Cerebrospinal Fluid Homeostasis and Hydrodynamics: A Review of Facts and Theories.

BACKGROUND AND PURPOSE: According to the classical hypothesis, the cerebrospinal fluid (CSF) is actively secreted inside the brain's ventricular system, predominantly by the choroid plexuses, before flowing unidirectionally in a cranio-caudal orientation toward the arachnoid granulations (AGs), where it is reabsorbed into the dural venous sinuses. This concept has been accepted as a doctrine for more than 100 years and was subjected only to minor modifications. Its inability to provide an adequate explanation to questions arising from the everyday clinical practice, in addition to the ever growing pool of experimental data contradicting it, has led to the identification of its limitations. Literature includes an increasing number of studies suggesting a more complex mechanism than that previously described. This review article summarizes the proposed mechanisms of CSF regulation, referring to the key clinical and experimental developments supporting or defying them. METHODS: A non-systematical literature search of the major databases was performed for studies on the mechanisms of CSF homeostasis. Gray literature was additionally assessed employing a hand-search technique. No restrictions were imposed regarding the time, language, or type of publication. CONCLUSION: CSF secretion and absorption are expected to take place throughout the entire brain's capillaries network under the regulation of hydrostatic and osmotic gradients. The unidirectional flow is defied, highlighting the possibility of its complete absence. The importance of AGs is brought into question, potentiating the significance of the lymphatic system as the primary site of reabsorption. However, the definition of hydrocephalus and its treatment strategies remain strongly associated with the classical hypothesis.

A comparative study of color Doppler imaging and contrast-enhanced ultrasound for the detection of ulceration in patients with carotid atherosclerotic disease.

OBJECTIVES: To evaluate the diagnostic accuracy of color Doppler imaging (CDI) and contrast-enhanced ultrasound (CEUS) for diagnosing carotid ulceration, having multi-detector computed tomography angiography (MDCTA) as the reference method. METHODS: Patients with carotid disease referred for ultrasound (US), either due to the occurrence of neurovascular symptoms or for screening purposes, were included in this study if at least one plaque causing moderate (50-69%) or severe (70-99%) internal carotid artery stenosis was detected. Carotid US with CDI technique, CEUS, and MDCTA were performed in all patients, investigating the presence of ulceration. The agreement between modalities was evaluated using kappa statistics. RESULTS: The study population included 54 patients (median age 62 years, inter-quartile range 16.2) and 66 carotid arteries. The mean degree of stenosis was 68.5% (SD 12.2%) while 47.1% of plaques were symptomatic. MDCTA characterized 28.8% of plaques as smooth, 45.5% irregular, and 24.3% ulcerated. Flow reversal was detected with CDI in 65.5% of ulcerations, while swirling of the microbubbles and neovessels adjacent to the ulcer were detected with CEUS in 17.64%. The agreement for ulceration diagnosis was moderate between CDI and CEUS (kappa 0.473) and between CDI and MDCTA (kappa 0.473) and very good between CEUS and MDCTA (kappa 0.921). The sensitivity, specificity, and positive and negative predictive values of CDI for the diagnosis of ulceration were 41.2%, 97.95%, 87.5%, 82.8% respectively, while CEUS respective measures were 94.1%, 97.95%, 94.1%, and 97.95%. CONCLUSION: CEUS outperformed CDI in terms of agreement with MDCTA and diagnostic accuracy for the diagnosis of ulcerated carotid plaque. KEY POINTS: • Superficial ulceration is a significant feature of carotid plaque vulnerability. • Color Doppler imaging has the potential to demonstrate carotid plaque ulceration but is characterized by limited sensitivity and moderate agreement with the reference method of multi-detector computed tomography angiography. • Contrast-enhanced ultrasound outperforms color Doppler imaging in terms of sensitivity for the detection of carotid plaque ulceration and in agreement with the reference method of multi-detector computed tomography angiography.

Extracranial internal carotid artery occlusive dissection - multimodality presentation in a case series.

Background: Carotid dissection is a rare disease, mainly affecting young and middle-aged patients potentially ending up in stroke. Multimodality imaging plays an essential role, both in terms of prompt and accurate diagnosis and follow-up of this entity. Patients and methods: We herein present a case series of patients with internal carotid artery dissection and compare the various imaging findings of ultrasonography, multidetector computed tomography angiography and magnetic resonance angiography, with a purpose to illustrate the value of multimodality imaging in the diagnosis of carotid dissection. Results: Ultrasound represents the first-line imaging modality for the evaluation of a suspected carotid pathology. Digital subtraction angiography is considered the gold standard method for evaluation of carotid luminal abnormalities and is currently reserved for those patients selected for endovascular surgery. Nevertheless, the widespread availability of modern cross-sectional techniques such as multi-detector computed tomography angiography and magnetic resonance angiography has made angiography marginalised. Computed tomography and magnetic resonance angiography offered accurate delineation of vascular lumen and providing valuable information for the vascular wall composition. Conclusions: Careful interpretation of imaging findings on various imaging modalities can lead to early and accurate diagnosis of carotid dissection.

Multiple variations of the coeliac axis, hepatic and renal vasculature as incidental findings illustrated by MDCTA.

Vascular anatomical variations are not uncommon and may affect any organ's arterial or venous vasculature. The coexistence of variations in different organic systems is less commonly found, but of great clinical significance in a series of clinical conditions like organ transplantation and surgical preoperative planning. Multidetector computed tomography angiography (MDCTA) has emerged as a valuable alternative to the conventional angiography for accurate evaluation of vascular anatomy and pathology. Radiologists should be familiar with each organ's vascular variations and always report them to the clinician, even if they represent an incidental finding. This case report presents a 52-year-old female patient undergoing abdominal MDCTA for characterization of a renal lesion. This examination revealed the presence of three hilar arteries on the left kidney, a main renal vein in combination with an additional renal vein in both sides along with a replaced right hepatic artery originating from the superior mesenteric artery. Moreover, both inferior phrenic arteries were found originating from the coeliac axis. 3D volume rendering technique images were used in the evaluation of vascular anatomy as illustrated in this case report.

Treatment of infected thoracic aortic prosthetic grafts with the in situ preservation strategy: a review of its history, surgical technique, and results.

For cardiothoracic surgeons prosthetic graft infection still represents a difficult diagnostic and treatment problem to manage. An aggressive surgical strategy involving removal and in situ replacement of all the prosthetic material combined with extensive removal of the surrounding mediastinal tissue remains technically challenging in any case. Mortality and morbidity rates following such a major and risky surgical procedure are high due to the nature of the aggressive surgical approach and multi-organ failure typically caused by sepsis. However, removal of the infected prosthetic graft in patients who had an operation to reconstruct the ascending aorta and/or the aortic arch is not always possible or necessary for selected patients according to current alternative treatment options. Rather than following the traditional surgical concept of aggressive graft replacement nowadays a more conservative surgical approach with in situ preservation and coverage of the prosthetic graft by vascular tissue flaps can result in a good outcome. In this article, we review the relevant literature on this specific topic, particularly in terms of graft-sparing surgery for infected ascending/arch prosthetic grafts with special emphasis on staged treatment and the use of omentum transposition.

Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Acute Coronary Syndrome: A Modern Cinderella?

PURPOSE: Atherosclerotic cardiovascular disease remains a prominent global cause of mortality, with coronary artery disease representing its most prevalent manifestation. Recently, a novel class of antidiabetic medication, namely sodium-glucose cotransporter-2 (SGLT2) inhibitors, has been reported to have remarkable cardiorenal advantages for individuals with type 2 diabetes mellitus (DM), and they may reduce cardiorenal risk even in individuals without pre-existing DM. Currently, there is no evidence regarding the safety and efficacy of these drugs in acute coronary syndrome (ACS), regardless of diabetes status. This review aims to comprehensively present the available preclinical and clinical evidence regarding the potential role of SGLT2 inhibitors in the context of ACS, as adjuncts to standard-of-care treatment for this patient population, while also discussing potential short- and long-term cardiovascular benefits. METHODS: A literature search was performed through MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Scopus until February 26, 2024. Eligible were preclinical and clinical studies, comprising randomized controlled trials (RCTs), real-world studies, and meta-analyses. FINDINGS: Evidence from preclinical models indicates that the use of SGLT2 inhibitors is associated with a blunted ischemia-reperfusion injury and decreased myocardial infarct size, particularly after prior treatment. Although RCTs and real-world data hint at a potential benefit in acute ischemic settings, showing improvements in left ventricular systolic and diastolic function, decongestion, and various cardiometabolic parameters such as glycemia,body weight, and blood pressure, the recently published DAPA-MI (Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure) trial did not establish a clear advantage regarding surrogate cardiovascular end points of interest. SGLT2 inhibitors appear to provide a benefit in reducing contrast-induced acute kidney injury events in patients with ACS undergoing percutaneous coronary intervention. However, data on other safety concerns, such as treatment discontinuation because of hypotension, hypovolemia, or ketoacidosis, are currently limited. IMPLICATIONS: Despite the well-established cardiovascular benefits observed in the general population with type 2 DM and, more recently, in other patient groups irrespective of diabetes status, existing evidence does not support the use of SGLT2 inhibitors in the context of ACS. Definitive answers to this intriguing research question, which could potentially expand the therapeutic indications of this novel drug class, require large-scale, well-designed RCTs.

Sparing the Hippocampus in Prophylactic Cranial Irradiation Using Three Different Linear Accelerators: A Comparative Study.

Hippocampus protection, as an organ at risk in brain radiotherapy, might protect patients' quality of life. Prophylactic cranial irradiation (PCI) has been used traditionally in small cell lung cancer (SCLC) patients as it increases survival. This study aimed to discover the contributing parameters for a successful PCI with simultaneous protection of the hippocampus by using three different treatment machines. For this purpose, treatment plans were generated for 45 SCLC patients using three half-arcs in three linear accelerators (LINACs; Elekta Infinity, Synergy, and Axesse; Elekta Ltd, Stockholm, Sweden) with different radiation field sizes and multileaf collimator (MLC) leaf thickness characteristics. The prescribed dose was 25 Gy in 10 fractions. Thresholds for the hippocampus were calculated based on the Radiation Therapy Oncology Group 0933 dose constraints. The planning and treatment system templates were common to all three LINACs. Plan evaluation was based on the dosimetric target coverage by the 95% isodose, the maximum dose of the plan, the conformity index (CI), the degree of plan modulation (MOD), and the patient-specific quality assurance (QA) pass rate. The mean target coverage was highest for Infinity (97.3%), followed by Axesse (96.6%) and Synergy (95.5%). The mean maximum dose was higher for Synergy (27.5 Gy), followed by Infinity (27.0 Gy) and Axesse (26.9 Gy). Axesse plans had the highest CI (0.93), followed by Infinity (0.91) and Synergy (0.88). Plan MOD was lower for Synergy (2.88) compared with Infinity (3.07) and Axesse (3.69). Finally, patient-specific QA was successful in all Infinity plans, in all but one Synergy plan, and in 17/45 Axesse plans, as was expected from the field size in that treatment unit. Based on overall performance, the most favorable combination of target coverage, hippocampus sparing, and plan deliverability was obtained with the LINAC, which has the largest field opening and thinnest MLC leaves.

Bilateral secondary neurolymphomatosis of the internal auditory canal nerves: a case report.

BACKGROUND: Neurolymphomatosis describes the malignant lymphomatous infiltration of nerves. METHODS: We encountered a unique case of a 47-year-old patient with non-Hodgkin's lymphoma presenting with bilateral sensorineural hearing loss, vestibular dysfunction and bilateral facial nerve palsy. RESULTS: Magnetic resonance imaging demonstrated enhancement and thickening of internal auditory canal nerves bilaterally consistent with neurolymphomatosis. Patient was treated with combined intrathecal chemotherapy and total brain irradiation. CONCLUSIONS: One must always remain vigilant for metastatic disease in patients with sensorineural hearing loss and/or vestibular dysfunction and facial nerve palsy in the context of known malignancy.

Microanatomic Morphometric Characteristics of the Third Ventricle Floor.

Background: Endoscopic third ventriculostomy (ETV) is an effective treatment for hydrocephalus. The in-depth understanding of microanatomy is essential for accurate diagnosis, treatment and complications prevention. The aim of this study is to supplement the knowledge gap regarding the microanatomical metrics and correlations for which the literature includes only scarce mentions at best. Methods: This is a descriptive microanatomical study including 25 cadaver brains. Specimens from donors with neurological, psychiatric disorders or alcohol abuse were excluded. Surgical loops were used for harvesting. High-precision tools were employed to dissect and measure the anatomical landmarks under a surgical microscope. Each measurement was performed in three consecutive attempts and outliers were rejected. RStudio was used for statistical analysis. Distribution was evaluated employing the Shapiro-Wilk test. Normally distributed values were presented as mean and standard deviation, and others as median and interquartile range. Results: The age of the donors was 61.72 (±10.08) years. The distance from the anterior aspect of the foramen of Monro to the anterior margin of the mamillary body was 16.83 (±1.04) mm, and to the posterior margin was 16.76 (±1.9) mm. The distance from the anterior mamillary body margin to the infundibulum was 6.39 (±1.9) mm, to the optic recess was 8.25 (±1.84) mm, and to the apex of the vertebral artery was 5.05 (±1.62) mm. The distance from the anterior commissure to the brain aqueduct was 22.46 (±2.29) mm, and to the infundibulum was 13.93 (±2.54) mm. The mamillary body diameter was 4.91 (±0.34) mm in the anteroposterior and 4.21 (±0.48) mm in the cranio-caudal plane. The intraventricular segment was protruding by 1.63 (±0.46) mm. The diameter of the hypothalamus on the anterior margin of mamillary bodies was 1.37 (±0.75) mm, of the Liliequist membrane was 0.19 (±0.07) mm and of the lamina terminalis was 0.35 (±0.32) mm. Conclusion: The presented microanatomical measurements and correlations are expected to contribute to the improvement of ETV safety.

Cardiovascular magnetic resonance for the evaluation of patients with cardiovascular disease: An overview of current indications, limitations, and procedures.

Cardiovascular disease (CVD) is the most common cause of morbidity/mortality worldwide. Early diagnosis is the key to improve CVD prognosis, and cardiovascular imaging plays a crucial role in this direction. Echocardiography is the most commonly used imaging modality. However, the need for early diagnosis/treatment favors the development of modalities providing information about tissue characterization beyond echocardiography. In this context, the rapid evolution of cardiovascular magnetic resonance (CMR) led to the coexistence of cardiologists and radiologists in the CMR field. Our aim was to provide an overview of indications, sequences, and reporting of CMR findings in various CVDs. The indications/limitations of CMR as well as the pathophysiological significance of various sequences in adult/pediatric CVDs are presented and discussed in detail. The role of CMR indices in the evaluation of the most common clinical scenarios in cardiology and their impact on CVD diagnosis/prognosis were analyzed in detail. Additionally, the comparison of CMR versus other imaging modalities is also discussed. Finally, future research directions are presented. CMR can provide cardiac tissue characterization and biventricular/biatrial functional assessment in the same examination, allowing for early and accurate identification of important subclinical abnormalities, before clinically overt CVD takes place.

Diagnostic Puzzles and Cause-Targeted Treatment Strategies in Myocardial Infarction with Non-Obstructive Coronary Arteries: An Updated Review.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a distinct subtype of myocardial infarction (MI), occurring in about 8-10% of spontaneous MI cases referred for coronary angiography. Unlike MI with obstructive coronary artery disease, MINOCA's pathogenesis is more intricate and heterogeneous, involving mechanisms such as coronary thromboembolism, coronary vasospasm, microvascular dysfunction, dissection, or plaque rupture. Diagnosing MINOCA presents challenges and includes invasive and non-invasive strategies aiming to differentiate it from alternative diagnoses and confirm the criteria of elevated cardiac biomarkers, non-obstructive coronary arteries, and the absence of alternate explanations for the acute presentation. Tailored management strategies for MINOCA hinge on identifying the underlying cause of the infarction, necessitating systematic diagnostic approaches. Furthermore, determining the optimal post-MINOCA medication regimen remains uncertain. This review aims to comprehensively address the current state of knowledge, encompassing diagnostic and therapeutic approaches, in the context of MINOCA while also highlighting the evolving landscape and future directions for advancing our understanding and management of this intricate myocardial infarction subtype.

Relationship between Coronary Arterial Geometry and the Presence and Extend of Atherosclerotic Plaque Burden: A Review Discussing Methodology and Findings in the Era of Cardiac Computed Tomography Angiography.

Coronary artery disease (CAD) represents a modern pandemic associated with significant morbidity and mortality. The multi-faceted pathogenesis of this entity has long been investigated, highlighting the contribution of systemic factors such as hyperlipidemia and hypertension. Nevertheless, recent research has drawn attention to the importance of geometrical features of coronary vasculature on the complexity and vulnerability of coronary atherosclerosis. Various parameters have been investigated so far, including vessel-length, coronary artery volume index, cross-sectional area, curvature, and tortuosity, using primarily invasive coronary angiography (ICA) and recently non-invasive cardiac computed tomography angiography (CCTA). It is clear that there is correlation between geometrical parameters and both the haemodynamic alterations augmenting the atherosclerosis-prone environment and the extent of plaque burden. The purpose of this review is to discuss the currently available literature regarding this issue and propose a potential non-invasive imaging biomarker, the geometric risk score, which could be of importance to allow the early detection of individuals at increased risk of developing CAD.

Primary Sjögren's Syndrome Presenting with Rapidly Progressive Dementia: A Case Report.

BACKGROUND: Rapidly progressive dementias (RPDs) are dementias that progress subacutely over a time period of weeks to months. Primary Sjögren's syndrome (pSS) is an autoimmune disease that can affect any organ system and may present with a wide range of clinical features that may mimic a plethora of medical conditions and, in rare cases, may manifest as RPD. We describe a unique case of pSS, in which rapidly progressive dementia (RPD) was the first disease manifestation, and the patient's radiological and electroencephalogram findings were compatible with Creutzfeldt- Jakob disease (CJD). CASE PRESENTATION: Here, we report a 58-year-old woman who presented with cognitive impairment rapidly deteriorating over the last 6 months prior to admission. Brain MRI and EEG were indicative of CJD. However, CSF 14-3-3 and tau/phospho tau ratio were within normal limits and therefore alternative diagnoses were considered. Blood tests were significant for positive antinuclear antibodies, anti-ENA, and anti-SSA and a lip biopsy was consistent with pSS. The patient was started on intravenous steroids followed by oral prednisone taper, which prevented further deterioration. CONCLUSION: This rare case expands the spectrum of neurological manifestations in pSS and highlights the importance of considering pSS in the differential diagnosis of RPDs in order to avoid misdiagnosis and provide appropriate treatment in a timely fashion.

Prognostic impact of secondary prevention medical therapy following myocardial infarction with non-obstructive coronary arteries: a Bayesian and frequentist meta-analysis.

Aims: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a clinical entity with several causes and pathophysiologic mechanisms. Secondary prevention with medical therapy used in patients with obstructive coronary artery disease has unclear benefits in MINOCA patients. Methods and results: A literature search was conducted until 8 March 2022. Random-effect frequentist and hierarchical Bayesian meta-analyses were performed to assess the clinical impact of medical therapy [renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, dual antiplatelet therapy (DAPT), ß-blockers] in MINOCA patients. Outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). A total of 12 663 MINOCA patients among five observational studies were analysed. The mean follow-up ranged from 12 to 90 months across studies. In frequentist meta-analysis, statins and ß-blockers were associated with a lower risk of all-cause mortality [pooled adjusted hazard ratios (aHRs) 0.53 and 0.81, with 95% confidence intervals (CIs) (0.37-0.76) and (0.67-0.97), respectively]. Only RAAS inhibitors were associated with a lower risk of MACE [pooled aHR: 0.69, with 95% CI (0.53-0.90)]. Bayesian meta-analysis based on informative prior assumptions offered strong evidence only for the benefit of statins on decreasing the risk of all-cause death [Bayes factor (BF): 33.2] and moderate evidence for the benefit of RAAS inhibitors on decreasing the risk of MACE (BF: 9); assigning less informative prior distributions did not affect the results, yet it downgraded the level of evidence to anecdotal. Conclusion: In this meta-analysis, statins and RAAS inhibitors were consistently associated with a lower risk of all-cause mortality and MACE, respectively, in patients with MINOCA. Neutral prognostic evidence was demonstrated for ß-blockers and DAPT.

Role of cardiac CT in the diagnostic evaluation and risk stratification of patients with myocardial infarction and non-obstructive coronary arteries (MINOCA): rationale and design of the MINOCA-GR study.

INTRODUCTION: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 5%-15% of all patients with acute myocardial infarction. Cardiac MR (CMR) and optical coherence tomography have been used to identify the underlying pathophysiological mechanism in MINOCA. The role of cardiac CT angiography (CCTA) in patients with MINOCA, however, has not been well studied so far. CCTA can be used to assess atherosclerotic plaque volume, vulnerable plaque characteristics as well as pericoronary fat tissue attenuation, which has not been yet studied in MINOCA. METHODS AND ANALYSIS: MINOCA-GR is a prospective, multicentre, observational cohort study based on a national registry that will use CCTA in combination with CMR and invasive coronary angiography (ICA) to evaluate the extent and characteristics of coronary atherosclerosis and its correlation with pericoronary fat attenuation in patients with MINOCA. A total of 60 consecutive adult patients across 4 participating study sites are expected to be enrolled. Following ICA and CMR, patients will undergo CCTA during index hospitalisation. The primary endpoints are quantification of extent and severity of coronary atherosclerosis, description of high-risk plaque features and attenuation profiling of pericoronary fat tissue around all three major epicardial coronary arteries in relation to CMR. Follow-up CCTA for the evaluation of changes in pericoronary fat attenuation will also be performed. MINOCA-GR aims to be the first study to explore the role of CCTA in combination with CMR and ICA in the underlying pathophysiological mechanisms and assisting in diagnostic evaluation and prognosis of patients with MINOCA. ETHICS AND DISSEMINATION: The study protocol has been approved by the institutional review board/independent ethics committee at each site prior to study commencement. All patients will provide written informed consent. Results will be disseminated at national meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT4186676.

A case of pulmonary arteriovenous malformation in the setting of Rendu Osler Weber syndrome.

Rendu Osler Weber syndrome is a rare disorder, in which arteriovenous malformations are a hallmark feature. We describe the case of a 77-year-old female patient who presented with dyspnea, recurrent epistaxis, and signs of right ventricular heart failure, along with hypoxia and severe anemia. Several imaging modalities facilitated diagnostic workup. The computed tomography revealed an area of pulmonary arteriovenous malformation. Visceral involvement, along with clinical criteria and medical history, established the diagnosis of Rendu Osler Weber syndrome. The patient was scheduled for embolization of the PAVM soon after the diagnosis. Proper imaging, guided by clinical suspicion can be extremely helpful in diagnosing and treating this rare entity.

Bolus Intravenous Procainamide in Patients with Frequent Ventricular Ectopics during Cardiac Magnetic Resonance Scanning: A Way to Ensure High Quality Imaging.

Acquiring high-quality cardiac magnetic resonance (CMR) images in patients with frequent ventricular arrhythmias remains a challenge. We examined the safety and efficacy of procainamide when administered on the scanner table prior to CMR scanning to suppress ventricular ectopy and acquire high-quality images. Fifty consecutive patients (age 53.0 [42.0-58.0]; 52% female, left ventricular ejection fraction 55 ± 9%) were scanned in a 1.5 T scanner using a standard cardiac protocol. Procainamide was administered at intermittent intravenous bolus doses of 50 mg every minute until suppression of the ectopics or a maximum dose of 10 mg/kg. The average dose of procainamide was 567 ± 197 mg. Procainamide successfully suppressed premature ventricular contractions (PVCs) in 82% of patients, resulting in high-quality images. The baseline blood pressure (BP) was mildly reduced (mean change systolic BP -12 ± 9 mmHg; diastolic BP -4 ± 9 mmHg), while the baseline heart rate (HR) remained relatively unchanged (mean HR change -1 ± 6 bpm). None of the patients developed proarrhythmic changes. Bolus intravenous administration of procainamide prior to CMR scanning is a safe and effective alternative approach for suppressing PVCs and acquiring high-quality images in patients with frequent PVCs and normal or only mildly reduced systolic function.