A
Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Rousselot A, Raje D, Gunasekeran DV, Kon OM, Barisani-Asenbauer T, Kempen JH, Gupta A, Jabs DA, Smith JR, Bodaghi B, Zierhut M, DeSmet M, McCluskey P, Agarwal M, Agarwal M, Aggarwal K, Agrawal M, Al-Dhibi H, Androudi S, Asyari F, Balasundaram MB, Murthy KB, Baglivo E, Banker A, Bansal R, Basu S, Behera D, Biswas J, Carreño E, Caspers L, Chee SP, Chhabra R, Cimino L, Del Rio LEC, Cunningham ET, Curi ALL, Das D, Denisova E, Denniston AK, Errera M-H, Fonollosa A, George A, Goldstein DA, Crosier YG, Gurbaxani A, Invernizzi A, Isa HM, Md Islam S, Jones N, Katoch D, Khairallah M, Khosla A, Kramer M, Kumar A, Kumar A, Distia Nora RL, Lee R, Lowder C, Luthra S, Mahendradas P, Makhoul D, Mazumdar S, Mehta S, Miserocchi E, Mochizuki M, Mohamed OS, Muccioli C, Munk MR, Murthy S, Narain S, Nascimento H, Neri P, Nguyen M, Okada AA, Ozdal P, Palestine A, Pichi F, Rathinam SR, Schlaen A, Sehgal S, Sen NH, Sharma A, Sharma K, Shoughy SS, Singh N, Singh R, Soheilian M, Sridharan S, Thorne JE, Tappeiner C, Teoh S, Tognon MS, Tugal-Tutkun I, Tyagi M, Uy H, Santos DVV, Valentincic NV, Westcott M, Yanai R, Alvarez BY, Zahedur R, Nguyen QD, Pavesio C, Gupta V.
The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) Group Meeting Proceedings. Ocul Immunol Inflamm 2020;:1-11.
AbstractAn international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.
Agrawal R, Ludi Z, Betzler BK, Testi I, Mahajan S, Rousellot A, Kempen JH, Smith JR, McCluskey P, Nguyen QD, Pavesio C, Gupta V.
The Collaborative Ocular Tuberculosis Study (COTS) calculator-a consensus-based decision tool for initiating antitubercular therapy in ocular tuberculosis. Eye (Lond) 2023;37(7):1416-1423.
AbstractOBJECTIVE: To introduce the Collaborative Ocular Tuberculosis Study (COTS) Calculator, an online clinical scoring system for initiating antitubercular therapy (ATT) in patients with ocular tuberculosis (TB). METHOD: The COTS Calculator was derived from COTS Consensus (COTS CON) data, which has previously published consensus guidelines. Using a two-step Delphi method, 81 experts evaluated 486 clinical scenario-based questions, ranking their likelihood of initiating ATT in each specific scenario. Each scenario was a permutation of the results and/or availability of five following components-clinical phenotype, endemicity, two immunological (tuberculin skin test, interferon-γ release assay) and one radiological (chest X-Ray) test results-and a sixth component further stratifying three of the clinical phenotypes. The median scores and interquartile ranges (IQR) of each scenario were tabulated, representing the expert consensus on whether to initiate ATT in that scenario. The consensus table was encoded to develop the COTS Calculator. RESULTS: The COTS Calculator can be accessed online at:
https://www.oculartb.net/cots-calc . The attending physician can select the conditions present in the patient, which will generate a median score from 1 to 5. 114 out of 486 scenarios (24%) deliberated had a median score of 5 indicating expert consensus to initiate ATT. CONCLUSION: The COTS Calculator is an efficient, low-cost, evidence and experience-based clinical tool to guide ATT initiation. While it holds substantial promise in improving standard-of-care for ocular-TB patients, future validation studies can help to as certain its clinical utility and reliability.
Agrawal R, Testi I, Bodaghi B, Barisani-Asenbauer T, McCluskey P, Agarwal A, Kempen JH, Gupta A, Smith JR, De Smet MD, Yuen YS, Mahajan S, Kon OM, Nguyen QD, Pavesio C, Gupta V, Gupta V.
Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis. Ophthalmology 2021;128(2):277-287.
AbstractTOPIC: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU). CLINICAL RELEVANCE: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition. METHODS: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process. RESULTS: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive. DISCUSSION: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.
Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Kon OM, Barisani-Asenbauer T, Kempen JH, Gupta A, Jabs DA, Smith JR, Nguyen QD, Pavesio C, Gupta V, Gupta V.
Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis. Ophthalmology 2021;128(2):266-276.
AbstractTOPIC: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis. CLINICAL RELEVANCE: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU. METHODS: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process. RESULTS: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis. DISCUSSION: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.
Agrawal R, Gunasekeran DV, Agarwal A, Carreño E, Aggarwal K, Gupta B, Raje D, Murthy SI, Westcott M, Chee SP, McCluskey P, Ling HS, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Mahajan S, Esposti S, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Lord J, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Kempen J, Cunningham ET, Rousselot A, Nguyen QD, Pavesio C, Gupta V.
The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Description of the Spectrum of Choroidal Involvement in 245 Patients with Tubercular Uveitis. Ocul Immunol Inflamm 2018;:1-11.
AbstractPURPOSE: To contribute a global description of the spectrum of choroidal involvement in tubercular uveitis (TBU). METHODS: Retrospective cohort study of TBU patients with choroidal involvement from 25 centers between January 2004 and December 2014. Medical records of patients with a minimum follow-up of 1 year were reviewed. RESULTS: 245 patients were included. The phenotypic variations included serpiginous-like choroiditis (SLC) (46%), tuberculoma (13.5%), multifocal choroiditis (MFC) (9.4%), ampiginous choroiditis (9%), among others. 219 patients were treated with anti-tubercular therapy (ATT) (n = 219/245, 89.38%), 229 patients with steroids (n = 229/245, 93.47%) and 28 patients with immunosuppressive agents (n = 28/245, 11.42%). Treatment failure was noted in 38 patients (n = 38/245, 15.5%). Patients with SLC and ampiginous choroiditis appeared to have superior outcomes on survival analysis (p = 0.06). CONCLUSION: This study provides a comprehensive description of choroidal involvement in TBU. Patients with SLC and ampiginous choroiditis may have better clinical outcomes.
Agrawal R MD FCRS, MBBS GDV, MS AA, MD TI, MD CE, FRCOphth WM, MBBS MS, PhD RD, MS AK, DNB MSI, FRCSEd CSP, MD MP, FRCSGlasg HSL, FRCSEd TS, MD CL, MS BJ, MD NS, MS AM, DNB MP, MD KM, FRCSOphth JN, MD T-TI, DNB BK, MS BS, PhD LR, MD A-DH, MD BB, MD IA, MD GDA, MD HCP, PhD B-AT, PhD G-LJJ, MD AS, MS BR, MS MB, MD ESD, MD TA, MD NS, DNB AM, MD AS, MD VR, MS SR, MD SA, PhD SK, PhD ZM, MRCP KOM, PhD CET, PhD KJH, PhD NQD, FRCSOphth PC, MS GV.
Visual Morbidity in Ocular Tuberculosis - Collaborative Ocular Tuberculosis Study (COTS)-1: Report #6. Ocul Immunol Inflamm 2020;:1-9.
Agyemang AA, Sveinsdóttir K, Vallius S, Sveinsdóttir S, Bruschettini M, Romantsik O, Hellström A, Smith LEH, Ohlsson L, Holmqvist B, Gram M, Ley D.
Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?. Transl Stroke Res 2017;
AbstractDecreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.
Ahangari N, Munoz DG, Coulombe J, Gray DA, Engle EC, Cheng L, Woulfe J.
Nuclear IMPDH Filaments in Human Gliomas. J Neuropathol Exp Neurol 2021;
AbstractThe analysis of nuclear morphology plays an important role in glioma diagnosis and grading. We previously described intranuclear rods (rods) labeled with the SDL.3D10 monoclonal antibody against class III beta-tubulin (TUBB3) in human ependymomas. In a cohort of adult diffuse gliomas, we identified nuclear rods in 71.1% of IDH mutant lower-grade gliomas and 13.7% of IDH wild-type glioblastomas (GBMs). The presence of nuclear rods was associated with significantly longer postoperative survival in younger (≤65) GBM patients. Consistent with this, nuclear rods were mutually exclusive with Ki67 staining and their prevalence in cell nuclei inversely correlated with the Ki67 proliferation index. In addition, rod-containing nuclei showed a relative depletion of lamin B1, suggesting a possible association with senescence. To gain insight into their functional significance, we addressed their antigenic properties. Using a TUBB3-null mouse model, we demonstrate that the SDL.3D10 antibody does not bind TUBB3 in rods but recognizes an unknown antigen. In the present study, we show that rods show immunoreactivity for the nucleotide synthesizing enzymes inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase. By analogy with the IMPDH filaments that have been described previously, we postulate that rods regulate the activity of nucleotide-synthesizing enzymes in the nucleus by sequestration, with important implications for glioma behavior.
Ahmed AH, Foster SC, Shields CL.
Association of Disease Location and Treatment With Survival in Diffuse Large B-Cell Lymphoma of the Eye and Ocular Adnexal Region. JAMA Ophthalmol 2017;135(10):1062-1068.
AbstractImportance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved. Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL. Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, conjunctiva, choroid, ciliary body, lacrimal gland, or orbit (OA-uveal lymphoma) were included. Patients diagnosed at autopsy or with additional neoplastic disease were excluded. Main Outcomes and Measures: Patient demographic characteristics, disease location, treatment modalities, and overall survival. Results: Forty-seven patients with PVRL (24 women [51.1%] and 23 men [48.9%]) and 349 with OA-uveal DLBCL (192 women [55.0%] and 157 men [45.0%]) had a similar mean (SD) age at diagnosis (69.6 [12.3] vs 66.1 [17.7] years). No difference in the use of surgery or radiation therapy by location was found. For all PVRL and OA-uveal DLBCL, a Cox proportional hazards regression model affirmed that age older than 60 years was associated with increased risk for death (hazard ratio [HR], 2.7; 95% CI, 1.9-4.0; P < .001). Gross total resection was associated with a decreased risk for death (HR, 0.5; 95% CI, 0.3-0.9; P = .04), whereas radiation therapy was not. The 5-year overall survival among patients with PVRL was 41.4% (SE, 8.6%); among those with OA-uveal DLBCL, 59.1% (SE, 2.8%; Mantel-Cox test, P = .007). Median overall survival was lower in PVRL (38.0 months; 95% CI, 14.2-61.8 months) than in OA-uveal DLBCL (96.0 months; 95% CI, 67.3-124.7 months; Mantel-Cox test, P = .007). In addition, median overall survival in ophthalmic-only disease was higher (84.0 months; 95% CI, 63.2-104.8 months) than that in primary DLBCL that occurred outside the central nervous system and ophthalmic regions (46.0 months; 95% CI, 44.4-47.6 months; Mantel-Cox test, P < .001). Conclusions and Relevance: The 5-year survival in PVRL vs OA-uveal DLBCL differed by 17.7%, and overall survival was greater in ophthalmic DLBCL than in DLBCL located outside the central nervous system and ophthalmic regions. Younger age (≤60 years) and gross total resection were associated with increased survival.
Ahmed I, Hoyek S, Patel NA.
Global Disparities in Retinopathy of Prematurity: A Literature Review. Semin Ophthalmol 2023;38(2):151-157.
AbstractPURPOSE: To provide an overview of the impact of retinopathy of prematurity (ROP), and the challenges in the screening, diagnosis, and treatment of ROP worldwide. METHODS: A comprehensive search was conducted using the PubMed database from January 2011 to October 2021 using the following keywords: retinopathy of prematurity, laser, and anti-vascular endothelial growth factor (VEGF). Data on patient characteristics, ROP treatment type, and recurrence rates were collected. The countries included in these studies were classified based on 2021-2022 World Bank definitions of high, upper-middle, lower-middle, and low-income groups. Moreover, a search for surgical outcomes for ROP and screening algorithms and artificial intelligence for ROP was conducted. RESULTS: Thirty-nine studies met the inclusion criteria. ROP treatment and outcomes showed a trend towards intravitreal anti-VEGF injections as the initial treatment for ROP globally and the treatment of recurrent ROP in high-income countries. However, laser remains the treatment of choice for ROP recurrence in middle-income countries. Surgical outcomes for ROP stage 4A, 4B and 5 are similar worldwide. The incidence of ROP and ROP-related visual impairment continue to increase globally. Although telemedicine and artificial intelligence offer potential solutions to ROP screening in resource-limited areas, the current models require further optimization to reflect the global diversity of ROP patients. CONCLUSION: ROP screening and treatment paradigms vary widely based on country income group due to disparities in resources, limited access to care, and lack of universal guidelines.
Aiello LP, Jacoba CMP, Ashraf M, Cavallerano JD, Tolson AM, Tolls D, Sun JK, Silva PS.
Integrating Macular Optical Coherence Tomography with Ultrawide Field Imaging in a Diabetic Retinopathy Telemedicine Program Using a Single Device. Retina 2023;
AbstractPURPOSE: To determine the effect of combined macular optical coherence tomography (SD-OCT) and ultrawide field retinal imaging (UWFI) within a telemedicine program. METHODS: Comparative cohort study of consecutive patients with both UWFI and SD-OCT. UWFI and SD-OOCT were independently evaluated for diabetic macular edema (DME) and non-diabetic macular pathology. Sensitivity and specificity were calculated with SD-OCT as gold standard. RESULTS: 422 eyes from 211 diabetic patients were evaluated. DME severity by UWFI: no DME 93.4%, non-center involved DME (nonciDME) 5.1%, ciDME 0.7%, ungradable DME 0.7%. SD-OCT was ungradable in 0.5%. Macular pathology was identified in 34 (8.1%) eyes by UWFI and in 44 (10.4%) eyes by SD-OCT. DME represented only 38.6% of referable macular pathology identified by SD-OCT imaging. Sensitivity/specificity of UWFI compared to SD-OCT was 59%/96% for DME and 33%/99% for ciDME. Sensitivity/specificity of UWFI compared to SDOCT was 3%/98% for ERM. CONCLUSIONS: Addition of SD-OCT increased the identification of macular pathology by 29.4%. Over 58.3% of the eyes thought to have any DME on UWF imaging alone were false positives by SD-OCT. The integration of SD-OCT with UWFI markedly increased detection and reduced false positive assessments of DME and macular pathology in a teleophthalmology program.
Aiello LP, Jacoba CMP, Ashraf M, Cavallerano JD, Tolson AM, Tolls D, Sun JK, Silva PS.
INTEGRATING MACULAR OPTICAL COHERENCE TOMOGRAPHY WITH ULTRAWIDE-FIELD IMAGING IN A DIABETIC RETINOPATHY TELEMEDICINE PROGRAM USING A SINGLE DEVICE. Retina 2023;43(11):1928-1935.
AbstractPURPOSE: To determine the effect of combined macular spectral-domain optical coherence tomography (SD-OCT) and ultrawide field retinal imaging (UWFI) within a telemedicine program. METHODS: Comparative cohort study of consecutive patients with both UWFI and SD-OCT. Ultrawide field retinal imaging and SD-OOCT were independently evaluated for diabetic macular edema (DME) and nondiabetic macular abnormality. Sensitivity and specificity were calculated with SD-OCT as the gold standard. RESULTS: Four hundred twenty-two eyes from 211 diabetic patients were evaluated. Diabetic macular edema severity by UWFI was as follows: no DME 93.4%, noncenter involved DME (nonciDME) 5.1%, ciDME 0.7%, ungradable DME 0.7%. SD-OCT was ungradable in 0.5%. Macular abnormality was identified in 34 (8.1%) eyes by UWFI and in 44 (10.4%) eyes by SD-OCT. Diabetic macular edema represented only 38.6% of referable macular abnormality identified by SD-OCT imaging. Sensitivity/specificity of UWFI compared with SD-OCT was 59%/96% for DME and 33%/99% for ciDME. Sensitivity/specificity of UWFI compared with SDOCT was 3%/98% for epiretinal membrane. CONCLUSION: Addition of SD-OCT increased the identification of macular abnormality by 29.4%. More than 58.3% of the eyes believed to have any DME on UWF imaging alone were false-positives by SD-OCT. The integration of SD-OCT with UWFI markedly increased detection and reduced false-positive assessments of DME and macular abnormality in a teleophthalmology program.
Aiello LP, Ayala AR, Antoszyk AN, Arnold-Bush B, Baker C, Bressler NM, Elman MJ, Glassman AR, Jampol LM, Melia M, Nielsen J, Wolpert HA, Wolpert HA.
Assessing the Effect of Personalized Diabetes Risk Assessments During Ophthalmologic Visits on Glycemic Control: A Randomized Clinical Trial. JAMA Ophthalmol 2015;133(8):888-96.
AbstractIMPORTANCE: Optimization of glycemic control is critical to reduce the number of diabetes mellitus-related complications, but long-term success is challenging. Although vision loss is among the greatest fears of individuals with diabetes, comprehensive personalized diabetes education and risk assessments are not consistently used in ophthalmologic settings. OBJECTIVE: To determine whether the point-of-care measurement of hemoglobin A1c (HbA1c) and personalized diabetes risk assessments performed during retinal ophthalmologic visits improve glycemic control as assessed by HbA1c level. DESIGN, SETTING, AND PARTICIPANTS: Ophthalmologist office-based randomized, multicenter clinical trial in which investigators from 42 sites were randomly assigned to provide either a study-prescribed augmented diabetes assessment and education or the usual care. Adults with type 1 or 2 diabetes enrolled into 2 cohorts: those with a more-frequent-than-annual follow-up (502 control participants and 488 intervention participants) and those with an annual follow-up (368 control participants and 388 intervention participants). Enrollment was from April 2011 through January 2013. INTERVENTIONS: Point-of-care measurements of HbA1c, blood pressure, and retinopathy severity; an individualized estimate of the risk of retinopathy progression derived from the findings from ophthalmologic visits; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant's understanding. These interventions were performed at enrollment and at routine ophthalmic follow-up visits scheduled at least 12 weeks apart. MAIN OUTCOMES AND MEASURES: Mean change in HbA1c level from baseline to 1-year follow-up. Secondary outcomes included body mass index, blood pressure, and responses to diabetes self-management practices and attitudes surveys. RESULTS: In the cohort with more-frequent-than-annual follow-ups, the mean (SD) change in HbA1c level at 1 year was -0.1% (1.5%) in the control group and -0.3% (1.4%) in the intervention group (adjusted mean difference, -0.09% [95% CI, -0.29% to 0.12%]; P = .35). In the cohort with annual follow-ups, the mean (SD) change in HbA1c level was 0.0% (1.1%) in the control group and -0.1% (1.6%) in the intervention group (mean difference, -0.05% [95% CI, -0.27% to 0.18%]; P = .63). Results were similar for all secondary outcomes. CONCLUSIONS AND RELEVANCE: Long-term optimization of glycemic control is not achieved by a majority of individuals with diabetes. The addition of personalized education and risk assessment during retinal ophthalmologic visits did not result in a reduction in HbA1c level compared with usual care over 1 year. These data suggest that optimizing glycemic control remains a substantive challenge requiring interventional paradigms other than those examined in our study. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01323348.
Aiello LP, Odia I, Glassman AR, Melia M, Jampol LM, Bressler NM, Kiss S, Silva PS, Wykoff CC, Sun JK, Sun JK.
Comparison of Early Treatment Diabetic Retinopathy Study Standard 7-Field Imaging With Ultrawide-Field Imaging for Determining Severity of Diabetic Retinopathy. JAMA Ophthalmol 2018;
AbstractImportance: Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective: To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants: This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures: Agreement between UWF images, UWF imagesmasked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. Results: A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance: Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.
Airaldi M, Zheng Y, Aiello F, Bachmann B, Baydoun L, Ní Dhubhghaill S, Dickman MM, Kaye SB, Fontana L, Gadhvi KA, Moramarco A, de Mora MRC, Rocha de Lossada C, Scorcia V, Viola P, Calza S, Levis HJ, Parekh M, Ruzza A, Ferrari S, Ponzin D, Semeraro F, Romano V.
Preoperative surgeon evaluation of corneal endothelial status: the Viability Control of Human Endothelial Cells before Keratoplasty (V-CHECK) study protocol. BMJ Open Ophthalmol 2023;8(1)
AbstractINTRODUCTION: The success of keratoplasty strongly depends on the health status of the transplanted endothelial cells. Donor corneal tissues are routinely screened for endothelial damage before shipment; however, surgical teams have currently no means of assessing the overall viability of corneal endothelium immediately prior to transplantation. The aim of this study is to validate a preoperative method of evaluating the endothelial health of donor corneal tissues, to assess the proportion of tissues deemed suitable for transplantation by the surgeons and to prospectively record the clinical outcomes of a cohort of patients undergoing keratoplasty in relation to preoperatively defined endothelial viability. METHODS AND ANALYSIS: In this multicentre cohort study, consecutive patients undergoing keratoplasty (perforating keratoplasty, Descemet stripping automated endothelial keratoplasty (DSAEK), ultra-thin DSAEK (UT-DSAEK) or Descemet membrane endothelial keratoplasty) will be enrolled and followed-up for 1 year. Before transplantation, the endothelial viability of the donor corneal tissue will be evaluated preoperatively through trypan blue staining and custom image analysis to estimate the overall percentage of trypan blue-positive areas (TBPAs), a proxy of endothelial damage. Functional and structural outcomes at the end of the follow-up will be correlated with preoperatively assessed TBPA values. ETHICS AND DISSEMINATION: The protocol will be reviewed by the ethical committees of participating centres, with the sponsor centre issuing the final definitive approval. The results will be disseminated on ClinicalTrials.gov, at national and international conferences, by partner patient groups and in open access, peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05847387.
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.
AbstractOver 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.
Akhlaq A, Colón C, Cavalcanti BM, Aggarwal S, Qazi Y, Cruzat A, Jersey C, Critser DB, Watts A, Beyer J, Sindt CW, Hamrah P.
Density and distribution of dendritiform cells in the peripheral cornea of healthy subjects using in vivo confocal microscopy. Ocul Surf 2022;
Akula JD, Lancos AM, AlWattar BK, De Bruyn H, Hansen RM, Fulton AB.
A Simplified Model of Activation and Deactivation of Human Rod Phototransduction-An Electroretinographic Study. Invest Ophthalmol Vis Sci 2023;64(12):36.
AbstractPURPOSE: To test the hypothesis that a simple model having properties consistent with activation and deactivation in the rod approximates the whole time course of the photoresponse. METHODS: Routinely, an exponential of the form f = α·(1 - exp(-(τ·(t - teff)s-1))), with amplitude α, rate constant τ (often scaled by intensity), irreducible delay teff, and time exponent s-1, is fit to the early period of the flash electroretinogram. Notably, s (an integer) represents the three integrating stages in the rod amplification cascade (rhodopsin isomerization, transducin activation, and cGMP hydrolysis). The time course of the photoresponse to a 0.17 cd·s·m-2 conditioning flash (CF) was determined in 21 healthy eyes by presenting the CF plus a bright probe flash (PF) in tandem, separated by interstimulus intervals (ISIs) of 0.01 to 1.4 seconds, and calculating the proportion of the PF a-wave suppressed by the CF at each ISI. To test if similar kinetics describe deactivation, difference of exponential (DoE) functions with common α and teff parameters, respective rate constants for the initiation (I) and quenching (Q) phases of the response, and specified values of s (sI, sQ), were compared to the photoresponse time course. RESULTS: As hypothesized, the optimal values of sI and sQ were 3 and 2, respectively. Mean ± SD α was 0.80 ± 0.066, I was 7700 ± 2400 m2·cd-1·s-3, and Q was 1.4 ± 0.47 s-1. Overall, r2 was 0.93. CONCLUSIONS: A method, including a DoE model with just three free parameters (α, I, Q), that robustly captures the magnitude and time-constants of the complete rod response, was produced. Only two steps integrate to quench the rod photoresponse.
Akula JD, Ambrosio L, Howard FI, Hansen RM, Fulton AB.
Extracting the ON and OFF contributions to the full-field photopic flash electroretinogram using summed growth curves. Exp Eye Res 2019;189:107827.
AbstractUnder cone-mediated (photopic) conditions, an "instantaneous" flash of light, including both stimulus onset and offset, will simultaneously activate both "ON" and "OFF" bipolar cells, which either depolarize (ON) or hyperpolarize (OFF) in response and, respectively, produce positive-going and negative-going deflections in the electroretinogram (ERG). The stimulus-response (SR) relationship of the photopic ON response demonstrates logistic growth, like that manifested in the rod-mediated (scotopic) b-wave, which is driven by a single class of depolarizing bipolar cell. However, the photopic b-wave SR function is importantly shaped by OFF responses, leading to a "photopic hill." Furthermore, both on and off stimuli elicit activity in both ON and OFF bipolar cells. This has made it difficult to produce meaningful parameters for ready interpretation of the photopic b-wave SR relationship. Therefore, we evaluated whether the sum of sigmoidal SR functions, as descriptors of the depolarizing and hyperpolarizing components of the photopic flash ERG, could be used to elucidate and quantitate the mechanisms that produce the photopic hill. We used a novel fitting routine to optimize a sum of simple sigmoidal curves to SR data in five groups of subjects: Healthy adult, 10-week-old infant, congenital stationary night blindness (CSNB), X-linked juvenile retinoschisis (XJR), and preterm-born, both without and with a history of retinopathy of prematurity (ROP). Differences in ON and OFF amplitude, sensitivity, and implicit time among the groups were then compared using parameters extracted from these fits. We found that our modeling procedure enabled plausible derivations of ON and OFF pathway contributions to the ERG, and that the parameters produced appeared to have physiological relevance. In adult subjects, the ON and OFF amplitudes were similar in magnitude with respectively longer and shorter implicit times. Infant, CSNB, and XJR subjects showed significant ON pathway deficits. History of preterm-birth, without or with a diagnosis of ROP, did not much affect cone responses.
