Space Shuttle/TDRSS communication and tracking systems analysis

In order to evaluate the technical and operational problem areas and provide a recommendation, the enhancements to the Tracking and Data Delay Satellite System (TDRSS) and Shuttle must be evaluated through simulation and analysis. These enhancement techniques must first be characterized, then modeled mathematically, and finally updated into LinCsim (analytical simulation package). The LinCsim package can then be used as an evaluation tool. Three areas of potential enhancements were identified: shuttle payload accommodations, TDRSS SSA and KSA services, and shuttle tracking system and navigation sensors. Recommendations for each area were discussed

Translational Retinal Research and Therapies.

The following review summarizes the state of the art in representative aspects of gene therapy/translational medicine and evolves from a symposium held at the School of Veterinary Medicine, University of Pennsylvania on November 16, 2017 honoring Dr. Gustavo Aguirre, recipient of ARVO's 2017 Proctor Medal. Focusing on the retina, speakers highlighted current work on moving therapies for inherited retinal degenerative diseases from the laboratory bench to the clinic

Reply to Townes-Anderson: RPE65 Gene Therapy Does Not Alter the Natural History of Retinal Degeneration

We appreciate the interest shown by TownesAnderson in our article examining the natural history of retinal degeneration in Leber congenital amaurosis caused by retinal pigment epithelium-specific protein 65kDa (RPE65) mutations and evaluating the consequences of gene augmentation therapy. Townes-Anderson’s remarks focused on the final phrase of the last sentence of the Discussion of our article. In the full sentence, we suggested that in the future, agents to reduce cell death could be delivered in combination with a more advanced version of the gene augmentation therapy that reaches not only remaining rods and extrafoveal cones but also foveal cone photoreceptors

Cone Deactivation Kinetics and GRK1/GRK7 Expression in Enhanced S Cone Syndrome Caused by Mutations in NR2E3

PURPOSE: To determine the relationship between cone deactivation kinetics in patients with the enhanced S cone syndrome (ESCS) caused by mutations in NR2E3 and the immunoreactivity to G-protein-coupled receptor kinase 1 (GRK1) and GRK7. METHODS: Electroretinogram (ERG) photoresponses were used to investigate activation kinetics of cones with a model of cone phototransduction. Deactivation kinetics of cones after bright flashes was quantified with a paired-flash ERG paradigm. Immunocytochemistry was performed with antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue. RESULTS: Activation kinetics of long/middle-wavelength-sensitive (L/M) cone-mediated responses in patients with ESCS were similar to those of normal L/M cones. Activation kinetics of ESCS short-wavelength-sensitive (S) cones, when compared with normal L/M cone responses evoked by the same stimulus, were slower by an amount consistent with the expected differences in spectral sensitivities. After bright flashes chosen to evoke identical activation kinetics, ESCS S cones deactivated much more slowly than ESCS or normal L/M cones. Normal human retina revealed strongly labeled cone outer segments with anti-GRK1 and anti-GRK7. In an ESCS retina, outer segments positive for L/M opsin were strongly labeled with anti-GRK1, whereas outer segments positive for S opsin showed no detectable GRK1 reactivity. GRK7 labeling was absent in all photoreceptors of the ESCS retina. CONCLUSIONS: The cone-dominant human retina resulting from NR2E3 mutations affords greater understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors. Normal deactivation kinetics in human L/M cones can occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is present but GRK1 is deficient in Oguchi disease. Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient

Visual Acuity Loss and Associated Risk Factors in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 2)

PURPOSE: To examine the association between characteristics of Stargardt disease and visual acuity (VA), to estimate the longitudinal rate of VA loss, and to identify risk factors for VA loss. DESIGN: Retrospective, multicenter cohort study. PARTICIPANTS: A total of 176 patients (332 eyes) with molecularly and clinically confirmed Stargardt disease enrolled from the United States and Europe. METHODS: Standardized data report forms were used to collect retrospective data on participants' characteristics and best-corrected or presenting VA from medical charts. Linear models with generalized estimating equations were used to estimate the cross-sectional associations, and linear mixed effects models were used to estimate the longitudinal VA loss. MAIN OUTCOME MEASURES: Yearly change in VA. RESULTS: The median duration of observation was 3.6 years. At baseline, older age of symptom onset was associated with better VA, and a longer duration of symptoms was associated with worse VA. Longitudinal analysis estimated an average of 0.3 lines loss (P 30 years showed 0.4 lines slower change of VA per year (P = 0.01) compared with patients with onset age ≤14 years. CONCLUSIONS: Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets

Improvement in Vision: A New Goal for Treatment of Hereditary Retinal Degenerations

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention

Comparison of Short-Wavelength Reduced-Illuminance and Conventional Autofluorescence Imaging in Stargardt Macular Dystrophy

Purpose To compare grading results between short-wavelength reduced-illuminance and conventional autofluorescence imaging in Stargardt macular dystrophy. Design Reliability study. Methods setting: Moorfields Eye Hospital, London (United Kingdom). patients: Eighteen patients (18 eyes) with Stargardt macular dystrophy. observation procedures: A series of 3 fundus autofluorescence images using 3 different acquisition parameters on a custom-patched device were obtained: (1) 25% laser power and total sensitivity 87; (2) 25% laser power and freely adjusted sensitivity; and (3) 100% laser power and freely adjusted total sensitivity (conventional). The total area of 2 hypoautofluorescent lesion types (definitely decreased autofluorescence and poorly demarcated questionably decreased autofluorescence) was measured. main outcome measures: Agreement in grading between the 3 imaging methods was assessed by kappa coefficients (κ) and intraclass correlation coefficients. Results The mean ± standard deviation area for images acquired with 25% laser power and freely adjusted total sensitivity was 2.04 ± 1.87 mm2 for definitely decreased autofluorescence (n = 15) and 1.86 ± 2.14 mm2 for poorly demarcated questionably decreased autofluorescence (n = 12). The intraclass correlation coefficient (95% confidence interval) was 0.964 (0.929, 0.999) for definitely decreased autofluorescence and 0.268 (0.000, 0.730) for poorly demarcated questionably decreased autofluorescence. Conclusions Short-wavelength reduced-illuminance and conventional fundus autofluorescence imaging showed good concordance in assessing areas of definitely decreased autofluorescence. However, there was significantly higher variability between imaging modalities for assessing areas of poorly demarcated questionably decreased autofluorescence

Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration

The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases

Phenotypic marker for early disease detection in dominant late-onset retinal degeneration

PURPOSE. To define early disease expression in autosomal dominant late-onset retinal degeneration (L-ORD), a retinopathy that becomes symptomatic after age 50 and is characterized histopathologically by sub-RPE deposits. METHODS. Three families with L-ORD were included; two families had postmortem eye donors with retina-wide sub-RPE deposits. Six patients with severe visual loss (ages 62-93) were examined clinically, and 17 available individuals (ages 35-60) at a 50:50 risk to inherit L-ORD were also studied with dark adaptometry. A short-term trial of vitamin A at 50,000 IU/day was conducted in three members. Three-year follow-up examinations were performed in a subset of members. RESULTS. Family 1 had 12 available members at risk. On initial examination, only one member had fundus abnormalities: yellow-white punctate lesions in the midperipheral fundus. Darkadaptation kinetics were abnormal in 6 of 12. The youngest age with an abnormality was 35. Family 2 had two available members at risk, both of whom had punctate fundus lesions and abnormal dark adaptation. Family 3 had three available members at risk. One had fundus lesions and abnormal dark adaptation, whereas the others had normal fundi and normal adaptometry. Vitamin A accelerated adaptation kinetics but not to normal rates. Three-year follow-up examinations demonstrated further slowing of adaptation kinetics, whereas rod and cone thresholds remained unchanged. CONCLUSIONS. Dark-adaptation abnormalities can precede symptoms and funduscopic signs of L-ORD by at least a decade. Short-term, high-dose vitamin A accelerates the kinetics of dark adaptation to a limited degree. The results contribute clues about early pathophysiology of this retinal degeneration and provide additional power for genetic mapping of the L-ORD locus. (Invest Ophthalmol Vis Sci

Groupwise Multimodal Image Registration using Joint Total Variation

In medical imaging it is common practice to acquire a wide range of modalities (MRI, CT, PET, etc.), to highlight different structures or pathologies. As patient movement between scans or scanning session is unavoidable, registration is often an essential step before any subsequent image analysis. In this paper, we introduce a cost function based on joint total variation for such multimodal image registration. This cost function has the advantage of enabling principled, groupwise alignment of multiple images, whilst being insensitive to strong intensity non-uniformities. We evaluate our algorithm on rigidly aligning both simulated and real 3D brain scans. This validation shows robustness to strong intensity non-uniformities and low registration errors for CT/PET to MRI alignment. Our implementation is publicly available at https://github.com/brudfors/coregistration-njtv