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Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28–0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. Pfizer, UK National Institute for Health Research Biomedical Research Centre.

The glaucomas form a heterogenous group of conditions, which collectively account for one of the most common irreversible causes of blindness worldwide. The only treatment, for which there is evidence, to stop or slow glaucomatous disease progression is to lower intraocular pressure (IOP); this is most often initially achieved with topical medication. Adherence to anti-glaucoma therapy is known to be low even when compared with adherence to therapy for other chronic conditions. We performed a PubMed search to review evidence as to how adherence to and persistence with anti-glaucoma medications might be improved. Approaches to improving adherence include technological (such as using smart drop bottles or automated reminders) use of instillation aids, improving communication with patient education and improving tolerability of eye drop formulations. There is limited short-term evidence that automated reminders can be effective and, unfortunately, instillation aids have not proved to be efficacious with respect to improving adherence. A range of factors have been identified which affect adherence and persistence, although only a multi-faceted approach has proven evidence of efficacy, compared to improved patient education alone. There is now a wider range of available preservative-free eye drops, which have been shown to be non-inferior in achieving IOP control, with fewer side effects and improved short-term adherence. Further studies relating to adherence are warranted, particularly given the projected increase in glaucoma prevalence worldwide. Keywords: tolerability, ocular hypotensives, interventions, persistence, intraocular pressure

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. One consequence of raised IOP is that ocular tissues are subjected to increased hydrostatic pressure (HP). The effect of raised HP on stress pathway signaling and retinal ganglion cell (RGC) survival in the human retina was investigated. A chamber was designed to expose cells to increased HP (constant and fluctuating). Accurate pressure control (10-100 mmHg) was achieved using mass flow controllers. Human organotypic retinal cultures (HORCs) from donor eyes (<24 h post mortem) were cultured in serum-free DMEM/HamF12. Increased HP was compared to simulated ischemia (oxygen glucose deprivation, OGD). Cell death and apoptosis were measured by LDH and TUNEL assays, RGC marker expression by qRT-PCR (THY-1) and RGC number by immunohistochemistry (NeuN). Activated p38 and JNK were detected by Western blot. Exposure of HORCs to constant (60 mmHg) or fluctuating (10-100 mmHg; 1 cycle/min) pressure for 24 or 48 h caused no loss of structural integrity, LDH release, decrease in RGC marker expression (THY-1) or loss of RGCs compared with controls. In addition, there was no increase in TUNEL-positive NeuN-labelled cells at either time-point indicating no increase in apoptosis of RGCs. OGD increased apoptosis, reduced RGC marker expression and RGC number and caused elevated LDH release at 24 h. p38 and JNK phosphorylation remained unchanged in HORCs exposed to fluctuating pressure (10-100 mmHg; 1 cycle/min) for 15, 30, 60 and 90 min durations, whereas OGD (3 h) increased activation of p38 and JNK, remaining elevated for 90 min post-OGD. Directly applied HP had no detectable impact on RGC survival and stress-signalling in HORCs. Simulated ischemia, however, activated stress pathways and caused RGC death. These results show that direct HP does not cause degeneration of RGCs in the ex vivo human retina.

Background To evaluate the haemodynamic features of young healthy myopes and emmetropes, in order to ascertain the perfusion profile of human myopia and its relationship with axial length prior to reaching a degenerative state. Methods The retrobulbar, microretinal and pulsatile ocular blood flow (POBF) of one eye of each of twenty-two high myopes ( N  = 22, mean spherical equivalent (MSE) ≤−5.00D), low myopes ( N  = 22, MSE−1.00 to−4.50D) and emmetropes ( N  = 22, MSE ± 0.50D) was analyzed using color Doppler Imaging, Heidelberg retinal flowmetry and ocular blood flow analyser (OBF) respectively. Intraocular pressure, axial length (AL), systemic blood pressure, and body mass index were measured. Results When compared to the emmetropes and low myopes, the AL was greater in high myopia ( p  < 0.0001). High myopes showed higher central retinal artery resistance index (CRA RI) ( p  = 0.004), higher peak systolic to end diastolic velocities ratio (CRA ratio) and lower end diastolic velocity (CRA EDv) compared to low myopes ( p  = 0.014, p  = 0.037). Compared to emmetropes, high myopes showed lower OBFamplitude (OBFa) ( p  = 0.016). The POBF correlated significantly with the systolic and diastolic blood velocities of the CRA ( p  = 0.016, p  = 0.036). MSE and AL correlated negatively with OBFa ( p  = 0.03, p  = 0.003), OBF volume ( p  = 0.02, p < 0.001), POBF ( p  = 0.01, p < 0.001) and positively with CRA RI ( p  = 0.007, p  = 0.05). Conclusion High myopes exhibited significantly reduced pulse amplitude and CRA blood velocity, the first of which may be due to an OBF measurement artefact or real decreased ocular blood flow pulsatility. Axial length and refractive error correlated moderately with the ocular pulse and with the resistance index of the CRA, which in turn correlated amongst themselves. It is hypothesized that the compromised pulsatile and CRA haemodynamics observed in young healthy myopes is an early feature of the decrease in ocular blood flow reported in pathological myopia. Such vascular features would increase the susceptibility for vascular and age-related eye diseases.

To examine the cross sectional and longitudinal relationship between cardiovascular risk factors and age-related macular degeneration (AMD) in a large British cohort study. The EPIC Norfolk Eye study is nested in a larger prospective cohort study. Data on cardiovascular risk factors were collected at baseline (1993-1997) and follow up (2006-2011) via clinical examination, validated lifestyle questionnaires and serum blood samples. AMD was ascertained using standardised grading of fundus photographs at the follow up. Logistic regression was used to examine associations between baseline and follow up risk factors with AMD. 5,344 pairs (62.0% of total 8623) of fundus photographs were of sufficient quality for grading of AMD in participants with mean age of 67.4 years old (range 44-91) at diagnosis. There were 28 cases of late AMD (0.5%, 95% confidence interval (CI)=0.3-0.8%) and 645 cases of early AMD (12.1%, 95%CI=11.2-13.0.%). In multivariable analysis, older people with higher levels of baseline high density lipoprotein- cholesterol (HDL-C ) and C-reactive protein (CRP) were more likely to have any signs of AMD, after adjusting for sex, education, smoking, and systolic blood pressure. In cross sectional analysis, only older age and higher HDL were significantly associated with AMD. We have found that older age and higher levels of CRP and HDL-C were associated with increased odds of AMD in this population in the longitudinal analysis, but older age and HDL-C, not CRP was significantly associated with AMD in the cross sectional analysis. The prevalence of AMD in this cohort was low compared to other cohorts in Europe, the US and Australia, and probably reflects the some selection biases in follow up participation as well as the low rate of smoking among our healthy participants.

The P2X7 receptor has been associated with the neurodegeneration of retinal ganglion cells (RGCs), which is central to the loss of vision in glaucoma. Furthermore, the activation of P2X7 has been shown to cause the death of RGCs, including in the human retina. Human organotypic retinal cultures (HORCs) were used to investigate the potential indirect mechanisms of RGC death. Of the 27 cytokine/growth factors assayed, the stimulation of P2X7 using BzATP (100 µM; 36 h) significantly increased the secretion of IL-1β and IL-10. IL-1β was selected for further investigation. BzATP (100 µM) caused an increase in the expression and release of IL-1β in a time-dependent manner; this increase was inhibited through a co-incubation with BBG (1 µM). Exogenous IL-1β alone (10 ng/mL) did not cause a loss of RGCs. However, IL-1β inhibited the loss of RGCs caused by BzATP, and this neuroprotection was prevented by the Interleukin-1 receptor-1 antagonist (IL-1ra) (100 ng/mL). The IL1 receptor IL-1R1 was localised to the inner retina close to the RGCs, although not predominantly co-localised with RGC bodies. The results suggest that the P2X7-mediated death of RGCs is not IL-1β mediated. Furthermore, IL-1β may be upregulated as part of a response to mitigate P2X7-mediated damage to the retina. Our research is the first to indicate the P2X7-mediated regulation of IL-1β in the human retina and supports the role of the ATP/P2X7/IL-1β axis in RGC survival and possible glaucomatous RGC degeneration.

Objectives To report the distribution of intraocular pressure (IOP) by age and sex and the prevalence of glaucoma.Design Community based cross sectional observational study.Setting EPIC-Norfolk cohort in Norwich and the surrounding rural and urban areas.Participants 8623 participants aged 48-92 recruited from the community who underwent ocular examination to identify glaucoma.Main outcome measures Prevalence and characteristics of glaucoma, distribution of IOP, and the sensitivity and specificity of IOP for case finding for glaucoma.Results The mean IOP in 8401 participants was 16.3 mm Hg (95% confidence interval 16.2 mm Hg to 16.3 mm Hg; SD 3.6 mm Hg). In 363 participants (4%), glaucoma was present in either eye; 314 (87%) had primary open angle glaucoma. In the remaining participants, glaucoma was suspected in 607 (7%), and 863 (10.0%) had ocular hypertension. Two thirds (242) of those with glaucoma had previously already received the diagnosis. In 76% of patients with newly diagnosed primary open angle glaucoma (83/107), the mean IOP was under the threshold for ocular hypertension (21 mm Hg). No one IOP threshold provided adequately high sensitivity and specificity for diagnosis of glaucoma.Conclusions In this British community, cases of glaucoma, suspected glaucoma, and ocular hypertension represent a large number of potential referrals to the hospital eye service. The use of IOP for detection of those with glaucoma is inaccurate and probably not viable.

Glaucoma is a leading cause of visual morbidity throughout the world and is an age-related condition, the prevalence of which rises significantly with increasing age. Glaucoma, a condition affecting the optic nerve, has a variety of subtypes with multiple aetiological factors, the most important of which are intraocular pressure (IOP) and increasing age. Treatment by lowering of IOP is the only current method, for which there is evidence, by which the rate of progressive visual deterioration can be slowed or halted. Although there are surgical and laser treatments that are efficacious in lowering IOP, the most common manner in which patients with glaucoma control their IOP is with administration of daily topical ocular hypotensive drugs (eye drops). The variety of topical drugs utilised in the management of glaucoma all have the potential to have adverse effects and/or interactions with concomitant medications, many of which may be used for other age-related conditions. Adherence with appropriate medicines has a major effect on the outcome of medical conditions and this aspect applies to the management of glaucoma. There are certain specific issues that relate to the administration of topical agents, with respect to both adverse effects and adherence. Although many suspect poor adherence in elderly patients with glaucoma, relative to younger patients, adequate evidence for this is lacking. Furthermore, the manner by which adherence issues could be improved remains inadequately understood and poorly addressed. The aims of this article were to review, from a clinical perspective, the medical therapies currently used for glaucoma and discuss adherence issues with respect to the population of patients with glaucoma, who tend to be relatively elderly.

Background/aimsThe association between the development of cystoid macular oedema (CMO) following uneventful cataract surgery and prostaglandin analogue (PGA) therapy has not been fully determined. The study aim was to investigate whether discontinuation of PGA therapy following uneventful cataract surgery affected the incidence of postoperative CMO.MethodsA prospective randomised controlled trial of 62 eyes of 62 participants with ocular hypertension (OH) or primary open angle glaucoma (POAG) treated with PGAs prior to cataract surgery. Participants were randomised to continue with PGA therapy after cataract surgery (CPGA) (n=31) or to discontinue PGA therapy (n=31). The primary outcome measure was the development of CMO at 1-month postoperatively, determined by a masked observer assessment of optical coherence tomography scans. The secondary outcome measure was change from baseline intraocular pressure (IOP).ResultsThe incidence of CMO was identical in both groups at 12.9% (4 of 31 eyes) at the 1-month postoperative visit (OR 1.000; 95% CI 0.227 to 4.415). At 1-month postoperatively, the IOP was significantly lower in the CPGA group compared with baseline IOP.ConclusionContinuation of PGA therapy following uneventful cataract surgery in eyes with normal macular morphology did not increase the incidence of CMO. Continuation of PGA therapy significantly reduced IOP at 1-month postoperatively suggesting that, when indicated, it might be beneficial to continue PGA therapy in patients with POAG or OH after uneventful cataract surgery in the absence of other risk factors for developing CMO.

Background and aimUndiagnosed glaucoma is an invisible but important public health issue. At least half of glaucoma cases are estimated to be undiagnosed in western populations. The aim of this study is to examine risk factors for previously undiagnosed primary open-angle glaucoma (POAG).DesignCross-sectional study within the European Prospective Investigation of Cancer-Norfolk Eye Study, a large-scale cohort study in the UK.Participants314 study participants with POAG in either eye.MethodsLogistic regression was used to examine associations with previously undiagnosed POAG compared with previously diagnosed POAG. The factors examined included sociodemographic, ocular, physical and economic factors that could be barriers to eye care access.Results217 participants had previously diagnosed POAG and 107 participants were newly diagnosed with POAG during the study. After adjusting for covariables, the factors significantly associated with previously undiagnosed POAG were: a lower pretreatment intraocular pressure (IOP) (OR 0.71/mm Hg, 95% CI 0.63 to 0.80, p<0.0001), and to have reported no problems with their eyesight (OR 0.03, 95% CI 0.01 to 0.10, p<0.0001).ConclusionsThe risk factors for previously undiagnosed POAG identified in this study highlight the over-reliance on IOP level in glaucoma screening and the risk of missing glaucoma among lower IOP cases. It also suggests a role in improving glaucoma awareness in the community.