Efficacy Of Endovascular Treatment Research Articles

Estudios IMS III, SYNTHESIS y MR-RESCUE: ¿el fin de la terapia endovascular en el ictus?

Last March, in a single issue New England Journal of Medicine published 3 studies that evaluated the efficacy of endovascular treatment for ischemic stroke, leading to a heated controversy between neurologists and interventional neuroradiologists. The negative results have resulted in numerous reviews pointing out serious methodological defects. In this article, we analyze the outcomes of thrombolytic treatment for stroke and discuss the strengths and weaknesses of the three above-mentioned studies. Despite the negative results, these studies can point the way for new trials that will justify this treatment modality that is backed up by scientific evidence.

Special issues in endovascular treatment of lower extremities arteriosclerosis obliterans

To explore the clinical efficacy of endovascular treatment for lower extremity arteriosclerosis obliterans. A total of 34 patients (43 limbs) with lower extremity arteriosclerosis obliterans undergoing endovascular treatment from July 2010 to July 2012 were analyzed. The cohort had Fontaine stage II b (n = 16), Fontaine stage III (n = 10) and Fontaine stage III (n = 8). Among them, the lesions were of TASC IIA (n = 4), TASC IIB (n = 8), TASC IIC (n = 9) and TASC IID (n = 13). All patients underwent percutaneous transluminal angioplasty (PTA) plus stents after computed tomographic angiography (CTA) or digital subtraction angiography (DSA). And 9 patients underwent femoral endarterectomy associated with endovascular treatment. The success rate of this technique was 100%. One iliac artery ruptured during endovascular surgery. One patient suffered intraoperatively from arterial perforation. One patient was amputated one week later. One patient had in-stent thrombosis at Week 3 post-treatment. One patient was amputated at Week 4 after endovascular treatment. Thirty patients (38 limbs) were followed up for 13.3 months. During the follow-up, 3, 4 and 4 limbs became occluded at Month 6, 12 and 24 post-treatment respectively. Endovascular treatment has an excellent early patency rate. Special issues should be properly handled during endovascular treatment.

“Picture to Puncture”

Background— Comprehensive stroke centers allow for regionalization of subspecialty stroke care. Efficacy of endovascular treatments, however, may be limited by delays in patient transfer. Our goal was to identify where these delays occurred and to assess the impact of such delays on patient outcome. Methods and Results— This was a retrospective study evaluating patients treated with endovascular therapy from November 2010 to July 2012 at our institution. We compared patients transferred from outside hospitals with locally treated patients with respect to demographics, imaging, and treatment times. Good outcomes, as defined by 90-day modified Rankin Scale scores of 0 to 2, were analyzed by transfer status as well as time from initial computed tomography to groin puncture (“picture-to-puncture” time). A total of 193 patients were analyzed, with a mean age of 65.8±14.5 years and median National Institutes of Health Stroke Scale score of 19 (interquartile range, 15–23). More than two thirds of the patients (132 [68%]) were treated from referring facilities. Outside transfers were noted to have longer picture-to-puncture times (205 minutes [interquartile range, 162–274] versus 89 minutes [interquartile range, 70–119]; P <0.001), which was attributable to the delays in transfer. This corresponded to fewer patients with favorable Alberta Stroke Program Early CT Scores on preprocedural computed tomographic imaging (Alberta Stroke Program Early CT Scores >7: 50% versus 76%; P <0.001) and significantly worse clinical outcomes (29% versus 51%; P =0.003). In a logistic regression model, picture-to-puncture times were independently associated with good outcomes (odds ratio, 0.994; 95% confidence interval, 0.990–0.999; P =0.009). Conclusions— Delays in picture-to-puncture times for interhospital transfers reduce the probability of good outcomes among treated patients. Strategies to reduce such delays herald an opportunity for hospitals to improve patient outcomes.

Safety and Efficacy of Endovascular Treatment in the "Hub and Spoke Model" (P07.267)

Safety and Efficacy of Endovascular Treatment in the "Hub and Spoke Model" (P07.267)

Abstract WP91: Open-cell Stent Design for Coil Embolization of Side Branching Vessel Internal Carotid Artery Aneurysms: Clinical and Angiographic Results

Background and Purpose: Treatment of side branch internal carotid artery (ICA) cerebral aneurysms, i.e. ophthalmic and anterior choroidal artery aneurysms, pose unique treatment difficulties. Visual loss or anterior choroidal artery territory infarcts have been reported as clinical sequelae for both surgical and endovascular treatment approaches for these aneurysms. Here we evaluate the safety and efficacy of endovascular treatment by use of open cell design for stent assisted coil embolization of side branch ICA aneurysms. Materials and Methods: Between 2007 and 2012, 60 consecutive patients treated with open cell stent assisted coil embolization for a cerebral aneurysm were reviewed. Inclusion criteria were wide neck aneurysms incorporating an ICA branching vessel at the neck of the aneurysm. Aneurysm occlusion was assessed on cerebral angiograms by using the Raymond Score immediately after endovascular treatment and at 6 months follow-up. Clinical outcomes were assessed by the modified Rankin Scale (mRS) at baseline, discharge and 6 months follow-up. Results: Of the 60 consecutive patients treated with open cell stent assisted coil embolization, 6 patients were identified as having side branching ICA cerebral aneurysms. In each of these 6 cases, the side branching ICA vessel originated from the neck of the aneurysm. Flat panel CTA obtained post open cell stent deployment showed preferential outward herniation of open cell stent struts towards the neck of the aneurysm, thus protecting the side branching vessel. On immediate post treatment angiograms, a Raymond Score of 1 was assessed on each of these 6 aneurysms with patency of the side branching vessel. A mRS of 0 or 1 was assessed at baseline and at discharge on all 6 patients. A Raymond Score of 1 was also identified on 3 of the 6 aneurysms on the 6 months follow-up exam. 3 additional patients are still awaiting their 6 months follow-up. Of the 3 patients that have received 6 months follow-up, all 3 patients have a stable mRS of 0 or 1. Conclusions: Our short to mid-term results for open cell stent assisted coil embolization of side branch ICA aneurysms is safe and effective. The independent open cell stent strut’s outward radial force protects side branching vessels that originate from the neck of these aneurysms.

Abstract TMP62: Safety and Efficacy of Endovascular Treatment in the “Hub and Spoke Model”

Background: There are three different pathways for receiving endovascular treatment: primary ED arrival, in-patient, and outside transfer. Each mode has unique attributes that influence the performance and possibly the results of endovascular treatment in acute ischemic stroke patients. Objective: To compare the rates of various outcomes among patients who receive endovascular treatment through primary ED arrival, in-patient, and outside transfer modes. Methods: We performed a review of acute ischemic stroke patients presenting to our facility who received endovascular treatment from 2004 until 2012. Patient route (ER, inpatient, transfer), rates of poor outcome at discharge (modified Rankin score [mRS] of >3), intracerebral hemorrhages (ICH), as well as patients’ clinical characteristics were obtained and analyzed. Results: Among the total 336 patients that underwent IA thrombolysis, 68 patients (mean age 69.1± 16.6; 54% men) were transferred, while 38 patients (mean age 61.1± 14.5; 58% men) were in-patient strokes. Demographics, clinical characteristics, and outcomes are detailed below (Table 1 & 2). The mean admission NIHSS was significantly higher in the transferred patients (16.2± 9.5 versus 15.5± 6.2, p<0.001), though there was no difference in discharge NIHSS. After adjusting for all potential confounders there was no significant difference in good outcomes (odds ratio [OR] 2.0 95% Confidence interval [CI] 0.9-4.3, p=0.06), ICH (OR 0.6 95% CI 0.3-1.3, p=0.2), or mortality (OR 0.6 95% CI 0.3-1.4, p=0.2) between ER patients and transferred patients. Conclusions: Despite the increased baseline stroke severity, there appears to be no significant risk of increased poor outcomes, ICH, or mortality in acute ischemic stroke patients transferred to endovascular centers. This further justifies the safety and efficacy of the hub and spoke model.

Endovascular treatment for saccular aneurysms of the proximal (M1) segment of the middle cerebral artery

Saccular aneurysms located at the M1 segment of the middle cerebral artery (MCA) are uncommon, and endovascular treatment (EVT) for them is not well documented. We performed this study to evaluate the feasibility, safety, and efficacy of EVT for proximal (M1) segment saccular aneurysm of the middle cerebral artery. Of 153 MCA aneurysms between January 2007 and September 2011, 29 patients with 29 M1 segment saccular aneurysms were treated at our institution via endovascular approach. There were 14 men and 15 women with a mean age of 56.2 years (range 36-78 years). Treatments were successful in 28 (96.6 %) cases, including coiling alone in 19 patients, stent-assisted coiling in 8, and balloon-assisted coiling in 1. In the failed case, coiling was not successful, and only a stent was deployed. Immediate angiograms showed total occlusion in 13 patients, neck remnant in 7, partial occlusion in 8, and contrast stasis in the patient who was not coiled successfully. Two (6.9 %) procedure-related complications occurred, including early temporal branch (ETB) obliteration in one patient and lenticulostriate artery (LSA) occlusion in the other one, which resulted in hemiparalysis of one patient. Three patients died from initial severe SAH during hospitalization. One patient died from heart infarction 1 month after operation. Twenty-three of 25 surviving patients underwent follow-up cerebral angiography at intervals ranging from 1 to 21 months (mean, 7.3 months). The result showed 14/23 (60.9 %) aneurysms were completely occluded, 3/23 (13 %) were recanalized, and others were stable or improved. The clinical follow-up (mean, 22.5 months) of all survived patients demonstrated no neurologic deterioration or rebleeding. Our preliminary experience demonstrates that EVT for proximal MCA aneurysm is feasible and safe. However, more adequate follow-up is required to evaluate its long-term results.

Diagnosis and treatment of carotid-cavernous fistula: analysis of 28 patients

To evaluate the feasibility and efficacy of endovascular treatment for different types of carotid cavernous fistula (CCF) via the approach of internal carotid artery (ICA) or inferior petrosal sinus (IPS). From April 2005 to June 2010, 28 CCF patients underwent endovascular treatment at our institution. There were 13 males and 15 females with a mean age of 39 years (range: 21 - 71). According to the Barrow's classification, they were classified into type A (n = 21), type B (n = 2) and type D (n = 5). Patients of type A underwent detachable balloon embolization of ipsilateral cavernous sinus or stent-graft placement via the ICA approach. Patients of types B and D received detachable coil plus n-BCA (n-butyl-2-cyanoacrylate) embolization of ipsilateral cavernous sinus via the IPS approach. The technical results, complications and therapeutic outcomes were reviewed. Detachable balloons (number: 1 - 4) were used in 16 patients of type A. Angiography at immediate postembolization showed a complete occlusion of fistula in 15 patients and a small residual fistula (< 20%) in 1 patient. Five patients of type A received stent-graft placement. One stent was placed in 4 patients and 2 stents in 1 patient. Complete fistula closures with preserved ICA were documented on immediate angiogram in 3 patients whereas a large residual flow (> 50%) persisted in 1. The fistula was completely occluded after 3 detachable balloons were deployed in affected cavernous sinus through a gap between stent and vascular wall. Both fistula and ICA were occluded in 1 patient after stenting. No cerebral infarction was observed due to the adequate collateral blood flow from contralateral ICA. Complete closures of affected cavernous sinus were achieved in 6 patients of types B and D while residual flow (< 50%) persisted in 1. The number of detachable coils for each embolization ranged from 3 to 8 (mean: 6.0). The volume of n-BCA mixture varied from 1.0 to 2.1 ml (mean: 1.3). The mean duration of n-BCA injection was 65 s (range: 45 - 90). Clinical symptoms were completely relieved in 26 patients. During the mean follow-up period of 30 months (range: 12 - 60), no recurrence of clinical symptoms was observed. No thrombosis or stenosis was found in the lumina of stents. Detachable balloon embolization is the preferential treatment for direct CCF. Detachable coil plus n-BCA embolization of cavernous sinus via the IPS approach is an efficient and safe treatment for indirect CCF.

Long-term efficacy of endovascular treatment of isolated iliac artery aneurysms

The aim of this study was to evaluate the efficacy of endovascular treatment of isolated iliac artery aneurysms (IIAA) and compare our data with those reported in the literature. From May 2005 to December 2010, 32 patients (31 men and one woman; mean age 73±12 years) with a total of 40 IIAAs underwent endovascular treatment at our institute. We evaluated technical success, long-term patency, early and late complications and overall mortality. At a median follow-up of 36 months, we achieved a technical success of 100%, a primary patency of 95% and a secondary patency of 100%, with complete exclusion of the aneurysm in 84.6% of cases. In 12.8% of cases, there was a reduction in aneurysm sac volume, with an incidence of type II endoleak of 12.8%. Overall survival at 1, 2, 3, and 6 years was 96.8%, 84.2%, 66.6% and 64%, respectively. Our study documents the effectiveness of endovascular treatment of iliac aneurysms, which has become the first-choice treatment at our institute. This finding is consistent with the most recent literature and confirms the safety and long-term patency of stent-graft placement.

Diagnosis and radiological treatment of digestive haemorrhage following supramesocolic surgery

Digestive haemorrhage following supramesocolic abdominal surgery (cephalic duodenopancreatectomy, cholecystectomy, total oesogastrectomy) is a rare but serious complication, which can be life-threatening. Improvement in scanning techniques has made it possible to modify the diagnostic strategy and improve the therapeutic management of the patients. The aim of this iconographic review is to recall the causes of digestive haemorrhage following supramesocolic surgery and to illustrate the dominant role of tomodensitometry in diagnosing it and in planning and controlling the efficacy of endovascular treatment.

Abstract 3311: Acute stroke and endovascular outcomes in Elderly Population: A Single Center Experience.

Background: In the setting of acute ischemic stroke, endovascular intervention, once considered experimental, is now gold standard of care of appropriately selected patients. Among the elderly, aged 80 and above, patients have multiple comorbidities, and little data exists regarding clinical outcome for those undergoing different endovascular treatment modalities. Objectives: To assess the safety and efficacy of different endovascular treatment modalities in elderly, aged 80 and above, compared to patients younger than 80 with acute ischemic stroke Methods: Restrospective chart review was performed in 150 consecutive patients who underwent endovascular treatments for acute ischemic stroke at our center between 2008 and 2011, between age range 17 -93 years. Elderly patients (EP) age 80 and above (n=34) were compared to nonelderly patients age &lt;80 (NEP) (n=116). The patients in both groups underwent mechanical (including MERCI and or Penumbra and/or angioplasty and stenting) and/or chemical thrombolysis (intra-arterial tPA). We compared the specific outcome parameters of EP vs NEP groups, including discharge NIHSS, modified Rankin Scale (mRS), rate of partial to complete recanalization (TIMI 2-3), symptomatic intracerebral hemorrhage (ICH), and all cause mortality. Results: In EP, mean age was 84.9 ± 3.3, with 32.3% (n=11) males and 67.6% (n=23) females. In NEP mean age was 63.6 ± 13.1, with 50.9% (n=59) males and 49.1% (n=57) females. 91.3% (n=106) In EP vs NEP, mean initial NIHSS were 19±7 and 16±6, and discharge NIHSS 9±7 and 12±8, respectively. Rates of recanalization occurred in 67.6% (n=23) in EP, and 71.6% (n=83) in NEP. Discharge mRS 3 or less was 2.9% (n=1) in EP, and 17.2% (n=20) in NEP. Symptomatic ICH occurred in 20.6% (n=7) in EP and 14.7% (n=17) in NEP. All cause mortality rate at discharge in EP group was 41.2% (n=14) and 19.8% (n=23) in NEP. Conclusions: In our experience EP had poor clinical outcomes with increased mortality and hemorrhage rate compared to NEP irrespective of similar recanalization rate. Further prospective trial is warranted to evaluate safety and efficacy of endovascular treatment in patients aged 80 years old and above.

TCT-77: Efficacy of Endovascular Treatment and predictor of mortality in Critical Limb Ischemia population after EVT

TCT-77: Efficacy of Endovascular Treatment and predictor of mortality in Critical Limb Ischemia population after EVT

Angioplasty for Acute Stroke With Pediatric Moyamoya Syndrome

Moyamoya vasculopathy is a progressive, occlusive vasculopathy leading to ischemic and hemorrhagic strokes. No treatments are established to treat acute ischemic stroke with moyamoya vasculopathy. A 3-year-old girl with moyamoya syndrome developed acute left hemiplegia. Emergent angiography showed near-occlusion of the supraclinoid segment of the right internal carotid artery. Balloon angioplasty was performed within 6 hours of symptom onset, with significant improvement in the child's neurological symptoms. This is the youngest case of intracranial balloon angioplasty, and this article discusses the paucity of data regarding angioplasty and other forms of endovascular intervention in pediatric cerebrovascular disease and moyamoya vasculopathy. Further study is needed to determine the safety and efficacy of endovascular intervention in these diseases.

Endovascular management of vertebral artery dissecting aneurysms: review of 25 patients.

Management of Vertebral Artery (VA) dissections remains controversial. The clinical and angiographic variables of VA dissections were evaluated to demonstrate the safety and efficacy of endovascular intervention in treatment of VA dissecting aneurysms. 25 patients with 27 VAdissecting aneurysms were treated with endovascular intervention during the last 10 years.17 patients were admitted with subarachnoid hemorrhage. 23 aneurysms treated using destructive endovascular trapping, while reconstructive techniques were used in 3 aneurysms treated with stent-assisted coiling and one aneurysm treated with false lumen embolization. The right VA was involved in 14 patients, the left VA in 9 patients, while 2 patients had bilateral VA dissection. The pearl and string sign was the commonest angiographic sign in 12 aneurysms. Perioperative complications included; rebleeding in one patient, symptomatic brain stem infarction in two patients and silent cerebellar ischemic lesion in one patient. Afavorable outcome was evident more in patients with unruptured VA dissection (100%) versus (76.5%) in patients presented with SAH. The endovascular technique should be individualized according to the clinical status of the patient, angiographic variables, condition of the posterior circulation and the available supplies.

Clinical manifestation and endovascular treatment of cavernous dural arteriovenous fistula

Objective To explore the clinical symptoms, performance and efficacy of endovascular treatment of cavernous sinus dural arteriovenous fistula. Method 16 cases of cavernous dural arteriovenous fistula admitted in our department from January 2006 to May 2009 and the retrospective analysis of clinical data and symptoms, vascular intervention and curative effects were analyzed. Result There were 13 patients with congestive eyes (or the merger exophthalmos), one with exophthalmos, two with temporal noise, one with subarachnoid hemorrhage. Six patients were treated by NBCA embolization through arterial approach. Immediate embolization was achieved in 3 cases after fistula occlusion. There was residual fistula in 1 case but the symptoms disappeared after 2 months. And there was residual fistula in another 2 cases, but notable improvements in symptoms were observed. 8 cases were treated through a simple approach of vein thrombosis. 2 cases in which were treated by ONYX and coil embolization and complete fistula occlusion was observed. These 2 cases were associated with postoperative oculomotor nerve palsy and outreach, the symptoms were better after 1 month. 5 cases were treated through simple ONYX embolism. 1 case was performed through combined arterial and venous approach for embolization and complete fistula occlusion was achieved. 1 cases of a small fistula was performed by carotid artery compression and the fistula was observed to be smaller after 2 month. The postoperative complications of eyes were found in 3 patients: 1 ocular and oculomotor nerve palsy, 1 diplopia and outreach nerve palsy, 1 conjunctival hyperemia and eye pain. All the complications of eyes were all alleviated. Conclusions The clinical manifestations of cavernous sinus dural arteriovenous fistula are varied. Endovascular treatment is safe and effective. Through arterial embolization approach, the possibility rate of fistula occlusion is lower than that of the intravenous approach. But the incidence of postoperative complications of eyes of arterial approach is also lower. A higher rate of fistula occlusion is observed in intravenous approach, hut it should be paid attention to the prevention of eye complications. Key words: Arteriovenous fistula; Cavernous sinus; Postoperative complication

Endarterectomy versus angioplasty and stenting for prevention of ischemic stroke in people with severe stenosis of the internal carotid artery

Introduction: Carotid endarterectomy is useful for lowering the risk of ischemic stroke among both symptomatic and asymptomatic persons with moderate to severe stenosis of the extracranial segment of the internal carotid artery. With advances in technology in endovascular interventions and increased numbers of physicians with expertise, there has been considerable interest in the role of angioplasty and stenting in prevention of stroke among high-risk patients, including those with severe disease of the internal carotid artery. Procedural advances, such as the development of distal protective devices and stents, have led to expansion of the use of endovascular therapy as a stroke-preventive treatment. Already, angioplasty and stenting is recommended for treatment of patients with severe carotid artery disease secondary to radiation therapy, those with narrowing ipsilateral to a radical neck dissection, patients with recurrent stenosis following carotid endarterectomy, and those judged to be at high operative risk for carotid endarterectomy. However, the spectrum of patients who might benefit from angioplasty and stenting may be much broader. Angioplasty and stenting may be useful for treatment of a wide range of patients with either symptomatic or asymptomatic stenosis secondary to atherosclerosis. However, before angioplasty and stenting can be considered as an alternative to carotid endarterectomy, both the safety and potential efficacy of endovascular treatment must be established by clinical trials. Although additional trials are under way in North America, including the large Carotid Revascularization Endartectomy versus Stenting Trial (CREST) program, the results of two European trials have already been published. Aims: Both trials compared the safety and potential efficacy of carotid endarterectomy or carotid angioplasty and stenting for treatment of patients with severe symptomatic stenoses of the internal carotid artery. Both trials were testing the hypothesis that carotid angioplasty and stenting is not inferior to carotid endarterectomy.

Current Issues in Endovascular Surgical Neuroradiology

Endovascular surgical neuroradiology is a newly recognized specialty within the American Medical Association. Remarkable advances in the specialty with regard to stroke prevention and therapy as well as the treatment of ruptured and unruptured cerebral aneurysms have provided patients and their treating physicians with novel treatment options that complement existing therapy. The issues surrounding the efficacy of endovascular treatment of intracranial atherosclerosis and cerebral aneurysms will be reviewed using a case-based learning format.

Packing efficacy of hydrocoil embolic system: in vitro study using ruptured aneurysm model

After endovascular coil embolization of cerebral aneurysms, coil compaction and late aneurysm recanalization have been ever observed. The HydroCoil Embolic System (HES) was developed to improve the packing efficacy of endovascular treatment of cerebral aneurysms. In this study, we evaluate the packing efficacy of HES using a silicone model of ruptured cerebral aneurysm. This silicone model was connected to a pulsatile flow pump and embolized with the initial framing coils followed by hydro coils (n = 3) or bare platinum coils (n = 3). The coils used in the two groups were identical to each other in size and length. In the hydro coil group, continuous outflow from ruptured aneurysm ceased in two out of three cases. On the other hand, in the bare platinum coil group, outflow from the ruptured point slightly decreased but did not stop in all cases. The hydro coil could result in a higher initial occlusion rate of silicone model. In addition, expanded hydrogel possibly sealed the ruptured point directly. Changes in the size of aneurysms were not detected, from which the risk of over-expansion seemed extremely low. The hydro Coil is a safe and feasible device for improving the packing efficacy in endovascular coil embolization.

Safety and Efficacy of Endovascular Treatment of Carotid Artery Stenosis Compared With Carotid Endarterectomy: A Cochrane Systematic Review of the Randomized Evidence

Safety and Efficacy of Endovascular Treatment of Carotid Artery Stenosis Compared With Carotid Endarterectomy: A Cochrane Systematic Review of the Randomized Evidence

Interventional treatment of infantile hepatic hemangioendothelioma

Background/Purpose: Hemangioendothelioma is the most frequent liver tumor in infancy. Untreated symptomatic patients with heart failure have a high mortality rate. Symptomatic forms may request nonoperative treatment, because surgery is burdened with high risks in patients with heart failure. The authors report their experience with interventional coil occlusion of infantile hepatic hemangioendothelioma (IHE). Methods: Four patients (age range, 2 to 146 days; mean, 53 days) suffering from IHE associated with heart failure were treated by endovascular coil occlusion of arterial feeders. Catheter intervention was performed via an arterial (n = 2) or venous (n = 2) approach. Results: Signs of heart failure resolved within 2 to 8 days after occlusion in 3 patients. Tumor regression could be observed sonographically within 4 weeks postinterventionally. In 3 children, tumor size was reduced from a mean of 544 mL (65 to 1,350) to a mean of 4 mL (2 to 6); Mean systolic peak velocity in the hepatic artery was decreased from 170 cm/s (140 to 200) before occlusion to 45 cm/s (36 to 70) during follow-up. In the fourth patient, endovascular intervention could not control a rapidly progressing hemangioendotheliomatosis, and finally a liver transplantation had to be performed. Conclusions: Interventional occlusion of feeding arteries in symptomatic IHE is a safe and effective alternative to early open surgery. The efficacy of endovascular intervention in multifocal tumors seems questionable.