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    Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Gazzard Gus,Konstantakopoulou Evgenia,Garway-Heath David,Garg Anurag,Vickerstaff Victoria,Hunter Rachael,Ambler Gareth,Bunce Catey,Wormald Richard,Nathwani Neil,Barton Keith,Rubin Gary,Buszewicz Marta, Lancet (London, England) BACKGROUND:Primary open angle glaucoma and ocular hypertension are habitually treated with eye drops that lower intraocular pressure. Selective laser trabeculoplasty is a safe alternative but is rarely used as first-line treatment. We compared the two. METHODS:In this observer-masked, randomised controlled trial treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities were recruited between 2012 and 2014 at six UK hospitals. They were randomly allocated (web-based randomisation) to initial selective laser trabeculoplasty or to eye drops. An objective target intraocular pressure was set according to glaucoma severity. The primary outcome was health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D). Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness, and safety. Analysis was by intention to treat. This study is registered at controlled-trials.com (ISRCTN32038223). FINDINGS:Of 718 patients enrolled, 356 were randomised to the selective laser trabeculoplasty and 362 to the eye drops group. 652 (91%) returned the primary outcome questionnaire at 36 months. Average EQ-5D score was 0·89 (SD 0·18) in the selective laser trabeculoplasty group versus 0·90 (SD 0·16) in the eye drops group, with no significant difference (difference 0·01, 95% CI -0·01 to 0·03; p=0·23). At 36 months, 74·2% (95% CI 69·3-78·6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intracoluar pressure at more visits (93·0%) than in the eye drops group (91·3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20 000 per quality-adjusted life-year gained. INTERPRETATION:Selective laser trabeculoplasty should be offered as a first-line treatment for open angle glaucoma and ocular hypertension, supporting a change in clinical practice. FUNDING:National Institute for Health Research, Health and Technology Assessment Programme. 10.1016/S0140-6736(18)32213-X
    Laser trabeculoplasty as first-line glaucoma treatment. Young Jonathan W,Caprioli Joesph Lancet (London, England) 10.1016/S0140-6736(18)32553-4
    Laser peripheral iridotomy for the prevention of angle closure: a single-centre, randomised controlled trial. He Mingguang,Jiang Yuzhen,Huang Shengsong,Chang Dolly S,Munoz Beatriz,Aung Tin,Foster Paul J,Friedman David S Lancet (London, England) BACKGROUND:Primary angle-closure glaucoma affects 20 million people worldwide. People classified as primary angle closure suspects have a higher but poorly quantified risk of developing glaucoma. We aimed to assess efficacy and safety of laser peripheral iridotomy prophylaxis against primary angle-closure glaucoma in Chinese people classified as primary angle closure suspects. METHODS:In this randomised controlled trial, bilateral primary angle closure suspects aged 50-70 years were enrolled at the Zhongshan Ophthalmic Center, a tertiary specialised hospital in Guangzhou, China. Eligible patients received laser peripheral iridotomy in one randomly selected eye, with the other remaining untreated. The primary outcome was incident primary angle closure disease as a composite endpoint of elevation of intraocular pressure, peripheral anterior synechiae, or acute angle-closure during 72 months of follow-up in an intention-to-treat analysis between treated eyes and contralateral controls. This trial is registered with the ISRCTN registry, number ISRCTN45213099. FINDINGS:Of 11 991 screened individuals, 889 individuals were randomly assigned from June 19, 2008 (889 treated and 889 untreated eyes). Incidence of the primary outcome was 4·19 per 1000 eye-years in treated eyes compared with 7·97 per 1000 eye-years in untreated eyes (hazard ratio 0·53; 95% CI 0·30-0·92; p=0·024). A primary outcome event occurred in 19 treated eyes and 36 untreated eyes with a statistically significant difference using pair-wise analysis (p=0·0041). No serious adverse events were observed during follow-up. INTERPRETATION:Incidence of angle-closure disease was very low among individuals classified as primary angle closure suspects identified through community-based screening. Laser peripheral iridotomy had a modest, albeit significant, prophylactic effect. In view of the low incidence rate of outcomes that have no immediate threat to vision, the benefit of prophylactic laser peripheral iridotomy is limited; therefore, widespread prophylactic laser peripheral iridotomy for primary angle-closure suspects is not recommended. FUNDING:Fight for Sight, the Sun Yat-Sen University 5010 Project Fund, Moorfields Eye Charity, and the National Natural Science Foundation of China. 10.1016/S0140-6736(18)32607-2
    Retinal oximetry: Metabolic imaging for diseases of the retina and brain. Stefánsson Einar,Olafsdottir Olof Birna,Eliasdottir Thorunn S,Vehmeijer Wouter,Einarsdottir Anna Bryndis,Bek Toke,Torp Thomas Lee,Grauslund Jakob,Eysteinsson Thor,Karlsson Robert Arnar,Van Keer Karel,Stalmans Ingeborg,Vandewalle Evelien,Todorova Margarita G,Hammer Martin,Garhöfer Gerhard,Schmetterer Leopold,Šín Martin,Hardarson Sveinn Hakon Progress in retinal and eye research Retinal oximetry imaging of retinal blood vessels measures oxygen saturation of hemoglobin. The imaging technology is non-invasive and reproducible with remarkably low variability on test-retest studies and in healthy cohorts. Pathophysiological principles and novel biomarkers in several retinal diseases have been discovered, as well as possible applications for systemic and brain disease. In diabetic retinopathy, retinal venous oxygen saturation is elevated and arteriovenous difference progressively reduced in advanced stages of retinopathy compared with healthy persons. This correlates with pathophysiology of diabetic retinopathy where hypoxia stimulates VEGF production. Laser treatment and vitrectomy both improve retinal oximetry values, which correlate with clinical outcome. The oximetry biomarker may allow automatic measurement of severity of diabetic retinopathy and predict its response to treatment. Central retinal vein occlusion is characterized by retinal hypoxia, which is evident in retinal oximetry. The retinal hypoxia seen on oximetry correlates with the extent of peripheral ischemia, visual acuity and thickness of macular edema. This biomarker may help diagnose and measure severity of vein occlusion and degree of retinal ischemia. Glaucomatous retinal atrophy is associated with reduced oxygen consumption resulting in reduced arteriovenous difference and higher retinal venous saturation. The oximetry findings correlate with worse visual field, thinner nerve fiber layer and smaller optic disc rim. This provides an objective biomarker for glaucomatous damage. In retinitis pigmentosa, an association exists between advanced atrophy, worse visual field and higher retinal venous oxygen saturation, lower arteriovenous difference. This biomarker may allow measurement of severity and progression of retinitis pigmentosa and other atrophic retinal diseases. Retinal oximetry offers visible light imaging of systemic and central nervous system vessels. It senses hypoxia in cardiac and pulmonary diseases. Oximetry biomarkers have been discovered in Alzheimer's disease and multiple sclerosis and oxygen levels in the retina correspond well with brain. 10.1016/j.preteyeres.2019.04.001
    Deep learning in ophthalmology: The technical and clinical considerations. Ting Daniel S W,Peng Lily,Varadarajan Avinash V,Keane Pearse A,Burlina Philippe M,Chiang Michael F,Schmetterer Leopold,Pasquale Louis R,Bressler Neil M,Webster Dale R,Abramoff Michael,Wong Tien Y Progress in retinal and eye research The advent of computer graphic processing units, improvement in mathematical models and availability of big data has allowed artificial intelligence (AI) using machine learning (ML) and deep learning (DL) techniques to achieve robust performance for broad applications in social-media, the internet of things, the automotive industry and healthcare. DL systems in particular provide improved capability in image, speech and motion recognition as well as in natural language processing. In medicine, significant progress of AI and DL systems has been demonstrated in image-centric specialties such as radiology, dermatology, pathology and ophthalmology. New studies, including pre-registered prospective clinical trials, have shown DL systems are accurate and effective in detecting diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), retinopathy of prematurity, refractive error and in identifying cardiovascular risk factors and diseases, from digital fundus photographs. There is also increasing attention on the use of AI and DL systems in identifying disease features, progression and treatment response for retinal diseases such as neovascular AMD and diabetic macular edema using optical coherence tomography (OCT). Additionally, the application of ML to visual fields may be useful in detecting glaucoma progression. There are limited studies that incorporate clinical data including electronic health records, in AL and DL algorithms, and no prospective studies to demonstrate that AI and DL algorithms can predict the development of clinical eye disease. This article describes global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable. Technical and clinical aspects to build a DL system to address those needs, and the potential challenges for clinical adoption are discussed. AI, ML and DL will likely play a crucial role in clinical ophthalmology practice, with implications for screening, diagnosis and follow up of the major causes of vision impairment in the setting of ageing populations globally. 10.1016/j.preteyeres.2019.04.003
    Is population-based glaucoma screening cost-effective in China? Zhang Lei,He Mingguang The Lancet. Global health 10.1016/S2214-109X(19)30229-3
    Laser eye procedure is safe and effective as an early treatment for glaucoma. Cook Rob,Thomas Vaughan,Martin Rosie, BMJ (Clinical research ed.) The studyGazzard G, Konstantakopoulou G, Garway-Heath E, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. 2019; doi:10.1016/S0140-6736(18)32213-XThis project was funded by the NIHR Health Technology Assessment Programme (project number 09/104/40) and was sponsored by the Moorfields Eye Hospital NHS Foundation Trust.To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000774/early-glaucoma-laser-eye-treatment-trabeculoplasty. 10.1136/bmj.l4235
    Melatonin and the control of intraocular pressure. Alkozi Hanan Awad,Navarro Gemma,Franco Rafael,Pintor Jesus Progress in retinal and eye research Melatonin is not only synthesized by the pineal gland but by several ocular structures. This natural indoleamine is of great importance for regulating several eye processes, among which pressure homeostasis is included. Glaucoma, the most prevalent eye disease, also known as the silent thief of vision, is a multifactorial pathology that is associated to age and, often, to intraocular hypertension (IOP). Indeed IOP is the only modifiable risk factor and as such medications are available to control it; however, novel medications are sought to minimize undesirable side effects. Melatonin and analogues decrease IOP in both normotensive and hypertensive eyes. Melatonin activates its cognate membrane receptors, MT and MT, which are present in numerous ocular tissues, including the aqueous-humor-producing ciliary processes. Melatonin receptors belong to the superfamily of G-protein-coupled receptors and their activation would lead to different signalling pathways depending on the tissue. This review describes the molecular mechanisms underlying differential functionalities that are attributed to melatonin receptors. Accordingly, the current work highlights the important role of melatonin and its analogues in the healthy and in the glaucomatous eyes, with special attention to the control of intraocular pressure. 10.1016/j.preteyeres.2019.100798
    Is it time to consider glaucoma screening cost-effective? Kanclerz Piotr,Grzybowski Andrzej,Tuuminen Raimo The Lancet. Global health 10.1016/S2214-109X(19)30395-X
    Is it time to consider glaucoma screening cost-effective? - Authors' reply. Tang Jianjun,Congdon Nathan,Liang Yuanbo The Lancet. Global health 10.1016/S2214-109X(19)30398-5
    Beyond intraocular pressure: Optimizing patient-reported outcomes in glaucoma. Fenwick Eva K,Man Ryan Ek,Aung Tin,Ramulu Pradeep,Lamoureux Ecosse L Progress in retinal and eye research Glaucoma, an irreversible blinding condition affecting 3-4% adults aged above 40 years worldwide, is set to increase with a rapidly aging global population. Raised intraocular pressure (IOP) is a major risk factor for glaucoma where the treatment paradigm is focused on managing IOP using medications, laser, or surgery regimens. However, notwithstanding IOP and other clinical parameters, patient-reported outcomes, including daily functioning, emotional well-being, symptoms, mobility, and social life, remain the foremost concerns for people being treated for glaucoma. These outcomes are measured using objective patient-centered outcome measures (PCOMs) and subjective patient-reported outcome measures (PROMs). Studies using PCOMs have shown that people with glaucoma have several mobility, navigational and coordination challenges; reading and face recognition deficits; and are slower in adapting to multiple real-world situations when compared to healthy controls. Similarly, studies have consistently demonstrated, using PROMs, that glaucoma substantially and negatively impacts on peoples' self-reported visual functioning, mobility, independence, emotional well-being, self-image, and confidence in healthcare, compared to healthy individuals, particularly in those with late-stage disease undergoing a heavy treatment regimen. The patient-centred effectiveness of current glaucoma treatment paradigms is equivocal due to a lack of well-designed randomized controlled trials; short post-treatment follow-up periods; an inappropriate selection or availability of PROMs; and/or an insensitivity of currently available PROMs to monitor changes especially in patients with newly diagnosed early-stage glaucoma. We provide a comprehensive, albeit non-systematic, critique of the psychometric properties, limitations, and recent advances of currently available glaucoma-specific PCOMs and PROMs. Finally, we propose that item banking and computerized adaptive testing methods can address the multiple limitations of paper-pencil PROMs; customize their administration; and have the potential to improve healthcare outcomes for people with glaucoma. 10.1016/j.preteyeres.2019.100801
    Nanotechnology in regenerative ophthalmology. Sahle Fitsum Feleke,Kim Sangyoon,Niloy Kumar Kulldeep,Tahia Faiza,Fili Cameron V,Cooper Emily,Hamilton David J,Lowe Tao L Advanced drug delivery reviews In recent years, regenerative medicine is gaining momentum and is giving hopes for restoring function of diseased, damaged, and aged tissues and organs and nanotechnology is serving as a catalyst. In the ophthalmology field, various types of allogenic and autologous stem cells have been investigated to treat some ocular diseases due to age-related macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, and corneal and lens traumas. Nanomaterials have been utilized directly as nanoscaffolds for these stem cells to promote their adhesion, proliferation and differentiation or indirectly as vectors for various genes, tissue growth factors, cytokines and immunosuppressants to facilitate cell reprogramming or ocular tissue regeneration. In this review, we reviewed various nanomaterials used for retina, cornea, and lens regenerations, and discussed the current status and future perspectives of nanotechnology in tracking cells in the eye and personalized regenerative ophthalmology. The purpose of this review is to provide comprehensive and timely insights on the emerging field of nanotechnology for ocular tissue engineering and regeneration. 10.1016/j.addr.2019.10.006
    Once Daily Pregabalin Eye Drops for Management of Glaucoma. Ibrahim Mohamed Moustafa,Maria Doaa Nabih,Mishra Sanjay R,Guragain Deepa,Wang XiangDi,Jablonski Monica M ACS nano Elevated intraocular pressure (IOP) is the most significant risk factor contributing to visual field loss in glaucoma. Unfortunately, the deficiencies associated with current therapies have resulted in reduced efficacy, several daily dosings, and poor patient compliance. Previously, we identified the calcium voltage-gated channel auxiliary subunit alpha2delta 1 gene () as a modulator of IOP and demonstrated that pregabalin, a drug with high affinity and selectivity for CACNA2D1, lowered IOP in a dose-dependent manner. Unfortunately, IOP returned to baseline at 6 h after dosing. In the current study, we develop a once daily topical pregabalin-loaded multiple water-in-oil-in-water microemulsion formulation to improve drug efficacy. We characterize our formulations using multiple and evaluations. Our lead formulation provides continuous release of pregabalin for up to 24 h. Because of its miniscule droplet size (<20 nm), our microemulsion has a transparent appearance and should not blur vision. It is also stable at one month of storage at temperatures ranging from 5 to 40 °C. Our formulation is nontoxic, as illustrated by a cell toxicity study and slit-lamp biomicroscopic exams. CACNA2D1 is highly expressed in both the ciliary body and the trabecular meshwork, where it functions to modulate IOP. A single drop of our lead pregabalin formulation reduces IOP by greater than 40%, which does not return to baseline until >30 h post-application. Although there were no significant differences in the amplitude of IOP reduction between the formulations we tested, a significant difference was clearly observed in their duration of action. Our multilayered microemulsion is a promising carrier that sustains the release and prolongs the duration of action of pregabalin, a proposed glaucoma therapeutic. 10.1021/acsnano.9b07214
    Glaucoma report: patients' sight is put at risk by treatment delays. Torjesen Ingrid BMJ (Clinical research ed.) 10.1136/bmj.m103
    A neuroglia-based interpretation of glaucomatous neuroretinal rim thinning in the optic nerve head. Lee Eun Jung,Han Jong Chul,Park Do Young,Kee Changwon Progress in retinal and eye research Neuroretinal rim thinning (NRR) is a characteristic glaucomatous optic disc change. However, the precise mechanism of the rim thinning has not been completely elucidated. This review focuses on the structural role of the glioarchitecture in the formation of the glaucomatous NRR thinning. The NRR is a glia-framed structure, with honeycomb geometry and mechanically reinforced astrocyte processes along the transverse plane. When neural damage selectively involves the neuron and spares the glia, the gross structure of the tissue is preserved. The disorganization and loss of the glioarchitecture are the two hallmarks of optic nerve head (ONH) remodeling in glaucoma that leads to the thinning of NRR tissue upon axonal loss. This is in contrast to most non-glaucomatous optic neuropathies with optic disc pallor where hypertrophy of the glioarchitecture is associated with the seemingly absent optic disc cupping. Arteritic anterior ischemic optic neuropathy is an exception where pan-necrosis of ONH tissue leads to NRR thinning. Milder ischemia indicates selective neuronal loss that spares glia in non-arteritic anterior ischemic optic neuropathy. The biological reason is the heterogeneous glial response determined by the site, type, and severity of the injury. The neuroglial interpretation explains how the cellular changes underlie the clinical findings. Updated understandings on glial responses illustrate the mechanical, microenvironmental, and microglial modulation of activated astrocytes in glaucoma. Findings relevant to the possible mechanism of the astrocyte death in advanced glaucoma are also emerging. Ultimately, a better understanding of glaucomatous glial response may lead to glia-targeting neuroprotection in the future. 10.1016/j.preteyeres.2020.100840
    Ocular blood flow as a clinical observation: Value, limitations and data analysis. Harris Alon,Guidoboni Giovanna,Siesky Brent,Mathew Sunu,Verticchio Vercellin Alice C,Rowe Lucas,Arciero Julia Progress in retinal and eye research Alterations in ocular blood flow have been identified as important risk factors for the onset and progression of numerous diseases of the eye. In particular, several population-based and longitudinal-based studies have provided compelling evidence of hemodynamic biomarkers as independent risk factors for ocular disease throughout several different geographic regions. Despite this evidence, the relative contribution of blood flow to ocular physiology and pathology in synergy with other risk factors and comorbidities (e.g., age, gender, race, diabetes and hypertension) remains uncertain. There is currently no gold standard for assessing all relevant vascular beds in the eye, and the heterogeneous vascular biomarkers derived from multiple ocular imaging technologies are non-interchangeable and difficult to interpret as a whole. As a result of these disease complexities and imaging limitations, standard statistical methods often yield inconsistent results across studies and are unable to quantify or explain a patient's overall risk for ocular disease. Combining mathematical modeling with artificial intelligence holds great promise for advancing data analysis in ophthalmology and enabling individualized risk assessment from diverse, multi-input clinical and demographic biomarkers. Mechanism-driven mathematical modeling makes virtual laboratories available to investigate pathogenic mechanisms, advance diagnostic ability and improve disease management. Artificial intelligence provides a novel method for utilizing a vast amount of data from a wide range of patient types to diagnose and monitor ocular disease. This article reviews the state of the art and major unanswered questions related to ocular vascular anatomy and physiology, ocular imaging techniques, clinical findings in glaucoma and other eye diseases, and mechanistic modeling predictions, while laying a path for integrating clinical observations with mathematical models and artificial intelligence. Viable alternatives for integrated data analysis are proposed that aim to overcome the limitations of standard statistical approaches and enable individually tailored precision medicine in ophthalmology. 10.1016/j.preteyeres.2020.100841
    Chronotherapy of hypertension, asleep ambulatory blood pressure, and glaucoma. Hermida Ramón C,Fernández José R,Mojón Artemio, European heart journal 10.1093/eurheartj/ehaa215
    Decreased melatonin secretion in patients with glaucoma: Quantitative association with glaucoma severity in the LIGHT study. Yoshikawa Tadanobu,Obayashi Kenji,Miyata Kimie,Saeki Keigo,Ogata Nahoko Journal of pineal research Glaucoma may be associated with circadian disruption due to its association with a loss of intrinsically photosensitive retinal ganglion cells. Clinical evidence demonstrating an association between glaucoma and circadian disruption is limited, and no large-scale studies have been performed. The purpose of this cross-sectional study was to determine whether the presence and severity of glaucoma is correlated with the urinary 6-sulfatoxymelatonin levels as a circadian rhythm parameter. We measured the level of urinary 6-sulfatoxymelatonin excretion (UME) in 118 glaucoma patients and 395 control participants without glaucoma. The UME in the glaucoma group was significantly lower than that of the control group without glaucoma (3.05 and 3.24 log ng/mg creatinine, respectively; P = .010). Next, we examined association of the severity of glaucoma and melatonin levels. In stratification analysis of the glaucoma groups, multivariable linear regression analyses adjusted for potential confounders indicated significantly lower UME by 0.30 log ng/mg creatinine in patients with functional severe glaucoma (visual field mean deviation ≤ -6 dB) compared with mild glaucoma (mean deviation > -6 dB; P = .040) and lower UME by 0.05 log ng/mg creatinine with each 10 μm thinning of the circumpapillary retinal nerve fiber layer thickness as the index of structural severity of glaucoma (P = .011). In conclusion, significant association between glaucoma and lower urinary 6-sulfatoxymelatonin was found. In addition, patients with functional and structural severe glaucoma were significantly associated with lower urinary 6-sulfatoxymelatonin levels. Our results indicate the possibility of a circadian disruption in patients with glaucoma. 10.1111/jpi.12662
    Personalising surgical treatments for glaucoma patients. Sunaric Megevand Gordana,Bron Alain M Progress in retinal and eye research Surgical treatments for glaucoma have relied for decades on traditional filtering surgery such as trabeculectomy and, in more challenging cases, tubes. Antifibrotics were introduced to improve surgical success in patients at increased risk of failure but have been shown to be linked to a greater incidence of complications, some being potentially vision-threatening. As our understanding of glaucoma and its early diagnosis have improved, a more individualised management has been suggested. Recently the term "precision medicine" has emerged as a new concept of an individualised approach to disease management incorporating a wide range of individual data in the choice of therapeutic modalities. For glaucoma surgery, this involves evaluation of the right timing, individual risk factors, targeting the correct anatomical and functional outflow pathways and appropriate prevention of scarring. As a consequence, there is an obvious need for better knowledge of anatomical and functional pathways and for more individualised surgical approaches with new, less invasive and safer techniques allowing for earlier intervention. With the recent advent of minimally invasive glaucoma surgery (MIGS) a large number of novel devices have been introduced targeting potential new sites of the outflow pathway for lowering intraocular pressure (IOP). Their popularity is growing in view of the relative surgical simplicity and apparent lack of serious side effects. However, these new surgical techniques are still in an era of early experiences, short follow-up and lack of evidence of their superiority in safety and cost-effectiveness over the traditional methods. Each year several new devices are introduced while others are withdrawn from the market. Glaucoma continues to be the primary cause of irreversible blindness worldwide and access to safe and efficacious treatment is a serious problem, particularly in the emerging world where the burden of glaucoma-related blindness is important and concerning. Early diagnosis, individualised treatment and, very importantly, safe surgical management should be the hallmarks of glaucoma treatment. However, there is still need for a better understanding of the disease, its onset and progression, the functional and structural elements of the outflow pathways in relation to the new devices as well as their long-term IOP-lowering efficacy and safety. This review discusses current knowledge and the future need for personalised glaucoma surgery. 10.1016/j.preteyeres.2020.100879
    Retinal energy metabolism in health and glaucoma. Casson Robert J,Chidlow Glyn,Crowston Jonathan G,Williams Pete A,Wood John P M Progress in retinal and eye research Energy metabolism refers to the processes by which life transfers energy to do cellular work. The retina's relatively large energy demands make it vulnerable to energy insufficiency. In addition, evolutionary pressures to optimize human vision have been traded against retinal ganglion cell bioenergetic fragility. Details of the metabolic profiles of the different retinal cells remain poorly understood and are challenging to resolve. Detailed immunohistochemical mapping of the energy pathway enzymes and substrate transporters has provided some insights and highlighted interspecies differences. The different spatial metabolic patterns between the vascular and avascular retinas can account for some inconsistent data in the literature. There is a consilience of evidence that at least some individuals with glaucoma have impaired RGC energy metabolism, either due to impaired nutrient supply or intrinsic metabolic perturbations. Bioenergetic-based therapy for glaucoma has a compelling pathophysiological foundation and is supported by recent successes in animal models. Recent demonstrations of visual and electrophysiological neurorecovery in humans with glaucoma is highly encouraging and motivates longer duration trials investigating bioenergetic neuroprotection. 10.1016/j.preteyeres.2020.100881
    Normal and glaucomatous outflow regulation. Acott Ted S,Vranka Janice A,Keller Kate E,Raghunathan VijayKrishna,Kelley Mary J Progress in retinal and eye research Glaucoma remains only partially understood, particularly at the level of intraocular pressure (IOP) regulation. Trabecular meshwork (TM) and Schlemm's canal inner wall endothelium (SCE) are key to IOP regulation and their characteristics and behavior are the focus of much investigation. This is becoming more apparent with time. We and others have studied the TM and SCE's extracellular matrix (ECM) extensively and unraveled much about its functions and role in regulating aqueous outflow. Ongoing ECM turnover is required to maintain IOP regulation and several TM ECM manipulations modulate outflow facility. We have established clearly that the outflow pathway senses sustained pressure deviations and responds by adjusting the outflow resistance correctively to keep IOP within an appropriately narrow range which will not normally damage the optic nerve. The glaucomatous outflow pathway has in many cases lost this IOP homeostatic response, apparently due at least in part, to loss of TM cells. Depletion of TM cells eliminates the IOP homeostatic response, while restoration of TM cells restores it. Aqueous outflow is not homogeneous, but rather segmental with regions of high, intermediate and low flow. In general, glaucomatous eyes have more low flow regions than normal eyes. There are distinctive molecular differences between high and low flow regions, and during the response to an IOP homeostatic pressure challenge, additional changes in segmental molecular composition occur. In conjunction with these changes, the biomechanical properties of the juxtacanalicular (JCT) segmental regions are different, with low flow regions being stiffer than high flow regions. The JCT ECM of glaucomatous eyes is around 20 times stiffer than in normal eyes. The aqueous humor outflow resistance has been studied extensively, but neither the exact molecular components that comprise the resistance nor their exact location have been established. Our hypothetical model, based on considerable available data, posits that the continuous SCE basal lamina, which lies between 125 and 500 nm beneath the SCE basal surface, is the primary source of normal resistance. On the surface of JCT cells, small and highly controlled focal degradation of its components by podosome- or invadopodia-like structures, PILS, occurs in response to pressure-induced mechanical stretching. Sub-micron sized basement membrane discontinuities develop in the SCE basement membrane and these discontinuities allow passage of aqueous humor to and through SCE giant vacuoles and pores. JCT cells then relocate versican with its highly charged glycosaminoglycan side chains into the discontinuities and by manipulation of their orientation and concentration, the JCT and perhaps the SCE cells regulate the amount of fluid passage. Testing this outflow resistance hypothesis is ongoing in our lab and has the potential to advance our understanding of IOP regulation and of glaucoma. 10.1016/j.preteyeres.2020.100897
    Extraocular, periocular, and intraocular routes for sustained drug delivery for glaucoma. Kompella Uday B,Hartman Rachel R,Patil Madhoosudan A Progress in retinal and eye research Although once daily anti-glaucoma drug therapy is a current clinical reality, most therapies require multiple dosing and there is an unmet need to develop convenient, safe, and effective sustained release drug delivery systems for long-term treatment to improve patient adherence and outcomes. One of the first sustained release drug delivery systems was approved for the reduction of intraocular pressure in glaucoma patients. It is a polymeric reservoir-type insert delivery system, Ocusert™, placed under the eyelid and on the ocular surface for zero-order drug release over one week. The insert, marketed in two strengths, released pilocarpine on the eye surface. While many clinicians appreciated this drug product, it was eventually discontinued. No similar sustained release non-invasive drug delivery system has made it to the market to date for treating glaucoma. Drug delivery systems under development include punctal plugs, ring-type systems, contact lenses, implants, microspheres, nanospheres, gels, and other depot systems placed in the extraocular, periocular, or intraocular regions including intracameral, supraciliary, and intravitreal spaces. This article discusses the advantages and disadvantages of the various routes of administration and delivery systems for sustained glaucoma therapy. It also provides the reader with some examples and discussion of drug delivery systems that could potentially be applied for glaucoma treatment. Interestingly, one intracamerally injected implant, Durysta™, was approved recently for sustained intraocular pressure reduction. However, long-term acceptance of such devices has yet to be established. The ultimate success of the delivery system will depend on efficacy relative to eye drop dosing, safety, reimbursement options, and patient acceptance. Cautious development efforts are warranted considering prior failed approaches for sustained glaucoma drug delivery. Neuroprotective approaches for glaucoma therapy including cell, gene, protein, and drug-combination therapies, mostly administered intravitreally, are also rapidly progressing towards assessment in humans. 10.1016/j.preteyeres.2020.100901
    Digital technology, tele-medicine and artificial intelligence in ophthalmology: A global perspective. Li Ji-Peng Olivia,Liu Hanruo,Ting Darren S J,Jeon Sohee,Chan R V Paul,Kim Judy E,Sim Dawn A,Thomas Peter B M,Lin Haotian,Chen Youxin,Sakomoto Taiji,Loewenstein Anat,Lam Dennis S C,Pasquale Louis R,Wong Tien Y,Lam Linda A,Ting Daniel S W Progress in retinal and eye research The simultaneous maturation of multiple digital and telecommunications technologies in 2020 has created an unprecedented opportunity for ophthalmology to adapt to new models of care using tele-health supported by digital innovations. These digital innovations include artificial intelligence (AI), 5th generation (5G) telecommunication networks and the Internet of Things (IoT), creating an inter-dependent ecosystem offering opportunities to develop new models of eye care addressing the challenges of COVID-19 and beyond. Ophthalmology has thrived in some of these areas partly due to its many image-based investigations. Tele-health and AI provide synchronous solutions to challenges facing ophthalmologists and healthcare providers worldwide. This article reviews how countries across the world have utilised these digital innovations to tackle diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, glaucoma, refractive error correction, cataract and other anterior segment disorders. The review summarises the digital strategies that countries are developing and discusses technologies that may increasingly enter the clinical workflow and processes of ophthalmologists. Furthermore as countries around the world have initiated a series of escalating containment and mitigation measures during the COVID-19 pandemic, the delivery of eye care services globally has been significantly impacted. As ophthalmic services adapt and form a "new normal", the rapid adoption of some of telehealth and digital innovation during the pandemic is also discussed. Finally, challenges for validation and clinical implementation are considered, as well as recommendations on future directions. 10.1016/j.preteyeres.2020.100900
    Laser treatment for glaucoma. Larkin John Lancet (London, England) 10.1016/S0140-6736(20)31059-X
    Laser treatment for glaucoma - Authors' reply. Gazzard Gus,Konstantakopoulou Evgenia,Ambler Gareth,Hunter Rachael,Vickerstaff Victoria, Lancet (London, England) 10.1016/S0140-6736(20)31060-6
    Inflammation in Glaucoma: From the back to the front of the eye, and beyond. Baudouin Christophe,Kolko Miriam,Melik-Parsadaniantz Stéphane,Messmer Elisabeth M Progress in retinal and eye research The pathophysiology of glaucoma is complex, multifactorial and not completely understood. Elevated intraocular pressure (IOP) and/or impaired retinal blood flow may cause initial optic nerve damage. In addition, age-related oxidative stress in the retina concurrently with chronic mechanical and vascular stress is crucial for the initiation of retinal neurodegeneration. Oxidative stress is closely related to cell senescence, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, which are involved in glaucoma progression. Accumulating evidence from animal glaucoma models and from human ocular samples suggests a dysfunction of the para-inflammation in the retinal ganglion cell layer and the optic nerve head. Moreover, quite similar mechanisms in the anterior chamber could explain the trabecular meshwork dysfunction and the elevated IOP in primary open-angle glaucoma. On the other hand, ocular surface disease due to topical interventions is the most prominent and visible consequence of inflammation in glaucoma, with a negative impact on filtering surgery failure, topical treatment efficacy, and possibly on inflammation in the anterior segment. Consequently, glaucoma appears as an outstanding eye disease where inflammatory changes may be present to various extents and consequences along the eye structure, from the ocular surface to the posterior segment, and the visual pathway. Here we reviewed the inflammatory processes in all ocular structures in glaucoma from the back to the front of the eye and beyond. Our approach was to explain how para-inflammation is necessary to maintain homoeostasis, and to describe abnormal inflammatory findings observed in glaucomatous patients or in animal glaucoma models, supporting the hypothesis of a dysregulation of the inflammatory balance toward a pro-inflammatory phenotype. Possible anti-inflammatory therapeutic approaches in glaucoma are also discussed. 10.1016/j.preteyeres.2020.100916
    Aqueous outflow regulation - 21st century concepts. Johnstone Murray,Xin Chen,Tan James,Martin Elizabeth,Wen Joanne,Wang Ruikang K Progress in retinal and eye research We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm's canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma. 10.1016/j.preteyeres.2020.100917