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Lu SY, Rong SS, Wu Z, Huang C, Matsushita K, Ng TK, Leung C, Kawashima R, Usui S, Tam P, Tsujikawa M, Young A, Zhang M, Wiggs J, Nishida K, Tham C, Pang CP, Chen LJ. Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese. Clin Exp Ophthalmol. 2020;48(5):658–665.
BACKGROUND: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese. METHODS: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis. RESULTS: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P = .0019, OR = 4.55, I = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P = .81, OR = 1.05; I = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects. CONCLUSIONS: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus.
Seminario-Vidal L, Kroshinsky D, Malachowski S, Sun J, Markova A, Beachkofsky T, Kaffenberger B, Ergen E, Mauskar M, Bridges A, Calhoun C, Cardones A, Chen S, Chodosh J, Cotliar J, Davis M, DeNiro K, Dominguez A, Eljure-Téllez J, Femia A, Fox L, Guda A, Mitchell C, Mostaghimi A, Ortega-Loayza A, Owen C, Pasieka H, Rahnama-Moghadam S, Saeed H, Saunderson R, Shanbhag S, Sharon V, Strowd L, Venkatesh S, Wanat K, Wetter D, Worswick S, Micheletti R. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82(6):1553–1567.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions with high morbidity and mortality. Supportive care management of SJS/TEN is highly variable. A systematic review of the literature was performed by dermatologists, ophthalmologists, intensivists, and gynecologists with expertise in SJS/TEN to generate statements for supportive care guideline development. Members of the Society of Dermatology Hospitalists with expertise in SJS/TEN were invited to participate in a modified, online Delphi-consensus. Participants were administered 9-point Likert scale questionnaires regarding 135 statements. The RAND/UCLA Appropriateness Method was used to evaluate and select proposed statements for guideline inclusion; statements with median ratings of 6.5 to 9 and a disagreement index of ≤1 were included in the guideline. For the final round, the guidelines were appraised by all of the participants. Included are an evidence-based discussion and recommendations for hospital setting and care team, wound care, ocular care, oral care, urogenital care, pain management, infection surveillance, fluid and electrolyte management, nutrition and stress ulcer prophylaxis, airway management, and anticoagulation in adult patients with SJS/TEN.
Tomita Y, Cakir B, Liu CH, Fu Z, Huang S, Cho S, Britton W, Sun Y, Puder M, Hellström A, Talukdar S, Smith L. Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice. Angiogenesis. 2020;23(3):385–394.
To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD). Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (Ffar4) and knock out (Ffar4) mice on a C57BL/6J/6N background. The ex vivo choroid-sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1β, Tnf-α, Vegf, and Nf-ĸb were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from Ffar4 and Ffar4 mice were used to assess RPE contribution to inflammation. The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in Ffar4 compared to Ffar4 mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-ĸB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of Ffar4 mice compared with Ffar4 RPE. In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.
Anesi S, Eggenschwiler L, Ferrara M, Artornsombudh P, Walsh M, Foster S. Reliability of Conjunctival Biopsy for Diagnosis of Ocular Mucous Membrane Pemphigoid: Redetermination of the Standard for Diagnosis and Outcomes of Previously Biopsy-Negative Patients. Ocul Immunol Inflamm. 2020;:1–8.
: To demonstrate the reliability of conjunctival biopsy analyzed by direct immunofluorescence (DIF) and supplemented with avidin-biotin complex immunoperoxidase (ABC) in diagnosing oMMP, and report therapy response in biopsy-positive patients, particularly when previously biopsy-negative elsewhere.: Retrospective outcomes review of 136 consecutive patients after conjunctival biopsy for suspected oMMP.: Among 136 patients, 66% were diagnosed with oMMP by DIF and 13% via supplemental ABC immunoperoxidase. Sensitivity increased from 79.6% with DIF to 95.6% with supplemental ABC. Among 57 biopsy-positive patients, 77% were in remission at 1-year follow-up and 88% after 2 years. Of 34 previous biopsy-negative but now biopsy-positive patients with a 2-year follow-up, 91% achieved remission, including all 16 diagnosed via DIF and ABC.: Conjunctival biopsy analyzed by histopathology and DIF supplemented by ABC has high reliability for diagnosing oMMP and is a useful tool to use before starting long-term immunomodulatory therapy in a patient with suspected oMMP.
Gise R, Heidary G. Update on Pediatric Optic Neuritis. Curr Neurol Neurosci Rep. 2020;20(3):4.
PURPOSE OF REVIEW: The purpose of this review is to provide an update on advances in the understanding of pediatric demyelinating optic neuritis. RECENT FINDINGS: In the past decade, the disease phenotypes for demyelinating syndromes in children have been more clearly defined. Pediatric optic neuritis may present as a clinically isolated syndrome or in the setting of underlying neurologic disease. In addition to optic neuritis associated with multiple sclerosis or neuromyelitis optica, recent work has identified antibodies to the myelin oligodendrocyte glycoprotein (MOG IgG) as a unique demyelinating cause with distinct features regarding treatment and prognosis. The disease phenotypes for demyelinating pediatric optic neuritis have expanded. Treatment strategies vary and are not universally effective for each cause of demyelinating disease. Accurately distinguishing among these unique clinical syndromes is therefore critical for initiation of appropriate treatment to prevent disability, to maximize visual outcomes, and to provide insight into long-term prognosis.
Li S, Datta S, Brabbit E, Love Z, Woytowicz V, Flattery K, Capri J, Yao K, Wu S, Imboden M, Upadhyay A, Arumugham R, Thoreson W, Deangelis M, Haider N. Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa. Gene Ther. 2021;28(5):223–241.
Recent advances in viral vector engineering, as well as an increased understanding of the cellular and molecular mechanism of retinal diseases, have led to the development of novel gene therapy approaches. Furthermore, ease of accessibility and ocular immune privilege makes the retina an ideal target for gene therapies. In this study, the nuclear hormone receptor gene Nr2e3 was evaluated for efficacy as broad-spectrum therapy to attenuate early to intermediate stages of retinal degeneration in five unique mouse models of retinitis pigmentosa (RP). RP is a group of heterogenic inherited retinal diseases associated with over 150 gene mutations, affecting over 1.5 million individuals worldwide. RP varies in age of onset, severity, and rate of progression. In addition, ~40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies. Remarkably, Nr2e3 administered therapy resulted in reduced retinal degeneration as observed by increase in photoreceptor cells, improved electroretinogram, and a dramatic molecular reset of key transcription factors and associated gene networks. These therapeutic effects improved retinal homeostasis in diseased tissue. Results of this study provide evidence that Nr2e3 can serve as a broad-spectrum therapy to treat multiple forms of RP.
Hanyuda A, Rosner B, Wiggs J, Willett W, Tsubota K, Pasquale L, Kang J. Low-carbohydrate-diet scores and the risk of primary open-angle glaucoma: data from three US cohorts. Eye (Lond). 2020;34(8):1465–1475.
BACKGROUND/OBJECTIVES: To assess the long-term association between low-carbohydrate dietary patterns and incident primary open-angle glaucoma (POAG), and POAG subtypes defined by highest untreated intraocular pressure (IOP) and by pattern of visual field (VF) loss at diagnosis. SUBJECTS/METHODS: We followed 185,638 participants of three large US prospective cohorts biennially (1976-2016, 1986-2016 and 1991-2017). Deciles of three low-carbohydrate-diet scores were calculated to represent adherence to diets lower in carbohydrate and higher in protein and fat from any source, animal sources or plant sources. We confirmed POAG cases (n = 2112) by medical record review and used Cox proportional hazards models to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs). RESULTS: There was no association between the three types of low-carbohydrate-diet scores and POAG: the MVRR for POAG in the highest vs. lowest deciles was 1.13 (95% CI, 0.91-1.39; P = 0.40) for the overall score; 1.10 (95% CI, 0.89-1.35; P = 0.38) for the animal score and 0.96 (95% CI, 0.79-1.18; P = 0.88) for the vegetable score. No differential associations by IOP level was found (P ≥ 0.06). However, the vegetable score showed a suggestive inverse association with early paracentral VF loss (highest vs. lowest decile MVRR = 0.78 [95% CI, 0.55-1.10]; P = 0.12) but not with peripheral VF loss only (MVRR = 1.09 [95% CI, 0.83-1.44]; P = 0.14; P = 0.03). CONCLUSIONS: Low-carbohydrate diets were not associated with risk of POAG. Our data suggested that higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with lower risk of the POAG subtype with initial paracentral VF loss.
Porporato N, Baskaran M, Perera S, Tun T, Sultana R, Tan M, Quah JH, Allen J, Friedman D, Cheng CY, Aung T. Evaluation of meridional scans for angle closure assessment with anterior segment swept-source optical coherence tomography. Br J Ophthalmol. 2021;105(1):131–134.
BACKGROUND/AIMS: As swept-source optical coherence tomography (SS-OCT) simultaneously obtains 128 meridional scans, it is important to identify which scans are playing the main role in classifying gonioscopic angle closure to simplify the analysis. We aimed to evaluate the diagnostic performance of every meridional scan in its ability to detect gonioscopic angle closure. METHODS: Observational study with 2027 phakic subjects consecutively recruited from a community polyclinic. Gonioscopy and SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle, while SS-OCT was defined as iridotrabecular contact anterior to the scleral spur. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic performance of each single scan, the sequential anticlockwise cumulative effect of those single scans and different combinations of them. RESULTS: The AUCs of each scan ranged from 0.73 to 0.82. The single scan at 80°-260° had the highest AUC (0.82, 95% CI 0.79 to 0.84) and performed significantly better than most of the temporonasal scans (from 0° to 52° and from 153° to 179°). The superoinferior scans achieved higher AUCs compared with the temporonasal ones. When assessing the cumulative effect of adding individual scans consecutively, the peak AUC (0.80) was obtained when considering the superoinferior scans closer to 80°-85°, but no further positive cumulative effect was seen when adding the rest of the temporonasal scans of the circumference. CONCLUSIONS: In conclusion, the single SS-OCT scan at 80°-260° had the highest diagnostic performance. Our study suggests that the 360° evaluation may not translate to better clinical utility for detection of gonioscopic angle closure.
Busch C, Okada M, Zur D, Fraser-Bell S, Rodríguez-Valdés P, Cebeci Z, Lupidi M, Fung A, Gabrielle PH, Giancipoli E, Chaikitmongkol V, Laíns I, Santos AR, Kunavisarut P, Sala-Puigdollers A, Chhablani J, Ozimek M, Hilely A, Degenhardt V, Loewenstein A, Iglicki M, Rehak M, International Retina Group. Baseline predictors for visual acuity loss during observation in diabetic macular oedema with good baseline visual acuity. Acta Ophthalmol. 2020;98(7):e801-e806.
PURPOSE: To investigate clinical baseline characteristics and optical coherence tomography biomarkers predicting visual loss during observation in eyes with diabetic macular oedema (DMO) and good baseline visual acuity (VA). METHODS: A sub-analysis of a 12-month, retrospective study, including patients with baseline VA ≤0.1 logMAR (≥20/25 Snellen) and centre-involving DMO. The primary outcome measure was the correlation between baseline characteristics and VA loss ≥10 letters during follow-up. RESULTS: A total of 249 eyes were included in the initial study, of which 147 eyes were observed and 80 eyes received anti-vascular endothelial growth factor (VEGF) treatment at baseline. Visual acuity (VA) loss ≥10 letters occurred in 21.8% (observed cohort) and in 24.3% (treated cohort), respectively. Within observed eyes, presence of hyperreflective foci [HRF; odds ratio (OR): 3.18, p = 0.046], and disorganization of inner retina layers (DRIL; OR: 2.71, p = 0.026) were associated with a higher risk of VA loss ≥10 letters. In observed eyes with a combined presence of HRF, DRIL and ellipsoid zone (EZ) disruption, the risk of VA loss was further increased (OR: 3.86, p = 0.034). In eyes with combined presence of DRIL, HRF and EZ disruption, risk of VA loss was 46.7% (7/15 eyes) in the observed cohort, and 26.3% (5/19 eyes) in the treated cohort (p = 0.26). CONCLUSION: Patients with DMO and good baseline VA, managed by observation, are of increased risk for VA loss if DRIL, HRF and EZ disruption are present at baseline. Earlier treatment with anti-VEGF in these patients may potentially decrease the risk of VA loss at 12 months.
Parikh R, Palmer V, Kumar A, Simon J. Surgical Confusions in Ophthalmology: Description, Analysis, and Prevention of Errors from 2006 through 2017. Ophthalmology. 2020;127(3):296–302.
PURPOSE: To characterize surgical confusions in ophthalmology to determine their incidence, root causes, and impact on patients and physicians. DESIGN: Retrospective cohort study of errors in ophthalmic surgical procedures between January 1, 2006, and December 31, 2017. PARTICIPANTS: One hundred forty-three cases involving surgical confusions. METHODS: Cases were identified by the Ophthalmic Mutual Insurance Company from closed case files and by the New York State Health Department from the New York Patient Occurrence Reporting and Tracking program that identified the surgical confusions. MAIN OUTCOME MEASURES: Incidence and impact by intended surgery, error type, and root cause as well as preventability by the Universal Protocol. RESULTS: Of the 143 cases of surgical confusions identified, 92 cases (64.3%) were deemed preventable by the Universal Protocol. Approximately two thirds, 95 cases (66.4%), were cases of incorrect implants being used during cataract surgery (cataract extraction and intraocular lens implantation), of which 33 cases (34.7%) were not preventable by the Universal Protocol. Wrong eye blocks or anesthesia accounted for 20 cases (14.0%), incorrect eye procedures accounted for 10 cases (7.00%), incorrect refractive surgery measurements accounted for 6 cases (4.20%), incorrect patient or procedure accounted for 5 cases (3.50%), incorrect intraocular gas concentration accounted for 4 cases (2.80%), and incorrect medication in surgery accounted for 3 cases (2.10%). The most common root cause of confusion was an inadequately performed time out, which was responsible for nearly one third of all surgical confusions, 46 cases (32.2%). Incorrect lens orders or calculations before surgery (so-called upstream errors) were the second most common cause of surgical confusion, involving 31 cases (21.7%). The average legal indemnity for incorrect implant during cataract surgery was $57 514 (United States dollars). The average indemnity for incorrect refractive surgery measurement was $123 125, that for incorrect eye procedure was $50 000, and that for incorrect gas concentration was $220 844. CONCLUSIONS: Most surgical confusions could have been prevented by following the Universal Protocol properly. However, upstream errors, originating in the clinic or office before surgery, and ineffective communication during time outs suggest a need for modification of the Universal Protocol.
Teran E, Yee-Rendon CM, Ortega-Salazar J, De Gracia P, Garcia-Romo E, Woods R. Evaluation of Two Strategies for Alleviating the Impact on the Circadian Cycle of Smartphone Screens. Optom Vis Sci. 2020;97(3):207–217.
SIGNIFICANCE: Electronic display devices used before bed may negatively affect sleep quality through the effects of short-wavelength (blue) light on melatonin production and the circadian cycle. We quantified the efficacy of night-mode functions and blue-light-reducing lenses in ameliorating this problem. PURPOSE: The purpose of this study was to compare the radiation produced by smartphones that reaches the eye when using night-mode functions or blue-light-reducing spectacle lenses. METHODS: Radiant flux of 64 smartphones was measured with an integrating sphere. The retinal illuminance was calculated from the radiant flux of the smartphones. For the night-mode functions, the spectra produced by the smartphones were measured. The transmittance of four blue-light-reducing spectacle lenses, which filter light with either antireflective coatings or tints, was measured using a spectrometer. To determine the impact of blue-light-reducing spectacles, the radiant flux of the smartphone was weighted by the transmission spectrum of these glasses. Visual and nonvisual (circadian) parameters were calculated to compute the melatonin suppression values (MSVs) through a logistic fitting of previously published data. The MSV was used as the figure of merit to evaluate the performance of blue-light spectacles and smartphone night-mode functions. RESULTS: Night-mode functions in smartphones reduced MSVs by up to 93%. The warmest mode produced the least suppression. Blue-light-reducing spectacles reduced melatonin suppression by 33%, the coated lenses being more efficient than tinted lenses. CONCLUSIONS: All smartphones in this study emit radiant power in the short-wavelength region of the visible spectrum. Such smartphones may impair the regulation of circadian cycles at nighttime. The activation of night-mode functions was more efficient than the commercially available blue-light-reducing spectacle lenses in reducing the amount of short-wavelength light (up to 2.25 times). These results can be extrapolated to most electronic devices because they share the same type of white radiant sources with smartphones.
Chang WC, Abe R, Anderson P, Anderson W, Ardern-Jones M, Beachkofsky T, Bellón T, Biala A, Bouchard C, Cavalleri G, Chapman N, Chodosh J, Choi H, Cibotti R, Divito S, Dewar K, Dehaeck U, Etminan M, Forbes D, Fuchs E, Goldman J, Holmes J, Hope E, Hung SI, Hsieh CL, Iovieno A, Jagdeo J, Kim MK, Koelle D, Lacouture M, Le Pallec S, Lehloenya R, Lim R, Lowe A, McCawley J, McCawley J, Micheletti R, Mockenhaupt M, Niemeyer K, Norcross M, Oboh D, Olteanu C, Pasieka H, Peter J, Pirmohamed M, Rieder M, Saeed H, Shear N, Shieh C, Straus S, Sukasem C, Sung C, Trubiano J, Tsou SY, Ueta M, Volpi S, Wan C, Wang H, Wang ZQ, Weintraub J, Whale C, Wheatley L, Whyte-Croasdaile S, Williams K, Wright G, Yeung S, Zhou L, Chung WH, Phillips E, Carleton B. SJS/TEN 2019: From science to translation. J Dermatol Sci. 2020;
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.
Feldstein I, Dyszak G. Road crossing decisions in real and virtual environments: A comparative study on simulator validity. Accid Anal Prev. 2020;137:105356.
Virtual reality (VR) is a valuable tool for the assessment of human perception and behavior in a risk-free environment. Investigators should, however, ensure that the used virtual environment is validated in accordance with the experiment's intended research question since behavior in virtual environments has been shown to differ to behavior in real environments. This article presents the street crossing decisions of 30 participants who were facing an approaching vehicle and had to decide at what moment it was no longer safe to cross, applying the step-back method. The participants executed the task in a real environment and also within a highly immersive VR setup involving a head-mounted display (HMD). The results indicate significant differences between the two settings regarding the participants' behaviors. The time-to-contact of approaching vehicles was significantly lower for crossing decisions in the virtual environment than for crossing decisions in the real one. Additionally, it was demonstrated that participants based their crossing decisions in the real environment on the temporal distance of the approaching vehicle (i.e., time-to-contact), whereas the crossing decisions in the virtual environment seemed to depend on the vehicle's spatial distance, neglecting the vehicle's velocity. Furthermore, a deeper analysis suggests that crossing decisions were not affected by factors such as the participant's gender or the order in which they faced the real and the virtual environment.
Akbari A, Jabbari N, Sharifi R, Ahmadi M, Vahhabi A, Seyedzadeh SJ, Nawaz M, Szafert S, Mahmoodi M, Jabbari E, Asghari R, Rezaie J. Free and hydrogel encapsulated exosome-based therapies in regenerative medicine. Life Sci. 2020;249:117447.
Over the last few decades, mesenchymal stem cells-derived exosomes (MSCs-Ex) have attracted a lot of attention as a therapeutic tool in regenerative medicine. Exosomes are extracellular vehicles (EVs) that play important roles in cell-cell communication through various processes such as stress response, senescence, angiogenesis, and cell differentiation. Success in the field of regenerative medicine sparked exploration of the potential use of exosomes as key therapeutic effectors of MSCs to promote tissue regeneration. Various approaches including direct injection, intravenous injection, intraperitoneal injection, oral administration, and hydrogel-based encapsulation have been exploited to deliver exosomes to target tissues in different disease models. Despite significant advances in exosome therapy, it is unclear which approach is more effective for administering exosomes. Herein, we critically review the emerging progress in the applications of exosomes in the form of free or association with hydrogels as therapeutic agents for applications in regenerative medicine.
Global Retinoblastoma Study Group, Fabian ID, Abdallah E, Abdullahi S, Abdulqader R, Adamou Boubacar S, Ademola-Popoola D, Adio A, Afshar A, Aggarwal P, Aghaji A, Ahmad A, Akib M, Al Harby L, Al Ani M, Alakbarova A, Portabella SA, Al-Badri S, Alcasabas AP, Al-Dahmash S, Alejos A, Alemany-Rubio E, Alfa Bio A, Alfonso Carreras Y, Al-Haddad C, Al-Hussaini H, Ali A, Alia D, Al-Jadiry M, Al-Jumaly U, Alkatan H, All-Eriksson C, Al-Mafrachi A, Almeida A, Alsawidi K, Al-Shaheen A, Al-Shammary E, Amiruddin P, Antonino R, Astbury N, Atalay H, Atchaneeyasakul LO, Atsiaya R, Attaseth T, Aung T, Ayala S, Baizakova B, Balaguer J, Balayeva R, Balwierz W, Barranco H, Bascaran C, Beck Popovic M, Benavides R, Benmiloud S, Bennani Guebessi N, Berete R, Berry J, Bhaduri A, Bhat S, Biddulph S, Biewald E, Bobrova N, Boehme M, Boldt, Bonanomi MT, Bornfeld N, Bouda G, Bouguila H, Boumedane A, Brennan R, Brichard B, Buaboonnam J, Calderón-Sotelo P, Calle Jara D, Camuglia J, Cano M, Capra M, Cassoux N, Castela G, Castillo L, Català-Mora J, Chantada G, Chaudhry S, Chaugule S, Chauhan A, Chawla B, Chernodrinska V, Chiwanga F, Chuluunbat T, Cieslik K, Cockcroft R, Comsa C, Correa Z, Correa Llano M, Corson T, Cowan-Lyn K, Csóka M, Cui X, Da Gama I, Dangboon W, Das A, Das S, Davanzo J, Davidson A, De Potter P, Delgado K, Demirci H, Desjardins L, Diaz Coronado R, Dimaras H, Dodgshun A, Donaldson C, Donato Macedo C, Dragomir M, Du Y, Du Bruyn M, Edison K, Eka Sutyawan W, El Kettani A, Elbahi A, Elder J, Elgalaly D, Elhaddad A, Elhassan MA, Elzembely M, Essuman V, Evina TG, Fadoo Z, Fandiño A, Faranoush M, Fasina O, Fernández D, Fernández-Teijeiro A, Foster A, Frenkel S, Fu L, Fuentes-Alabi S, Gallie B, Gandiwa M, Garcia J, García Aldana D, Gassant P, Geel J, Ghassemi F, Girón A, Gizachew Z, Goenz M, Gold A, Goldberg-Lavid M, Gole G, Gomel N, Gonzalez E, Gonzalez Perez G, González-Rodríguez L, Garcia Pacheco H, Graells J, Green L, Gregersen P, Grigorovski N, Guedenon K, Gunasekera S, Gündüz A, Gupta H, Gupta S, Hadjistilianou T, Hamel P, Hamid S, Hamzah N, Hansen E, Harbour W, Hartnett E, Hasanreisoglu M, Hassan S, Hassan S, Hederova S, Hernandez J, Hernandez LMC, Hessissen L, Hordofa D, Huang L, Hubbard, Hummlen M, Husakova K, Hussein Al-Janabi A, Ida R, Ilic V, Jairaj V, Jeeva I, Jenkinson H, Ji X, Jo DH, Johnson K, Johnson W, Jones M, Kabesha TA, Kabore R, Kaliki S, Kalinaki A, Kantar M, Kao LY, Kardava T, Kebudi R, Kepak T, Keren-Froim N, Khan Z, Khaqan H, Khauv P, Kheir W, Khetan V, Khodabande A, Khotenashvili Z, Kim J, Kim JH, Kiratli H, Kivelä T, Klett A, Komba Palet JEK, Krivaitiene D, Kruger M, Kulvichit K, Kuntorini M, Kyara A, Lachmann E, Lam C, Lam G, Larson S, Latinovic S, Laurenti K, Le BH, Lecuona K, Leverant A, Li C, Limbu B, Long QB, López J, Lukamba R, Lumbroso L, Luna-Fineman S, Lutfi D, Lysytsia L, Magrath G, Mahajan A, Majeed AR, Maka E, Makan M, Makimbetov E, Manda C, Martín Begue N, Mason L, Mason J, Matende I, Materin M, Mattosinho C, Matua M, Mayet I, Mbumba F, McKenzie J, Medina-Sanson A, Mehrvar A, Mengesha A, Menon V, Mercado GJ, Mets M, Midena E, Mishra D, Mndeme F, Mohamedani A, Mohammad M, Moll A, Montero M, Morales R, Moreira C, Mruthyunjaya P, Msina M, Msukwa G, Mudaliar S, Muma K, Munier F, Murgoi G, Murray T, Musa K, Mushtaq A, Mustak H, Muyen O, Naidu G, Nair AG, Naumenko L, Ndoye Roth PA, Nency Y, Neroev V, Ngo H, Nieves R, Nikitovic M, Nkanga E, Nkumbe H, Nuruddin M, Nyaywa M, Obono-Obiang G, Oguego N, Olechowski A, Oliver S, Osei-Bonsu P, Ossandon D, Paez-Escamilla M, Pagarra H, Painter S, Paintsil V, Paiva L, Pal B, Palanivelu MS, Papyan R, Parrozzani R, Parulekar M, Pascual Morales C, Paton K, Pawinska-Wasikowska K, Pe’er J, Peña A, Peric S, Pham C, Philbert R, Plager D, Pochop P, Polania R, Polyakov V, Pompe M, Pons J, Prat D, Prom V, Purwanto I, Qadir A, Qayyum S, Qian J, Rahman A, Rahman S, Rahmat J, Rajkarnikar P, Ramanjulu R, Ramasubramanian A, Ramirez-Ortiz M, Raobela, Rashid R, Reddy A, Reich E, Renner L, Reynders D, Ribadu D, Riheia M, Ritter-Sovinz P, Rojanaporn D, Romero L, Roy S, Saab R, Saakyan S, Sabhan A, Sagoo M, Said A, Saiju R, Salas B, San Román Pacheco S, Sánchez G, Sayalith P, Scanlan T, Schefler A, Schoeman J, Sedaghat A, Seregard S, Seth R, Shah A, Shakoor S, Sharma M, Sherief S, Shetye N, Shields C, Siddiqui SN, Sidi Cheikh S, Silva S, Singh A, Singh N, Singh U, Singha P, Sitorus R, Skalet A, Soebagjo H, Sorochynska T, Ssali G, Stacey A, Staffieri S, Stahl E, Stathopoulos C, Stirn Kranjc B, Stones D, Strahlendorf C, Suarez MEC, Sultana S, Sun X, Sundy M, Superstein R, Supriyadi E, Surukrattanaskul S, Suzuki S, Svojgr K, Sylla F, Tamamyan G, Tan D, Tandili A, Tarrillo Leiva F, Tashvighi M, Tateshi B, Tehuteru E, Teixeira L, Teh KH, Theophile T, Toledano H, Trang D, Traoré F, Trichaiyaporn S, Tuncer S, Tyau-Tyau H, Umar A, Unal E, Uner O, Urbak S, Ushakova T, Usmanov R, Valeina S, Hoefen Wijsard M, Varadisai A, Vasquez L, Vaughan L, Veleva-Krasteva N, Verma N, Victor A, Viksnins M, Villacís Chafla E, Vishnevskia-Dai V, Vora T, Wachtel A, Wackernagel W, Waddell K, Wade P, Wali A, Wang YZ, Weiss A, Wilson M, Wime A, Wiwatwongwana A, Wiwatwongwana D, Wolley Dod C, Wongwai P, Xiang D, Xiao Y, Yam J, Yang H, Yanga J, Yaqub M, Yarovaya V, Yarovoy A, Ye H, Yousef Y, Yuliawati P, Zapata López A, Zein E, Zhang C, Zhang Y, Zhao J, Zheng X, Zhilyaeva K, Zia N, Ziko O, Zondervan M, Bowman R. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol. 2020;
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
Jamali A, Harris D, Blanco T, Lopez M, Hamrah P. Resident plasmacytoid dendritic cells patrol vessels in the naïve limbus and conjunctiva. Ocul Surf. 2020;18(2):277–285.
Plasmacytoid dendritic cells (pDCs) constitute a unique population of bone marrow-derived cells that play a pivotal role in linking innate and adaptive immune responses. While peripheral tissues are typically devoid of pDCs during steady state, few tissues do host resident pDCs. In the current study, we aim to assess presence and distribution of pDCs in naïve murine limbus and bulbar conjunctiva. Immunofluorescence staining followed by confocal microscopy revealed that the naïve bulbar conjunctiva of wild-type mice hosts CD45 CD11c PDCA-1 pDCs. Flow cytometry confirmed the presence of resident pDCs in the bulbar conjunctiva through multiple additional markers, and showed that they express maturation markers, the T cell co-inhibitory molecules PD-L1 and B7-H3, and minor to negligible levels of T cell co-stimulatory molecules CD40, CD86, and ICAM-1. Epi-fluorescent microscopy of DPE-GFP×RAG1 transgenic mice with GFP-tagged pDCs indicated lower density of pDCs in the bulbar conjunctiva compared to the limbus. Further, intravital multiphoton microscopy revealed that resident pDCs accompany the limbal vessels and patrol the intravascular space. In vitro multiphoton microscopy showed that pDCs are attracted to human umbilical vein endothelial cells and interact with them during tube formation. In conclusion, our study shows that the limbus and bulbar conjunctiva are endowed with resident pDCs during steady state, which express maturation and classic T cell co-inhibitory molecules, engulf limbal vessels, and patrol intravascular spaces.
Tomita Y, Fu Z, Wang Z, Cakir B, Cho S, Britton W, Sun Y, Hellström A, Talukdar S, Smith L. Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models. Int J Mol Sci. 2020;21(4).
The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21- or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicle- treated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.
Chauhan MZ, Arcuri J, Park K, Zafar MK, Fatmi R, Hackam A, Yin Y, Benowitz L, Goldberg J, Samarah M, Bhattacharya S. Multi-Omic Analyses of Growth Cones at Different Developmental Stages Provides Insight into Pathways in Adult Neuroregeneration. iScience. 2020;23(2):100836.
Growth cones (GCs) are structures associated with growing neurons. GC membrane expansion, which necessitates protein-lipid interactions, is critical to axonal elongation in development and in adult neuritogenesis. We present a multi-omic analysis that integrates proteomics and lipidomics data for the identification of GC pathways, cell phenotypes, and lipid-protein interactions, with an analytic platform to facilitate the visualization of these data. We combine lipidomic data from GC and adult axonal regeneration following optic nerve crush. Our results reveal significant molecular variability in GCs across developmental ages that aligns with the upregulation and downregulation of lipid metabolic processes and correlates with distinct changes in the lipid composition of GC plasmalemma. We find that these processes also define the transition into a growth-permissive state in the adult central nervous system. The insight derived from these analyses will aid in promoting adult regeneration and functional innervation in devastating neurodegenerative diseases.
Yanagida K, Engelbrecht E, Niaudet C, Jung B, Gaengel K, Holton K, Swendeman S, Liu C, Levesque M, Kuo A, Fu Z, Smith L, Betsholtz C, Hla T. Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization. Dev Cell. 2020;52(6):779–793.e7.
Transcriptional mechanisms that drive angiogenesis and organotypic vascular endothelial cell specialization are poorly understood. Here, we show that retinal endothelial sphingosine 1-phosphate receptors (S1PRs), which restrain vascular endothelial growth factor (VEGF)-induced angiogenesis, spatially restrict expression of JunB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs). Mechanistically, VEGF induces JunB expression at the sprouting vascular front while S1PR-dependent vascular endothelial (VE)-cadherin assembly suppresses JunB expression in the nascent vascular network, thus creating a gradient of this TF. Endothelial-specific JunB knockout mice showed diminished expression of neurovascular guidance genes and attenuated retinal vascular network progression. In addition, endothelial S1PR signaling is required for normal expression of β-catenin-dependent genes such as TCF/LEF1 and ZIC3 TFs, transporters, and junctional proteins. These results show that S1PR signaling restricts JunB function to the expanding vascular front, thus creating an AP-1 gradient and enabling organotypic endothelial cell specialization of the vascular network.
Ashraf M, Sampani K, AbdelAl O, Fleming A, Cavallerano J, Souka A, El Baha SM, Silva P, Sun J, Aiello LP. Disparity of microaneurysm count between ultrawide field colour imaging and ultrawide field fluorescein angiography in eyes with diabetic retinopathy. Br J Ophthalmol. 2020;104(12):1762–1767.
AIMS: To compare microaneurysm (MA) counts using ultrawide field colour images (UWF-CI) and ultrawide field fluorescein angiography (UWF-FA). METHODS: Retrospective study including patients with type 1 or 2 diabetes mellitus receiving UWF-FA and UWF-CI within 2 weeks. MAs were manually counted in individual Early Treatment Diabetic Retinopathy Study (ETDRS) and extended UWF zones. Fields with MAs ≥20 determined diabetic retinopathy (DR) severity (0 fields=mild, 1-3=moderate, ≥4=severe). UWF-FA and UWF-CI agreement was determined and UWF-CI DR severity sensitivity analysis adjusting for UWF-FA MA counts performed. RESULTS: In 193 patients (288 eyes), 2.4% had no DR, 29.9% mild non-proliferative DR (NPDR), 32.6% moderate (NPDR), 22.9% severe NPDR and 12.2% proliferative DR. UWF-FA MA counts were 3.5-fold higher (p<0.001) than UWF-CI counts overall, 3.2x-fold higher in ETDRS fields (p<0.001) and 5.3-fold higher in extended ETDRS fields (p<0.001) and higher in type 1 versus type 2 diabetes (p<0.001). In eyes with NPDR on UWF-CI (n=246), UWF-FA images had 1.6x-3.5x more fields with ≥20 MAs (p<0.001). Fair agreement existed between imaging modalities (k=0.221-0.416). In ETDRS fields, DR severity agreement increased from k=0.346 to 0.600 when dividing UWF-FA counts by a factor of 3, followed by rapid decline in agreement thereafter. Total UWF area agreement increased from k=0.317 to 0.565 with an adjustment factor of either 4 or 5. CONCLUSIONS: UWF-FA detects threefold to fivefold more MAs than UWF-CI and identifies 1.6-3.5-fold more fields affecting DR severity. Differences exist at all DR severity levels, thus limiting direct comparison between the modalities. However, correcting UWF-FA MA counts substantially improves DR severity agreement between the modalities.
Fu Z, Sun Y, Cakir B, Tomita Y, Huang S, Wang Z, Liu CH, Cho S, Britton W, Kern T, Antonetti D, Hellström A, Smith L. Targeting Neurovascular Interaction in Retinal Disorders. Int J Mol Sci. 2020;21(4).
The tightly structured neural retina has a unique vascular network comprised of three interconnected plexuses in the inner retina (and choroid for outer retina), which provide oxygen and nutrients to neurons to maintain normal function. Clinical and experimental evidence suggests that neuronal metabolic needs control both normal retinal vascular development and pathological aberrant vascular growth. Particularly, photoreceptors, with the highest density of mitochondria in the body, regulate retinal vascular development by modulating angiogenic and inflammatory factors. Photoreceptor metabolic dysfunction, oxidative stress, and inflammation may cause adaptive but ultimately pathological retinal vascular responses, leading to blindness. Here we focus on the factors involved in neurovascular interactions, which are potential therapeutic targets to decrease energy demand and/or to increase energy production for neovascular retinal disorders.
Vongsachang H, Friedman, Inns, Kretz, Mukherjee, Callan, Wahl, Repka, Collins. Parent and Teacher Perspectives on Factors Decreasing Participation in School-Based Vision Programs. Ophthalmic Epidemiol. 2020;27(3):226–236.
: To examine factors decreasing participation in school-based vision programs from parent and teacher perspectives.: We conducted 41 semi-structured focus groups (20 parent groups, 21 teacher/staff groups), at 10 Baltimore and 11 Chicago public elementary and middle schools offering school-based vision programs. School-based vision programs provided vision screening, eye exams, and eyeglasses if needed. Focus groups ranged in size from 2-9 participants (median = 5). Sessions were recorded, transcribed, and coded through an iterative process to develop themes using inductive analysis.: Ninety parents and 117 teachers/staff participated. Participants identified five major factors decreasing participation in school-based vision programs: (1) challenges with the consent form, including distribution, collection, and literacy and language barriers; (2) having existing eye care; (3) misunderstandings about the program, especially related to cost and insurance; (4) difficulty raising parental awareness of the program; and (5) certain attitudes towards vision, eye care, and school-based programs, including low prioritization of eye care, mistrust of the program, fear of sharing private information, not believing their child needs glasses, and reluctance accepting 'subsidized' services.: Parents and teachers identified important structural barriers to participation (i.e., consent form challenges and low parental awareness) and specific reasons for non-participation (i.e., attitudes, misunderstanding of the program, existing eye care) in school-based vision programs. Effective strategies are needed to facilitate return of consent forms and promote awareness of school-based vision programs among parents. Programs should also target services towards those currently without access to eye care and increase awareness about paediatric vision needs.