Macular Laser Research Articles

Early Response to Ranibizumab Is Associated with 12-Month Outcome in Diabetic Macular Edema after Prior Macular Laser Therapy

Purpose: To evaluate the efficacy of ranibizumab in persistent or recurrent diabetic macular edema (DME) after previous laser therapy. Methods: This prospective, interventional study consisted of a 3-month period of scheduled ranibizumab treatment followed by a 9-month period of pro re nata treatment. Results: A total of 21 eyes (18 patients) were included. Both best corrected visual acuity and central retinal thickness had statistically significantly improved from baseline at month 12 (p < 0.001). The mean number of injections within these 12 months was 7.8 ± 2.6 (range 3-11). The visual change at month 12 did not vary by more than 5 letters from the response observed at week 12. Conclusions: Our study showed a beneficial effect from ranibizumab in DME patients previously treated with macular laser therapy. The response at week 12 was sustained up to 1 year. A suboptimal early visual response may predict a long-term suboptimal response and help identify patients who would benefit from an alternative regimen.

Laser Treatment, Photodynamic Therapy, and Radiation Therapy in Wet-Form (Neovascular) Age-Related Macular Degeneration

Age-related macular degeneration is the leading cause of legal blindness in developed countries. The decrease in central vision, metamorphopsia, and central scotoma affect the reading capacity even in the early stages of the disease. In the historical point of treatment for age-related macular degeneration, laser treatment, radiation treatment, and photodynamic therapy have been used. Today, drugs that inhibit the vascular endothelial growth factor are used widely. In this article, we will discuss the treatment modalities that were used widely before the era of anti-vascular endothelial growth factor drugs.

Clinical effect of Conbercept intravitreal injection combined with macular grid laser photocoagulation on the treatment of diabetic macular edema

Clinical effect of Conbercept intravitreal injection combined with macular grid laser photocoagulation on the treatment of diabetic macular edema

Therapies for Macular Edema Associated with Branch Retinal Vein Occlusion: A Report by the American Academy of Ophthalmology

To evaluate the available evidence on the ocular safety and efficacy of current therapeutic alternatives for the management of macular edema (ME) secondary to branch retinal vein occlusion (BRVO). Literature searches were last conducted on January 31, 2017, in PubMed with no date restrictions and limited to articles published in English, and in the Cochrane Database without language limitations. The searches yielded 321 citations, of which 109 were reviewed in full text and 27 were deemed appropriate for inclusion in this assessment. The panel methodologist assigned ratings to the selected studies according to the level of evidence. Level I evidence was identified in 10 articles that addressed anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME, including intravitreal bevacizumab (5), aflibercept (2), and ranibizumab (4). Level I evidence was identified in 6 studies that examined intravitreal corticosteroids, including triamcinolone (4) and the dexamethasone implant (2). Level I evidence also was available for the role of macular grid laser photocoagulation (7) and scatter peripheral laser surgery (1). The inclusion of level II and level III studies was limited given the preponderance of level I studies. The number of studies on combination therapy is limited. Current level I evidence suggests that intravitreal pharmacotherapy with anti-VEGF agents is effective and safe for ME secondary to BRVO. Prolonged delay in treatment is associated with less improvement in visual acuity (VA). Level I evidence also indicates that intravitreal corticosteroids are effective and safe for the management of ME associated with BRVO; however, corticosteroids are associated with increased potential ocular side effects (e.g., elevated intraocular pressure, cataracts). Laser photocoagulation remains a safe and effective therapy, but VA results lag behind the results for anti-VEGF therapies.

PARS PLANA VITRECTOMY FOR DIABETIC MACULAR EDEMA: A Systematic Review, Meta-Analysis, and Synthesis of Safety Literature.

To assess the risk and benefit of pars plana vitrectomy for diabetic macular edema. The authors conducted a systematic literature review using PubMed, EMBASE, Web of Science, and Cochrane Central Database of Controlled Trials until September 2014. The population was patients with diabetic macular edema, intervention vitrectomy, comparator macular laser or observation, and efficacy outcome visual acuity and central retinal thickness. Safety outcomes were intraoperative and postoperative surgical complications. The efficacy meta-analysis included only randomized controlled trials. The safety analysis included prospective, retrospective, controlled, and uncontrolled studies. Five studies were eligible for the efficacy meta-analysis (n = 127 eyes) and 40 for the safety analysis (n = 1,562 eyes). Combining follow-up intervals from 6 to 12 months, the meta-analysis found a nonsignificant 2 letter visual acuity difference favoring vitrectomy, and a significant 102 μm greater reduction in central retinal thickness favoring vitrectomy, but a post hoc subgroup analysis found that a 6-month central retinal thickness benefit reversed by 12 months. The most frequent complications were retinal break (7.1%), elevated intraocular pressure (5.2%), epiretinal membrane (3.3%), and vitreous hemorrhage (2.4%). Cataract developed in 68.6% of 121 phakic eyes. Vitrectomy produces structural and functional improvements in select eyes with diabetic macular edema, but the visual gains are not significantly better than with laser or observation. No major safety concerns were identified.

Teleophthalmology image-based navigated retinal laser therapy for diabetic macular edema: a concept of retinal telephotocoagulation.

To determine the feasibility and efficacy of a retinal telephotocoagulation treatment plan for diabetic macular edema. Prospective, interventional cohort study at two clinical sites. Sixteen eyes of ten subjects with diabetic macular edema underwent navigated focal laser photocoagulation using a novel teleretinal treatment plan. Clinic 1 (King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia) collected retinal images and fundus fluorescein angiogram. Clinic 2 (Palmetto Retina Center, West Columbia, SC, USA) created image-based treatment plans based on which macular laser photocoagulation was performed back at clinic 1. The primary outcome of the study was feasibility of image transfer and performing navigated laser photocoagulation for subjects with diabetic macular edema between two distant clinics. Secondary measures were change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by spectral-domain optical coherence tomography at 3months after treatment. The teleretinal treatment plan was able to be successfully completed in all 16 eyes. The mean logMAR BCVA at baseline was 0.49±0.1, which remained stable (0.45±0.1) 3months after treatment (p=0.060). The CRT improved from 290.1±37.6μm at baseline to 270.8±27.7μm 3months after treatment (p=0.005). All eyes demonstrated improvement in the area of retinal edema after laser photocoagulation, and no eyes demonstrated visual acuity loss 3months after treatment. This study introduces the concept of retinal telephotocoagulation for diabetic macular edema, and demonstrates the feasibility and safety of using telemedicine to perform navigated retinal laser treatments regardless of geographical distance.

Damage to the macula associated with LED-derived blue laser exposure: A case report

BackgroundLight emitting diodes laser is emerging as an important source of light replacing conventional lights. It is widely used for illumination in the bar where young people love to go. But not everyone knows about the light damage to the eye especially to the macula. In this article, we report the case of a macular damage induced by LED-derived blue laser in a bar, studied with optical coherence tomography (OCT) to evaluate the retinal lesion and multifocal electroretinography (mfERG) to evaluate functional damage.Case presentationFour days after the photo injury to the right eye, the visual acuity was 0.5. Funduscopy revealed a round red lesion in the macula of the right eye. Fluorescein angiography (FA) revealed no leakage. OCT revealed a deficiency in the center of the fovea. MfERG revealed a reduction of the peak value in the right eye compared to the left eye. One month later, although the vision was 1.0 in the right eye, OCT revealed a hyporeflectivity of the ellipsoid zone. MfERG still showed a reduction of the peak value in the right eye compared to the left eye.ConclusionWe believe that general knowledge about laser injuries to the eye should be realized widely. We also think in cases of macular laser damage, the recovery of vision can not demonstrate the recovery of the function of photoreceptors.

Outcomes of Diabetic Macular Edema Patients by Baseline Hemoglobin A1c: Analyses from VISTA and VIVID

To examine the relationship between glycemic control at baseline and response to anti-vascular endothelial growth factor treatment for diabetic macular edema (DME). Post hoc analysis of 2 similarly designed phase III trials, VISTA and VIVID. Patients with central-involved DME. Both VISTA and VIVID compared efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for DME. Current analysis focused on comparison within each treatment group in an integrated VISTA and VIVID dataset. Baseline hemoglobin A1c (HbA1c) was partitioned into 4 quartiles: 4.5% to <6.7% (n= 233), 6.7% to <7.4% (n= 206), 7.4% to <8.6% (n= 209), and 8.6% to <14.7% (n= 208). Outcomes were analyzed by mixed model for repeated measures. Intragroup differences were quantified by a regression model. Change from baseline best-corrected visual acuity (BCVA), central subfield thickness (CST), and HbA1c. In the IAI group, mean BCVA improvement from baseline did not depend on baseline HbA1c at week 52 (P= 0.1852), but seemed to be dependent at week 100 (P= 0.0425). The mean CST reduction from baseline was independent of baseline HbA1c at both weeks 52 (P= 0.1857) and 100 (P= 0.7346). Mean HbA1c change from baseline in IAI group was small across all HbA1c quartiles. In the laser group, the mean BCVA gain decreased with increasing baseline HbA1c at both weeks 52 (P= 0.0421) and 100 (P= 0.0001). Similarly, the mean CST decrease was greater with decreasing baseline HbA1c, at both weeks 52 (P= 0.0065) and 100 (P=0.0162). The mean HbA1c change from baseline in the laser group was minimal across HbA1c quartiles, although glycemic control tended to worsen in upper quartiles. The benefit of IAI in patients with DME was less dependent on their presenting glycemic status as opposed to laser.

Aflibercept: A Review in Macular Oedema Secondary to Branch Retinal Vein Occlusion.

Aflibercept (Eylea®) is a fully human, recombinant fusion protein available in various countries worldwide, including those of the EU, as well as the USA, for intravitreal use in the treatment of macular oedema secondary to branch retinal vein occlusion (BRVO) in adults. Aflibercept acts as a soluble decoy receptor, binding with high affinity to vascular endothelial growth factor (VEGF)-A and placental growth factor (PIGF), preventing these angiogenic factors from binding to and activating their cognate receptors. In a multinational, phase III study in this patient population, aflibercept was associated with a statistically significant and clinically relevant improvement in best-corrected visual acuity (BCVA) [as assessed by the proportion of eyes that gained ≥15 Early Treatment Diabetic Retinopathy Study letters from baseline] relative to macular laser photocoagulation during the first 24-week treatment period (aflibercept injections were administered every 4weeks). Significant mean improvements from baseline in BCVA and central retinal thickness (CRT) relative to macular laser photocoagulation were also seen. These improvements were maintained relative to macular laser photocoagulation plus rescue aflibercept in a subsequent 24-week period (aflibercept injections were administered every 8weeks). Aflibercept was generally well tolerated, locally and systemically, in this study, with a tolerability profile generally consistent with the known tolerability profile of the agent in other indications. Thus, intravitreal aflibercept extends the treatment options available for the management of macular oedema secondary to BRVO in adults.

Efficacité précoce de l’implant de dexaméthasone (OZURDEX®) évaluée en vraie vie dans le traitement de l’œdème maculaire diabétique

To assess early efficacy of dexamethasone intravitreal implant 0.7mg (OZURDEX®) at the time of peak efficacy (2 months after injection) in patients with decreased visual acuity secondary to diabetic macular edema (DME). Retrospective monocentric study. Inclusion criteria were best-corrected visual acuity (BCVA)≤70 letters (20/40) due to DME and central retinal thickness (CRT)≥300 microns (Cirrus 2, Carl Zeiss Meditec, Inc, Dublin). Enrolled patients could be treatment naive or not (after failure of laser photocoagulation and/or anti-VEGF therapy). Follow-up was at least 6 months. Our primary endpoint was BCVA gain at M2 after injection. Secondary endpoints were best-corrected visual acuity at 2 and 4 months, central retinal thickness at 2 and 4 months, mean interval between 2 injections, and adverse events. Nineteen eyes of 19 patients were included in this study. The mean age was 67.45 years, sex ratio was 2.17 men/women, and the patients were all type 2 diabetics. Three of 19 patients were treatment naive for anti-VEGF intravitreal injection, and 52.3% were pseudophakic (10/19 patients). The mean gain of BCVA at M2 was +7.7 letters. The mean BCVA was 51.1 ETDRS letters at baseline and 58.8 at M2. Mean CRT was 568.9μm at baseline and 291.2μm at M2. Treatment with dexamethasone implant was mainly a second-line treatment after failure of other treatments (macular laser photocoagulation and/or intravitreal injection of anti-VEGF). Three patients were naive of anti-VEGF treatment. Intraocular pressure≥25mmHg was found in 2 patients, and controlled medically. No glaucoma surgery was performed. The dexamethasone implant (OZURDEX®) allows an anatomical and functional improvement in patients suffering from vision loss due to DME. In this series, the implant was well tolerated.

Fluocinolone Acetonide Intravitreal Implant 0.19mg (ILUVIEN®): A Review in Diabetic Macular Edema.

Fluocinolone acetonide intravitreal implant 0.19mg (ILUVIEN®) is a nonbiodegradable, injectable, corticosteroid implant that is approved in several countries, including the USA, for the treatment of diabetic macular edema (DME). ILUVIEN® releases fluocinolone acetonide at an initial rate of 0.25µg/day (average rate 0.2µg/day) and lasts 36months. In the two pooled pivotal FAME trials in patients with DME previously treated with macular laser photocoagulation, fluocinolone acetonide intravitreal implant 0.2µg/day was significantly more effective than sham injection with respect to the proportion of patients with an improvement from baseline in best-corrected visual acuity of ≥15 letters at 24months (primary endpoint). This therapeutic effect was maintained at 36months. The implant also significantly decreased foveal thickness at 24months. FAME study results are broadly supported by real-world studies in patients with chronic DME considered insufficiently responsive to available therapies. Consistent with corticosteroid class-specific adverse events, cataract and elevated intraocular pressure (IOP) were the most common adverse events with the fluocinolone acetonide intravitreal implant. Raised IOP was treated with medications in most patients, with <5% requiring incisional IOP-lowering surgery. In the USA, fluocinolone acetonide intravitreal implant should be used only in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant increase in IOP. Available data indicate that fluocinolone acetonide intravitreal implant 0.19mg is a useful option for the treatment of DME in these patients.

Clinical utility of intravitreal fluocinolone acetonide (Iluvien®) implant in the management of patients with chronic diabetic macular edema: a review of the current literature.

The first-line therapy for patients with center-involving diabetic macular edema (DME) is with intravitreal anti-vascular endothelial growth factor (VEGF) agents, with or without adjunctive macular laser treatment. However, a significant proportion of patients have persistent and recurrent edema despite repeated anti-VEGF injections. The fluocinolone acetonide (FA) 190 μg intravitreal implant has been shown in pivotal clinical trials to be efficacious for the treatment of DME and has been approved in many countries for use in patients who have not responded to first-line therapy. In this report, we have collated the latest data from the increasing number of studies to illustrate the pattern of usage of the Iluvien FA implant for DME during the current anti-VEGF era. We have shown that there is now a wealth of published evidence from real-world studies to support the clinical utility of the FA implant in achieving further resolution of edema and improving visual acuity outcomes in this challenging group of patients.

Intravitreal Ranibizumab in Diabetic Macular Edema: Long-Term Outcomes.

Intravitreal ranibizumab (RBZ) has been shown in multiple randomized clinical trials to be a valuable treatment for diabetic macular edema (DME), promoting a significant improvement in best-corrected visual acuity (BCVA) and in anatomic outcomes. Compared to sham (RISE and RIDE studies), RBZ rapidly and sustainably improved BCVA and decreased macular edema at 2 years, reducing the risk of further vision loss, with low rates of local or systemic side effects. Compared to macular laser photocoagulation (READ-2 study), RBZ provided a greater improvement in BCVA and regression in foveal thickness, but required a higher number of injections compared to patients treated with both RBZ and laser. In RESTORE trial, RBZ alone or combined with macular laser turned out to be superior to laser alone, without significant differences between the 2 RBZ groups. Compared to combined treatment (RBZ or triamcinolone associated with macular laser) or photocoagulation laser alone (Diabetic Retinopathy Clinical Research Network trial), RBZ with prompt or deferred laser was more effective than laser alone at 1-year follow-up. At 3 years, prompt laser was not better than deferring laser for 24 weeks or more. At 5 years, subjects treated with RBZ achieved better long-term visual outcomes than patients managed with triamcinolone or laser followed by very deferred RBZ. In conclusion, randomized clinical trials showed that RBZ was superior to laser in DME treatment, providing excellent long-term visual outcomes. Frequent injections were necessary in most of the patients to properly control DME and maximize the visual benefits.

Is Laser Still Important in Diabetic Macular Edema as Primary or Deferral Therapy?

Laser treatment was used in the past to reduce the visual loss due to diabetic macular edema. The recent advent of anti-vascular endothelial growth factor (anti-VEGF) has completely revolutionized the management of diabetic retinopathy, with a significant improvement in the overall prognosis. Nevertheless, macular laser can still be applied in selected cases characterized by retinal thickness ≤400 microns, high visual acuity, extrafoveal location, and contraindications to the intravitreal approach with anti-VEGF and steroids. In addition, the combined therapy with anti-VEGF and macular laser can exploit the synergistic effects of both therapies, leading to a simpler and more practical management of patients over the long-term follow-up.

Efficacy of intravitreal triamcinolone acetonide with thermal combination therapy versus intravitreal triamcinolone acetonide monotherapy on diffuse diabetic macular edema

Purpose The aim of this study was to compare the efficacy of intravitreal triamcinolone acetonide (IVTA) monotherapy with IVTA plus macular grid laser photocoagulation combination therapy on the treatment of diffuse diabetic macular edema.Patients and methods Fifty eyes of 38 patients exhibiting diffuse diabetic macular edema were evaluated in this prospective comparative study. The patients were divided into two groups: IVTA monotherapy group and combination therapy group (IVTA plus grid laser). The main outcome measures of the study were best-corrected visual acuity (VA) scored in logMAR and the central macular thickness (CMT) as estimated at 3 and 6 months after treatment. The study further assessed the potential complications associated with IVTA injection.Results The baseline logMAR VA and CMT were 0.46±0.22 and 445.2±123.91 µm for the IVTA monotherapy group and 0.57±0.27 and 456.91 ±134.32 µm for the combination therapy group, respectively. The post-treatment logMAR VA at 3 and 6 months were 0.24±0.12 and 0.28±0.09 for the IVTA monotherapy group and 0.22±0.13 and 0.18±0.16 for the combination therapy group, respectively. The CMT values at 3 and 6 months were 305.5±115.30 and 310.8±86.8 µm for the IVTA monotherapy group and 280.9±43.9 and 254.2±45.95 for the combination therapy group. Improvement in VA and CMT after treatment was statistically significant in both groups. Approximately 10% of patients developed cataract after 5 months of intravitreal injection. The mean pretreatment intraocular pressure and the mean post-treatment intraocular pressure were 15.49±2.47 and 14.56±2.26 and 14.92±2.80 and 13.55±2.02 mmHg in both the IVTA monotherapy and combination therapy groups, respectively.Conclusion Macular grid laser photocoagulation after IVTA effectively maintains the VA and macular thickness of the patients included in this study during the first 6 months of treatment.

An Evidence-based Approach to Using Intravitreal Steroids in the Management of Diabetic Macular Oedema

Diabetic macular oedema (DMO) is the leading cause of acquired visual loss in the working age population. The landscape for DMO treatment has changed significantly over the past decade. Macular laser has been reported to reduce the risk of moderate visual loss in seminal clinical trials from the 1980s, but relatively few patients achieved visual gain. With the advent of intravitreal pharmacotherapy it is now possible to achieve visual gains in the majority of patients. Intravitreal anti-vascular endothelial growth factor (VEGF) agents are now a first-line treatment option in centre-involving DMO. This review assesses clinical trial and more recent real-world evidence to guide clinicians as to when intravitreal steroids should be considered in the management of DMO. In particular, intravitreal steroids can be considered in pseudophakic patients, or those due to undergo cataract surgery, in patients unable to attend for regular intravitreal procedures, and non-responders to intravitreal anti-VEGF therapy. Assessing clinical trial data, the dexamethasone implant appears to have a more predictable intraocular rise profile than triamcinolone or fluocinolone with a lower requirement for incisional glaucoma surgery. There is a need for consensus regarding real-world outcome measures for intravitreal steroids in the management of DMO to allow easier comparison across studies.

Intravitreal bevacizumab alone or combined with macular laser for treatment of diabetic macular edema

Purpose: We aimed to evaluate the best-corrected visual acuity (BCVA) and assess improvement of central macular thickness (CMT) in patients with diffuse diabetic macular edema (DDME) after an intravitreal injection of bevacizumab (Avastin®) alone, or followed by modified grid macular laser photocoagulation. Subjects and Methods: This was a randomized prospective interventional study that included 78 eyes of 40 patients with DDME, divided into two groups of interventions: Group A received bevacizumab (Avastin®) injections monthly for 3 months then pro re nata, and Group B received bevacizumab as Group A but followed by grid macular laser photocoagulation 2 weeks after the first injection. Patients were observed monthly for a 12-month period and their BCVA, intraocular pressure, and CMT were recorded. Results: Compared with the baseline, there was a significant decrease of CMT in both groups of patients (−138.3 ± 40.15 vs. −156.5 ± 33.47, respectively). The improvement in ME was more in the combined group than the Avastin® group (P

Combination of Anti-VEGF and Laser Photocoagulation for Diabetic Macular Edema: A Review.

Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. Thirty years ago, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid laser photocoagulation reduces moderate vision loss from DME by 50% or more; thus, macular photocoagulation became the gold standard treatment for DME. However, with the development of anti-VEGF drugs (bevacizumab, ranibizumab, and aflibercept), better outcomes were obtained in terms of visual acuity gain and decrease in macular thickness in some studies when antiangiogenic drugs were administered in monotherapy. Macular laser therapy may still play an important role as an adjuvant treatment because it is able to improve macular thickness outcomes and reduce the number of injections needed. Here, we review some of the clinical trials that have assessed the efficacy of macular laser treatment, either as part of the treatment protocol or as rescue therapy.

Update on the Use of Anti-VEGF Intravitreal Therapies for Retinal Vein Occlusions.

The use of anti-vascular endothelial growth factor (VEGF) therapy in ophthalmology has profoundly changed our management and treatment of conditions such as cystoid macular edema, diabetic macular edema, choroidal neovascularization, and other proliferative retinopathies. Although initially used for the treatment of choroidal neovascularization in neovascular age-related macular degeneration, their application has spread rapidly for other indications as their outcomes have often outperformed previously existing treatments. Retinal vein occlusion (RVO) continues to be one of the leading causes of vision loss secondary to macular edema, in addition to macular ischemia and neovascularization in more severe cases. Before the availability of anti-VEGF therapy, the use of macular grid laser and panretinal photocoagulation was the mainstay of treatment of macular edema and neovascularization, respectively, in patients with RVOs. Two landmarks studies established the guidelines of these treatments for nearly a quarter century. Since the availability of anti-VEGF agents, there has been a paradigm shift in the treatment of RVO. Most importantly, there has also been a significant improvement in visual outcomes in these patients. The goal of this article is to provide a review of the pertinent clinical studies that have investigated the use of anti-VEGF in patients with retinal vein occlusions.

Intravitreal Aflibercept in Diabetic Macular Edema: Long-Term Outcomes.

For decades, macular laser photocoagulation has been the standard of care in the treatment of diabetic macular edema (DME). With the relatively recent advent of anti-vascular endothelial growth factor (VEGF) agents, DME treatment has entered a new era. VEGF is a well-known pro-angiogenic and pro-permeability factor involved in the pathogenesis of DME. VEGF blockade has proven remarkably effective at reducing DME and improving visual acuity (VA) in eyes with center involved DME causing VA loss in several randomized controlled trials (RCTs). Intravitreal aflibercept, ranibizumab, and bevacizumab (the latter used off-label) are 3 anti-VEGF molecules currently available for DME treatment. Aflibercerpt is a 115-kDA recombinant fusion protein consisting of VEGF binding domains of human VEGF receptors-1 and -2 fused to the Fc domain of human immunoglobulin-G1. The ability to bind placental growth factors 1 and 2 (which is another pro-permeability mediator) and a theoretically long half-life are potential advantages of aflibercept over other anti-VEGF agents. The use of intravitreal aflibercept in DME treatment has been investigated in several RCTs. The aim of this chapter is to briefly report on the current evidence for treating DME with intravitreal aflibercept.