BACKGROUND: Pulmonary emboli (PE), or blood clots in the lungs,can be potentially fatal. Anticoagulation is the first line therapy to prevent PE. In some instances anticoagulation fails to prevent more emboli, or cannot be given because the person has a high risk of bleeding. Inferior vena caval filters (VCFs) are metal alloy devices that mechanically trap fragmented emboli from the deep leg veins en route to the pulmonary circulation. Retrievable filters are designed to be introduced and removed percutaneously. Although their deployment seems of theoretical benefit, their clinical efficacy and adverse event profile is unclear. This is the third update of a Cochrane Review first published in 2007.
OBJECTIVES: To assess the evidence for the effectiveness and safety of vena caval filters (VCFs) in preventing pulmonary embolism (PE).
SEARCH METHODS: For this review update, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 10 September 2019) and the Cochrane Register of Controlled Trials (CENTRAL) (2019, Issue 8) via the Cochrane Register of Studies Online. The CIS also searched MEDLINE Ovid, EMBASE Ovid, CINAHL, and AMED (1 January 2017 to 10 September 2019) and trials registries to 10 September 2019.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that examined the efficacy of VCFs in preventing PE.
DATA COLLECTION AND ANALYSIS: For this update, studies were assessed and data extracted independently. We assessed study quality with Cochrane's 'Risk of bias' tool and used the GRADE approach to assess the overall certainty of the evidence. The outcomes of interest were PE, mortality, lower limb venous thrombosis, filter-related complications and major bleeding.
MAIN RESULTS: We identified four new studies for this update, bringing the total to six included studies involving 1388 participants. The six studies were clinically heterogeneous and we were unable to carry out meta-analysis. Only two studies were considered to be both applicable in current clinical settings and of good methodological quality. One was a randomised open-label trial studying the effect of a retrievable inferior vena caval filter plus anticoagulation versus anticoagulation alone on risk of recurrent pulmonary embolism (PE) in 399 participants over three months. There was no evidence of a difference in the rates of PE, death, lower extremity deep vein thrombosis (DVT), or bleeding at three and six months after the intervention (moderate-certainty evidence). A filter was inserted in 193 people, but could only be successfully retrieved from 153. Minor filter complications were noted at six months. The second clinically relevant study was a randomised open-label trial of 240 participants who had sustained multiple traumatic injuries, allocated to a filter or no filter, three days after injury, in conjunction with anticoagulation and intermittent pneumatic compression. Prophylactic anticoagulation was initiated in both groups when it was thought safe to do so. There was no evidence of a difference in symptomatic PE, death, or lower limb venous thrombosis rates (moderate-certainty evidence). The only major filter complication was that one person required surgical removal of the filter. We are unable to draw any conclusions from the remaining four included studies. One study showed an increased incidence of long-term lower extremity DVT at eight years. Three studies are no longer clinically applicable because they utilised permanent filters which are seldom used now, or they did not use routine prophylactic anticoagulation which is current standard practice. The fourth study compared two filter types and was terminated prematurely as one filter group had a higher rate of thrombosis compared to the other filter type.
AUTHORS' CONCLUSIONS: Two of the six identified studies were relevant for current clinical settings. One showed no evidence of a benefit of retrievable filters in acute PE for the outcomes of PE, death, DVT and bleeding during the initial three months in people who can receive anticoagulation (moderate-certainty evidence). The other study did not show any benefit for prophylactic filter insertion in people who sustained multiple traumatic injuries, with respect to symptomatic PE, mortality, or lower extremity venous thrombosis (moderate-certainty evidence). We can draw no firm conclusions regarding filter efficacy in the prevention of PE from the remaining four RCTs identified in this review. Further trials are needed to assess vena caval filter effectiveness and safety, and clinical differences between various filter types.
BACKGROUND: Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999.
OBJECTIVES: To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism).
SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries.
SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed for quality and extracted data.
MAIN RESULTS: Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence).
AUTHORS' CONCLUSIONS: This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.
OBJECTIVES: To perform a meta-analysis of randomized controlled trials assessing the effectiveness of inferior vena cava filters in patients with deep vein thrombosis for preventing pulmonary embolism. METHOD: Relevant randomized controlled trials of inferior vena cava filters for the prevention of pulmonary embolism were identified by searching electronic databases updated in February 2016. Relative risks of recurrent pulmonary embolism, recurrent deep vein thrombosis, and mortality at three months were analyzed. RESULTS: Three published randomized controlled trials were included involving a total of 863 deep vein thrombosis patients. No significant differences were detected with inferior vena cava filters placement with regard to the incidence of recurrent pulmonary embolism or fatal pulmonary embolism. There were also no significant differences in the incidence of recurrent deep vein thrombosis or mortality with inferior vena cava filters placement at three months. CONCLUSIONS: Inferior vena cava filter in addition to anticoagulation was not associated with a reduction in the incidence of recurrent pulmonary embolism as compared with anticoagulation alone in patients with deep vein thrombosis in the short term.
BACKGROUND: Inferior vena cava filters (IVC) have been used in addition to oral anticoagulation (OC) in patients at high-risk for development of new pulmonary embolism (PE). There is few data comparing the risk-benefit from adding IVC. We sought to compare the clinical outcomes from using IVC combined to OC to OC alone. METHODS: We searched Pub Med and Cochrane trough October 2015 for RCTs that directly compared IVC + OC to OC only in patients at high-risk for new development or recurrence of PE. Primary outcome was development of new PE. Secondary outcomes included recurrence of DVT, major bleeding and death. We used Fixed or Random Effect analysis using the Cochrane Handbook of Systematic Reviews and RevMan 5.2 for statistical analysis. RESULTS: Out of 571 articles, four RCTs were included. The pooled data provided 1004 patients; 503 treated with IVC+ OC and 501 with OC. Mean follow up were 3 months. IVC + OC group presented with significant less new PE compared to OC only group (1.3% vs. 3.5%, p=0.03). There was no difference between IVC + OC compared to OC only for new DVT (7.7% vs. 7.7%), major bleeding (4.3% vs. 4.1%) and death (7.3% vs. 5.5%) respectively (Figure 1). CONCLUSIONS: Our study suggests that among patients at high-risk for venous thromboembolic events, IVC use is associated with significant less development of PE. It is yet to be determined if this benefit is sustained at long-term follow and associated with survival benefit. Therefore further randomized trials are warranted.
Many inferior vena cava (IVC) filter types, along with their specific risks and complications, are not recognized. The purpose of this study was to evaluate the various FDA-approved IVC filter types to determine device-specific risks, as a way to help identify patients who may benefit from ongoing follow-up versus prompt filter retrieval. An evidence-based electronic search (FDA Premarket Notification, MEDLINE, FDA MAUDE) was performed to identify all IVC filter types and device-specific complications from 1980 to 2014. Twenty-three IVC filter types (14 retrievable, 9 permanent) were identified. The devices were categorized as follows: conical (n = 14), conical with umbrella (n = 1), conical with cylindrical element (n = 2), biconical with cylindrical element (n = 2), helical (n = 1), spiral (n = 1), and complex (n = 1). Purely conical filters were associated with the highest reported risks of penetration (90-100%). Filters with cylindrical or umbrella elements were associated with the highest reported risk of IVC thrombosis (30-50%). Conical Bard filters were associated with the highest reported risks of fracture (40%). The various FDA-approved IVC filter types were evaluated for device-specific complications based on best current evidence. This information can be used to guide and optimize clinical management in patients with indwelling IVC filters.
IMPORTANCE: Trauma est connu pour être l'un des plus importants facteurs de risque d'embolie pulmonaire (PE). Les directives actuelles recommandent de faible poids moléculaire héparine thérapie pour la prévention de la PE, mais les traumatismes lieux certains patients à risque de saignement excessif. Les experts sont divisés sur le rôle des filtres prophylactiques la veine cave inférieure (VCI) pour empêcher PE.
OBJECTIF: Pour effectuer une revue systématique et méta-analyse portant sur l'efficacité comparative des filtres IVC prophylactiques chez les patients traumatisés, en particulier dans la prévention de PE, PE fatale, et la mortalité.
SOURCES DE DONNÉES: Nous avons cherché les bases de données suivantes pour les études primaires: Medline, Embase, Scopus, CINAHL, International Pharmaceutical Abstracts, clinicaltrial.gov, et la Bibliothèque Cochrane (tous jusqu'au 31 Juillet, 2012). Nous avons développé une stratégie de recherche en utilisant l'objet médical termes de rubriques et des mots de texte des articles clés que nous avons identifiés a priori. Nous avons examiné les références de tous les articles inclus, articles de revue pertinents, et des examens systématiques liés à identifier les articles les recherches de base de données peuvent avoir manquées.
SÉLECTION DES ÉTUDES: Nous avons examiné les titres suivis par des résumés pour identifier les essais cliniques randomisés ou des études d'observation avec des groupes de comparaison des rapports sur l'efficacité et / ou la sécurité des filtres IVC pour la prévention de la thromboembolie veineuse chez les patients traumatisés.
EXTRACTION DE DONNÉES ET SYNTHÈSE: résumés examinés Deux enquêteurs indépendamment et extrait les données. Pour les études qui se prêtent à la mise en commun avec méta-analyse, nous avons regroupé en utilisant le modèle à effets aléatoires pour analyser les risques relatifs. Nous classé les quantités, la qualité et la cohérence de la preuve en adaptant un système preuves classement recommandé par l'Agence pour la recherche en santé et de la qualité.
RÉSULTATS: Huit études contrôlées ont comparé l'efficacité d'aucun filtre IVC vs filtre IVC sur PE, PE fatale, la thrombose veineuse profonde, et / ou de la mortalité chez les patients traumatisés. La preuve a montré une réduction constante de PE (risque relatif, 0,20 [IC 95%, 0,06 à 0,70]; I (2) = 0%) et PE fatale (0,09 [0,01 à 0,81]; I (2) = 0%) avec placement d'un filtre IVC, sans aucune hétérogénéité statistique. Nous avons trouvé aucune différence significative dans l'incidence de la thrombose veineuse profonde (risque relatif, 1,76 [IC 95%, 0,50 à 6,19]; P = 0,38; I (2) = 56,8%) ou de la mortalité (0,70 [0,40 à 1,23]; I (2) = 6,7%). Le nombre nécessaire pour traiter et pour prévenir 1 PE supplémentaire avec filtres IVC est estimé entre 109 (IC à 95%, 93-190) à 962 (819-2565), en fonction du risque de base de PE.
CONCLUSIONS ET PERTINENCE: La solidité des preuves est faible, mais soutient l'association d'IVC placement d'un filtre avec une incidence plus faible de PE et PE fatale chez les patients traumatisés. Quels patients éprouvent suffisamment d'avantages l'emportent sur les méfaits associés à l'emplacement du filtre IVC reste incertaine. études de cohortes supplémentaires bien conçues d'observation ou potentiels peuvent être informatif.
Inferior vena cava filter (IVCF) use continues to increase in the United States (US) despite questionable clinical benefit and increasing concerns over long-term complications. For this review we comprehensively examine the randomized, prospective data on IVC filter efficacy, compare relative rates of IVCF placement in the US and Europe, compare commonly considered guidelines for IVCF indications, and the current data on IVCF complications. Searches of MEDLINE and Cochrane databases were conducted for randomized prospective IVCF studies. Only three randomized prospective studies for IVCFs were identified. Commonly cited IVCF guidelines were reviewed with attention to their evolution over time. No evidence has shown a survival benefit with IVCF use. Despite this, continued rising utilization, especially for primary prophylactic indications, is concerning, given increasing evidence of long-term filter-related complications. This is particularly noted in the US where IVCF placements for 2012 are projected to be 25 times that of an equivalent population in Europe (224,700 versus 9,070). Pending much-needed randomized controlled trials that also evaluate long-term safety, we support the more stringent American College of Chest Physicians (ACCP) guidelines for IVCF placement indications and advocate a close, structured follow-up of retrievable IVCFs to improve filter retrieval rates.
BACKGROUND: Venous thromboembolism (VTE) is a prevalent and avoidable complication of hospitalization. Patients hospitalized with trauma, traumatic brain injury, burns, or liver disease; patients on antiplatelet therapy; obese or underweight patients; those having obesity surgery; or with acute or chronic renal failure have unequal risks for bleeding and thrombosis and may benefit differently from prophylactic therapy medication.
OBJECTIVES: To systematically review the comparative effectiveness and safety of pharmacological and mechanical methods of prophylaxis of VTE in these special populations.
DATA SOURCES: We searched MEDLINE(®), Embase(®), SCOPUS, CINAHL(®), www.clinicaltrials.gov, International Pharmaceutical Abstracts (IPA), and the Cochrane Library in July 2012. This was complemented by hand searches from the reference lists and unpublished studies provided by sponsors.
REVIEW METHODS: We included randomized controlled trials on these special populations. Since these populations may be excluded from trials, we also included controlled observational studies of pharmacologic agents, and uncontrolled observational studies and case series of inferior vena cava (IVC) filter use. Two reviewers evaluated studies for eligibility, serially abstracted data using standardized forms, and independently evaluated the risk of bias in the studies and strength of evidence for major outcomes and comparisons. We qualitatively synthesized the evidence and also pooled the relative risks from the controlled studies.
RESULTS: After a review of 30,902 unique citations, we included 101 studies of which just 6 were trials. The majority of observational studies had a high risk of bias. The strength of evidence is low that IVC filter placement is associated with a lower incidence of pulmonary embolism and fatal pulmonary embolism in hospitalized patients with trauma compared with no IVC filter placement. The strength of evidence is low that enoxaparin reduces deep vein thrombosis and that unfractionated heparin reduces mortality in patients with traumatic brain injury when compared with patients without anticoagulation. Low-grade evidence supports the idea that IVC filters with usual care are associated with increased mortality and do not decrease the risk of pulmonary embolism in patients undergoing bariatric surgery compared with usual care alone. All other comparisons, for all of the Key Questions, had insufficient evidence to permit conclusions.
CONCLUSIONS: Our systematic review demonstrates that there is a paucity of high-quality evidence to inform treatment of these special populations. Future research using robust observational studies that control for confounding by indication and disease severity are needed as randomized controlled trials typically exclude or do not report on these populations.
INTRODUCTION: Pulmonary embolisms (PE) are an often preventable cause of late morbidity and mortality after trauma. Although there is evidence for the use of therapeutic inferior vena cava (IVC) filters (defined as IVC filters implanted in those with proven deep venous thrombosis [DVT] in order to prevent PE), there is not as much evidence to support the use of prophylactic IVC filters. Thus, we undertook a systematic review of the literature to assess the following in prophylactic IVC filters: efficacy in PE reduction, prevalence of filter-related complications and the indications for use.
MATERIALS AND METHODS: After screening 249 studies, 24 studies met inclusion criteria for qualitative synthesis.
RESULTS: Overall, the literature is supportive of the use of prophylactic IVC filters in high-risk poly-trauma patients who may have contraindications to DVT prophylaxis. Filter-associated complications are uncommon and, when they do occur, tend to be of limited clinical significance. Limited data, mostly in the form of case series, supports a reduction in PE and PE-related mortality. There has been increasing use of retrievable filters as well as the ability to safely retrieve them at longer intervals.
CONCLUSION: Despite the addition of a few matched-control studies, the literature is still plagued by a lack of high quality data, and therefore the true efficacy of prophylactic IVC filters for prevention of PE in trauma patients remains unclear. Further studies are required to determine the true role of prophylactic IVC filters in trauma patient.
CONTEXTE: Les héparines de bas poids moléculaire (HBPM) sont au moins aussi efficaces que les médicaments antithrombotiques héparine non fractionnée (HNF). Cependant, il n'est pas encore clair si les profils de sécurité des HBPM et de l'HNF diffèrent. Nous avons effectué une revue systématique de comparer le risque d'hémorragie de la dose sous-cutanée HBPM fixe et l'HNF à dose ajustée pour le traitement de la thromboembolie veineuse (TEV) ou les syndromes coronariens aigus (SCA). Saignements majeurs était le point final primaire.
MÉTHODES: bases de données électroniques (Medline, Embase et Cochrane Library) ont été fouillés jusqu'à mai 2010, sans restriction de langue. Des essais contrôlés randomisés où HBPM sous-cutanée ont été comparées à l'HNF par voie intraveineuse pour le traitement des thromboses aiguës ont été sélectionnés. Deux examinateurs ont indépendamment des études et extrait les données sur la conception de l'étude, la qualité de l'étude, l'incidence des saignements majeurs, des caractéristiques du patient, le type, la dose et le nombre de prises quotidiennes d'HBPM, co-traitements, les points finaux de l'étude et les résultats d'efficacité. Odds ratio combiné (OR) et les intervalles de confiance de 95% (IC) ont été calculés en utilisant le modèle à effets aléatoires.
RÉSULTATS: Vingt-Sept études ont été incluses. Un total de 14.002 patients ont reçu l'HNF et HBPM 14.635 patients. Dans l'ensemble, aucune différence de saignement majeur n'a été observée entre les patients HBPM et l'HNF (OR = 0,79, IC 0,60 à 1,04 95%). Chez les patients ayant un ETEV HBPM semblait plus sûre que l'HNF (OR = 0,68, IC 0,47 à 1,00 95%).
CONCLUSION: Les résultats de notre revue systématique suggèrent que l'utilisation des HBPM pour le traitement de la TEV pourrait être associée à une réduction des saignements majeurs par rapport à l'héparine non fractionnée. Le choix de l'héparine à utiliser pour minimiser le risque de saignement doit être fondée sur le seul patient, en tenant compte du profil des saignements de différentes héparines dans différents contextes.
Pulmonary emboli (PE), or blood clots in the lungs,can be potentially fatal. Anticoagulation is the first line therapy to prevent PE. In some instances anticoagulation fails to prevent more emboli, or cannot be given because the person has a high risk of bleeding. Inferior vena caval filters (VCFs) are metal alloy devices that mechanically trap fragmented emboli from the deep leg veins en route to the pulmonary circulation. Retrievable filters are designed to be introduced and removed percutaneously. Although their deployment seems of theoretical benefit, their clinical efficacy and adverse event profile is unclear. This is the third update of a Cochrane Review first published in 2007.
OBJECTIVES:
To assess the evidence for the effectiveness and safety of vena caval filters (VCFs) in preventing pulmonary embolism (PE).
SEARCH METHODS:
For this review update, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 10 September 2019) and the Cochrane Register of Controlled Trials (CENTRAL) (2019, Issue 8) via the Cochrane Register of Studies Online. The CIS also searched MEDLINE Ovid, EMBASE Ovid, CINAHL, and AMED (1 January 2017 to 10 September 2019) and trials registries to 10 September 2019.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that examined the efficacy of VCFs in preventing PE.
DATA COLLECTION AND ANALYSIS:
For this update, studies were assessed and data extracted independently. We assessed study quality with Cochrane's 'Risk of bias' tool and used the GRADE approach to assess the overall certainty of the evidence. The outcomes of interest were PE, mortality, lower limb venous thrombosis, filter-related complications and major bleeding.
MAIN RESULTS:
We identified four new studies for this update, bringing the total to six included studies involving 1388 participants. The six studies were clinically heterogeneous and we were unable to carry out meta-analysis. Only two studies were considered to be both applicable in current clinical settings and of good methodological quality. One was a randomised open-label trial studying the effect of a retrievable inferior vena caval filter plus anticoagulation versus anticoagulation alone on risk of recurrent pulmonary embolism (PE) in 399 participants over three months. There was no evidence of a difference in the rates of PE, death, lower extremity deep vein thrombosis (DVT), or bleeding at three and six months after the intervention (moderate-certainty evidence). A filter was inserted in 193 people, but could only be successfully retrieved from 153. Minor filter complications were noted at six months. The second clinically relevant study was a randomised open-label trial of 240 participants who had sustained multiple traumatic injuries, allocated to a filter or no filter, three days after injury, in conjunction with anticoagulation and intermittent pneumatic compression. Prophylactic anticoagulation was initiated in both groups when it was thought safe to do so. There was no evidence of a difference in symptomatic PE, death, or lower limb venous thrombosis rates (moderate-certainty evidence). The only major filter complication was that one person required surgical removal of the filter. We are unable to draw any conclusions from the remaining four included studies. One study showed an increased incidence of long-term lower extremity DVT at eight years. Three studies are no longer clinically applicable because they utilised permanent filters which are seldom used now, or they did not use routine prophylactic anticoagulation which is current standard practice. The fourth study compared two filter types and was terminated prematurely as one filter group had a higher rate of thrombosis compared to the other filter type.
AUTHORS' CONCLUSIONS:
Two of the six identified studies were relevant for current clinical settings. One showed no evidence of a benefit of retrievable filters in acute PE for the outcomes of PE, death, DVT and bleeding during the initial three months in people who can receive anticoagulation (moderate-certainty evidence). The other study did not show any benefit for prophylactic filter insertion in people who sustained multiple traumatic injuries, with respect to symptomatic PE, mortality, or lower extremity venous thrombosis (moderate-certainty evidence). We can draw no firm conclusions regarding filter efficacy in the prevention of PE from the remaining four RCTs identified in this review. Further trials are needed to assess vena caval filter effectiveness and safety, and clinical differences between various filter types.
