[Lens injury as a complication of intravitreal medication injection]. / Linsenverletzungen als Komplikation bei intravitrealer Medikamenteneingabe.

BACKGROUND: Intravitreal medication injections are an efficient and low-risk delivery technique for treating various retinal diseases. Rare serious complications include increased intraocular pressure, vitreous hemorrhage, retinal tears and detachment, intraocular inflammation and endophthalmitis. In the case series presented here, we report iatrogenic lens injuries caused by inadequate performance of intravitreal injections. METHODS: A multicenter data collection of patients treated with intravitreal injections with visible iatrogenic lens defects from 2016 to 2023 was retrospectively performed. RESULTS: Lens trauma after intravitreal injections was identified in six cases (69.3±6.5 years). While five cases were observed after anti-VEGF therapy, we identified lens injury after dexamethasone implantation in one patient. CONCLUSION: Iatrogenic lens injury during intravitreal injection is preventable with the correct injection technique. Knowledge of individual axis length and lens status also helps to avoid this complication.

Clinical Landscape of Central Serous Chorioretinopathy in Germany: Retina.net CSC Registry Report Number 1.

INTRODUCTION: The German Registry of central serous chorioretinopathy (CSC) collects data on CSC patients in a nationwide multicenter approach to analyze epidemiology, risk factors, clinical presentations, as well as diagnosis and treatment patterns. METHODS: In this multicenter cohort study, patients with CSC were enrolled in nine tertiary referral centers in Germany between January 2022 and June 2023. After consenting to the study, demographic data, risk factors, reported symptoms, best-corrected visual acuity (BCVA), funduscopic findings, disease severity, and diagnostic and treatment decisions were recorded and analyzed. RESULTS: A total of 539 eyes of 411 CSC patients were enrolled in this study including 308 males (75%) and 103 females (25%). Patients were predominantly of Caucasian origin and had a mean age of 55.5 years (IQR 41.0-70.0). 28% of eyes were classified as acute (<4 months duration) CSC, 28% as chronic (>4 months duration) CSC, 21% as inactive CSC, 11% as chronic atrophic CSC, and 12% as CSC with secondary CNV. 128 patients (31%) demonstrated bilateral CSC. The most common risk factors reported were psychological stress (52%), smoking (38%), arterial hypertension (38%), and a history of or current use of steroids (30%). Most frequently encountered symptoms included decreased visual acuity (76%), metamorphopsia (49%), relative scotoma (47%), blurred vision (19%), and dyschromatopsia (9%). The mean logMAR BCVA on initial examination was 0.2 (≈20/30, IQR 0.2-0.4) but showed significant variation with a tendency of lower BCVA in chronic cases. At the baseline visit, 74% of the overall cohort received no treatment, while 19% underwent local treatment and only 2% underwent systemic treatment. Of the local therapies, anti-VEGF injections were the most frequently performed procedure (33%, mainly for secondary CNV), followed by micropulse laser (28%), focal nonpulsed laser (23%), verteporfin photodynamic therapy (14%), and nonsteroidal anti-inflammatory eye drops (2%). Among intravitreal anti-VEGF agents, aflibercept was used most frequently, followed by bevacizumab and ranibizumab. CONCLUSION: This registry represents one of the largest cohorts of European patients with CSC to date. Patient age and the proportion of women were higher than expected and bilateral active disease was lower than anticipated, highlighting that neither age nor gender should be overemphasized when diagnosing CSC. Therapeutic interventions are heterogeneous and include verteporfin photodynamic therapy, micropulse laser, and anti-VEGF injections in case of secondary CNV.

Current Perspectives on Type 3 Macular Neovascularization due to Age-Related Macular Degeneration.

BACKGROUND: The aim of this review was to systematically summarize the current knowledge on type 3 macular neovascularization (MNV3) in age-related macular degeneration (AMD). SUMMARY: Recent histopathologic and multimodal imaging findings led to the consensus definition of the new term "type 3 macular neovascularization" in AMD. MNV3 originates in the deep vascular plexus as a neovascular process without connection with the retinal pigment epithelium in the initial stages. This type has numerous clinical and pathomorphologic features that separate it from the other two types of MNV in AMD. Besides, its frequency appears to be higher than previously thought. In optical coherence tomography (OCT), MNV3 can be classified into stages 1-3. Hyperreflective foci in the outer retina possibly represent a precursor lesion. In addition, MNV3 is characterized by a strong association with reticular pseudodrusen, a high rate of bilaterality, close associations with advanced age and arterial hypertension, decreased choroidal thickness, and decreased choriocapillaris flow signals. Data from latest anti-vascular endothelial growth factor studies in MNV3 suggest that the OCT biomarkers in intraretinal and subretinal fluids should be interpreted differently than in the other types. Additionally, data from MNV3 eyes should be analyzed separately, allowing optimal type-specific treatment strategies in the future. KEY MESSAGES: This review highlights the need for accurate characterization of neovascular AMD lesions and an MNV type-specific approach, particularly for MNV3.

[Iatrogenic retinal defects after intravitreal operative drug injections]. / Iatrogene Netzhautdefekte nach intravitrealer operativer Medikamenteneingabe.

BACKGROUND: Intravitreal operative drug injections represent one of the most frequently performed medical interventions. The risk profile is low. In addition to intraocular pressure elevation, the most frequent complications include exogenous endophthalmitis, vitreous hemorrhage and rhegmatogenous retinal detachment. Furthermore, isolated cases of lens injuries, macular holes associated with vitreoretinal traction and peripheral retinal defects have been described. In the present case series sharp iatrogenic macular and retinal defects are described. METHODS: Retrospective multicenter case collection of patients with iatrogenic retinal defects after intravitreal injections from 2016 to 2023. RESULTS: Iatrogenic retinal trauma after intravitreal injections for treatment of neovascular age-related macular degeneration was identified in 9 cases (72 years ± 8.1, 3 eyes pseudophakic). While sharp injuries within the macula occurred in six cases, extramacular lesions were detected in the other cases. CONCLUSION: Iatrogenic retinal and macular injuries are rare complications of intravitreal injections and when correctly carried out are preventable, especially with respect to use of cannulas and the choice of the distance from the limbus.

Old Problem in a New Guise: Retinal Pigment Epithelium Tear after Intravitreal Faricimab (Vabysmo®) Injection.

This case report describes a 78-year-old patient who developed a tear of the retinal pigment epithelium (RPE) during faricimab (Vabysmo®) therapy. After three consecutive intravitreal aflibercept (Eylea®) injections with persistent disease activity, therapy was switched to faricimab. The patient experienced a tear in the RPE 4 weeks postinjection. We report the first published case of RPE tear development after intravitreal faricimab injection in neovascular age-related macular degeneration. Faricimab has a new target structure in the angiopoietin-2 receptor in addition to VEGF. Patients at risk for RPE rupture were excluded from pivotal studies. Further investigation is needed to understand the effect of faricimab not only on visual acuity and intraretinal and subretinal fluid but also on mechanical stress on the RPE monolayer.

Development of an Inductive Rain Gauge.

Measuring weather data in an urban environment is an important task on the journey towards smart cities. Heavy rain can cause flooding in cities and prevent emergency services from reaching their destination because roads or underpasses are blocked. In order to provide a high-resolution site-specific overview in urban areas during heavy rainfall, a dense measurement network is necessary. To achieve this, a smart low-cost rain gauge is needed. In this paper, the current status of the development of an inductive rain gauge is presented. The sensor is based on the eddy current principle and evaluates the frequency of an electrical resonant circuit. For this purpose, a coil is placed under a metal plate. When raindrops hit the plate, it starts to oscillate, which changes the distance to the coil accordingly and causes changes in the frequency of the resonant circuit. Since the sensor is cost-effective, operates self-sufficiently in terms of energy and transmits data wirelessly via LoRaWAN, it can be used flexibly. This enables dense, area-wide coverage over the urban area of interest. The first experimental investigations show a correlation between the size of the rain droplets and the frequency change. Small droplets cause a shift of about 8 kHz and larger droplets of up to 40 kHz. The results prove that raindrops can be detected and categorized using this measurement principle. These data will be used as a basis for future work on calculating precipitation.

High User Acceptance of a Retina e-Learning App in Times of Increasing Digitalization of Medical Training for Ophthalmologists.

INTRODUCTION: The aim was to identify changes in continuing education and training in ophthalmology in the context of the COVID-19 pandemic and advancing digitalization and to analyse the acceptance of e-learning tools among German ophthalmologists using a novel Retina Case App as an example. METHODS: The participants' training behaviour before and during the COVID-19 pandemic was surveyed. Furthermore, the acceptance and usability of the Retina Case App were evaluated using the System Usability Scale (SUS). A possible influence of the app on everyday clinical practice was assessed. RESULTS: A total of 145 ophthalmologists participated in the survey. The frequency of continuing medical education did not decrease for 62.8% of ophthalmologists during the pandemic. A significant increase in at least monthly use of online courses or lectures has been observed (90.3% vs. 28.2%, p < 0.001). No significant difference was identified in terms of frequency of use of print and digital journals or printed textbooks. The majority of participants stated that online training platforms are well suited to replace the absence of face-to-face events (73.8%). The mean SUS score was 87.7 (SD 11.9), which categorizes the app's usability as excellent. The majority agreed that the newly developed app enables faster learning (82.1%) and leads to increased motivation (71.7%). Most ophthalmologists (80.7%) felt that regular use of the app would improve confidence in the treatment of retinal diseases. CONCLUSIONS: The COVID-19 pandemic has led to a significant change in training behaviour in ophthalmology towards e-learning and online courses, which has not been accompanied by a general decline in training activity. The exemplarily investigated application showed a high user acceptance among ophthalmologists.

Longitudinal choriocapillaris changes in the presence of reticular pseudodrusen.

To determine longitudinal changes in choriocapillaris (CC) measures in eyes with reticular pseudodrusen (RPD) using optical coherence tomography angiography (OCTA). In this observational prospective study, 20 patients with exclusively RPD and no other alteration due to age-related macular degeneration were included. Eight RPD patients were re-examined at 5-year follow-up. Multimodal imaging was performed at baseline and at 5-year follow-up. OCTA CC images were analyzed for number, size and total area of flow deficits (FD), mean signal intensity, signal intensity standard deviation and kurtosis of signal intensity distribution in the ring area between a circle of 4 mm diameter and a circle of 6 mm diameter and in the superior ring quadrant. Area affected by RPD increased from 19.36 ± 8.39 mm2 at baseline to 37.77 ± 9.03 mm2 at 5-year follow-up. At baseline, percent of CC FD area was greater in RPD eyes (quadrant: p < 0.001; ring: p < 0.001) compared to controls. Besides, RPD eyes revealed a lower mean intensity signal (quadrant: p < 0.001; ring: p < 0.001). Evaluation of CC parameters suggested significant group × time interaction effects for CC FD (p = 0.04) and mean intensity signal (p = 0.004), in that RPD eyes presented increased CC FD and decreased mean intensity signal at follow-up. OCTA CC decorrelation signal further decreases in RPD patients over 5 years in both RPD-affected and RPD-unaffected macular areas.

Generic and specific recurrent neural network models: Applications for large and small scale biopharmaceutical upstream processes.

The calculation of temporally varying upstream process outcomes is a challenging task. Over the last years, several parametric, semi-parametric as well as non-parametric approaches were developed to provide reliable estimates for key process parameters. We present generic and product-specific recurrent neural network (RNN) models for the computation and study of growth and metabolite-related upstream process parameters as well as their temporal evolution. Our approach can be used for the control and study of single product-specific large-scale manufacturing runs as well as generic small-scale evaluations for combined processes and products at development stage. The computational results for the product titer as well as various major upstream outcomes in addition to relevant process parameters show a high degree of accuracy when compared to experimental data and, accordingly, a reasonable predictive capability of the RNN models. The calculated values for the root-mean squared errors of prediction are significantly smaller than the experimental standard deviation for the considered process run ensembles, which highlights the broad applicability of our approach. As a specific benefit for platform processes, the generic RNN model is also used to simulate process outcomes for different temperatures in good agreement with experimental results. The high level of accuracy and the straightforward usage of the approach without sophisticated parameterization and recalibration procedures highlight the benefits of the RNN models, which can be regarded as promising alternatives to existing parametric and semi-parametric methods.

[Choroidal neovascularization due to a punctate inner choroidopathy visualized by optical coherence tomography angiography]. / Choroidale Neovaskularisation infolge einer "punctate inner choroidopathy", dargestellt mittels optischer Kohärenztomographie-Angiographie.

Punctate inner choroidopathy (PIC) is often accompanied by the development of choroidal neovascularization (CNV). The identification of a fresh CNV in the context of PIC is often difficult. We present the case of a 30-year-old female patient with typical morphological features of PIC. A CNV could not be detected with certainty by optical coherence tomography (OCT) or by fluorescein angiography (FAG); however, OCT angiography (OCT-A) revealed a circumscribed CNV. The case suggests that there are a high number of undiagnosed, subclinical secondary CNVs not requiring treatment in PIC patients.

The visual pigment xenopsin is widespread in protostome eyes and impacts the view on eye evolution.

Photoreceptor cells in the eyes of Bilateria are often classified into microvillar cells with rhabdomeric opsin and ciliary cells with ciliary opsin, each type having specialized molecular components and physiology. First data on the recently discovered xenopsin point towards a more complex situation in protostomes. In this study, we provide clear evidence that xenopsin enters cilia in the eye of the larval bryozoan Tricellaria inopinata and triggers phototaxis. As reported from a mollusc, we find xenopsin coexpressed with rhabdomeric-opsin in eye photoreceptor cells bearing both microvilli and cilia in larva of the annelid Malacoceros fuliginosus. This is the first organism known to have both xenopsin and ciliary opsin, showing that these opsins are not necessarily mutually exclusive. Compiling existing data, we propose that xenopsin may play an important role in many protostome eyes and provides new insights into the function, evolution, and possible plasticity of animal eye photoreceptor cells.

Optical coherence tomography angiography image quality assessment at varying retinal expertise levels.

PURPOSE: To compare optical coherence tomography angiography (OCT-A) image quality gradings performed by readers of varying retinal expertise levels in different retinal diseases. METHODS: Central 3 × 3 mm2 OCT-A images (AngioVue, Optovue) of 57 healthy controls (50.9 ± 22.4 years) and 148 patients (66.5 ± 14.1 years) affected by various chorioretinal diseases were retrospectively analyzed including early age-related macular degeneration (AMD, n = 26), neovascular AMD (nAMD, n = 22), and geographic atrophy due to AMD (GA, n = 6), glaucoma (n = 28), central serous chorioretinopathy (CSC, n = 14), epiretinal membrane (EM, n = 26), retinitis pigmentosa (RP, n = 16), and retinal venous occlusion (RVO, n = 10). A senior expert in medical retina (SE), an ophthalmology resident (OR), and a non-ophthalmologic medical doctor (MD) independently assessed OCT-A image quality using the motion artifact score (MAS) and the segmentation accuracy score (SAS). RESULTS: Regarding MAS, inter-reader agreement between SE and OR was 93.7% (Cohen's kappa = 0.907) and 85.4% (Cohen's kappa = 0.786) between SE and MD. Regarding SAS, inter-reader agreement between SE and OR was 95.1% (Cohen's kappa = 0.92) and 92.2% (Cohen's kappa = 0.874) between SE and MD. In the SAS analysis, signal strength index (SSI) and presence of retinal pathology had a significant influence on the overall agreement (P = 0.046; P < 0.001). CONCLUSIONS: OCT-A image quality assessment can be performed most reliably by an ophthalmologist with knowledge in retinal image analysis. Yet, well-instructed non-ophthalmologic assessors show only slightly inferior results and, thus, may be integrated in routine OCT-A image quality assessment as well.

RANIBIZUMAB IN PIGMENT EPITHELIAL TEARS SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Prospective Study.

PURPOSE: To assess efficacy of intravitreal ranibizumab in retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. METHODS: The Ranibizumab In Pigment epithelial tears secondary to age-related macular degeneration (RIP) study is a prospective, single-arm, multicenter, investigator-initiated trial. Twenty four eyes of 24 patients with a retinal pigment epithelium tear secondary to age-related macular degeneration received monthly intravitreal injection of 0.5mg ranibizumab for 12 months, together with monthly assessments of morphologic and functional efficacy parameters. Primary outcome measure was mean best-corrected visual acuity at final visit compared with baseline. RESULTS: Mean best-corrected visual acuity remained stable over the 12-month study period with 50.3 Early Treatment of Diabetic Retinopathy Study letters (±18.7; Snellen equivalent 20/100) at baseline and 52.9 letters (±19.7; Snellen equivalent 20/100) at final visit (P = 0.39). One eye (4%) experienced a vision loss of ≥15 letters, and 2 eyes (8%) gained ≥15 letters. Mean central retinal thickness decreased from 571 µm (±185 µm) to 436 µm (±171 µm; P = 0.0001). Vision-related quality of life was stable with a mean VFQ-25 score of 79.0 (±10.8) at baseline and 74.3 (±13.9) at final visit (P = 0.12). CONCLUSION: In retinal pigment epithelium tears secondary to age-related macular degeneration, monthly intravitreal ranibizumab therapy results in stabilization of visual acuity over 12 months.

OCT-Angiography reveals reduced vessel density in the deep retinal plexus of CADASIL patients.

Optical coherence tomography angiography (OCT-A) represents the most recent tool in ophthalmic imaging. It allows for a non-invasive, depth-selective and quantitative visualization of blood flow in central retinal vessels and it has an enormous diagnostic potential not only in ophthalmology but also with regards to neurologic and systemic diseases. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular small-vessel disease caused by Notch3 mutations and represents the most common form of hereditary stroke disorder. In this study, CADASIL patients prospectively underwent OCT-A imaging to evaluate retinal and choriocapillaris blood flow as well as blood flow at the optic nerve head. The vessel density of the macular region and the size of the foveal avascular zone in the superficial and deep retinal plexus were determined as well as the vessel density at the optic nerve head and in the choriocapillaris. Additionally, cerebral magnetic resonance images were evaluated. The main finding was that vessel density of the deep retinal plexus was significantly decreased in CADASIL patients compared to healthy controls which may reflect pericyte dysfunction in retinal capillaries.

Workflow for Target-Oriented Parametrization of an Enhanced Mechanistic Cell Culture Model.

The goal of this study is to develop a macroscopic mechanistic model describing growth and production within fed-batch cultivations of CHO cells. The model should be used for process characterization as well as for process monitoring including real-time parameter adaptations. The model proved to be able to describe a data-set of 40 processes differing in clones, scales, and process conditions with a normalized root mean square error of approximately 10%. However, due to limited parameter identifiability and limited knowledge about physiologically meaningful parameter values, a broad range of parameters could describe the data with similar quality. This hampered comparison of the model parameters as well as their real-time estimation. Therefore an iterative workflow combining techniques like sensitivity and identifiability analysis, analysis of the specific rates as well as structural adaptations of the parameter space is developed. By applying it the parameter variability could be reduced by 80% with similar predictive power as the original parameters. Summing up, based on a mechanistic CHO model, a generic and transferrable workflow is created for target-oriented parameter estimation in case of limited parameter identifiability. Finally, we suggest a methodology, which fits ideally into the frame of Process Analytical Technology aiming to increase process understanding.

Is the reliability of 3D kinematics of young obese participants dependent on the hip joint center localization method used?

The aim of this study was to investigate if the test-retest reliability for three-dimensional (3D) gait kinematics in a young obese population is affected by using either a predictive (Davis) or a functional (SCoRE) hip joint center (HJC) localization approach. A secondary goal was to analyze how consistent both methods perform in estimating the HJC position. A convenience sample of ten participants, two females and eight males with an age-based body mass index (BMI) above the 97th percentile (mean±SD: 34.2±3.9kg/m2) was recruited. Participants underwent two 3D gait analysis sessions separated by a minimum of one day and a maximum of seven days. The standard error of measurement (SEM) and the root mean square error (RMSE) of key kinematic parameters along with the root mean square deviation (RMSD) of the entire waveforms were used to analyze the test-retest reliability. To get an estimate of the consistency of both HJC localization methods, the HJC positions determined by both methods were compared to each other. SEM, RMSE, and RMSD results indicate that the HJC position estimations between both methods are not different and demonstrate moderate to good reliability to estimate joint kinematics. With respect to the localization of the HJC, notable inconsistencies ranging from 0 to 5.4cm were observed. In conclusion, both approaches appear equally reliable. However, the inconsistent HJC estimation points out, that accuracy seems to be a big issue in these methods. Future research should attend to this matter.

Desgarros del epitelio pigmentario de la retina: factores de riesgo, mecanismo y control terapéutico.

Los desgarros del epitelio pigmentario de la retina (EPR) se asocian en la mayoría de los casos con los desprendimientos vascularizados del EPR debido a una degeneración macular asociada a la edad (DMAE), y normalmente implican una pérdida adversa de la agudeza visual. Estudios recientes indican que ha habido un aumento en la incidencia de desgarros del EPR desde la introducción de fármacos anti-factor de crecimiento del endotelio vascular (anti-VEGF) así como una asociación temporal entre el desgarro y la inyección intravítrea. Dado que el número de pacientes con DMAE y el número de inyecciones anti-VEGF va en aumento, tanto la dificultad de prevenir desgarros del EPR como el tratamiento tras la formación de los desgarros han adquirido una mayor relevancia. De forma paralela, la evolución de la imagenología de la retina ha contribuido de manera significativa a comprender mejor el desarrollo de los desgarros del EPR en los últimos años. Esta revisión resume los conocimientos que se poseen actualmente sobre el desarrollo, los factores pronósticos y las estrategias terapéuticas de los desgarros del EPR antes y después de que estos se formen.

Comparison of Choriocapillaris Flow Measurements between Two Optical Coherence Tomography Angiography Devices.

PURPOSE: To evaluate choriocapillaris (CC) perfusion in healthy subjects using 2 different optical coherence tomography angiography (OCT-A) devices. PROCEDURES: Macular OCT-A imaging (36 eyes of 36 subjects) was performed using Optovue AngioVue and Zeiss AngioPlex devices. CC decorrelation signal index was assessed, and CC data were analyzed regarding intra-device variability, inter-device correlation, age, signal strength, and fields of view. RESULTS: The intra-device variability of CC measurements in the 3 × 3 mm2 field was 5.3 and 2.6% (Angiovue and Angioplex, coefficients of variation; 6 × 6 mm2: 8.0 and 2.8%, respectively). Mean CC decorrelation signal index in 3 × 3 mm2 was 104.3 ± 6.7 (Angiovue) and 81.3 ± 9.2 (Angioplex) (6 × 6 mm2: 95.6 ± 8.1, 81.1 ± 6.5) with high correlation between both devices (3 × 3 mm2: p = 0.0053; 6 × 6 mm2: p = 0.0139). CC decorrelation signal index in 3 × 3 mm2 was significantly higher in subjects aged ≤58 years compared to subjects aged ≥59 years (Angiovue: 107.3 ± 3.6, 101.3 ± 7.7, p = 0.0156; Angioplex: 84.6 ± 7.6, 78.0 ± 9.5, p = 0.0371). Signal strength was 64.6 ± 8.9 (Angiovue) and 9.5 ± 0.8 (Angioplex). CONCLUSION: Both devices showed low intra-device variability and a high inter-device correlation. CC decorrelation signal index was negatively correlated with advancing age.