bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive optics – basic optical principles
Authors: Irsch Kristina
Published: December 2022

Adaptive Optics (AO) refers to a technique to compensate for distortions caused by optical aberrations in the media between the camera and the object being imaged. It was originally developed for use in astronomical telescopes to compensate for optical distortions induced by the inhomogeneous earth atmosphere. It has since evolved to become a powerful clinical tool in ophthalmology. In the eye, a “wavefront sensor” (aberrometer) measures the distortion of incoming light induced by inhomogeneities within the cornea and crystalline lens, which is then “undistorted” via reflection by a deformable mirror. AO thus enables imaging of the human retina with unprecedented resolution in vivo, such as revealing individual photoreceptors or the walls of blood vessels. One should note that AO by itself does not provide an image; rather an AO subsystem is incorporated into an existing imaging device. AO subsystems have thus far been successfully integrated into three ophthalmic imaging devices: fundus cameras, scanning laser ophthalmoscopes, and the OCT device. This lecture will introduce the basic principles of AO, illustrate its value with state‐of‐the‐art clinical examples, and discuss potential future applications in ophthalmology.
Retinal imaging – a window into brain mechanisms
Authors: Castelo‐Branco Miguel
Published: December 2022

The retina is increasingly being recognized as a window to brain neurodevelopment, ageing and degeneration. This non‐invasive window to vascular and neural function has shown promise to modify disease diagnosis, follow‐up and management. Here we review imaging evidence reflecting critical interactions between ageing, systemic disorders (diabetes) and neurodegenerative diseases. We will also address neural and vascular compartments and their critical interfaces, blood‐retinal and blood–brain barriers. It remains to be clarified how brain neuroinflammation and amyloid deposition can be mirrored by surrogate markers at the level of the retina. We also address the intriguing link with diabetes as a systemic disease where all these factors are important in relation to barrier function and neurodegeneration associated with normal/pathological ageing. The association between abnormal retina and brain development will also be discussed, in relation to imaging approaches using the retina as a window into the brain.
Update on current anti‐glaucomatous drugs
Authors: Cvenkel Barbara
Published: December 2022

This update summarizes current and recently launched intraocular pressure (IOP)‐lowering medications. Reducing IOP remains the mainstay of glaucoma treatment. Different classes of IOP‐lowering eye drops have different mechanism of action, efficacy and side effects. The eye drops available in Europe include prostaglandin analogues, β‐blockers, carbonic anhydrase inhibitors, α‐2 adrenergic agonists, and parasympathomimetic drugs. In addition, systemic carbonic‐anhydrase inhibitor drugs are available and can be considered for short time use when eye drops are not effective. Prostaglandin analogues are recommended as first choice treatment for POAG, because of their efficacy, limited systemic side effects and once daily dosing. Combining agents of different classes with different mechanism of action is associated with superior IOP‐lowering efficacy compared to each of the components used alone. Fixed combinations are preferable than concomitant treatment. Novel IOP‐lowering medications have been approved by the Food and Drug Administration and are not yet available in most of the European countries. These include nitric‐oxide donating prostaglandin analogue latanoprostene bunod, rho‐kinase inhibitor netarsudil and fixed combination netarsudil/latanoprost.
10 coomon mistakes in uveitis. A guide to escape disasters
Authors: Tranos Paris
Published: December 2022

Intraocular inflammatory diseases are relatively rare, involving predominantly younger patients and are usually characterized by rapid progression. Consequently, effective management of uveitis requires prompt diagnosis and initiation of the correct treatment regimen without delay, an occasionally challenging task for the non‐specialist ophthalmologist. Despite the frequent overlap of clinical features in uveitis patients, certain disease characteristics should be recognized to facilitate efficacy and avoidance of pitfalls. We provide a survival guide of 10 crucial key points, essential to ensure the optimum outcome and safe management in inflammatory conditions.
Dealing with the complications of uveitis
Authors: Koufakis Dimitris
Published: December 2022

The most frequent complications of uveitis are cataract, glaucoma and uveitic macular edema. The successful management of cataract requires uveitis remission for at least 3 months before surgery and perioperative intensification of anti‐inflammatory medication in order to prevent uveitis recurrences. Intraocular strategy is also important for the final.

outcome. Uveitic glaucoma management comprises medical and surgical treatment, considering that about 30% of cases.

will need invasive methods. Uveitic macular edema is commonly seen in intermediate, posterior or panuveitis. The base of treatment are corticosteroids and also dealing with the underlying cause of edema. The role of immunosuppressives and biological agents is very important too.
Abnormal findings in the angle and possible consequences
Authors: Hommer Anton
Published: December 2022

In the presentation the abnormal findings, depending on the different structures in the angle will be presented with pictures and movies. Out of these, the possible, individual therapeutic consequences will be discussed. Developmental disorders, like Axenfeld and Rieger, as well required changes e.g. like pigment dispersion and pseudoexfoliation will be shown. The pathological configurations of the angle and how to handle will be shown.
First principles of perimetry
Authors: Redmond Tony
Published: December 2022

Clinical visual field tests are adaptations of classic psychophysical approaches to measuring the minimum value of a stimulus that can be seen (threshold or sensitivity). Although the classic approaches can be highly accurate and precise, they are also lengthy and unsuitable for clinical practice. Therefore, the design of a clinical visual field test must strike a balance between accuracy, precision, speed, and ease of understanding. Such a compromise brings both advantages and pitfalls. In this course, we will discuss the psychophysical underpinnings of conventional visual field tests and their standard parameters, why they were chosen, and how they might influence interpretation of clinical findings.
Perimetric variability – psychophysics
Authors: Redmond Tony
Published: December 2022

The human visual system is inherently noisy and the limits of vision can fluctuate during and between measurements. The way in which tests of vision are designed can also introduce variability. This can make it difficult to discern true changes in the visual field from fluctuations around normal levels. Variability can come from the choice of parameters such as the stimulus, thresholding algorithm, step size, and test duration. The ability to identify visual field damage from normality, and changes in vision from stability, relies greatly upon having a test that has a high disease signal and low variability, while also keeping the test at a manageable duration for patients. In this course, we will discuss the importance of understanding variability, how it is related to visual field test design, as well as the efforts that are being made to reduce it.
Dealing with perimetric variability in clinical practice
Authors: Jansonius Nomdo
Published: December 2022

The perimetric follow‐up of glaucoma patients seems a complex task. However, with a limited number of basic rules, it can be done well organized and efficiently. We first address the why would we do perimetry in glaucoma follow‐up. After that, we focus on the how. What is the optimal timing of visual fields? Which variables should be monitored? How do we define a change? What is rate‐of‐progression? How can we incorporate age and glaucoma stage in our decision making?
Endophthalmitis prophylaxis in cataract surgery and intravitreal injection in the US
Authors: Schwartz Stephen G.
Published: December 2022

Endophthalmitis is not a “never event” following cataract surgery or intravitreal injection, therefore the occurrence of endophthalmitis does not necessarily imply a break in technique or that the surgeon somehow “did something wrong”. Endophthalmitis cannot be prevented, but its rate can be reduced using evidence‐based measures. Endophthalmitis prophylaxis techniques include more than the use of antibiotics; specifically, prep/drape, speculum use, wound construction, etc.

In the US, intracameral antibiotics are not universally used. The decision to use routine intracameral antibiotics appears to depend on many “non‐medical” factors, including internal health system policies, local standards of care, and other concerns. In the US, there is no packaged antibiotic that is specifically approved for intracameral use so all such agents are used “off‐label”; this factor appears to be suppressing the use of intracameral antibiotics at least in some locations.

In the US, intravitreal injections are almost always performed in the clinic rather than in an operating room or similar setting. (In fact, it can be difficult to get reimbursed for anti‐VEGF drugs injected in an operating room.) Many practices use a standard examination room rather than a minor procedure room or a room dedicated to performing injections. Eyelid speculums are very widely used, although there is a growing acceptance of the use of bimanual retraction from a skilled assistant, rather than an eyelid speculum. In many practices, topical antibiotics are not used.

It is the author's opinion (although there is little or no evidence from randomized clinical trials to support this opinion) that post‐surgical endophthalmitis differs from post‐injection endophthalmitis in how the microorganisms gain access to the intraocular space. Following cataract surgery, it seems most likely that microorganisms enter the eye through the incision in the postoperative period; this would explain the relatively later onset of infection, as well as the apparent benefits of postoperative topical antibiotics, proper wound construction, and suturing the incision when necessary. Following intravitreal injection, it seems most likely that microorganisms enter the eye at the moment of the injection; this would explain the relatively sooner onset of infection, as well as the apparent lack of benefit of postoperative topical antibiotics.
Endophthalmitis prophylaxis in cataract surgery and intravitreal injection in Europe
Authors: Grzybowski Andrzej
Published: December 2022

Endophthalmitis is a significant complication of cataract surgery and intravitreal injections (IVI), leading in severe cases to blindness. The improvements of surgical technology, techniques and procedures have significantly reduced the incidence of postoperative infections in recent years; however, it is impossible to eliminate this problem completely. The incidence of post‐cataract endophthalmitis varies among several countries from 0.03% to 0.7%. The recommendations of the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO), have set the maximum acceptable level of postoperative endophthalmitis (POE) after cataract extractions at 0.05%. Awareness about risk factors and prevention measures is necessary for ophthalmic surgeons. Surgical complications (wound leak, posterior capsule rupture, vitreous loss or zonular complications) are related with higher incidence of postoperative endophthalmitis. Elderly patients (>85 years), those with clear corneal incisions versus scleral tunnel incisions, and those without intracameral injection of cefuroxime have also a higher risk of infection.

The available evidence suggests that intracameral antibiotic lowers the POE. Of the two most commonly used IC antibiotics, moxifloxacin and cefuroxime, there is no clear evidence that one is better than the other. Vancomycin is not recommended for routine ICAP because of both the risk of HORV (extremely low) and concerns regarding the use of an indispensable agent to treat multi‐drug‐resistant endophthalmitis as routine prophylaxis. Topical antibiotics may not provide an additional benefit, as has been suggested by several studies.

In IVI, perioperative antibiotics cannot be considered the standard of care, as there is no evidence of prophylactic effects with regard to POE when using perioperative antibiotics. Topical administrations of 5% povidone‐iodine over at least 30 s into the conjunctival sac is recommended. Current clinical practices include minimized physician/patient talking during IVI, wearing of surgical face masks, and using face masks for nurses, technicians and physicians.
Novel options in diagnosis and treatment of endophthalmitis
Authors: Lytvynchuk Lyubomyr
Published: December 2022

Endophthalmitis remains the most vision‐threatening condition that in most severe cases can result in a loss of an eye and systemic spreading of the infection. It is defined as an acute inflammation of the inner tissues of the eyeball and is usually caused by intraocular contamination and colonization of infectious agents with exudation within intraocular space. The development of endophthalmitis as well as its clinical presentation and functional and anatomical outcomes is predefined by its type, kind of infection and therapy applied. There is a risk of progression of endophthalmitis to panophthalmitis, which could end up with evisceration or enucleation. The involvement of the general physician and other medical specialists into the treatment of the patients with endophthalmitis shall be always considered and should not be underestimated. As one of the most severe emergencies in ophthalmology, this condition requires urgent therapeutical or/and surgical intervention. Numerous studies compare the efficacy of the first line treatment for different types of endophthalmitis. Since decades the management of endophthalmitis is based on prompt recognition of infectious agents, immediate intraocular antimicrobial therapy and removal of the purulent exudate form the eye. Novel diagnostic options for endophthalmitis shall be considered in order to increase the precision of to treat patients with endophthalmitis. Improvement of the surgical techniques with the development of the new less traumatic instruments and he novel antimicrobial drugs can stablish a new standards of endophthalmitis care.
New strategies that can be neuroprotective
Authors: Cvenkel Barbara
Published: December 2022

Glaucoma is considered a neurodegenerative disease and shares some common mechanisms with other neurodegenerative diseases. Therefore, research into the triggers and drivers of neurodegeneration can identify novel areas of therapeutic intervention to preserve and restore vision. Neuroprotection in glaucoma is focused on preserving the neuronal structure and/or function. Currently, lowering of intraocular pressure (IOP) is the only clinically proven neuroprotective strategy. Alternatives to IOP‐lowering approach can be grouped into targets that interfere with excitotoxicity, oxidative stress and mitochondrial dysfunction, inflammation‐abnormal immune response, glial cell modulation, and stem cell therapy. However, any division is arbitrary as most targets are involved in several pathways and/or mechanism of action are incompletely understood. Many agents have shown neuroprotective effect in glaucoma research models but translation into well‐designed human trials and clinical practice represents a major challenge. Several compounds with antioxidant function including vitamin E, C, flavonoids, coenzyme Q10, and citicoline have shown neuroprotective effect in neurodegenerative diseases. Recently, oral nicotinamide supplementation has led to a short‐term improvement of inner retinal function in glaucoma patients. Immune system modulation such as blocking selectively excessive TNF‐alpha and targeting antibodies against ϒ‐Synuclein may prove beneficial. Recently, the receptor agonists of the incretin hormone glucagon‐like‐peptide‐1 (GLP‐1), used for the treatment of diabetes, have shown neuroprotective effects in preclinical and clinical studies on neurodegenerative diseases in both the brain and the retina. Platelet‐derived growth factor and ciliary neurotrophic factor (CNTF) protect cells from neurodegeneration and phase I studies using intraocular implants with slow CNTF release are ongoing. Intravitreal administration of mesenchymal stromal stem cells has shown neuroprotective effect. Gene therapy in glaucoma is still in preclinical phase. A novel adeno‐associated viral vector gene therapy increased production of brain‐derived neurotrophic factor and its receptor and had neuroprotective effect over several months. Altered levels of microRNAs, small non‐coding RNAs involved in post transcriptional regulation of gene expression, were found to be implicated in retinal ganglion cell apoptosis in glaucoma. MicroRNAs may become a novel neuroprotective strategy.
Algorithms for decision on intrastromal ring segment implantation
Authors: Barraquer Rafael I.
Published: December 2022

Success in improving vision with intracorneal ring segment (ICRS) implantation for keratoconus depends on understanding the phenotype/pattern present in a particular cornea, the relative weight of the different aberrations (astigmatism, coma, spherical), the mechanism of action of the implants, and the possible modalities of implantation. The application of a particular nomogram makes sense only there has been a decision on the location of the implants relative to the selected landmarks (axis of refractive or topographic astigmatism, coma axis, etc.). It is possible to define all possible modalities of implantation of 1 or 2 ICRS based on only two features: whether there is implantation symmetry and the position of the center of the implant relative to one significant landmark (usually the flat topographic meridian) what we call “axiality”. The resulting matrix/classification includes 6 possible modalities. This presentation will develop on the author's methodology for ICRS selection based on this concept.
The origin of the cyclops myth
Authors: Ascaso Francisco Javier
Published: December 2022

Since Polyphemus's appearance in The Odyssey nearly three millennia ago, the cyclops has been always linked to the human imagination. Ancient sources for the depiction of a cyclops are numerous. Although Homer's classical poem appears to be the earliest, other Greek and Latin authors mention this group of oddly visaged giants with one large eye in the middle of their foreheads. If adult cyclopes cannot possibly exist, where did the ancient Greeks and Romans get this idea? The answer is unclear, although researchers in a variety of fields have several hypotheses. Throughout this session I will try to solve this question.
The influence of visual pathology on painting
Authors: Mateo Javier
Published: December 2022

Painting is, along with sculpture and architecture, the most visual of the Fine Arts and it is probably the most ancient of them. The oldest known paintings were discovered on the walls of caves in Indonesia and Spain and are believed to be more than 40 000 years old.

In painting, vision is crucial both for the artists and for the viewers. Diseases affecting the eyes can have a huge impact in the artistic expression of the painters, for instance refractive errors like myopia, hyperopia and astigmatism, disorders related with age such as cataracts, presbyopia and age related macular degeneration or different pathologies including colour blindness, diabetic retinopathy, vitreal haemorrhage, retinal dystrophies, strabismus, tumours… seem to have influenced the paintings of many artists.

However, it is difficult to evaluate the degree of the impact that these disorders actually have on the works of the painters. The style of an artist depends on many factors including the time or era they live in, the School of painting they belonged to, religion, politics, the influence of teachers and colleagues and, of course, their own stylistic choice. The way they perceive the world that surrounds them is surely an important factor that affects their creations, but not the only one.

In this speech, we will try to look over some famous painters' works and try to explain how their ocular problems influenced their production. We will also discuss some widespread theories about alleged visual problems affecting various artists and their (lack of) accuracy.
History of diagnosis and treatment of cystoid macular edema
Authors: Schwartz Stephen G.
Published: December 2022

Following the introduction of the ophthalmoscope by Helmholtz in 1851, very early descriptions of macular edema were reported by Jaeger in 1856 and Nettleship in 1872. Macular disease following cataract surgery was described by Hruby in 1950, Irvine in 1953, Chandler in 1954, Nicholls in 1954, and Maumenee in 1957, among others. The introduction of fluorescein angiography by Novotny and Alvis in 1961, with subsequent modifications by David, Sever and Justice, greatly facilitated the diagnosis of this condition. Using fluorescein angiography, Gass and Norton reported 44 patients with “cystoid macular edema” (CME) in 1966, which appears to be the first use of this term. The eponym “Irvine‐Gass syndrome” appears to have been published first in 1971. In 1991, Puliafito and colleagues reported the first use of optical coherence tomography, and published one case of postoperative CME in 1995.

Treatments for CME developed as the pathophysiology became better understood. Early reported treatments included oral vasodilators (Laws, 1964), oral prednisone (Gehring, 1968), and pulsed ruby photocoagulation (Zweng and colleagues, 1968). Alternatively, other investigators recommended observation for at least 12 months, including Gass and Norton in 1969 and Jacobson and Dellaporta in 1974. Miyake reported good results with topical indomethacin prophylaxis in 1977; other investigators subsequently reported benefit with topical or oral indomethacin, including Yannuzzi and colleagues in 1979 and Kraff and colleagues in 1982. Various surgical factors, including posterior (rather than anterior) chamber intraocular lenses, were found to be beneficial during the 1980s. Multiple topical medications, including prednisolone acetate, flurbiprofen, ketorolac, diclofenac, and others, were investigated in the 1990s and 2000s. Gaudric and colleagues published treatment of CME with intravitreal triamcinolone acetonide in 2003.

At the present time, the use of topical corticosteroids and nonsteroidal anti‐inflammatory agents is widely used in the prophylaxis and treatment of CME, but there is relatively little evidence from randomized clinical trials to support this practice. In both the US and Europe, no agent has achieved regulatory approval for the treatment of postoperative CME; all agents are used “off‐label”.
A comparative map of macroautophagy and mitophagy in retinal cells
Authors: Boya Patricia
Published: December 2022

Autophagy is a catabolic pathway that promotes the degradation and recycling of cellular components. This process degrades proteins, lipids, and even whole organelles, which are engulfed in autophagosomes and delivered to the lysosome. Autophagy is a stress‐response that mediates the elimination of harmful cell components and recycles them to generate the nutrients and building blocks required to sustain cellular homeostasis. In addition, it plays an important role in cellular quality control, particularly in neurons, in which the total burden of altered proteins and damaged organelles cannot be reduced by redistribution to daughter cells through cell division. The role of autophagy in the retina and eye diseases is started to be investigated. I will review our main studies describing the role of autophagy in retinal development and cell differentiation, and discuss the implications of autophagy dysregulation both in physiological aging and in important diseases such as glaucoma and retinal dystrophies. Our findings reinforce the essential role of autophagy in maintaining proper retinal function and highlight novel therapeutic approaches for blindness and other diseases of the eye.
The French approach
Authors: Rousseau Antoine
Published: December 2022

If one could define one French specificity regarding the medical management of glaucoma, it would certainly be a high propensity to consider the ocular surface when treating a patient. Therefore, the first part will focus on why the interactions between ocular surface and glaucoma treatments are so important, and how to manage them.

Regarding the surgical aspect, French ophthalmologists, more than other, have a preference for non‐penetrating deep sclerectomy, which is considered for many as the reference surgical procedure for open angle glaucoma. Thus, in the second part, we'll consider the pros and cons, and some tips to succeed with this technique.
The aging retina of wild‐type and mouse model of Alzheimer's disease
Authors: Bernardes Rui
Published: December 2022

Several neurological diseases have been shown to have measurable correlates in the eye, thus further supporting the idea of the retina as a window to brain and neurodegeneration. Retinal imaging techniques, way less complex, more affordable and widely available than their counterparts for the brain, have the potential to provide alternatives to brain imaging techniques such as magnetic resonance imaging (MRI). Also, animal models of disease are expected to allow the investigation of neurodegenerative diseases at states that would be inaccessible in a human patient, particularly at the onset of diseases that may occur decades before diagnosis. In this talk, we will present and discuss data and findings from wild‐type and triple‐transgenic mouse model of Alzheimer's disease by optical coherence tomography (OCT) at the ages of 1, 2, 3, 4, 8, 12, and 16 months old. In addition to commonplace retinal thickness measurements, texture analysis findings and findings from a neural network fed with OCT B‐scans and a neural network fed with OCT computed fundus images will be present and discussed.

Funding: This study was funded by The Portuguese Foundation for Science and Technology (FCT) through PTDC/EMD‐EMD/28039/2017 and by FEDER‐COMPETE through POCI‐01‐0145‐FEDER‐028039.
Interaction of immune cells and lymphatic vessels in corneal transplantation
Authors: Bock Felix
Published: December 2022

Immune‐mediated graft rejections remain the most common cause for graft failure after organ and tissue transplantation. There is a great unmet medical need for pharmacologic strategies to promote graft survival without unduly compromising the health of the recipient.

Corneal allograft rejection is histologically characterized by massive infiltration of CD4+ T‐cells, macrophages and the invasion of blood and lymphatic vessels.

We could show that lymphatic vessels determine the high‐risk status of a corneal graft recipient. The healthy cornea is devoid of blood and lymphatic vessels. In contrast, in the high risk situation graft rejection is highly correlated with the degree of corneal vascularisation and presence of numerous pro‐inflammatory immune cells.

CD11c+ CD11b+ myeloid dendritic cells (DCs) are present throughout the anterior stroma – even in the healthy cornea. Inflammatory stimuli determine the maturation stage of DCs and their immunogenic properties. It is known that an increasing number of MHC class II‐bearing, antigen specific DCs in cervical draining lymph nodes arise only a few hours after transplantation. This implies that DCs at different maturation stages might be the main initiators of this devastating tissue destruction.

The origin of donor antigen presenting cells can be either from the donor tissue or the host. Thereby allo‐antigens from the grafted tissues travel via lymphatic vessels towards the draining lymph nodes of the recipient. Here they are recognized by host T cells either by the direct pathway, which involves the recognition of intact donor MHC molecules on donor‐derived APCs, or by the indirect pathway, which involves the recognition of donor major or minor MHC‐derived peptides, processed and presented by recipient APCs to host T cells. Nowadays it is widely accepted that resident MHC class II APC populations are present in the cornea. These cells are capable of expressing MHC class II antigen and accessory molecules (CD40, CD80) after transplantation. We and others could demonstrate that the immune reaction is triggered by the above described “direct allo‐sensitisation” where APCs travel from the donor tissue via corneal pathological lymphatic vessels into the local draining lymph nodes of the recipient and present the foreign antigen.

Recent studies could show that lymphatic vessels not just display an exit route for leukocytes but are in close interaction with these cells and regulate the entry and trafficking of antigen presenting cells into and via lymphatic vessels.

This presentation will summarize the current knowledge about the interaction of immune cells and lymphatic vessels in corneal transplantation.
Mesenchymal stromal cell therapy to modulate corneal allograft rejection: From bench to bedside
Authors: Ritter Thomas
Published: December 2022

Cornea transplantation has been a target for mesenchymal stromal cell (MSC) therapy for several years with a number of publications highlighting the therapeutic potential and mechanism of action of these cells. It is widely known that MSC possess potent anti‐inflammatory capabilities and are able to modulate the activity of a wide array of immune cells including T cells, B cells, dendritic cells and macrophages. This modulation occurs through both cell–cell contact and the paracrine release of soluble factors such as nitric oxide and prostaglandin E2.

Although the mechanism of MSC‐mediated immunomodulation following intravenous administration (i.v.) remains to be fully elucidated, it is evident that the lung (where the majority of MSCs become trapped and are subsequently cleared within 24 hours) plays an important role. Our group and others have reported that MSCs enrich innate immune regulatory cells in the lung following i.v. administration.

Previous results from our laboratory have demonstrated the efficacy of pre‐transplant infusion of allogeneic (allo) but not autologous (auto) MSC in a fully allogeneic, MHC‐mismatched rat model of cornea transplantation. This suggests that in our previous work the expression of allo‐antigen by allo‐MSCs provides a priming stimulus that enhances their immune modulatory effects while auto‐MSCs administered to an immunologically compatible non‐inflamed (pre‐transplantation) host did not receive the required priming stimulus. We hypothesized that pre‐emptive priming (“licensing”) of auto‐MSC could overcome the lack of efficacy in preventing cornea transplantation rejection by better promoting regulatory innate and adaptive immune cells. We demonstrate that auto‐MSCs administered post‐operatively promote rejection free graft survival upon licensing with a cocktail of pro‐ or anti‐inflammatory cytokines. Interestingly, while the different licensing strategies promote corneal allograft survival in rodents overall, the mechanisms of action appear to be different how these licensed MSC operate in vivo. Finally, the potential of extracellular vesicles secreted from licensed MSC as potential cell‐free therapy will also be discussed.

This work contributes to the growing body of literature highlighting the fact that MSC require a pre‐activation stimulus in order to be therapeutically active and the importance of.

regulatory cells in mediating MSCs immunomodulatory function.

Funding received for this work.

This work was supported by Science Foundation Ireland (12/IA/1624), by a grant from the European Commission [FP7 Collaborative Health Project VISICORT (grant number 602470), www.visicort.eu], by infrastructural funds from the European Regional Development Fund and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 814439.

Keywords: corneal transplantation, mesenchymal stromal cells, licensing, cytokines, immunomodulation, regulatory cells.
Loss of colour vision in patients at risk of developing diabetes
Authors: Rodriguez‐Carmona Marisa , Bastaki Qais , Barbur John L.
Published: December 2022

Recent studies carried out in diabetic patients with no more than moderate maculopathy revealed that over 70% had significant losses of both Yellow/Blue (YB) and Red/Green (RG) colour vision (https://doi.org/10.1111/j.1755-3768.2012.F073.x). The purpose of this study was to investigate whether clinically ‘normal’ subjects, identified as being at ‘risk’ of developing diabetes show significant changes in rod‐ and cone‐mediated rapid flicker sensitivity as well as RG and YB colour vision.

Three groups of subjects were recruited; a normal subject group (n = 40), a ‘high‐risk’ group (n = 150) and subjects diagnosed with diabetes (n = 23). The inclusion criteria for ‘high‐risk’ group required 3 or more recognized risk factors for diabetes (e.g., age > 45, HbA1C >5.7, high blood pressure, smoking history, high BMI, family history of diabetes, FPG levels >100 mg/dL). All subjects had full ophthalmic assessment and their RG and YB colour vision, Functional Contrast Sensitivity (FCS), Visual Acuity (VA) and Rod‐ and Cone‐mediated flicker sensitivity were measured using AVOT tests (https://researchcentres.city.ac.uk/applied-vision/avot).

Consistent with previous findings, the diabetic group show significant loss of both RG and YB colour vision. Our findings show that these subjects also exhibit higher thresholds for rod and cone mediated vision. In addition, the ‘high‐risk’ group who are clinically classified as ‘normal’, also show significant loss of colour vision and rod and cone sensitivity. The latter group, do not, however, show significant differences in either VA or FCS. These findings suggest that accurate assessment of colour vision and rod‐ and cone‐ mediated rapid flicker sensitivity qualify as important risk factors in prediabetic screening.
Potential challenges in AI application in the clinical setting
Authors: Schmetterer Leopold
Published: December 2022

Artificial intelligence (AI) solutions have attracted much interests in ophthalmology. Whereas multiple papers have been published the translation to clinical ophthalmology is challenging. The present talk will summarize five key elements that hamper translation. 1. Applicability of AI solutions to external real world datasets. Convolutional neural networks (CNNs) may fail if they were trained on datasets that do not match the target population in terms of ethnicity, age, disease severity and/or diagnostic criteria. 2. Burden of false negatives and false positives. Although the Area under the Curve (AUC) for detection of disease is often high, the application of the CNN still results in many false positives due to the low prevalence. In addition, false security is feigned in false negatives. 3. Inadequate facilities. Whereas CNNs have often been proposed for screening, the screening facilities are frequently not in place. Establishing a screening facility is expensive and requires support from health care providers. 4. Inadequate image quality. Even the best CNN does not perform well if image quality is insufficient. Continuous training and quality control is an expensive task for achieving optimal results. 5. Human interaction studies. Little is known to which degree AI based solutions will be accepted by health care providers and by patients.
Unilateral corneal insult also alters sensory nerve activity in the contralateral eye
Authors: Acosta M. Carmen
Published: December 2022

When the ocular surface of one eye is inflamed or injured, its corneal sensory nerve activity is modified, which in turn evokes ocular discomfort, irritation, and pain sensations referred to the affected eye. Some patients with unilateral ocular inflammation, infection, or surgery also report discomfort and pain in the contralateral eye. Are these sensations experienced at the fellow eye due to alterations of its sensory nerve activity?

To test this hypothesis, we recorded in vitro the activity of corneal mechanonociceptor, polymodal nociceptor and cold thermoreceptor nerves of both eyes of guinea pigs previously subjected unilaterally to three different experimental inflammatory and lesion conditions: UV‐induced photokeratitis, microkeratome corneal surgery, and chronic tear deficiency caused by removal of the main lacrimal gland. Recordings from the eyes of naïve animals were used as control.

Compared with the naïve guinea pigs, animals subjected to unilateral UV‐induced mild corneal inflammation, showed inhibition of the spontaneous and stimulus‐evoked activity of cold thermoreceptors, and increased activity (sensitization) of nociceptors affecting both the ipsilateral and the contralateral eye. Unilateral microkeratome surgery affected the activity of nociceptors mostly, inducing sensitization in both eyes. Chronic eye dryness by removal of the main lacrimal gland increased cold thermoreceptor activity in both eyes. These results show that after unilateral eye damage, corneal sensory nerve activity is altered in both eyes, although to a lesser degree in the contralateral eye.

This is the first direct demonstration that unilateral corneal nerve insult, and especially ocular surface inflammation, functionally affects the activity of the different types of corneal sensory nerves in both the ipsilateral and contralateral eyes. The mechanisms underlying the changes of contralateral sensory nerve activity remain to be determined, although available data support the involvement of the immune system. The present results have two main implications: (a) contralateral eyes cannot be considered as a control in experimental designs of both preclinical and clinical studies; and, (b) clinicians must consider the convenience of treating both eyes of patients with unilateral ocular conditions to avoid pain and secondary undesirable effects in the fellow eye.
Contralateral inflammatory effects on the trigeminal ganglion after unilateral corneal lesion
Authors: Ferrari Giulio
Published: December 2022

The purpose of this study was to test whether a corneal injury can stimulate inflammation in the trigeminal ganglion (TG) located (i) on the same side, or (ii) on the opposite site of a cornea alkali burn.

Following monolateral administration of a corneal alkali burn, we performed in vivo magnetic resonance imaging (MRI) of the brain before and after ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) contrast to track macrophages. Trigeminal ganglia were stained for Prussian Blue and inflammatory cell markers. Moreover, the tissue levels of pro‐inflammatory cytokines Interleukin‐1β, TNF‐α, and VEGF were quantified on days 1, 4, and 8, and 4 days after corneal topical anti‐inflammatory treatment with 0.2% dexamethasone. The expression of Substance P and its receptor NK‐1R was measured in the TG on day 4.

Corneal alkali burn induced leukocyte infiltration, including T cells, in the right TG at 4 and 8 days. In vivo MRI showed an increased contrast uptake in the right TG, which peaked at day 8. Prussian Blue(+) USPIO(+) macrophages were observed in the right TG and exhibited an M2 phenotype. The M2‐macrophage infiltration was preponderant in the TG after damage. The proinflammatory cytokines Substance P and NK‐1R were significantly increased in both the TGs. The expression of IL‐1β and VEGF‐A was significantly reduced in the right TG with dexamethasone treatment.

Our data support: (i) bilateral onset of inflammation in the TG following ocular surface damage; (ii) involvement of the neuropeptide Substance P in the propagation of inflammation from the cornea to the TG through corneal nerves.
Shedding light on myopia by studying complete congenital stationary night blindness
Authors: Zeitz Christina , Roger Jerome E. , Michiels Christelle , Sánchez‐Farías Nuria , Varin Juliette , Frederiksen Helen , Wilmet Baptiste , Gimenez Marie‐Laure , Bouzidi Nassima , Blond Frederic , Guilllonneau Xavier , Léveillard Thierry , Sahel José‐Alain , Picaud Serge , Audo Isabelle
Published: December 2022

Purpose: Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signalling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON‐bipolar cell signal transmission defect and is also associated with high myopia. The purpose of this work was to identify the molecular cause of myopia present in cCSNB.

Methods: A whole transcriptome sequencing (RNA‐seq) approach was performed using retina from three mouse lines with cCSNB, Gpr179−/−, Lrit3−/− and Grm6−/− and the expression data compared to data of age‐matched wild‐type littermates (n = 5). DEGs with fold changes of at least 1.2, p‐values of ≤0.01, an expression value of at least 5 transcripts per million reads and appearing in at least two cCSNB mouse lines were investigated in detail. A meta‐analysis was performed by (a) comparing our data with published transcriptome data from purified retinal cells and single cell RNA‐Seq data, (b) pathway analyses, (c) myopia databases and publications concerning their role in normal vision. Several of the DEGs were validated by RT‐qPCR experiments and analysed by western blot and immunolocalization studies.

Results: More than 50 DEGs were found in at least two cCSNB mouse lines. Expression of those was found in different retinal cell types. The difference in expression was independent of the number of nuclei present in wild‐type and mutant inner retina. Pathway analysis revealed that mitogen‐activated protein kinase pathways, synaptic signalling, G protein‐coupled receptor ligand binding pathways, and proteins implicated in eye, endoderm and connective tissue development were affected in cCSNB. More than half of the genes were already associated with myopia.

Conclusions: Our study reveals DEGs in all retinal cell types of cCSNB models, previously associated with myopia and novel candidates. These studies combined with pathway analyses provide the basis for the development of pharmacological and optical myopia therapies.
Ocular blood flow and myopia
Authors: Świątczak Barbara
Published: December 2022

Purpose: It has previously been found that imposing positive defocus changes axial length and choroidal thickness after only 30 minutes. In the present study, we investigated whether these changes may result from an altered choroidal blood flow.

Methods: Eighteen young adult subjects watched a movie from a large screen (65 inch) in a dark room at 2 m distance. A fifteen‐minute wash‐out period was followed by 30 minutes of watching the movie with a monocular positive defocus (+2.5D). Changes in axial length and ocular blood flow were measured before and after the defocus, by using low‐coherent interferometer (LS 900, Haag‐Streit, Switzerland) and a laser speckle flowgraphy (LSFG) RetFlow unit (Nidek Co., LTD, Japan), respectively. Three regions were analysed: (1) the macular area, where choroidal blood flow can be measured, (2) the optic nerve head (ONH), and (3) retinal vessel segments.

Results: Changes in choroidal blood flow were significantly and negatively correlated with changes in axial length that followed positive defocus in exposed eyes (R = −0.67, p < 0.01). The absolute values of changes in choroidal blood flow in the defocused eyes were significantly larger than in the fellow control eyes. ONH and retinal blood flow were not associated with the induced changes in axial length.

Conclusions: Positive defocus selectively alters choroidal, but not retinal or ONH blood flow in young human subjects after short‐term visual exposure. The results suggest that blood flow modulation is involved in the mechanism of choroidal responses to optical defocus.
Insights into myopia gleaned from retinal electrophysiology
Authors: Mahroo Omar A. , Jiang Xiaofan , Xu Zihe , Hammond Christopher J. , Hysi Pirro G.
Published: December 2022

The prevalence of myopia is increasing dramatically. Retinal signalling controls eye growth and a retinal myopia‐signalling cascade has been postulated. One of the strongest genetic associations with myopia susceptibility is a locus near the GJD2 gene which codes for a protein forming gap junctions in the retina. We explored whether any parameters of retinal electrophysiology were associated with presence of the risk allele. Full‐field scotopic and photopic electroretinogram (ERG) recording was performed in over 200 healthy volunteers from the TwinsUK cohort. Responses were elicited by stimuli conforming to international standard protocols and additional experimental protocols aimed at isolating rod and cone system responses. The majority of participants had been genotyped previously for their identity at the relevant locus. A mixed linear model was employed with ERG parameters (amplitudes and peak times) as outcomes and allelic dosage at the relevant locus as a predictor, adjusting for age, sex and inter‐individual relatedness. ERG recordings and genotype data were available for the majority of participants (95% female; mean (SD) age 64.2 (9.7) years). Light adapted single‐flash a‐waves and b‐waves associated significantly with allelic identity at the locus of interest. None of the standard dark‐adapted ERG parameters associated significantly with genotype at this locus. Further investigation of responses to experimental protocols, and those obtained from patients with loss of ON or both ON and OFF bipolar cell responses, suggested changes specific to the cone‐driven OFF pathway. The findings suggest associations between photopic cone‐driven retinal electrophysiological signalling and one of the genetic polymorphisms most strongly linked to myopia. Higher environmental light levels are known to be protective in myopia, and our results support the hypothesis that changes in light‐adapted cone system signalling might play a role in myopia development.
Genetics of myopia: Gene finding and beyond
Authors: Haarman A. E. G. , Tedja M. S. ,   The Erasmus MC Myopia Research Group,   Consortium of Refractive Error, Myopia (CREAM), Verhoeven V. J. M. , Klaver C. C. W.
Published: December 2022

The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. To date, over 500 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. However, also patients with low scores can develop myopia and vice versa. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances including large‐scale, in‐depth genetic studies using complementary big data analytics, consideration of gene–environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence are needed. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth.