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Favorable functional outcomes have been reported after excimer laser-assisted penetrating keratoplasty (EXL PKP). But this technique has not been widely adopted, and there are reports on EXL PKP from only a very limited number of institutions. Some of these results refer to operations carried out with laser systems that are not commercially available. In this retrospective case series, we report the long-term outcome of EXL PKP using the Schwind Amaris 500E laser system.This retrospective consecutive case series included 30 eyes of 29 patients who had undergone EXL PKP between 2010 and 2013. Primary outcome measures were topographic astigmatism and visual acuity. Secondary outcome measures were the rates of graft rejection and graft failure, and the rate of grafts with an endothelial cell density below 500 cells/mmThe median interquartile range (IQR) duration of follow-up was 45 (36) months. The indications for PKP were keratoconus (n = 21), corneal scarring (n = 6), Fuchs endothelial dystrophy (n = 1), and corneal dystrophy other than Fuchs endothelial dystrophy (n = 2). The median (IQR) topographic astigmatism at the end of the follow-up period was 5.3 (2.9) D. Forty-five months after surgery, 73% of all eyes had a visual acuity better than 0.3 LogMAR. The rate of graft rejection after 45 months of follow-up was 32%. All eyes maintained endothelial cell densities higher than 500 cells/mmEXL PKP is a safe and effective surgical procedure. No general conclusions can be drawn on the refractive outcome of EXL PKP. Potential advantages, such as a higher degree of graft-host congruity, that could possibly improve the refractive outcome should be weighed against the higher costs of EXL PKP.Es wurde berichtet, dass durch die Verwendung des Excimerlasers die funktionellen Ergebnisse der perforierenden Keratoplastik verbessert werden können. Da die Excimerlaser-assistierte (EXL PKP) jedoch nicht breitflächig eingesetzt wird, liegen bisher lediglich Ergebnisse einer kleinen Zahl operativer Zentren vor. Einige dieser Ergebnisse beziehen sich auf Eingriffe, die mit Lasersystemen durchgeführt wurden, die nicht kommerziell erhältlich sind. In dieser retrospektiven Fallserie berichten wir über die Langzeitergebnisse nach EXL PKP unter Verwendung des Lasersystems Schwind Amaris 500E.Es wurden 30 Augen von 29 Patienten, bei denen zwischen 2010 und 2013 eine EXL PKP durchgeführt worden war, konsekutiv eingeschlossen. Die primären Endpunkte waren topografischer Astigmatismus sowie der Visus. Die sekundären Endpunkte waren die Raten an Transplantatabstoßungen, Transplantatversagen und Transplantaten mit einer Endothelzelldichte von weniger als 500 Zellen/mmDie mediane (Interquartilsabstand [IQR]) Nachbeobachtungszeit betrug 45 (36) Monate. Die Indikationen zur perforierenden Keratoplastik waren Keratokonus (n = 21), Hornhautnarben (n = 6), Fuchs-Endotheldystrophie (n = 1) und andere Hornhautdystrophien (n = 2). Der mediane (IQR) topografische Astigmatismus lag am Ende der Nachbeobachtungszeit bei 5,3 (2,9) dpt. Nach 45 Monaten erreichten 73% aller operierten Augen einen Visus von 0,3 LogMAR oder besser. Die Rate an Transplantatabstoßungen lag nach 45 Monaten bei 32%. Die Endothelzelldichte lag während des gesamten Nachbeobachtungszeitraums bei 500 Zellen/mmDie EXL PKP ist eine sichere und effektive Operationsmethode. Der retrospektive Charakter der Studie erlaubt keine verallgemeinernden Aussagen hinsichtlich des refraktiven Potenzials der EXL PKP. Mögliche refraktive Vorteile sollten gegen die bei der Verwendung des Excimerlasers entstehenden höheren Kosten abgewogen werden.

Zusammenfassung Hintergrund Die Entschlüsselung des Transkriptoms hat in den letzten Jahren unser Verständnis zahlreicher Erkrankungen verbessert. Öffentlich zugängliche Datenbanken, wie z. B. die Gene Expression Omnibus-Datenbank des National Center for Biotechnology Information, sammeln Transkriptomrohdaten aus einer Vielfalt von Proben, ohne jedoch dem bioinformatischen Laien einen intuitiven Zugang zu den Daten zu gewähren. Daher wurden in den vergangenen Jahren spezielle Transkriptomdatenbanken programmiert, die eine benutzerfreundliche Web-basierte Datenanalyse ermöglichen und damit niederschwellig molekulare Einblicke in okuläre Gewebe ermöglichen. Fragestellung Ziel dieser Arbeit ist es, einen Überblick über die aktuell verfügbaren okulären Transkriptomdatenbanken zu geben und diese mit dem in Freiburg neu etablierten Human Eye Transcriptome Atlas zu vergleichen. Methoden Literatursuche in PubMed. Ergebnisse Neun okuläre Transkriptomdatenbanken mit unterschiedlichem Anwendungsschwerpunkt wurden identifiziert. Die Plattformen iSyTE und Express spezialisieren sich auf die Genexpression während der Linsen- und Netzhautentwicklung der Maus, wohingegen retina.tigem.it, Eye in a Disk und Spectacle ihren Fokus auf einzelne okuläre Gewebe wie die Netzhaut legen. Spectacle, UCSC Cell Browser und Single Cell Portal erlauben die intuitive Exploration von Einzelzell-RNA-Sequenzierungsdaten von Netzhaut‑, Aderhaut‑, Kornea‑, Iris‑, Trabekelmaschenwerk- und Skleragewebe. Die Microarray-Profile verschiedener gesunder okulärer Gewebe werden in der Ocular Tissue Database bereitgestellt. Der Human Eye Transcriptome Atlas erfasst derzeit die größte Vielfalt an Augengeweben und Erkrankungen des Auges. Er zeichnet sich durch einen hohen Qualitätsstandard aus, der durch methodische Homogenität erreicht wird. Schlussfolgerungen Okuläre Transkriptomdatenbanken bieten einen umfassenden und intuitiven Einblick in die Transkriptionsprofile verschiedener gesunder und erkrankter Augengewebe. So verbessern sie unser Verständnis der zugrunde liegenden molekularen Krankheitsprozesse, unterstützen die Hypothesengenerierung und helfen bei der Suche nach neuen diagnostischen und therapeutischen Zielen für verschiedene Augenerkrankungen.

Background Descemet membrane endothelial keratoplasty (DMEK) may be an elegant solution for endothelial failure after penetrating keratoplasty (PK). However, it is currently unclear whether this approach comes with any long-term drawbacks concerning chronic endothelial cell loss, rebubbling rates, graft survival and severity of immune reactions. We therefore herein compare the outcomes of DMEK to repair failed PK to the outcomes of DMEK to repair failed DMEK grafts. Methods This retrospective study included 117 patients with DMEK after keratoplasty (82 following DMEK and 35 following PK). Postoperative visual acuity, endothelial cell count, rebubbling rates, graft survival and rejection rates were recorded. Kaplan-Meier-analysis was used to assess survival rates. Results Visual acuity improved, but stayed at a lower level in PK patients. Endothelial cell loss was more severe in patients with DMEK as an initial procedure, whereas rebubbling rates, graft failure and immune reactions did not differ significantly between both groups. Ratios of graft diameters of the first and second graft did not influence survival or rejection of the graft. Conclusions Repeat DMEK is an appropriate method of treating endothelial graft failure after both DMEK and PK. The higher endothelial cell loss in the DMEK-DMEK group may be due to a different recipient endothelial reservoir and assimilate in the long term follow-up. These data may encourage treating endothelial graft failure with DMEK even in PK eyes.

Purpose The Eye Drops for Early Morning-Associated Swelling (EDEMAS) trial assessed the efficacy of hyperosmolar eye drops on corneal edema resolution. Design Double-masked, randomized controlled trial of hyperosmolar eye drops. Participants Participants with Fuchs’ dystrophy scheduled for Descemet membrane endothelial keratoplasty. Methods One eye was randomized to hyperosmolar eye drops (treatment); the fellow eye was randomized to artificial tears (placebo). After baseline examination in the afternoon, corneas were examined using Scheimpflug tomography after eye opening in the morning. Participants received eye drops twice. Imaging was repeated every 30 minutes up to 4 hours. Main Outcome Measures Decrease in central corneal thickness 1 hour after eye opening (primary end point), corneal thickness, subjective visual function, glare, visual acuity, and adverse events (AEs) (secondary end points). Results A total of 68 participants received the allocated intervention (59 eyes received treatment; 55 eyes received placebo). All eyes had stromal edema; none had epithelial edema. Corneal thickness was 626 μm in the treatment arm and 622 μm in the placebo arm after eye opening, indicating an early morning edema compared with baseline of +21 μm and +24 μm, respectively. Decrease in corneal thickness after 1 hour was −10.5 μm in the treatment arm (95% confidence interval [CI], −12.8 to −8.2) and −11.2 μm (95% CI, −13.6 to −8.9) in the placebo arm (between-arm difference, 0.7 μm, 95% CI, −2.0 to 3.5; P = 0.59), indicating no clinically relevant effect of hyperosmolar eye drops on early morning corneal edema. Results were not compatible with a relevant treatment effect on corneal thickness, visual acuity, and glare over the entire course of the study. Increase in subjective visual function was less rapid in the treatment arm than in the placebo arm. Adverse events, most commonly burning after eye drop application, were more common with treatment (30 eyes) than placebo (1 eye; risk difference, 49 percentage points; 95% CI, 36–62). Conclusions In this double-masked, randomized controlled trial, resolution of early morning stromal edema was not accelerated by hyperosmolar eye drops, which more frequently caused AEs. These results are not compatible with a clinically relevant effect of hyperosmolar eye drops and do not support their routine use.

Gene expression analysis using RNA sequencing has helped to improve the understanding of many diseases. Databases, such as the Gene Expression Omnibus database of the National Center for Biotechnology Information provide RNA sequencing raw data from various diseased tissue types but their analysis requires advanced bioinformatics skills. Therefore, specific ocular databases provide the transcriptional profiles of different ocular tissues and in addition enable intuitive web-based data analysis.The aim of this narrative review is to provide an overview of ocular transcriptome databases and to compare them with the Human Eye Transcriptome Atlas newly established in Freiburg.PubMed literature search.A total of nine ocular transcriptome databases focusing on different aspects were identified. The iSyTE and Express platforms specialize in gene expression during lens and retinal development in mice, whereas retina.tigem.it, Eye in a Disk, and Spectacle focus on selected ocular tissues such as the retina. Spectacle, UCSC Cell Browser and Single Cell Portal allow intuitive exploration of single cell RNA sequencing data derived from retinal, choroid, cornea, iris, trabecular meshwork and sclera specimens. The microarray profiles of a variety of healthy ocular tissues are included in the Ocular Tissue Database. The Human Eye Transcriptome Atlas provides the largest collection of different ocular tissue types, contains the highest number of ocular diseases and is characterized by a high level of quality achieved by methodological consistency.Ocular transcriptome databases provide comprehensive and intuitive insights into the transcriptional profiles of a variety of healthy and diseased ocular tissues. Thus, they improve our understanding of the underlying molecular mediators, support hypothesis generation and help in the search for new diagnostic and therapeutic targets for various ocular diseases.HINTERGRUND: Die Entschlüsselung des Transkriptoms hat in den letzten Jahren unser Verständnis zahlreicher Erkrankungen verbessert. Öffentlich zugängliche Datenbanken, wie z. B. die Gene Expression Omnibus-Datenbank des National Center for Biotechnology Information, sammeln Transkriptomrohdaten aus einer Vielfalt von Proben, ohne jedoch dem bioinformatischen Laien einen intuitiven Zugang zu den Daten zu gewähren. Daher wurden in den vergangenen Jahren spezielle Transkriptomdatenbanken programmiert, die eine benutzerfreundliche Web-basierte Datenanalyse ermöglichen und damit niederschwellig molekulare Einblicke in okuläre Gewebe ermöglichen.Ziel dieser Arbeit ist es, einen Überblick über die aktuell verfügbaren okulären Transkriptomdatenbanken zu geben und diese mit dem in Freiburg neu etablierten Human Eye Transcriptome Atlas zu vergleichen.Literatursuche in PubMed.Neun okuläre Transkriptomdatenbanken mit unterschiedlichem Anwendungsschwerpunkt wurden identifiziert. Die Plattformen iSyTE und Express spezialisieren sich auf die Genexpression während der Linsen- und Netzhautentwicklung der Maus, wohingegen retina.tigem.it, Eye in a Disk und Spectacle ihren Fokus auf einzelne okuläre Gewebe wie die Netzhaut legen. Spectacle, UCSC Cell Browser und Single Cell Portal erlauben die intuitive Exploration von Einzelzell-RNA-Sequenzierungsdaten von Netzhaut‑, Aderhaut‑, Kornea‑, Iris‑, Trabekelmaschenwerk- und Skleragewebe. Die Microarray-Profile verschiedener gesunder okulärer Gewebe werden in der Ocular Tissue Database bereitgestellt. Der Human Eye Transcriptome Atlas erfasst derzeit die größte Vielfalt an Augengeweben und Erkrankungen des Auges. Er zeichnet sich durch einen hohen Qualitätsstandard aus, der durch methodische Homogenität erreicht wird.Okuläre Transkriptomdatenbanken bieten einen umfassenden und intuitiven Einblick in die Transkriptionsprofile verschiedener gesunder und erkrankter Augengewebe. So verbessern sie unser Verständnis der zugrunde liegenden molekularen Krankheitsprozesse, unterstützen die Hypothesengenerierung und helfen bei der Suche nach neuen diagnostischen und therapeutischen Zielen für verschiedene Augenerkrankungen.

Purpose Immune reactions following corneal transplantation are the most common cause of transplant failure. However, the underlying mechanisms of corneal graft rejection are not yet fully understood but increasing evidence points to a crucial role of the innate immune system in this context. Using a human in vitro model, we aimed to assess the response of human macrophages to stimulation with human corneal tissue and whether corneal endothelial cells (CEC) have immune-modulating properties. Methods Human monocytes were isolated from peripheral blood mononuclear cells and differentiated into monocyte-derived macrophages (MDM). A standardized protocol was used for disaggregation of human corneas into fragments of defined sizes. MDMs were stimulated using processed corneal material with or without CEC. Lipopolysaccharide (LPS) or interferon-gamma (IFNγ) served as controls. RNA sequencing was applied to analyze the impact of differential stimulation of MDMs on their transcriptional profile. RNA sequencing results were validated using digital PCR. Results The transcriptional profile of MDMs was significantly modulated by the type of stimulus used for MDM activation as well as by the individual MDM donor. LPS- or IFNγ-stimulation resulted in distinct transcriptional alterations compared to unstimulated MDMs including an upregulation of various cytokines such as CCL3, 4, 5, 19 or CXCL9. Corneal tissue induced the differential expression of 45 genes when compared to unstimulated MDMs, with several metallothioneins (MTs) among the upregulated factors (MT1A, MT1E, MT1F, MT1G, MT1H, MT1L, MT1M, MT1X, MT2A). This effect was independent of the presence or absence of CEC. PCR validation confirmed induction of 3 different metallothioneins (MT1G, MT1H and MT2A) in MDMs stimulated by corneal tissue. Conclusions The MDM in vitro model proved to be a robust tool to study the effects of LPS, IFNγ and corneal tissue homogenates on the transcriptional activity of MDM. Human macrophages showed a distinct upregulation of various MTs when challenged with human corneal allogen with or without corneal endothelium, which might have an immune-modulatory effect. As a general observation, it appears that in MDM-based studies a significant donor-dependent effect on the transcriptional profile of MDMs needs to be considered and adjusted before downstream analysis.

Zusammenfassung Hintergrund Die Keratoplastik zählt weltweit zu den am häufigsten durchgeführten Gewebetransplantationen. Traditionell entfiel die überwiegende Mehrheit der Eingriffe auf die perforierende Keratoplastik. Mit deren Weiterentwicklung in den vergangenen 15 Jahren gewann jedoch insbesondere die posteriore lamellierende Keratoplastik zur Behandlung der Fuchs-Endotheldystrophie sowie der bullösen Keratopathie zunehmend an Bedeutung. Basierend auf informellen Umfrageergebnissen wurde postuliert, dass sich auch in Deutschland ein Trend hin zur posterioren lamellierenden Keratoplastik abzeichnet. Ziel der Arbeit Anhand der Qualitätsberichte der Krankenhäuser sollte geprüft werden, ob der Anteil der lamellierenden Keratoplastik in Deutschland im Zeitraum 2006 bis 2017 zugenommen hat. Zudem sollte die Zahl der HLA-kompatibel (HLA: humanes Leukozytenantigen) durchgeführten Keratoplastiken ermittelt werden. Material und Methoden Die Operationszahlen der perforierend/lamellierend bzw. HLA-kompatibel durchgeführten Keratoplastiken wurden anhand der OPS-Ziffern aus den Krankenhausqualitätsberichten der Jahre 2006 bis einschließlich 2017 extrahiert. Die deskriptive statistische Auswertung erfolgte mit dem Softwarepaket R (www.r-project.org). Ergebnisse Von 2006 bis 2017 wurden deutschlandweit insgesamt 43 021 Keratoplastiken durchgeführt. Die Zahl der durchgeführten Keratoplastiken stieg von 2849 im Jahr 2006 auf 8231 im Jahr 2017. Die absolute Zahl perforierender Keratoplastiken blieb insgesamt konstant. Der relative Anteil lamellierender Keratoplastiken stieg von 6,5% (2006) auf 61,4% (2017) an. Die Zahl der HLA-kompatibel durchgeführten Keratoplastiken lag stets unter 20% und war ab 2010 rückläufig (2010: 19,7%; 2017: 9,8%). Diskussion Die posteriore lamellierende Keratoplastik hat auch in Deutschland stark an Stellenwert gewonnen und seit 2014 die perforierende Keratoplastik als häufigste Form der Keratoplastik abgelöst. Die perforierende Keratoplastik, deren absolute Zahl über den gesamten Untersuchungszeitraum insgesamt konstant blieb, hat jedoch nach wie vor einen hohen Stellenwert bei der Behandlung von vorwiegend stromalen oder durchgreifenden Hornhautdefekten. Der Anteil HLA-kompatibler Keratoplastiken hat vermutlich insbesondere vor dem Hintergrund fehlender eindeutiger Nachweise einer Verringerung der Abstoßungsraten in Standardsituationen in den letzten Jahren weiter abgenommen.

Zusammenfassung Hintergrund Für eine wissenschaftliche Auswertung von Arztbriefen bedarf es aufgrund unterschiedlicher Terminologien und dem häufigen Gebrauch von Synonymen der Transformation in ein normiertes Codesystem wie bspw. ICD-10 oder Alpha-ID. Das sog. „Word Vector Embedding“ erscheint für die Generierung des dafür erforderlichen Thesaurus geeignet, da hierüber – nach geeignetem Training des zugrunde liegenden neuronalen Netzwerkes – synonyme Diagnosen unabhängig von der Schreibweise automatisch identifiziert werden können. Methoden Es wurden alle Arztbriefe von insgesamt 50 000 Patienten anonymisiert extrahiert. Diagnosen, die aus mehreren Wörtern bestehen, wurden mittels Phrasenerkennung in Einzelwörter verschmolzen und das „word2vec“-Modell auf dem Textkorpus von 352 Megabytes trainiert. Insgesamt 3742 Diagnosen bzw. ophthalmologische Interventionen wurden aus den Arztbriefen halbautomatisch extrahiert. Die ophthalmologischen ICD- und Alpha-ID-Codes wurden zusammen mit den offiziellen Beschreibungen von der Website des DIMDI heruntergeladen und die ophthalmologischen Diagnosen/Interventionen aus den Arztbriefen mit den jeweils im „word2vec“-Modell nächstgelegenen ICD- und Alpha-ID-Codes automatisiert verknüpft. Ergebnisse Es wurden von „word2vec“-Modell 90% der Arztbriefdiagnosen den korrekten ICD-10-Codes zugeordnet. Auf Ebene der viel feiner aufgelösten Alpha-ID-Codes betrug die Quote korrekter Zuordnungen nur 76%. Die Interventionen wurden in 92% der korrekten Indikation zugewiesen. Als Fehlerquellen für inkorrekte oder fehlende Zuordnungen wurden seltene Erkrankungen, ungewöhnliche Bezeichnungen und Codedegeneration in der offiziellen DIMDI-Datei identifiziert. Diskussion Aus „Real-World“-Arztbriefen und der offiziellen Alpha-ID-Datei und lässt sich mit der „word2vec“-Methode ein Diagnosenthesaurus generieren. Dieser könnte, eine geringfügige manuelle Überarbeitung vorausgesetzt, zukünftig für eine automatische Extraktion von Diagnosen aus Arztbriefen verwendet werden.

Corneal transplantation is one of the most common forms of tissue transplantation worldwide. Donor corneal tissue used in transplantation is provided by eye banks, which store the tissue in culture medium after procurement. To date, the effects of cell culture on human corneal tissue have not been fully elucidated. Using the 3′ RNA sequencing method for massive analysis of cDNA ends (MACE), we show that cultivation of corneal tissue leads to significant changes in a variety of molecular processes in human corneal tissue that go well beyond aspects of previously known culture effects. Functionally grouped network analysis revealed nine major groups of biological processes that were affected by corneal organ culture, among them keratinization, hypoxia, and angiogenesis, with genes from each group being affected by culture time. A cell type deconvolution analysis revealed significant modulations of the corneal immune cell profile in a time dependent manner. The results suggest that current culture conditions should be further refined and that prolonged cultivation may be detrimental. Recently, we showed that MACE enables transcriptional profiling of formalin-fixed and paraffin-embedded (FFPE) conjunctival tissue with high accuracy even after more than 10 years of storage. Here we demonstrate that MACE provides comparable results for native and FFPE corneal tissue, confirming that the technology is suitable for transcriptome analysis of a wide range of archived diseased corneal samples stored in histological archives. Finally, our data underscore the feasibility of bioinformatics cell-type enrichment analysis in bulk RNA-seq data to profile immune cell composition in fixed and archived corneal tissue samples, for which RNA-seq analysis of individual cells is often not possible.

With a worldwide prevalence of ~12%, pterygium is a common degenerative and environmentally triggered ocular surface disorder characterized by wing-shaped growth of conjunctival tissue onto the cornea that can lead to blindness if left untreated. This study characterizes the transcriptional profile and the cellular microenvironment of conjunctival pterygia and identifies novel pterygia-specific biomarkers. Formalin-fixed and paraffin-embedded pterygia as well as healthy conjunctival specimens were analyzed using MACE RNA sequencing (n = 8 each) and immunohistochemistry (pterygia n = 7, control n = 3). According to the bioinformatic cell type enrichment analysis using xCell, the cellular microenvironment of pterygia was characterized by an enrichment of myofibroblasts, T-lymphocytes and various antigen-presenting cells, including dendritic cells and macrophages. Differentially expressed genes that were increased in pterygia compared to control tissue were mainly involved in autophagy (including DCN, TMBIM6), cellular response to stress (including TPT1, DDX5) as well as fibroblast proliferation and epithelial to mesenchymal transition (including CTNNB1, TGFBR1, and FN1). Immunohistochemical analysis confirmed a significantly increased FN1 stromal immunoreactivity in pterygia when compared to control tissue. In addition, a variety of factors involved in apoptosis were significantly downregulated in pterygia, including LCN2, CTSD, and NISCH. Furthermore, 450 pterygia-specific biomarkers were identified by including transcriptional data of different ocular surface pathologies serving as controls (training group), which were then validated using transcriptional data of cultured human pterygium cells. Among the most pterygia-specific factors were transcripts such as AHNAK, RTN4, TPT1, FSTL1, and SPARC. Immunohistochemical validation of SPARC revealed a significantly increased stromal immunoreactivity in pterygia when compared to controls, most notably in vessels and intravascular vessel wall-adherent mononuclear cells. Taken together, the present study provides new insights into the cellular microenvironment and the transcriptional profile of pterygia, identifies new and specific biomarkers and in addition to fibrosis-related genes, uncovers autophagy, stress response and apoptosis modulation as pterygium-associated processes. These findings expand our understanding of the pathophysiology of pterygia, provide new diagnostic tools, and may enable new targeted therapeutic options for this common and sight-threatening ocular surface disease.

PURPOSE The posterior cornea is rotationally asymmetric, and Descemet membrane endothelial keratoplasty (DMEK) grafts preferentially scroll vertically. This prospective study assessed whether graft attachment after DMEK differed depending on the rotational alignment of the donor graft in the recipient eye. METHODS Pseudo-randomization and blinding of the graft orientation in the recipient's eye were possible by procedural separation: (1) The eye bank recorded the position of an orientation marker in the donor cornea; (2) the surgeon preparing the DMEK graft recorded an upside-down marker relative to the eye bank marker; and (3) the surgeon assessed the position of the upside-down marker in the recipient after DMEK. Surgeons were masked towards the eye bank marker. Using mixed-effects models, we assessed graft attachment relative to the rotational alignment of the donor graft. RESULTS Postoperatively, the graft was not fully attached in 59 of 179 eyes (33%). A second air fill (rebubbling) was performed in 11%. The graft axis was in line with the recipient cornea axis in 40%, oblique in 28% and orthogonal in 32%. We did not detect an elevated risk of incomplete attachment (odds ratio [OR], 1.16; 95% CI, 0.61-2.20), risk of rebubbling (OR, 1.25; 95% CI, 0.47-3.31) or larger areas of graft detachment in non-aligned grafts compared to aligned grafts. CONCLUSION Rotational alignment was not strongly associated with the risk of incomplete graft attachment, although modestly elevated risks cannot be ruled out. Efforts are needed to reduce the need for rebubbling after DMEK and to identify modifiable risk factors for graft detachment.

The applications of deep sequencing technologies in life science research and clinical diagnostics have increased rapidly over the last decade. Although fast algorithms for data processing exist, intuitive, portable solutions for data analysis are still rare. For this purpose, we developed a web-based transcriptome database, which provides a platform-independent, intuitive solution to easily explore and compare ocular gene expression of 100 diseased and healthy human tissue samples from 15 different tissue types collected at the Eye Center of the University of Freiburg. To ensure comparability of expression between different tissues, reads were normalized across all 100 samples. Differentially expressed genes were calculated between each tissue type to determine tissue-specific genes. Unsupervised analysis of all 100 samples revealed an accurate clustering according to different tissue types. Cluster analysis based on known cell type-specific marker genes allowed differentiation of respective tissues. Several tissue-specific marker genes were identified. These genes were involved in tissue- or disease-specific processes, such as myelination for the optic nerve, visual perception for retina, keratinocyte differentiation for conjunctival carcinoma, as well as endothelial cell migration for choroidal neovascularization membranes. The results are accessible at the Human Eye Transcriptome Atlas website at https://www.eye-transcriptome.com. In summary, this searchable transcriptome database enables easy exploration of ocular gene expression in healthy and diseased human ocular tissues without bioinformatics expertise. Thus, it provides rapid access to detailed insights into the molecular mechanisms of various ocular tissues and diseases, as well as the rapid retrieval of potential new diagnostic and therapeutic targets.

The Eye Drops for Early Morning-Associated Swelling (EDEMAS) trial assessed the efficacy of hyperosmolar eye drops on corneal edema resolution.Double-masked, randomized controlled trial of hyperosmolar eye drops.Participants with Fuchs' dystrophy scheduled for Descemet membrane endothelial keratoplasty.One eye was randomized to hyperosmolar eye drops (treatment); the fellow eye was randomized to artificial tears (placebo). After baseline examination in the afternoon, corneas were examined using Scheimpflug tomography after eye opening in the morning. Participants received eye drops twice. Imaging was repeated every 30 minutes up to 4 hours.Decrease in central corneal thickness 1 hour after eye opening (primary end point), corneal thickness, subjective visual function, glare, visual acuity, and adverse events (AEs) (secondary end points).A total of 68 participants received the allocated intervention (59 eyes received treatment; 55 eyes received placebo). All eyes had stromal edema; none had epithelial edema. Corneal thickness was 626 μm in the treatment arm and 622 μm in the placebo arm after eye opening, indicating an early morning edema compared with baseline of +21 μm and +24 μm, respectively. Decrease in corneal thickness after 1 hour was -10.5 μm in the treatment arm (95% confidence interval [CI], -12.8 to -8.2) and -11.2 μm (95% CI, -13.6 to -8.9) in the placebo arm (between-arm difference, 0.7 μm, 95% CI, -2.0 to 3.5; P = 0.59), indicating no clinically relevant effect of hyperosmolar eye drops on early morning corneal edema. Results were not compatible with a relevant treatment effect on corneal thickness, visual acuity, and glare over the entire course of the study. Increase in subjective visual function was less rapid in the treatment arm than in the placebo arm. Adverse events, most commonly burning after eye drop application, were more common with treatment (30 eyes) than placebo (1 eye; risk difference, 49 percentage points; 95% CI, 36-62).In this double-masked, randomized controlled trial, resolution of early morning stromal edema was not accelerated by hyperosmolar eye drops, which more frequently caused AEs. These results are not compatible with a clinically relevant effect of hyperosmolar eye drops and do not support their routine use.

Recent studies have described conjunctivitis in approximately 1% of COVID-19 patients and speculated that SARS-CoV‑2 can be transmitted via the conjunctiva. In this article we recapitulate the molecular mechanisms of host cell entry of SARS-CoV‑2 and discuss the current evidence for a potential conjunctival transmission of SARS-CoV‑2. The current body of evidence indicates that SARS-CoV‑2 requires the membrane-bound angiotensin-converting enzyme 2 (ACE2) and the membrane-bound serine protease TMPRSS2 to enter cells. Recent studies suggest that COVID-19 patients rarely exhibit viral RNA in tear film and conjunctival smears and that, ACE2 and TMPRSS2 are only expressed in small amounts in the conjunctiva, making conjunctival infection with SARS-CoV‑2 via these mediators unlikely. Nevertheless, we consider the current evidence to be still too limited to provide a conclusive statement and recommend appropriate protective measures for healthcare personnel who are in close contact with suspected and confirmed COVID-19 patients.Aktuelle Studien haben bei ca. 1 % aller COVID-19-Patienten eine Bindehautentzündung beschrieben und spekuliert, dass SARS-CoV‑2 über die Bindehaut übertragen werden kann. In der vorliegenden Arbeit rekapitulieren wir die molekularen Mechanismen des Eintritts von SARS-CoV‑2 in die Wirtszelle und diskutieren die aktuelle Studienlage zu einer möglichen konjunktivalen Transmission. Derzeit geht man davon aus, dass SARS-CoV‑2 das membrangebundene Angiotensin-konvertierende Enzym 2 (ACE2) sowie die Membran-gebundene Serinprotease TMPRSS2 benötigt, um in die Wirtszelle einzudringen. Aktuelle Studien weisen darauf hin, dass COVID-19-Patienten nur selten Virus-RNA im Tränenfilm und Bindehautabstrichen aufweisen und dass ACE2 und TMPRSS2 in der Bindehaut nur in sehr geringen Mengen gebildet werden, was eine konjunktivale Infektion durch SARS-CoV‑2 über diese Mediatoren wenig wahrscheinlich macht. Dennoch halten wir die derzeitige Studienlage für zu begrenzt, um eine abschließende Aussage treffen zu können, und empfehlen konsequente und adäquate Schutzmaßnahmen für medizinisches Personal, das in engem Kontakt mit verdächtigen und bestätigten COVID-19-Patienten steht.

Recent advances in the field of biomedical research allow for elucidation of the transcriptional signature of rare tumors such as conjunctival squamous cell carcinoma (SCC). In this study we compare its expression profile to conjunctival papilloma (Pap) and healthy conjunctival tissue (Ctrl) and develop a classification tool to differentiate these entities. Seven conjunctival SCC, seven Pap and ten Ctrl were formalin-fixed and paraffin-embedded (FFPE) and analyzed using Massive Analysis of cDNA Ends (MACE) RNA sequencing. Differentially expressed genes (DEG) and gene ontology (GO) clusters were explored and the abundance of involved cell types was quantified by xCell. Finally, a classification model was developed to distinguish SCC from Pap and Ctrl. Among the most prominent DEG in SCC a plethora of keratins were upregulated when compared to Pap and Ctrl. xCell analysis revealed an enrichment of immune cells, including activated dendritic cells and T-helper type 1 cells (Th1), in SCC when compared to Ctrl. The generated classification model could reliably discriminate between the three entities according to the expression pattern of 30 factors. This study provides a transcriptome-wide gene expression profile of rare conjunctival SCC. The analysis identifies distinct keratins, as well as dendritic and Th1 cells as important mediators in SCC. Finally, the provided gene expression classifier may become an aid to the conventional histological classification of conjunctival tumors in uncertain cases.

Purpose: To investigate immunological differences and the role of CD38+/F4/80 + M1 macrophages in C57BL/6J- and BALB/c-recipient mouse corneal transplantation models. Methods: Allogeneic transplantation was performed crosswise in BALB/c mice and C57BL/6J mice; syngeneic transplantation was performed in both strains. Anterior chamber depth (ACD) was measured before and central corneal thickness (CCT) was measured both before and after transplantation. In vivo graft rejection was monitored using anterior eye segment optical coherence tomography (ASOCT) evaluating the CCT and grading of corneal oedema using a well-established clinical score (CS). Histology of corneal grafts was performed 18 or 21 days after surgery. Immunohistochemistry with anti-F4/80 antibody and anti-CD38 antibody was used for detecting M1 macrophages within the grafts. Results: High CS and CCT values after allogeneic transplantation persisted in both BALB/c (n = 18) and C57BL/6J recipients (n = 20). After syngeneic transplantation, CS and CCT values increased in both models in the early phase after surgery due to the surgical trauma. Surprisingly, in the syngeneic C57BL/6J model, high CCT values persisted. Furthermore, anterior synechiae developed in C57BL/6 recipients after both syngeneic and allogeneic transplantation, whereas BALB/c recipients showed almost no synechiae – even though C57/BL6J animals tended to have a deeper anterior chamber (281 ± 11 pixels [mean ± SD]) compared with BALB/c animals of the same age (270 ± 9 pixels [mean ± SD]). Immunohistochemistry revealed numerous CD38+/F4/80 + M1 macrophages in grafts of C57BL/6J recipients following both syngeneic and allogeneic transplantation. However, in BALB/c-recipient mice only sparse M1 macrophages were detectable (CD38 + M1 macrophages relative to all F4/80 + cells: 75 vs. 17% [after allogeneic transplantation] and 66 vs. 17% [after syngeneic transplantation]; p < 0.05). Conclusions: Allogeneic corneal transplants are rejected in BALB/c as well as C57BL/6J mice, but tissue alterations with anterior synechiae are more pronounced in C57BL/6J recipients. Following syngeneic transplantation, C57BL/6J-recipient animals show a persistent graft swelling with increased numbers of CD38+/F4/80 + M1 macrophages in grafted tissue, in contrast to the common model using BALB/c-recipient mice. Our data strongly suggest that strain-dependent differences convey different innate immune responses in BALB/c and C57BL/6J strains. Accordingly, in murine keratoplasty experiments, the mouse line of both donor and recipient animals must be carefully considered. C57BL/6J-recipient mice might be particularly suited to study corneal graft rejection in a clinical setting considered “high risk.”

ZusammenfassungAktuelle Studien haben bei ca. 1 % aller COVID-19-Patienten eine Bindehautentzündung beschrieben und spekuliert, dass SARS-CoV‑2 über die Bindehaut übertragen werden kann. In der vorliegenden Arbeit rekapitulieren wir die molekularen Mechanismen des Eintritts von SARS-CoV‑2 in die Wirtszelle und diskutieren die aktuelle Studienlage zu einer möglichen konjunktivalen Transmission. Derzeit geht man davon aus, dass SARS-CoV‑2 das membrangebundene Angiotensin-konvertierende Enzym 2 (ACE2) sowie die Membran-gebundene Serinprotease TMPRSS2 benötigt, um in die Wirtszelle einzudringen. Aktuelle Studien weisen darauf hin, dass COVID-19-Patienten nur sehr selten Virus-RNA im Tränenfilm und Bindehautabstrichen aufweisen und dass ACE2 und TMPRSS2 in der Bindehaut nur in sehr geringen Mengen gebildet werden, was eine konjunktivale Infektion durch SARS-CoV‑2 über diese Mediatoren wenig wahrscheinlich macht. Dennoch halten wir die derzeitige Studienlage für zu begrenzt, um eine abschließende Aussage treffen zu können, und empfehlen konsequente und adäquate Schutzmaßnahmen für medizinisches Personal, das in engem Kontakt mit verdächtigen und bestätigten COVID-19-Patienten steht.

SARS-CoV-2 is assumed to use angiotensin-converting enzyme 2 (ACE2) and other auxiliary proteins for cell entry. Recent studies have described conjunctival congestion in 0.8% of patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and there has been speculation that SARS-CoV-2 can be transmitted through the conjunctiva. However, it is currently unclear whether conjunctival epithelial cells express ACE2 and its cofactors. In this study, a total of 38 conjunctival samples from 38 patients, including 12 healthy conjunctivas, 12 melanomas, seven squamous cell carcinomas, and seven papilloma samples, were analyzed using high-throughput RNA sequencing to assess messenger RNA (mRNA) expression of the SARS-CoV-2 receptor ACE2 and its cofactors including TMPRSS2, ANPEP, DPP4, and ENPEP. ACE2 protein expression was assessed in eight healthy conjunctival samples using immunohistochemistry. Our results show that the SARS-CoV-2 receptor ACE2 is not substantially expressed in conjunctival samples on the mRNA (median: 0.0 transcripts per million [TPM], min: 0.0 TPM, max: 1.7 TPM) and protein levels. Similar results were obtained for the transcription of other auxiliary molecules. In conclusion, this study finds no evidence for a significant expression of ACE2 and its auxiliary mediators for cell entry in conjunctival samples, making conjunctival infection with SARS-CoV-2 via these mediators unlikely.

Purpose It is unclear which patients unexpectedly have a hyperopic refractive outcome after combined Descemet membrane endothelial keratoplasty and cataract surgery (triple DMEK). We assessed how corneal shape predicts hyperopia after triple DMEK. Design Retrospective cohort study. Methods Patients with Fuchs endothelial corneal dystrophy (FECD) with Scheimpflug examinations before uncomplicated triple DMEK at a tertiary referral center were included. The arithmetic error was calculated (stable postoperative refraction minus predicted refraction). Using multinomial logistic regression, risk ratios of > +0.5 diopter (D) hyperopic and > 0.5 D myopic arithmetic errors were calculated. Results In 112 eyes, the median predicted refraction was −0.43 D (interquartile range [IQR], −0.47 to −0.17) with an achieved refraction of −0.63 to 0.56 (IQR). The arithmetic error was 0.34 D (IQR, −0.22 to 0.81). A hyperopic arithmetic error was present in 46% of eyes. FECD eyes with an oblate posterior cornea (Q value >0) had a 3.0 times higher risk of hyperopic shift after triple DMEK (95% confidence interval [CI], 1.3–7.0; P = .011), compared to spherical or prolate corneas (Q value ≤ 0). In eyes with posterior Q > 0, the mean prediction error was +0.50 D higher than in eyes with negative Q values (95% CI, 0.19–0.82; P = .002), independent of corneal thickness. Conclusions Hyperopic surprises after triple DMEK particularly occur in corneas that are flatter centrally than the periphery because of edematous changes (oblate posterior profile). Eyes with a positive Q value on Scheimpflug imaging should be considered for additional power at the intraocular lens level.

PURPOSE Descemet membrane endothelial keratoplasty (DMEK) seems to be the most promising technique for treating endothelium-related disorders of the cornea. However, graft detachment is a frequent complication. It often can be treated by rebubbling procedures. Unfortunately, this increases the risk of subsequent graft failure. It is therefore essential to define risk factors for graft detachment in DMEK. In this study, postoperative intraocular pressure (IOP) is investigated in this regard. METHODS In total, 1047 DMEK procedures in patients with Fuchs endothelial dystrophy or bullous keratopathy were reviewed. All rebubbling procedures were recorded as well as postoperative IOP values (first measure 2 hours postoperatively and highest and lowest value within 3 days after surgery), donor factors (donor age, organ culture time, and endothelial cell count), and whether DMEK surgery had been combined with cataract surgery (triple-DMEK). Incidence rates were estimated with the Kaplan-Meier method. Cox regression was used to assess statistical significance. RESULTS The overall rebubbling rate was 24% after 8 weeks. Relative dips in IOP may be associated with a higher risk for graft detachment (hazards ratio = 0.41; P < 0.001). Graft detachment was neither significantly influenced by donor factors, first or maximum IOP, nor by simultaneous cataract surgery (triple-DMEK). CONCLUSIONS Avoiding dips in IOP may reduce the risk for graft detachment after DMEK. To prevent lowering of IOP values in the early postsurgical period, it may be advisable to achieve tight surgical wounds at the end of DMEK surgery and optimal filling of the anterior chamber with air and optionally with gas.

ZusammenfassungDie homologe Limbokeratoplastik (Limbo-KP) wurde initial zur Behandlung von Formen schwerer Limbusinsuffizienz etabliert, um nach Transplantation einen vollständigen und dauerhaften Epithelschluss im Bereich der Hornhaut zu gewährleisten. Nach Erweiterung des Indikationsspektrums kommt die Limbo-KP mittlerweile auch bei epithelialen/stromalen Hornhautdystrophien wie der gittrigen und der granulären Hornhautdystrophie (die mit einer Mutation im TGFBI-Gen [TGFBI: transforming growth factor beta-induced] assoziiert sind) zum Einsatz. Ziel der Limbo-KP hierbei ist es, ein klares Transplantatüberleben ohne Rezidiv der Dystrophie im Transplantat zu erreichen, da es nach konventioneller Keratoplastik stets zu Rezidiven und einer damit einhergehenden Visusminderung kommt.

Chemokine sind chemotaktisch wirksame Zytokine, die einerseits die Verteilung von Immunzellen im Korper koordinieren und andererseits die Migration von Leukozyten bei malignen und inflammatorischen Prozessen regulieren. Bei den Chemokinen handelt es sich um eine heterogene Gruppe kurzkettiger Proteine, die anhand ihrer Struktur in verschiedene Untergruppen eingeteilt werden. Neben den Chemokinen (Liganden) existieren verschiedene Chemokinrezeptoren. Komplexitat erhalt das Chemokinsystem aufgrund einer hohen Redundanz bei den Liganden-Rezeptoren-Interaktionen: Ein Ligand kann an verschiedene Rezeptoren binden – ein Rezeptor kann mit verschiedenen Liganden interagieren. Bezuglich der Rezeptoren weisen unterschiedliche Immunzellen ein charakteristisches Rezeptorexpressionsmuster auf, das u. a. fur eine immunologische Charakterisierung von Leukozyten genutzt werden kann. Wichtige Arbeiten in den Grundlagenwissenschaften fuhren zu einem besseren Verstandnis fur das Chemokinsystem. Vermehrt wird auch eine essenzielle Bedeutung des Chemokinsystems bei verschiedenen Erkrankungen des vorderen und hinteren Augenabschnitts ersichtlich. Die nachfolgende Ubersicht beleuchtet einzelne klinische Aspekte und grundlegende wissenschaftliche Arbeiten im Kontext der „Chemokine in der Augenheilkunde“.

Atopic dermatitis (AD) is a systemic inflammatory disease, which is characterized by pronounced eczema and pruritus. In addition to the involvement of the entire integument, the periocular lid skin and the surface of the eye are frequently involved. Ocular involvement may occur solely without dermatitis of facial or body skin. Pathophysiologically, besides a dysregulated immune response, genetic changes can occur in various dermal structural proteins which will lead to a disturbed skin barrier. Furthermore, there is a regular colonization with bacterial pathogens and an increased susceptibility for viral skin infections. The lid margin reveals a loss of Meibomian glands whereas the conjunctiva shows reduced goblet cells. Consecutively, eye surface defects and recurrent conjunctival and corneal defects can be found. Increased mechanical manipulation in atopia-associated pruritus is seen as a cause of increased comorbidity with keratoconus. In addition, individual cases are reported of various malignomas of the eye surface, which are present in patients with AD. Understanding of the pathophysiological connections is essential for the correct diagnosis and therapy of this clinically very complex disease picture.

Keratoplasty is considered the most frequently performed type of transplantation in humans. Traditionally, penetrating keratoplasty has been the most common procedure. However, over the last 15 years, the importance of posterior lamellar keratoplasty has increased for the treatment of Fuchs endothelial dystrophy and bullous keratopathy. In Germany, based on national surveys, it was suggested that there was a trend towards lamellar keratoplasty.The main objective of this study was to determine whether the proportion of lamellar keratoplasties carried out in Germany between 2006 and 2017 had increased. Furthermore, the number of keratoplasties carried out as HLA-matched (HLA: human leukocyte antigen) keratoplasties should be calculated.The numbers of all keratoplasties carried out as lamellar/penetrating and HLA-matched keratoplasties was extracted from the hospital quality reports published between 2006 and 2017. Descriptive statistical analysis was carried out in R (www.r-project.org).Between 2006 and 2017, 43,021 keratoplasties were carried out in Germany. The number of keratoplasties increased from 2,849 (2006) to 8,231 (2017). The number of penetrating keratoplasties remained stable. The proportion of lamellar keratoplasties increased from 6.5% (2006) to 61.4% (2017). The proportion of HLA-matched keratoplasties was below 20% and declined between 2010 and 2017 (2010: 19.7%; 2017: 9.8%).In Germany, posterior lamellar keratoplasty has become increasingly important. Since 2014, the number of lamellar keratoplasties has exceeded the number of penetrating keratoplasties. However, the number of penetrating keratoplasties remained stable between 2006 and 2017 and still plays an important role in the management of patients with predominantly stromal or corneal defects affecting all layers. The decreasing number of HLA-matched keratoplasties is most likely due to the lack of clear evidence of a significant reduction in the rejection rates in cases of normal risk keratoplasty.Die Keratoplastik zählt weltweit zu den am häufigsten durchgeführten Gewebetransplantationen. Traditionell entfiel die überwiegende Mehrheit der Eingriffe auf die perforierende Keratoplastik. Mit deren Weiterentwicklung in den vergangenen 15 Jahren gewann jedoch insbesondere die posteriore lamellierende Keratoplastik zur Behandlung der Fuchs-Endotheldystrophie sowie der bullösen Keratopathie zunehmend an Bedeutung. Basierend auf informellen Umfrageergebnissen wurde postuliert, dass sich auch in Deutschland ein Trend hin zur posterioren lamellierenden Keratoplastik abzeichnet.Anhand der Qualitätsberichte der Krankenhäuser sollte geprüft werden, ob der Anteil der lamellierenden Keratoplastik in Deutschland im Zeitraum 2006 bis 2017 zugenommen hat. Zudem sollte die Zahl der HLA-kompatibel (HLA: humanes Leukozytenantigen) durchgeführten Keratoplastiken ermittelt werden.Die Operationszahlen der perforierend/lamellierend bzw. HLA-kompatibel durchgeführten Keratoplastiken wurden anhand der OPS-Ziffern aus den Krankenhausqualitätsberichten der Jahre 2006 bis einschließlich 2017 extrahiert. Die deskriptive statistische Auswertung erfolgte mit dem Softwarepaket R (www.r-project.org).Von 2006 bis 2017 wurden deutschlandweit insgesamt 43 021 Keratoplastiken durchgeführt. Die Zahl der durchgeführten Keratoplastiken stieg von 2849 im Jahr 2006 auf 8231 im Jahr 2017. Die absolute Zahl perforierender Keratoplastiken blieb insgesamt konstant. Der relative Anteil lamellierender Keratoplastiken stieg von 6,5% (2006) auf 61,4% (2017) an. Die Zahl der HLA-kompatibel durchgeführten Keratoplastiken lag stets unter 20% und war ab 2010 rückläufig (2010: 19,7%; 2017: 9,8%).Die posteriore lamellierende Keratoplastik hat auch in Deutschland stark an Stellenwert gewonnen und seit 2014 die perforierende Keratoplastik als häufigste Form der Keratoplastik abgelöst. Die perforierende Keratoplastik, deren absolute Zahl über den gesamten Untersuchungszeitraum insgesamt konstant blieb, hat jedoch nach wie vor einen hohen Stellenwert bei der Behandlung von vorwiegend stromalen oder durchgreifenden Hornhautdefekten. Der Anteil HLA-kompatibler Keratoplastiken hat vermutlich insbesondere vor dem Hintergrund fehlender eindeutiger Nachweise einer Verringerung der Abstoßungsraten in Standardsituationen in den letzten Jahren weiter abgenommen.

Transformation into a standardised code system such as ICD-10 or Alpha-ID is required before medical reports can be scientifically analysed. This is due to the use of different terminologies and the frequent use of synonyms. The so-called "word vector embedding" seems to be suitable for the generation of the required thesaurus, because synonymous diagnoses can be identified independently of the spelling - after suitable training of the underlying neural network.All letters from a total of 50,000 patients were extracted anonymously. Diagnoses consisting of several words were merged into single words by means of phrase recognition and the "word2vec" model was trained on the text corpus of 352 megabytes. A total of 3742 diagnoses and ophthalmological interventions were extracted semi-automatically. The ophthalmological ICD and Alpha-ID codes were downloaded together with the official descriptions from the DIMDI website and the ophthalmological diagnoses/interventions were automatically linked with the nearest ICD- and Alpha-ID codes in the "word2vec" model.The "word2vec" model assigned 90% of the doctor's letter diagnoses correctly to appropriate ICD-10 codes. At the finer level of Alpha-ID, the rate of correct assignments was only 76%. The interventions were assigned to the correct indication in 92% of cases. Rare diseases, unusual designations and code degeneration in the official DIMDI file were identified as sources of error for incorrect or missing allocations.A diagnostic thesaurus can be generated with the "word2vec" method from a corpus of anonymised medical reports and the official Alpha-ID file from the DIMDI website. This thesaurus could be used for automatic extraction of diagnoses from doctor's letters in the future, given appropriate manual revision.Für eine wissenschaftliche Auswertung von Arztbriefen bedarf es aufgrund unterschiedlicher Terminologien und dem häufigen Gebrauch von Synonymen der Transformation in ein normiertes Codesystem wie bspw. ICD-10 oder Alpha-ID. Das sog. „Word Vector Embedding“ erscheint für die Generierung des dafür erforderlichen Thesaurus geeignet, da hierüber – nach geeignetem Training des zugrunde liegenden neuronalen Netzwerkes – synonyme Diagnosen unabhängig von der Schreibweise automatisch identifiziert werden können.Es wurden alle Arztbriefe von insgesamt 50 000 Patienten anonymisiert extrahiert. Diagnosen, die aus mehreren Wörtern bestehen, wurden mittels Phrasenerkennung in Einzelwörter verschmolzen und das „word2vec“-Modell auf dem Textkorpus von 352 Megabytes trainiert. Insgesamt 3742 Diagnosen bzw. ophthalmologische Interventionen wurden aus den Arztbriefen halbautomatisch extrahiert. Die ophthalmologischen ICD- und Alpha-ID-Codes wurden zusammen mit den offiziellen Beschreibungen von der Website des DIMDI heruntergeladen und die ophthalmologischen Diagnosen/Interventionen aus den Arztbriefen mit den jeweils im „word2vec“-Modell nächstgelegenen ICD- und Alpha-ID-Codes automatisiert verknüpft.Es wurden von „word2vec“-Modell 90% der Arztbriefdiagnosen den korrekten ICD-10-Codes zugeordnet. Auf Ebene der viel feiner aufgelösten Alpha-ID-Codes betrug die Quote korrekter Zuordnungen nur 76%. Die Interventionen wurden in 92% der korrekten Indikation zugewiesen. Als Fehlerquellen für inkorrekte oder fehlende Zuordnungen wurden seltene Erkrankungen, ungewöhnliche Bezeichnungen und Codedegeneration in der offiziellen DIMDI-Datei identifiziert.Aus „Real-World“-Arztbriefen und der offiziellen Alpha-ID-Datei und lässt sich mit der „word2vec“-Methode ein Diagnosenthesaurus generieren. Dieser könnte, eine geringfügige manuelle Überarbeitung vorausgesetzt, zukünftig für eine automatische Extraktion von Diagnosen aus Arztbriefen verwendet werden.

Purpose The extent of diurnal variation in corneal edema in Fuchs dystrophy is unknown. We measured corneal thickness and posterior profile over the course of the day using Scheimpflug imaging. Design Prospective cohort study. Methods Participants with clinically advanced Fuchs dystrophy eyes undergoing endothelial keratoplasty and participants with healthy corneas were assessed around noon the day before surgery and late afternoon, in presumed steady state. After controlled overnight patching to standardize eyelid closure, participants were assessed immediately upon eye opening in hospital the morning of surgery. Results Directly upon awakening, patients had mean corneal thickness of 663 μm (interquartile range [IQR], 625-707) in Fuchs dystrophy (n = 44) and controls (n = 11) had thickness of 557 μm (IQR, 527-601). In control corneas, there were no systematic changes with time. In Fuchs dystrophy eyes, corneal thickness decreased after awakening. Ninety-five percent of patients can be expected to have a decrease in corneal thickness over the first 4 hours after awakening between 31 μm and 58 μm (95% prediction interval). Posterior Q decreased on average by 0.15 (95% confidence interval [CI], 0.07-0.23) and posterior radius of curvature decreased by 0.20 mm (95% CI, 0.14-0.27) over the first 4 hours, indicating that edema resolution steepened the central posterior cornea. Beyond 4 hours after awakening, corneas no longer changed considerably in Fuchs dystrophy. Conclusion Impaired hydration control in clinically advanced Fuchs dystrophy makes measurements of key corneal parameters unreliable directly after eye opening. Beyond the first hours after eye opening, corneal thickness measurements are unlikely to vary more in Fuchs dystrophy eyes than in normal eyes.

Importance Predicting the extent of corneal edema resolution after Descemet membrane endothelial keratoplasty (DMEK) may help in preoperative decision-making by identifying patients who may benefit from restoring endothelial function. Objective To develop and validate a predictive model for edema resolution after DMEK using Scheimpflug tomographic imaging. Design, setting, and participants Two prospective studies recruited participants with advanced Fuchs dystrophy at a university-based tertiary referral center between July 1, 2017, and August 31, 2019. Analyses were designed in November 2019 and completed on June 30, 2020. Development of a predictive model using linear least absolute shrinkage and selection operator regression was conducted in a derivation cohort (100 eyes). Overall performance, discrimination, and calibration were tested in the separate validation cohort (32 eyes). Exposures Preoperative Scheimpflug parameters and patient-reported visual disability were considered as potential predictors of edema resolution: (1) tomographic features (irregularity of lines of equal corneal thickness, displacement of the thinnest point of corneal thickness from the inferior-temporal quadrant, and absolute amount of focal posterior corneal depression), (2) standardized anterior and posterior corneal backscatter, (3) preoperative central corneal thickness, and (4) Fuchs dystrophy-specific visual disability. Main outcomes and measures Decrease in central corneal thickness after DMEK indicative of edema resolution. Results Of the 88 patients included in the analysis, 54 were women (61%); median age was 68 years (interquartile range [IQR], 59-76 years). A median of 13 months after DMEK (IQR, 9-16 months), median corneal thickness was 77 μm lower (IQR, 51-94 μm) in the derivation cohort and 75 μm lower in the validation cohort (IQR, 54-96 μm) than before surgery. Per 10-μm edema resolution, eyes gained 0.66 Early Treatment Diabetic Retinopathy Study letters (95% CI, 0.09-1.23) in best-corrected visual acuity. Three tomographic features were present in 68 of 100 eyes (68%) in the derivation cohort and in 18 of 32 eyes (56%) in the validation cohort before DMEK and in only 1 of 132 eyes (1%) after DMEK. To predict edema resolution after DMEK based on preoperative assessment, 5 variables were selected by the statistical learning algorithm: nonparallel isopachs, focal posterior depression, anterior and posterior corneal backscatter, and central corneal thickness. In the separate validation cohort, the model showed high overall performance, discrimination, and calibration. Conclusions and relevance These post hoc analyses of prospective cohorts support a model for use in the prediction of edema resolution after DMEK using Scheimpflug measurement to identify patients benefitting most from DMEK.

Descemet membrane endothelial keratoplasty (DMEK) is superior to penetrating keratoplasty (PK) in terms of visual rehabilitation, intraoperative safety and risk of rejection. Therefore, it seems reasonable to perform DMEK in eyes with endothelial failure following PK. We herein report our first clinical results. Nineteen eyes with endothelial graft failure following PK were treated with DMEK. The majority of these eyes (12) had limited visual potential. The major indication for DMEK was pain relief in patients with bullous keratopathy. Visual acuity (VA), central corneal thickness (CCT), rate of graft dislocations, graft survival, graft rejections and other complications were extracted from the medical records. Although comorbidities limiting VA were present in 12 of the 19 eyes, VA increased from 0.05 to 0.1 (median) in 16 eyes. CCT decreased substantially (range 63–363 μm). Rebubbling was necessary in five eyes with incomplete graft adherence. There were two immunologic graft reactions and three graft failures. No major complications like endophthalmitis or expulsive bleeding occurred. DMEK is feasible to treat endothelial graft failure following PK. This is even true for eyes with limited visual potential.

Die Augeninnendruck(IOD)-Messwerte nach Laser-in-situ-Keratomileusis (LASIK) bedurfen durch den Abtrag von Hornhautgewebe und dadurch bedingter Verdunnung der Hornhaut einer Korrektur. Mit dem Messgerat Corneal Visualization Scheimpflug Technology (CorVis ST, Oculus, Wetzlar, Germany) werden neben dem IOD und der zentralen Hornhautdicke (CCT), 10 Verformungseigenschaften der Hornhaut quantifiziert. Um die Anderung dieser Parameter und mogliche geeignete Korrekturfaktoren fur die IOD-Messung nach LASIK zu detektieren, wurden Pra- und Post-LASIK-IOD-Messungen mit dem CorVis ST miteinander verglichen. 45 myope Patienten (45 linke Augen) wurden jeweils vor und nach LASIK mit dem CorVis ST gemessen. Messpaare von IOD, CCT und den Verformungseigenschaften (z. B. der Applanationsradius) wurden mittels gepaartem t‑Test verglichen. Zusatzlich wurde die Anderung des IOD-Messwertes in Bezug zu Anderungen der Verformungseigenschaften gesetzt. Es bestatigte sich eine Korrelation der IOD-Messwerte mit der Hornhautdicke. Pro Mikrometer Reduktion der Hornhautdicke misst das CorVis ST den IOD postoperativ um 0,039 mmHg niedriger als praoperativ. Im mehrfaktoriellen linearen Modell zeigen sich auserdem Abhangigkeiten der IOD-Anderung von der A2 velocity und dem Applanationsradius. Nach LASIK zeigt sich auch im CorVis eine Abhangigkeit der IOD-Messung von der Anderung der Hornhautdicke. Die postoperative Anderung der A2 velocity sowie des Applanationsradius haben einen zwar geringen, jedoch ebenfalls signifikanten Einfluss auf die Post-LASIK-IOD-Messung. Unter Berucksichtigung dieser CorVis-Parameter konnte in Zukunft die Druckmessung nach LASIK spezifisch korrigiert werden.

The surgical technique of limbokeratoplasty (limbo-KP) was initially established for the treatment of severe limbal deficiencies. Besides improving visual acuity, surgery is aimed at ensuring complete, long-lasting epithelialization of the ocular surface. Due to the extension of the indication spectrum, limbo-KPs are also used in various forms of epithelial/stromal corneal dystrophies such as lattice and granular (transforming growth factor beta-induced [TGFBI] gene mutation associated) dystrophies. The objective of limbo-KP is to ensure prolonged clear graft survival without a recurrence of the dystrophy as otherwise observed after conventional keratoplasty.Die homologe Limbokeratoplastik (Limbo-KP) wurde initial zur Behandlung von Formen schwerer Limbusinsuffizienz etabliert, um nach Transplantation einen vollständigen und dauerhaften Epithelschluss im Bereich der Hornhaut zu gewährleisten. Nach Erweiterung des Indikationsspektrums kommt die Limbo-KP mittlerweile auch bei epithelialen/stromalen Hornhautdystrophien wie der gittrigen und der granulären Hornhautdystrophie (die mit einer Mutation im TGFBI-Gen [TGFBI: transforming growth factor beta-induced] assoziiert sind) zum Einsatz. Ziel der Limbo-KP hierbei ist es, ein klares Transplantatüberleben ohne Rezidiv der Dystrophie im Transplantat zu erreichen, da es nach konventioneller Keratoplastik stets zu Rezidiven und einer damit einhergehenden Visusminderung kommt.

The prevalence of pseudophakia increases with age and affects more than 30% of people older than 80 years. Because grafts from older donors seem to be more suitable for Descemet membrane endothelial keratoplasty (DMEK) surgery rather than grafts from younger donors, eye bank technicians and corneal surgeons have to deal with corneas from pseudophakic donors for DMEK graft preparation. However, graft preparation from corneas of pseudophakic donors can be more complicated.We retrospectively analyzed our donor registry for the prevalence of pseudophakia. We compared grafts from phakic and pseudophakic donors concerning graft survival, rebubbling rates, and endothelial cell loss after DMEK surgery.More than 20% of our donors were pseudophakic, of which 35% were primarily suitable for transplantation. Regarding the comparison of grafts from phakic and pseudophakic donors used for DMEK, we observed comparable survival rates (90% after 3 years) and similar endothelial cell loss (30% with an endothelial cell density above 1000 cell/mm after 3 years) but significantly lower rebubbling rates for grafts from pseudophakic donors (18% vs. 28%).Our data strongly suggest that pseudophakic persons should not be excluded from corneal donation because success rates after DMEK with grafts from pseudophakic eyes are comparable to those with grafts from phakic eyes. However, in the eye bank, grafts from pseudophakic donors have a higher primary discard rate because of low endothelial cell counts.

Purpose To study distinct aspects of human monocyte-derived macrophage (MDM) activation by human corneal tissue as a possible initial stage in human corneal allograft rejection. Methods Human monocytes were isolated from peripheral blood mononuclear cells (PBMC) and differentiated into MDM. Human corneas with or without endothelium were fragmented using a standardized protocol. MDM were stimulated with human corneal fragments, corneal fragment supernatant, lipopolysaccharide (LPS) or interferon-gamma (IFNγ), and expression profiles for 34 cytokines were determined in MDM-conditioned media using a Luminex bead-based multiplex assay. Data from clinical aqueous humour samples served for comparison and validation. To assess cell recruitment, immunogenicity of corneal endothelial cells (CEC), monocyte survival and differentiation, we applied transwell migration assays, cell viability assays and fluorescence-activated cell sorting, respectively. Results Corneal fragments induced MDM to release distinct cytokines into the medium. Media thus conditioned in vitro by stimulated MDM shared cytokine patterns, namely MCP-1, MIP-1α and MIP-1β, with human aqueous humor samples obtained in human corneal allograft rejection. The presence of CEC in tissue fragments used for MDM stimulation attenuated the upregulation of distinct pro-inflammatory chemokines, like MCP-3 and IL-8, reduced the monocyte survival time, and diminished monocyte-to-macrophage differentiation induced by conditioned media. Distinct anti-inflammatory cytokines, like IL-4 and IL-13, were upregulated in the presence of corneal endothelium. Cornea fragment-stimulated MDMs induced recruitment of monocytes from a PBMC pool in a transwell migration model, modulated immune cell viability and promoted further immune cell recruitment and differentiation. Conclusions Human macrophages respond to allogenic corneal tissue and generate an inflammatory milieu. This can drive further recruitment of immunocompetent cells and modulate cell survival and differentiation of the cells recruited. These observations are consistent with the hypothesis that macrophages play a significant role in the initiation of corneal transplant rejection. Our data also indicate that distinct aspects of early human corneal transplant rejection can be modelled in vitro.

Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host–pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB–regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2–associated responses were preserved. Experiments using leukocytes from IL-1R–associated kinase-4–deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R–associated kinase-4–mediated inflammatory responses to S. pneumoniae.

Hintergrund: Ein wichtiger Erfolgsparameter bei der refraktiven Hornhautchirurgie zur Myopiekorrektur ist die Langzeitstabilitat der Korrektur. Gewebeparameter, welche die Stabilitat und damit die Regression beeinflussen, lassen sich nur schwer untersuchen. Durch das ReLEx®flex-Verfahren, bei dem Hornhautlentikel mit einem Femtosekunden-Laser (fs-Laser) geschnitten und dann chirurgisch entfernt werden, besteht erstmals die Moglichkeit, gesundes humanes Hornhautgewebe fur eine weitere Untersuchung zu gewinnen. Unter Einsatz der Elektronenmikroskopie wurden die Gewebeparameter der entnommenen Lentikel analysiert, um mogliche Beziehungen zwischen der Hornhautbeschaffenheit und der Stabilitat refraktiver Ergebnisse zu untersuchen. Zusatzlich wurden die Auswirkungen von vorherigem Kontaktlinseneinsatz (CL) auf die Stabilitat der refraktiven Ergebnisse untersucht. Patienten und Methoden: 19 Lentikel von 11 Patienten (Alter 24–56 Jahre; 8 w, 3 m) wurden fur die Elektronenmikroskopie prapariert. Die zentralen Bereiche der Praparate wurden fotografiert und der Abstand zwischen den Kollagenfasern sowie ihr Durchmesser digital erfasst. Mittels ANOVA-Analyse wurde die pra- und postoperative Brechwertstabilitat mit der Tragezeit von Kontaktlinsen, dem Faserdurchmesser und dem Variationskoeffizienten des Faserabstands korreliert. Ergebnisse: 14 von 19 Lentikeln stammten von Patienten, die praoperativ Kontaktlinsen getragen hatten. Praoperatives Tragen von Kontaktlinsen beeinflusste die postoperative Regression deutlich: Je langer die Patienten Kontaktlinsen trugen, desto groser war die Regression in Richtung Myopie (p = 0,01). Auch die morphologischen Parameter Faserdurchmesser (p = 0,09) und Variationskoeffizienten des Faserabstands (p = 0,07) hatten einen Einfluss auf die Regression. Schlussfolgerung: Verlangertes Tragen von Kontaktlinsen und Veranderungen in den morphologischen Parametern beeinflussen die Stabilitat der Ergebnisse nach refraktiver Hornhautchirurgie. Obwohl die pathophysiologischen Beziehungen zwischen dem Tragen von Kontaktlinsen, den morphologischen Parametern der Kornea und der Brechwertstabilitat bisher kaum bekannt sind, konnten diese Ergebnisse moglicherweise als Prognosemarker fur die postoperative Refraktion nach ReLExflex genutzt werden.

In order to prevent rejection of an allogeneic corneal transplant after perforating (high risk) keratoplasty, active agents from different classes of pharmacological substances are used, as with solid organ transplantation. In addition to glucocorticoids, antiproliferative agents, small molecule inhibitors and antibodies, those belonging to the group of macrolides with their many derivatives represent an interesting class of substances in this context. As a supplement to cyclosporin A (CSA) the most successful macrolide in transplantation medicine, animal experiments are currently being carried out to test newer macrolide derivatives, such as sanglifehrin A (SFA). This overview describes the classes of drugs and modes of action of currently administered standard medications in the clinical routine and new developments are presented.

Various inflammatory and non-inflammatory eye diseases are associated with specific HLA isotypes. Therefore, HLA isotyping can be a useful diagnostic tool for these diseases and has already been shown to reduce the rejection rate of corneal allografts. Unfortunately, the volume of published data and the varying quality of these publications complicate obtaining good overview in this field. This review briefly summarizes the genetic structure of the HLA system and elucidates differences between HLA classes I and II in the context of antigen presentation. Possible mechanisms of HLA associations in the field of ophthalmology are discussed, and finally different tools (e.g. genome wide association studies) for assessing associations of HLA isotypes with different ocular diseases are examined.

Purpose To evaluate the feasibility of anterior segment spectral domain optic coherence tomography (ASOCT) as rejection readout in a keratoplasty mouse model and to compare ASOCT against the current standard (i.e., a clinical score system). Furthermore, to compare both approaches with respect to intra- and inter-individual observer variability and to calculate a critical point that distinguishes between rejection and non-rejection in ASOCT analysis. Methods Allogeneic penetrating keratoplasties (PKs) were performed using C3H/He donor mice and BALB/c recipient mice; syngeneic transplantations served as controls using BALB/c donors and recipients. Corneal graft rejection was determined with a clinical score. ASOCT was used to determine the central thickness of the corneal grafts in the same animals. The rejection status was corroborated with histopathological examination. Results The median survival time (MST) of the corneal allografts in the wild-type BALB/c mice was 12 days. Allogeneic transplantation led to a 100% rejection rate, whereas signs of rejection after syngeneic transplantation appeared in up to 20% of the mice. Central corneal thickness (CCT) determination via customized software revealed a direct correlation with the clinical score. Receiver operating curve (ROC) analysis confirmed CCT as a valid surrogate for rejection. Calculation of the area under the curve (AUC) revealed a value of 0.88 with an optimal cut-off at 267 pixels. Conclusions An increase in the CCT during acute allogeneic corneal graft rejection significantly correlated with the clinical surrogate parameter “corneal opacity.” ASOCT not only generates source data, but also analysis of the ASOCT data shows lower readout variability and fewer interpreter variations than the clinical score commonly used to define the time point of graft rejection in mice.