Preoperative corrected distance visual acuity (CDVA) was 20/30 with a maximum keratometry (K)-value of 58.6 diopter (D) and the thinnest point measured 414 μm. The preoperative endothelial cell density (ECD) was 2414 cells/mm 2 . During treatment, corneal thickness was 325 μm after epithelial debridement and 375 μm after the application of 0.1 % riboflavin containing HPMC. After the treatment, antibiotic and steroid drops were prescribed for 5 days and 3 weeks, respectively. At the 1-month post-CXL visit the patient had no complaints, visual acuity and clinical examination showed no irregularities. At the 4-months post-CXL visit the patient complained of blurry vision. The CDVA was 20/100 and slit-lamp examination showed microcystic corneal edema. The corneal thickness at the thinnest point measured 440 μm. One month later the edema had resolved spontaneously and CDVA had restored to 20/25. Corneal thickness at the thinnest point measured 415 μm, the ECD was 1514 cells/mm 2 and confocal microscopy showed normal structural changes in the anterior stroma after CXL, with the demarcation line located at a depth of 414 μm, just above the corneal endothelium., Conclusions and Importance: We report a case of corneal edema following customized CXL with endothelial cell loss that resolved spontaneously. We recommend either adhering to a minimal stromal thickness of 400 μm before administering UV-A irradiation, using a contact lens or adjusting the irradiation to prevent this complication., Competing Interests: M.M. Dickman: Carl-Zeiss: consultant. R.M.M.A. Nuijts: Alcon: consultant, research grant; 10.13039/100005565Johnson & Johnson: consultant; Théa Pharma: consultant; 10.13039/100007569Carl-Zeiss: consultant; Teleon: research grant The other authors have no financial disclosures or competing interests., (© 2024 The Authors.)

Fundus cameras are widely used by ophthalmologists for monitoring and diagnosing retinal pathologies. Unfortunately, no optical system is perfect, and the visibility of retinal images can be greatly degraded due to the presence of problematic illumination, intraocular scattering, or blurriness caused by sudden movements. To improve image quality, different retinal image restoration/enhancement techniques have been developed, which play an important role in improving the performance of various clinical and computer-assisted applications. This paper gives a comprehensive review of these restoration/enhancement techniques, discusses their underlying mathematical models, and shows how they may be effectively applied in real-life practice to increase the visual quality of retinal images for potential clinical applications including diagnosis and retinal structure recognition. All three main topics of retinal image restoration/enhancement techniques, i.e., illumination correction, dehazing, and deblurring, are addressed. Finally, some considerations about challenges and the future scope of retinal image restoration/enhancement techniques will be discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Webers and Berendschot.)

Purpose: To compare the prediction accuracy of toric intraocular lens calculations using estimated vs measured posterior corneal astigmatism (PCA)., Design: Retrospective case series., Methods: A total of 110 eyes of 110 patients with uncomplicated toric intraocular lens implantation were included in this study. Predicted postoperative refractive astigmatism was calculated with the Barrett Toric Calculator using the estimated PCA (E-PCA), the measured IOLMaster 700 PCA (I-PCA), and the measured Pentacam PCA (P-PCA). Refractive astigmatism prediction errors (RA-PEs), including their trimmed (tr-) centroid (mean vector), spread (precision), tr-mean absolute RA-PE (accuracy), and percentage within a certain threshold, were determined using vector analysis and compared between groups., Setting: University Eye Clinic, Maastricht University Medical Center+, the Netherlands., Results: The tr-centroid RA-PEs of the E-PCA (0.02 diopter [D] at 82.2°), the I-PCA (0.08 D at 35.5°), and the P-PCA (0.09 D at 69.1°) were significantly different from each other (P < .01), but not significantly different from zero (P = .75, P = .05, and P = .05, respectively). The E-PCA had the best precision (tr-mean 0.40 D), which was not significantly lower than the I-PCA (0.42 D, P = .53) and P-PCA (0.43 D, P = .06). The E-PCA also had the best accuracy (0.40 D), which was not significantly different from the I-PCA (0.42 D, P = .26) and significantly better than the P-PCA (0.44 D, P < .01). The precision and accuracy of the I-PCA did not significantly differ from those of the P-PCA. There were no statistically significant differences in the percentage of eyes within a certain absolute RA-PE threshold., Conclusions: The Barrett Toric Calculator using the E-PCA, I-PCA, or P-PCA showed a comparable prediction of postoperative refractive astigmatism in standard clinical practice., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To adapt the Quality of Vision Questionnaire (QoV) for measuring negative dysphotopsia and to validate the original and modified versions in the Dutch population., Methods: The QoV was translated into Dutch according to standardized methodology. Negative dysphotopsia items were constructed based on focus group interviews, literature review and clinical data. The questionnaire was completed by 404 subjects, including contact lens wearers, patients with cataract and after cataract surgery (95.5% with a monofocal, 4.5% with a multifocal intraocular lens). Rasch analysis was applied for evaluation of reliability and validity of the original QoV and modified version, Negative Dysphotopsia QoV (ND-QoV)., Results: The frequency, severity and bothersome scales of the QoV and ND-QoV demonstrated good measurement precision, good fit statistics for all but one item, but significant mistargeting of more than one logit. Item estimations were stable across the study groups and scales were unidimensional with more than 50% of variance explained by the measurements. There was a positive correlation between questionnaire scores and best corrected visual acuity (r = 0.3, p < 0.01). The quality of vision measured by all three scales was significantly poorer (p < 0.01) in patients with negative dysphotopsia compared to asymptomatic pseudophakic patients., Conclusion: The Dutch version of the QoV questionnaire has shown good psychometric properties comparable to the native version as well as good reliability and validity. The addition of negative dysphotopsia items is a valuable modification for the reliable assessment of quality of vision in pseudophakic patients., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std β = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std β = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std β = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Neurodegenerative disorders are characterized by the progressive loss of structure and function of neurons, often including the death of the neuron. Previously, we reported that, by removing the cell death stimulus, dying/injured neurons could survive and recover from the process of regulated cell death, even if the cells already displayed various signs of cellular damage. Now we investigated the role of mitochondrial dynamics (fission/fusion, biogenesis, mitophagy) in both degeneration and in recovery of neuronal cells. In neuronal PC12 cells, exposure to ethanol (EtOH) induced massive neurite loss along with widespread mitochondrial fragmentation, mitochondrial membrane potential loss, reduced ATP production, and decreased total mitochondrial volume. By removing EtOH timely all these mitochondrial parameters recovered to normal levels. Meanwhile, cells regrew neurites and survived. Study of the mitochondrial dynamics showed that autophagy was activated only during the cellular degeneration phase (EtOH treatment) but not in the recovery phase (EtOH removed), and it was not dependent on the Parkin/PINK1 mediated mitophagy pathway. Protein expression of key regulators of mitochondrial fission, phospho-Drp1 Ser616 and S-OPA1, increased during EtOH treatment and recovered to normal levels after removing EtOH. In addition, the critical role of PGC-1α mediated mitochondrial biogenesis in cellular recovery was revealed: inhibition of PGC-1α using SR-18292 after EtOH removal significantly impeded recovery of mitochondrial damage, regeneration of neurites, and cell survival in a concentration-dependent manner. Taken together, our study showed reversibility of mitochondrial morphological and functional damage in stressed neuronal cells and revealed that PGC-1α mediated mitochondrial biogenesis played a critical role in the cellular recovery. This molecular mechanism could be a target for neuroprotection and neurorescue in neurodegenerative diseases., (© 2024. The Author(s).)

Thyroid eye disease (TED) is an autoimmune orbital inflammatory disease which ranges from mild to severe. Tissue remodeling, fibrosis and fat proliferation cause changes in the orbital tissues which can affect esthetics and visual function. In its severe form, it is sight threatening, debilitating, and disfiguring and may lead to social stigma, the embarrassment about which has an impact on the quality of life of those affected and the family members. The pathogenesis of TED, which is influenced by genetic, immunological, and environmental factors, is complex and not fully elucidated. However, it remains unknown what factors determine the severity of the disease. Recent research has revealed a number of diagnostic and prognostic biomarkers of this disease. In this overview of TED, we focus on new insights and perspectives regarding biological agents that may provide a basis for new treatment modalities., (© 2023. The Author(s).)

Background: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity., Methods and Results: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (β per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures., Conclusions: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.

Background: Retinal ganglion cell (RGC) degeneration and death cause vision loss in patients with glaucoma. Regulated cell death, once initiated, is generally considered to be an irreversible process. Recently, we showed that, by timely removing the cell death stimulus, stressed neuronal PC12 cells can recover from phosphatidylserine (PS) exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation, mitochondrial membrane potential loss, and retraction of neurites, all hallmarks of an activated cell death program. Whether the cell death process can be reversed in neurons of the central nervous system, like RGCs, is still unknown. Here, we studied reversibility of the activated cell death program in primary rat RGCs (prRGCs)., Methods: prRGCs were exposed to ethanol (5%, vol/vol) to induce cell death. At different stages of the cell death process, ethanol was removed by washing and injured prRGCs were further cultured in fresh medium to see whether they recovered. The dynamics of single cells were monitored by high-resolution live-cell spinning disk microscopy. PS exposure, mitochondrial structure, membrane potential, and intracellular Ca 2+ were revealed by annexin A5-FITC, Mito-tracker, TMRM, and Fluo 8-AM staining, respectively. The distribution of cytochrome c was investigated by immunofluorescence. The ultrastructure of mitochondria was studied by electron microscopy., Results: Analysis of temporal relationships between mitochondrial changes and PS exposure showed that fragmentation of the mitochondrial network and loss of mitochondrial membrane potential occurred before PS exposure. Mitochondrial changes proceeded caspase-independently, while PS exposure was caspase dependent. Interestingly, prRGCs recovered quickly from these mitochondrial changes but not from PS exposure at the plasma membrane. Correlative light and electron microscopy showed that stress-induced decrease in mitochondrial area, length and cristae number was reversible. Intracellular Ca 2+ was elevated during this stage of reversible mitochondrial injury, but there was no sign of mitochondrial cytochrome c release., Conclusions: Our study demonstrates that RGCs with impaired mitochondrial structure and function can fully recover if there is no mitochondrial cytochrome c release yet, and no PS is exposed at the plasma membrane. This finding indicates that there is a time window for rescuing dying or injured RGCs, by simply removing the cell death stimulus. Video Abstract., (© 2024. The Author(s).)

Introduction: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all-cause dementia and Alzheimer's disease (AD)., Methods: We performed an individual participant data meta-analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all-cause dementia; n = 520 cases incident AD; follow-up time median [interquartile range] 11.3 [8.8-11.5] years)., Results: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all-cause dementia and AD, respectively. Lower baseline macular ganglion cell-inner plexiform layer thickness was not significantly associated with these outcomes., Discussion: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration., Methods: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency)., Results: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency., Discussion: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Keratoconus is characterized by the progressive thinning of the cornea, which leads to a cone-like appearance of the eye over time. Although conventionally defined as a noninflammatory condition, a number of recent studies have associated keratoconus (KC) with allergic conjunctivitis (AC) based on clinical parameters. This study aimed to consolidate this association by performing a proteomic analysis of tear fluid from patients with keratoconus and/or allergic conjunctivitis., Methods: Of 51 patients, 17 were diagnosed with KC, 17 were diagnosed with AC, and 17 were diagnosed with both KC and AC (combined). Nine of 34 patients with KC had a progressive form of the disease. Tear fluid samples (n = 51, one eye per patient) were collected by the Schirmer's strips. Tear proteins were extracted from the Schirmer's strips. Proteomic profiling of 384 inflammatory proteins was assessed by a multiplex proximity extension assay (Olink Explore 384 Inflammation Panel I)., Results: A total of 384 inflammatory proteins were measured. Two hundred seventy-two of the 384 proteins passed stringent data cleaning and were compared among the patient groups. Compared to the 2 other groups, LGALS9 was upregulated uniquely in KC, whereas FGF19, PDGFB, HPCAL1, OSM, and FCAR were downregulated in KC. Similarly, TNFRSF4 and CCL13 were specifically upregulated in AC, whereas ectodysplasin A receptor (EDAR) was uniquely downregulated in AC., Conclusions: High-throughput proteomic profiling of tear fluid confirms the association between KC and AC on a molecular level and raise the importance of redefining KC as an inflammatory condition.

Purpose: The purpose of this systematic review is to identify techniques used for quantification of choriocapillaris (CC) flow in eyes with uveitis using optical coherence tomography angiography (OCTA), report reliability and level of correlation with techniques such as indocyanine green angiography (ICGA)., Methods: A systematic search of several databases was done. The studies were analyzed for techniques of measurement, reliability, and correlation with other modalities. Risk of bias assessment was performed., Results: Thirteen studies were included. CC vessel density (7 studies) and flow deficit area (4 studies) were the most used indices. There was significant heterogeneity in the studies due to differences in the scan protocol, thresholding strategy, and analysis. Comparison with ICGA was performed by only one study, and reliability indices were reported by only two studies., Conclusion: OCTA is a useful tool to measure the CC vascularity in eyes with uveitis. However, standardized acquisition and analysis protocols are needed.

Aims/hypothesis: To assess the associations between glucose metabolism status and a range of continuous measures of glycaemia with corneal nerve fibre measures, as assessed using corneal confocal microscopy., Methods: We used population-based observational cross-sectional data from the Maastricht Study of N=3471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, 21.0% with type 2 diabetes) to study the associations, after adjustment for demographic, cardiovascular risk and lifestyle factors, between glucose metabolism status (prediabetes and type 2 diabetes vs normal glucose metabolism) plus measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA 1c , skin autofluorescence [SAF] and duration of diabetes) and composite Z-scores of corneal nerve fibre measures or individual corneal nerve fibre measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length and fractal dimension). We used linear regression analysis, and, for glucose metabolism status, performed a linear trend analysis., Results: After full adjustment, a more adverse glucose metabolism status was associated with a lower composite Z-score for corneal nerve fibre measures (β coefficients [95% CI], prediabetes vs normal glucose metabolism -0.08 [-0.17, 0.03], type 2 diabetes vs normal glucose metabolism -0.14 [-0.25, -0.04]; linear trend analysis showed a p value of 0.001), and higher levels of measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA 1c , SAF and duration of diabetes) were all significantly associated with a lower composite Z-score for corneal nerve fibre measures (per SD: -0.09 [-0.13, -0.05], -0.07 [-0.11, -0.03], -0.08 [-0.11, -0.04], -0.05 [-0.08, -0.01], -0.09 [-0.17, -0.001], respectively). In general, directionally similar associations were observed for individual corneal nerve fibre measures., Conclusions/interpretation: To our knowledge, this is the first population-based study to show that a more adverse glucose metabolism status and higher levels of glycaemic measures were all linearly associated with corneal neurodegeneration after adjustment for an extensive set of potential confounders. Our results indicate that glycaemia-associated corneal neurodegeneration is a continuous process that starts before the onset of type 2 diabetes. Further research is needed to investigate whether early reduction of hyperglycaemia can prevent corneal neurodegeneration., (© 2023. The Author(s).)

Objectives: Due to the common neurodevelopmental origin and easy accessibility, the retina serves as a surrogate marker for changes in the brain. Hence, Optical Coherence Tomography (OCT), a tool to examine the neuronal layers of retina has gained importance in investigating psychiatric disorders. Several studies in the last decade have reported retinal structural alterations in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, the findings are inconsistent. Hence, we conducted a meta-analysis to investigate alterations in OCT parameters in patients with SCZ, BD and MDD., Methods: We searched electronic databases for studies that examined OCT parameters in patients with SCZ, BD and MDD published up to January 2023. The primary outcome measures were thickness and volumes of the retinal Nerve Fibre Layer (RNFL). We conducted meta-analysis using a random effects model., Results: The searches yielded 2638 publications of which 43 studies were included in the final analysis across all disorders. Compared to controls, the RNFL was thinner in SCZ patients (SMD = -0.37, p = <0.001) and BD patients (SMD = -0.67, p = < 0.001), but not in MDD patients (SMD = -0.08, p  = 0.54). On quadrant wise analysis, temporal quadrant RNFL was thinner in SCZ but not in BD, while all other quadrants were thinner in both SCZ and BD., Conclusion: We found significant reductions in RNFL thickness in SCZ and BD, but not in MDD. The differential involvement in various quadrants and parameters across the disorders has potential implications for using retinal parameters as a diagnostic biomarker.

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 Aβ38, Aβ40, Aβ42, 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)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this research, we studied the duality between cataractous retinal image dehazing and image denoising and proposed that the dehazing task for cataractous retinal images can be achieved with the combination of image denoising and sigmoid function. To do so, we introduce the double-pass fundus reflection model in the YPbPr color space and developed a multilevel stimulated denoising strategy termed MUTE. The transmission matrix of the cataract layer is expressed as the superposition of denoised raw images of different levels weighted by pixel-wise sigmoid functions. We further designed an intensity-based cost function that can guide the updating of the model parameters. They are updated by gradient descent with adaptive momentum estimation, which gives us the final refined transmission matrix of the cataract layer. We tested our methods on cataract retinal images from both public and proprietary databases, and we compared the performance of our method with other state-of-the-art enhancement methods. Both visual assessments and objective assessments show the superiority of the proposed method. We further demonstrated three potential applications including blood vessel segmentation, retinal image registrations, and diagnosing with enhanced images that may largely benefit from our proposed methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Loss of neurons in chronic neurodegenerative diseases may occur over a period of many years. Once initiated, neuronal cell death is accompanied by distinct phenotypic changes including cell shrinkage, neurite retraction, mitochondrial fragmentation, nuclear condensation, membrane blebbing and phosphatidylserine (PS) exposure at the plasma membrane. It is still poorly understood which events mark the point of no return for dying neurons. Here we analyzed the neuronal cell line SH-SY5Y expressing cytochrome C (Cyto.C)-GFP. Cells were exposed temporarily to ethanol (EtOH) and tracked longitudinally in time by light and fluorescent microscopy. Exposure to EtOH induced elevation of intracellular Ca 2+ and reactive oxygen species, cell shrinkage, neurite retraction, mitochondrial fragmentation, nuclear condensation, membrane blebbing, PS exposure and Cyto.C release into the cytosol. Removing EtOH at predetermined time points revealed that all phenomena except Cyto.C release occurred in a phase of neuronal cell death in which full recovery to a neurite-bearing cell was still possible. Our findings underscore a strategy of treating chronic neurodegenerative diseases by removing stressors from neurons and harnessing intracellular targets that delay or prevent trespassing the point of no return., (© 2023. The Author(s).)

Primary open-angle glaucoma (POAG) is characterized by optic nerve degeneration and irreversible loss of retinal ganglion cells (RGCs). The pathophysiology is not fully understood. Since RGCs have a high energy demand, suboptimal mitochondrial function may put the survival of these neurons at risk. In the present study, we explored whether mtDNA copy number or mtDNA deletions could reveal a mitochondrial component in POAG pathophysiology. Buffy coat DNA was isolated from EDTA blood of age- and sex-matched study groups, namely POAG patients with high intraocular pressure (IOP) at diagnosis (high tension glaucoma: HTG; n = 97), normal tension glaucoma patients (NTG, n = 37), ocular hypertensive controls (n = 9), and cataract controls (without glaucoma; n = 32), all without remarkable comorbidities. The number of mtDNA copies was assessed through qPCR quantification of the mitochondrial D-loop and nuclear B2M gene. Presence of the common 4977 base pair mtDNA deletion was assessed by a highly sensitive breakpoint PCR. Analysis showed that HTG patients had a lower number of mtDNA copies per nuclear DNA than NTG patients (p-value <0.01, Dunn test) and controls (p-value <0.001, Dunn test). The common 4977 base pair mtDNA deletion was not detected in any of the participants. A lower mtDNA copy number in blood of HTG patients suggests a role for a genetically defined, deficient mtDNA replication in the pathology of HTG. This may cause a low number of mtDNA copies in RGCs, which together with aging and high IOP, may lead to mitochondrial dysfunction, and contribute to glaucoma pathology., Competing Interests: Declaration of competing interest The authors declare no relevant conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Keratoconus is a degenerative disorder of the cornea leading to a protrusion and thinning with loss of visual acuity. The only treatment to halt the progression is corneal crosslinking (CXL), which uses riboflavin and UV-A light to stiffen the cornea. Recent ultra-structural examinations show that the disease is regional and does not affect the entire cornea. Treating only the affected zone with CXL could be as good as the standard CXL, that treats the entire cornea., Methods: We set up a multicentre non-inferiority randomized controlled clinical trial comparing standard CXL (sCXL) and customized CXL (cCXL). Patients between 16 and 45 years old with progressive keratoconus were included. Progression is based on one or more of the following changes within 12 months: 1 dioptre (D) increase in keratometry (Kmax, K1, K2); or 10% decrease of corneal thickness; or 1 D increase in myopia or refractive astigmatism, requiring corneal crosslinking., Discussion: The goal of this study is to evaluate whether the effectiveness of cCXL is non-inferior to sCXL in terms of flattening of the cornea and halting keratoconus progression. Treating only the affected zone could be beneficial for minimalizing the risk of damaging surrounding tissues and faster wound healing. Recent non-randomized studies suggest that a customized crosslinking protocol based on the tomography of the patient's cornea may stop the progression of keratoconus and result in flattening of the cornea., Trial Registration: This study was prospectively registered at ClinicalTrials.gov on August 31 st , 2020, the identifier of the study is NCT04532788., (© 2023. The Author(s).)

Background: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD., Objective: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex., Design: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status., Results: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (P interaction  = 0.03), history of cardiovascular disease (P interaction  < 0.001), and glucose metabolism status (P interaction  = 0.02)., Conclusions: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions., (© 2023. The Author(s).)

Background and Objective: The quality of quantitative differential phase contrast reconstruction (qDPC) can be severely degenerated by the mismatch of the background of two oblique illuminated images, yielding problematic phase recovery results. These background mismatches may result from illumination patterns, inhomogeneous media distribution, or other defocusing layers. In previous reports, the background is manually calibrated which is time-consuming, and unstable, since new calibrations are needed if any modification to the optical system was made. It is also impossible to calibrate the background from the defocusing layers, or for high dynamic observation as the background changes over time. The background mismatch reduces the experimental robustness of qDPC and largely limits its applications. To tackle the mismatch of background and increases the experimental robustness, we propose the Retinex-qDPC., Methods: In Retinex-qDPC, we replace the data fidelity term of the previous cost function for qDPC inverse problem, by the images' edge features yielding L 2 -Retinex-qDPC and L 1 -Retinex-qDPC for high background-robustness qDPC reconstruction. The split Bregman method is used to solve the L 1 -Retinex DPC. We compare both Retinex-qDPC models against state-of-the-art DPC reconstruction algorithms including total-variation regularized qDPC, and isotropic-qDPC using both simulated and experimental data., Results: Retinex qDPC can significantly improve the phase recovery quality by suppressing the impact of mismatch background. Within, the L 1 -Retinex-qDPC is better than L 2 -Retinex and other state-of-the-art qDPC algorithms., Conclusions: The Retinex-qDPC increases the experimental robustness against background illumination without any modification of the optical system, which will benefit all qDPC applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the prediction accuracy of the Barrett True-K for keratoconus with standard formulas (SRK/T, Barrett Universal II, and Kane) and the Kane keratoconus formula., Setting: Shaare Zedek Medical Center, Jerusalem, Israel, and University Eye Clinic, Maastricht, the Netherlands., Design: Multicenter retrospective case series., Methods: Eyes with stable keratoconus undergoing cataract surgery were included. The predicted refractions were calculated for SRK/T, Barrett Universal II, Barrett True-K for keratoconus (predicted and measured), Kane, and Kane adjusted for keratoconus formulas. Primary outcomes were prediction error (PE), absolute error (AE), and percentage of eyes with PE ±0.25 diopters (D), ±0.50 D, and ±1.00 D. Subgroup analyses were performed based on the severity of the keratoconus., Results: 57 eyes were included in the study. The PE was not significantly different from zero for SRK/T, Barrett True-K (predicted and measured), and Kane keratoconus formulas (range 0.09 to 0.22 D, P > .05). The AE of Barrett True-K predicted (median 0.14 D) and Barrett True-K measured (median 0.10 D) were significantly lower from Barrett Universal II (median 0.47 D) and Kane (median 0.50 D), P < .001., Conclusions: The Barrett True-K formulas for keratoconus had higher prediction accuracy as compared with new generation formulas and a similar prediction accuracy as compared with the Kane keratoconus formula., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Purpose: To validate the Easee web-based tool for the assessment of visual acuity in patients who underwent cataract surgery., Setting: University Eye Clinic Maastricht, Maastricht, the Netherlands., Design: Prospective method comparison study., Methods: Subjects aged between 18 and 69 years who underwent cataract surgery on 1 or both eyes at the Maastricht University Medical Center+ were eligible to participate in this study. The uncorrected (UDVA) and corrected distance visual acuity (CDVA) assessments were performed using the web-based tool (index test) and conventional ETDRS and Snellen charts (reference tests). The outcomes of the different tests were expressed in logMAR, and a difference of <0.15 logMAR was considered clinically acceptable., Results: 46 subjects with 75 operated eyes were included in this study. The difference of the UDVA between the web-based tool and ETDRS or Snellen was -0.05 ± 0.10 logMAR ( P < .001 [0.15; -0.26]) and -0.04 ± 0.15 logMAR ( P = .018 [0.24; -0.33]), respectively. For the CDVA, these differences were -0.04 ± 0.08 logMAR ( P < .001 [0.13; -0.21]) and -0.07 ± 0.10 logMAR ( P < .001 [0.13; -0.27]), respectively. The Pearson correlation coefficients between the web-based tool and ETDRS were maximally 0.94 and compared with Snellen 0.92. In total, 73% to 88% of the visual acuity measurement differences were within 0.15 logMAR., Conclusions: The web-based tool was validated for the assessment of visual acuity in patients who underwent cataract surgery and showed clinically acceptable outcomes in up to 88% of patients. Most of the participants had a positive attitude toward the web-based tool, which requires basic digital skills., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Background and Objective: Due to imperfect imaging conditions, retinal images can be degraded by uneven/insufficient illumination, blurriness caused by optical aberrations and unintentional motions. Degraded images reduce the effectiveness of diagnosis by an ophthalmologist. To restore the image quality, in this research we propose the luminosity rectified Richardson-Lucy (LRRL) blind deconvolution framework for single retinal image restoration., Methods: We established an image formation model based on the double-pass fundus reflection feature and developed a differentiable non-convex cost function that jointly achieves illumination correction and blind deconvolution. To solve this non-convex optimization problem, we derived the closed-form expression of the gradients and used gradient descent with Nesterov-accelerated adaptive momentum estimation to accelerate the optimization, which is more efficient than the traditional half quadratic splitting method., Results: The LRRL was tested on 1719 images from three public databases. Four image quality matrixes including image definition, image sharpness, image entropy, and image multiscale contrast were used for objective assessments. The LRRL was compared against the state-of-the-art retinal image blind deconvolution methods., Conclusions: Our LRRL corrects the problematic illumination and improves the clarity of the retinal image simultaneously, showing its superiority in terms of restoration quality and implementation efficiency. The MATLAB code is available on Github., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes., Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure., Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders)., Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness., Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Background: Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously and also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown., Objectives: We sought to examine the associations of dietary dicarbonyl intake with low-grade inflammation and microvascular function., Methods: In 2792 participants (mean ± SD age: 60 ± 8 y; 50% men; 26% type 2 diabetes) of the population-based cohort the Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking FFQ outcome data to our food composition database of the MGO, GO, and 3-DG content of >200 foods. Low-grade inflammation was assessed as six plasma biomarkers, which were compiled in a z score. Microvascular function was assessed as four plasma biomarkers, compiled in a zscore; as diameters and flicker light-induced dilation in retinal microvessels; as heat-induced skin hyperemic response; and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and microvascular function were investigated using linear regression with adjustments for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle and dietary factors., Results: Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z score for inflammation [standardized β coefficient (STD β): -0.05; 95% CI: -0.09 to -0.01, with strongest inverse associations for hsCRP and TNF-α: both -0.05; -0.10 to -0.01]. In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (STD β: -0.07; 95% CI: -0.12 to -0.01), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes., Conclusion: Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation of an association between MGO intake and health outcomes in humans and warrants further investigation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively - 0.16 [- 0.25; - 0.08]; - 0.05 [- 0.13;  0.03]; P trend  = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively - 0.05 [- 0.08; - 0.01]; - 0.06 [- 0.09; - 0.02]; - 0.05 [- 0.08; - 0.02]; - 0.04 [- 0.07; - 0.01]; - 0.06 [- 0.12; - 0.01]; and - 0.07 [- 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy., (© 2022. The Author(s).)

Purpose: To quantify retinochoroidal vascular parameters using swept-source optical coherence tomography (SS-OCTA) in quiescent posterior and panuveitis., Methods: In this cross-sectional study, subjects with quiescent posterior and panuveitis underwent fundus imaging using SS-OCTA (DRI Triton®, Topcon, Japan). The metrics calculated were fractal dimension (FD), foveal avascular zone (FAZ) area, retinal vascularity index (capillary density index-CDI), and choroidal vascularity index (CVI)., Results: We included 38 eyes of 20 patients, 9 males aged 34.7 ± 10.5 years, 30 eyes of 30 age- and gender-matched healthy controls, 10 females aged 33.6 ± 8.5 years. Comparing patients with controls, we found a lower FD ( p < .001), larger FAZ ( p > .001), lower CDI in the superficial plexus ( p = .019), and lower CVI ( p < .001). We also found lower retinal and choroidal and thicknesses ( p < .001 and p = .025, respectively)., Conclusions: Patients with quiescent posterior and panuveitis have a significantly reduced retinochoroidal vascular density compared to healthy control subjects.

Background and Aims: The easily accessible retinal vessels provide a unique opportunity to study a proxy for cerebral small vessels. Associations between retinal vessel diameters and macrostructural brain white matter changes have already been demonstrated. Alterations in microvascular function, likely precede these structural abnormalities. We examined whether retinal microvascular function is related to cerebral microvascular properties, assessed by the intravoxel incoherent motion (IVIM) effect in brain MRI., Methods: Seventy participants (age 60 ± 8 years, 41% women) from the population-based Maastricht Study underwent brain IVIM diffusion imaging (3 Tesla) to determine the microvascular measures f (perfusion volume fraction) and D* (pseudo-diffusion of circulating blood). The retinal arteriolar and venular dilation response to flicker light stimulation were measured by a dynamic vessel analyzer. Linear regression analysis was used to investigate associations between retinal vasoreactivity and IVIM measures in white matter hyperintensities (WMH), normal-appearing white matter (NAWM) and cortical gray matter (CGM)., Results: More retinal arteriolar dilation was significantly associated with stronger pseudo-diffusion (D*) in the NAWM and CGM (β 0.280 [95% CI 0.084-0.475], and β 0.310 [95% CI 0.091-0.528], respectively), but not with the cerebral blood volume fraction (f). No associations were observed between retinal venular dilation response and cerebrovascular IVIM measures., Conclusions: Variations in retinal arteriolar microvascular function and microcirculatory properties in the brain are linked. The retina could serve as a proxy for early detection of brain microvascular dysfunction., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine corneal cross-linking (CXL) efficacy and chromophore penetration after excimer laser-assisted patterned de-epithelialization., Methods: Two-hundred-twenty porcine eyes were de-epithelialized ex vivo, either fully (mechanical; n = 88) or patterned (excimer laser; n = 132). Consecutively, corneas were impregnated with hypo- or hyperosmolar riboflavin (RF; n = 20, RF-D; n = 40, respectively) or water-soluble taurine (WST11; n = 40, and WST-D; n = 40, respectively), or kept unimpregnated (n = 80). Sixty corneas were subsequently irradiated, inducing CXL, with paired contralateral eyes serving as controls. Outcome measurements included strip extensiometry to assess CXL efficacy, and spectrophotometry and fluorescence microscopy to determine stromal chromophore penetration., Results: All tested chromophores induced significant CXL (p < 0.001), ranging from 7.6% to 14.6%, with similar stiffening for all formulations (p = 0.60) and both de-epithelialization methods (p = 0.56). Light transmittance was significantly lower (p < 0.001) after full compared with patterned de-epithelialization. Stromal chromophore penetration was comparable between fully and patterned de-epithelialized samples, with full penetration in RD and RF-D samples and penetration depths measuring 591.7 ± 42.8 µm and 592.9 ± 63.5 µm for WST11 (p = 0.963) and 504.2 ± 43.2 µm and 488.8 ± 93.1 µm for WST-D (p = 0.669), respectively., Conclusions: Excimer laser-assisted patterned de-epithelialization allows for effective CXL. Stromal chromophore concentration is, however, reduced, which may have safety implications given the need for sufficient UVA attenuation in RF/UVA CXL. The different safety profile of near-infrared (NIR) may allow safe WST11/NIR CXL even with reduced stromal chromophore concentration values. In vivo studies are needed to evaluate the benefits and further assess safety of excimer laser-assisted patterned de-epithelialization for corneal CXL., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To evaluate refractive outcomes for the Clareon monofocal intraocular lens (IOL) in terms of achieved target refraction for the ORA (ALCON) intraoperative wavefront aberrometry device and preoperative noncontact biometry., Setting: University Eye Clinic Maastricht, Maastricht University Medical Center+, the Netherlands., Design: Prospective observational clinical trial., Methods: Patients with bilateral age-related cataracts undergoing phacoemulsification, either by delayed sequential surgery or on the same day, were included in the study. Exclusion criteria were an increased risk for refractive surprise or complicated surgery. Implanted IOL power was based on noncontact optical biometry data using the Barrett Universal II (BU-II) formula, optimized for the Clareon IOL. Postoperative subjective refraction was measured 4 to 6 weeks after surgery. Catquest-9SF questionnaires were completed preoperatively and 3 months after surgery., Results: 100 eyes (51 patients) were included. The percentages of eyes within 1.0 diopters (D), 0.75 D, 0.50 D, and 0.25 D of target for ORA vs BU-II were 84% (84 eyes), 72% (72 eyes), 57% (57 eyes), and 21% (21 eyes) vs 97% (97 eyes), 88% (88 eyes), 77% (77 eyes), and 53% (53 eyes), respectively. Mean absolute prediction error was significantly higher for ORA vs preoperative biometry (P < .001). After global optimization, the prediction accuracy of ORA improved significantly (P < .001). Catquest-9SF questionnaires showed improved levels of ability at 3 months after surgery (P < .001)., Conclusions: This study showed lower percentages of eyes within target refraction for ORA (prior to lens constant optimization) compared with the BU-II formula when implanting the Clareon IOL. However, prediction accuracy of ORA improved significantly after global optimization. Therefore, further intraoperative measurements, postoperative measurements, and optimization are needed to improve the ORA prediction for this IOL., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Purpose: To evaluate the refractive, visual, and morphometric changes after implantation with a foldable iris-fixated phakic intraocular lens (pIOL) to correct myopia or astigmatism., Setting: University Eye Clinic Maastricht, the Netherlands., Design: Prospective case series., Methods: We evaluated patients implanted with the Artiflex Myopia Toric (Ophtec B.V.) iris-fixated pIOL as of January 2004. Measurements were performed annually and reported after 1 and 5 years., Results: The study included 481 eyes (277 patients; age 39.8 ± 10.9 years [SD]). 5 years postoperatively, 91% of eyes were within ±1.0 diopter (D) of target, and the mean myopization over a 5-year period was 0.22 D (P < .001). The logMAR corrected distance visual acuity (CDVA) increased by a mean 0.015 (P = .015) over 5 years; 88% of eyes had a CDVA of 20/20 or better, and 5.5% lost 2 or more lines of CDVA. Mean uncorrected distance visual acuity (UDVA) increased by 0.045 logMAR over 5 years (P < .001); 96% reached an UDVA of 20/40 or more. Anterior chamber depth (ACD) decreased by 0.04 mm (P < .001), and axial length (AL) increased by 0.23 mm (P < .001) over 5 years. Chronic endothelial cell loss showed a 5-year decline of 320 cells/mm2 in the myopic and 310 cells/mm2 in the toric subgroups (P < .001). Cataract resulted in pIOL explantation in 4.0% of eyes (mean survival 59.0 ± 40.0 months); higher preoperative age (hazard ratio [HR], 1.13; P < .001) and smaller ACD (HR, 6.80; P = .035) were risk factors for shorter survival due to cataract formation., Conclusions: Over 5 years, logMAR CDVA and UDVA decreased significantly due to myopization caused by lenticular changes and AL elongation., (Copyright © 2021 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: To compare differences in choriocapillaris flow deficit (CC FD) in multifocal choroiditis (MFC) between two treatment arms using optical coherence tomography angiography (OCTA)., Methods: In this prospective randomized clinical trial, patients were randomized to either Group 1 which received standard tapering dose of oral corticosteroids, or Group 2 which received additional dexamethasone implant (or intravitreal methotrexate). The patients were followed-up until 12 weeks using OCTA and other imaging tools. CC FD and visual acuity between the two groups were compared at each visit., Results: Twenty-five subjects (17 males; 25 eyes) were studied (11 eyes in Group 1). There were no differences between the visual acuity or CC FD (1.12 versus 1.08 mm 2 ; p = 0.86) at baseline between the groups. However, patients in Group 2 achieved better visual acuity (0.32 ± 0.23 versus 0.15 ± 0.11; p = 0.025) and CC FD (0.54 versus 0.15 mm 2 ; p = 0.008) at 12 weeks., Conclusions: OCTA is a useful tool in monitoring the CC FD recovery after treatment in MFC. Patients receiving intravitreal corticosteroid/methotrexate in addition to systemic corticosteroid showed greater resolution of CC FD on OCTA compared to those receiving only oral corticosteroids., (© 2022. The Author(s).)

Contemporary psychiatric diagnosis still relies on the subjective symptom report of the patient during a clinical interview by a psychiatrist. Given the significant variability in personal reporting and differences in the skill set of psychiatrists, it is desirable to have objective diagnostic markers that could help clinicians differentiate patients from healthy individuals. A few recent studies have reported retinal vascular abnormalities in patients with schizophrenia (SCZ) using retinal fundus images. The goal of this study was to use a trained convolution neural network (CNN) deep learning algorithm to detect SCZ using retinal fundus images. A total of 327 subjects [139 patients with Schizophrenia (SCZ) and 188 Healthy volunteers (HV)] were recruited, and retinal images were acquired using a fundus camera. The images were preprocessed and fed to a convolution neural network for the classification. The model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The CNN achieved an accuracy of 95% for classifying SCZ and HV with an AUC of 0.98. Findings from the current study suggest the potential utility of deep learning to classify patients with SCZ and assist clinicians in clinical settings. Future studies need to examine the utility of the deep learning model with retinal vascular images as biomarkers in schizophrenia with larger sample sizes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neurodegenerative diseases are generally characterized clinically by the selective loss of a distinct subset of neurons and a slow progressive course. Mounting evidence in vivo indicates that large numbers of neurons pass through a long period of injury and dysfunction before the actual death of the cells. Whether these dying neurons can be rescued and return to a normal, functional state is uncertain. In the present study, we explored the reversibility of the neuronal cell death pathway at various stages by monitoring the dynamics of single cells with high-resolution live-cell spinning disk confocal microscopy in an in vitro neuronal cell death model. We exposed differentiated neuronal PC12 cells to ethanol as our cell death model. Results showed that exposure to 5% ethanol for 24 h induced cell death in >70% of the cells. Ethanol treatment for 3 h already induced cellular changes and damage such as reactive oxygen species generation, elevation of intracellular Ca2+ level, phosphatidylserine exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation and membrane potential loss, and retraction of neurites. These phenomena are often associated with programmed cell death. Importantly, after removing ethanol and further culturing these damaged cells in fresh culture medium, cells recovered from all these cell injuries and generated new neurites. Moreover, results indicated that this recovery was not dependent on exogenous NGF and other growth factors in the cell culture medium. Overall, our results suggest that targeting dying neurons can be an effective therapeutic strategy in neurodegenerative diseases.

Background: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat., Objectives: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort., Methods: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors., Results: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned., Conclusions: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)