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1.
N Engl J Med ; 385(10): 885-895, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34469646

RESUMO

BACKGROUND: Immune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks. METHODS: In this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events. RESULTS: A total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P = 0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group. CONCLUSIONS: The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.).


Assuntos
Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Fadiga/induzido quimicamente , Feminino , Glucocorticoides/efeitos adversos , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/complicações , Qualidade de Vida , Adulto Jovem
2.
Blood ; 137(13): 1731-1740, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33150355

RESUMO

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.


Assuntos
Fibrinolíticos/uso terapêutico , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Anticorpos de Domínio Único/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/epidemiologia , Anticorpos de Domínio Único/efeitos adversos , Resultado do Tratamento , Reino Unido/epidemiologia , Adulto Jovem , Fator de von Willebrand/antagonistas & inibidores
3.
Blood ; 133(15): 1644-1651, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30770395

RESUMO

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.


Assuntos
Proteína ADAMTS13/genética , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Proteína ADAMTS13/deficiência , Adulto , Pré-Escolar , Fator VIII/uso terapêutico , Feminino , Humanos , Masculino , Mutação , Plasma , Gravidez , Pré-Medicação/métodos , Púrpura Trombocitopênica Trombótica/complicações , Púrpura Trombocitopênica Trombótica/genética , Acidente Vascular Cerebral/prevenção & controle
4.
Haemophilia ; 27(2): 192-198, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33639027

RESUMO

INTRODUCTION: One of the most often stated tenets of haemophilia care is that prophylaxis converts a person from a severe to a moderate phenotype. In this review, we argue that this is not an accurate assumption and that people on prophylaxis predominantly have factor VIII/IX levels in the mild range. MODERATE HAEMOPHILIA AND PROPHYLAXIS: People with moderate haemophilia, who are treating with on-demand regimens, experience joint bleeds and often develop significant arthropathy. This is especially true for people with a baseline level of 1-3 IU/dl, as first reported 55 years ago, and confirmed in more recent studies. Evidence is emerging suggesting that people with severe haemophilia who are using prophylaxis have better musculoskeletal outcomes than people with moderate haemophilia treated episodically. TROUGH LEVELS: The debate around the optimum trough level whilst on prophylaxis is ongoing. It is not appropriate to extrapolate information about baseline levels to recommendations about target trough levels on prophylaxis because these are different situations. Studies are emerging that support higher target trough levels than previously used, but in spite of this, the aim of achieving zero bleeds remains elusive with both factor replacement and non-replacement therapies. CONCLUSIONS: We recommend that people with moderate haemophilia, especially those with a baseline of 1-3 IU/dl, should be offered prophylaxis based on the same criteria as people with severe haemophilia. Trough levels should be maintained above 3 IU/dl or higher if a level of 3 IU/dl does not control breakthrough bleeding and prophylaxis should be tailored to the bleeding phenotype. This advice is in line with recently published guidelines from the World Federation of Haemophilia and the UK Haemophilia Centre Doctors' Organisation.


Assuntos
Hemofilia A , Fator VIII , Hemartrose , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Humanos , Fenótipo
5.
Blood ; 124(11): 1727-36, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25024304

RESUMO

This prospective, observational study investigated the utility of Fibtem A5 and Clauss fibrinogen as predictors of progression of postpartum hemorrhage (PPH). A consecutive cohort of 356 women experiencing 1000 to 1500 mL PPH was recruited. Fibtem and fibrinogen were measured and subsequent transfusions, invasive procedures, and bleed volume recorded. Women progressing to 8 U blood products (red blood cells [RBCs] + fresh frozen plasma [FFP] + platelets) had a median (interquartile range) fibrinogen and Fibtem A5 of 2.1 (1.8-3.4) g/L and 12 (7-17) mm, respectively, compared with 3.9 (3.2-4.5) and 19 (17-23) for those not progressing. On multivariate analysis, Fibtem was an independent predictor for progression to bleeds >2500 mL (95% confidence interval [CI], 0.85 [0.77-0.95]). Receiver operating characteristic area under the curve (95% CI) for progression to RBC transfusion was 0.67 (0.60-0.74) for fibrinogen and 0.61 (0.54-0.68) for Fibtem, and progression to >2500 mL was 0.71 (0.61-0.81) and 0.75 (0.66-0.85) for fibrinogen and Fibtem, respectively. Fibtem A5 <10 mm was associated with more prolonged bleeds (median [95% CI], 127 [44-210] compared with 65 [59-71] minutes; P = .018) and longer stay in the high-dependency unit (23.5 [18.4-28.5] compared with 10.8 [9.7-11.8] hours). Fibtem is a rapidly available early biomarker for progression of PPH.


Assuntos
Coagulação Sanguínea , Transfusão de Eritrócitos , Fibrina/metabolismo , Hemorragia Pós-Parto/sangue , Hemorragia Pós-Parto/terapia , Adulto , Biomarcadores/sangue , Feminino , Humanos
6.
Blood ; 124(2): 211-9, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-24859360

RESUMO

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes.


Assuntos
Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , Resultado da Gravidez , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Proteínas ADAM/sangue , Proteínas ADAM/genética , Proteínas ADAM/imunologia , Proteína ADAMTS13 , Feto Abortado , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Placenta/patologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Complicações Hematológicas na Gravidez/genética , Resultado da Gravidez/epidemiologia , Púrpura Trombocitopênica Trombótica/epidemiologia , Púrpura Trombocitopênica Trombótica/genética
10.
Emerg Med J ; 31(2): 163-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23435652

RESUMO

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not 'routine'. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s).


Assuntos
Antitrombinas/efeitos adversos , Benzimidazóis/efeitos adversos , Overdose de Drogas/terapia , Hemorragia/induzido quimicamente , beta-Alanina/análogos & derivados , Testes de Coagulação Sanguínea , Dabigatrana , Gerenciamento Clínico , Serviço Hospitalar de Emergência , Hemorragia/terapia , Humanos , Hemorragia Pós-Operatória/induzido quimicamente , Hemorragia Pós-Operatória/terapia , beta-Alanina/efeitos adversos
12.
J Immunol ; 183(1): 677-86, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19535639

RESUMO

Maternal alloantibodies against the human platelet Ag (HPA)-1a allotype of the platelet beta(3) integrin GpIIb/IIIa can cause severe fetal or neonatal hemorrhage. Almost all anti-HPA-1a-immune mothers are homozygous for HPA-1b and carry HLA-DR52a (DRB3*0101). The single Pro(33) -->Leu substitution (HPA-1b-->HPA-1a) was previously predicted to create a binding motif for HLA-DR52a that can lead to alloimmunization. We have isolated six CD4(+) T cell clones from three such mothers, which all respond to intact HPA-1a(+), but not HPA-1b(+), platelets. We used them to define the "core" and "anchor" residues of this natural T cell epitope. Molecular modeling based on a recently published crystal structure can explain the preferential presentation of the Leu(33) (but not Pro(33) variant) by HLA-DR52a rather than the linked HLA-DR3 or the allelic DR52b. The modeling also predicts efficient anchoring at position 33 by several alternative hydrophobic alpha-amino acids; indeed, a recently identified variant with Val(33) is presented well to two clones, and is therefore potentially alloimmunogenic. Finally, these HPA-1a-specific T cell clones use a variety of T cell receptors, but all have a "Th1" (IFN-gamma-producing) profile and are suitable for testing selective immunotherapies that might be applicable in vivo.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Plaquetas Humanas/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-DR/imunologia , Isoanticorpos/sangue , Mães , Células Th1/imunologia , Sequência de Aminoácidos , Antígenos de Plaquetas Humanas/metabolismo , Células Cultivadas , Células Clonais , Técnicas de Cocultura , Epitopos de Linfócito T/metabolismo , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Integrina beta3 , Isoanticorpos/biossíntese , Dados de Sequência Molecular , Células Th1/metabolismo
13.
Cochrane Database Syst Rev ; (5): CD004226, 2011 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-21563140

RESUMO

BACKGROUND: Fetomaternal alloimmune thrombocytopenia results from the formation of antibodies by the mother which are directed against a fetal platelet alloantigen inherited from the father. The resulting fetal thrombocytopenia (reduced platelet numbers) may cause bleeding, particularly into the brain, before or shortly after birth. Antenatal treatment of fetomaternal alloimmune thrombocytopenia includes the administration of intravenous immunoglobulin (IVIG) and/or corticosteroids to the mother to prevent severe fetal thrombocytopenia. IVIG and corticosteroids both have short-term and possibly long-term side effects. IVIG is also costly and optimal regimens need to be identified. OBJECTIVES: To determine the optimal antenatal treatment of fetomaternal alloimmune thrombocytopenia to prevent fetal and neonatal haemorrhage and death. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2011) and bibliographies of relevant publications and review articles. SELECTION CRITERIA: Randomised controlled studies comparing any intervention with no treatment, or comparing any two interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: We included four trials involving 206 people. One trial involving 39 people compared a corticosteroid (prednisone) versus IVIG alone. In this trial, where analysable data were available, there was no statistically significant differences between the treatment arms for predefined outcomes. Three trials involving 167 people compared IVIG plus a corticosteroid (prednisone in two trials and dexamethasone in one trial) versus IVIG alone. In these trials there was no statistically significant difference in the findings between the treatment arms for predefined outcomes (intracranial haemorrhage; platelet count at birth and preterm birth). Lack of complete data sets and important differences in interventions precluded the pooling of data from these trials. AUTHORS' CONCLUSIONS: The optimal management of fetomaternal alloimmune thrombocytopenia remains unclear. Lack of complete data sets for two trials and differences in interventions precluded the pooling of data from these trials which may have enabled a more developed analysis of the trial findings. Further trials would be required to determine optimal treatment (the specific medication and its dose and schedule). Such studies should include long-term follow up of all children and mothers.


Assuntos
Doenças Fetais/tratamento farmacológico , Glucocorticoides/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Prednisona/uso terapêutico , Trombocitopenia/tratamento farmacológico , Antígenos de Plaquetas Humanas/imunologia , Dexametasona/uso terapêutico , Feminino , Doenças Fetais/imunologia , Humanos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombocitopenia/imunologia , Trombocitopenia Neonatal Aloimune/tratamento farmacológico , Trombocitopenia Neonatal Aloimune/imunologia
14.
Obstet Med ; 12(1): 45-51, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30891093

RESUMO

Antithrombin deficiency is identified as one of the most potent risk factors for venous thromboembolism during pregnancy. Therapeutic low molecular weight heparin is recommended, but it can be difficult to attain sufficient anticoagulation since low molecular weight heparin requires antithrombin to exert its anticoagulant effect. We carried out a multicentre case-series assessing the dose of low molecular weight heparin required to achieve therapeutic anti-activated factor X levels in pregnant women with antithrombin deficiency. We assessed 27 pregnancies in 18 women with severe antithrombin deficiency, which we defined as an antithrombin level of <0.55 IU/ml (with or without prior venous thromboembolism) or an antithrombin level < 0.8 IU/ml and a personal history of venous thromboembolism. Our data illustrate the need for high doses of low molecular weight heparin to achieve therapeutic anti-activated factor X levels (average 20,220 IU/day). All pregnancies ended in live birth (excluding one elective termination), although intrauterine growth restriction occurred in five (18%).

16.
Trials ; 16: 169, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25906770

RESUMO

BACKGROUND: Postpartum haemorrhage (PPH) is a major cause of maternal morbidity. Bleeding is caused by a combination of physical causes, such as failure of the uterus to contract or operations, and is made worse by impairment of the blood clotting system. A number of studies have shown that low levels of the blood clotting factor fibrinogen are associated with progression of bleeding, the need for invasive interventions and transfusions of red blood cells and fresh frozen plasma (FFP). This trial will investigate whether early infusion of fibrinogen concentrate during a major PPH, with the aim of correcting a low fibrinogen to a level that is normal for delivery, based on the Fibtem test, reduces the total number of allogeneic blood products (red blood cells, FFP, cryoprecipitate and platelets) transfused after study medication until discharge, compared to placebo. METHODS/DESIGN: This is a prospective, randomised, double-blind placebo controlled trial. Women will enter an observational phase and if their Fibtem levels fall they will be randomised in the interventional phase. A total of 60 women will be randomised and women are eligible for the trial if they meet all of the following inclusion criteria: age 18 years or over, gestation ≥24 + 0 weeks, haemorrhage of about 1500 ml and on-going bleeding without another complication or haemorrhage of about 1000 ml and caesarean section/uterine atony/placental abruption/placenta praevia/cardiovascular instability or microvascular oozing. Participants with a Fibtem A5 < 16 mm will be randomly allocated to receive either a bolus infusion of fibrinogen concentrate or placebo (isotonic saline). The dose of fibrinogen concentrate or placebo will be calculated based on the woman's ideal body weight for height and the measured Fibtem A5 with the aim of increasing the Fibtem A5 to 23 mm. DISCUSSION: The trial aims to provide evidence on the efficacy and safety of fibrinogen concentrate during acute bleeding in an obstetric setting. TRIAL REGISTRATION: ISRCTN ref: ISRCTN46295339 (01.07.2013); EudraCT: 2012-005511-11 (28.11.2012), UKCRN ref: 13940.


Assuntos
Fibrinogênio/administração & dosagem , Hemostasia/efeitos dos fármacos , Hemostáticos/administração & dosagem , Hemorragia Pós-Parto/tratamento farmacológico , Adolescente , Adulto , Testes de Coagulação Sanguínea , Transfusão de Sangue , Protocolos Clínicos , Método Duplo-Cego , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Fibrinogênio/efeitos adversos , Hemostáticos/efeitos adversos , Humanos , Infusões Parenterais , Hemorragia Pós-Parto/sangue , Hemorragia Pós-Parto/diagnóstico , Gravidez , Estudos Prospectivos , Projetos de Pesquisa , Fatores de Tempo , Resultado do Tratamento , País de Gales , Adulto Jovem
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