Publications by authors named "Ala Moshiri"

44 Publications

MicroRNA Signatures of the Developing Primate Fovea.

Front Cell Dev Biol 2021 8;9:654385. Epub 2021 Apr 8.

Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States.

Rod and cone photoreceptors differ in their shape, photopigment expression, synaptic connection patterns, light sensitivity, and distribution across the retina. Although rods greatly outnumber cones, human vision is mostly dependent on cone photoreceptors since cones are essential for our sharp visual acuity and color discrimination. In humans and other primates, the (fovea), a specialized region of the central retina, contains the highest density of cones. Despite the vast importance of the fovea for human vision, the molecular mechanisms guiding the development of this region are largely unknown. MicroRNAs (miRNAs) are small post-transcriptional regulators known to orchestrate developmental transitions and cell fate specification in the retina. Here, we have characterized the transcriptional landscape of the developing rhesus monkey retina. Our data indicates that non-human primate fovea development is significantly accelerated compared to the equivalent retinal region at the other side of the optic nerve head, as described previously. Notably, we also identify several miRNAs differentially expressed in the presumptive fovea, including miR-15b-5p, miR-342-5p, miR-30b-5p, miR-103-3p, miR-93-5p as well as the miRNA cluster miR-183/-96/-182. Interestingly, miR-342-5p is enriched in the nasal primate retina and in the peripheral developing mouse retina, while miR-15b is enriched in the temporal primate retina and increases over time in the mouse retina in a central-to-periphery gradient. Together our data constitutes the first characterization of the developing rhesus monkey retinal miRNome and provides novel datasets to attain a more comprehensive understanding of foveal development.
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http://dx.doi.org/10.3389/fcell.2021.654385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060505PMC
April 2021

Natural History and Predictors of Vision Loss in Eyes with Diabetic Macular Edema and Good Initial Visual Acuity.

Retina 2021 Mar 9. Epub 2021 Mar 9.

Department of Ophthalmology and Vision Science, University of California Davis, 4860 Y Street Suite 2400, Sacramento, CA, 95817, United States California Northstate University College of Medicine, 9700 W Taron Drive, Elk Grove, CA, 95757, United States University of Nevada, Reno School of Medicine, 1664 North Virginia Street, Reno, NV 89557-0357, United States Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, United States Department of Public Health Sciences/Division of Biostatistics, University of California Davis, 1 Shields Ave, Davis, CA, 95616, United States.

Purpose: To identify clinical and anatomic factors associated vision loss in eyes with treatment-naïve diabetic macular edema (DME) and good initial visual acuity (VA).

Methods: Retrospective cohort study following long-term history of eyes with untreated center-involving DME and baseline VA ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007-March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, VA, and diabetic retinopathy (DR) severity; and spectral domain-optical coherence tomography (SD-OCT) biomarkers including central subfield thickness (CST),intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy.

Results: 56 eyes (48 patients) with untreated DME and mean baseline VA of logMAR 0.05 ± 0.05 (Snellen 20/22) was followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio (HR) 1.04/year, P=0.0195), and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative DR (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the SD-OCT cyst diameter (HR 1.0, P = 0.0094).

Conclusions: In eyes with DME and good initial vision, those with older age and worse DR severity should be monitored closely for prompt treatment initiation when vision loss occurs.
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http://dx.doi.org/10.1097/IAE.0000000000003167DOI Listing
March 2021

Involving Patients in Their Own Health Care Choices-Altruism Begets Altruism.

JAMA Netw Open 2021 02 1;4(2):e210152. Epub 2021 Feb 1.

Division of Dermatology, Department of Medicine, University of Washington, Seattle.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.0152DOI Listing
February 2021

Identification of Patients with Pentosan Polysulfate Sodium-Associated Maculopathy through Screening of the Electronic Medical Record at an Academic Center.

J Ophthalmol 2020 17;2020:8866961. Epub 2020 Dec 17.

Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Sacramento, CA, USA.

Aims: This chart review of a quaternary academic medical center electronic medical record (EMR) aimed to identify patients at risk of development of maculopathy with exposure to pentosan polysulfate sodium (PPS).

Methods: A review of electronic medical records of a quaternary medical center of patients with either documented exposure to PPS or diagnosis of interstitial cystitis (IC) from 2007 to 2019 was performed for retinal imaging and visual acuity; the study was conducted in August of 2019.

Results: 216 charts were included for analysis, of which 96 had documented eye exams and 24 had retinal imaging done. We identified three patients with maculopathy in the context of long-term exposure to PPS via chart review, and one additional patient was identified by referral. The median PPS exposure duration was 11 years (range 7 to 19 years). Median logMAR BCVA OD 0.6 range was 0.0-1.9 (approximate Snellen equivalent 20/80 range (20/20-20/1600)) and OS 0.7 range was 0.1-1.9 (approximate Snellen equivalent 20/100 range (20/25-20/1600)). Ultrawidefield color fundus imaging and fundus autofluorescence revealed findings of pigmentary changes and patchy macular atrophy. Optical coherence tomography (OCT) demonstrated outer retinal thinning and increased choroidal transmission coincident with areas of atrophy seen on fundus imaging.

Conclusions: Less than half of patients at risk for development of maculopathy due to exposure to PPS had received eye examinations, suggesting that those at risk are not receiving adequate screening. We found two patients with PPS maculopathy who had relatively preserved central vision, one patient with bitemporal vision loss, and one patient who developed vision loss in both eyes.
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http://dx.doi.org/10.1155/2020/8866961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803106PMC
December 2020

Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay.

Genet Med 2021 Apr 8;23(4):661-668. Epub 2021 Jan 8.

Division of Medical Genetics, Department of Pediatric, Stanford University School of Medicine, Stanford, CA, USA.

Purpose: To identify novel genes associated with intellectual disability (ID) in four unrelated families.

Methods: Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A.

Results: Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals.

Conclusion: These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.
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http://dx.doi.org/10.1038/s41436-020-01047-zDOI Listing
April 2021

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

PLoS Genet 2020 12 28;16(12):e1009190. Epub 2020 Dec 28.

Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.
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http://dx.doi.org/10.1371/journal.pgen.1009190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822523PMC
December 2020

Off-Label Use as a Standard of Care.

Am J Ophthalmol 2021 04 14;224:A6-A8. Epub 2020 Oct 14.

Department of Ophthalmology & Visual Sciences, University of California, Davis, Davis, California, USA.

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http://dx.doi.org/10.1016/j.ajo.2020.09.014DOI Listing
April 2021

Quantitative Fundus Autofluorescence in Rhesus Macaques in Aging and Age-Related Drusen.

Invest Ophthalmol Vis Sci 2020 07;61(8):16

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Purpose: To employ quantitative fundus autofluorescence (qAF) imaging in rhesus macaques to noninvasively assess retinal pigment epithelial (RPE) lipofuscin in nonhuman primates (NHPs) as a model of aging and age-related macular degeneration (AMD).

Methods: The qAF imaging was performed on eyes of 26 rhesus macaques (mean age 18.8 ± 8.2 years, range 4-27 years) with normal-appearing fundus or with age-related soft drusen using a confocal scanning laser ophthalmoscope with 488 nm excitation and an internal fluorescence reference. Eyes with soft drusen also underwent spectral-domain optical coherence tomography imaging to measure drusen volume and height of individual drusen lesions. The qAF levels were measured from the perifoveal annular ring (quantitative autofluorescence 8 [qAF8]) using the Delori grid, as well as focally over individual drusen lesions in this region. The association between qAF levels and age, sex, and drusen presence and volume were determined using multivariable regression analysis.

Results: Mean qAF levels increased with age (P < 0.001) and were higher in females (P = 0.047). Eyes with soft drusen exhibited reduced mean qAF compared with age-matched normal eyes (P = 0.003), with greater drusen volume showing a trend toward decreased qAF levels. However, qAF levels are focally increased over most individual drusen (P < 0.001), with larger drusen appearing more hyperautofluorescent (R2 = 0.391, P < 0.001).

Conclusions: In rhesus macaques, qAF levels are increased with age and female sex, but decreased in eyes with soft drusen, similar to human AMD. However, drusen lesions appear hyperautofluorescent unlike those in humans, suggesting similarities and differences in RPE lipofuscin between humans and NHPs that may provide insight into drusen biogenesis and AMD pathogenesis.
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http://dx.doi.org/10.1167/iovs.61.8.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425688PMC
July 2020

Imaging oxygenation of retinal capillaries with depth resolution.

Proc Natl Acad Sci U S A 2020 06 18;117(26):14626-14628. Epub 2020 Jun 18.

Department of Ophthalmology and Vision Science, University of California Davis School of Medicine, Sacramento, CA 95817.

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http://dx.doi.org/10.1073/pnas.2008404117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334518PMC
June 2020

Phase I/II randomized study of proton beam with anti-VEGF for exudative age-related macular degeneration: long-term results.

Eye (Lond) 2020 12 13;34(12):2271-2279. Epub 2020 Feb 13.

Vitreoretinal Service, Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.

Background/objective: To determine if treatment of exudative age-related macular degeneration (eAMD) using proton beam therapy (PBT) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is safe and effective long term.

Subject/methods: Thirty eyes with newly diagnosed eAMD were enrolled in a phase I/II prospective, sham-controlled double-masked university study. Eyes were randomized 1:1:1-24 GyE, 16 GyE or sham radiation, and treated with three initial monthly intravitreal ranibizumab or bevacizumab. Subsequent anti-VEGF reinjection was based on monthly optical coherence tomography and examination for 2 years and standard of care thereafter.

Results: A total of 23 eyes completed 2-year study follow-up, of which 16 maintained monthly follow-up. Mean best-correct visual acuity (BCVA) at 2 years was similar among treatment groups (p > 0.05). The 24 GyE group required fewer anti-VEGF injections when compared with the sham group at 2 years (4.67 ± 1.9 vs 9.67 ± 3.5; p = 0.017). Extended follow-up (mean 4 years) available in 22 eyes showed persistent reduced need for anti-VEGF therapy among eyes treated with 24 GyE compared with sham radiation (2.0 ± 1.6 vs 4.84 ± 2.4 per year, p = 0.008). New and increasing geographic atrophy (GA), noted in some eyes in all treatment groups, resulted in decreased mean BCVA from baseline for the 24 GyE group on extended follow-up (p = 0.009). Possible mild radiation retinopathy noted in 15% of eyes was not visually significant.

Conclusions: Initial treatment combining PBT (24 GyE) with intravitreal anti-VEGF therapy appears to decrease the need for anti-VEGF reinjection in eyes with newly diagnosed eAMD. Radiation retinopathy risk was low and does not appear visually significant. Long-term vision was limited by GA development especially in the 24 GyE group.
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http://dx.doi.org/10.1038/s41433-020-0807-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784696PMC
December 2020

Retinal Vessel Density in Exudative and Nonexudative Age-Related Macular Degeneration on Optical Coherence Tomography Angiography.

Am J Ophthalmol 2020 04 16;212:7-16. Epub 2019 Dec 16.

Department of Ophthalmology and Vision Science, University of California, Davis, Sacramento, California. Electronic address:

Purpose: Although the choroid contributes to the pathogenesis of age-related macular degeneration (AMD), the role of retinal perfusion is unclear. We sought to compare retinal vascular measurements between eyes with nonexudative and exudative AMD using optical coherence tomography angiography (OCT-A).

Design: Retrospective, cross-sectional study.

Methods: OCT-A images were analyzed from 310 eyes of 182 patients (mean age ± standard deviation [SD], 78.8 ± 8.8 years) with nonexudative (54.2%) and exudative (45.8%) AMD to measure retinal vessel density (VD) from the superficial capillary plexus in the foveal, parafoveal, and full macular regions and foveal avascular zone (FAZ) area, perimeter, and circularity. Multivariate regressions were used to compare nonexudative and exudative AMD eyes and the impact of anti-vascular endothelial growth factor (anti-VEGF) treatments or geographic atrophy (GA).

Results: In eyes with AMD, VD decreases with age in the foveal (β = -0.211, P < .001), parafoveal (β = -0.305, P < .001), and full macular regions (β = -0.295, P < .001). Eyes with exudative AMD demonstrated lower VD, especially in the parafoveal (29.8% ± 6.3% vs 33.0% ± 5.7%, P < .001) and full regions (27.9% ± 6.2% vs 31.2% ± 5.5%, P < .001) compared with nonexudative AMD. There were no differences in FAZ area, perimeter, or circularity between the 2 groups (P = .503-.907). In eyes with exudative AMD, previous anti-VEGF treatments did not impact retinal vascular measurements (P = .324-.986). Nonexudative AMD severity and presence of central GA also impacted retinal VD and FAZ morphology.

Conclusions: Retinal VD is decreased in eyes with exudative AMD compared with nonexudative AMD but is unaffected by anti-VEGF treatments, suggesting a retinal vascular contribution to the pathogenesis of AMD.
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http://dx.doi.org/10.1016/j.ajo.2019.11.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113105PMC
April 2020

Real-world management and long-term outcomes of diabetic macular oedema with good visual acuity.

Eye (Lond) 2020 06 28;34(6):1108-1115. Epub 2019 Oct 28.

Department of Ophthalmology & Vision Sciences, University of California, Davis, Sacramento, CA, USA.

Purpose: To evaluate the management and long-term outcomes of patients with diabetic macular oedema (DMO) and good initial visual acuity in real-world settings.

Methods: We reviewed 122 eyes of 100 patients with treatment-naive DMO and initial best-corrected visual acuity (BCVA) of 20/25 or better. We assessed clinical characteristics, logMAR BCVA, central subfield thickness (CST), cumulative intravitreal injections and laser treatments at yearly intervals, and characteristics at time of initial treatment. Linear mixed effects models were used to identify predictors of visual outcomes.

Results: At presentation, mean BCVA was 0.057 ± 0.048 logMAR (Snellen 20/23) and mean CST was 288 ± 57 μm. After a median follow-up of 3 years, 51% of eyes underwent treatment. More eyes underwent intravitreal injection as initial treatment (54%), but lasers were initiated at an earlier time and at better BCVA. Final BCVA was associated with better BCVA (P < 0.001) and earlier timing (P = 0.017) at initial treatment, but not CST at first treatment (P = 0.634) or cumulative number of injections or lasers (P = 0.441-0.606).

Conclusion: DMO with good initial visual acuity should be monitored closely, as delay in treatment initiation is associated with worse visual outcomes. BCVA at time of initial treatment is the strongest determinant of final visual acuity.
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http://dx.doi.org/10.1038/s41433-019-0647-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253473PMC
June 2020

Cytoglobin deficiency potentiates Crb1-mediated retinal degeneration in rd8 mice.

Dev Biol 2020 02 18;458(2):141-152. Epub 2019 Oct 18.

Department of Ophthalmology and Vision Science, School of Medicine, U.C. Davis, Sacramento, CA, United States. Electronic address:

Purpose: The purpose of this study is to determine the effect of Cytoglobin (Cygb) deficiency on Crb1-related retinopathy. The Crb1 cell polarity complex is required for photoreceptor function and survival. Crb1-related retinopathies encompass a broad range of phenotypes which are not completely explained by the variability of Crb1 mutations. Genes thought to modify Crb1 function are therefore important targets of research. The biological function of Cygb involves oxygen delivery, scavenging of reactive oxygen species, and nitric oxide metabolism. However, the relationship of Cygb to diseases involving the Crb1 cell polarity complex is unknown.

Methods: Cygb knockout mice homozygous for the rd8 mutation (Cygb) were screened for ocular abnormalities and imaged using optical coherence tomography and fundus photography. Electroretinography was performed, as was histology and immunohistochemistry. Quantitative PCR was used to determine the effect of Cygb deficiency on transcription of Crb1 related cell polarity genes.

Results: Cygb mice develop an abnormal retina with severe lamination abnormalities. The retina undergoes progressive degeneration with the ventral retina more severely affected than the dorsal retina. Cygb expression is in neurons of the retinal ganglion cell layer and inner nuclear layer. Immunohistochemical studies suggest that cell death predominates in the photoreceptors. Electroretinography amplitudes show reduced a- and b-waves, consistent with photoreceptor disease. Cygb deficient retinas had only modest transcriptional perturbations of Crb1-related cell polarity genes. Cygb mice without the rd8 mutation did not exhibit obvious retinal abnormalities.

Conclusions: Cygb is necessary for retinal lamination, maintenance of cell polarity, and photoreceptor survival in rd8 mice. These results are consistent with Cygb as a disease modifying gene in Crb1-related retinopathy. Further studies are necessary to investigate the role of Cygb in the human retina.
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http://dx.doi.org/10.1016/j.ydbio.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995765PMC
February 2020

Genome-wide screening of mouse knockouts reveals novel genes required for normal integumentary and oculocutaneous structure and function.

Sci Rep 2019 08 1;9(1):11211. Epub 2019 Aug 1.

Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Sacramento, CA, United States.

Oculocutaneous syndromes are often due to mutations in single genes. In some cases, mouse models for these diseases exist in spontaneously occurring mutations, or in mice resulting from forward mutatagenesis screens. Here we present novel genes that may be causative for oculocutaneous disease in humans, discovered as part of a genome-wide screen of knockout-mice in a targeted single-gene deletion project. The International Mouse Phenotyping Consortium (IMPC) database (data release 10.0) was interrogated for all mouse strains with integument abnormalities, which were then cross-referenced individually to identify knockouts with concomitant ocular abnormalities attributed to the same targeted gene deletion. The search yielded 307 knockout strains from unique genes with integument abnormalities, 226 of which have not been previously associated with oculocutaneous conditions. Of the 307 knockout strains with integument abnormalities, 52 were determined to have ocular changes attributed to the targeted deletion, 35 of which represent novel oculocutaneous genes. Some examples of various integument abnormalities are shown, as well as two examples of knockout strains with oculocutaneous phenotypes. Each of the novel genes provided here are potentially relevant to the pathophysiology of human integumentary, or oculocutaneous conditions, such as albinism, phakomatoses, or other multi-system syndromes. The novel genes reported here may implicate molecular pathways relevant to these human diseases and may contribute to the discovery of novel therapeutic targets.
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http://dx.doi.org/10.1038/s41598-019-47286-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672016PMC
August 2019

Posterior Segment Complications and Impact on Long-Term Visual Outcomes in Eyes With a Type 1 Boston Keratoprosthesis.

Cornea 2019 Sep;38(9):1111-1116

Department of Ophthalmology and Vision Science, School of Medicine, University of California, Sacramento, CA.

Purpose: To determine the spectrum of retinal complications (RCs) in a cohort of eyes with a type 1 Boston keratoprosthesis (KPro).

Methods: All patients (36 eyes of 31 patients) who received a type 1 Boston KPro from January 2004 to December 2015 at the University of California, Davis, were included. Electronic medical records were reviewed for relevant clinical data. Demographic information, initial corneal diagnosis, postoperative course, posterior segment complications, preoperative and final visual acuity were tabulated and analyzed.

Results: Posterior segment complications after type 1 Boston KPro were identified in 56% of eyes (n = 20). They included retinal detachment (n = 11; 31%), retroprosthetic membrane (n = 10; 28%), endophthalmitis (n = 7; 19%), cystoid macular edema (n = 5; 14%), epiretinal membrane (n = 4; 11%), vitreous hemorrhage (n = 2; 6%), choroidal detachment (n = 2; 6%), retinal vein occlusion (n = 1; 3%), and macular hole (n = 1; 3%). During the average follow-up period of 53.8 months (median, 57.1 months; range, 1.8-108.7 months) after type 1 Boston KPro, final best-corrected visual acuity improved by a mean of 0.12 logarithm of the minimum angle of resolution (LogMAR) units (range, -2.26 to +2.26) overall. The proportion of eyes with final best-corrected visual acuity better than 20/200 was 2 of 20 (10%) in the group with RCs, in contrast to 7 of 16 eyes (44%) noted among eyes without RCs.

Conclusions: Long-term visual outcomes in eyes after type 1 Boston KPro may depend, in part, on maintaining a healthy posterior pole. Retinal detachment, in particular, may represent a threat to ultimate visual functioning. Regular examination of the peripheral fundus is recommended.
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http://dx.doi.org/10.1097/ICO.0000000000001983DOI Listing
September 2019

Long-term natural history of idiopathic epiretinal membranes with good visual acuity.

Eye (Lond) 2019 05 19;33(5):714-723. Epub 2019 Apr 19.

Department of Ophthalmology & Vision Sciences, University of California, Davis, Sacramento, CA, USA.

Background/objectives: To evaluate the long-term progression of idiopathic epiretinal membranes (iERMs) with good baseline visual acuity, and to identify predictors of visual decline.

Design: Retrospective case series SUBJECTS METHODS: We reviewed records of 145 eyes with iERM and best-corrected visual acuity (BCVA) of 20/40 or greater at presentation, including BCVA, lens status, and central macular thickness (CMT) at yearly visits; as well as anatomic biomarkers including vitreomacular adhesion, pseudohole, lamellar hole, intraretinal cysts, disorganization of the inner retinal layers (DRIL), and disruption of outer retinal layers. Linear mixed effects and mixed-effects Cox proportional hazards models were used to identify clinical and anatomic predictors of vision change and time to surgery.

Results: At presentation, mean BCVA was 0.17 ± 0.10 logMAR units (Snellen 20/30) and mean CMT was 353.3 ± 75.4 μm. After a median follow-up of 3.7 years (range 1-7 years), BCVA declined slowly at 0.012 ± 0.003 logMAR units/year, with phakic eyes declining more rapidly than pseudophakic eyes (0.019 ± 0.003 vs. 0.010 ± 0.004 logMAR units/year). Metamorphopsia, phakic lens status, lamellar hole, and inner nuclear layer cysts were associated with faster visual decline. Cumulative rates of progression to surgery were 2.9, 5.6, 12.2, and 21.1% at years 1-4. Visual symptoms, metamorphopsia, greater CMT, and disruption of outer retinal layers were associated with greater hazard for surgery.

Conclusion: Eyes with iERM and visual acuity ≥ 20/40 experience slow visual decline, with 21% of eyes requiring surgery after 4 years. Clinical and anatomic predictors of vision loss may be distinct from factors associated with earlier surgical intervention.
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http://dx.doi.org/10.1038/s41433-019-0397-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707144PMC
May 2019

The Management of Retinal Detachment: Techniques and Perspectives 2018.

J Ophthalmol 2019 3;2019:8185619. Epub 2019 Feb 3.

Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.

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http://dx.doi.org/10.1155/2019/8185619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377983PMC
February 2019

Ocular phenotypic consequences of a single copy deletion of the gene () in mice.

Mol Vis 2019 17;25:129-142. Epub 2019 Feb 17.

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA.

Purpose: To identify the effects of a single copy deletion of () in the mouse eye, the ocular phenotypic consequences of were determined in detail.

Methods: Complete ophthalmic examinations, as well as corneal esthesiometry, the phenol red thread test, intraocular pressure, and Fourier-domain optical coherence tomography were performed on and age-matched wild-type (WT) mice between eyelid opening (2 weeks after birth) and adulthood (2 months and 1 year after birth). Following euthanasia, enucleated eyes were characterized histologically.

Results: Microphthalmia with small palpebral fissures, corneal fibrosis, and reduced corneal sensation were common findings in the mice. Generalized corneal fibrosis precluded clinical examination of the posterior structures. Histologically, thinning and keratinization of the corneal epithelium were observed in the mice in comparison with the WT mice. Distorted collagen fiber arrangement and hypercellularity of keratocytes were observed in the stroma. Descemet's membrane was extremely thin and lacked an endothelial layer in the mice. The iris was adherent to the posterior cornea along most of its surface creating a distorted contour. Most of the eyes were microphakic with swollen fibers and bladder cells. The retinas of the mice were normal at 2 weeks and 2 months of age, but the presence of retinal abnormalities, including retinoschisis and detachment, was markedly increased in the mice at 1 year of age.

Conclusions: The results show that the heterozygous deletion of the gene in mice leads to complex ocular abnormalities, including microphthalmia, corneal fibrosis, anterior segment dysgenesis, and cataract.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382475PMC
June 2019

A nonhuman primate model of inherited retinal disease.

J Clin Invest 2019 02 22;129(2):863-874. Epub 2019 Jan 22.

Department of Ophthalmology & Vision Science, School of Medicine, UC Davis, Sacramento, California, USA.

Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.
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http://dx.doi.org/10.1172/JCI123980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355306PMC
February 2019

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Commun Biol 2018 21;1:236. Epub 2018 Dec 21.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.
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http://dx.doi.org/10.1038/s42003-018-0226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303268PMC
December 2018

Chronic lymphocytic leukaemia presenting as branch retinal artery occlusion and optic disc infiltration.

BMJ Case Rep 2018 Oct 12;2018. Epub 2018 Oct 12.

Department of Ophthalmology, UC Davis, Sacramento, California, USA.

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http://dx.doi.org/10.1136/bcr-2018-227691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194429PMC
October 2018

A Population Study of Common Ocular Abnormalities in C57BL/6N rd8 Mice.

Invest Ophthalmol Vis Sci 2018 05;59(6):2252-2261

Department of Ophthalmology & Vision Science, School of Medicine, University of California-Davis, Sacramento, California, United States.

Purpose: The purpose of this study was to quantify the frequency and severity of ocular abnormalities affecting wild-type C57BL/6N mice, the most common strain used worldwide for the creation of single-gene knockouts.

Methods: A total of 2773 animals (5546 eyes) were examined at one colony at UC Davis and in three more colonies at the Institut Clinique de la Souris in Strasbourg, France. Mice were examined at 15 to 16 weeks postnatal age by performing anterior segment biomicroscopy, posterior segment examination by indirect ophthalmoscopy, intraocular pressure measurement, and optical coherence tomography of anterior and posterior segment structures.

Results: Common ocular findings in the C57BL/6N strain included corneal deposits (3%), increased optical density of the anterior lens capsule (67%), punctate nuclear cataracts (98%), vitreous crystalline deposits (61%), hyaloid vascular remnant (6%), and retinal dysplasia attributed to the rd8 mutation (58%). Interestingly, retinal dysplasia was more common in male mice in all four breeding colonies evaluated in this study. The thickness of ocular tissues and compartments were measured by spectral-domain optical coherence tomography, including the central cornea, anterior chamber, vitreous, and retinal layers. Intraocular pressure was measured by rebound tonometry.

Conclusions: Ocular abnormalities are common in anterior and posterior segments of the C57BL/6N mouse, the most common background on which single-gene knockout mice have been made. It is important that vision scientists understand the extent and variability of ocular findings associated with this particular genetic background of mice.
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http://dx.doi.org/10.1167/iovs.17-23513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935295PMC
May 2018

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

Nat Commun 2018 01 18;9(1):288. Epub 2018 Jan 18.

Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Adriano Buzzati-Traverso Campus, Via E. Ramarini 32, Monterotondo Scalo, RM, 00015, Italy.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
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http://dx.doi.org/10.1038/s41467-017-01995-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773596PMC
January 2018

The Management of Retinal Detachment: Techniques and Perspectives.

J Ophthalmol 2017 23;2017:5807653. Epub 2017 Oct 23.

Department of Ophthalmology & Vision Science, University of California Davis Eye Center, Sacramento, CA, USA.

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http://dx.doi.org/10.1155/2017/5807653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694614PMC
October 2017

OUTCOMES OF PNEUMATIC RETINOPEXY PERFORMED BY VITREORETINAL FELLOWS.

Retina 2019 Jan;39(1):186-192

Department of Ophthalmology & Vision Science, University of California, Davis, Sacramento, California.

Purpose: To evaluate the anatomical and visual outcomes of patients who underwent pneumatic retinopexy by vitreoretinal fellows.

Methods: We included 198 eyes (198 patients) that underwent pneumatic retinopexy by vitreoretinal fellows at a single academic institution between November 2002 and June 2016. Main outcomes were single-operation success and final anatomical success in retinal reattachment, as well as visual acuity at 3 months and 6 months after treatment.

Results: Single-operation success rate was 63.6% at 3 months and 59.5% at 6 months. Final anatomical reattachment was achieved in 92.9% (n = 184) and 96.6% (n = 143) at 3 months and 6 months, respectively. Logarithm of the minimum angle of resolution visual acuity improved from 0.72 ± 0.1 (∼20/100 Snellen) at baseline to 0.36 ± 0.06 (∼20/40 Snellen) at 6 months (P < 0.001). There was no statistical difference in anatomical success rates or visual outcomes between cases performed by first- or second-year fellows (P > 0.50). Single-operation success was associated only with size of detachment (P = 0.01). Visual outcome was associated with macula status at baseline (P = 0.032) and number of reoperations (P < 0.001).

Conclusion: Anatomical and visual outcomes of fellow-performed pneumatic retinopexy are comparable with those reported in the previous literature.
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http://dx.doi.org/10.1097/IAE.0000000000001932DOI Listing
January 2019

Macular Fluid Reduces Reproducibility of Choroidal Thickness Measurements on Enhanced Depth Optical Coherence Tomography.

Am J Ophthalmol 2017 Dec 14;184:108-114. Epub 2017 Oct 14.

Department of Ophthalmology, University of California, Davis, Sacramento, California. Electronic address:

Purpose: To determine if different types of retinal fluid in the central macula affect the reproducibility of choroidal thickness (CT) measurements on enhanced depth imaging optical coherence tomography (EDI-OCT).

Design: Retrospective reliability analysis.

Methods: EDI-OCT images were obtained and the choroidal-scleral junction was analyzed through semiautomated segmentation. CT was measured at the fovea and averaged across the central 3-mm horizontal segment. Demographic data, central macular thickness, and type of fluid present were recorded. Intragrader and intergrader repeatability were assessed using the intraclass correlation coefficient (ICC) and coefficient of repeatability (CR).

Results: Of 124 eyes analyzed, 60 (48.4%) had diabetic macular edema, 32 (25.8%) had neovascular age-related macular degeneration, and 32 (25.8%) had other causes of fluid. Intergrader ICC (CR) was 0.95 (74.1 μm) and 0.96 (63.9 μm) for subfoveal and average CT, respectively. CR was similar across various causes of retinal fluid, but was worst for subretinal fluid compared to intraretinal or sub-retinal pigment epithelial fluid. CR also worsened with increasing choroidal thickness, but was not affected by retinal thickness. Intragrader repeatability was generally greater than intergrader values, and followed the same trend.

Conclusions: The presence of macular fluid reduces CT measurement reproducibility, particularly in eyes with subretinal fluid and greater choroidal thickness. A difference of 74.1 μm in subfoveal CT or 63.9 μm in average CT may be necessary to detect true clinical change in eyes with macular fluid.
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http://dx.doi.org/10.1016/j.ajo.2017.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705394PMC
December 2017

Favorable Outcome in Coccidioides Endophthalmitis-A Combined Medical and Surgical Treatment Approach.

Cornea 2017 Nov;36(11):1423-1425

*Department of Ophthalmology and Vision Science, University of California Davis Medical Center, Sacramento, CA; †Department of Internal Medicine, Division of Infectious Diseases, University of California Davis Medical Center, Sacramento, CA; and ‡Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA.

Purpose: To describe a case of Coccidioides endophthalmitis that resulted in a favorable visual outcome after a combined medical and surgical approach.

Methods: A 33-year-old previously healthy woman was referred for evaluation of dyspnea and left-sided vision loss, which began 3 months before, after a trip to Nevada. She was found to have a pulmonary cavitary lesion and fluffy white material in the anterior chamber. An aqueous and vitreous paracentesis grew Coccidioides species. She was managed medically with a total of 7 weekly intravitreal injections of amphotericin B and intravenous liposomal amphotericin B followed by transition to oral posaconazole. Seven months after presentation, to ensure ocular sterilization and to clear the visual axis, she underwent temporary keratoprosthesis implantation, anterior segment reconstruction, removal of a cyclitic membrane and the crystalline lens, pars plana vitrectomy, placement of a pars plana Ahmed drainage device, and penetrating keratoplasty.

Results: After surgical intervention and with maintenance posaconazole therapy, the patient had resolution of her dyspnea and improved uncorrected (aphakic) vision with a clear corneal graft, quiet anterior chamber, and normal optic nerve and retina.

Conclusions: A combined medical and surgical approach resulted in a favorable visual outcome and avoided the need for enucleation.
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http://dx.doi.org/10.1097/ICO.0000000000001353DOI Listing
November 2017

A Review of Innovations in Rhegmatogenous Retinal Detachment Surgical Techniques.

J Ophthalmol 2017 7;2017:4310643. Epub 2017 May 7.

Department of Ophthalmology, Tel Aviv Medical Center Affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Rhegmatogenous retinal detachment (RRD) requires surgical intervention for its repair. There are variable techniques used for this purpose, and they are all being continuously refined. In this review, we detail the recent innovations in surgical management of RRD and proliferative vitreoretinopathy (PVR).
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http://dx.doi.org/10.1155/2017/4310643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444028PMC
May 2017

Venous Neovascularization in a Recipient of a Pediatric Kidney Transplant.

J Vasc Interv Radiol 2017 04;28(4):623-625

Surgery, University of California Davis Medical Center, 4860 Y Street, Suite 3100, Sacramento, CA 95817.

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http://dx.doi.org/10.1016/j.jvir.2016.08.016DOI Listing
April 2017