Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

TTF-1 status in early-stage lung adenocarcinoma is an independent predictor of relapse and survival superior to tumor grading.

OBJECTIVES: Thyroid transcription factor 1 (TTF-1) is a well-established independent prognostic factor in lung adenocarcinoma (LUAD), irrespective of stage. This study aims to determine if TTF-1's prognostic impact is solely based on histomorphological differentiation (tumor grading) or if it independently relates to a biologically more aggressive phenotype. We analyzed a large bi-centric LUAD cohort to accurately assess TTF-1's prognostic value in relation to tumor grade. PATIENTS AND METHODS: We studied 447 patients with resected LUAD from major German lung cancer centers (Berlin and Cologne), correlating TTF-1 status and grading with clinical, pathologic, and molecular data, alongside patient outcomes. TTF-1's impact was evaluated through univariate and multivariate Cox regression. Causal graph analysis was used to identify and account for potential confounders, improving the statistical estimation of TTF-1's predictive power for clinical outcomes. RESULTS: Univariate analysis revealed TTF-1 positivity associated with significantly longer disease-free survival (DFS) (median log HR -0.83; p = 0.018). Higher tumor grade showed a non-significant association with shorter DFS (median log HR 0.30; p = 0,62 for G1 to G2 and 0.68; p = 0,34 for G2 to G3). In multivariate analysis, TTF-1 positivity resulted in a significantly longer DFS (median log HR -0.65; p = 0.05) independent of all other parameters, including grading. Adjusting for potential confounders as indicated by the causal graph confirmed the superiority of TTF-1 over tumor grading in prognostics power. CONCLUSIONS: TTF-1 status predicts relapse and survival in LUAD independently of tumor grading. The prognostic power of tumor grading is limited to TTF-1-positive patients, and the effect size of TTF-1 surpasses that of tumor grading. We recommend including TTF1 status as a prognostic factor in the diagnostic guidelines of LUAD.

Evaluating Contrast Sensitivity in Early and Intermediate Age-Related Macular Degeneration With the Quick Contrast Sensitivity Function.

Purpose: The purpose of this study was to describe, validate, and compare the contrast sensitivity functions (CSFs) acquired with the novel quick CSF (qCSF) method from patients with early and intermediate age-related macular degeneration (eAMD and iAMD) and healthy controls. Methods: This is a cross-sectional analysis of contrast sensitivity (CS) and visual acuity (VA) baseline data from the prospective Multimodal Functional and Structural Visual System Characterization (MUMOVI) study. The qCSF testing was conducted with the manifold contrast vision meter (Adaptive Sensory Technology, San Diego, CA, USA). CS levels at spatial frequencies from 1 cycle per degree (CPD) to 18 CPD, the area underneath the logarithmic contrast sensitivity function (AULCSF), and contrast acuity (CA) were analyzed. The association of functional metrics with variables of interest was tested with linear models. Results: Ninety-four study eyes from 94 study patients were included in the analysis (13 patients with eAMD, 33 patients with iAMD, and 48 healthy controls). Significant differences between the eAMD and the iAMD model estimates were only found for CS at 1 CPD (t value = -2.9, P value = 0.006) and CS at 1.5 CPD (-2.7, 0.01). A specific association between smoking years and CS at 1 CPD (P = 0.02) and CS at 1.5 CPD (P = 0.03) could be described in patients with AMD. Conclusions: The qCSF testing allows the fast measurement of the whole CSF, enabling the integration into clinical routine. We showed that novel qCSF-derived metrics detect slight functional differences between AMD stages, which testing by Pelli-Robson charts or VA testing would miss. This study, therefore, yields novel qCSF-derived candidate metrics for therapeutic trials in AMD.

The Optical Coherence Tomography and Microperimetry Biomarker Evaluation in Patients with Geographic Atrophy (OMEGA) Study: Design and Baseline Characteristics - OMEGA Report 1.

INTRODUCTION: The aim of this study was to describe the design and the participants' baseline characteristics of a prospective natural history study of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: The optical coherence tomography (OCT) and microperimetry biomarker evaluation in patients with GA (OMEGA) study was conducted at a tertiary referral center (ClinicalTrials.gov identifier: NCT05963646). Participants were followed for 12 months during 4 visits (baseline and follow-up exams at weeks 12, 24, and 48) with best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity, low-luminance visual acuity (LLVA), and quick contrast sensitivity function testing. Further, participants underwent spectral-domain OCT, OCT angiography, fundus autofluorescence imaging, and mesopic microperimetry testing. RESULTS: Thirty participants (median [IQR] age of 79 [77, 84] years) and 37 study eyes were included with a (median [IQR]) GA area of 1.40 mm2 (0.49, 5.24) at baseline. Out of 37 study eyes, six developed macular neovascularizations (16%). The study-eye best-corrected visual acuity was (median [IQR]) 0.18 logarithm of the minimum angle of resolution (logMAR) (0.06, 0.26), LLVA 0.66 logMAR (0.36, 0.88), and the microperimetry mean sensitivity 18.4 dB (9.21, 20.9). The highest correlation between square root GA area and a visual function test was evident for LLVA (R2 of 0.578), followed by area under the log contrast sensitivity function curve (0.519) and microperimetral retinal sensitivity (0.487). CONCLUSION: This report lays out the design and baseline characteristics of the OMEGA study, which aims to contribute to the understanding of the natural history of GA. The OMEGA study will provide estimates of the ability to detect change and retest reliability for a panel of structure and functional assessments.

Comparison of Novel Volumetric Microperimetry Metrics in Intermediate Age-Related Macular Degeneration: PINNACLE Study Report 3.

Purpose: To investigate and compare novel volumetric microperimetry (MP)-derived metrics in intermediate age-related macular degeneration (iAMD), as current MP metrics show high variability and low sensitivity. Methods: This is a cross-sectional analysis of microperimetry baseline data from the multicenter, prospective PINNACLE study (ClinicalTrials.gov NCT04269304). The Visual Field Modeling and Analysis (VFMA) software and an open-source implementation (OSI) were applied to calculate MP-derived hill-of-vison (HOV) surface plots and the total volume (VTOT) beneath the plots. Bland-Altman plots were used for methodologic comparison, and the association of retinal sensitivity metrics with explanatory variables was tested with mixed-effects models. Results: In total, 247 eyes of 189 participants (75 ± 7.3 years) were included in the analysis. The VTOT output of VFMA and OSI exhibited a significant difference (P < 0.0001). VFMA yielded slightly higher coefficients of determination than OSI and mean sensitivity (MS) in univariable and multivariable modeling, for example, in association with low-luminance visual acuity (LLVA) (marginal R2/conditional R2: VFMA 0.171/0.771, OSI 0.162/0.765, MS 0.133/0.755). In the multivariable analysis, LLVA was the only demonstrable predictor of VFMA VTOT (t-value, P-value: -7.5, <0.001) and MS (-6.5, <0.001). Conclusions: The HOV-derived metric of VTOT exhibits favorable characteristics compared to MS in evaluating retinal sensitivity. The output of VFMA and OSI is not exactly interchangeable in this cross-sectional analysis. Longitudinal analysis is necessary to assess their performance in ability-to-detect change. Translational Relevance: This study explores new volumetric MP endpoints for future application in therapeutic trials in iAMD and reports specific characteristics of the available HOV software applications.

Intratumoral Heterogeneity of Molecular Subtypes in Muscle-invasive Bladder Cancer-An Extensive Multiregional Immunohistochemical Analysis.

BACKGROUND: Molecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant settings. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients. OBJECTIVE: To comprehensively assess the ITH of molecular subtypes in a cohort of muscle-invasive BC. DESIGN, SETTING, AND PARTICIPANTS: A total of 251 patients undergoing radical cystectomy were screened. Three cores of the tumor center (TC) and three cores of the invasive tumor front (TF) of each patient were assembled in a tissue microarray. Molecular subtypes were determined employing 12 pre-evaluated immunohistochemical markers (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3, TUBB2B, EPCAM, CDH1, and vimentin). A total of 18 072 spots were evaluated, of which 15 002 spots were assessed based on intensity, distribution, or combination. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Allocation to one of five different molecular subtypes-urothelial like, genomically unstable, small-cell/neuroendocrine like, basal/squamous cell carcinoma like, and mesenchymal like-was conducted for each patient for the complete tumor, individual cores, TF, and TC separately. The primary objective was to assess the ITH between the TF and TC (n = 208 patients). The secondary objective was the evaluation of multiregion ITH (n = 191 patients). An analysis of the composition of ITH cases, association with clinicopathological parameters, and prognosis was conducted. RESULTS AND LIMITATIONS: ITH between the TF and TC was seen in 12.5% (n = 26/208), and ITH defined by at least two different subtypes of any location was seen in 24.6% (n = 47/191). ITH was more frequent in locally confined (pT2) versus advanced (pT ≥3) BC stages (38.7% vs 21.9%, p = 0.046), and pT4 BC presented with significantly more basal subtypes than pT2 BC (26.2% vs 11.5%, p = 0.049). In our cohort, there was no association of subtype ITH with prognosis or accumulation of specific molecular subtypes in ITH cases. The key limitations were missing transcriptomic and mutational genetic validation as well as investigation of ITH beyond subtypes. CONCLUSIONS: Several molecular subtypes can be found in nearly every fourth case of muscle-invasive BC, when using immunohistochemistry. ITH must be given due consideration for subtype-guided strategies in BC. Genomic validation of these results is needed. PATIENT SUMMARY: Different molecular subtypes can be found in many cases of muscle-invasive bladder cancer. This might have implications for individualized, subtype-based therapeutic approaches.

Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol.

AIMS: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD. METHODS: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models. CONCLUSIONS: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

Intraocular lens power calculation in eyes with previous corneal refractive surgery.

Intraocular lens (IOL) power calculation after corneal refractive surgery (CRS) becomes an expanding challenge for ophthalmologists as more and more cataract surgeries after CRS are required. These patients typically also have high expectations as to visual performance. Conventional IOL power calculation schemes frequently provide inaccurate results in these cases. This review aims to summarize and recommend currently available IOL power calculation methods for eyes with the most common CRS methods: radial keratotomy (RK), photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), and small incision lenticule extraction (SMILE). To this end, biometry measuring methods and IOL formulas will be explained and combinations of both are proposed. In synopsis, it is evident that the latest generation of vergence formulas exhibit favorable IOL power prediction accuracy in post-CRS eyes, even though the predictive precision of methods in eyes without CRS is not attained. Ray tracing computation, intraoperative aberrometry, and machine learning-based formulas hold potential to further improve refractive outcomes in post-CRS eyes.

Effect of intracorneal ring segment implantation on high order aberrations comparing patients with eccentric versus central keratoconus.

PURPOSE: To assess potential differences between central and eccentric cones in the aberrometric corneal profile and in visual and keratometric outcomes 6 months after intracorneal ring segment (ICRS) implantation for keratoconus. METHODS: This study compared two groups consisting of 12 patients each, with central or eccentric keratoconus who were treated with femtosecond laser-assisted Keraring implantation. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, keratometric readings and higher order aberrations (HOAs) including high order aberrations root mean square (HOARMS), coma, spherical aberration and trefoil were measured preoperatively and 6 months after ICRS implantation. RESULTS: Trefoil and spherical aberration were significantly reduced after ICRS implantation compared to preoperative values in eccentric keratoconus (Trefoil, p = 0.0049; Spherical aberration, p < 0.0001). In central keratoconus spherical aberration was reduced not significantly after ICRS implantation compared to preoperative values (p = 0.087). Coma showed a significant reduction in central (p = 0.0001) and in eccentric keratoconus (p = 0.0001). The reduction of spherical aberration in central keratoconus was significantly positively correlated to improvement in UDVA (Pearson's correlation coefficient, r = -0.66; p = 0.02). In eccentric keratoconus there was a significant positive correlation between reduction of trefoil and improvement in UDVA (Spearmans R, r = -0.69; p = 0.01). CONCLUSION: Patients both with central and eccentric keratoconus benefit from ICRS implantation. Specifically, our data provide a slightly higher gain in visual performance for eccentric cones 6 month after ICRS implantation, which is accentuated by a greater reduction in spherical aberration and trefoil. Improvements in UDVA are positively correlated with reductions in HOAs.

Prognostic Impact of Acute Cardiovascular Events in COVID-19 Hospitalized Patients-Results from the CORONA Germany Study.

BACKGROUND: Acute myocardial injury (AMJ), assessed by elevated levels of cardiac troponin, is associated with fatal outcome in coronavirus disease 2019 (COVID-19). However, the role of acute cardiovascular (CV) events defined by clinical manifestation rather than sole elevations of biomarkers is unclear in hospitalized COVID-19 patients. OBJECTIVE: The aim of this study was to investigate acute clinically manifest CV events in hospitalized COVID-19 patients. METHODS: From 1 March 2020 to 5 January 2021, we conducted a multicenter, prospective, epidemiological cohort study at six hospitals from Hamburg, Germany (a portion of the state-wide 45-center CORONA Germany cohort study) enrolling all hospitalized COVID-19 patients. Primary endpoint was occurrence of a clinically manifest CV-event. RESULTS: In total, 132 CV-events occurred in 92 of 414 (22.2%) patients in the Hamburg-cohort: cardiogenic shock in 10 (2.4%), cardiopulmonary resuscitation in 12 (2.9%), acute coronary syndrome in 11 (2.7%), de-novo arrhythmia in 31 (7.5%), acute heart-failure in 43 (10.3%), myocarditis in 2 (0.5%), pulmonary-embolism in 11 (2.7%), thrombosis in 9 (2.2%) and stroke in 3 (0.7%). In the Hamburg-cohort, mortality was 46% (42/92) for patients with a CV-event and 33% (27/83) for patients with only AMJ without CV-event (OR 1.7, CI: (0.94-3.2), p = 0.077). Mortality was higher in patients with CV-events (Odds ratio(OR): 4.8, 95%-confidence-interval(CI): [2.9-8]). Age (OR 1.1, CI: (0.66-1.86)), atrial fibrillation (AF) on baseline-ECG (OR 3.4, CI: (1.74-6.8)), systolic blood-pressure (OR 0.7, CI: (0.53-0.96)), potassium (OR 1.3, CI: (0.99-1.73)) and C-reactive-protein (1.4, CI (1.04-1.76)) were associated with CV-events. CONCLUSION: Hospitalized COVID-19 patients with clinical manifestation of acute cardiovascular events show an almost five-fold increased mortality. In this regard, the emergence of arrhythmias is a major determinant.

Effect of prolactin on normal and keratoconus human corneal stromal fibroblasts in vitro.

PURPOSE: To examine the effect of prolactin (PRL) on human corneal stromal fibroblasts (CSFs), derived from healthy individuals and from keratoconus (KC) patients, in vitro, specifically assessing physiological and elevated PRL concentrations as apparent during pregnancy. METHODS: Eye bank corneas of 3 female and 3 male healthy individuals as well as the corneal buttons of 3 female and 3 male KC patients were utilized for this study. The endothelium of the cornea was removed with sterile surgical scalpels, the probes were washed repeatedly with Dulbecco's PBS and corneoscleral rims were trimmed off. Subsequently the corneal stroma was digested with collagenase type I and the harvested CSFs were cultured. We then examined (1) cell proliferation, (2) cell viability and (3) cytokine release of CSFs upon exposure to prolactin in vitro. RESULTS: With respect to viability and proliferation our experiments did not show significant differences between CSFs exposed to different PRL concentrations. Our data show a significantly lower IL-8 concentration in normal CSFs exposed to 10ng/ml PRL compared to 0ng/ml and 1000ng/ml at 5 hours post exposition. Moreover, we can report significantly lower secretion of IL-8, IL-6, HGF, VEGF and FGFb in KC CSFs compared to normal CSFs, independent of PRL exposure, as determined by cytokine ELISA. CONCLUSION: Our data in part points towards corneal cytokine secretion as a possible link between altered stromal PRL concentrations and KC progression. However, in our small dataset a significant influence of PRL concentration on cytokine secretion can only be described for IL-8 in normal CSFs. Further our results contribute to existing reports on the importance of cytokines in KC development, with an emphasis on significantly lower cytokine secretion in KC CSFs compared to normal controls.