Plaque components affect wall stress in stented human carotid artery: A numerical study

Carotid artery stenting presents challenges of in-stent restenosis and late thrombosis, which are caused primarily by alterations in the mechanical environment of the artery after stent implantation. The present study constructed patient-specific carotid arterial bifurcation models with lipid pools and calcified components based on magnetic resonance imaging. We numerically analyzed the effects of multicomponent plaques on the distributions of von Mises stresses (VMSs) in the patient-specific models after stenting. The results showed that when a stent was deployed, the large soft lipid pool in atherosclerotic plaques cushioned the host artery and reduced the stress within the arterial wall; however, this resulted in a sharp increase of VMS in the fibrous cap. When compared with the lipid pool, the presence of the calcified components led to slightly increased stresses on the luminal surface. However, when a calcification was located close to the luminal surface of the host artery and the stenosis, the local VMS was elevated. Overall, compared with calcified components, large lipid pools severely damaged the host artery after stenting. Furthermore, damage due to the calcified component may depend on location.

Relation between Carotid Artery Plaques Characteristics as a Predictor of Haemodynamics Changes after Carotid Artery Stenting

Objectives: To study relationship between carotid artery plaques characteristics and haemodynamic changes after carotid stenting. Patients and Methods: This observational prospective (pilot) study included 20 patients—who underwent CAS. The study was carried out in Ain shams university hospitals—Railway hospital (ERMED) and Suez insurance hospital from December 2018 to February 2020. Inclusion criteria, Symptomatic (defined as amaurosis fugax, TIA, Minor stroke or Major stroke) stenosis > 70%. Asymptomatic stenosis > 80% (accidentally discovered during pre-operative assessment for CABG and during full assessment for irrelevant stroke). Results: Regarding to plaque character for degree of stenosis, calcification and ulceration revealed significantly higher degree of stenosis in hemodynamic events group (P = 0.024). On the other hand, that there was no statistically significant difference between the two groups as regard calcification, ulceration and lesion location. Conclusion: The study revealed that HI is a common occurrence following CAS procedures and significantly higher degree of stenosis in hemodynamic events group. Plaque shape, ulcerations hardly affect haeodynamic instability after carotid stenting.

Contrast-enhanced ultrasound imaging of the vasa vasorum of carotid artery plaque

The vasa vasorum of carotid artery plaque is a novel marker of accurately evaluating the vulnerability of carotid artery plaque, which was associated with symptomatic cerebrovascular and cardiovascular disease. The presence of ultrasound contrast agents in carotid artery plaque represents the presence of the vasa vasorum in carotid artery plaque because the ultrasoundcontrast agents are strict intravascular tracers. Therefore, contrast-enhanced ultrasound(CEUS) is a novel and safe imaging modality for evaluating the vasa vasorum in carotid artery plaque. However, there are some issues that needs to be assessed to embody fully the clinical utility of the vasa vasorum in carotid artery plaque with CEUS.

Ultrasound assessment of carotid artery elasticity in patients with coronary heart disease and its correlation with plaque stability and platelet function

Objective:To study the ultrasound assessment of carotid artery elasticity in patients with coronary heart disease and its correlation with plaque stability and platelet function. Methods: Patients with stable angina pectoris, patients with unstable angina pectoris and healthy volunteers were selected and included in SAP group, UAP group and control group respectively. Carotid ultrasonography was conducted to determine single point pulse wave velocity (PWVβ);serum and peripheral blood samples were collected to determine plaque stability-related indexes and platelet function-related indexes.Results:Carotid artery PWVβlevel, serum ICTP, MMP1, MMP3, MMP7, CatK, CD62p and CD63 contents as well as peripheral blood PAR1 and LOX1 expression of SAP group and UAP group were significantly higher than those of control group, and carotid artery PWVβ level, serum ICTP, MMP1, MMP3, MMP7, CatK, CD62p and CD63 contents as well as peripheral blood PAR1 and LOX1 expression of UAP group were significantly higher than those of SAP group;peripheral blood PAR1 and LOX1 expression as well as serum CD62p, CD63, ICTP, MMP1, MMP3, MMP7, CatK, CD62p and CD63 contents of coronary heart disease patients with high PWVβ levels were significantly higher than those of coronary heart disease patients with low PWVβ levels. Conclusion:The carotid artery elasticity ultrasound parameter PWVβ has assessment value for the plaque stability and platelet function in patients with coronary heart disease angina pectoris.

Imaging characteristics and treatment strategies for carotid artery occlusion caused by skull base fracture:Three case reports

BACKGROUND Traumatic internal carotid artery(ICA)occlusion is a rare complication of skull base fractures,characterized by high mortality and disability rates,and poor prognosis.Therefore,timely discovery and correct management are crucial for saving the lives of such patients and improving their prognosis.This article retrospectively analyzed the imaging and clinical data of three patients,to explore the imaging characteristics and treatment strategies for carotid artery occlusion,combined with severe skull base fractures.CASE SUMMARY This case included three patients,all male,aged 21,63,and 16 years.They underwent plain film skull computed tomography(CT)examination at the onset of their illnesses,which revealed fractures at the bases of their skulls.Ultimately,these cases were definitively diagnosed through CT angiography(CTA)examinations.The first patient did not receive surgical treatment,only anticoagulation therapy,and recovered smoothly with no residual limb dysfunction(Case 1).The other two patients both developed intracranial hypertension and underwent decompressive craniectomy.One of these patients had high intracranial pressure and significant brain swelling postoperatively,leading the family to choose to take him home(Case 2).The other patient also underwent decompressive craniectomy and recovered well postoperatively with only mild limb motor dysfunction(Case 3).We retrieved literature from PubMed on skull base fractures causing ICA occlusion to determine the imaging characteristics and treatment strategies for this type of disease.CONCLUSION For patients with cranial trauma combined with skull base fractures,it is essential to complete a CTA examination as soon as possible,to screen for blunt cerebrovascular injury.

Low testosterone levels are inversely correlated with carotid artery plaque formation in elderly women

Objective To study the relationship between serum testosterone levels and the plaque formation of the carotid artery in a population-based cohort of independently living healthy women above 60 years of age. Methods Analysis of the healthy elders from a population-based cohort study in 9 communities of Beijing. Carotid intima-media thickness and atherosclerotic plaques were determined ultrasonographically. Serum testosterone levels were measured by immunoassay. The data were analyzed with ANOVA and logistic regression analysis. Results There was an inverse correlation between testosterone and plaque formation in old females(P<0.01), while no association was found in males. Female with testosterone levels in the lowest quartile(<0.49 nmol/L) had more risk of plaque formation(OR=3.805, P<0.01) after adjusted with age and other traditional factors of atherosclerosis. Conclusion Testosterone concentrations are negatively associated with carotid artery atherosclerosis in old women in Beijing, experimental and prospective studies are needed to determine the possible therapeutic role of testosterone in atherosclerosis.

Early diagnostic value of carotid artery ultrasound parameters combined with epicardial adipose layer thickness in coronary heart disease

BACKGROUND Coronary heart disease is associated with coronary atherosclerosis indicated by carotid intima-media thickness(CIMT)thickening and altered vascular elasticity.The epicardial adipose layer can secrete proinflammatory factors that promote the formation of coronary atherosclerosis.Thus,the epicardial fat layer thickness(EAT)may also predict coronary heart disease.AIM To determine the role of common carotid artery ultrasound parameters and EAT in the early diagnosis of coronary artery disease.METHODS Based on coronary angiography,patients with newly suspected coronary heart disease were divided into case(n=107)and control(n=41)groups.The carotid ultrasound parameters,including vascular stiffness(β),elastic coefficient(EP),pulse wave conduction velocity(PWV-β),CIMT,and EAT were compared between the case and control groups and among patients with different lesion numbers in the case group.Pearson correlation was used to evaluate the early diagnostic value of EAT,common carotid artery elasticity,and CIMT for coronary heart disease.RESULTS EP,β,PWV-β,CIMT,and EAT were significantly higher in the case group compared with the levels in the control group(all P<0.001).In the case group,lesions were detected in one vessel in 34 patients,two vessels in 38 patients,and three vessels in 35 patients.Within the case group,β,EP,PWV-β,CIMT,and EAT levels significantly increased with an increased number of lesions(all P<0.001).EAT positively correlated withβ,EP,PWV-β,and CIMT(all P<0.01).The area under the curve for diagnosing coronary heart disease using EAT combined with CIMT and carotid elasticity was 0.893,and the sensitivity and specificity were 0.890 and 0.837.CONCLUSION EAT correlated well with changes in carotid artery elasticity and CIMT in patients with coronary heart disease.The combination of EAT,carotid artery elasticity,and CIMT facilitates the early diagnosis of coronary heart disease.

Imaging characteristics and treatment strategies for carotid artery occlusion caused by skull base fracture

The internal carotid artery occlusion caused by head and neck trauma,also known as traumatic intracranial artery occlusion,is relatively rare clinically.Traumatic skull base fracture is a common complication of traumatic brain injury.Traumatic skull base fracture is one of the causes of traumatic internal carotid artery occlusion.If not detected early and treated in time,the prognosis of patients is poor.This editorial makes a relevant analysis of this disease.

Cerebral perfusion in patients with unilateral internal carotid artery occlusion by dual post-labeling delays arterial spin labeling imaging

BACKGROUND Global and regional cerebral blood flow(CBF)changes in patients with unilateral internal carotid artery occlusion(ICAO)are unclear when the dual post-labeling delays(PLD)arterial spin labeling(ASL)magnetic resonance imaging(MRI)technique is used.Manual delineation of regions of interest for CBF measurement is time-consuming and laborious.AIM To assess global and regional CBF changes in patients with unilateral ICAO with the ASL-MRI perfusion technique.METHODS Twenty hospitalized patients with ICAO and sex-and age-matched controls were included in the study.Regional CBF was measured by Dr.Brain's ASL software.The present study evaluated differences in global,middle cerebral artery(MCA)territory,anterior cerebral artery territory,and Alberta Stroke Program Early Computed Tomography Score(ASPECTS)regions(including the caudate nucleus,lentiform nucleus,insula ribbon,internal capsule,and M1-M6)and brain lobes(including frontal,parietal,temporal,and insular lobes)between ICAO patients and controls at PLD 1.5 s and PLD 2.5 s.RESULTS When comparing CBF between ICAO patients and controls,the global CBF in ICAO patients was lower at both PLD 1.5 s and PLD 2.5 s;the CBF on the occluded side was lower in 15 brain regions at PLD 1.5 s,and it was lower in 9 brain regions at PLD 2.5 s;the CBF in the contralateral hemisphere was lower in the caudate nucleus and internal capsule at PLD 1.5 s and in M6 at PLD 2.5 s.The global CBF in ICAO patients was lower at PLD 1.5 s than at PLD 2.5 s.The ipsilateral CBF at PLD 1.5 s was lower than that at PLD 2.5 s in 15 regions,whereas the contralateral CBF was lower at PLD 1.5 s than at PLD 2.5 s in 12 regions.The ipsilateral CBF was lower than the contralateral CBF in 15 regions at PLD 1.5 s,and in M6 at PLD 2.5 s.CONCLUSION Unilateral ICAO results in hypoperfusion in the global and MCA territories,especially in the ASPECTS area.Dual PLD settings prove more suitable for accurate CBF quantification in ICAO.

Massive Epistaxis Revealing a Post-Traumatic Aneurysm of the Internal Carotid Artery: A Clinical Case and Review of the Literature

Internal carotid artery (ICA) aneurysms are an unusual but serious cause of epistaxis. This epistaxis is massive and sometimes uncontrollable threatening the vital prognosis of patients. We report the case of a 16-year-old adolescent received in emergency with severe bilateral epistaxis, asthenia and grade-3 left exophthalmos. In his history, the subject had been the victim of an assault six months before consultation. He had received blows on the cephalic extremity with light but repeated epistaxis. The treatment consisted to blood products transfusion and local compression by sterile gazes. An ICA aneurysm in sphenoid sinus has been confirmed in a craniofacial CT scan coupled to vascular opacification. Although the ICA has a variable course in contact with the sphenoid sinus, massive epistaxis would be the consequence of a pronounced dehiscence of the ICA in the sphenoid sinus, particularly in a traumatic context. In front of this type of epistaxis in our context, general practitioners must be able to suspect a ruptured ICA aneurysm in the presence of exophthalmos and a notion of old or recent cranio-encephalic injury. Additionally, due to the high morbidity and mortality of this condition, a monitoring algorithm is necessary for patients with head trauma to facilitate early detection.

Ultrasound Combined with CTA in Diagnosis of Painless Aortic Dissection Combined with Carotid Artery Active Thrombosis: A Case Report

Background: Aortic dissection (AD) is a relatively rare but dreadful illness, often accompanied by severe, sharp (or tearing) back pain or anterior chest pain, as well as acute hemodynamic compromise. Painless dissection has also been reported in rare cases and might be misdiagnosed due to its atypical symptoms leading to catastrophic outcomes. Case presentation: The patient was admitted to the hospital due to right limb weakness with speech inability for more than 10 hours. In the routine cardiac ultrasound examination, the avulsion intimal echo was found in the initial segment of the descending aorta. The rupture range was about 11 mm, and the lumen was separated into real and false lumen. Further computed tomography angiography (CTA) examination confirmed the major arterial dissection (De Bakey Type I). Conclusion: We report a case of painless aortic dissection with active carotid artery thrombosis diagnosed by ultrasound and CTA, and to improve the understanding of painless aortic dissection by reviewing relevant domestic and foreign literature.

Choroidal infarction after internal carotid artery stenting

Dear Editor,We present a case of choroidal infarction along with retinal infarction after carotid artery stenting(CAS),which is a rare condition not reported in the literature.CAS has increasingly been accepted as the mainstay reconstruction method for carotid artery stenosis compared with carotid endarterectomy(CEA)due to no need for general anesthesia.

Ultrafast pulse wave velocity technique for evaluating changes of carotid artery elasticity in Hashimoto thyroiditis patients with euthyroidism

Objective To explore the value of ultrafast pulse wave velocity(UFPWV)technique for evaluating changes of carotid artery elasticity in Hashimoto thyroiditis(HT)patients with euthyroidism.Methods Conventional ultrasound and UFPWV for carotid artery were prospectively performed in 91 HT patients with euthyroidism(HT group)and 81 healthy subjects(control group).Clinical data and ultrasonic parameters were compared between groups.Spearman correlation analysis was performed to observe the correlations of carotid pulse wave velocity in end of systole(PWV-ES)with clinical indexes and other ultrasonic parameters in HT group.Multiple stepwise linear regression analysis was used to screen the independent impact factors of increased carotid PWV-ES in HT group.Results Significant differences of thyroid peroxidase antibody(TPOAb),thyroglobulin antibody(TgAb),total cholesterol(TC),low density lipoprotein and neutrophil-lymphocyte ratio(NLR)were found between groups(all P<0.05).The carotid PWV-ES in HT group was significantly higher than that in control group(P<0.05),while no significant difference of carotid artery intima-media thickness(CIMT)nor carotid pulse wave velocity in beginning of systole(PWV-BS)was found between groups(both P>0.05).Carotid PWV-ES in HT group was positively correlated with patients'age,body mass index,TPOAb,TC,triglyceride,NLR and CIMT(r=0.217—0.707,all P<0.05).Patients'age,TPOAb and NLR were all independent impact factors of increased carotid PWV-ES in HT patients with euthyroidism(all P<0.05).Conclusion UFPWV technique could be used to evaluate changes of carotid artery elasticity in HT patients with euthyroidism,among which PWV-ES was relatively sensitive.

Intravascular ultrasonography assisted carotid artery stenting for treatment of carotid stenosis: Two case reports

BACKGROUND Digital subtraction angiography(DSA),the gold standard of cerebrovascular disease diagnosis,is limited in its diagnostic ability to evaluate arterial diameter.Intravascular ultrasonography(IVUS)has advantages in assessing stenosis and plaque nature and improves the evaluation and effectiveness of carotid artery sten-ting(CAS).CASE SUMMARY Case 1:A 65-year-old man presented with a five-year history of bilateral lower limb weakness due to stroke.Physical examination showed decreased strength(5-/5)in both lower limbs.Carotid artery ultrasound,magnetic resonance angiography,and computed tomography angiography(CTA)showed a right proximal internal carotid artery(ICA)stenosis(70%-99%),acute cerebral infarction,and severe right ICA stenosis,respectively.We performed IVUS-assisted CAS to measure the stenosis and detected a low-risk plaque at the site of stenosis prior to stent implantation.Post-stent balloon dilatation was performed and postoperative IVUS demonstrated successful expansion and adherence.CTA six months postoperatively showed no significant increase in in-stent stenosis.Case 2:A 36-year-old man was admitted with a right common carotid artery(CCA)dissection detected by ultrasound.Physical examination showed no positive neurological signs.Carotid ultrasound and CTA showed lumen dilation in the proximal CCA with an intima-like structure and bulging in the proximal segment of the right CCA with strip-like low-density shadow(dissection or carotid web).IVUS-assisted DSA confirmed right CCA dissection.CAS was performed and intraoperative IVUS suggested a large residual false lumen.Post-stent balloon dilatation was performed reducing the false lumen.DSA three months postoperatively indicated good stent expansion with mild stenosis.CONCLUSION IVUS aids decision-making during CAS by accurately assessing carotid artery wall lesions and plaque nature preoperatively,dissection and stenosis morphology intraoperatively,and visualizing and confirming CAS postoperatively.

Metformin effect on internal carotid artery blood flow assessed by area under the curve of carotid artery Doppler in women with polycystic ovarian syndrome

BACKGROUND Insulin resistance(IR)was reported in most polycystic ovarian syndrome(PCOS)cases.Metformin,a biguanide drug,successfully reduced IR.Homeostatic Model Assessment for IR(HOMA-IR)and Doppler parameters assessed metformin's effectiveness.AIM To verify whether the area under the curve of the internal carotid artery(AUC-ICA)Doppler wave can be a useful marker for assessing IR among PCOS cases who presented with menstrual irregularity and were treated with metformin over 6 mo.METHODS An observational,cross-sectional study recruited 54 eligible PCOS women;the anthropometrics were as follows:age,body mass index(BMI),menstrual cycle days,biochemical serum cholesterol,low and high-density lipoprotein,sex hormone-binding globulin,fasting blood glucose,and HOMA-IR,hormonal testosterone,luteinizing hormone over follicle-stimulating hormone ratio,and ultrasonic pulsatility index(PI)and resistance index(RI),carotid artery intima-media thickness(CIMT)and(AUC-ICA)parameters were initially recorded and repeated 3 mo and 6 mo later with metformin tab 500 mg;three times/day for 6 mo.In addition,AUC-ICA was assessed by taking repeated systolic and diastolic wave height measurements.RESULTS Metformin caused a progressive reduction in BMI,menstrual cycle days,biochemical hormonal,and Doppler parameters(CIMT,PI,RI,and AUC-ICA).AUC-ICA correlated strongly to all PCOS parameters.AUC-ICA correlated inversely with treatment time(r=-0.98,P<0.001)and positively with HOMA-IR(r=0.98,P<0.0001).Via the best subset regression model,the AUC-ICA had the highest predictive value for HOMA-IR.CONCLUSION AUC-ICA preceded PI,RI,and CIMT with a strong,meaningful correlation to all PCOS parameters,making it a reliable marker for the assessment of IR,especially during metformin therapy.Further studies are recommended to promote the application in practice.

Idiopathic steno-occlusive disease with bilateral internal carotid artery occlusion:A Case Report

BACKGROUND Moyamoya disease(MMD)is a rare cause of acute stroke and transient ischemic attacks in children.We described clinical,diagnostic features and follow-ups of a young child with acute stroke.CASE SUMMARY We report a 4-year-old girl with left hemiparesis after an acute ischemic stroke.Her history was also significant for repeated left or right focal motor seizures,generalized tonic-clonic convulsions and transient ischemic attacks.Her magnetic resonance imaging and computed tomography(CT)of the brain and magnetic resonance angiography,CT angiography and venography on the cerebral vessels revealed evidence of bilateral fronto-parietal ischemic infarctions,occlusion of the right and left internal carotid arteries started at its bifurcation and non-visualization of right and left anterior and middle cerebral arteries.There was evidence of progression in angiography manifested as development of collaterals from the basal perforating vessels,increase in the extent of large intracranial arterial stenosis/occlusion and extensive collateral circulation with predominance from the posterior circulation.Physical and neurological evaluation and comprehensive laboratory investigations excluded an obvious comorbid disease or risk factor for the child’s condition.The diagnosis of MMD was highly suggested as a cause of the child’s steno-occlusive condition.She was treated symptomatically with levetiracetam,an antiepileptic medication.Aspirin was prescribed for secondary prevention.Her clinical manifestations were improved during the three years of follow-up.Revascularization surgery was postponed.CONCLUSION Up to our knowledge,this is the first report for MMD in a child in our country.The clinical improvement and the stabilization of the child’s condition over the 3 years of follow-up could be attributed to the rapid and extensive recruitment of collaterals and absence of risk factors or comorbidities.Revascularization surgery is highly recommended.

Endovascular Therapy of Internal Carotid Artery Tandem Occlusions and Literature Review

Acute large vessel occlusion is a common cause of acute ischemic stroke (AIS), with high rates of disability and lethality. The incidence of tandem occlusion of the internal carotid artery accounts for about 20% of patients with large vessel occlusion of the anterior circulation in acute ischemic stroke. The low rate of recanalization by intravenous thrombolysis in AIS due to internal carotid artery tandem occlusion, the poor establishment of collateral circulation within a short time, and the complex pathogenesis often suggest a poor prognosis for patients. Mechanical thrombectomy (MT) is beneficial for the opening of intracranial large vessel occlusion with internal carotid artery tandem occlusion, there are many problems regarding the emergency management of carotid artery occlusion or stenosis after mechanical thrombectomy, and there are currently no standardized treatment recommendations;The sequential approach to the management of carotid tandem occlusion, the timing of carotid stenting, and the use of antiplatelet agents remain controversial. The current state of research on carotid tandem occlusion is analyzed in the literature to promote clinical understanding of endovascular treatment for patients with acute ischemic stroke due to carotid tandem occlusion.

Initial clinical experience with Xpert-Pro peripheral self-expanding stent system for internal carotid artery dissection:Two case reports

Background:The standard treatment for internal carotid artery(ICA)dissection is obscure.Current therapeutic strategies include the use of antiplatelet drugs,anticoagulant drugs,intravenous thrombolysis,and endovascular treatment.Endovascular treatment is important in acute internal carotid artery dissection.This study reports two acute internal carotid artery dissection cases that were treated successfully using the Xpert-Pro peripheral selfexpanding stent system.Case summary:The first case was of a 38-year-old male patient with transient speechlessness and paralysis of the right limb in July 2021.Cervical computed tomographic angiography(CTA)showed ICA occlusion on the left side.Digital subtraction angiography(DSA)showed severe stenosis of the C1 segment of the left internal carotid artery with intermural hematoma.The patient subsequently underwent Xpert-Pro peripheral self-expanding stent implantation,and his condition stabilized.The second case was of a 56-year-old male patient with speechlessness and paralysis of the right limb.Cervical CTA showed a dissected left ICA,and DSA showed an occluded left ICA and middle cerebral artery.The patient subsequently underwent stent implantation,and his condition stabilized.

Efficacy of Willis covered stent of intracranial pseudoaneurysms in the internal carotid artery: A systematic review and meta-analysis

Objective:To evaluate the efficacy of a novel coated stent in the treatment of intracranial pseudoaneurysm.Methods:MEDLINE,EMBASE,and PubMed databases were searched for literature published between 1990 and April 2022 according to PRISMA guidelines.All studies with≥10 patients reporting successful implantation of Willis covered stent,therapeutic effect,complications,and postoperative follow-up were included.The combined incidence and corresponding 95%confidence intervals were assessed using a generalized linear mixed method and random effects model.Results:Five studies(116 patients with pseudoaneurysms)were included.The experimental groups in the selected studies showed a combined technical success rate of 81.03%(OR=18.31,95%CI=9.39-35.69,I^(2)=79%,P<0.001).Clinical follow-up showed that the complete cure rate was as high as 94.4%after the follow-up(OR=106.81,95%CI=39.08-291.88,I^(2)=0%,P=0.71).Conclusions:Willis covered stent is feasible,safe,and effective in the treatment of intracranial pseudoaneurysm.

Research Progress in Surgical Management of Head and Neck Tumors Involving the Carotid Artery

The surgeons adopt the comprehensive treatment method basing on surgery When head and neck tumors involve the carotid artery. At present, there are four surgical treatments, namely, dissection of carotid artery tumor, resection of carotid artery, revascularization after carotid resection, endoarterial implantation of covered stent combined with surgical resection. However, there is currently no consensus on the standard surgical approach to choose. This paper describes the four surgical methods, which are expected to be helpful for head and neck surgeons to choose the surgical methods for head and neck tumors involving the carotid artery.