Transvenous embolization of cerebrospinal fluid-venous fistulas: Independent validation and feasibility of upper-extremity approach and using dual-microcatheter and balloon pressure cooker technique.

BACKGROUND: Transvenous embolization is emerging as a promising treatment for cerebrospinal fluid-venous fistulas (CVF) associated with spontaneous intracranial hypotension (SIH). OBJECTIVE: To perform an independent validation of the efficacy and safety of the procedure and describe the procedural techniques used at our institution. METHODS: A retrospective review was performed including consecutive patients with SIH who had undergone CVF embolization with 3-month clinical and imaging follow-up. Clinical evaluation included the Patient Global Impression of Change (PGIC) Scale and six-item Headache Impact Test (HIT-6). Bern SIH score was used for imaging evaluation on brain MRI. Post-treatment changes in scores were assessed by Wilcoxon signed rank test. Procedural technical details, including use of upper-extremity access and dual-microcatheter pressure cooker technique, were recorded. RESULTS: 18 patients (13 female, median age 60 years) were included. 17 (94%) procedures were performed with upper-extremity access and 12 (67%) using dual-microcatheter pressure cooker technique. After embolization, 16 (89%) patients reported much or very much improved at follow-up PGIC; median (IQR) HIT-6 score improved from 68 (62-72) to 36 (36-38) and Bern SIH score improved from 8 (6-8) to 3 (1.5-3.5), p values <0.001. Side effects were transient embolization site back pain in 15 (83%) and rebound intracranial hypertension requiring medical management in 9 (50%) patients. HIT-6 and Bern SIH score changes were similar between conventional and pressure cooker techniques (p values >0.05). CONCLUSION: Transvenous embolization is independently validated as a highly effective and safe treatment for CVF and is feasible using upper-extremity venous access. Dual-microcatheter and balloon/coil pressure cooker techniques may be used to optimize distribution of embolic material and potentially, treatment efficacy.

Dual microcatheter and coil/balloon pressure cooker technique for transvenous embolization of cerebrospinal fluid-venous fistulas.

Cerebrospinal fluid-venous fistula is increasingly recognized as a cause of spontaneous intracranial hypotension.1 Transvenous embolization is emerging as an efficacious minimally invasive treatment.2-4 The procedure aims to embolize paraspinal and foraminal veins draining the fistula; however, complete embolization may be challenging as numerous small venous tributaries at the foraminal venous plexus, including dorsal muscular branches, may serve as additional routes of cerebrospinal fluid egress.5 To ensure curative embolization, we adopted a dual microcatheter pressure cooker technique, previously used for treatment of brain arteriovenous malformations.6 This allows improved control of embolic material reflux and greater chance of complete embolization of the site of the fistula and all potential venous tributaries. Video 1 demonstrates this technique employed in a typical case using Onyx (Medtronic, Minnesota, USA) to embolize a cerebrospinal fluid-venous fistula at the left L1 neural foramen. neurintsurg;15/6/614/V1F1V1Video 1Technical video demonstrating dual-microcatheter and coil/balloon pressure cooker technique.

Lateral Decubitus Dynamic CT Myelography with Real-Time Bolus Tracking (dCTM-BT) for Evaluation of CSF-Venous Fistulas: Diagnostic Yield Stratified by Brain Imaging Findings.

BACKGROUND AND PURPOSE: CSF-venous fistulas (CVFs) associated with spontaneous intracranial hypotension (SIH) may have a transient appearance, relative to contrast arrival, which may influence the diagnostic performance of lateral decubitus CT myelography (CTM). We developed a dynamic CTM protocol using real-time bolus-tracking (dCTM-BT) to improve the temporal resolution and standardize the timing of CTM acquisitions post-intrathecal contrast administration. The purpose of our study was to evaluate the feasibility of the dCTM-BT technique and evaluate its diagnostic yield for CVF detection, stratified by brain MRI SIH findings. MATERIALS AND METHODS: Patients with suspected SIH without extradural fluid collection on spine MRI who underwent dCTM-BT were retrospectively reviewed. CT bolus monitoring was performed at the upper thoracic level. Following the visualization of dense intrathecal contrast, at least 3 CTM acquisitions of the spine were obtained and reviewed by 2 neuroradiologists. The Bern SIH score was calculated on the brain MRI. The diagnostic yield for CVF detection was evaluated, stratified by Bern score categories and a receiver operating characteristic (ROC) analysis. RESULTS: Out of 48 patients, 23 (48%) had a CVF on dCTM-BT, located at T1-5 (n = 4), T6-12 (n = 18), L1 (n = 1), with 70% on the right. CVF was identified in 22/22 (100%) of patients who had a high Bern score, 1/7 (14%) of those who had an intermediate score, and 0/19 (0%) of those who had a low score. The area under the ROC curve was 0.99 (95% CI, 0.98-1.00). The optimal cutoff was a Bern score of ≥5 (96% sensitivity, 100% specificity). CONCLUSIONS: dCTM-BT is feasible and has excellent diagnostic performance for CVF identification/localization. The Bern score is strongly associated with CVF detection and may help inform who will benefit from dCTM-BT.

Sex differences in the association between diabetes and hypertension and the risk of stroke: cohort of the Tehran Lipid and Glucose Study.

BACKGROUND: We assessed the sex differences in the association between blood pressure categories and glucose intolerance status with overall and ischemic stroke among Iranian adults. METHODS: This prospective study was conducted on 5349 individuals (2446 men) aged ≥ 40 years. Cox models were used to estimate adjusted hazard ratios (HRs) and men-to-women ratios of HRs (RHRs) of overall and ischemic stroke for systolic (SBP) and diastolic (DBP) blood pressure, pre-hypertension, hypertension, fasting plasma glucose (FPG), pre-diabetes and type 2 diabetes (T2D). RESULTS: Each 0.55 mmol/L increase in FPG was associated with a higher HR of overall stroke in men than women [RHRs 1.05 (1.01-1.09)]. The associations between each 10 mmHg increase in DBP and stroke events were stronger in men than women, with RHRs of 1.20 (1.00-1.45) and 1.29 (1.04-1.60) for overall and ischemic stroke, respectively. Hypertension was associated with a higher HR of overall [RHRs: 2.41 (1.21-4.8)] and ischemic stroke [2.37 (1.12-5.01)] in men than women. We also found that T2D was associated with higher risks of overall and ischemic stroke in men than women: the RHRs were 2.16 (1.24-3.75) and 1.93 (1.05-3.55) for overall and ischemic stroke, respectively. CONCLUSION: Hypertension and T2D induced higher risk of overall and ischemic stroke in men than women among Iranian population.

Diabetes, Hypertension, and Incidence of Chronic Kidney Disease: Is There any Multiplicative or Additive Interaction?

BACKGROUND: The burden of chronic kidney disease (CKD) is on the rise worldwide; diabetes and hypertension are mentioned as the main contributors. OBJECTIVES: The current study aimed to investigate the multiplicative and additive interaction of diabetes and hypertension in the incidence of CKD. METHODS: In this population-based cohort study, 7342 subjects aged 20 years or above (46.8% male) were divided into four groups: no diabetes and hypertension; diabetes and no hypertension; hypertension and no diabetes; and both diabetes and hypertension. The multivariable Cox regression was used to determine the effect of diabetes, hypertension, and their multiplicative interaction on CKD. The following indices were used to determine the additive interaction of diabetes and hypertension: the relative excess risk of interaction, the attributable proportion due to interaction, and the synergism index. RESULTS: Diabetes and hypertension had no significant multiplicative interaction in men (hazard ratio of 0.93, P value: 0.764) and women (hazard ratio of 0.79, P value: 0.198); furthermore, no additive interaction was found in men (relative excess risk due to interaction of 0.79, P value: 0.199; attributable proportion due to interaction of 0.22, P value: 0.130; synergy index of 1.44, P value: 0.183) and women (relative excess risk due to interaction of -0.26, P value: 0.233, attributable proportion due to interaction of -0.21, P value: 0.266; synergy index of 0.48, P value: 0.254). CONCLUSIONS: This study demonstrated no synergic effect between diabetes and hypertension on the incidence of CKD.

Sex-specific prevalence of coronary heart disease among Tehranian adult population across different glycemic status: Tehran lipid and glucose study, 2008-2011.

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of death. Alarmingly Iranian populations had a high rank of CHD worldwide. The current study aimed to assess the prevalence of CHD across different glycemic categories. METHODS: This study was conducted on 7718 Tehranian participants (Men = 3427) aged ≥30 years from 2008 to 2011. They were categorized based on glycemic status. The prevalence of CHD was calculated in each group separately. CHD was defined as hospital records adjudicated by an outcome committee. The association of different glycemic categories with CHD was calculated using multivariate logistic regression, compared with normal fasting glucose /normal glucose tolerance (NFG/NGT) group as reference. RESULTS: The age-standardized prevalence of isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT), both impaired fasting glucose and impaired glucose tolerance (IFG/IGT), newly diagnosed diabetes mellitus (NDM), and known diabetes mellitus (KDM) were 14.30% [95% confidence interval (CI): 13.50-15.09], 4.81% [4.32-5.29], 5.19% [4.71-5.67], 5.79% [5.29-6.28] and 7.72% [7.17-8.27], respectively. Among a total of 750 individuals diagnosed as cases of CHD (398 in men), 117 (15.6%), 453 (60.4%), and 317 (42.3%) individuals had a history of myocardial infarction (MI), cardiac procedure, and unstable angina, respectively. The age-standardized prevalence of CHD for the Tehranian population was 7.71% [7.18-8.24] in the total population, 8.62 [7.81-9.44] in men and 7.19 [6.46-7.93] in women. Moreover, among diabetic participants, the age-standardized prevalence of CHD was 13.10 [9.83-16.38] in men and 10.67 [8.90-12.44] in women, significantly higher than corresponding values for NFG/NGT and prediabetic groups. Across six levels of glycemic status, CHD was associated with IFG/IGT [odds ratio (OR) and 95% CI: 1.38 (1.01-1.89)], NDM [1.83 (1.40-2.41)], and KDM [2.83 (2.26-3.55)] groups, in the age- and sex-adjusted model. Furthermore, in the full-adjusted model, only NDM and KDM status remained to be associated with the presence of CHD by ORs of 1.40 (1.06-1.86) for NDM and 1.91 (1.51-2.43) for KDM. CONCLUSION: The high prevalence of CHD, especially among diabetic populations, necessitates the urgent implementation of behavioral interventions in the Tehranian population, according to evidence-based guidelines for the clinical management of diabetic patients.

Endogenous testosterone does not improve prediction of incident cardiovascular disease in a community-based cohort of adult men: results from the Tehran Lipid and Glucose Study.

Introduction: To explore the predictive value of testosterone added to the Framingham Risk Score (FRS) for cardiovascular disease (CVD).Methods: Among 816 men, 30-70 years/old, without prevalent CVD, from a community-based cohort (Tehran Lipid and Glucose Study), we assessed the predictive value of testosterone with incident CVD, using three multivariate Cox proportional-hazards models. Model I: FRS variables; model II: Model I plus total testosterone; model III: Model II plus Systolic blood pressure (SBP) * total testosterone (the best fit interaction-term between testosterone and FRS variables). Discriminations and goodness-of-fit were assessed by the C-statistic and the approach of Grønnesby, respectively. p Value <.05 was significant.Results: During 12 years of follow-up, 121 CVD events occurred. In all models, age, treated SBP, smoking, and diabetes were associated with increased CVD (p values <.05). Neither testosterone (models II and III), nor SBP * testosterone (model III) were associated with CVD (p values >.05). The C-statistics for models I, II, and III were 0.819, 0.820, and 0.821, respectively, indicating no significant improvement in the discrimination power. The models' goodness-of-fit did not improve compared with the FRS.Conclusion: Testosterone could not add to the predictive value of FRS for CVD in men, either directly, or through interactions with FRS variables.

Sex-specific initiation rates of tobacco smoking and its determinants among adults from a Middle Eastern population: a cohort study.

OBJECTIVES: To assess the initiation rate and determinants of tobacco smoking among adults. METHODS: In the Tehran Lipid and Glucose Study, a population-based cohort from Iran, 6101 participants ≥ 18 years old who had never smoked tobacco at baseline (phase II: 2002-2006) were followed until phase VI (2015-2018). Sex-specific initiation rates per 1000 person-years for self-reported tobacco smoking and hazard ratios (HR) for its potential determinants (using Cox proportional hazards models) were calculated. RESULTS: The age- and sex-adjusted smoking initiation rate was 13.77 [95% confidence interval (CI) 12.59-14.94] per 1000 person-years, of which 78% was attributed to water pipe use. Initiation rate was remarkably higher among men [19.1 (16.9-21.2)] than women [8.3 (7.4-9.2)] and declined in older age-groups. Among both genders, being married was protective [men: HR 0.67 (CI 95% 0.48-0.92); women: 0.58 (0.45-0.74)], while intermediate-level education (compared with high level) [men: 1.61 (1.14-2.26); women: 1.33 (0.95-1.84, p value = 0.092)] and passive smoking [men: 1.76 (1.36-2.28); women: 1.82 (1.42-2.33)] increased the risk. Educational intervention decreased the risk among women [0.74 (0.58-0.94)]. CONCLUSIONS: The majority of adult smoking initiators started smoking with water pipe. The initiation rate was remarkably higher in men and younger age-groups. Passive smoking, being single and lower education were risk factors. Educational intervention was protective among women.

Impaired fasting glucose prevalence surge among Iranian adolescents in a decade: The Tehran Lipid and Glucose Study.

PURPOSE: Impaired fasting glucose (IFG) is associated with incident diabetes, cardiovascular risk, and markers of atherosclerosis in early adulthood. We aimed to explore the 10-year change in IFG prevalence among adolescent participants of the Tehran Lipid and Glucose Study, a population-based study from Iran. METHODS: For our study, we used data on fasting plasma glucose (FPG), anthropometric, and demographic information of 11 to 19-year-old adolescents in study periods I (1999-2005; 1415 boys, 1583 girls) and II (2011-2014; 477 boys, 469 girls). Sex-adjusted and sex-stratified multivariable logistic regression models were used to assess the relationship of the study period (reference: study period I) with IFG. RESULTS: The prevalence of IFG, general obesity, and central obesity increased from 7%, 13.3%, and 18.8% in study period I to 16.6%, 24%, and 37.4% in study period II; while a favorable trend was seen for blood pressure, triglycerides, and high-density lipoprotein cholesterol. In the fully adjusted model, being older (age group 15-19 vs 11-14 years) and female sex were associated with lower risk. Being overweight and obese increased the risk by risk ratios (confidence interval) of 1.57 (1.17-2.11) and 1.63 (1.15-2.30), respectively. Central adiposity did not remain as an independent risk factor. Nevertheless, study period persisted as a significant factor despite all adjustments [2.20 (1.81-2.68)]. Results in the sex-stratified models were generally the same. CONCLUSION: Our results demonstrated that the over 2-fold rise in IFG prevalence among adolescents was not solely dependent on general and central obesity.

Metabolic health in the Middle East and north Africa.

The Middle East and north Africa are home to different populations with widely varying cultures, histories, and socioeconomic settings. Hence, their health status, health management, and access to appropriate health care differ accordingly. In this Review, we examine data on the historical and prospective status of metabolic diseases in this region including obesity, diabetes, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. Women in the Middle East and north Africa have the highest risk of metabolic diseases of all women globally, whereas men rank second of all men in this respect. Metabolic risk factors are responsible for more than 300 deaths per 100 000 individuals in this region, compared with a global mean of fewer than 250. Physical inactivity, especially in women, and an unhealthy diet (ie, low consumption of whole grains, nuts, and seafoods) stand out. More than one in every three women are obese in most countries of the region. Prevention programmes have not fully been achieved in most of these countries and the projected future is not optimistic. Comprehensive surveillance and monitoring of metabolic diseases, robust multisectoral systems that support primordial and primary preventions, continuous education of health-care providers, as well as collaboration between countries for joint projects in this region are urgently needed to overcome the paucity of data and to improve the metabolic health status of inhabitants in the Middle East and north Africa.

Sex-specific clinical outcomes of impaired glucose status: A long follow-up from the Tehran Lipid and Glucose Study.

AIMS: To investigate the sex-specific associations of prediabetes with major clinical outcomes including incident type 2 diabetes, chronic kidney disease, hypertension, coronary heart disease, stroke and all-cause mortality. METHODS: Among 8498 Iranian adults from the Tehran Lipid and Glucose Study, aged ≥30 years and without diagnosed type 2 diabetes, gender-interactions were assessed for each outcome, followed by sex-separated multivariate-adjusted Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals (CIs) of different prediabetes categories, including impaired fasting glucose (IFG), defined by the American Diabetes Association (ADA) and World Health Organization (WHO), as fasting plasma glucose of 5.6-6.9 mmol/L and 6.1-6.9 mmol/L, respectively, and impaired glucose tolerance, defined as 2-h post challenge plasma glucose of 7.8-11 mmol/L. RESULTS: Sex-specific associations existed for men between IFG-ADA and chronic kidney disease (hazard ratio: 1.28, 95% CI 0.99-1.65; pinteraction = 0.008) and between IFG-WHO and stroke (hazard ratio: 2.15, 95% CI 1.08-4.27; pinteraction = 0.21); and for women between IFG-ADA and hypertension (hazard ratio: 1.24, 95% CI 1.04-1.48; pinteraction = 0.06) and between impaired glucose tolerance and coronary heart disease (hazard ratio: 1.57, 95% CI 1.14-2.16; pinteraction = 0.05). Among both genders, all prediabetes definitions were associated with type 2 diabetes but none with mortality. CONCLUSIONS: The hazards of prediabetes definitions may differ between genders depending on the outcome of interest. IFG-WHO among men and impaired glucose tolerance among women are particularly important because of their association with incident stroke and coronary heart disease, respectively. Considering these sex differences could improve personalized management of prediabetes.

Tobacco Smoking: Findings from 20 Years of the Tehran Lipid and Glucose Study.

CONTEXT: Smoking is a global public health priority and accurate data of the local population is essential to improve the health policies against its use. Hence, this study aimed to summarize the important findings available on the prevalence of smoking and its association with non-communicable diseases, documented by one of the largest prospective community-based studies of Iran. EVIDENCE ACQUISITION: All articles derived from the Tehran Lipid and Glucose Study (TLGS) in the last two decades, from the earliest publications until 30 January 2018 were reviewed for their findings on tobacco smoking. RESULTS: The prevalence of smoking in non-diabetic adults ≥ 20 years increased between baseline (phase I, 1999 - 2001) and follow-up (phase V, 2008 - 2011) from 25.5% to 35.4% among men and from 3.4% to 6.8% among women. In TLGS adolescents (10 - 18 years) water pipe use increased between 2003 and 2005 from 35.5% to 40.9% among boys and from 19.7% to 26.1% among girls. Regarding health hazards, smoking in men was associated with increased risk of combined impaired fasting glucose/impaired glucose tolerance [hazard ratio (HR) 1.69; confidence interval (CI) 95% 1.15 - 2.48] and hypertension (HR 1.26; CI 95% 0.98 - 1.63). Moreover, men, even smoking less than 10 cigarettes per day, were at increased risk for cardiovascular diseases by HR 2.12 (CI 95% 1.14 - 3.95). For women, the risk of chronic kidney disease dramatically increased 5.74-fold (CI 95% 2.71 - 12.15) among smokers. In the whole population, smoking contributed to 7.7% of all-cause mortality with HR 1.75 (CI 95% 1.38 - 2.22). Other health aspects of tobacco smoke, including its impact on metabolic status, thyroid function, female reproductive system and life style have also been reviewed. CONCLUSION: Considering hazards of smoking, there is the urgency for more effective preventive measures in Iran; emphasizing the need for further local studies on the hazards of smoking with special attention to women and adolescents and the independent hazards of water pipe use.

The association between changes in blood pressure components and incident cardiovascular diseases.

PURPOSE: To determine the association of changes in blood pressure (BP) components between baseline examination (1999-2001) and a second visit (2002-2005) with incident cardiovascular diseases (CVD). METHODS: In 3569 (2048 female) Iranian subjects ≥30 y, systolic BP, diastolic BP, mean arterial pressure (MAP) and pulse pressure (PP) were evaluated in two consecutive visits. Subjects were then followed for cardiovascular events. Multivariate sex-adjusted Cox Proportional-Hazards models were built for each BP component's change, and further adjusted for baseline BP values, traditional cardiovascular risk factors, and their changes. RESULTS: During a median follow-up of 6.09 years after the second examination, 303 CVD cases occurred. A 1 SD increase in systolic BP, diastolic BP and MAP were significantly associated with 21%, 22%, and 95% increased CVD risk after adjustments for baseline values of BP components and other common risk factors (all p-values <0.05). Importantly, diastolic BP change resisted after further adjustment with systolic BP change (hazard ratio 1.21, CI 95% 1.05-1.39). PP change showed no significant association with CVD. CONCLUSIONS: In a middle-aged population, three-year rises in systolic BP, diastolic BP, MAP, but not PP were associated with increased incident CVD. The significant association between diastolic BP change and CVD was shown independent of systolic BP change.

Exploring risk patterns for incident ischemic stroke during more than a decade of follow-up: A survival tree analysis.

BACKGROUND AND PURPOSE: The burden of stroke is increasing in low to middle income countries. Identifying risk patterns for ischemic stroke (IS) can help develop individualized preventive measures for at risk populations. METHODS: The study population included 3088 Iranian subjects (1426 men) aged ≥50 years, free of cardiovascular diseases at baseline. The risk factors for ischemic stroke were identified by multivariate Cox analysis. A survival tree model was used to explore interactions between risk factors. RESULTS: During 12years of follow-up, 106 cases of IS occurred. Age (hazard ratio (HR): 1.08), male gender (HR: 1.69), diastolic blood pressure (DBP) (HR: 1.04), fasting plasma glucose (HR: 1.10), waist circumference (WC) (HR: 1.03) and smoking (HR: 1.96), were associated with increased risk and estimated glomerular filtration rate (eGFR) (HR: 0.97) and wrist circumference (HR: 0.68) decreased the risk of IS (all P-values <0.05). The survival tree identified six risk patterns. The highest and lowest risks were related to subjects ≥60.5years with DBP ≥100mmHg and subjects <60.5years with DBP<97mmHg, respectively. In subjects ≥60.5years with DBP <100mmHg, risk of ischemic stroke was determined by WC ≥96.5cm or (eGFR) <60.87ml/min/1.73m2. CONCLUSION: By applying survival tree as a complementary method to the conventional Cox-analysis, for the first time, we identified risk patterns of ischemic stroke and explored the interactions between risk factors of the disease. DBP was the most important predictor of ischemic stroke in middle-aged and old subjects. In elderly subjects with DBP <100mmHg, abdominal obesity was associated with high risk; however, among non-obese subjects, kidney dysfunction increased the risk of ischemic stroke. Wrist circumference was reported as a novel predictor.

The hypertriglyceridemic waist and waist-to-height ratio phenotypes and chronic kidney disease: Cross-sectional and prospective investigations.

AIMS: We investigated the association between two hypertriglyceridemic waist (HW) and waist-to height ratio (HWHtR) phenotypes and chronic kidney disease (CKD) using cross sectional and prospective analysis. METHODS: Data of 12,012 individuals (44% men) of the Tehran Lipid and Glucose Study (TLGS) at two phases [(1999-2001) and (2002-2005)], were used for cross-sectional analysis. This population was followed until 2014 with median follow-up 12.4 years (95% confidence interval (CI): 11.8; 12.4). The data of 8225 individuals (45% men) were used for prospective analysis. The outcome was the development of CKD defined as estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2. The HW phenotype was defined as waist circumference (WC) >90cm in men and >85cm in women, along with TGs >2.0mmol/L. The HWHtR phenotype was defined as waist-to-height ratio (WHtR) >0.5 and TGs >2mmol/L. Multivariable logistic and Cox regression were used to statistical analysis. RESULTS: Cross sectional analysis showed that in women, both HW and HWHtR phenotypes were associated with CKD after controlling for confounders [(OR: 1.37, CI: 1.01-1.86, p<0.05) and (OR: 1.58, CI: 1.03-2.41, p<0.05)], respectively. Among men, HW and HWHtR were associated with prevalent CKD in unadjusted and age adjusted models; these associations were not significant after further adjustment for confounders. In prospective analysis, neither HW nor HWHtR phenotypes were significant predictor for CKD progression. CONCLUSION: HW and HWHtR phenotypes were associated with prevalent CKD in cross sectional setting. In prospective analysis HW and HWHtR did not show significant effect in prediction of CKD.