Ahmed glaucoma valve implant: experience in East Africa.

PURPOSE: To describe short term outcomes of Ahmed Glaucoma Valve [AGV] implantation in East African patients. MATERIALS AND METHODS: In this multi-center retrospective case series we reviewed eyes of Black African patients with refractory glaucoma, treated consecutively with Ahmed Glaucoma Valve implantation, in two centers in Kenya between January 2006 and October 2007. RESULTS: About 25 cases including 18 [72%] pediatric eyes and seven [28%] adult eyes were identified. Results have been presented with a median follow-up of two months with inter-quartile range [IQR] of one to 12 months. intraocular pressure [IOP] was reduced from a mean of 36.4 mmHg preoperatively to 16.7 mmHg and glaucoma medications were lowered from a mean of 1.32 before surgery to 0.2 after surgery. The success rate during short term follow-up was 79%. The mean visual acuity dropped slightly from 6/18 pre-operatively to 6/24. There was only one major complication of an extruded, infected valve in a child. CONCLUSIONS: The Ahmed Valve Implant is safe and effective in lowering IOP for the short term in pediatric and adult East African patients with refractory glaucoma. Further studies with more patients and longer term follow-up are needed in this population.

Clinical features distinguishing angle closure from pseudoplateau versus plateau iris.

PURPOSE: To evaluate clinical aspects of patients with the diagnosis of plateau iris (PI) or pseudoplateau iris (PPI) made by ultrasound biomicroscopy (UBM) in order to determine if there are any clinical factors that can help differentiate between these two entities. METHOD: A retrospective cohort of consecutive UBM patients with the diagnosis of PI or PPI. The diagnosis of PI was based on an anteriorly positioned ciliary body that abutted the peripheral iris, a narrow (<10 degrees) or closed angle for at least 180 degrees, and the anterior portion of the iris positioned anterior to scleral spur. The diagnosis of PPI was similar to plateau except that large or a cluster of small cysts had to be present in the iridociliary sulcus. RESULTS: There were a total of 76 patients (29% male), 21 with PPI and 55 with PI. Patients with PPI were more likely to be male (p = 0.005), slightly younger (51.5 (SD 10.7) vs 57.9 (10.2) p = 0.0190), have a "bumpy" peripheral iris appearance (p = 0.003), have greater trabecular meshwork pigmentation (2.0 (0.7) vs 1.3 (0.6) p = 0.004) and have fewer clock hours of gonioscopic angle closure versus plateau iris patients (5.1 (4.3) vs 9.2 (4.2) p = 0.0009). Spherical equivalent was not significantly different between groups (0.50D (1.69) PPI vs 1.33D (2.42) PI; p = 0.187). CONCLUSIONS: In patients being referred to a UBM clinic for evaluation of angle-closure mechanism, younger males with a bumpy peripheral iris have a higher likelihood of having a diagnosis of pseudoplateau iris. However, clinical factors do not appear to discriminate well between PPI and PI. UBM is extremely helpful in confirming underlying mechanism and guiding therapy.

Selective laser trabeculoplasty versus argon laser trabeculoplasty: results from a 1-year randomised clinical trial.

AIMS: To compare selective laser trabeculoplasty (SLT) and argon laser trabeculoplasty (ALT), in terms of intraocular pressure (IOP) lowering, in patients with open-angle glaucoma. METHODS: 176 eyes of 152 patients were enrolled in this study, 89 in the SLT and 87 in the ALT groups. Patients were randomised to receive either SLT or ALT treatment to 180 degrees of the trabecular meshwork. Patients were followed up to 12 months after treatment. The main outcome measured was IOP lowering at 12 months after treatment, compared between the SLT and ALT groups. RESULTS: No significant difference (p = 0.846) was found in mean decrease in IOP between the SLT (5.86 mm Hg) and ALT (6.04 mm Hg) groups at 1 year or at any other time points, nor were there any significant differences in the rate of early or late complications between the two groups. CONCLUSIONS: SLT is equivalent to ALT in terms of IOP lowering at 1 year, and is a safe and effective procedure for patients with open-angle glaucoma.

Intraocular pressure following phacoemulsification in patients with and without exfoliation syndrome: a 2 year prospective study.

AIM: To determine the long term intraocular pressure (IOP) response to phacoemulsification in patients with and without exfoliation syndrome (XFS). METHODS: Prospective, multicentre, cohort study with the following inclusion criteria: age over 50 years, open iridocorneal angle, and cataract. Two groups were enrolled: those with XFS and those without. The main outcome was mean IOP reduction 2 years after phacoemulsification cataract extraction (PCE). Univariate and multivariate analyses were performed. RESULTS: 183 patients were enrolled, 71 with and 112 without XFS. There were 29 patients with glaucoma in both groups. Mean baseline IOP was higher in XFS compared to control eyes (17.60 (SD 3.23) mm Hg v 16.08 (3.18) mm Hg, p = 0.002). Overall IOP reduction was significantly greater in the XFS group at the 2 year time point (-1.85 mm Hg v -0.62 mm Hg in the controls (p = 0.0037)). Multivariate analysis demonstrated that the IOP lowering effect in the XFS group may be related to irrigation volume at the time of surgery. In the subgroup analyses IOP lowering was significantly greater in the XFS and XFG patients than in controls without glaucoma, and POAG controls, respectively. The percentage of patients with a postoperative IOP spike was similar and relatively high in both XFS and control groups (34% v 25%; p = 0.54). CONCLUSION: IOP decreases more in patients with XFS following PCE compared to control eyes without XFS. This effect is more pronounced in glaucoma patients and persists for at least 2 years.

Baseline IOP predicts selective laser trabeculoplasty success at 1 year post-treatment: results from a randomised clinical trial.

BACKGROUND/AIMS: The efficacy and safety of selective laser trabeculoplasty (SLT) has been found to be equivalent to argon laser trabeculoplasty (ALT). Since SLT produces significantly less disturbance to the trabecular meshwork and is theoretically more repeatable than ALT, it has potential to replace ALT as the standard procedure to treat medically uncontrolled open angle glaucoma. This study's objective is to determine factors that predict successful SLT at 1 year post-treatment. METHODS: As part of a randomised clinical trial comparing the efficacy and safety of SLT to ALT, data on 72 SLT patients were collected, and successful SLT defined as having an SLT induced intraocular pressure (IOP) reduction of >or=20% at 1 year post-treatment follow up. RESULTS: 43 out of the 72 patients who had completed their 1 year follow up visit had an IOP reduction of >or=20% from baseline. No glaucoma risk factors studied predicted successful SLT. The amount of trabecular meshwork pigmentation was not a significant predictor. However, it was discovered that baseline IOP strongly predicted SLT success (odds ratio=1.16; p=0.0001). CONCLUSION: SLT success was significantly predicted by baseline IOP but not by age, sex, other glaucoma risk factors, type of open angle glaucoma, or by degree of trabecular meshwork pigmentation.

Epidemiology of the optic nerve grey crescent in the Reykjavik Eye Study.

AIM: To establish the epidemiology of the grey crescent in a white population within the age range most susceptible to glaucoma. METHODS: Bruce Shields was first to use this term to describe a localised, physiological pigmentation of the optic nerve neuroretinal rim tissue that is distinct from peripapillary pigmentation. An experienced glaucomatologist (KFD) evaluated stereofundus photographs of the participants of the Reykjavik Eye Study (RES)-a random sample from the national population census including people 50 years and older. 1012 right eyes could be evaluated for grey crescent. RESULTS: The prevalence of grey crescent in the right eyes was 22.0% (95% CI 10 to 25). It was more commonly found in women (27.0%: 95% CI 23 to 30) than in men (17.0%: 95% CI 14 to 21), and was most often located temporally (36.9%), 360 degrees (15.9%), or nasally (15.4%). The spherical equivalent was +1.30 dioptres (D) for those with and +0.80 D for those without grey crescent (p = 0.002), respectively. Vertical optic disc diameters were 0.203 v 0.195 units (p<0.001). There was no difference in the prevalence of grey crescent in glaucomatous or non-glaucomatous eyes (OR = 1.05, 95% CI 0.49 to 2.26). The prevalence of a grey crescent was inversely related to the prevalence of peripapillary atrophy (p = 0.001). CONCLUSIONS: The grey crescent needs to be recognised as a physiological variant in order to avoid falsely labelling eyes as having glaucomatous optic nerve damage.

Prevalence of open-angle glaucoma in Iceland: Reykjavik Eye Study.

PURPOSE: To establish the age- and sex-specific prevalence of open-angle glaucoma (OAG) subsuming pseudoexfoliation (PEX) in the city of Reykjavik. METHODS: Participants 50 years of age and older who were part of the Reykjavik Eye Study and classified as having glaucoma were divided into three categories:Category 1: two or more of the following based on optic nerve stereophotograph reading: vertical cup to disc ratio (VCDR) 97.5th percentile (>0.7), focal glaucomatous disc change, C/D asymmetry of 97.5th percentile difference between eyes (>0.2) as well as glaucomatous visual field defect (GVFD). Category 2: 99.5th percentile of VCDR (>0.8) and 99.5% percentile difference between eyes (>/=0.3), without a GVFD. Category 3: VA<3/60 and IOP>99.5th percentile or VA <3/60 and evidence of filtering surgery. For a glaucoma suspect, one of the following was present: VCDR>99.5th percentile (>0.8), focal glaucomatous disc change, C/D asymmetry of 99.5th percentile (> or =0.3), GVFD only, IOP> or =23 mmHg (97.5 percentile). PEX was diagnosed by the presence of a central shield and/or a peripheral band on the anterior lens capsule. RESULTS: Of 42 persons (22 males and 20 females) with OAG, 13 (31.0%) had PEX. The minimum prevalence of OAG was 4.0% (42/1045) (95% CI 2.8-5.2) for those 50 years and older and 10.3% (95% CI 8.5-12.2) for PEX. The prevalence of OAG increases with age (OR=1.10/year, 95% CI 1.07-1.13, P=0.000) and the same applies for the prevalence of PEX, OR=1.10 (95% CI 1.07-1.12, P=0.000). CONCLUSION: There is a 10% annual increase for both OAG and PEX in persons 50 years and older.

Leber's congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p.

BACKGROUND: Leber's congenital amaurosis (LCA) represents the earliest and severest form of retinal dystrophy leading to congenital blindness. A total of 20% of children attending blind schools have this disease. LCA has a multigenic basis and is proving central to our understanding of the development of the retina. We describe the clinical and molecular genetic features of four inbred pedigrees from neighbouring remote villages in northern Pakistan, in which some of the affected members have concurrent keratoconus. METHODS: History-taking and physical and eye examinations were performed in the field. Venipuncture, DNA extraction, studies of linkage to known LCA genes, automated sequencing and polymorphism analyses for haplotype assessments were done. RESULTS: We examined 12 affected and 15 unaffected family members. By history, there were an additional nine blind people in the four pedigrees. In each pedigree a consanguineous marriage was evident. We found a homozygous nonsense mutation in the AIPL1 gene, which replaces a tryptophan with a stop codon (Trp278X). The phenotype is severe and variable, despite the common molecular genetic etiology in each family. Affected patients had hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy. Three affected members had definite keratoconus, and two were suspects based on mild cone formation in the cornea of at least one eye. INTERPRETATION: We have identified four Pakistani families with a severe form of LCA that is associated with severe keratoconus in some affected members. The molecular etiology in all four families is a homozygous nonsense mutation, Trp278X, in the photoreceptor-pineal gene AIPL1. To our knowledge, this is one of the first phenotype-genotype correlations of AIPL1-associated LCA.

Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma.

OBJECTIVE: In patients with dominant optic atrophy (DOA, Kjer type), excavation of the optic nerve develops, and these patients may be misdiagnosed as having normal tension glaucoma (NTG). This study examined disc morphologic features in patients with DOA and explored features that help distinguish this condition from NTG. DESIGN: Noncomparative, observational case series. PARTICIPANTS: Patients with DOA who were seen at the Duke University Eye Center between 1987 and 1996 and who had bilateral optic nerve photographs. METHODS: Retrospective chart review of the results of visual acuity testing, visual field testing by Goldmann perimetry, color vision testing, intraocular pressure measurement, and observation of bilateral optic nerve photographs. MAIN OUTCOME MEASURES: Appearance of the optic disc and peripapillary zone in patients with DOA. RESULTS: Nine patients were identified. The mean age at the time of evaluation was 28 years (range, 11-62 years). Most patients had a mild to moderate reduction in visual acuity. Color vision as tested with Hardy-Rand-Rittler plates was reduced (4.0/10 +/- 4.2/10). A cup-to-disc ratio of more than 0.5 was observed in at least one eye of eight patients. A temporal wedge-shaped area of excavation was observed in 14 of the 18 eyes studied. Moderate to severe temporal pallor was observed in all of the eyes. Pallor of the remaining (noncupped) neuroretinal rim was also observed consistently, ranging from mild to moderate. A gray crescent and some degree of peripapillary atrophy were noted in all eyes. CONCLUSIONS: Several clinical features, including early age of onset, preferential loss of central vision, sparing of the peripheral fields, pallor of the remaining neuroretinal rim, and a family history of unexplained visual loss or optic atrophy, help to distinguish patients with DOA from those with NTG.

Changes in measured intraocular pressure after hyperopic photorefractive keratectomy.

PURPOSE: To investigate the effect of hyperopic photorefractive keratectomy (PRK) on intraocular pressure (IOP) measurements. SETTING: University of Ottawa Eye Institute, Ottawa Hospital, Ottawa, Canada. METHODS: In this retrospective cohort study, IOP and central corneal thickness (CCT) were measured preoperatively and at 1, 2, 3, 6, 12, 18, and 24 months in 191 eyes that had hyperopic PRK with the VISX Star excimer laser. All corrections applied were between +1.00 and +6.50 diopters (D) of sphere and less than 3.75 D of cylinder. RESULTS: At all postoperative examinations, the mean IOP in the hyperopic PRK group was 1.0 to 1.8 mm Hg lower than the preoperative IOP (P <.001). A large range of IOP changes was found across the population; eg, at 6 months, 49% of the eyes had a change in IOP from baseline of at least +/-3 mm Hg. A mean reduction of 19 microm of CCT was found with pachymetry after surgery (P < .001). The change in IOP readings postoperatively was not correlated with age, sex, keratometric readings, or applied correction. Changes in IOP were strongly correlated with preoperative IOP at all time points and with preoperative CCT at 18 and 24 months (P < .001). After hyperopic PRK, the measured IOP was more likely to increase in patients with preoperative IOPs less than 14.5 mm Hg and more likely to decrease in patients with preoperative IOPs above 14.5 mm Hg. CONCLUSION: Changes in IOP after hyperopic PRK were similar to changes after myopic PRK, despite only minimal changes in the CCT. This suggests that hyperopic PRK results in biomechanical effects that modify the elastic properties of the cornea beyond the changes in rigidity expected from central corneal thinning. There was a strong negative correlation between the measured preoperative IOP and the change in IOP postoperatively that was likely the result of regression of the mean effect.

Demonstration of retroiridal extension of an epithelial membrane by ultrasound biomicroscopy: a clinicopathologic correlation.

PURPOSE: To report the utilization of ultrasound biomicroscopy (UBM) in identifying the extension into the posterior segment of an epithelial membrane, as correlated by the histopathologic findings. METHOD: Case report. UBM findings before enucleation with histopathologic correlation. RESULTS: UBM demonstrated a membrane tracking from the posterior iris surface over the ciliary body and towards the retina. Light microscopic examination disclosed the epithelial nature of this membrane. CONCLUSION: UBM can identify extension of an epithelial membrane into the posterior segment and thereby guide the approach to surgical management.

Pseudoexfoliation syndrome in Icelandic families.

AIM: To examine the distribution and clinical ophthalmic characteristics of pseudoexfoliation syndrome (pseudoexfoliation) and glaucoma in Icelandic families. METHODS: Icelandic families containing three or more members aged 70 or older with at least one member with pseudoexfoliation were identified. All family members over age 45 were invited to participate. Visual acuity, Goldmann applanation tonometry, gonioscopy, slit lamp examination before and after dilatation, and dilated fundus examination were performed on all available family members. Pertinent data were obtained from medical records, including ophthalmic history and a medical history of cardiovascular disease, cerebrovascular disease, systemic hypertension, and diabetes mellitus. Participants were classified according to affected status for pseudoexfoliation, glaucoma, and age related macular degeneration. RESULTS: Six families were identified who met the criteria for entry into the study. Of 94 family members who were invited to participate 82 were enrolled (87%). Of these 25 (30%) had pseudoexfoliation syndrome, 51 (62%) were unaffected, and six (7%) were suspects. At least one individual with pseudoexfoliation was identified in the second generation of every family. A parent with pseudoexfoliation was identified in all cases either by examination (4/6) or a review of ophthalmic records (2/6). In all cases the mother was the affected parent. The prevalence of glaucoma was significantly greater in the group with pseudoexfoliation (p <0.0001). Although the presence of age related macular degeneration (ARMD) was highly associated with the presence of pseudoexfoliation, the significance was lost after correction for age (p = 0.69). Although the sample size was small, no association between pseudoexfoliation affected status and cardiovascular disease, cerebrovascular disease, systemic hypertension, or diabetes mellitus was found. CONCLUSIONS: Multiple Icelandic families with pseudoexfoliation in two generations were identified. In all cases where determination was possible, transmission to the second generation was through an affected parent. In each case the affected parent was the mother. Pseudoexfoliation was strongly associated with the presence of glaucoma, but was not associated with either ARMD or systemic disease in this study. These data clearly indicate that pseudoexfoliation is a familial condition and although not conclusive, supports the hypothesis that pseudoexfoliation syndrome is genetically inherited.

Intraocular pressure decrease after phacoemulsification in patients with pseudoexfoliation syndrome.

PURPOSE: To determine the intraocular pressure (IOP) response to phacoemulsification cataract extraction with posterior chamber intraocular lens (PC IOL) implantation in patients with pseudoexfoliation syndrome. SETTING: Eye clinics at the University of Ottawa Eye Institute, Ottawa, Ontario, Canada. METHODS: A retrospective cohort study design assigned patients to 1 of 3 subgroups: pseudoexfoliation syndrome (PEX) (n = 21), primary open-angle glaucoma (POAG) control (n = 23), and cataract control (n = 23). Inclusion criteria consisted of age older than 50 years, open angle by gonioscopy, and a cataract requiring phacoemulsification. The IOP response was determined at intervals up to 18 months. RESULTS: Postoperative IOP changes from baseline in the PEX group were -1.81, -4.52, and -2.31 mm Hg at 3, 6, and 12 months, respectively. The changes in the POAG control group were -2.22, -2.32, and -1.88 mm Hg, respectively, and in the cataract control group, -2.49, +0.45, and +0.28 mm Hg. Patients in the PEX group had a reduction in IOP from baseline at all postoperative measurements. That reduction was significantly greater than in the POAG and cataract control groups at 6 months (P =.012 and P =.002, respectively) and 12 months (P =.001 and P =.050, respectively). CONCLUSIONS: Patients with pseudoexfoliation syndrome had a postoperative IOP reduction from baseline at all measurements and a significantly greater reduction than patients in the POAG and cataract control groups at 6 and 12 months. Phacoemulsification cataract surgery with PC IOL implantation may be effective in managing patients with pseudoexfoliation syndrome who have elevated IOP and visually significant cataract but no advanced optic nerve damage.

Familial occurrence of pigment dispersion syndrome.

BACKGROUND: Pigment dispersion syndrome affects up to 4% of the white population. It is characterized by the presence of transillumination defects, Krukenberg's spindle and dense trabecular meshwork pigmentation. Open-angle glaucoma will develop in as many as 50% of affected patients. In this study we describe the familial occurrence of pigment dispersion syndrome in six North American pedigrees and the phenotypic characteristics with respect to pigment dispersion syndrome and glaucoma. METHODS: Probands with pigment dispersion syndrome were identified in glaucoma clinics at university eye centres in Ottawa and Durham, NC. Families with two or more affected members were evaluated. All willing members in each family underwent a thorough clinical examination and were classified as affected with pigment dispersion syndrome, suspect or unaffected. The previous medical records were reviewed to obtain the past medical and ocular history, including risk factors for glaucoma. RESULTS: All six families are white. Three families show at least two generations of affected members. Of the 43 subjects examined 58% were women. All 14 affected members showed moderate to heavy trabecular meshwork pigmentation and either Krukenberg's spindle or transillumination defects. The affected members were also considerably more myopic (mean spherical equivalent for the right eye -4.72 dioptres) than the suspect group or the unaffected group (mean spherical equivalent -0.79 D and +1.19 D respectively) (p < or = 0.001), and the intraocular pressure was higher for the affected than the unaffected group (mean for the right eye 20 mm Hg vs. 16 mm Hg) (p = 0.004). Half of those affected also had open-angle glaucoma. INTERPRETATION: We have identified and phenotypically characterized six North American families with autosomal dominant pigment dispersion syndrome. Our ultimate goal is to identify the gene(s) that causes this disorder in order to clarify its molecular etiology and pathophysiology. This may give rise to a molecular classification of the disease as well as provide the foundation for genetic testing and new treatment approaches.

Familial occurrence of artefactual ocular hypertension from thick corneas and of primary open angle glaucoma in a French Canadian kindred.

We describe the coexistence of artefactual ocular hypertension due to increased central corneal thickness (CCT>585 microm), with primary open angle glaucoma (POAG) in a French Canadian kindred. Seventeen members of the family were examined and classified as to their glaucoma status. The mean CCT for our glaucoma patients (580 microm; n=5) and that for normals (552 microm; n=6) were within two standard deviations of the mean value provided in the literature (531 microm +/- SD=29 microm). The mean CCT of 611 microm for the suspect group (n=6) was considerably higher than for the glaucoma and normal groups. All but one of the suspects were classified as ocular hypertensives on the basis of high intraocular pressures (IOPs). When the IOPs for these patients (mean 22.6 mmHg) were corrected for their CCTs, all had pressures of <21 mmHg (mean 16.4 mmHg). Ten of the seventeen family members had thick CCTs, and transmission of thick corneas was seen in two generations. A number of individuals in this family had optic nerve head drusen (9/17) and the mean CCT of these individuals (601 microm) was higher than the mean CCT (560 microm) of the group without drusen (P=0.020 by t test). Artefactual ocular hypertension and POAG can be present in different members of the same family. The presence of a thick cornea appears to be an inherited trait and may be associated with the presence of optic nerve drusen. This association suggests a developmental relationship between thick corneas and optic nerve head drusen which needs to be studied further.

Familial occurrence of pseudoexfoliation in Canada.

BACKGROUND: Genetic factors may play an important role in pseudoexfoliation syndrome. We describe the familial occurrence of pseudoexfoliation in Canadian families. METHODS: Probands with pseudoexfoliation were referred to a tertiary care glaucoma service in Ottawa because of a family history of pseudoexfoliation or glaucoma, or both. Probands and family members who agreed to participate underwent a systematic interview and eye examination. The pseudoexfoliation status was classified as affected, suspect or unknown based on preestablished criteria for the diagnosis of pseudoexfoliation and glaucoma. RESULTS: Thirty-four members of 10 families were assessed (18 affected, 2 suspect and 14 status unknown). Six families had two or more generations with pseudoexfoliation, and four families had one generation affected. There was a predominance of females among the affected subjects (17:1), and transmission in all cases appeared to be maternal. Eight of the families were of Irish/Scottish ancestry. Nine (50%) of the affected subjects had cardiovascular disease. Affected subjects tended to be older than suspects and those whose status was unknown (mean age 77, 67 and 55 years respectively). Seven subjects were affected unilaterally and 11 bilaterally. Affected subjects had moderate angle pigmentation in both eyes (mean +2.7, where 0 = no pigment and +4 = dense homogeneous pigment). The mean intraocular pressure in both eyes was higher for the affected subjects (23.1 [standard deviation (SD) 8.6] mm Hg) than for the suspects (16.8 [SD 6.1] mm Hg) and those of unknown status (16.8 [SD 2.9] mm Hg). An enlarged cup:disc ratio was seen in the affected subjects (mean 0.62). Eleven (61%) of the affected subjects had open angles on gonioscopy, and five had occludable angles and required peripheral iridectomy. Ten (56%) of the affected subjects were classified as having glaucoma, and 14 (78%) had evidence of cataract formation in at least one eye. INTERPRETATION: Pseudoexfoliation appears to be transmitted matrilineally, which raises the possibility of mitochondrial inheritance, X-linked inheritance or autosomal inheritance with genomic imprinting. A larger study of families with pseudoexfoliation is necessary to clarify the mode of transmission and to identify the gene(s) involved in the etiology of this disorder.