Progression of Age-Related Macular Degeneration Among Individuals Homozygous for Risk Alleles on Chromosome 1 (CFH-CFHR5) or Chromosome 10 (ARMS2/HTRA1) or Both

Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized. Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss. Design, Setting, and Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy. Main Outcomes and Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines. Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years). Conclusions and Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials

Distinct Genetic Risk Profile of the Rapidly Progressing Diffuse-Trickling Subtype of Geographic Atrophy in Age-Related Macular Degeneration (AMD)

PURPOSE. To genetically characterize a subphenotype of geographic atrophy (GA) in AMD associated with rapid progression and a diffuse-trickling appearance on fundus autofluorescence imaging. METHODS. Patients from the Fundus Autofluorescence in Age-Related Macular Degeneration Study were phenotyped for diffuse-trickling GA (dt-GA; n = 44). DNA was analyzed for 10 known AMD-associated genetic variants. A genetic risk score (GRS) was calculated and compared with patients with nondiffuse-trickling GA (ndt-GA; n = 311) and individuals from the 1000 genomes project (1000G; n = 267). Given the phenotypic overlap between diffuse trickling and late-onset retinal degeneration (LORD), all C1QTNF5 exons and their exon/ intron boundaries were sequenced. RESULTS. A statistically significant difference in allele frequencies between dt-GA and ndt-GA were found for CFH: rs1061170 and CFH: rs800292 (P-corrected = 0.03). The ARMS2 variant rs10490924 was significantly more frequent in dt-GA than in 1000G individuals (P-corrected < 0.01). The GRS of dt-GA patients was in-between the score of the 1000G individuals and that of patients with ndt-GA, significantly differing from both (P-corrected < 0.01). Sequencing of C1QTNF5 revealed 28 unique variants although none showed a statistically significant association with dt-GA when compared with 1000G individuals. CONCLUSIONS. The dt-GA phenotype shows a remarkably different genetic risk profile from other GA phenotypes secondary to AMD. Disease-associated C1QTNF5 mutations were not identified. Together, these results suggest that the dt-GA phenotype is associated with a genetic background substantially different from other GA phenotypes and underlines the necessity to refine the clinical phenotyping, specifically when aiming for individualized therapies in AMD

Helden in der Schule. Akten der Tagung Kloster Banz 2014

Ausgehend von der Feststellung, dass die Integration mittelalterlicher Texte im Deutschunterricht in der Schulpraxis weitgehend ein Desiderat darstellt, präsentierten Beitragende aus Schule und Wissenschaft bei der Tagung „Helden in der Schule“ im Oktober 2014 ihre Projekte und Ideen zu und Erfahrungen mit der Implementation germanistisch-mediävistischer Inhalte im Deutschunterricht. Dabei reichen die Beiträge von allgemeinen Überlegungen zum Nutzen mittelalterlicher Literatur in der Schule über konkrete Unterrichtsentwürfe bis hin zur Umsetzung in der Waldorfschule und der Integration schulbezogener Lehrveranstaltungen in der Universität. Bei aller Verschiedenheit in den Herangehensweisen wird in allen Beiträgen eindrucksvoll deutlich gemacht, dass mittelalterliche Literatur auch im 21. Jahrhundert überaus lohnend in die Unterrichtspraxis einbezogen werden kann.Since medieval texts are not treated enough in school, lecturers working in school and university presented their projects, ideas and experiences concerning the implementation of German-mediavistic contents in German school lessons during the conference “Heroes in School” in October 2014. The topics concern general reflection about the profitability of medieval literature in school, concrete lesson plans, the implementation in Rudolf Steiner schools, the integration of seminars in university that deal with the work in school etc. All articles demonstrate that the integration of medieval literature in school worth the effort – also in the 21st century

Progression of Late-Onset Stargardt Disease

PURPOSE. Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure. METHODS. We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset >= 45 years. We analyzed RPE atrophy progression on fundus autofluorescence and near-infrared reflectance imaging using semiautomated software and a linear mixed model. We performed sample size calculations to assess the power in a simulated 2-year interventional study and assessed visual endpoints using time-to-event analysis. RESULTS. Over time, progression of RPE atrophy was observed (mean: 0.22 mm/year, 95% confidence interval [CI]: 0.19-0.27). By including only patients with bilateral RPE atrophy in a future trial, 32 patients are needed to reach a power of 83.9% (95% CI: 83.1-84.6), assuming a fixed therapeutic effect size of 30%. We found a median interval between disease onset and visual acuity decline to 20/32, 20/80, and 20/200 of 2.74 (95% CI: 0.54-4.41), 10.15 (95% CI: 6.13-11.38), and 11.38 (95% CI: 6.13-13.34) years, respectively. CONCLUSIONS. We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high

CFH, C3 and ARMS2 Are Significant Risk Loci for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to AMD

Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL- 12–dependent IFN-? immunity and IL-23–dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL- 12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL- 23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that aß T, ?d T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-? in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-? in response to IL-23. We also show that the development of IFN-?–producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R– and IL-12Rß2–deficient than IL-12Rß1–deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-?, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-?–dependent immunity to mycobacteria, both individually and much more so cooperatively

Schwierigkeiten und Potentiale der Kunsttherapie mit erwachsenen Flüchtlingen : Mit Beispielen der Kunsttherapie im Psychosozialen Zentrum für Flüchtlinge in Nürnberg

Die Kunsttherapie findet in der psychosozialen Versorgung von Geflüchteten immer mehr Anklang. Die Masterarbeit behandelt darum die Frage, wo die „Schwierigkeiten und Potentiale der Kunsttherapie mit erwachsenen Flüchtlingen“ liegen. Hierbei werden die Stärken der Kunsttherapie mit Geflüchteten untersucht, die allgemeinen Schwierigkeiten in dieser Arbeit, die Förderung der Handlungsfähigkeit der Kunsttherapieklienten sowie der Umgang mit einem stark ausgeprägten Merkmal wie strenge Religiosität. Mit der Kombination verschiedener Methoden wurden aus unterschiedlichen Perspektiven Daten gesammelt, um diese Fragen sowohl mit quantitativen als auch qualitativen Ergebnissen zu beantworten. Zur Klärung der Fragen dienten zum einen Ergebnisse eines kunsttherapeutischen Evaluationsprojektes zum Thema „Förderung der Handlungsfähigkeit“ im Psychosozialen Zentrum für Flüchtlinge in Nürnberg mit drei Teilnehmern. Daneben sorgten vor allem die Resultate der schriftlichen Befragung anderer Kunsttherapeuten bundesweiter Behandlungszentren für eine vielschichtige Ergebnisdarstellung, die unmittelbar an der kunsttherapeutischen Praxis mit erwachsenen Flüchtlingen anknüpft