Myocardial longitudinal strain as the first herald of cardiac impairment in very early iron overload state: an echocardiography and biosusceptometry study on beta-thalassemia patients.

BACKGROUND: Heart diseases due to iron overload are still the main cause of mortality in patients affected by beta-thalassemia. Detection of cardiac iron overload in pre-clinical stage allows tailoring of chelation therapy and follow-up strategies. Echocardiographic longitudinal strain analysis may be a useful tool for early detection of cardiac functional impairment iron-related. METHODS: We examined 58 patients with beta-thalassemia on regular blood transfusion and iron chelation, without overt cardiac disease who had recent Biosusceptometry SQUID to quantify liver iron concentration and cardiac assessment by CMR T2*. RESULTS: Average global longitudinal strain (GLS) was able to identify abnormal (<20 ms) cardiac T2* values with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.01). Apical 4-ch GLS may help identify early longitudinal impairment associated with severe liver iron overload with 96% specificity and negative predictive value of 92% (AUC 0.84, P=0.02). Patients with severe liver iron overload had lower average Global Longitudinal Strain values compared to other patients (P-value =0.005). CONCLUSION: GLS was a sensitive marker to detect both myocardial and liver iron overload in a population that is still free from cardiac symptoms. Thus, strain echocardiography may be a useful tool for early detection of iron overload in Beta-thalassemia.

Higher Vascular Density of the Superficial Retinal Capillary Plexus in Degenerative Lamellar Macular Holes.

BACKGROUND AND OBJECTIVE: Optical coherence tomography angiography (OCTA) comparison between vessel density in patients with degenerative-subtype lamellar macular hole (LMH) and healthy individuals. Unaffected fellow eyes were also included in the study. PATIENTS AND METHODS: This observational, cross-sectional study examined 32 eyes affected by unilateral degenerative-subtype LMH, as well as the 32 fellow eyes of the enrolled population. Thirty healthy eyes were used as controls. ImageJ software was used to calculate macular vessel density in the three vascular plexuses (superficial capillary plexus [SCP], deep capillary plexus [DCP], choriocapillaris [CC]) in two regions: (1) a fovea-centered 1.5-mm diameter circular area after subtracting the foveal avascular zone (FAZ) area, obtaining a "ring" in the immediate FAZ proximity (peri-FAZ); (2) the area external to (1) included in the scan. RESULTS: In the peri-FAZ, the SCP of both LMH and fellow eyes showed higher vascular density than in controls (P = .004 for LMH; P = .015 for fellow eye), whereas no difference was evident between LMH and fellow eyes (P = .190). No changes were found in the DCP or the CC. No differences in vessel density of the three plexuses in the area outside the peri-FAZ were evident in any of the three groups. The FAZ in the SCP was larger in the LMH (0.39 ± 0.16 mm2) and in the fellow eye (0.39 ± 0.21 mm2) groups compared with controls (0.27 ± 0.07 mm2; P = .021 for LMH; P = .0043 for fellow eye), whereas it was similar between LMH and fellow eyes (P = .967). CONCLUSIONS: Degenerative-subtype LMH in the immediate proximity of the FAZ has a larger FAZ and higher vascular density in the SCP compared with healthy eyes. Unaffected fellow eyes also have increased vascular density compared with controls. Microvascular changes are evident in both LMH and unaffected fellow eyes and might play a role in disease pathogenesis. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e112-e117.].

The Use of OCT and OCT Angiography in Detecting an Atypical Case of Retinal Capillary Hemangioma.

Retinal capillary hemangioma (RCH) is a benign retinal tumor defined by a vascular proliferation localized in the peripheral retina, juxtapapillary retina, or the intraneural portion of the optic nerve. In most cases, diagnosis of RCH is performed by fundus evaluation and confirmed by fluorescein fundus angiography. Nevertheless, a small RCH localized on or adjacent to the optic nerve head could be difficult to detect by fundus examination. Here, the authors report an atypical case of RCH, not ophthalmoscopically visible, but successfully detected first by optical coherence tomography (OCT) and then by OCT angiography, which confirmed its vascular nature. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e81-e83.].

Vascular Density of Retinal Capillary Plexuses in Different Subtypes of Macular Hole.

BACKGROUND AND OBJECTIVE: To compare vessel density and the foveal avascular zone (FAZ) area among eyes with full-thickness macular hole (FTMH), lamellar macular hole (LMH), and macular pseudohole (MPH) using optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: Cross-sectional study involving 10 eyes with idiopathic FTMH, 10 eyes with LMH, 10 eyes with MPH, 17 unaffected fellow eyes, and 10 healthy controls. All patients underwent 3 mm × 3 mm OCTA centered on the macula. Vessel density and FAZ area were calculated. RESULTS: In the deep capillary plexus, FTMHs disclosed the highest vessel density (82.7% ± 16.8%), superior to LMHs (63.7% ± 5.9%; P = .0092), MPHs (37.8% ± 2.5%; P = .0011), and controls (53.0% ± 12.2%; P < .0001). In the superficial capillary plexus (SCP), MPHs had the lowest vascular density. Fellow eyes had reduced vascular density at SCP compared to control eyes. CONCLUSIONS: Microvascular changes are evident in different subtypes of macular holes. Unaffected fellow eyes exhibit early involvement of SCP. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:648-654.].

Optical Coherence Tomography Angiography of Retinal Cavernous Hemangioma.

Retinal cavernous hemangioma is a rare, benign, retinal tumor characterized by angiomatous proliferation of vessels within the inner retina or the optic disc.1 Here we report a case of retinal cavernous hemangioma on the margin of the optic disc in the right eye of a 61-year-old asymptomatic female. The lesion was studied with multimodal imaging which included structural optical coherence tomography, fluorescein angiography, blue fundus auto-fluorescence, optical coherence tomography angiography (OCTA) (DRI OCT Triton; Topcon, Tokyo, Japan) and visual field examination. Blood circulation inside retinal cavernous hemangioma lesion is typically low-stagnant.2 However, OCTA demonstrated blood flow inside the lesion, illustrating its vascular circulation.3 Visual field was within the normal limits, except from a slight enlargement of the blind spot. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:684-685.].

EFFECT OF INTRAVITREAL RANIBIZUMAB ON GANGLION CELL COMPLEX AND PERIPAPILLARY RETINAL NERVE FIBER LAYER IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To analyze the changes in ganglion cell complex and peripapillary retinal nerve fiber layer thickness, in central macular thickness and choroidal thickness on spectral domain optical coherence tomography in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab injections. METHODS: All consecutive patients with untreated neovascular age-related macular degeneration received loading phase of three monthly intravitreal ranibizumab, followed by retreatments on a pro re nata protocol for 12 months. PRIMARY OUTCOME: changes in ganglion cell complex and retinal nerve fiber layer at the end of follow-up. Secondary outcome: changes in best-corrected visual acuity, central macular thickness, and choroidal thickness at the end of follow-up. Choroidal thickness was measured at 500 µm, 1000 µm, and 1,500 µm intervals nasally, temporally, superiorly, and inferiorly to the fovea, respectively, on horizontal and vertical line scans centered on the fovea. RESULTS: Twenty-four eyes were included. Ganglion cell complex and peripapillary retinal nerve fiber layer thickness did not show statistically significant changes through 12 months (55.6 ± 18.5 and 81.9 ± 9.9 µm at baseline, 52.7 ± 19.3 and 84.6 ± 15.5 µm at month 12, P > 0.05). Central macular thickness showed progressive decrease from baseline to month 12, with maximum reduction at month 3 (P < 0.001). Statistically significant reduction in choroidal thickness was registered in the nasal 500, 1000, and 1,500 µm from the fovea, corresponding to the papillomacular region (from 169.6 ± 45.3 to 153.9 ± 46.9, P < 0.001). CONCLUSION: Intravitreal ranibizumab injections did not affect retinal nerve fiber layer and ganglion cell complex thickness in 1-year follow-up. Choroidal thickness in papillomacular area and central macular thickness was significantly reduced at the end of treatment. Further studies, with larger sample, longer follow-up, and greater number of injections, are warranted.

Optimal Medical Therapy in Patients with Malignancy Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome: a BleeMACS Sub-Study.

OBJECTIVE: Our objective was to define the most appropriate treatment for acute coronary syndrome (ACS) in patients with malignancy. METHODS AND RESULTS: The BleeMACS project is a worldwide multicenter observational prospective registry in 16 hospitals enrolling patients with ACS undergoing percutaneous coronary intervention. Primary endpoints were death, re-infarction, and major adverse cardiac events (MACE; composite of death and re-infarction) after 1 year of follow-up. The secondary endpoint was bleeding events during follow-up. We performed sub-study analyses according to whether ß-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, or proton pump inhibitors (PPIs) were prescribed at discharge. We also calculated the propensity score for optimal medical therapy (OMT; combination of BB, ACEI/ARB, and statins). The study included 926 patients. According to the multivariate analysis, ACEIs/ARBs (hazard ratio [HR] 0.58, 95 % confidence interval [CI] 0.36-1.94; p = 0.03) and statins (HR 0.37, 95 % CI 0.23-0.61; p < 0.01) reduced the risk of MACE, while the effects of BBs (HR 0.85, 95 % CI 0.55-1.32; p = 0.48) and PPIs (HR 1.33, 95 % CI 0.83-2.12; p = 0.23) were not significant. OMT was prescribed at discharge in 300 (32.4 %) patients; after propensity score analysis, OMT showed a significant reduction in death (3 % vs. 12.5 %, HR 0.21, 95 % CI 0.1-0.4; log-rank p < 0.001) and MACE (6.7 vs. 15.2 %, log-rank p = 0.01). CONCLUSION: In patients with ACS and malignancy, OMT reduces the risk of adverse events at 1 year; in particular, ACEIs/ARBs and statins were the most protective drugs. (Clinical trials identifier: NCT02466854).

64 slice-coronary computed tomography sensitivity and specificity in the evaluation of coronary artery bypass graft stenosis: A meta-analysis.

A non-invasive approach to define grafts patency and stenosis in the follow-up of coronary artery bypass graft (CABG) patients may be an interesting alternative to coronary angiography. 64-slice-coronary computed tomography is nowadays a diffused non-invasive method that permits an accurate evaluation of coronary stenosis, due to a high temporal and spatial resolution. However, its sensitivity and specificity in CABG evaluation has to be clearly defined, since published studies used different protocols and scanners. We collected all studies investigating patients with stable symptoms and previous CABG and reporting the comparison between diagnostic performances of invasive coronary angiography and 64-slice-coronary computed tomography. As a result, sensitivity and specificity of 64-slice-coronary computed tomography for CABG occlusion were 0.99 (95% CI 0.97-1.00) and 0.99 (95% CI: 0.99-1.00) with an area under the curve (AUC) of 0.99. 64-slice-coronary computed tomography sensitivity and specificity for the presence of any CABG stenosis >50% were 0.98 (95% CI: 0.97-0.99) and 0.98 (95% CI: 0.96-0.98), while AUC was 0.99. At meta-regression, neither the age nor the time from graft implantation had effect on sensitivity and specificity of 64-slice-coronary computed tomography detection of significant CABG stenosis or occlusion. In conclusion 64-slice-coronary computed tomography confirmed its high sensitivity and specificity in CABG stenosis or occlusion evaluation.

Correlation of SD-OCT findings and visual function in patients with retinitis pigmentosa.

PURPOSE: To describe the morphological macular changes detected by spectral domain optical coherence tomography (SD-OCT) in eyes with retinitis pigmentosa (RP) and to analyze their correlation with the visual function. METHODS: Twenty-two patients (44 eyes) patients affected by RP were recruited. The following structures were evaluated on SD-OCT: outer plexiform layer (OPL), outer nuclear layer (ONL), external limiting membrane (ELM), photoreceptor inner/outer segment (IS/OS) junction, photoreceptor outer segment/retinal pigmented epithelium (OS/RPE) junction, inner limiting membrane thickening (ILMT), ganglion cell complex (GCC), and cystoid macular edema (CME). The relation between each SD-OCT finding and BCVA was evaluated at uni- and multivariate analysis. RESULTS: Mean age and mean best-corrected visual acuity (BCVA) were 51 ± 17.5 years and 0.4 ± 0.5 LogMAR, respectively. Univariate linear regression model revealed a correlation between BCVA and the absence of ELM, IS/OS, ONL, and OS/RPE layers (R (2) values were, respectively, 0.51, 0.57, 0.48, and 0.68, with p values all <0.0001). At multivariate regression analysis, the absence of OS/RPE and ELM layers remained the only variables independently associated with a decrease of BCVA (R (2) = 0.85, t = 3.49, p = 0.0014). CONCLUSIONS: Data show that in patients afflicted with RP, ELM and OS/RPE layers are independently associated with BCVA on multivariate regression analysis. These results highlight the key-role of external retinal layers in determining the visual function impairment attributable to RP.

Natural course of symptomatic focal choroidal excavation.

A 32-year-old man was referred to the authors' department for nonspecified macular dystrophy with persistent metamorphopsia in the right eye diagnosed 10 years before and followed using optical coherence tomography. The patient underwent a comprehensive ocular examination, including multimodal imaging evaluation and electrofunctional testing. The diagnosis was consistent with nonconforming focal choroid excavation. Over 10 years, no complications occurred, visual acuity was stable, and optical coherence tomography showed no progression of the lesion during follow-up. In this case, nonconforming symptomatic focal choroid excavation was a nonprogressive condition with good long-term visual outcome.

Role of ganglion cell complex in visual recovery following surgical internal limiting membrane peeling.

PURPOSE: To investigate the Ganglion Cell Complex (GCC) thickness change and visual recovery correlation after surgery for an idiopathic epiretinal membrane (ERM). METHODS: In this prospective, observational, case control study 30 eyes underwent vitrectomy for idiopathic ERM. We analysed best-corrected visual acuity (BCVA), mean macular thickness and mean GCC thickness one day before surgery, seven days and six months after surgery. Internal segment/outer segment junction, external limiting membrane, cone outer segment tips defects and intraretinalfluid were also investigated throughout the follow-up. RESULTS: Baseline GCC thickness was higher in patients with ERM (130 ± 13 µm) compared with healthy eyes (94 ± 5 µm; p < 0.0001). GCC thickness decreased after surgery to 89 ± 11 µm (p < 0.0001), reaching a value similar to controls (p = 0.12). Preoperative macular thickness was 318 ± 32 µm and decreased to 281 ± 18 µm (p < 0.0001), remaining significantly higher than controls (260 ± 8 µm; p < 0.0001). The GCC proportion of the whole macular thickness was also reduced six months after surgery (p < 0.0001). Post-operative BCVA gain showed direct correlation with GCC reduction (R = 0.67, p < 0.0001), but did not correlate with the mean macular thickness reduction (R < 0.01, p = 0.97). CONCLUSIONS: Ganglion cell complex thickness is higher in eyes with idiopathic ERM, and after surgery turns back to similar values of healthy eyes. Post-operative GCC reduction is proportionally higher than thinning of the whole retina, and this reduction is correlated with visual restoration.

Natural history of premacular hemorrhage due to severe acute anemia: clinical and anatomical features in two untreated patients.

Premacular retrohyaloid hemorrhage is a rare complication of acute severe anemia. The authors report two cases of premacular hemorrhage in which no treatment other than clinical and spectral-domain optical coherence tomography observation was performed. The natural history of this condition reveals that complete clinical resolution is not accompanied by full anatomical restoration. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:E5-E7.].

Spectral-domain optical coherence tomography evaluation of vitreoretinal adhesions in idiopathic epiretinal membranes.

BACKGROUND: Vitreoretinal adhesions play a key role in the vector forces exerted on the vitreoretinal interface, leading to tractional retina deformation and macular hole formation. The aim of this study was to identify the presence of vitreopapillary and vitreofoveal adhesions in idiopathic epiretinal membranes (ERMs) with spectral-domain optical coherence tomography (SD-OCT) and to evaluate their influence on the vitreoretinal interface. METHODS: Sixty-five eyes (65 patients) with idiopathic ERM and 64 healthy eyes (64 patients) underwent SD-OCT analysis. We studied vitreopapillary and vitreofoveal adhesion prevalence in eyes with idiopathic ERM using different SD-OCT patterns ("adherent" or "tractional"). We analyzed their influence on central foveal thickness (CFT), on retinal nerve fiber layer (RNFL) thickness, and on morphological modifications (foveal depression profile and inner/outer photoreceptor junction). RESULTS: Vitreopapillary adhesion was present in 51.6 % of normal eyes and in 24.6 % of eyes with idiopathic ERM, while vitreofoveal adhesion was found in 14.1 % of normal eyes and in 15.4 % of eyes with ERM. Vitreopapillary adhesion prevalence was significantly higher in the tractional ERM subgroup (p = 0.01), than in the adherent ERM subgroup. Both adhesions had no influence on CFT, RNFL thickness, or inner segment/outer segment junction status. CONCLUSIONS: Our study suggests that vitreoretinal adhesions may influence the pathogenesis and course of idiopathic ERM. The absence of vitreopapillary adhesion in the adherent type, and its presence in the tractional type, seems to play a key role in ERM characterization.

Spectral domain optical coherence tomography findings in patients with retinitis pigmentosa.

BACKGROUND: To report the morphological macular findings detected by spectral domain optical coherence tomography (SD-OCT) and to determine their prevalence in patients with retinitis pigmentosa (RP). METHODS: SD-OCT scans of 176 eyes from 90 patients affected by RP were reviewed. A careful evaluation was carried out on photoreceptor inner/outer segment (IS/OS) junction, external limiting membrane (ELM), inner limiting membrane thickening (ILMT), epiretinal membranes (ERMs), retinal micropseudocysts (MPCs), cystoid macular edema (CME), macular holes (MHs) and choroidal neovascularization (CNV). RESULTS: The photoreceptor IS/OS junction was absent in the foveal region of 24 eyes (13.6%) and disrupted in 84 eyes (47.7%). The ELM was absent in 24 eyes (13.6%), whereas the ILMT was found in 118 eyes (67%). The presence of an ERM was detected in 48 eyes (27.3%). Some sort of vitreomacular alteration (ILMT and/or ERM) was identifiable in a total of 94.3% of eyes with RP. The presence of MPCs was detected in 32 eyes (18.2%). An evident CME was found in 22 eyes (12.5%). We also found MHs in 8 eyes (4.5%) and CNV in 3 eyes (1.7%). CONCLUSIONS: Our data indicate that RP is associated with alterations of many retinal layers. In particular, the vitreoretinal interface is affected in 94% of patients, and MPC can be identified in 18% of eyes. SD-OCT may contribute to the understanding of the pathophysiological mechanism involved in RP.

Intravitreal ranibizumab for pigment epithelium detachment with subfoveal occult choroidal neovascularization: a prospective 24-month case series.

PURPOSE: To assess the effects of intravitreal ranibizumab injection in patients affected by pigment epithelial detachment associated with occult subfoveal choroidal neovascularization. DESIGN: Prospective, interventional case series. PARTICIPANTS: Forty eyes of 40 patients were considered for the purpose of the study. Consecutive patients were recruited for a 24-month study. All patients underwent a complete ophthalmic examination, including best-corrected visual acuity on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 3-monthly loading phase, further intravitreal ranibizumab injections were administered on the basis of detection of any type of fluid on optical coherence tomography. PRIMARY OUTCOME MEASURES: Changes in mean best-corrected visual acuity at 12 and 24 months and the proportion of eyes losing fewer than 15 letters (corresponding to 3 ETDRS lines) from baseline visual acuity. SECONDARY OUTCOME MEASURES: Changes in central macular thickness on optical coherence tomography and variation in mean area of the entire lesion. RESULTS: Forty patients were included. Mean best-corrected visual acuity decreased from 20/66 (58 ETDRS letters) to 20/83 (53 letters) at 12 months and 20/112 (489 ETDRS letters) at 24 months (P = .003). Eighty percent and 67.5% of eyes lost fewer than 3 lines at 12 and 24 months, respectively. Mean central macular thickness passed from 545 µm to 428 µm at 12 months and 426 µm at 24 months. Mean lesion area changed from 6826 µm(2) to 6312 µm(2) at 12 months and 6010 µm(2) at 24 months. CONCLUSIONS: The treatment of pigment epithelial detachment associated with occult subfoveal choroidal neovascularization with intravitreal ranibizumab injection after a 3-monthly loading phase and pro re nata strategy can lead to partial results over a 24-month follow-up. Further investigations are warranted to establish the best therapeutic approach to this disease.

SD-OCT patterns of the different stages of choroidal metastases.

A diagnosis of choroidal metastasis is based on the patient's clinical history, the tumor's ophthalmoscopic appearance, and instrumental imaging results such as ultrasonography, fluorescein angiography, fundus autofluorescence, indocyanine green angiography, and optical coherence tomography. Spectral-domain optical coherence tomography (SD-OCT) has provided additional useful information for clinical diagnosis: a pattern of hyperintense irregular spots in the context of the photoreceptor layer and in the retinal pigment epithelium, subretinal fluid, and marked irregularity of the retinal pigment epithelium with thickening and gross undulation. The authors describe a case of bilateral choroidal metastasis presenting peculiar SD-OCT features acquired at different stages. They emphasize the central role of SD-OCT among instrumental imaging procedures and for final successful diagnosis.

Characteristic SD-OCT findings in preeclampsia.

High-resolution spectral-domain optical coherence tomography of a patient affected by acute macular edema secondary to preeclampsia is described. The particular optical coherence tomography pattern was characterized by bilateral macular edema with a tent-shaped organization, associated with massive neurosensorial retinal detachment. Many hyperreflective irregular dots were evident in the context of a subfoveal clear cystic lesion. A different hyperreflective irregularity was detected in the retinal pigment epithelium. The central role of spectral-domain optical coherence tomography among instrumental imaging procedures and for final successful diagnosis in this particular macular edema is emphasized.

Macular micropseudocysts in early stages of diabetic retinopathy.

PURPOSE: To identify by noninvasive means early retinal abnormalities that may predict diabetic macular edema. METHODS: The authors analyzed retrospectively data from consecutive patients with Type 1 (n = 16) or Type 2 (n = 23) diabetes who presented for routine follow-up of early retinopathy, had no clinical signs or symptoms of diabetic macular edema, and were evaluated with spectral-domain optical coherence tomography. Age- and gender-matched nondiabetic subjects provided normative data. RESULTS: Spectral-domain optical coherence tomography revealed in the macular region of diabetic patients small hyporeflective areas (median diameter, 55 µm) contained within discrete retinal layers that we named micropseudocysts (MPCs). Micropseudocysts are associated with vascular leakage. The patients showing MPCs had more frequently systemic hypertension and increased central foveal thickness than those without MPCs. The association with increased central foveal thickness was only in the patients with Type 2 diabetes. CONCLUSION: Macular MPCs in patients with mild diabetic retinopathy appear to reflect leakage and can precede macular thickening. The association of MPCs with increased central foveal thickness in patients with Type 2 diabetes, but not in patients with Type 1 diabetes, points to a greater tendency to retinal fluid accumulation in patients with Type 2 diabetes. Studies in larger cohorts will determine the usefulness of MPCs in strategies to abort diabetic macular edema.

SD OCT features of dry arcuate longstanding retinal folds.

PURPOSE: To report the spectral domain (SD) findings in a retinal fold secondary to vitrectomy surgery. METHODS: A 57-year-old man presented 1 month after vitrectomy surgery with gas injection (C3F8 6%) in his left eye for treatment of a macula-on retinal detachment and was noted to have a retinal fold in the superior aspect of the macula. Complete ocular examination, fundus photography, fluorescein angiography, autofluorescence, and SD optical coherence tomography (OCT) were performed. RESULTS: Spectral domain OCT revealed a slightly hyperreflective lesion in the outer retina, which occupied a discontinuity in the inner segment outer segment junction and extended superiorly with apparent indentation of the overlying retinal layers. CONCLUSIONS: This case illustrates how SD OCT may be useful in describing the morphologic substrate of retinal fold after retinal surgery.