Resources
The North American Neuro-Ophthalmology Society (NANOS)
· Patient Brochure
· DrusenLP
· NOVEL- AAO- NANOS Clinical Collection: “Optic Disc Drusen”
American Academy of Ophthalmology (AAO)
· Optic disc drusen
· Diagnostic uncertainty due to optic disc drusen
· Buried optic disc drusen
Eyewiki
Publications
Optic Disc Drusen Papers
We are pleased to highlight 4 recent publications on optic disc drusen.
1. Yan Y, Ludwig CA, Liao YJ: Multimodal Imaging Features of Optic Disc Drusen. American journal of ophthalmology 2021, 225:18-26.
Highlights from this paper: This is a large study of 786 patients with optic disc drusen and analysis of their ophthalmic imaging features.
How to read this paper: The PDF version of the complete paper is free to download here
2. Yan Y, Liao YJ: Updates on ophthalmic imaging features of optic disc drusen, papilledema, and optic disc edema. Current opinion in neurology 2021, 34(1):108-115.
Highlights from this paper: This is a review of on optic disc drusen and other optic nerve diseases that mimick this condition. There are useful tables and figures highlighting the key features of optic nerve head swelling.
How to read this paper: The PDF version of the complete paper is free to download here
3. Yan Y, Zhou X, Chu Z et al: Vision Loss in Optic Disc Drusen Correlates With Increased Macular Vessel Diameter and Flux and Reduced Peripapillary Vascular Density. American journal of ophthalmology 2020, 218:214-224.
Highlights from this paper: Optic disc drusen is the most common risk factor associated with loss of blood supply to the anterior optic nerve. This is the first large study analyzing vascular changes in optic disc drusen. Analysis of optical coherence tomography angiography allows future prediction of who is more likely to develop vision loss in optic disc drusen
How to read this paper: The PDF version of the complete paper is free to download here
4. Sangeethabalasri Pugazhendhi S, Yan Y, Liao YJ. Multimodal Ophthalmic Imaging of Nonarteritic Anterior Ischemic Optic Neuropathy With and Without Optic Disc Drusen. J Neuroophthalmol. 2021 Apr 14. doi: 10.1097/WNO.0000000000001242. PMID: 33870937. Online ahead of print.
Highlights from this paper: This case series compares detailed ophthalmic imaging features of young onset anterior ischemic optic neuropathy in a patient with optic disc drusen compared with another patient with older onset anterior ischemic optic neuropathy not associated with optic disc drusen.
How to read this paper: This paper is currently only accessible to those with subscription to Journal of Neuro-Ophthalmology. Please email Brianna at bdenyven@stanford.edu to get a copy of the PDF.
Ophthalmology Faculty
Publications
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Bilateral Marcus Gunn jaw-Winking Syndrome in a Neonate with Congenital Neurosyphilis
JOURNAL OF PEDIATRICS
Johnson, A., Silverman, A., Segal, J., Beres, S.
2023; 252: 223-224
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View details for DOI 10.1018/j.jpeds.2022.09.023
View details for Web of Science ID 000903976100005
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Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial.
The Lancet. Neurology
Masson, R., Mazurkiewicz-Beldzinska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, E., Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., FIREFISH Study Group, Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonca, R., Matsui, C. J., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Comi, G. P., Govoni, A., Osnaghi, S. G., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Pane, M., Palermo, C., Pera, M. C., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Leone, D., Laura, A., De Sanctis, R., Berti, B., Kimura, N., Takeshima, Y., Shimomura, H., Lee, T., Gomi, F., Morimatsu, T., Furukawa, T., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Modrzejewska, S., Lemska, A., Melnik, E., Artemyeva, S., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Litvinova, E., Enzmann, C., Galiart, E., Gugleta, K., Wondrusch Haschke, C., Topaloglu, H., Oncel, I., Ertugrul, N. E., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Sari, S., Bilgin, N., Karaduman, A. A., Sarikaya, F. G., Graham, R. J., Ghosh, P., Casavant, D., Levine, A., Titus, R., Engelbrekt, A., Ambrosio, L., Fulton, A., Baglieri, A. M., Dias, C., Maczek, E., Pasternak, A., Beres, S., Duong, T., Gee, R., Young, S.
2022
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Abstract
BACKGROUND: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment.METHODS: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing.FINDINGS: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%).INTERPRETATION: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.
View details for DOI 10.1016/S1474-4422(22)00339-8
View details for PubMedID 36244364
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Bilateral Marcus Gunn Jaw-Winking Syndrome in a Neonate with Congenital Neurosyphilis.
The Journal of pediatrics
Johnson, A., Silverman, A., Segal, J. B., Beres, S.
2022
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View details for DOI 10.1016/j.jpeds.2022.09.023
View details for PubMedID 36152687
Publications
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Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.
Ophthalmology. Retina
Ehlers, J. P., Uchida, A., Hu, M., Figueiredo, N., Kaiser, P. K., Heier, J. S., Brown, D. M., Boyer, D. S., Do, D. V., Gibson, A., Saroj, N., Srivastava, S. K.
2019
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Abstract
PURPOSE: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.DESIGN: A post hoc subanalysis of a phase III, prospective clinical trial.PARTICIPANTS: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).METHODS: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.MAIN OUTCOME MEASURES: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).RESULTS: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 mum to 31.6 mum, P < 0.001; 2q8: 25.2 mum to 31.4 mum, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.CONCLUSIONS: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
View details for DOI 10.1016/j.oret.2019.06.010
View details for PubMedID 31473172
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Traumatic chorioretinitis sclopetaria: Risk factors, management, and prognosis.
American journal of ophthalmology case reports
Ludwig, C. A., Shields, R. A., Do, D. V., Moshfeghi, D. M., Mahajan, V. B.
2019; 14: 39–46
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Abstract
Purpose: To describe new cases of sclopetaria and evaluate the risk factors, management, and visual prognosis of all reported cases in the literature.Observations: We performed a retrospective, observational case series. This study included six cases (median age 23, interquartile range 33) of sclopetaria. Additionally, literature searches were conducted in the PubMed and Cochrane Library databases to uncover risk factors associated with all published cases of sclopetaria. Main outcome measure was best corrected visual acuity (BCVA) worse than 20/20. Sixty-seven cases (71 eyes) of sclopetaria have been reported, of which 59 cases (61 eyes) met inclusion criteria in this study. Most were young (median age 19.5 years) men (51/59, 88.1%). Thirty-seven eyes were observed while 24 underwent immediate surgery including six pars plana vitrectomies and three scleral buckles. Compared to initial presentation, BCVA improved in 31/48 (64.6%) eyes, remained stable in 12/48 eyes (25.0%), and worsened in 5/48 eyes (10.4%). Ten patients (16.4%) achieved a final BCVA of 20/20 with median follow up time of seven months. In a multivariate model, location of sclopetaria in the macula, temporal retina, or immediate orbital foreign body removal predicted poor final BCVA with an area under receiver operating characteristic curve of 0.767.Conclusions and importance: Traumatic chorioretinitis sclopetaria is rare, but reports have increased dramatically over the past two decades. While pars plana vitrectomy may be required for the management of retinal detachments and non-clearing vitreous hemorrhage, close observation is appropriate in most cases. Visual prognosis is poor with most patients attaining 20/200 vision or worse.
View details for PubMedID 30834355
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Alendronate induced chorioretinitis: The importance of meticulous assessments.
American journal of ophthalmology case reports
Hassan, M., Maleki, A., Ying, Q., Nguyen, N., Halim, M. S., Sepah, Y. J., Do, D. V., Nguyen, Q. D.
2019; 14: 21–25
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Abstract
Purpose: To report a case of presumed bilateral chorioretinitis secondary to alendronate therapy.Observations: A 71-year-old female presented to the clinic in July 2017 with six months history of difficulty in reading along with floaters in both eyes which were more severe in the right eye. Past medical and surgical history revealed a history of hypertension, gout, hyperthyroidism, osteoporosis, and humerus fracture. She was started on alendronate three months before developing ocular symptoms. On ocular examination, best corrected visual acuity was 20/30 in the right and 20/25 in the left eye. Slit-lamp examination demonstrated normal anterior chamber examination in both eyes. Dilated fundus examination revealed geographic chorioretinal lesions around the optic nerve head in both eyes, more extensively in the right eye; and superior and temporal to the macula in the right eye. Past ocular records in February 2015 did not reveal any such findings. Fundus autofluorescence demonstrated hyper-autofluorescence in the peripapillary lesions in both eyes. The lesion adjacent to the macula in right eye displayed mixed hyper and hypo-autofluorescence. Fluorescein angiography showed combined hyper- and hypo-fluorescence compatible with window defect, staining and blockage. However, no leakage was appreciated in the macula, peripapillary, and peripheral lesions in both eyes. Optical coherence tomography scan showed septate hyporeflective intraretinal spaces in the right eye.Conclusion and importance: The index report underscore the importance of considering alendronate as an etiologic cause of chorioretinitis, especially in subjects with atypical lesions developing after alendronate therapy. We, therefore, recommend discontinuation of this medication in subjects who develop chorioretinitis after employing this medication.
View details for PubMedID 30809598
Publications
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Insights into Sickle Cell Disease through the Retinal Microvasculature: Adaptive Optics Scanning Light Ophthalmoscopy Correlates of Clinical OCT Angiography.
Ophthalmology science
Pinhas, A., Migacz, J. V., Zhou, D. B., Castanos Toral, M. V., Otero-Marquez, O., Israel, S., Sun, V., Gillette, P. N., Sredar, N., Dubra, A., Glassberg, J., Rosen, R. B., Chui, T. Y.
2022; 2 (4): 100196
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Purpose: Clinical OCT angiography (OCTA) of the retinal microvasculature offers a quantitative correlate to systemic disease burden and treatment efficacy in sickle cell disease (SCD). The purpose of this study was to use the higher resolution of adaptive optics scanning light ophthalmoscopy (AOSLO) to elucidate OCTA features of parafoveal microvascular compromise identified in SCD patients.Design: Case series of 11 SCD patients and 1 unaffected control.Participants: A total of 11 eyes of 11 SCD patients (mean age, 33 years; range, 23-44; 8 female, 3 male) and 1 eye of a 34-year-old unaffected control.Methods: Ten sequential 3 * 3 mm parafoveal OCTA full vascular slab scans were obtained per eye using a commercial spectral domain OCT system (Avanti RTVue-XR; Optovue). These were used to identify areas of compromised perfusion near the foveal avascular zone (FAZ), designated as regions of interest (ROIs). Immediately thereafter, AOSLO imaging was performed on these ROIs to examine the cellular details of abnormal perfusion. Each participant was imaged at a single cross-sectional time point. Additionally, 2 of the SCD patients were imaged prospectively 2 months after initial imaging to study compromised capillary segments across time and with treatment.Main Outcome Measures: Detection and characterization of parafoveal perfusion abnormalities identified using OCTA and resolved using AOSLO imaging.Results: We found evidence of abnormal blood flow on OCTA and AOSLO imaging among all 11 SCD patients with diverse systemic and ocular histories. Adaptive optics scanning light ophthalmoscopy imaging revealed a spectrum of phenomena, including capillaries with intermittent blood flow, blood cell stasis, and sites of thrombus formation. Adaptive optics scanning light ophthalmoscopy imaging was able to resolve single sickled red blood cells, rouleaux formations, and blood cell-vessel wall interactions. OCT angiography and AOSLO imaging were sensitive enough to document improved retinal perfusion in an SCD patient 2 months after initiation of oral hydroxyurea therapy.Conclusions: Adaptive optics scanning light ophthalmoscopy imaging was able to reveal the cellular details of perfusion abnormalities detected using clinical OCTA. The synergy between these clinical and laboratory imaging modalities presents a promising avenue in the management of SCD through the development of noninvasive ocular biomarkers to prognosticate progression and measure the response to systemic treatment.
View details for DOI 10.1016/j.xops.2022.100196
View details for PubMedID 36531581
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Widespread subclinical cellular changes revealed across a neural-epithelial-vascular complex in choroideremia using adaptive optics.
Communications biology
Aguilera, N., Liu, T., Bower, A. J., Li, J., Abouassali, S., Lu, R., Giannini, J., Pfau, M., Bender, C., Smelkinson, M. G., Naik, A., Guan, B., Schwartz, O., Volkov, A., Dubra, A., Liu, Z., Hammer, D. X., Maric, D., Fariss, R., Hufnagel, R. B., Jeffrey, B. G., Brooks, B. P., Zein, W. M., Huryn, L. A., Tam, J.
2022; 5 (1): 893
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Abstract
Choroideremia is an X-linked, blinding retinal degeneration with progressive loss of photoreceptors, retinal pigment epithelial (RPE) cells, and choriocapillaris. To study the extent to which these layers are disrupted in affected males and female carriers, we performed multimodal adaptive optics imaging to better visualize the in vivo pathogenesis of choroideremia in the living human eye. We demonstrate the presence of subclinical, widespread enlarged RPE cells present in all subjects imaged. In the fovea, the last area to be affected in choroideremia, we found greater disruption to the RPE than to either the photoreceptor or choriocapillaris layers. The unexpected finding of patches of photoreceptors that were fluorescently-labeled, but structurally and functionally normal, suggests that the RPE blood barrier function may be altered in choroideremia. Finally, we introduce a strategy for detecting enlarged cells using conventional ophthalmic imaging instrumentation. These findings establish that there is subclinical polymegathism of RPE cells in choroideremia.
View details for DOI 10.1038/s42003-022-03842-7
View details for PubMedID 36100689
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Reflectance adaptive optics findings in a patient with Vogt-Koyanagi-Harada disease.
American journal of ophthalmology case reports
Pham, A. T., Onghanseng, N., Halim, M. S., Ormaechea, M. S., Hassan, M., Akhavanrezayat, A., Uludag, G., Tran, A. N., Razeen, M. M., Sredar, N., Dubra, A., Nguyen, Q. D.
2022; 27: 101660
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Abstract
To describe the reflectance adaptive optics scanning laser ophthalmoscopy (AOSLO) findings in different stages of Vogt-Koyanagi-Harada (VKH) disease and correlate them to visual gain post treatment. Confocal (cAOSLO) and non-confocal split-detector AOSLO (sdAOSLO) were used to assess longitudinally the status of the photoreceptors in a patient with VKH managed on corticosteroid and immunomodulatory therapy.A 32-year-old Japanese American female presented with a 2-week history of blurred vision in both eyes (OU) and worsening headache previously diagnosed as a case of VKH and treated with high dose oral prednisone. At the time of presentation, though vision was improving, and frank serous retinal detachments were absent, spectral domain optical coherence tomography (SD-OCT) showed presence of residual subretinal fluid with disruption of the photoreceptor inner segments and outer segments (IS/OS) involving OU. The photoreceptor mosaic at the foveal center appeared very sparse with large areas devoid of visible photoreceptors on cAOSLO, in agreement with the SD-OCT data. sdAOSLO imaging over the same location shows a higher number of contiguous photoreceptors. After imaging, the patient was started on mycophenolate mofetil as steroid-sparing long-term therapy. Three months later, visual acuity improved to 20/20 OU, and SD-OCT showed almost complete resolution of subretinal fluid with significant improvement of the IS/OS SD-OCT signal, OU. cAOSLO imaging revealed a contiguous photoreceptor mosaic without gaps and of normal appearance.VKH patients may demonstrate transient photoreceptor abnormalities on SD-OCT and cAOSLO imaging. sdAOSLO imaging revealed intact photoreceptor segments in areas that appeared as voids on cAOSLO, which later showed structural recovery on SD-OCT and cAOSLO. Therefore, sdAOSLO may predict potential for improvement in patients wherein there appears to be photoreceptor loss in cAOSLO and/or SD-OCT.
View details for DOI 10.1016/j.ajoc.2022.101660
View details for PubMedID 35880207
View details for PubMedCentralID PMC9307596
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Post-translational modification of Sox11 regulates RGC survival and axon regeneration.
eNeuro
Chang, K., Bian, M., Xia, X., Madaan, A., Sun, C., Wang, Q., Li, L., Nahmou, M., Noro, T., Yokota, S., Galvao, J., Kreymerman, A., Tanasa, B., Hu, Y., Goldberg, J. L.
2021
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Abstract
The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury, but exacerbates the death of a subset of retinal ganglion cells, alpha-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent sumoylation at lysine 91 (K91) increased nuclear localization and RGC differentiation in vitro Here we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in adult mouse. RNA sequence data showed that Sox11 and Sox11K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of alpha-RGCs and ipRGCs. Thus Sox11 and its sumoylation site at K91 regulate gene expression, survival and axon growth in RGCs and may be explored further as potential regenerative therapies for optic neuropathy.Significance Statement Sox11 expression promotes optic nerve regeneration but also increases RGC death after optic nerve injury. Here we demonstrate that mutation of a single SUMOylation site on Sox11 (Sox11K91A) leads to stronger effects in vivo RNA sequencing analysis reveals that Sox11 and Sox11K91A differentially regulate downstream gene expression related to axon growth and guidance. Understanding these effects of post-translational modification of Sox11 in regulating regeneration in vivo suggests a potent therapeutic strategy for vision restoration in optic neuropathies.
View details for DOI 10.1523/ENEURO.0358-20.2020
View details for PubMedID 33441400
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Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy.
Current eye research
Kumar, V., Ali Shariati, M., Mesentier-Louro, L., Jinsook Oh, A., Russano, K., Goldberg, J. L., Liao, Y. J.
2020: 1–9
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Abstract
PURPOSE: Understanding molecular changes is essential for designing effective treatments for nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults older than 50years. We investigated changes in the mitogen-activated protein kinase (MAPK) pathway after experimental AION and focused on dual specificity phosphatase 14 (Dusp14), an atypical MAPK phosphatase that is downstream of Kruppel-like transcription factor (KLF) 9-mediated inhibition of retinal ganglion cell (RGC) survival and axonal regeneration.MATERIALS AND METHODS: We induced severe AION in a photochemical thrombosis model in adult C57BL/6 wild-type and Dusp14 knockout mice. For comparison, some studies were performed using an optic nerve crush model. We assessed changes in MAPK pathway molecules using Western blot and immunohistochemistry, measured retinal thickness using optical coherence tomography (OCT), and quantified RGCs and axons using histologic methods.RESULTS: Three days after severe AION, there was no change in the retinal protein levels of MAPK ERK1/2, phosphorylated-ERK1/2 (pERK1/2), downstream effector Elk-1 and phosphatase Dusp14 on Western blot. Western blot analysis of purified RGCs after a more severe model using optic nerve crush also showed no change in Dusp14 protein expression. Because of the known importance of the Dusp14 and MAPK pathway in RGCs, we examined changes after AION in Dusp14 knockout mice. Three days after AION, Dusp14 knockout mice had significantly increased pERK1/2+, Brn3A+ RGCs on immunohistochemistry. Three weeks after AION, Dusp14 knockout mice had significantly greater preservation of retinal thickness, increased number of Brn3A+ RGCs on whole mount preparation, and increased number of optic nerve axons compared with wild-type mice.CONCLUSIONS: Genetic deletion of Dusp14, a MAPK phosphatase important in KFL9-mediated inhibition of RGC survival, led to increased activation of MAPK ERK1/2 and greater RGC and axonal survival after experimental AION. Inhibiting Dusp14 or activating the MAPK pathway should be examined further as a potential therapeutic approach to treatment of AION.Abbreviations: AION: anterior ischemic optic neuropathy; Dusp14: dual specific phosphatase 14; ERK1/2: extracellular signal-regulated kinases 1/2; Elk-1: ETS Like-1 protein; GCC: ganglion cell complex; GCL: ganglion cell layer; inner nuclear layer; KO: knockout; MAPK: mitogen-activated phosphokinase; OCT: optical coherence tomography; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer.
View details for DOI 10.1080/02713683.2020.1826976
View details for PubMedID 33107352
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Dynamics of Contrast Decrement and Increment Responses in Human Visual Cortex.
Translational vision science & technology
Norcia, A. M., Yakovleva, A., Hung, B., Goldberg, J. L.
2020; 9 (10): 6
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Purpose: The goal of the present experiments was to determine whether electrophysiologic response properties of the ON and OFF visual pathways observed in animal experimental models can be observed in humans.Methods: Steady-state visual evoked potentials (SSVEPs) were recorded in response to equivalent magnitude contrast increments and decrements presented within a probe-on-pedestal Westheimer sensitization paradigm. The probes were modulated with sawtooth temporal waveforms at a temporal frequency of 3 or 2.73 Hz. SSVEP response waveforms and response spectra for incremental and decremental stimuli were analyzed as a function of stimulus size and visual field location in 67 healthy adult participants.Results: SSVEPs recorded at the scalp differ between contrast decrements and increments of equal Weber contrast: SSVEP responses were larger in amplitude and shorter in latency for contrast decrements than for contrast increments. Both increment and decrement responses were larger for displays that were scaled for cortical magnification.Conclusions: In a fashion that parallels results from the early visual system of cats and monkeys, two key properties of ON versus OFF pathways found in single-unit recordings are recapitulated at the population level of activity that can be observed with scalp electrodes, allowing differential assessment of ON and OFF pathway activity in human.Translational Relevance: As data from preclinical models of visual pathway dysfunction point to differential damage to subtypes of retinal ganglion cells, this approach may be useful in future work on disease detection and treatment monitoring.
View details for DOI 10.1167/tvst.9.10.6
View details for PubMedID 32953246
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Silicone Oil-Induced Glaucomatous Neurodegeneration in Rhesus Macaques.
International journal of molecular sciences
Moshiri, A., Fang, F., Zhuang, P., Huang, H., Feng, X., Li, L., Dalal, R., Hu, Y.
2022; 23 (24)
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Abstract
Previously, we developed a simple procedure of intracameral injection of silicone oil (SO) into mouse eyes and established the mouse SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation and significant glaucomatous neurodegeneration. Because the anatomy of the non-human primate (NHP) visual system closely resembles that of humans, it is the most likely to predict human responses to diseases and therapies. Here we tried to replicate the mouse SOHU glaucoma model in rhesus macaque monkeys. All six animals that we tested showed significant retinal ganglion cell (RGC) death, optic nerve (ON) degeneration, and visual functional deficits at both 3 and 6 months. In contrast to the mouse SOHU model, however, IOP changed dynamically in these animals, probably due to individual differences in ciliary body tolerance capability. Further optimization of this model is needed to achieve consistent IOP elevation without permanent damage of the ciliary body. The current form of the NHP SOHU model recapitulates the severe degeneration of acute human glaucoma, and is therefore suitable for assessing experimental therapies for neuroprotection and regeneration, and therefore for translating relevant findings into novel and effective treatments for patients with glaucoma and other neurodegenerations.
View details for DOI 10.3390/ijms232415896
View details for PubMedID 36555536
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Longitudinal in vivo Ca2+ imaging reveals dynamic activity changes of diseased retinal ganglion cells at the single-cell level.
Proceedings of the National Academy of Sciences of the United States of America
Li, L., Feng, X., Fang, F., Miller, D. A., Zhang, S., Zhuang, P., Huang, H., Liu, P., Liu, J., Sredar, N., Liu, L., Sun, Y., Duan, X., Goldberg, J. L., Zhang, H. F., Hu, Y.
2022; 119 (48): e2206829119
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Retinal ganglion cells (RGCs) are heterogeneous projection neurons that convey distinct visual features from the retina to brain. Here, we present a high-throughput in vivo RGC activity assay in response to light stimulation using noninvasive Ca2+ imaging of thousands of RGCs simultaneously in living mice. Population and single-cell analyses of longitudinal RGC Ca2+ imaging reveal distinct functional responses of RGCs and unprecedented individual RGC activity conversions during traumatic and glaucomatous degeneration. This study establishes a foundation for future in vivo RGC function classifications and longitudinal activity evaluations using more advanced imaging techniques and visual stimuli under normal, disease, and neural repair conditions. These analyses can be performed at both the population and single-cell levels using temporal and spatial information, which will be invaluable for understanding RGC pathophysiology and identifying functional biomarkers for diverse optic neuropathies.
View details for DOI 10.1073/pnas.2206829119
View details for PubMedID 36409915
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Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells.
Nature communications
Chen, W., Liu, P., Liu, D., Huang, H., Feng, X., Fang, F., Li, L., Wu, J., Liu, L., Solow-Cordero, D. E., Hu, Y.
2022; 13 (1): 6796
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When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.
View details for DOI 10.1038/s41467-022-34682-y
View details for PubMedID 36357388
Publications
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Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy.
Translational vision science & technology
Mesentier-Louro, L. A., Stell, L., Yan, Y., Montague, A. A., de Jesus Perez, V., Liao, Y. J.
2021; 10 (8): 17
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Abstract
Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION.Methods: We conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors.Results: In acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1alpha and CXCL10 emerged as the strongest therapeutic targets.Conclusions: Post-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION.Translational Relevance: We identified blood molecular targets to improve NAION diagnosis and treatment.
View details for DOI 10.1167/tvst.10.8.17
View details for PubMedID 34264294
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Multimodal Imaging Features of Optic Disc Drusen.
American journal of ophthalmology
Yan, Y., Ludwig, C. A., Liao, Y. J.
2021
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Abstract
PURPOSE: Identify key en face multimodal imaging features of optic disc drusen (ODD).DESIGN: Retrospective cross-sectional study.METHODS: .SETTING: Single academic center.PATIENT OR STUDY POPULATION: 786 patients (age 10-82 years) with diagnostic codes for ODD or the term "optic disc drusen" in clinical notes extracted using natural language processing.INTERVENTION OR OBSERVATION PROCEDURES: Color fundus image, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT).MAIN OUTCOME MEASURES: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT.RESULTS: 38 (61 eyes) of 786 patients had high-quality EDI-OCT and en face multimodal imaging. Green-light FAF had the highest sensitivity (96.8%) and showed homogeneously hyperautofluorescence while blue-light FAF differentiated superficial and deep ODD by the heterogeneous brightness of FAF. Blue-light FAF (93.5%) and NIR (91.8%) were also sensitive and provided important features including the location, size, and depth of ODD and morphology of the optic disc and ODD-associated features such as horizontal hyperreflective lines and peripapillary hyperreflective ovoid mass-like structures (PHOMS), respectively. Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all).CONCLUSIONS: Green-light FAF had the highest sensitivity in diagnosis of ODD, while blue-light FAF and NIR provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT can be performed and provides the highest-resolution characterization of the entire optic disc to rule out ODD.
View details for DOI 10.1016/j.ajo.2020.12.023
View details for PubMedID 33485838
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The Project Baseline Health Study: a step towards a broader mission to map human health
NPJ DIGITAL MEDICINE
Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A.
2020; 3 (1): 84
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Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for Web of Science ID 000538242900001
View details for PubMedID 32550652
View details for PubMedCentralID PMC7275087
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Dock10 Regulates Cardiac Function under Neurohormonal Stress
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Segal, L., Etzion, S., Elyagon, S., Shahar, M., Klapper-Goldstein, H., Levitas, A., Kapiloff, M. S., Parvari, R., Etzion, Y.
2022; 23 (17)
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Dedicator of cytokinesis 10 (Dock10) is a guanine nucleotide exchange factor for Cdc42 and Rac1 that regulates the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) signaling cascades. In this study, we characterized the roles of Dock10 in the myocardium. In vitro: we ablated Dock10 in neonatal mouse floxed Dock10 cardiomyocytes (NMCMs) and cardiofibroblasts (NMCFs) by transduction with an adenovirus expressing Cre-recombinase. In vivo, we studied mice in which the Dock10 gene was constitutively and globally deleted (Dock10 KO) and mice with cardiac myocyte-specific Dock10 KO (Dock10 CKO) at baseline and in response to two weeks of Angiotensin II (Ang II) infusion. In vitro, Dock10 ablation differentially inhibited the α-adrenergic stimulation of p38 and JNK in NMCM and NMCF, respectively. In vivo, the stimulation of both signaling pathways was markedly attenuated in the heart. The Dock10 KO mice had normal body weight and cardiac size. However, echocardiography revealed mildly reduced systolic function, and IonOptix recordings demonstrated reduced contractility and elevated diastolic calcium levels in isolated cardiomyocytes. Remarkably, Dock10 KO, but not Dock10 CKO, exaggerated the pathological response to Ang II infusion. These data suggest that Dock10 regulates cardiac stress-related signaling. Although Dock10 can regulate MAPK signaling in both cardiomyocytes and cardiofibroblasts, the inhibition of pathological cardiac remodeling is not apparently due to the Dock10 signaling in the cardiomyocyte.
View details for DOI 10.3390/ijms23179616
View details for Web of Science ID 000851094300001
View details for PubMedID 36077014
View details for PubMedCentralID PMC9455810
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A perinuclear calcium compartment regulates cardiac myocyte hypertrophy.
Journal of molecular and cellular cardiology
Turcotte, M. G., Thakur, H., Kapiloff, M. S., Dodge-Kafka, K. L.
2022; 172: 26-40
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The pleiotropic Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of pathological cardiac myocyte hypertrophy. The selective activation of hypertrophic calcineurin signaling under stress conditions has been attributed to compartmentation of Ca2+ signaling in cardiac myocytes. Here, perinuclear signalosomes organized by the scaffold protein muscle A-Kinase Anchoring Protein beta (mAKAPbeta/AKAP6beta) are shown to orchestrate local Ca2+ transients, inducing calcineurin-dependent NFATc nuclear localization and myocyte hypertrophy in response to beta-adrenergic receptor activation. Fluorescent biosensors for Ca2+ and calcineurin and protein kinase A (PKA) activity, both diffusely expressed and localized by nesprin-1alpha to the nuclear envelope, are used to define an autonomous mAKAPbeta signaling compartment in adult and neonatal rat ventricular myocytes. Notably, beta-adrenergic-stimulated perinuclear Ca2+ and PKA and CaN activity transients depended upon mAKAPbeta expression, while Ca2+ elevation and PKA and CaN activity in the cytosol were mAKAPbeta independent. Buffering perinuclear cAMP and Ca2+ prevented calcineurin-dependent NFATc nuclear translocation and myocyte hypertrophy, without affecting cardiac myocyte contractility. Additional findings suggest that the perinuclear Ca2+ transients were mediated by signalosome-associated ryanodine receptors regulated by local PKA phosphorylation. These results demonstrate the existence of a functionally independent Ca2+ signaling compartment in the cardiac myocyte regulating hypertrophy and provide a premise for targeting mAKAPbeta signalosomes to prevent selectively cardiac hypertrophy in disease.
View details for DOI 10.1016/j.yjmcc.2022.07.007
View details for PubMedID 35952391
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Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion.
Physiological genomics
Li, J., Kelly, S. C., Ivey, J. R., Thorne, P. K., Yamada, K. P., Aikawa, T., Mazurek, R., Turk, J. R., Silva, K. A., Amin, A. R., Tharp, D. L., Mueller, C. M., Thakur, H., Leary, E. V., Domeier, T. L., Rector, R. S., Fish, K., Cividini, F., Ishikawa, K., Emter, C. A., Kapiloff, M. S.
2022
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Abstract
Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomyocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein beta (mAKAPbeta) and an anchoring disruptor peptide for p90 ribosomal S6 kinase type 3 (RSK3), respectively. Quantitative PCR was used to assess viral genome (vg) delivery and transcript expression in Ossabaw and Yorkshire swine tissues. Myocardial viral delivery was 2-5 x 105 vg/g gDNA for both infusion techniques at a dose ~1013 vg/kg body weight, demonstrating a delivery of ~1-3 viral particles per cardiac diploid genome. Myocardial RNA levels for each expressed transgene were generally proportional to dose and genomic delivery, and comparable to levels for moderately expressed endogenous genes. Despite significant AAV9sc delivery to other tissues, including the liver, neither biologic induced toxic effects as assessed using functional, structural, and circulating cardiac and systemic markers. These results indicate successful targeted delivery of cardiomyocyte-selective viral vectors in swine without negative side effects, an important step in establishing efficacy in a preclinical experimental setting.
View details for DOI 10.1152/physiolgenomics.00032.2022
View details for PubMedID 35648460
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Conjunctival Swabs Reveal Higher Detection Rate Compared to Schirmer Strips for SARS-CoV-2 RNA Detection in Tears of Hospitalized COVID-19 Patients.
Journal of clinical medicine
Sabage, L. E., Sun, Y. J., Wolf, J., Sabage, J., Mazzo, A., Santos, C. F., Mahajan, V. B., Manzoni Lourençone, L. F.
2022; 11 (23)
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To determine the prevalence of SARS-CoV-2 in tear samples and to investigate whether it correlates with ocular findings and patients' prognosis in Brazil.Tears were collected using Schirmer strips (SS) and conjunctival swabs (CS) from patients hospitalized with laboratory-confirmed SARS-CoV-2 infection. Samples were analyzed using qRT-PCR. Demographic and clinical data, ocular symptoms, and Schirmer tests (ST) were collected from patients. Charlson Comorbidity Index (CCI) was used to rate comorbidities, and patients were monitored until hospital discharge or death.There were 61 hospitalized patients, 33 of which were diagnosed with COVID-19. Within the confirmed COVID-19 patients, SARS-CoV-2 was detected in 18.2% (n = 6) of CS and 12.1% (n = 4) of SS samples. Subjective and objective parameters for dry eye syndrome (e.g., ST COVID-19: 8.3 ± 6.4mm, non-COVID-19: 8.9 ± 6.6mm, p > 0.05) were comparable between COVID-19 (n = 33) and non-COVID-19 patients (n = 28). Among the 16 COVID-19 patients exhibiting ocular symptoms, only tearing was reported significantly more frequently when tear samples were positive for SARS-CoV-2 (p < 0.05). Strikingly, patients whose tears tested positive for SARS-CoV-2 had significantly inferior CCI (pos.: 34.0 ± 31.8%, neg.: 67.6 ± 36.4%, p < 0.05) and higher mortality rates (pos.: 50.0%, neg.: 7.4%, p < 0.01).SARS-CoV-2 was detected with a prevalence of 18.2% on the ocular surface. Decreased CCI and increased mortality rate in the positive tear group suggests that viral detection may relate to prognosis and highlight the need of personal protective measures for healthcare professionals. Most of the patients, regardless of COVID-19 diagnosis, had low tear production and eye discomfort, possibly pointing to the need for artificial tear use during hospitalization.
View details for DOI 10.3390/jcm11236929
View details for PubMedID 36498504
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Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence.
Molecular genetics & genomic medicine
Kolesnikova, M., Lima de Carvalho, J. R., Parmann, R., Kim, A. H., Mahajan, V. B., Tsang, S. H., Sparrow, J. R.
2022: e2038
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INTRODUCTION: Leber congenital amaurosis (LCA) type 2, due to disease-causing variants in RPE65, is characterized by severe visual loss in early infancy. Current treatments include voretigene neparvovec-rzyl (VN) for RPE65-associated LCA. Herein, we present the long-term follow-up of a patient treated with VN using quantitative autofluorescence (488nm excitation).CASE REPORT: A 9-year-old girl with a diagnosis of LCA with biallelic variants in RPE65 presented for evaluation. The patient underwent VN treatment at the age of 11. The patient returned to clinic at age of 19 at which time imaging revealed evidence of chorioretinal atrophy. Quantitative autofluorescence performed prior to gene therapy and at 6- and 8-year follow-up revealed a central area of fundus autofluorescence.DISCUSSION: This case report demonstrates acquisition of fundus autofluorescence at 6- and 8-year follow-up despite the development of chorioretinal atrophy.
View details for DOI 10.1002/mgg3.2038
View details for PubMedID 36225124
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Protocol to quantify enzymatic effects on vitreous liquefaction in porcine eyes using a transwell-plate system.
STAR protocols
Wolf, J., Sabage, L. E., Sun, Y. J., Mahajan, V. B.
2022; 3 (4): 101754
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This protocol describes an exvivo model to quantify enzymatic effects on vitreous liquefaction using porcine eyes in a transwell-plate system via induced syneresis. It provides a standardized dissection process and performs critical steps for gel-liquid separation with high precision, minimal tissue loss, and scalability. The protocol can be applied to other studies investigating vitreous liquefaction or gelatinous tissue analysis and can also serve to study vitreous liquefaction invivo as it may occur during aging or disease progression.
View details for DOI 10.1016/j.xpro.2022.101754
View details for PubMedID 36208453
Publications
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Accuracy of International Classification of Diseases Codes for Identifying Acute Optic Neuritis.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Muro-Fuentes, E. A., Villarreal Navarro, S. E., Moss, H. E.
2023
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The accuracy of International Classification of Diseases (ICD) codes for identifying cases of acute optic neuritis (aON) is not known. A prior study reported 61% accuracy for ICD code plus MRI consistent with aON within 2 months. This study determined accuracy for ICD code plus MRI within 2 months regardless of results.Retrospective chart review was conducted using a medical record research repository of a tertiary care institution from 1998 to 2019. Subjects with ICD-9/10 codes for ON and an MRI brain and/or orbits within 2 months of earliest (initial) ICD code were included. MRI was classified as positive or negative for aON based on report noting gadolinium-contrast enhancement. Clinical diagnosis at the time of initial code was classified as aON, prior ON, considered ON, alternative diagnosis, or unknown based on review of physician authored clinical notes within 7 days of the initial code. Accuracy of ICD code for aON, acute or prior ON, and acute, prior, or considered ON were calculated for all subjects and stratified based on MRI result.Two hundred fifty-one subjects had MRI results within 2 months of their initial ON ICD code (49 positive MRI [previously reported]; 202 negative MRI). Among those with negative MRI, 32 (16%) had aON, 40 (20%) had prior ON, 19 (9%) considered ON as a diagnosis, 92 (46%) had other confirmed diagnoses, and 19 (9%) had unknown diagnosis at time of code. Considering all subjects, accuracy for ICD code was 25% for acute ON, 41% for acute or prior ON, and 48% for acute, prior, or considered ON. Positive MRI, increased number of ON ICD codes, a code given by an ophthalmologist or neurologist within 2 months, and the presence of a neurology encounter within 2 months were associated with an increased accuracy for clinical aON diagnosis.In the setting of an MRI within 2 months, ICD codes for ON have low accuracy for acute ON and only slightly better accuracy for acute or prior ON. Accuracy is higher for cases with a positive MRI than those with a negative MRI, suggesting positive MRI in conjunction with ICD codes may help more accurately identify cases. Reliance on ICD and Current Procedural Terminology codes alone to identify aON cases may introduce substantial misclassification bias in claims-based research.
View details for DOI 10.1097/WNO.0000000000001805
View details for PubMedID 36696226
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Atypical Presentations of Extraparenchymal Neurocysticercosis.
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
Fan, J., Tang, R., Zhang, L., Hoang, P. T., Ayoade, F., Diaz-Perez, J. A., Moss, H. E., Jiang, H.
2023
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Abstract
Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and is typically diagnosed through visualization of the cysts in the cerebral parenchyma by neuro-imaging. However, neuro-imaging may not detect extraparenchymal neurocysticercosis (EPNCC), which is a rare manifestation of the disease involving the subarachnoid, meningeal, and intraventricular spaces. We report 2 cases of extraparenchymal neurocysticercosis, and discuss the diagnostic challenges and management of this entity.Two cases were identified through clinical records.Both patients had an insidious onset with slow progression of disease, and presented with papilledema and cerebrospinal fluid (CSF) eosinophilia. One case was diagnosed with spinal cord biopsy. The other was diagnosed with CSF serology and next-generation sequencing-based pathogen analysis. Both patients were treated with ventriculoperitoneal shunt, systemic antiparasitic agents, and immunosuppression.EPNCC is less common than parenchymal NCC. A high level of clinical suspicion is required given its rarity, long incubation period, and slow progression. Diagnosis and treatment can be challenging and requires a multidisciplinary approach.
View details for DOI 10.1097/WNO.0000000000001782
View details for PubMedID 36637411
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Pituitary macroadenoma causing vision loss in Wyburn-Mason syndrome: illustrative case.
Journal of neurosurgery. Case lessons
Hug, N. F., Purger, D. A., Moss, H. E., Dodd, R. L.
2022; 4 (26)
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BACKGROUND: Wyburn-Mason syndrome (WMS) is a neurocutaneous disorder consisting of vascular malformations of the brain, eye, and skin. These include characteristically high-flow intracranial and intraorbital arteriovenous malformations (AVMs) that present commonly with visual deterioration, headache, and hemiplegia. Complete removal of these lesions is challenging. Most patients are followed closely, and intervention occurs only in the setting of worsening symptoms secondary to AVM growth or hemorrhage. Here the authors present the first known case of a patient with WMS and a pituitary macroadenoma.OBSERVATIONS: A 62-year-old man with a 30-year history of WMS with right basal ganglia and orbital AVMs and right eye blindness presented for new-onset left-sided vision loss. A pituitary adenoma was identified compressing the optic chiasm and left optic nerve. Magnetic resonance imaging and digital subtraction angiography studies were obtained for surgical planning, and the patient underwent an endoscopic transnasal transsphenoidal resection, with significant postoperative vision improvement.LESSONS: Given the variable presentation and poor characterization of this rare syndrome, patients with WMS presenting with new symptoms must undergo evaluation for growth and hemorrhage of known AVMs, as well as new lesions. Further, in patients undergoing intracranial surgery, extensive preoperative imaging and planning are crucial for safe and successful procedures.
View details for DOI 10.3171/CASE22236
View details for PubMedID 36572974
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Tear Film Stability as a Function of Tunable Mucin Concentration Attached to Supported Lipid Bilayers
JOURNAL OF PHYSICAL CHEMISTRY B
Cui, K. W., Myung, D. J., Fuller, G. G.
2022
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View details for DOI 10.1021/acs.jpcb.2c04154AJ
View details for Web of Science ID 000842923500001
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In Situ-forming Collagen Hydrogels Crosslinked by Multifunctional Polyethylene Glycol as a Matrix Therapy for Corneal Defects: 2-Month Follow-Up In Vivo.
Cornea
Logan, C. M., Fernandes-Cunha, G. M., Chen, F., Le, P., Mundy, D., Na, K. S., Myung, D.
2022
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PURPOSE: We recently showed that in situ-forming collagen gels crosslinked through multifunctional polyethylene glycol (PEG) supported corneal epithelialization 7 days after treatment of lamellar keratectomy wounds. In this study, we aimed to evaluate the longer-term regenerative effects of this gel in animals.METHOD: Corneal wound healing was assessed 60 days after lamellar keratectomy and gel treatment using slitlamp examination, optical coherence tomography (OCT), pachymetry, corneal topography, an ocular response analyzer, and tonometry. The corneas were evaluated for the presence of beta-tubulin, cytokeratin 3, zonula occludens-1, and alpha smooth muscle actin (SMA) markers. Gene expression of aldehyde dehydrogenase 3A1 (ALDH3A1), cluster of differentiation 31, CD163, alpha-SMA, hepatocyte growth factor, and fibroblast growth factor 2 (FGF-2) and protein expression of CD44 and collagen VI were evaluated.RESULTS: Intraocular pressure, corneal thickness, and hysteresis for the corneas treated with collagen-PEG gels did not significantly change compared with the saline group. However, placido disk topography revealed greater regularity of the central cornea in the gel-treated group compared to the saline group. The gel-treated group exhibited a lower degree of epithelial hyperplasia than the saline group. Immunohistochemical and gene expression analysis showed that the gel-treated corneas exhibited lower alpha-SMA expression compared with the saline group. CD163 and CD44 were found to be elevated in the saline-treated group compared with normal corneas.CONCLUSIONS: The in situ-forming collagen-PEG gel promoted epithelialization that improved central corneal topography, epithelial layer morphology, and reduced expression of fibrotic and inflammatory biomarkers after 60 days compared to the saline group.
View details for DOI 10.1097/ICO.0000000000003104
View details for PubMedID 35965399
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Predicting Systemic Health Features from Retinal Fundus Images Using Transfer-Learning-Based Artificial Intelligence Models.
Diagnostics (Basel, Switzerland)
Khan, N. C., Perera, C., Dow, E. R., Chen, K. M., Mahajan, V. B., Mruthyunjaya, P., Do, D. V., Leng, T., Myung, D.
2022; 12 (7)
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While color fundus photos are used in routine clinical practice to diagnose ophthalmic conditions, evidence suggests that ocular imaging contains valuable information regarding the systemic health features of patients. These features can be identified through computer vision techniques including deep learning (DL) artificial intelligence (AI) models. We aim to construct a DL model that can predict systemic features from fundus images and to determine the optimal method of model construction for this task. Data were collected from a cohort of patients undergoing diabetic retinopathy screening between March 2020 and March 2021. Two models were created for each of 12 systemic health features based on the DenseNet201 architecture: one utilizing transfer learning with images from ImageNet and another from 35,126 fundus images. Here, 1277 fundus images were used to train the AI models. Area under the receiver operating characteristics curve (AUROC) scores were used to compare the model performance. Models utilizing the ImageNet transfer learning data were superior to those using retinal images for transfer learning (mean AUROC 0.78 vs. 0.65, p-value < 0.001). Models using ImageNet pretraining were able to predict systemic features including ethnicity (AUROC 0.93), age > 70 (AUROC 0.90), gender (AUROC 0.85), ACE inhibitor (AUROC 0.82), and ARB medication use (AUROC 0.78). We conclude that fundus images contain valuable information about the systemic characteristics of a patient. To optimize DL model performance, we recommend that even domain specific models consider using transfer learning from more generalized image sets to improve accuracy.
View details for DOI 10.3390/diagnostics12071714
View details for PubMedID 35885619
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Effects of Two Different Doses of Ranibizumab on Diabetic Retinopathy Severity
Ophthalmology Retina
Sadiq, M. A., Hassan, M., Soliman, M. K., Afridi, R., Do, D. V., Nguyen, Q. D., Sepah, Y. J.
2017; 1 (6): 566-567
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View details for DOI 10.1016/j.oret.2017.03.002
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A complementary note for the analytical method to estimate individual attention fluctuation using steady-state evoked potentials
Biomedical Signal Processing and Control
Norouzpour, A., Roberts, T. L., Klein, S. A.
2023
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View details for DOI 10.1016/j.bspc.2022.104406
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Strabismus and Nystagmus in Patients with Pediatric Cataracts: Study using Insurance Claims Data.
American journal of ophthalmology
Kim, S. J., Slinger, K., Lambert, S. R., Koo, E., Shue, A., Roberts, T. L.
2022
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To describe the characteristics and prevalence of strabismus and nystagmus in children diagnosed with cataracts using a national insurance claims database.Population-based retrospective cohort study METHODS: Patients <13 years diagnosed with cataracts (traumatic cataracts excluded) and enrolled continuously in their healthcare program for ≥5 years after their first cataract diagnosis were identified in a retrospective review of 66 million charts in Optum's de-identified Clinformatics Data Mart Database between 2003 and 2015. Patients were categorized based on age of their first diagnosed cataract, and if cataract surgery was performed. Clinical and demographic factors associated with the occurrence of strabismus and nystagmus were evaluated.Of 1,636 children diagnosed with cataract, 434 (26.5%) and 109 (6.7%) were diagnosed with strabismus and nystagmus, respectively. Both strabismus and nystagmus were more common in those who underwent cataract surgery (P <0.001) and in patients diagnosed with cataract ≤ 12 months of age (P <0.001). Survival analysis demonstrated that strabismus and nystagmus may be diagnosed 8 years following the initial cataract diagnosis. Cox proportional hazard regression analyses revealed strabismus was associated with cataract surgery, nystagmus, and the diagnosis with cataract ≤ 12 months and cataract surgery > 12 months.As strabismus and nystagmus occur more frequently in children diagnosed with cataracts necessitating cataract surgery, regular long-term follow-up is crucial for these children to monitor for the development of strabismus and nystagmus.
View details for DOI 10.1016/j.ajo.2022.11.014
View details for PubMedID 36410473
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Vergence/accommodative therapy for symptomatic convergence insufficiency in children: Time course of improvements in convergence function.
Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)
Jenewein, E. C., Cotter, S., Roberts, T., Kulp, M., Mitchell, G. L., Jones-Jordan, L. A., Chen, A. M., Hopkins, K., Huang, K., Amster, D., Fecho, G., Tyler, J., Meiyeppen, S., Scheiman, M., Convergence Insufficiency Treatment Trial - Attention and Reading Trial (CITT-ART) Investigator Group, Cooper, J., Schulman, E., Hamian, K., Iacono, D., Larson, S., Leung, V., Meeder, S., Ramos, E., Ritter, S., Steiner, A., Stormann, A., Vricella, M., Zhu, X., Tamkins, S., Aguilera, N., Brafman, E., Capo, H., Cavuoto, K., Crespo, I., Dowling, M., Draskovic, K., Farag, M., Fischer, V., Grace, S., Gutierrez, A., Manchola-Orozco, C., Martinez, M., McKeown, C., Osigian, C., Pham, T., Small, L., Townsend, N., Gallaway, M., Boas, M., Calvert, C., Franz, T., Gerrouge, A., Hayden, D., Margolies, Z., Myung, J., Pollack, K., Shoge, R., Tang, A., Tannen, N., Trieu, L., Trujillo, L., Buckland, M., Ellis, A., Fogt, J., McDaniel, C., McGann, T., Morrison, A., Mulvihill, S., Peiffer, A., Plaumann, M., Pierce, G., Preston, J., Reuter, K., Stevens, N., Teeny, J., Toole, A., Widmer, D., Zimmerman, A., Barnhardt, C., Borsting, E., Chu, R., Parker, S., Retnasothie, D., Wu, J., Hertle, R., Clark, P., Culp, K., Fraley, K., Grant, D., Hanna, N., Knox, S., Lawhon, W., Li, L., Mitcheff, S., Ricker, I., Solis, C., Wall, P., Zaczyk, S., Marsh-Tootle, W., Bowen, M., Call, T., Domnanovich, K., Frazier, M., Guyette, N., Hayes, O., Houser, J., Lee, S., Montejo, J., Oechslin, T., Turner, C., Weise, K., Coulter, R., Bade, A., Bansal, S., Falco, L., Green, K., Irizarry, G., Jhajj, J., Patterson, N., Rodena, J., Tea, Y., Weiss, D., Zakaib, L., Lorenzana, I., Meza, Y., Mann, R., Quezada, M., Rein, S., Rudaitis, I., Stepleton, S., Wajs, B., Redford, M., Hertle, R., Redford, M., Denton, C., Arnold, E., Borsting, E., Chase, C., Denton, C., Wee, S., Dahl-Leonard, K., Powers, K., Alaniz, A., Diener-West, M., Good, W. V., Grisham, D., Kratochvil, C. J., Revicki, D., Wanzek, J., Pollack, K., Abraham, M., Dangelo, J., Hegedus, J., Jones, I., Junglas, A., Lee, J., Nettles, J., Mitchell, C., Osman, M., Scott-Tibbs, G., Sinnott, L., Teasley, C., Vang, V., Varghese, R.
2022
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Abstract
PURPOSE: To evaluate the time course of improvements in clinical convergence measures for children with symptomatic convergence insufficiency treated with office-based vergence/accommodative therapy.METHODS: We evaluated convergence measures from 205, 9- to 14-year-old children with symptomatic convergence insufficiency randomised to office-based vergence/accommodative therapy in the Convergence Insufficiency Treatment Trial - Attention and Reading Trial (CITT-ART). Near-point of convergence (NPC) and near-positive fusional vergence (PFV) were measured at baseline and after 4, 8, 12 and 16weeks of therapy; mean change in NPC and PFV between these time points were compared using repeated measures analysis of variance. Rates of change in NPC and PFV from: (1) baseline to 4weeks and (2) 4-16weeks were calculated. For each time point, the proportion of participants to first meet the normal criterion for NPC (<6cm), PFV blur (break if no blur; >15Delta and >2 times the exodeviation) and convergence composite (NPC and PFV both normal) were calculated.RESULTS: The greatest change in NPC and PFV (7.6cm and 12.7 Delta) and the fastest rate of improvement in NPC and PFV (1.9cm/week and 3.2 Delta/week, respectively) were both found during the first 4weeks of therapy, with both slowing over the subsequent 12weeks. After 12weeks of therapy, the NPC, PFV and convergence composite were normal in 93.2%, 91.7% and 87.8% of participants, respectively, and normalised with another 4weeks of therapy in 4.4%, 2.0% and 4.4% of participants, respectively.CONCLUSION: Although the greatest improvements in NPC and PFV occurred in the first 4weeks of therapy, most participants had weekly improvements over the subsequent 12weeks of treatment. While most children with convergence insufficiency obtained normal convergence following 12weeks of therapy, an additional 4weeks of vergence/accommodative therapy may be beneficial for some participants.
View details for DOI 10.1111/opo.13062
View details for PubMedID 36271753
Publications
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Epigenetics in glaucoma: a link between DNA methylation and neurodegeneration.
The Journal of clinical investigation
Liu, W. W., Sun, Y.
2022; 132 (21)
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Normal-tension glaucoma is a form of optic nerve degeneration that is characterized by loss of retinal ganglion cells independent of eye pressure elevation. In this issue of the JCI, Pan et al. report the discovery in a Japanese family of a mutation in the METTL23 gene, which encodes a DNA methyltransferase that causes normal-pressure glaucoma in haploinsufficiency. Inherited as an autosomal dominant condition, METTL23 deficiency revealed an important function in the regulation of pS2 and the downstream NF-kappaB signaling pathway, which has previously been linked to glaucomatous optic nerve degeneration. These findings are the first direct link between defective epigenetic regulatory machinery and genetic forms of optic nerve degeneration.
View details for DOI 10.1172/JCI163670
View details for PubMedID 36317630
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Clinical characteristics of high myopia in female carriers of pathogenic RPGR mutations: a case series and review of the literature.
Ophthalmic genetics
Tran, M., Kolesnikova, M., Kim, A. H., Kowal, T., Ning, K., Mahajan, V. B., Tsang, S. H., Sun, Y.
2022: 1-9
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Abstract
BACKGROUND: RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described.MATERIALS AND METHODS: Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected.RESULTS: Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium.CONCLUSION: RPGR-related high myopia has been associated with mutations in exons 1-14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers.
View details for DOI 10.1080/13816810.2022.2113544
View details for PubMedID 36017691
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Structural and Metabolic Imaging after Short-term Use of the Balance Goggles System in Glaucoma Patients: A Pilot Study.
Journal of glaucoma
Sun, M. T., Beykin, G., Lee, W. S., Sun, Y., Chang, R., Nunez, M., Li, K. Z., Knasel, C., Rich, C., Goldberg, J. L.
2022
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Abstract
Short-term use of the Balance Goggles System in glaucoma patients was not associated with observable changes in conventional OCT imaging but metabolic imaging using peripapillary flavoprotein fluorescence may represent a useful adjuctive investigation.To determine whether the intraocular pressure (IOP)-lowering effects of the Balance Goggles System (BGS) are accompanied by changes in retinal thickness measured by ocular coherence tomography, retinal vascular density measured by OCT-angiography, or novel peripapillary metabolic profiling using flavoprotein fluorescence (FPF) measured by a fundus camera.Prospective comparative case-series.8 eyes from 8 patients with open-angle glaucoma ranging from mild to severe.In this prospective, single-center, open-label, non-randomized, single-arm study patients received a baseline evaluation including retinal imaging, then one hour of negative pressure application through the BGS, followed by repeat retinal imaging. Participants then used the BGS at home for 1 month and underwent a repeat evaluation at the conclusion of the trial.Changes in nerve fiber layer thickness, OCTA vascular parameters and FPF scores.Mean baseline IOP was 18.0±3.1 mmHg and there was no significant change in IOP at follow-up. At 1 month compared to baseline, there was a statistically significant improvement in FPF optic nerve head rim scores (12.7±11.6 to 10.5±7.5; P=0.04). Additionally, there was there was a trend towards an increase in RNFL thickness after 1 month (69.5±14.2 to 72.0±13.7; P=0.1), but there were no statistically significant differences observable with any of the OCTA vascular parameters either at 1 hour or after 1 month.There were no significant changes observable using conventional OCT imaging following short-term use of the BGS, although metabolic imaging using FPF may be a useful potential biomarker to complement existing investigations. Additional studies are warranted to further investigate these changes.
View details for DOI 10.1097/IJG.0000000000002066
View details for PubMedID 35696700
Publications
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Pathway of care for visual and vestibular rehabilitation after mild traumatic brain injury: a critical review.
Brain injury
Xiang, L., Bansal, S., Wu, A. Y., Roberts, T. L.
2022: 1-10
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To review the pathway to care for treatment and management of patients receiving visual and vestibular rehabilitation after mild traumatic brain injury (mTBI).English scientific peer-reviewed articles from PubMed, CINAHL, Embase, and PsycINFO between 2000 and 2020 were first screened by title and abstract, then those selected underwent full-text review and analysis.The database search yielded 1640 results and after title and abstract review, 75 articles were selected for full-text screening, from which 8 were included in the qualitative synthesis. Current evidence includes a limited number of retrospective cohort studies and case studies.Many patients with visual and vestibular deficits following mTBI do not receive rehabilitation services until months following their injury as there is no standardized pathway to care for patients for visual and vestibular rehabilitation. Barriers to establishing a standardized pathway are the lack of natural history data for visual and vestibular function following mTBI and the lack of randomized clinical trials establishing the efficacy of rehabilitation in patients following mTBI.
View details for DOI 10.1080/02699052.2022.2105399
View details for PubMedID 35918848
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The Use of Panitumumab-IRDye800CW in a Novel Murine Model for Conjunctival Squamous Cell Carcinoma.
Translational vision science & technology
Youn, G. M., Case, A. G., Jarin, T., Li, B., Swarup, A., Naranjo, A., Bou-Khalil, C., Yao, J., Zhou, Q., Hom, M. E., Rosenthal, E. L., Wu, A. Y.
2022; 11 (7): 23
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Abstract
Purpose: Conjunctival squamous cell carcinoma (SCC) is a sight-threatening ocular surface malignancy with the primary treatment modality being surgical resection. To evaluate surgical imaging modalities to improve surgical resection, we established a novel murine model for conjunctival SCC to demonstrate the utility of panitumumab-IRDye800, a fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibody.Methods: NOD-scid IL2Rgammanull (NSG) mice received subconjunctival injection of UM-SCC-1 or SCC-9, head and neck SCC cell lines. On tumor growth, mice were injected with Panitumumab-IRDye800CW, and imaged with a small animal imaging system and optical coherence tomography (OCT). Immunohistochemistry for SCC markers were used to confirm tumor origin.Results: Seventy-five percent (N = 4) of the UM-SCC-1 group developed aggressive, rapidly growing tumors that were P40 and EGFR positive within two weeks of inoculation. The SCC-9 tumors failed to demonstrate any growth (N = 4). Ocular tumors demonstrated high fluorescence levels with a tumor to background ratio of 3.8.Conclusions: Subconjunctival injections are an appropriate technique to create in vivo models for assessing treatment modalities and novel therapies in conjunctival SCC.Translational Relevance: This model demonstrates Panitumumab-IRDye800CW's utility in the ophthalmic setting and suggests that clinical trials may be warranted.
View details for DOI 10.1167/tvst.11.7.23
View details for PubMedID 35895055
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Distribution Of Primary Cilia In hESC-Derived Retinal Organoid
Jarin, T., Ning, K., Luo, Z., Kowal, T., Li, B., Hu, Y., Wu, A. Y., Goldberg, J. L., Sun, Y.
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022
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View details for Web of Science ID 000844437004144
Other Stanford Faculty
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Texture-like representation of objects in human visual cortex.
Proceedings of the National Academy of Sciences of the United States of America
Jagadeesh, A. V., Gardner, J. L.
2022; 119 (17): e2115302119
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SignificanceHumans are exquisitely sensitive to the spatial arrangement of visual features in objects and scenes, but not in visual textures. Category-selective regions in the visual cortex are widely believed to underlie object perception, suggesting such regions should distinguish natural images of objects from synthesized images containing similar visual features in scrambled arrangements. Contrarily, we demonstrate that representations in category-selective cortex do not discriminate natural images from feature-matched scrambles but can discriminate images of different categories, suggesting a texture-like encoding. We find similar insensitivity to feature arrangement in Imagenet-trained deep convolutional neural networks. This suggests the need to reconceptualize the role of category-selective cortex as representing a basis set of complex texture-like features, useful for a myriad of behaviors.
View details for DOI 10.1073/pnas.2115302119
View details for PubMedID 35439063
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Population Models, Not Analyses, of Human Neuroscience Measurements.
Annual review of vision science
Gardner, J. L., Merriam, E. P.
2021
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Selectivity for many basic properties of visual stimuli, such as orientation, is thought to be organized at the scale of cortical columns, making it difficult or impossible to measure directly with noninvasive human neuroscience measurement. However, computational analyses of neuroimaging data have shown that selectivity for orientation can be recovered by considering the pattern of response across a region of cortex. This suggests that computational analyses can reveal representation encoded at a finer spatial scale than is implied by the spatial resolution limits of measurement techniques. This potentially opens up the possibility to study a much wider range of neural phenomena that are otherwise inaccessible through noninvasive measurement. However, as we review in this article, a large body of evidence suggests an alternative hypothesis to this superresolution account: that orientation information is available at the spatial scale of cortical maps and thus easily measurable at the spatial resolution of standard techniques. In fact, a population model shows that this orientation information need not even come from single-unit selectivity for orientation tuning, but instead can result from population selectivity for spatial frequency. Thus, a categorical error of interpretation can result whereby orientation selectivity can be confused with spatial frequency selectivity. This is similarly problematic for the interpretation of results from numerous studies of more complex representations and cognitive functions that have built upon the computational techniques used to reveal stimulus orientation. We suggest in this review that these interpretational ambiguities can be avoided by treating computational analyses as models of the neural processes that give rise to measurement. Building upon the modeling tradition in vision science using considerations of whether population models meet a set of core criteria is important for creating the foundation for a cumulative and replicable approach to making valid inferences from human neuroscience measurements. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-vision-093019-111124
View details for PubMedID 34283926
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Optimality and heuristics in perceptual neuroscience
NATURE NEUROSCIENCE
Gardner, J. L.
2019; 22 (4): 514–23
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View details for DOI 10.1038/s41593-019-0340-4
View details for Web of Science ID 000462154300005
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TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.
Nature
Ma, X. R., Prudencio, M., Koike, Y., Vatsavayai, S. C., Kim, G., Harbinski, F., Briner, A., Rodriguez, C. M., Guo, C., Akiyama, T., Schmidt, H. B., Cummings, B. B., Wyatt, D. W., Kurylo, K., Miller, G., Mekhoubad, S., Sallee, N., Mekonnen, G., Ganser, L., Rubien, J. D., Jansen-West, K., Cook, C. N., Pickles, S., Oskarsson, B., Graff-Radford, N. R., Boeve, B. F., Knopman, D. S., Petersen, R. C., Dickson, D. W., Shorter, J., Myong, S., Green, E. M., Seeley, W. W., Petrucelli, L., Gitler, A. D.
2022
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Abstract
A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.
View details for DOI 10.1038/s41586-022-04424-7
View details for PubMedID 35197626
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A prion-like protein regulator of seed germination undergoes hydration-dependent phase separation.
Cell
Dorone, Y., Boeynaems, S., Flores, E., Jin, B., Hateley, S., Bossi, F., Lazarus, E., Pennington, J. G., Michiels, E., De Decker, M., Vints, K., Baatsen, P., Bassel, G. W., Otegui, M. S., Holehouse, A. S., Exposito-Alonso, M., Sukenik, S., Gitler, A. D., Rhee, S. Y.
2021
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Abstract
Many organisms evolved strategies to survive desiccation. Plant seeds protect dehydrated embryos from various stressors and can lay dormant for millennia. Hydration is the key trigger to initiate germination, but the mechanism by which seeds sense water remains unresolved. We identified an uncharacterized Arabidopsis thaliana prion-like protein we named FLOE1, which phase separates upon hydration and allows the embryo to sense water stress. We demonstrate that biophysical states of FLOE1 condensates modulate its biological function invivo in suppressing seed germination under unfavorable environments. We find intragenic, intraspecific, and interspecific natural variation in FLOE1 expression and phase separation and show that intragenic variation is associated with adaptive germination strategies in natural populations. This combination of molecular, organismal, and ecological studies uncovers FLOE1 as a tunable environmental sensor with direct implications for the design of drought-resistant crops, in the face of climate change.
View details for DOI 10.1016/j.cell.2021.06.009
View details for PubMedID 34233164
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Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons.
Nature neuroscience
Blum, J. A., Klemm, S., Shadrach, J. L., Guttenplan, K. A., Nakayama, L., Kathiria, A., Hoang, P. T., Gautier, O., Kaltschmidt, J. A., Greenleaf, W. J., Gitler, A. D.
2021
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Abstract
The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (gamma*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.
View details for DOI 10.1038/s41593-020-00795-0
View details for PubMedID 33589834
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Brief structured respiration practices enhance mood and reduce physiological arousal.
Cell reports. Medicine
Balban, M. Y., Neri, E., Kogon, M. M., Weed, L., Nouriani, B., Jo, B., Holl, G., Zeitzer, J. M., Spiegel, D., Huberman, A. D.
2023: 100895
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Controlled breathwork practices have emerged as potential tools for stress management and well-being. Here, we report a remote, randomized, controlled study (NCT05304000) of three different daily 5-min breathwork exercises compared with an equivalent period of mindfulness meditation over 1 month. The breathing conditions are (1) cyclic sighing, which emphasizes prolonged exhalations; (2) box breathing, which is equal duration of inhalations, breath retentions, and exhalations; and (3) cyclic hyperventilation with retention, with longer inhalations and shorter exhalations. The primary endpoints are improvement in mood and anxiety as well as reduced physiological arousal (respiratory rate, heart rate, and heart rate variability). Using a mixed-effects model, we show that breathwork, especially the exhale-focused cyclic sighing, produces greater improvement in mood (p < 0.05) and reduction in respiratory rate (p < 0.05) compared with mindfulness meditation. Daily 5-min cyclic sighing has promise as an effective stress management exercise.
View details for DOI 10.1016/j.xcrm.2022.100895
View details for PubMedID 36630953
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Corrigendum to "Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function".
Experimental neurology
Hunyara, J. L., Foshe, S., Varadarajan, S. G., Gribble, K. D., Huberman, A. D., Kolodkin, A. L.
2023; 359: 114256
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View details for DOI 10.1016/j.expneurol.2022.114256
View details for PubMedID 36457222
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Characterization of non-alpha retinal ganglion cell injury responses reveals a possible block to restoring ipRGC function.
Experimental neurology
Hunyara, J. L., Foshe, S., Varadarajan, S. G., Gribble, K. D., Huberman, A. D., Kolodkin, A. L.
2022: 114176
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Abstract
Visual impairment caused by retinal ganglion cell (RGC) axon damage or degeneration affects millions of individuals throughout the world. While some progress has been made in promoting long-distance RGC axon regrowth following injury, it remains unclear whether RGC axons can properly reconnect with their central targets to restore visual function. Additionally, the regenerative capacity of many RGC subtypes remains unknown in part due to a lack of available genetic tools. Here, we use a new mouse line that labels On direction-selective RGCs (oDSGCs) and characterize the survival and regenerative potential of these cells following optic nerve crush (ONC). In parallel, we use a previously characterized mouse line to answer these same questions for M1 intrinsically photosensitive RGCs (ipRGCs). We find that both M1 ipRGCs and oDSGCs are resilient to injury but do not display long-distance axon regrowth following Lin28a overexpression. Unexpectedly, we found that M1 ipRGC, but not oDSGC, intraretinal axons exhibit ectopic branching and are misaligned near the optic disc between one- and three-weeks following injury. Additionally, we observe that numerous ectopic presynaptic specializations associate with misguided ipRGC intraretinal axons. Taken together, these results reveal insights into the injury response of M1 ipRGCs and oDSGCs, providing a foundation for future efforts seeking to restore visual system function following injury.
View details for DOI 10.1016/j.expneurol.2022.114176
View details for PubMedID 35870522
Publications
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Preferential Loss of Contrast Decrement Responses in Human Glaucoma.
Investigative ophthalmology & visual science
Norcia, A. M., Yakovleva, A., Jehangir, N., Goldberg, J. L.
2022; 63 (11): 16
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Purpose: The purpose of this study was to determine whether glaucoma in human patients produces preferential damage to OFF visual pathways, as suggested by animal experimental models, patient electroretinogram (ERG), and retinal imaging data.Methods: Steady-state visual evoked potentials (SSVEPs) were recorded monocularly from 50 patients with glaucoma and 28 age-similar controls in response to equal Weber contrast increments and decrements presented using 2.73 hertz (Hz) sawtooth temporal waveforms.Results: The eyes of patients with glaucoma were separated into mild (better than -6 decibel [dB] mean deviation; n = 28) and moderate to severe (worse than -6 dB mean deviation, n = 22) groups based on their Humphrey 24-2 visual field measurements. Response amplitudes and phases from the two glaucoma-severity groups were compared to controls at the group level. SSVEP amplitudes were depressed in both glaucoma groups, more so in the moderate to severe glaucoma group. The differences between controls and the moderate-severe glaucoma groups were more statistically reliable for decrements than for increments. Mean responses to decremental sawtooth stimuli were larger than those to increments in controls and in the mild glaucoma but not in the moderate to severe glaucoma group at the first harmonic. OFF/decrement responses at the first harmonic were faster in controls, but not in patients.Conclusions: The observed pattern of preferential loss of decremental responses in human glaucoma is consistent with prior reports of selective damage to OFF retinal ganglion cells in murine models and in data from human ERG and retinal imaging. These data motivate pursuit of SSVEP as a biomarker for glaucoma progression.
View details for DOI 10.1167/iovs.63.11.16
View details for PubMedID 36264656
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PseudoSloan: A perimetric-complexity and area-controlled font for vision and reading research.
Journal of vision
Vildavski, V. Y., Lo Verde, L., Blumberg, G., Parsey, J., Norcia, A. M.
2022; 22 (10): 7
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Artificial orthographies have long been used in studies of verbal learning and reading. These orthographies, also known as pseudo or false fonts, are designed to match the letters of an existing alphabet on a range of visual features, isolating effects of orthography from those owing to lexical processing. In a parallel line of research, there has been much interest in the design of optotypes for measuring visual acuity that have good properties in terms of character complexity and graceful degradation under blur. Here we merge these two traditions by designing a fully scalable pseudofont, "PseudoSloan," that is based on the design rubric of the widely used Sloan optotypes. The font includes 26 Latin letters as well as two sets of letter-like symbols matching the Latin alphabet on a letter-by-letter basis. Quantitative matching of the pairs of Sloan and PseudoSloan glyphs is done on the basis of ink area and perimetric complexity. We provide the installable PseudoSloan font in TrueType and OpenType formats, plus a large number of PseudoSloan glyphs in .svg format that vary over wide ranges in their perimetric complexity and ink area (https://osf.io/qhj2b/).
View details for DOI 10.1167/jov.22.10.7
View details for PubMedID 36074477
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Automatic retinal layer segmentation of visible-light optical coherence tomography images using deep learning
Gopal, B., Zhang, T., Norcia, A., Goldberg, J. L., Dubra, A., Zhang, H., Soetikno, B.
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022
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View details for Web of Science ID 000844401306115
1. Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration.
Nguyen QD, Das A, Do DV, Dugel PU, Gomes A, Holz FG, Koh A, Pan CK, Sepah YJ, Patel N, MacLeod H, Maurer P.
Ophthalmology. 2020 Jul;127(7):963-976. doi: 10.1016/j.ophtha.2019.12.031. Epub 2020 Jan 17.
PMID: 32107066
2. Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration.
Haug SJ, Hien DL, Uludag G, Ngoc TTT, Lajevardi S, Halim MS, Sepah YJ, Do DV, Khanani AM.Am J Ophthalmol Case Rep. 2020 Mar 31;18:100680. doi: 10.1016/j.ajoc.2020.100680. eCollection 2020 Jun.
PMID: 32258827
3. Interleukin-6 inhibition in the management of non-infectious uveitis and beyond.
Karkhur S, Hasanreisoglu M, Vigil E, Halim MS, Hassan M, Plaza C, Nguyen NV, Afridi R, Tran AT, Do DV, Sepah YJ, Nguyen QD.J Ophthalmic Inflamm Infect. 2019 Sep 16;9(1):17. doi: 10.1186/s12348-019-0182-y.
PMID: 31523783
Publications
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Measuring brain beats: Cardiac-aligned fast functional magnetic resonance imaging signals.
Human brain mapping
Hermes, D., Wu, H., Kerr, A. B., Wandell, B. A.
2022
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Abstract
Blood and cerebrospinal fluid (CSF) pulse and flow throughout the brain, driven by the cardiac cycle. These fluid dynamics, which are essential to healthy brain function, are characterized by several noninvasive magnetic resonance imaging (MRI) methods. Recent developments in fast MRI, specifically simultaneous multislice acquisition methods, provide a new opportunity to rapidly and broadly assess cardiac-driven flow, including CSF spaces, surface vessels and parenchymal vessels. We use these techniques to assess blood and CSF flow dynamics in brief (3.5min) scans on a conventional 3T MRI scanner in five subjects. Cardiac pulses are measured with a photoplethysmography (PPG) on the index finger, along with functional MRI (fMRI) signals in the brain. We, retrospectively, align the fMRI signals to the heartbeat. Highly reliable cardiac-gated fMRI temporal signals are observed in CSF and blood on the timescale of one heartbeat (test-retest reliability within subjects R2 >50%). In blood vessels, a local minimum is observed following systole. In CSF spaces, the ventricles and subarachnoid spaces have a local maximum following systole instead. Slower resting-state scans with slice timing, retrospectively, aligned to the cardiac pulse, reveal similar cardiac-gated responses. The cardiac-gated measurements estimate the amplitude and phase of fMRI pulsations in the CSF relative to those in the arteries, an estimate of the local intracranial impedance. Cardiac aligned fMRI signals can provide new insights about fluid dynamics or diagnostics for diseases where these dynamics are important.
View details for DOI 10.1002/hbm.26128
View details for PubMedID 36308417
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Validation of Physics-Based Image Systems Simulation With 3-D Scenes
IEEE SENSORS JOURNAL
Lyu, Z., Goossens, T., Wandell, B., Farrell, J.
2022; 22 (20): 19400-19410
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View details for DOI 10.1109/JSEN.2022.3199699
View details for Web of Science ID 000870341900036
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Visual encoding: Principles and software.
Progress in brain research
Wandell, B. A., Brainard, D. H., Cottaris, N. P.
2022; 273 (1): 199-229
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Abstract
For more than two centuries scientists and engineers have worked to understand and model how the eye encodes electromagnetic radiation (light). We now understand the principles of how light is transmitted through the optics of the eye and encoded by retinal photoreceptors and light-sensitive neurons. In recent years, new instrumentation has enabled scientists to measure the specific parameters of the optics and photoreceptor encoding. We implemented the principles and parameter estimates that characterize the human eye in an open-source software toolbox. This chapter describes the principles behind these tools and illustrates how to use them to compute the initial visual encoding.
View details for DOI 10.1016/bs.pbr.2022.04.006
View details for PubMedID 35940717