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J Michael Jumper,1 Pravin U Dugel,2,3 Sanford Chen,4 Kevin J Blinder,5 John G Walt6 On behalf of the ECHO Study Group 1West Coast Retina Medical Group, San Francisco, CA, USA; 2Retinal Consultants of Arizona, Phoenix, AZ, USA; 3USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 4Orange County Retina, Santa Ana, CA, USA; 5The Retina Institute, St Louis, MO, USA; 6Allergan plc, Irvine, CA, USA Purpose: To evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) antagonists in the treatment of macular edema secondary to retinal vein occlusion (RVO) in clinical practice.Patients and methods: A multicenter retrospective study of the medical records of 165 patients (95 branch RVO, 70 central RVO) treated with at least three anti-VEGF injections in the study eye was conducted. Available data collected for at least 6 months after the first injection included Snellen best-corrected visual acuity (BCVA), central retinal thickness (CRT) by time-domain optical coherence tomography (TD-OCT) or spectral-domain optical coherence tomography (SD-OCT), anti-VEGF injections, other treatments/procedures for RVO, and adverse events.Results: At baseline prior to anti-VEGF treatment, mean BCVA was 20/80 Snellen equivalent and mean CRT was 499 µm. Mean number of anti-VEGF injections received was 7.1 during the first year, 5.4 during the second year, and 5.9 during the third year; 51.3% (842/1,641) of injections were ranibizumab, 44.1% (724/1,641) were bevacizumab, and 4.6% (75/1,641) were aflibercept. One in five patients received concomitant focal laser treatment. The percentage of patients achieving both BCVA of 20/40 or better and CRT ≤250 µm on TD-OCT or ≤300 µm on SD-OCT at the same visit (primary endpoint) was 26.1% (30/115) after the first anti-VEGF injection and ranged from 20.0% (7/35) to 36.7% (11/30) after the first 16 injections. After each anti-VEGF injection from the 1st to the 16th,

Kevin J Blinder,1 Pravin U Dugel,2,3 Sanford Chen,4 J Michael Jumper,5 John G Walt,6 David A Hollander,6 Lanita C Scott6 On behalf of the ECHO Study Group 1The Retina Institute, St Louis, MO, 2Retinal Consultants of Arizona, Phoenix, AZ, 3USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, 4Orange County Retina, Santa Ana, 5West Coast Retina Medical Group, San Francisco, 6Allergan plc, Irvine, CA, USA Purpose: To evaluate the efficacy, safety, and injection frequency of vascular endothelial growth factor (VEGF) inhibitors as used in clinical practice for the treatment of diabetic macular edema.Methods: Multicenter (10 sites), retrospective chart review in patients (n=156) who received ≥3 anti-VEGF injections. Data collected for ≥6 months after the first injection included Snellen best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by time-domain or spectral-domain optical coherence tomography (TD-OCT or SD-OCT).Results: Mean number of anti-VEGF injections (627 bevacizumab, 594 ranibizumab, 1 aflibercept) was 5.8 (year 1), 5.0 (year 2), and 3.4 (year 3). Percentage of patients with BCVA of 20/40 or better and CRT ≤250 µm on TD-OCT or ≤300 µm on SD-OCT at the same visit (primary endpoint) ranged from 16.4% to 38.9% after the first 10 injections; 51.9%–62.3% achieved ≥20/40 BCVA and 26.2%–48.0% met CRT criteria. Therapy was well tolerated with 19 treatment-related adverse events (all ocular) reported.Conclusion: Anti-VEGF injections were administered less frequently and were less effective than those in the ranibizumab registration trials. After each of the first 9 injections,

We report clinical and imaging features of Valsalva-induced choroidal hemorrhage (VICH) in high myopia, highlighting choroidal venous congestion, and hyperpermeability in dominant vortex vein systems, and luminal compression at the crest of deep myopic staphylomas., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration., Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices., Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US., Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures., Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes., Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

Purpose: There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in β-adrenergic receptor (ADRβ) pathways could protect against ROP. Antagonists for the ADRβ are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRβ signaling pathways associate with risk of developing ROP., Design: An observational case-control targeted genetic analysis., Methods: A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRβ pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort., Results: The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRβ pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings., Conclusion: SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The introduction of AlphaFold 2 1 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design 2-6 . Here we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture that is capable of predicting the joint structure of complexes including proteins, nucleic acids, small molecules, ions and modified residues. The new AlphaFold model demonstrates substantially improved accuracy over many previous specialized tools: far greater accuracy for protein-ligand interactions compared with state-of-the-art docking tools, much higher accuracy for protein-nucleic acid interactions compared with nucleic-acid-specific predictors and substantially higher antibody-antigen prediction accuracy compared with AlphaFold-Multimer v.2.3 7,8 . Together, these results show that high-accuracy modelling across biomolecular space is possible within a single unified deep-learning framework., (© 2024. The Author(s).)

Purpose: To report an increasingly prevalent fundoscopic manifestation of syphilitic uveitis., Methods: Case report of a patient with acute retinal necrosis secondary to syphilis., Results: A 48-year-old man presented with decreased vision, anterior segment inflammation, and a wedge-shaped retinal lesion in the superior periphery, with a diaphanous leading edge extending down toward the superior arcade. The patient was HIV+ and poorly compliant with therapy. The top three differential diagnoses were herpetic necrotizing retinitis, syphilis, and lymphoma. An extensive lab workup was positive for syphilis. The patient was treated with IV penicillin G and demonstrated improvement in visual acuity and examination., Conclusion: There have been an increasing number of reports of syphilis patients, especially in the population of men who have sex with men, who present with fundus findings similar to acute retinal necrosis. These findings include a characteristic ground glass, translucent appearance of unifocal or multifocal lesions, primarily affecting the inner retina and sometimes associated with co-localizing occlusive vasculitis. Treatment with IV penicillin G is warranted and has demonstrated good visual recovery.

Purpose: To report a case of presumed intraretinal tuberculosis evaluated with optical coherence tomography angiography., Methods: Case report., Results: A 61-year-old woman recently immigrated from China presented with round yellow-white retinal lesions in the left eye. The lesions were evaluated with multimodal imaging, including optical coherence tomography angiography. Subsequent serologic testing revealed a positive QuantiFERON-TB Gold test, whereas workup for other entities was negative. The patient was diagnosed with presumed intraretinal tuberculosis. She was started on systemic antitubercular therapy and the lesions regressed. The regression was documented with optical coherence tomography angiography., Conclusion: Case reports of primary intraretinal tuberculosis are uncommon. To the best of our knowledge, this is the first case to demonstrate optical coherence tomography angiography findings of presumed intraretinal tuberculosis.

Purpose: To describe two cases of catastrophic, bilateral retinal vascular occlusion after intravitreal (IVT) bevacizumab injection., Methods: Case series. Main outcome measures included clinical and fluorescein angiography findings., Results: Case 1-A 65-year-old woman with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasis syndrome developed acute, severe, bilateral visual loss 2 weeks after bilateral IVT bevacizumab injection for proliferative diabetic retinopathy. Examination and fluorescein angiography revealed moderate anterior chamber inflammation, bilateral perivascular retinal hemorrhages, and near total retinal vascular occlusion. Extensive testing revealed moderately elevated anti-B2 glycoprotein (antiphospholipid) antibodies. Case 2-An 85-year-old man with polymyalgia rheumatica and left eye exudative age-related macular degeneration experienced severe, bilateral, sequential visual loss in the left eye and then right eye approximately 3 weeks after IVT bevacizumab left eye injection. Examination revealed bilateral panuveitis, diffuse perivascular exudates, and intraretinal hemorrhages. Fluorescein angiography showed diffuse venous leakage. Extensive testing revealed an elevated antinuclear antibody and mildly elevated anticardiolipin antibody., Conclusion: Patients with underlying retinal vascular vulnerabilities may be at increased risk of catastrophic, bilateral retinal vascular occlusion after treatment with IVT bevacizumab. The moderate-to-severe intraocular inflammation in both cases and the contralateral involvement after unilateral IVT injection in Case 2 suggest a possible delayed immune-mediated mechanism.

Purpose: To assess the impact of submacular fluid (SMF) after pneumatic retinopexy for primary rhegmatogenous retinal detachment repair., Methods: Retrospective review of consecutive patients treated with pneumatic retinopexy for primary rhegmatogenous retinal detachment repair. 387 eyes (374 patients) were included, of which 166 underwent optical coherence tomography imaging after successful pneumatic retinopexy. Foveal-centered optical coherence tomography scans were reviewed., Results: SMF occurred in 59 eyes (35.5%) and was associated with macular detachment ( P ≤ 0.001) and phakic lens status ( P = 0.007). Submacular fluid resolved over an average of 9.39 months and was associated with worse preprocedure best-corrected visual acuity and delayed visual recovery. The mean final best-corrected visual acuity was 0.277 logarithm of the minimum angle of resolution (20/40) in eyes with SMF and 0.162 logarithm of the minimum angle of resolution (20/30) in those without SMF ( P < 0.001). Submacular fluid was associated with discontinuity of the interdigitation zone ( P = 0.003), ellipsoid zone ( P = 0.005), and external limiting membrane ( P ≤ 0.001) after SMF resolution. Ellipsoid zone discontinuity was associated with worse visual prognosis ( P = 0.009)., Conclusion: Trace SMF detected by optical coherence tomography is common after successful pneumatic retinopexy and resulted in delayed visual recovery and increased rates of outer retinal discontinuity after SMF resorption, although the final difference in best-corrected visual acuity in those with and without SMF was minimal.

Purpose: To investigate the clinical and anatomic characteristics of soccer ball-induced posterior segment injuries in the era of modern multi-modal imaging., Methods: Retrospective case series of patients with soccer ball injury and diagnostic imaging from 2007 to 2020 at a single vitreoretinal practice., Results: Eight patients met inclusion criteria. Fundus photographs (FP) and optical coherence tomography (OCT) were obtained in eight patients, fundus autofluorescence (FAF) in five patients, fluorescein angiography (FA) in three patients, and en-face OCT and OCT-Angiography (OCT-A) were obtained in two patients each. FA and FAF identified traumatic pigment epitheliopathy secondary to commotio. Increased hypo-autofluorescence was associated with shallow, peripheral retinal detachment on FAF. OCT of the macula displayed outer retinal changes associated with commotio, and offered insight into the acute and subacute changes of traumatic macular hole formation. A patient displayed foveal hyper-reflectivity in the shape of an hourglass with retinal cyst at the level of the external limiting membrane (ELM) as seen on OCT and En-face OCT. A patient with commotio involving the macula lacked microvascular changes on OCT-A., Conclusion: OCT, FA, and FAF imaging may aid in the work-up and management of the soccer ball-related posterior segment injuries.

Purpose: To discuss the mechanism of injury and characterize the clinical features of ocular trauma associated with elastic cord exercise equipment band injuries in a consecutive series of patients seen at a single vitreoretinal surgery practice., Methods: We performed a retrospective review of all patients who were treated for blunt trauma from 2013 to 2020 at a single vitreoretinal practice., Results: Thirteen eyes from 11 patients met the inclusion criteria of possessing ocular trauma secondary to recoil from exercise bands. Presenting visual acuity ranged from 20/16 to HM (median: 20/32). The most frequently observed anterior segment pathologies were traumatic iritis (54%) and angle recession (31%). The most common posterior segment findings were vitreous hemorrhage (54%) and peripheral commotio retinae (54%). Three eyes (23%) required surgical intervention. Follow-up intervals ranged from 0 to 10 months (median: 1.75 months). Visual acuity at last examination ranged from 20/13 to 20/400 (median: 20/40)., Conclusion: A wide spectrum of serious ocular injuries requiring medical and surgical intervention can result from this form of blunt ocular trauma. The frequency of this event would be decreased by the use of sports goggles and careful inspection of equipment for wear and over use., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: This work analyzes data from a series of surveys developed by the American Society of Retina Specialists (ASRS) that assesses the impact of COVID-19 on physicians, their practices, and their patients., Methods: Five surveys were sent by the ASRS between March and July 2020 to more than 2600 US and international retina specialists. Data and trends from these surveys were analyzed., Results: Most responding retina specialists (87%-95% in the United States and internationally) reported having no known COVID-related symptoms despite reported limitations in personal protective equipment. Clinic volumes globally were drastically reduced in March 2020 with only partial recovery through July 2020, which was slower internationally than in the United States. Practices were compelled to reduce staff and physician employment levels. Most respondents estimated some degree of delay in patient treatment with corresponding declines in vision and/or anatomy that were attributed most frequently to patients' fears of the pandemic and least frequently to office unavailability., Conclusions: The reported impact of COVID-19 on retina specialists, their practices, and their patients has been substantial. Although retina specialists were quickly resilient in optimizing delivery of patient care in a manner safe for patients and providers, the reduction in clinic volume has been devastating in the United States and internationally, with negative impacts on patient outcomes, reductions in practices' volume and employment, and risk to practices' financial health. Future studies will be required to quantify losses associated with these unprecedented and ongoing circumstances caused by the pandemic., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.H.: ASRS (board of directors), Alimera (consultant, honoraria), DORC International (consultant, lecture fees), and Genentech (consultant, honoraria, lecture fees), J.F.B.: ASRS (executive vice president; employee); K.P.: none; J.M.J.: ASRS (board of directors) and DORC International (consultant, lecture fees); T.M.: ASRS (board of directors) and Alcon Surgical (FDA Committee); and C.C.A.: ASRS (board of directors), Adverum Biotechnologies Inc (investigator, grants), Allergan (advisory board, honoraria), Apellis Pharmaceuticals (investigator, grants), ArcticDX (consultant, stockholder, stock), Bausch + Lomb (consultant, honoraria), Chengdu Kanghong Biotechnology Co (consultant, honoraria), Genentech (consultant, investigator, grants, honoraria), Glaxo Smith Kline (investigator, grants), Hoffman-La Roche (investigator, grants), Katalyst Surgical (consultant, stockholder, royalty, stock), Kodiak Sciences (investigator, grants), Merck & Co (investigator, grants), Ophthotech/Iveric Bio (investigator, grants), Panoptica (investigator, grants), Regeneron (investigator, grants), Stealth Biotherapeutics (investigator, grants), and Volk Optical (consultant, honoraria)., (© The Author(s) 2021.)

Purpose: Intravitreal injection is the most frequently performed eye procedure in the world and is an essential component in the management of sight-threating retinal diseases and conditions. Given the seriousness and range of diseases treated and the risks of the procedure, retina specialists must weigh the pros and cons of each individual treatment. Complexities guiding injection treatment are multifaceted and involve patient-history review, careful examination, diagnostic testing selection and interpretation, customized medical decision-making, and follow-up considerations., Methods: This article by the Intravitreal Injection Task Force Committee of the American Society of Retina Specialists documents the intricacies and necessary components of the intravitreal injection procedure., Results: By expert consensus, the task force further recommends ancillary services and decision-making that may accompany intravitreal injection visits, when appropriate, to monitor response to treatment, adjust treatment, and manage additional considerations in the same or fellow eye., Conclusions: Retina specialists can optimize safety and therapeutic outcomes with individualized consideration and customization of intravitreal injection treatment for each patient., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Purpose : To report novel mutations in the FZD4 and LRP5 genes , associated with familial exudative vitreoretinopathy (FEVR), and to correlate with clinical features of 7 FEVR patients. Methods : In this retrospective case series, 7 patients who had undergone genetic panel testing and carried a diagnosis of FEVR were identified. Comprehensive ophthalmic examination and direct DNA sequencing of FEVR-associated genes were performed in all patients. Identified sequence variants were analyzed in silico . Results : Eight mutations were identified amongst the 7 patients, that included 4 FZD4 mutations and 4 LRP5 mutations. Four novel mutations were identified, two in FZD4 (c.615delC, p.Y206MfsX34) and (c.964A>T, p.I322F), and two in LRP5 (c.2585A>T, p.D862V) and (c.1412 + 1 G > A, splice donor). A broad phenotypic spectrum was noted and no clear genotypic-phenotypic correlation was observed. Conclusion : These findings expand the mutation spectrum of FZD4 and LRP5 .

This is a case report detailing a pars plana vitrectomy and resection of a retinal capillary hemangioblastoma in a 19-year-old female with a history of von Hippel-Lindau syndrome with secondary retinal detachment and sub-retinal exudates limiting her vision. Intraoperatively, long duration endolaser and generous endodiathermy applied to the feeder vessels are essential to minimize bleeding. Complete and careful resection of the lesion and installation of a silicone oil tamponade are recommended. This technique can allow for retinal reattachment and improvement in visual acuity in advanced cases of secondary retinal detachment.

Purpose: To describe the appearance of concentric, fingerprint-like waves within the Henle fiber layer (HFL) using en face optical coherence tomography in patients with tractional pathologies of the retina., Methods: Retrospective analysis of six eyes of six patients imaged by optical coherence tomography with volumetric slabs positioned at the level of the HFL., Results: Optical coherence tomography data from six patients with tractional vitreoretinal pathology were reviewed. Concentric, fingerprint-like microwaves were visualized through en face optical coherence tomography in all six study eyes at the level of the HFL. This finding resembled the finding of HFL waves previously noted histopathologically from force exerted on this layer., Conclusion: In retinal pathologies in which specific physical forces act on the retina, volumetric optical coherence tomography may permit visualization of en face concentric, fingerprint-like hyperreflective rings within the HFL. This "fingerprint sign" may represent a biomechanical consequence of traction on the retina and allow clinical decision making based on improved recognition of the existence of such traction.

Single-molecule force spectroscopy has proven extremely beneficial in elucidating folding pathways for membrane proteins. Here, we simulate these measurements, conducting hundreds of unfolding trajectories using our fast Upside algorithm for slow enough speeds to reproduce key experimental features that may be missed using all-atom methods. The speed also enables us to determine the logarithmic dependence of pulling velocities on the rupture levels to better compare to experimental values. For simulations of atomic force microscope measurements in which force is applied vertically to the C-terminus of bacteriorhodopsin, we reproduce the major experimental features including even the back-and-forth unfolding of single helical turns. When pulling laterally on GlpG to mimic the experiment, we observe quite different behavior depending on the stiffness of the spring. With a soft spring, as used in the experimental studies with magnetic tweezers, the force remains nearly constant after the initial unfolding event, and a few pathways and a high degree of cooperativity are observed in both the experiment and simulation. With a stiff spring, however, the force drops to near zero after each major unfolding event, and numerous intermediates are observed along a wide variety of pathways. Hence, the mode of force application significantly alters the perception of the folding landscape, including the number of intermediates and the degree of folding cooperativity, important issues that should be considered when designing experiments and interpreting unfolding data., (Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

To address the large gap between time scales that can be easily reached by molecular simulations and those required to understand protein dynamics, we present a rapid self-consistent approximation of the side chain free energy at every integration step. In analogy with the adiabatic Born-Oppenheimer approximation for electronic structure, the protein backbone dynamics are simulated as preceding according to the dictates of the free energy of an instantaneously-equilibrated side chain potential. The side chain free energy is computed on the fly, allowing the protein backbone dynamics to traverse a greatly smoothed energetic landscape. This computation results in extremely rapid equilibration and sampling of the Boltzmann distribution. Our method, termed Upside, employs a reduced model involving the three backbone atoms, along with the carbonyl oxygen and amide proton, and a single (oriented) side chain bead having multiple locations reflecting the conformational diversity of the side chain's rotameric states. We also introduce a novel, maximum-likelihood method to parameterize the side chain interactions using protein structures. We demonstrate state-of-the-art accuracy for predicting χ1 rotamer states while consuming only milliseconds of CPU time. Our method enables rapidly equilibrating coarse-grained simulations that can nonetheless contain significant molecular detail. We also show that the resulting free energies of the side chains are sufficiently accurate for de novo folding of some proteins., Competing Interests: The authors have declared that no competing interests exist.

An ongoing challenge in protein chemistry is to identify the underlying interaction energies that capture protein dynamics. The traditional trade-off in biomolecular simulation between accuracy and computational efficiency is predicated on the assumption that detailed force fields are typically well-parameterized, obtaining a significant fraction of possible accuracy. We re-examine this trade-off in the more realistic regime in which parameterization is a greater source of error than the level of detail in the force field. To address parameterization of coarse-grained force fields, we use the contrastive divergence technique from machine learning to train from simulations of 450 proteins. In our procedure, the computational efficiency of the model enables high accuracy through the precise tuning of the Boltzmann ensemble. This method is applied to our recently developed Upside model, where the free energy for side chains is rapidly calculated at every time-step, allowing for a smooth energy landscape without steric rattling of the side chains. After this contrastive divergence training, the model is able to de novo fold proteins up to 100 residues on a single core in days. This improved Upside model provides a starting point both for investigation of folding dynamics and as an inexpensive Bayesian prior for protein physics that can be integrated with additional experimental or bioinformatic data., Competing Interests: The authors have declared that no competing interests exist.

We use the statistics of a large and curated training set of transmembrane helical proteins to develop a knowledge-based potential that accounts for the dependence on both the depth of burial of the protein in the membrane and the degree of side-chain exposure. Additionally, the statistical potential includes depth-dependent energies for unsatisfied backbone hydrogen bond donors and acceptors, which are found to be relatively small, ∼2 RT. Our potential accurately places known proteins within the bilayer. The potential is applied to the mechanosensing MscL channel in membranes of varying thickness and curvature, as well as to the prediction of protein structure. The potential is incorporated into our new Upside molecular dynamics algorithm. Notably, we account for the exchange of protein-lipid interactions for protein-protein interactions as helices contact each other, thereby avoiding overestimating the energetics of helix association within the membrane. Simulations of most multimeric complexes find that isolated monomers and the oligomers retain the same orientation in the membrane, suggesting that the assembly of prepositioned monomers presents a viable mechanism of oligomerization., (Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe a technique of combined scleral buckle with external needle drainage and vitrectomy in the treatment of bullous exudative retinal detachment, schisis detachment, or bullous retinoschisis threatening the fovea., Methods: A retrospective chart review of four eyes of four patients who underwent the procedure described., Results: Four eyes of four patients who underwent combined scleral buckling with external needle drainage and vitrectomy by a single surgeon for a bullous exudative retinal detachment, schisis detachment, or bullous retinoschisis threatening the fovea were included in this series. All four patients were attached after a single surgical intervention. No patient developed complications from the external drainage., Conclusion: External needle drainage of bullous subretinal or intraschisis fluid in combination with vitrectomy is a successful technique for treating bullous exudative retinal detachments, schisis detachment, or foveal-threatening retinoschisis. The technique avoids many complications associated with conventional drainage procedures. Long-term results seem promising because of extended follow-up demonstrating sustained anatomical success with a single intervention.

A substantial fraction of the proteome is intrinsically disordered, and even well-folded proteins adopt non-native geometries during synthesis, folding, transport, and turnover. Characterization of intrinsically disordered proteins (IDPs) is challenging, in part because of a lack of accurate physical models and the difficulty of interpreting experimental results. We have developed a general method to extract the dimensions and solvent quality (self-interactions) of IDPs from a single small-angle x-ray scattering measurement. We applied this procedure to a variety of IDPs and found that even IDPs with low net charge and high hydrophobicity remain highly expanded in water, contrary to the general expectation that protein-like sequences collapse in water. Our results suggest that the unfolded state of most foldable sequences is expanded; we conjecture that this property was selected by evolution to minimize misfolding and aggregation., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV)., Design: Retrospective case series., Participants: Thirty-six eyes of 23 patients., Methods: The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases., Main Outcome Measures: Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes., Results: Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements., Conclusions: Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected., (Published by Elsevier Inc.)

Purpose: To describe the ocular findings and subsequent workup of a 21-year-old woman with previously undiagnosed Fanconi anemia., Methods: Observational case report and literature review., Results: A 21-year-old healthy woman presented with bilateral retinal hemorrhages, telangiectasia, and severe ischemia with vascular leak. Systemic workup revealed anemia and thrombocytopenia. A diepoxybutane chromosomal breakage test confirmed the diagnosis of Fanconi anemia., Conclusion: Ocular complications are common in patients with Fanconi anemia and may be the presenting manifestation of the disease.

Purpose: To describe the clinical characteristics and surgical management of rhegmatogenous retinal detachment (RD) in patients with acute syphilitic panuveitis., Methods: Retrospective case series and comprehensive literature review., Results: Including present and previously reported cases, we identified 11 eyes in 8 patients with acute syphilitic panuveitis that developed a rhegmatogenous RD. Seven of 11 eyes (63.6%) were repaired with a combined scleral buckling, vitrectomy, and endolaser photocoagulation surgery; 1 eye (9.1%) was repaired with scleral buckling only; and 2 eyes (18.2%) with vitrectomy only. Cryotherapy was used to treat a giant retinal tear in 1 eye (9.1%). Four eyes (36.4%) redetached and 3 underwent a second vitrectomy surgery., Conclusions: Although uncommon, rhegmatogenous RD can occur in patients with moderate to severe acute syphilitic panuveitis. We believe scleral buckling, vitrectomy, endolaser photocoagulation, and silicone oil tamponade give the best chance for successful retinal reattachment.

Purpose: The purpose of this study was to report a case of a Filipino woman with a history of breast cancer who presented with unilateral choroidal infiltration, which led to the diagnosis of sarcoidosis., Methods: Case report and literature review., Results: A 64-year-old Filipino woman with a history of breast cancer presented with unilateral choroidal nodules. Her blood tests were negative for common causes of choroidal infiltration (angiotensin-converting enzyme, lysozyme, Treponema pallidum particle agglutination), and Mantoux skin test and a chest x-ray were negative. Her diagnosis could only be made by biopsy of the two hypermetabolic paratracheal nodes seen on the positron emission tomography-computed tomography., Conclusion: Choroidal infiltration may be the presenting feature of sarcoidosis even in ethnicities known to have very low incidence of the disease. If the chest x-ray is negative and the clinical suspicion warrants it, a CT or positron emission tomography-computed tomography of the thorax may be helpful in identifying nonhilar mediastinal lymphadenopathy. As in our case, fine-needle aspiration biopsy of these nodes may lead to confirmation of the diagnosis.

Silicon nanowires (SiNWs) have emerged as a new class of materials with important applications in biology and medicine with current efforts having focused primarily on using substrate bound SiNW devices. However, developing devices capable of free-standing inter- and intracellular operation is an important next step in designing new synthetic cellular materials and tools for biophysical characterization. To demonstrate this, here we show that label free SiNWs can be internalized in multiple cell lines, forming robust cytoskeletal interfaces, and when kinked can serve as free-standing inter- and intracellular force probes capable of continuous extended (>1 h) force monitoring. Our results show that intercellular interactions exhibit ratcheting like behavior with force peaks of ∼69.6 pN/SiNW, while intracellular force peaks of ∼116.9 pN/SiNW were recorded during smooth muscle contraction. To accomplish this, we have introduced a simple single-capture dark-field/phase contrast optical imaging modality, scatter enhanced phase contrast (SEPC), which enables the simultaneous visualization of both cellular components and inorganic nanostructures. This approach demonstrates that rationally designed devices capable of substrate-independent operation are achievable, providing a simple and scalable method for continuous inter- and intracellular force dynamics studies.

Acute retinal ischaemia presents in various forms depending on the type and location of the associated vascular occlusion. Cotton wool spots have been considered one manifestation of ischaemia and represent swelling in the nerve fibre layer. However, clinical retinal whitening also occurs in areas not affected by cotton wool spots, and has distinguishing spectral domain optical coherence tomography (SD-OCT) features. We present SD-OCT findings of hyper-reflectivity and thickening in four eyes with representative retinal arterial or retinal venous occlusions, specifically branch retinal artery occlusion, central retinal vein occlusion, Purtscher-like retinopathy and ophthalmic artery occlusion. The spectrum of retinal ischaemia from various causes was found to manifest in inner nuclear layer hyper-reflectivity and thickening on SD-OCT. En Face OCT imaging further characterises the topographical distribution of ischaemia, and reveals patterns which provide insight into the pathological processes involved., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring., Methods: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists., Results: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone-iodine to and avoiding eyelid contact with the intended injection site and needle., Conclusion: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.

Purpose: To describe the nature and evolution of paraneoplastic cloudy vitelliform submaculopathy in patients with primary vitreoretinal lymphoma and propose a mechanism for its development and course., Design: Retrospective, observational case series., Methods: Three patients presenting with unilateral cloudy vitelliform submaculopathy based on clinical examination, fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography (SD OCT) imaging and ultimately diagnosed with primary vitreoretinal lymphoma and/or primary central nervous system lymphoma were analyzed., Results: In all 3 patients, cloudy vitelliform submaculopathy appeared with hazy indistinct yellow subretinal material resembling the vitelliform lesions found in acute exudative paraneoplastic polymorphous vitelliform maculopathy, although with less distinct appearance and without intense hyper-autofluorescence. In all 3 patients, cloudy vitelliform submaculopathy was transient, showed spontaneous regression within 3 months, and preceded the diagnosis of lymphoma, suggestive of a paraneoplastic process. The diagnosis of primary vitreoretinal lymphoma and/or primary central nervous system lymphoma was made within 6 months with classic features of new intraretinal or sub-retinal pigment epithelium infiltration of lymphoma in the peripheral retina (n = 2) and hyperintense lesions on brain magnetic resonance imaging (n = 2). With SD OCT imaging, the cloudy vitelliform subretinal lesions appeared as hyperreflective debris above the retinal pigment epithelium band in all 3 eyes, and were associated with an irregularly thickened and rippled retinal pigment epithelium band in 2 eyes. Resolution of the cloudy submacular lesions resulted in outer retinal atrophic changes in all 3 eyes., Conclusion: Paraneoplastic cloudy vitelliform submaculopathy, a form of lymphoma-associated retinopathy, can precede the diagnosis of primary vitreoretinal lymphoma or primary central nervous system lymphoma and can regress spontaneously, leaving outer retinal abnormalities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The loss of conformational entropy is a major contribution in the thermodynamics of protein folding. However, accurate determination of the quantity has proven challenging. We calculate this loss using molecular dynamic simulations of both the native protein and a realistic denatured state ensemble. For ubiquitin, the total change in entropy is TΔSTotal = 1.4 kcal⋅mol(-1) per residue at 300 K with only 20% from the loss of side-chain entropy. Our analysis exhibits mixed agreement with prior studies because of the use of more accurate ensembles and contributions from correlated motions. Buried side chains lose only a factor of 1.4 in the number of conformations available per rotamer upon folding (ΩU/ΩN). The entropy loss for helical and sheet residues differs due to the smaller motions of helical residues (TΔShelix-sheet = 0.5 kcal⋅mol(-1)), a property not fully reflected in the amide N-H and carbonyl C=O bond NMR order parameters. The results have implications for the thermodynamics of folding and binding, including estimates of solvent ordering and microscopic entropies obtained from NMR.

Purpose: To describe a peculiar case of paraneoplastic vitelliform maculopathy/retinopathy in a patient with treated choroidal melanoma., Methods: A case report of a 58-year-old woman with a history of treated choroidal melanoma 16 years before developing visual changes in the setting of metastatic choroidal melanoma., Results: We demonstrate bilateral, multifocal vitelliform subretinal lesions and focal, neurosensory retinal detachment associated with metastatic melanoma., Conclusion: Paraneoplastic vitelliform maculopathy/retinopathy should be considered in patients with or without a history of melanoma, who have unexplained serous, vitelliform retinal detachments, especially with atypical or absence of leakage on fluorescein angiography.

Purpose: To report the clinical course of a patient with acute retinal necrosis resulting from a multidrug-resistant strain of herpes simplex virus 2., Methods: Observational case report., Results: A 17-year-old man with no identifiable immune deficiency presented with pain and decreased vision in his left eye. He had dense anterior and posterior segment inflammation with retinal whitening suggestive of acute retinal necrosis, which progressed despite treatment with intravenous acyclovir, methylprednisolone, and ganciclovir. A transition to intravitreal and intravenous foscarnet led to clinical improvement. Genetic analysis revealed the etiology to be a multidrug-resistant strain of herpes simplex virus 2., Conclusion: Antiviral resistance is an uncommon finding among viruses causing acute retinal necrosis in immunocompetent patients. Patients with these infections may be adequately treated with prompt recognition and a change in therapy to alternative antiviral agents such as foscarnet.

Purpose: To describe a case of chronic exogenous Exophiala dermatitidis endophthalmitis., Methods: Retrospective chart review and case report., Results: A 60-year-old man with history of chronic herpes zoster keratitis complicated by secondary fungal keratitis treated with penetrating keratoplasty presented with a white cataract, chronic anterior uveitis, and counting fingers vision in the left eye. Combined cataract extraction and diagnostic vitrectomy revealed positive cultures and polymerase chain reaction-based testing for E. dermatitidis-the same organism responsible for the keratitis. The patient was treated with multiple oral, intravenous, and intravitreal antifungal agents. Ultimately, the corneal infection recurred and the patient elected to undergo enucleation. Filamentous fungi consistent with E. dermatitidis infection were identified in the cornea of the enucleation specimen., Conclusion: Although rare, Exophiala species can cause exogenous endophthalmitis. Chronic endophthalmitis should be suspected in patients who develop persistent intraocular inflammation after infectious keratitis.

Purpose: To analyze the anatomical characteristics of lamellar macular holes using cross-sectional and en face spectral domain optical coherence tomography., Methods: Forty-two lamellar macular holes were retrospectively identified for analysis. The location, cross-sectional length, and area of lamellar holes were measured using B-scans and en face imaging. The presence of photoreceptor inner segment/outer segment disruption and the presence or absence of epiretinal membrane formation were recorded., Results: Forty-two lamellar macular holes were identified. Intraretinal splitting occurred within the outer plexiform layer in 97.6% of eyes. The area of intraretinal splitting in lamellar holes did not correlate with visual acuity. Eyes with inner segment/outer segment disruption had significantly worse mean logMAR visual acuity (0.363 ± 0.169; Snellen = 20/46) than in eyes without inner segment/outer segment disruption (0.203 ± 0.124; Snellen = 20/32) (analysis of variance, P = 0.004). Epiretinal membrane was present in 34 of 42 eyes (81.0%)., Conclusion: En face imaging allowed for consistent detection and quantification of intraretinal splitting within the outer plexiform layer in patients with lamellar macular holes, supporting the notion that an area of anatomical weakness exists within Henle's fiber layer, presumably at the synaptic connection of these fibers within the outer plexiform layer. However, the en face area of intraretinal splitting did not correlate with visual acuity, disruption of the inner segment/outer segment junction was associated with significantly worse visual acuity in patients with lamellar macular holes.