Cascade enzymatic synthesis of a statin side chain precursor - the role of reaction engineering in process optimization.

Statins are an important class of drugs used to lower blood cholesterol levels and are often used to combat cardiovascular disease. In view of the importance of safe and reliable supply and production of statins in modern medicine and the global need for sustainable processes, various biocatalytic strategies for their synthesis have been investigated. In this work, a novel biocatalytic route to a statin side chain precursor was investigated in a one-pot cascade reaction starting from the protected alcohol N-(3-hydroxypropyl)-2-phenylacetamide, which is oxidized to the corresponding aldehyde in the first reaction step, and then reacts with two equivalents of acetaldehyde to form the final product N-(2-((2S,4S,6S)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl)-2-phenylacetamide (phenylacetamide-lactol). To study this complex reaction, an enzyme reaction engineering approach was used, i.e. the kinetics of all reactions occurring in the cascade (including side reactions) were determined. The obtained kinetic model together with the simulations gave an insight into the system and indicated the best reactor mode for the studied reaction, which was fed-batch with acetaldehyde feed to minimize its negative effect on the enzyme activity during the reaction. The mathematical model of the process was developed and used to simulate different scenarios and to find the reaction conditions (enzyme and coenzyme concentration, substrate feed concentration and flow rate) at which the highest yield of phenylacetamide-lactol (75%) can be obtained. In the end, our goal was to show that this novel cascade route is an interesting alternative for the synthesis of the statin side chain precursor and that is why we also calculated an initial estimate of the potential value addition.

A case of hemorrhage at the junctions of the posterior intercostal arteries-a vital sign?

The authors present the case of a 58-year-old man found hanging from a radiator by his shoelaces. The time of death was approximately 6 h before the body was discovered. An autopsy was performed approximately 24 h after the body was found, which revealed hemorrhages in the thoracic aorta at the junctions of the posterior intercostal arteries. Before autopsy, a routine whole-body CT scan was performed. Histologic examination of the aorta and the posterior intercostal arteries revealed a fresh hemorrhage into the tunica adventitia of the aorta. To our knowledge, there is no case description of such findings in hanged persons in the literature. Conclusion: Hemorrhages into the tunica adventitia of the junction of the posterior costal arteries may occur in association with suicidal hanging. The significance of these hemorrhages as a sign of vitality may be debated.

Influence of sandblasting and bonding on the shear bond strength between differently pigmented polyetheretherketone (PEEK) and veneering composite after artificial aging.

OBJECTIVE: Achieving a strong bond between Polyetheretherketone (PEEK) and veneering composites is challenging due to PEEKs low surface energy. This study examined the effects of sandblasting and bonding on the shear bond strength (SBS) between veneering composite and pigmented PEEK, considering artificial aging. METHODS: Of three pigmented PEEK compounds (DC4420R, DC4450R, DC4470R; Evonic Operations GmbH, Marl, Germany), 40 specimens each were milled and polished up to 2500 grit. Prior to veneering, specimens were divided into 4 subgroups: Subgroup 1: Polishing; 2: Polishing + bonding; 3: Sandblasting; 4: Sandblasting + bonding. Sandblasting was performed using Al2O3. Adhesive was an agent containing MMA (Signum Universal Bond, Kulzer GmbH, Hanau, Germany). After veneering (Composite, Kulzer GmbH) the subgroups were divided into 2 subgroups. One subgroup was immersed in 37 °C warm distilled water for 24 h. The second subgroup was artificially aged by thermocycling (TCL) with 5000 cycles in distilled water (5 °C / 55 °C; 30 s). Surface roughness, water contact angles and failure modes were recorded. SBS was measured using a universal testing machine. RESULTS: Results demonstrated that the combination of sandblasting and bonding significantly improved the SBS compared to polishing alone. PEEK color did not significantly influence the SBS. Aging by TCL had a negative effect on the SBS. SIGNIFICANCE: Sandblasting and the use of an adhesive containing MMA were found to be effective in achieving satisfactory SBS between veneering composite and pigmented PEEK surfaces. These pretreatment methods demonstrate their potential for establishing durable and reliable bonding in clinical applications.

Early Results With the New Active Bone-Conduction Hearing Implant: A Systematic Review and Meta-Analysis.

OBJECTIVE: The bone conduction implant (BCI) 602 is a new transcutaneous BCI with smaller dimensions. However, limited patient numbers restrict the statistical power and generalizability of the current studies. The present systematic review and meta-analysis summarize early audiological and medical outcomes of adult and pediatric patients implanted with the BCI 602 due to mixed or conductive hearing loss. DATA SOURCE: Following the Preferred Reporting items for Systematic Reviews and Meta-analyses guidelines, 108 studies were reviewed, and 6 (5.6%) were included in the meta-analysis. REVIEW METHOD: The data on study and patient characteristics, surgical outcomes, and audiological test results were extracted from each article. Meta-analysis employed the fixed-effect and random-effects models to analyze the mean differences (MDs) between pre- and postoperative performances. RESULTS: In total, 116 patients were evaluated, including 64 (55%) adult and 52 (45%) pediatric patients. No intraoperative adverse events were reported, while postoperative complications were reported in 2 (3.1%) adult and 2 (3.8%) pediatric patients. Studies consistently showed significant improvements in audiological outcomes, quality of life, and sound localization in the aided condition. In the meta-analysis, we observed a significant difference in the unaided compared to the aided condition in sound field thresholds (n = 112; MD, -27.05 dB; P < 0.01), signal-to-noise ratio (n = 96; MD, -6.35 dB; P < 0.01), and word recognition scores (n = 96; MD, 68.89%; P < 0.01). CONCLUSION: The implantation of the BCI 602 was associated with minimal surgical complications and excellent audiological outcomes for both the pediatric and the adult cohort. Therefore, our analysis indicates a high level of safety and reliability. Further research should focus on direct comparisons with other BCIs and long-term functional outcomes.

Imaging of alert patients after non-self-inflicted strangulation: MRI is superior to CT.

OBJECTIVE: To assess the accuracy of CT and MRI reports of alert patients presenting after non-self-inflicted strangulation (NSIS) and evaluate the appropriateness of these imaging modalities in NSIS. MATERIAL AND METHODS: The study was a retrospective analysis of patient characteristics and strangulation details, with a comparison of original radiology reports (ORR) to expert read-outs (EXR) of CT and MRI studies of all NSIS cases seen from 2008 to 2020 at a single centre. RESULTS: The study included 116 patients (71% women, p < .001, χ2), with an average age of 33.8 years, mostly presenting after manual strangulation (97%). Most had experienced intimate partner violence (74% of women, p < .001, χ2) or assault by unknown offender (88% of men, p < 0.002 χ2). Overall, 132 imaging studies (67 CT, 51% and 65 MRI, 49%) were reviewed. Potentially dangerous injuries were present in 7%, minor injuries in 22%, and no injuries in 71% of patients. Sensitivity and specificity of ORR were 78% and 97% for MRI and 30% and 98% for CT. Discrepancies between ORR and EXR occurred in 18% of all patients, or 62% of injured patients, with a substantial number of unreported injuries on CT. CONCLUSIONS: The results indicate that MRI is more appropriate than CT for alert patients presenting after non-self-inflicted strangulation and underline the need for radiologists with specialist knowledge to report these cases in order to add value to both patient care and potential future medico-legal investigations. CLINICAL RELEVANCE STATEMENT: MRI should be preferred over CT for the investigation of strangulation related injuries in alert patients because MRI has a higher accuracy than CT and does not expose this usually young patient population to ionizing radiation. KEY POINTS: • Patients presenting after strangulation are often young women with a history of intimate partner violence while men typically present after assault by an unknown offender. • Expert read-outs of CT and MRI revealed potentially dangerous injuries in one of 14 patients. • MRI has a significantly higher sensitivity than CT and appears to be more appropriate for the diagnostic workup of alert patients after strangulation.

Diagnostic accuracy of coronary artery stenosis and thrombosis assessment using unenhanced multiplanar 3D post-mortem cardiac magnetic resonance imaging.

BACKGROUND: A 3D sequence was introduced to unenhanced post-mortem cardiac magnetic resonance imaging (PMCMR) to enable multiplanar coronary artery image analysis and to investigate its diagnostic accuracy for the diagnosis of coronary artery stenosis and thrombosis. MATERIALS AND METHODS: N = 200 forensic cases with suspected coronary artery pathology underwent 3 Tesla PMCMR (sequence used: T2 weighted transversal 3D turbo spin echo) before autopsy. Main coronary artery stenosis and thrombosis were assessed in PMCMR by multiplanar image analysis by two observers. Coronary artery histology was determined as the gold standard and compared to PMCMR. Sensitivity, specificity, negative (NPV) and positive predictive values (PPV) with 95% confidence intervals were calculated. RESULTS: For all coronary arteries combined, sensitivity was 75% (PPV 73%) for the diagnosis of stenosis and 72% (PPV 71%) for the diagnosis of thrombosis. Specificity was 92% (NPV 90%) for correct diagnosis of non-existing stenosis and 97% (NPV 97%) for non-existing thrombosis. Sensitivity for correct diagnosis of different degrees of stenosis ranged between 67% and 80% (PPVs 67-82%); specificity ranged between 96% and 99% (NPVs 96-99%). CONCLUSION: Multiplanar PMCMR coronary artery stenosis and thrombosis assessment based on an unenhanced T2 weighted 3D sequence provide moderate sensitivity and high specificity for the diagnosis of coronary artery stenosis and/or thrombosis. Hence, 3D T2w PMCMR cannot reliably detect existing coronary artery stenosis and thrombosis but may be particularly useful for the exclusion of stenosis or thrombosis of the main coronary arteries.

Impact of manual toothbrush design on plaque removal efficacy.

BACKGROUND: Effective dental plaque removal is essential for oral health. Different toothbrush parameters including head-size, filament-diameter and interdent-height and different brushing movements like horizontal, rotating and vertical may affect plaque removal efficacy. The purpose of the study was to examine plaque removal efficacy of different design parameters of manual toothbrushes. METHODS: Eight manual toothbrushes were tested using a validated robot test to examine efficacy of toothbrush on replicated human teeth. Characteristics tested were: (i) head-size, (ii) filament-diameter, (iii) cutting-height, (iv) hardness, (v) interdental-height. Each test ran five times in horizontal, rotating, vertical movements. Simulated Plaque removal was evaluated using automated plaque planimetry: 30 fields/tooth, 13 areas representing buccal, lingual, proximal tooth sites. The Kolmogorov-Smirnov-test was applied to test tooth surface variables for normal distribution of plaque removal values. Parameters were analysed by independent two-sample t-test to assess mean differences. Where null hypothesis of normality was rejected, the Wilcoxon-Mann-Whitney-U-test was used. RESULTS: Plaque removal was significantly better with toothbrush having smaller head-size (compact vs. full-size); smaller filament-diameter (0.12 mm vs. 0.15 mm); larger cutting-height (12 mm vs. 9 mm); softer filaments (0.15 or 0.18 mm vs. 0.23 mm) and greater interdent-height difference (8.5/11 mm vs. 10/11 mm). CONCLUSIONS: Manual brushes allowing filaments free to flex with longer, softer and/or having a difference in filament length overall removed significantly more simulated plaque as compared to more standard flat trim, stiff brushes with shorter, harder bristles and a larger head size. While limited by the in vitro nature of the study design, this indicates that the advances in toothbrush design can further enhance plaque removal.

Anti-Inflammatory and Antifibrotic Potential of Longidaze in Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, characterized by progressive parenchymal fibrosis and respiratory failure. In a model of bleomycin-induced pulmonary fibrosis, the antifibrotic and anti-inflammatory activity of Longidaze (Bovhyaluronidase Azoxymer), which contains a conjugate of the hyaluronidase enzyme with a high molecular weight synthetic carrier azoxymer bromide, was investigated. Experiments were conducted in male C57BL/6 mice. Longidaze was administered at different doses by intranasal and intramuscular routes. Histology, hematology, and enzyme-linked immunosorbent assay were used in the study. The use of Longidaze reduced pulmonary fibrosis, as evidenced by an improvement in histopathologic damage to the lungs, a decrease in the area of connective tissue, and the levels of profibrotic factors (TGF-ß1, hydroxyproline, collagen I) in lung tissue. In addition, Longidaze inhibited the inflammatory response in pulmonary fibrosis, and decreased the levels of IL-6, TNF-α, and hyaluronic acid in lung tissue and the recruitment of inflammatory cells into lung tissue. The highest therapeutic efficacy was observed with the use of Longidaze at doses of 120 and 1200 U/kg intramuscularly, which was superior to that of the reference drug pirfenidone axunio. The data presented in this study suggest that Longidaze is a new and promising drug for the treatment of IPF that warrants further investigation in patients with fibrotic interstitial lung disease.

Standards of practice in forensic age estimation with CT of the medial clavicular epiphysis-a systematic review.

The AGFAD (Arbeitsgemeinschaft für Forensische Alterdiagnostik, Study Group on Forensic Age Diagnostics) has published several recommendations regarding both technical aspects of computed tomography (CT) of the medial clavicular epiphysis (MCE) and the process of reading and interpreting the CT images for forensic age estimations (FAE). There are, however, no published recommendations regarding CT scan protocols and no dose reference values for CT of the MCE. The objective of this analysis was to assess adherence to AGFAD recommendations among practitioners of FAE and analyse reported dose-relevant CT scan parameters with the objective of helping to establish evidence-based dose reference values for FAE. A systematic literature search was conducted in PubMed and in Google Scholar with specific MeSH terms to identify original research articles on FAE with CT of the MCE from 1997 to 2022. A total of 48 studies were included. Adherence to AGFAD recommendations among practitioners of FAE is high regarding the use of Schmeling main stages (93%), bone window (79%), ≤ 1 mm CT slices (67%), axial/coronal CT images (65%), and Kellinghaus sub-stages (59%). The reporting of CT technique and CT dose-relevant scan parameters is heterogeneous and often incomplete in the current literature. Considering the success achieved by the AGFAD in creating standards of practice of FAE in living subjects, there is potential for the AGFAD to establish standards for radiation protection in FAE as well.

[Monitoring of the progression of geographic atrophy with optical coherence tomography]. / Monitoring der Progression von geografischer Atrophie in der optischen Kohärenztomographie.

With the prospect of available therapy for geographic atrophy in the near future and consequently increasing patient numbers, appropriate management strategies for the clinical practice are needed. Optical coherence tomography (OCT) as well as automated OCT analysis using artificial intelligence algorithms provide optimal conditions for assessing disease activity as well as the treatment response for geographic atrophy through a rapid, precise and resource-efficient evaluation.

Deep survival modeling of longitudinal retinal OCT volumes for predicting the onset of atrophy in patients with intermediate AMD.

In patients with age-related macular degeneration (AMD), the risk of progression to late stages is highly heterogeneous, and the prognostic imaging biomarkers remain unclear. We propose a deep survival model to predict the progression towards the late atrophic stage of AMD. The model combines the advantages of survival modelling, accounting for time-to-event and censoring, and the advantages of deep learning, generating prediction from raw 3D OCT scans, without the need for extracting a predefined set of quantitative biomarkers. We demonstrate, in an extensive set of evaluations, based on two large longitudinal datasets with 231 eyes from 121 patients for internal evaluation, and 280 eyes from 140 patients for the external evaluation, that this model improves the risk estimation performance over standard deep learning classification models.

Structural and biophysical characterization of the secreted, ß-helical adhesin EtpA of Enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) is a diarrhoeal pathogen associated with high morbidity and mortality especially among young children in developing countries. At present, there is no vaccine for ETEC. One candidate vaccine antigen, EtpA, is a conserved secreted adhesin that binds to the tips of flagellae to bridge ETEC to host intestinal glycans. EtpA is exported through a Gram-negative, two-partner secretion system (TPSS, type Vb) comprised of the secreted EtpA passenger (TpsA) protein and EtpB (TpsB) transporter that is integrated into the outer bacterial membrane. TpsA proteins share a conserved, N-terminal TPS domain followed by an extensive C-terminal domain with divergent sequence repeats. Two soluble, N-terminal constructs of EtpA were prepared and analysed respectively including residues 67 to 447 (EtpA67-447) and 1 to 606 (EtpA1-606). The crystal structure of EtpA67-447 solved at 1.76 Å resolution revealed a right-handed parallel ß-helix with two extra-helical hairpins and an N-terminal ß-strand cap. Analyses by circular dichroism spectroscopy confirmed the ß-helical fold and indicated high resistance to chemical and thermal denaturation as well as rapid refolding. A theoretical AlphaFold model of full-length EtpA largely concurs with the crystal structure adding an extended ß-helical C-terminal domain after an interdomain kink. We propose that robust folding of the TPS domain upon secretion provides a template to extend the N-terminal ß-helix into the C-terminal domains of TpsA proteins.

NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma.

∼30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Although anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

Progression Dynamics of Early versus Later Stage Atrophic Lesions in Nonneovascular Age-Related Macular Degeneration Using Quantitative OCT Biomarker Segmentation.

PURPOSE: To investigate the progression of geographic atrophy secondary to nonneovascular age-related macular degeneration in early and later stage lesions using artificial intelligence-based precision tools. DESIGN: Retrospective analysis of an observational cohort study. SUBJECTS: Seventy-four eyes of 49 patients with ≥ 1 complete retinal pigment epithelial and outer retinal atrophy (cRORA) lesion secondary to age-related macular degeneration were included. Patients were divided between recently developed cRORA and lesions with advanced disease status. METHODS: Patients were prospectively imaged by spectral-domain OCT volume scans. The study period encompassed 18 months with scheduled visits every 6 months. Growth rates of recent cRORA-converted lesions were compared with lesions in an advanced disease status using mixed effect models. MAIN OUTCOME MEASURES: The progression of retinal pigment epithelial loss (RPEL) was considered the primary end point. Secondary end points consisted of external limiting membrane disruption and ellipsoid zone loss. These pathognomonic imaging biomarkers were quantified using validated deep-learning algorithms. Further, the ellipsoid zone/RPEL ratio was analyzed in both study cohorts. RESULTS: Mean (95% confidence interval [CI]) square root progression of recently converted lesions was 79.68 (95% CI, -77.14 to 236.49), 68.22 (95% CI, -101.21 to 237.65), and 84.825 (95% CI, -124.82 to 294.47) mm/half year for RPEL, external limiting membrane loss, and ellipsoid zone loss respectively. Mean square root progression of advanced lesions was 131.74 (95% CI, -22.57 to 286.05), 129.96 (95% CI, -36.67 to 296.59), and 116.84 (95% CI, -90.56 to 324.3) mm/half year for RPEL, external limiting membrane loss, and ellipsoid zone loss, respectively. RPEL (P = 0.038) and external limiting membrane disruption (P = 0.026) progression showed significant differences between the 2 study cohorts. Further recent converters had significantly (P < 0.001) higher ellipsoid zone/RPEL ratios at all time points compared with patients in an advanced disease status (1.71 95% CI, 1.12-2.28 vs. 1.14; 95% CI, 0.56-1.71). CONCLUSION: Early cRORA lesions have slower growth rates in comparison to atrophic lesions in advanced disease stages. Differences in growth dynamics may play a crucial role in understanding the pathophysiology of nonneovascular age-related macular degeneration and for the interpretation of clinical trials in geographic atrophy. Individual disease monitoring using artificial intelligence-based quantification paves the way toward optimized geographic atrophy management. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Point-to-point associations of drusen and hyperreflective foci volumes with retinal sensitivity in non-exudative age-related macular degeneration.

OBJECTIVES: To evaluate the quantitative impact of drusen and hyperreflective foci (HRF) volumes on mesopic retinal sensitivity in non-exudative age-related macular degeneration (AMD). METHODS: In a standardized follow-up scheme of every three months, retinal sensitivity of patients with early or intermediate AMD was assessed by microperimetry using a custom pattern of 45 stimuli (Nidek MP-3, Gamagori, Japan). Eyes were consecutively scanned using Spectralis SD-OCT (20° × 20°, 1024 × 97 × 496). Fundus photographs obtained by the MP-3 allowed to map the stimuli locations onto the corresponding OCT scans. The volume and mean thickness of drusen and HRF within a circle of 240 µm centred at each stimulus point was determined using automated AI-based image segmentation algorithms. RESULTS: 8055 individual stimuli from 179 visits from 51 eyes of 35 consecutive patients were matched with the respective OCT images in a point-to-point manner. The patients mean age was 76.85 ± 6.6 years. Mean retinal sensitivity at baseline was 25.7 dB. 73.47% of all MP-spots covered drusen area and 2.02% of MP-spots covered HRF. A negative association between retinal sensitivity and the volume of underlying drusen (p < 0.001, Estimate -0.991 db/µm3) and HRF volume (p = 0.002, Estimate -5.230 db/µm3) was found. During observation time, no eye showed conversion to advanced AMD. CONCLUSION: A direct correlation between drusen and lower sensitivity of the overlying photoreceptors can be observed. For HRF, a small but significant correlation was shown, which is compromised by their small size. Biomarker quantification using AI-methods allows to determine the impact of sub-clinical features in the progression of AMD.

eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content.

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5'-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.

Clinical validation for automated geographic atrophy monitoring on OCT under complement inhibitory treatment.

Geographic atrophy (GA) represents a late stage of age-related macular degeneration, which leads to irreversible vision loss. With the first successful therapeutic approach, namely complement inhibition, huge numbers of patients will have to be monitored regularly. Given these perspectives, a strong need for automated GA segmentation has evolved. The main purpose of this study was the clinical validation of an artificial intelligence (AI)-based algorithm to segment a topographic 2D GA area on a 3D optical coherence tomography (OCT) volume, and to evaluate its potential for AI-based monitoring of GA progression under complement-targeted treatment. 100 GA patients from routine clinical care at the Medical University of Vienna for internal validation and 113 patients from the FILLY phase 2 clinical trial for external validation were included. Mean Dice Similarity Coefficient (DSC) was 0.86 ± 0.12 and 0.91 ± 0.05 for total GA area on the internal and external validation, respectively. Mean DSC for the GA growth area at month 12 on the external test set was 0.46 ± 0.16. Importantly, the automated segmentation by the algorithm corresponded to the outcome of the original FILLY trial measured manually on fundus autofluorescence. The proposed AI approach can reliably segment GA area on OCT with high accuracy. The availability of such tools represents an important step towards AI-based monitoring of GA progression under treatment on OCT for clinical management as well as regulatory trials.