Aspects of Histopathological and Ultrastructural Retinal Changes in Chronic Exposure to Hydroxychloroquine.

Background and Objective: Hydroxychloroquine sulfate (HCQ) is a lysosomotropic agent administered in systemic lupus erythematosus and rheumatoid arthritis that has fewer toxic effects than chloroquine. However, HCQ may still be responsible for retinal toxicity. In this study, we observed structural changes in the retinas of experimental rats after prolonged exposure to HCQ. Matherials and Methods: We investigated several aspects regarding retinal changes, at both the histopathological and ultrastructural levels. We used 96 male albino Wistar rats distributed into four equal groups (n = 24 per group): the first three groups were treated with different doses of HCQ (50, 100, and 200 mg/kg HCQ, injected intraperitoneally in a single dose daily), and the last group (the control group, n = 24) was treated with saline solution administered in the same way (0.4 mL of saline solution). The treated groups received HCQ daily for 4 months, and every month, six animals from each group were sacrificed to assess retinal changes. The eyes were examined via optical (OM) and electronic microscopy (EM). Statistical analysis was deployed, and results regarding retinal morpho-photometry were acquired. Results: We observed structural retinal changes in both high and low doses of HCQ; while high doses determined a significant thinning of the retina, lower doses caused retinal thickening. Morphological retinal changes upon exposure to HCQ are believed to be caused by accumulated HCQ in lysosomes found in retinal ganglion cells and in the inner nuclear and photoreceptor cell layers. Such changes were most evident in the group receiving HCQ intraperitoneally in doses of 100 mg/kg for a longer period (4 months). Conclusions: The present study highlights histopathological and ultrastructural retinal changes induced by chronic HCQ administration, which were strongly connected to the dosage and period of exposure.

Titanium Implants Coated with Hydroxyapatite Used in Orbital Wall Reconstruction-A Literature Review.

With the increasing incidences of orbital wall injuries, effective reconstruction materials and techniques are imperative for optimal clinical outcomes. In this literature review, we delve into the efficacy and potential advantages of using titanium implants coated with nanostructured hydroxyapatite for the reconstruction of the orbital wall. Titanium implants, recognized for their durability and mechanical strength, when combined with the osteoconductive properties of hydroxyapatite, present a potentially synergistic solution. The purpose of this review was to critically analyze the recent literature and present the state of the art in orbital wall reconstruction using titanium implants coated with nanostructured hydroxyapatite. This review offers clinicians detailed insight into the benefits and potential drawbacks of using titanium implants coated with nanostructured hydroxyapatite for orbital wall reconstruction. The highlighted results advocate for its benefits in terms of osseointegration and provide a novel strategy for orbital reconstruction, though further studies are essential to establish long-term efficacy and address concerns.

Ocular adverse effects of anti-cancer chemotherapy.

Cancer ranks as the second leading cause of mortality in Europe, following cardiovascular diseases. Every year, 2.6 million people are diagnosed with this disease, and 1.2 million die. It has an impact not only on individual health but also on society and the economy. The survival rate has improved with the introduction of new diagnostic methods and anti-cancer chemotherapy. While more aggressive chemotherapeutic regimens and combination therapies have demonstrated efficacy against cancer cells, they also have detrimental effects on normal cells, leading to systemic and ocular adverse reactions associated with cytotoxicity, inflammation, and neurotoxicity. Consequently, we have an increased survival rate, but the appearance of these ocular adverse effects decreases the quality of life. Ocular toxicity induced by chemotherapeutic agents is often underestimated. While prevention may not be possible, proper management by an ophthalmologist, an integral part of the oncology patient's medical team, is crucial. The ophthalmologist should assess the patient before initiating chemotherapeutic treatment and continue monitoring throughout to identify any adverse ocular reactions resulting from the systemic chemotherapy. This article aimed to briefly highlight the adverse reactions occurring at the ocular surface in patients undergoing chemotherapeutic treatment. Fortunately, these ocular side effects are limited only to the period in which the chemotherapeutic treatment is done, with most of them disappearing a few weeks after stopping the treatment.

Combining retinal structural and vascular measurements improves discriminative power for multiple sclerosis patients.

Data on how retinal structural and vascular parameters jointly influence the diagnostic performance of detection of multiple sclerosis (MS) patients without optic neuritis (MSNON) are lacking. To investigate the diagnostic performance of structural and vascular changes to detect MSNON from controls, we performed a cross-sectional study of 76 eyes from 51 MS participants and 117 eyes from 71 healthy controls. Retinal macular ganglion cell complex (GCC), retinal nerve fiber layer (RNFL) thicknesses, and capillary densities from the superficial (SCP) and deep capillary plexuses (DCP) were obtained from the Cirrus AngioPlex. The best structural parameter for detecting MS was compensated RNFL from the optic nerve head (AUC = 0.85), followed by GCC from the macula (AUC = 0.79), while the best vascular parameter was the SCP (AUC = 0.66). Combining structural and vascular parameters improved the diagnostic performance for MS detection (AUC = 0.90; p<0.001). Including both structure and vasculature in the joint model considerably improved the discrimination between MSNON and normal controls compared to each parameter separately (p = 0.027). Combining optical coherence tomography (OCT)-derived structural metrics and vascular measurements from optical coherence tomography angiography (OCTA) improved the detection of MSNON. Further studies may be warranted to evaluate the clinical utility of OCT and OCTA parameters in the prediction of disease progression.

Therapeutic Potential of Cannabinoids in Glaucoma.

Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB1 and CB2, knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.

OCT and OCT-A biomarkers in multiple sclerosis - review.

Objective: Retinal neuronal and vascular changes have been observed in multiple sclerosis (MS) patients. The aim of this review was to highlight the most current optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) data in MS and to provide information about the possibility of using OCT / OCT-A parameters as biomarkers for screening, diagnosis and monitoring of MS. Methods: To carry out this review, a meticulous literature search was undergone on PubMed between 2014 and the present day, using the following terms: "multiple", "sclerosis", "optical", "coherence", "tomography" and "angiography". Additional studies were found via references, being chosen according to relevance. Results: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) were significantly lower in MS patients compared to controls, and correlated with clinical and paraclinical variables, such as visual function, disability, and magnetic resonance imaging (MRI). Retinal capillary plexuses could be higher, lower or the same, and the best OCT-A microvasculature parameter for the detection of MS was the superficial capillary plexus (SCP). The reduced retinal vessel density (VD) was correlated with the disability in MS. Conclusions: OCT and OCT-A parameters could improve the development of retinal biomarkers for screening, early diagnosis and monitoring the disease progression of MS, and they could improve the development of potential future therapies that could slow or stop the course of this incurable disease. Abbreviations: DCP = deep capillary plexus; EDSS = Expanded Disability Status Scale; GCC = ganglion cell complex; GCL = ganglion cell layer; MRI = magnetic resonance imaging; MS = Multiple sclerosis; OCT = optical coherence tomography; OCT-A = optical coherence tomography angiography; ON = optic neuritis; RNFL = retinal nerve fiber layer; SCP = superficial capillary plexus; VD = vessel density.

Assessing the external validity of machine learning-based detection of glaucoma.

Studies using machine learning (ML) approaches have reported high diagnostic accuracies for glaucoma detection. However, none assessed model performance across ethnicities. The aim of the study is to externally validate ML models for glaucoma detection from optical coherence tomography (OCT) data. We performed a prospective, cross-sectional study, where 514 Asians (257 glaucoma/257 controls) were enrolled to construct ML models for glaucoma detection, which was then tested on 356 Asians (183 glaucoma/173 controls) and 138 Caucasians (57 glaucoma/81 controls). We used the retinal nerve fibre layer (RNFL) thickness values produced by the compensation model, which is a multiple regression model fitted on healthy subjects that corrects the RNFL profile for anatomical factors and the original OCT data (measured) to build two classifiers, respectively. Both the ML models (area under the receiver operating [AUC] = 0.96 and accuracy = 92%) outperformed the measured data (AUC = 0.93; P < 0.001) for glaucoma detection in the Asian dataset. However, in the Caucasian dataset, the ML model trained with compensated data (AUC = 0.93 and accuracy = 84%) outperformed the ML model trained with original data (AUC = 0.83 and accuracy = 79%; P < 0.001) and measured data (AUC = 0.82; P < 0.001) for glaucoma detection. The performance with the ML model trained on measured data showed poor reproducibility across different datasets, whereas the performance of the compensated data was maintained. Care must be taken when ML models are applied to patient cohorts of different ethnicities.

Evaluation of Generative Adversarial Networks for High-Resolution Synthetic Image Generation of Circumpapillary Optical Coherence Tomography Images for Glaucoma.

Importance: Deep learning (DL) networks require large data sets for training, which can be challenging to collect clinically. Generative models could be used to generate large numbers of synthetic optical coherence tomography (OCT) images to train such DL networks for glaucoma detection. Objective: To assess whether generative models can synthesize circumpapillary optic nerve head OCT images of normal and glaucomatous eyes and determine the usability of synthetic images for training DL models for glaucoma detection. Design, Setting, and Participants: Progressively growing generative adversarial network models were trained to generate circumpapillary OCT scans. Image gradeability and authenticity were evaluated on a clinical set of 100 real and 100 synthetic images by 2 clinical experts. DL networks for glaucoma detection were trained with real or synthetic images and evaluated on independent internal and external test data sets of 140 and 300 real images, respectively. Main Outcomes and Measures: Evaluations of the clinical set between the experts were compared. Glaucoma detection performance of the DL networks was assessed using area under the curve (AUC) analysis. Class activation maps provided visualizations of the regions contributing to the respective classifications. Results: A total of 990 normal and 862 glaucomatous eyes were analyzed. Evaluations of the clinical set were similar for gradeability (expert 1: 92.0%; expert 2: 93.0%) and authenticity (expert 1: 51.8%; expert 2: 51.3%). The best-performing DL network trained on synthetic images had AUC scores of 0.97 (95% CI, 0.95-0.99) on the internal test data set and 0.90 (95% CI, 0.87-0.93) on the external test data set, compared with AUCs of 0.96 (95% CI, 0.94-0.99) on the internal test data set and 0.84 (95% CI, 0.80-0.87) on the external test data set for the network trained with real images. An increase in the AUC for the synthetic DL network was observed with the use of larger synthetic data set sizes. Class activation maps showed that the regions of the synthetic images contributing to glaucoma detection were generally similar to that of real images. Conclusions and Relevance: DL networks trained with synthetic OCT images for glaucoma detection were comparable with networks trained with real images. These results suggest potential use of generative models in the training of DL networks and as a means of data sharing across institutions without patient information confidentiality issues.

Retinal Oxygen Extraction in Patients with Primary Open-Angle Glaucoma.

Objective: To compare total retinal oxygen extraction between patients with primary open-angle glaucoma (POAG) and healthy control subjects. Design: A prospective, single-center, cross-sectional, case−control study performed at the Medical University of Vienna. Subjects: Forty patients with POAG and 40 age- and sex-matched control subjects. Methods: Total retinal blood flow was measured using Doppler optical coherence tomography (OCT). Retinal arterial and venous oxygen saturation was measured using reflectance spectroscopy. From these parameters, oxygen content in the retinal arterial and venous circulation as well as total retinal oxygen extraction were calculated. Results: Total retinal blood flow was lower in POAG (25.2 ± 6.7 µL/min) as compared to healthy control subjects (35.6 ± 8.3 µL/min, p < 0.001). Retinal arterial oxygen content was not different between the two groups (0.18 ± 0.01 mL(O2)/mL in both groups, p < 0.761), but retinal venous oxygen content was higher in POAG (0.15 ± 0.01 mL(O2)/mL) than in healthy controls (0.14 ± 0.01 mL(O2)/mL p < 0.001). Accordingly, retinal oxygen extraction was reduced in POAG (0.8 ± 0.3 µL(O2)/min as compared to healthy controls: 1.4 ± 0.4 µL(O2)/min, p < 0.001). There was a significant association between total retinal blood flow and total retinal oxygen extraction with measures of structural and functional damage (p < 0.001 each). Conclusions: This study indicates that POAG is associated with a reduction in total retinal oxygen extraction linked to structural and functional damage of the disease. Since the technology is non-invasive, it allows for longitudinal studies investigating to which degree low retinal oxygen extraction is linked to the progression of the disease.

Age-Related Eye Diseases in Individuals With Mild Cognitive Impairment and Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) and age-related eye diseases pose an increasing burden as the world's population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases. Methods: In this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases. Results: Over half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15-7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45-1.24). Conclusion: Patients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases.

Microvascular changes in the macular and parafoveal areas of multiple sclerosis patients without optic neuritis.

Retinal imaging has been proposed as a biomarker for neurological diseases such as multiple sclerosis (MS). Recently, a technique for non-invasive assessment of the retinal microvasculature called optical coherence tomography angiography (OCTA) was introduced. We investigated retinal microvasculature alterations in participants with relapsing-remitting MS (RRMS) without history of optic neuritis (ON) and compared them to a healthy control group. The study was performed in a prospective, case-control design, including 58 participants (n = 100 eyes) with RRMS without ON and 78 age- and sex-matched control participants (n = 136 eyes). OCTA images of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) were obtained using a commercial OCTA system (Zeiss Cirrus HD-5000 Spectral-Domain OCT with AngioPlex OCTA, Carl Zeiss Meditec, Dublin, CA). The outcome variables were perfusion density (PD) and foveal avascular zone (FAZ) features (area and circularity) in both the SCP and DCP, and flow deficit in the CC. MS group had on average higher intraocular pressure (IOP) than controls (P < 0.001). After adjusting for confounders, MS participants showed significantly increased PD in SCP (P = 0.003) and decreased PD in DCP (P < 0.001) as compared to controls. A significant difference was still noted when large vessels (LV) in the SCP were removed from the PD calculation (P = 0.004). Deep FAZ was significantly larger (P = 0.005) and less circular (P < 0.001) in the eyes of MS participants compared to the control ones. Neither LV, PD or FAZ features in the SCP, nor flow deficits in the CC showed any statistically significant differences between the MS group and control group (P > 0.186). Our study indicates that there are microvascular changes in the macular parafoveal retina of RRMS patients without ON, showing increased PD in SCP and decreased PD in DCP. Further studies with a larger cohort of MS patients and MRI correlations are necessary to validate retinal microvascular changes as imaging biomarkers for diagnosis and screening of MS.

Comparison of machine learning approaches for structure-function modeling in glaucoma.

To evaluate machine learning (ML) approaches for structure-function modeling to estimate visual field (VF) loss in glaucoma, models from different ML approaches were trained on optical coherence tomography thickness measurements to estimate global VF mean deviation (VF MD) and focal VF loss from 24-2 standard automated perimetry. The models were compared using mean absolute errors (MAEs). Baseline MAEs were obtained from the VF values and their means. Data of 832 eyes from 569 participants were included, with 537 Asian eyes for training, and 148 Asian and 111 Caucasian eyes set aside as the respective test sets. All ML models performed significantly better than baseline. Gradient-boosted trees (XGB) achieved the lowest MAE of 3.01 (95% CI: 2.57, 3.48) dB and 3.04 (95% CI: 2.59, 3.99) dB for VF MD estimation in the Asian and Caucasian test sets, although difference between models was not significant. In focal VF estimation, XGB achieved median MAEs of 4.44 [IQR 3.45-5.17] dB and 3.87 [IQR 3.64-4.22] dB across the 24-2 VF for the Asian and Caucasian test sets and was comparable to VF estimates from support vector regression (SVR) models. VF estimates from both XGB and SVR were significantly better than the other models. These results show that XGB and SVR could potentially be used for both global and focal structure-function modeling in glaucoma.

A multi-regression approach to improve optical coherence tomography diagnostic accuracy in multiple sclerosis patients without previous optic neuritis.

BACKGROUND: Optical coherence tomography (OCT) is a retinal imaging system that may improve the diagnosis of multiple sclerosis (MS) persons, but the evidence is currently equivocal. To assess whether compensating the peripapillary retinal nerve fiber layer (pRNFL) thickness for ocular anatomical features as well as the combination with macular layers can improve the capability of OCT in differentiating non-optic neuritis eyes of relapsing-remitting MS patients from healthy controls. METHODS: 74 MS participants (n = 129 eyes) and 84 age- and sex-matched healthy controls (n = 149 eyes) were enrolled. Macular ganglion cell complex (mGCC) thickness was extracted and pRNFL measurement was compensated for ocular anatomical factors. Thickness measurements and their corresponding areas under the receiver operating characteristic curves (AUCs) were compared between groups. RESULTS: Participants with MS showed significantly thinner mGCC, measured and compensated pRNFL (p ≤ 0.026). Compensated pRNFL achieved better performance than measured pRNFL for MS differentiation (AUC, 0.75 vs 0.80; p = 0.020). Combining macular and compensated pRNFL parameters provided the best discrimination of MS (AUC = 0.85 vs 0.75; p < 0.001), translating to an average improvement in sensitivity of 24 percent for differentiation of MS individuals. CONCLUSION: The capability of OCT in MS differentiation is made more robust by accounting OCT scans for individual anatomical differences and incorporating information from both optic disc and macular regions, representing markers of axonal damage and neuronal injury, respectively.

Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis.

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 µl O2/min), higher in MS-ON (2.1 ± 0.5 µl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 µl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 µl/min) compared to MS-ON (38.3 ± 4.6 µl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 µl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation. Clinical Trial Registration: ClinicalTrials.gov registry, NCT03401879.

Hypervirulent Klebsiella pneumoniae Endogenous Endophthalmitis-A Global Emerging Disease.

The review aims to document the new emerging hypervirulent Klebsiella pneumoniae (Kp) endogenous endophthalmitis (EKE) in terms of incidence, microbiological characterization of the pathogenic agent, associated risk factors, management, and outcomes. Hypervirulent (hv) strains of KP (hvKp) induce invasive liver abscesses (LA) with specific clinical features. Up to 80-90% of cases have hepatic liver abscess as a primary focus of infection, followed by renal or lung hvKp infections. However, the incidence of EKE in patients with KPLA varied between 3.4% (19) and 12.6% (13), with a total of 95 cases of endophthalmitis in 1455 cases of KPLA (6.5%). Severe visual loss was encountered in 75% of cases, with 25% bilateral involvement. Intravitreal antibiotics are the mainstay therapeutic approach. Pars plana vitrectomy is a subject of controversy. HvKp strains present mostly natural "wild-type" antibiotic resistance profile suggestive for community-acquired infections, being highly susceptive to the third and fourth generation of cephalosporins and carbapenems. Antimicrobial resistance in hypervirulent strains was recently documented via plasmid transfer and may result in extremely difficult to treat cases. Global dissemination of these strains is a major epidemiologic shift that should be considered in the diagnostic and therapeutic management of patients with endogenous endophthalmitis. Ophthalmologic screening in patients with KPLA and other hvKp infections and a multidisciplinary therapeutic approach is extremely important for early diagnosis and preservation of the visual function.

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

The effects of prostaglandins and endocannabinoids on iris arterial vascularization in Wistar rats - Experimental analysis.

Introduction: The iris vascular supply originates in the anterior and long posterior ciliary arteries. The endothelium influences local blood flow by releasing endothelium relaxing and contracting substances. From a functional perspective, the ocular vascular tonus adjustment is humoral and neural dependent. Objectives: The present article aims to evaluate the possible implications of topical administration of selective COX2 and nonselective COX inhibitors generically named nonsteroidal anti-inflammatory drugs (NSAIDs) and their possible interactions with the endocannabinoid system and the way they could interfere with the vascular tone at the level of ocular iris territory in Wistar rats. Materials and methods: Experimental protocol on Wistar rats was performed in accordance with present laws regarding animal welfare and ethics in animal experiments (Directive 86/ 609EEC/ 1986; Romanian Law 205/ 2004; Romanian Laws 206/ 2004, 471/ 2002 and 9/ 2008; Romanian Order 143/ 400). The studied substances were instilled topically under general anesthesia, and images of the rat iris vessels were captured over a period of 10 minutes. The obtained images were further analyzed using an appropriate hardware and software program. Results: The nonselective NSAIDs induced vascular dilation in the iris vessels, while the selective COX2 inhibitors determined a variable degree of vasoconstriction. Conclusion: In view of the results of this experiment and the added evidence found in literature, we consider that further research will show the potential benefits for the additional use of NSAIDs in ocular pathology, otherwise unaffected by this medication until the present time (for example, glaucoma treatment).

Regulation of Choroidal Blood Flow During Isometric Exercise at Different Levels of Intraocular Pressure.

Purpose: There is evidence that choroidal blood flow (ChBF) is regulated in a complex way during changes in ocular perfusion pressure (OPP). We hypothesized that ChBF regulates better in response to changes in mean arterial pressure (MAP) than in intraocular pressure (IOP). Methods: Eighteen volunteers (mean age, 26 years) were recruited for a randomized, three-way crossover design. MAP was varied via isometric exercise. IOP was either kept normal or elevated by 10 or 20 mm Hg by using a suction cup. Subfoveal ChBF was measured continuously for 8 minutes with laser Doppler flowmetry and OPP was calculated as 2/3*MAP-IOP. For data analysis, values from all subjects were pooled according to either IOP or MAP values, and correlation analyses were done. Results: When data were grouped according to IOP, no correlation was observed between ChBF and MAP, but ChBF was lower the higher the IOP (P < 0.001). When data were grouped according to MAP, a significant correlation was found between ChBF and IOP (P < 0.001). When data were pooled according to IOP, the correlation between ChBF and OPP was weaker (P < 0.05). The OPP at which ChBF significantly increased from baseline was 61.3% ± 4.9% without suction cup, 65.2% ± 3.5% when IOP was increased by 10 mm Hg, and slightly lower when IOP was increased by 20 mm Hg (56.3% ± 4.8%, P = 0.07), but this effect did not reach the level of significance. Conclusions: The present study provides further evidence that the regulation of ChBF during changes in OPP is controlled by complex mechanisms in humans and has less capacity to adapt to IOP elevation than to MAP increase.

Optic nerve head blood flow regulation during changes in arterial blood pressure in patients with primary open-angle glaucoma.

PURPOSE: Abnormal autoregulation of optic nerve head blood flow (ONHBF) has been postulated to play an important role in primary open-angle glaucoma (POAG). We used laser Doppler flowmetry (LDF) to estimate quantitatively the ONHBF and compared ONHBF autoregulation between glaucoma patients and healthy controls during isometric exercise. METHODS: Forty patients with POAG and 40 healthy age- and sex-matched subjects underwent three periods of isometric exercise, each consisting of 2 min of handgripping. Optic nerve head blood flow (ONHBF) was measured continuously using LDF. Systemic blood pressure, intraocular pressure and ocular perfusion pressure were assessed in all participants. RESULTS: Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods in both groups (p < 0.001). However, there was no change in ONHBF in either group. Three of the glaucoma patients and two of the healthy subjects showed a consistent 10% decrease in blood flow during isometric exercise, in spite of an increase in their blood pressure. This difference between groups was not significant (p = 0.61). Four other glaucoma subjects showed a consistent increase in blood flow of more than 10% during isometric exercise, whereas this was not seen in healthy subjects (p = 0.035). CONCLUSION: This study suggests that abnormal ONHBF autoregulation is more often seen in patients with POAG than healthy control subjects. The relationship to the glaucoma disease process is currently unknown and requires further investigation.

Effect of Hyaluronic Acid/Trehalose in Two Different Formulations on Signs and Symptoms in Patients with Moderate to Severe Dry Eye Disease.

PURPOSE: This randomized, observer-masked, crossover study investigated the effect of two hyaluronic acid/trehalose-based containing formulations, with different physical properties, on the signs and symptoms in patients with moderate to severe dry eye disease (DED). METHODS: In one group, patients received a mixture of sodium hyaluronate and trehalose (HT, Thealoz Duo®) for use during the day. In the other group, patients received a more viscous formulation consisting of hyaluronic acid, trehalose, and carbomer (HTC-gel, Thealoz Duo Gel) to use pro re nata. Both groups used HTC-gel before going to bed. Clinical standard tests for DED were performed at the beginning and end of each one-week period. Further, patient satisfaction including quality of sleep was assessed using a visual analogue scale. RESULTS: Corneal fluorescein and conjunctival lissamine green staining scores decreased, and tear breakup time (BUT) increased for both groups (p < 0.001 each). Mean instillation frequency was 3.1 ± 2.6 drops/day when using HT and 1.9 ± 2.2 drops/day when using HTC-gel (p=0.02). A significant improvement in the quality of sleep was observed with both treatments (p=0.01). CONCLUSIONS: Our results show improvement in signs and symptoms of DED in both groups. While instillation of HTC-gel resulted in a lower instillation frequency, both formulations of trehalose showed good clinical efficacy. This trial is registered with NCT02980913.