Publications
347 results found
Gill D, Monori G, Georgakis MK, et al., 2018, Genetically determined platelet count and risk of cardiovascular disease: Mendelian randomization study, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 38, Pages: 2862-2869, ISSN: 1079-5642
Objective—Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk.Approach and Results—A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98–1.04; P=0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04–1.11; P<1×10−5), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants.Conclusions—This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.
Tan MKH, Onida S, Laffan M, et al., 2018, Thrombophilia in non-thrombotic chronic venous disease of the lower limb - a systematic review, British Journal of Haematology, Vol: 183, Pages: 703-716, ISSN: 1365-2141
Chronic venous disease (CVD) represents a significant healthcare burden. Thrombophilia is proposed as a risk factor, particularly for post‐thrombotic CVD. A systematic review was performed to determine the relationship between thrombophilia and non‐thrombotic CVD. MEDLINE® and Embase® databases were searched from 1946 up to March 2018. Case‐control studies, cohort studies or randomised clinical trials reporting on thrombophilias in non‐thrombotic lower limb CVD in adult patients were included. Non‐English and post‐thrombotic syndrome studies were excluded. Study selection and data extraction were performed by two reviewers. Fifteen studies were included, reporting on 916 cases and 1261 controls. Studies largely focused on venous ulceration and investigated multiple haemostatic factors. An association between thrombophilia and non‐thrombotic CVD was identified, with greater prevalence and factor concentration alteration reported in patients compared to controls. Concomitant thrombophilia presence was associated with earlier CVD onset. Relationship strength varied, with commoner aetiologies showing clearer correlation than rarer ones. Thrombophilia is associated with non‐thrombotic CVD but the mechanism is unclear and causation cannot be determined. Future research should focus on prospective studies with larger populations and identify adjunct therapies targeting thrombophilia.
Sivapalaratnam S, Melissa H, Lentaigne C, et al., 2018, Congenital Aspirin-like Defect As a Result of Autosomal Recessive Variants in <i>PTGS1</i>, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Arachchillage DJ, Alavian S, Griffin J, et al., 2018, Efficacy and Safety of Prothrombin Complex Concentrate in Patients Treated with Rivaroxaban or Apixaban Compared to Warfarin Presenting with Major Bleeding, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Arachchillage DJ, Khanna S, Vandenbriele C, et al., 2018, Incidence of Thrombocytopenia and Heparin induced thrombocytopenia in patients receiving Extracorporeal Membrane Oxygenation (ECMO) compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology, ISSN: 0006-4971
Luo P-L, Austin SK, Parmar K, et al., 2018, The Relationship between Thrombin Generation Assay and FVIII Levels in Patients with Mild to Moderate Haemophilia (A), 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Gill D, Georgakis MK, Laffan M, et al., 2018, Genetically determined FXI (Factor XI) levels and risk of stroke, Stroke, Vol: 49, Pages: 2761-2763, ISSN: 0039-2499
Background and Purpose—FXI (factor XI) is involved in thrombus propagation and stabilization. It is unknown whether lower FXI levels have a protective effect on risk of ischemic stroke (IS) or myocardial infarction. This study investigated the effect of genetically determined FXI levels on risk of IS, myocardial infarction, and intracerebral hemorrhage.Methods—Two-sample Mendelian randomization analysis was performed. Instruments and genetic association estimates for FXI levels were obtained from a genome-wide association study of 16 169 individuals. Genetic association estimates for IS and its etiological subtypes were obtained from a study of 16 851 cases and 32 473 controls. For myocardial infarction, estimates were obtained from a study of 43 676 cases and 123 504 controls and for intracerebral hemorrhage from a study of 1545 cases and 1481 controls.Results—After applying a Bonferroni correction for multiple testing, the Mendelian randomization analysis supported a causal effect of higher, genetically determined FXI levels on risk of any IS (odds ratio [OR] per 1-unit increase in natural logarithm-transformed FXI levels, 2.54; 95% CI, 1.68–3.84; P=1×10−5) but not myocardial infarction (OR, 1.01; 95% CI, 0.76–1.34; P=0.94) or intracerebral hemorrhage (OR, 1.81; 95% CI, 0.44–7.38; P=0.41). Examining IS subtypes, the main results supported an effect of higher, genetically determined FXI levels on risk of cardioembolism (OR, 4.23; 95% CI, 1.94–9.19; P=3×10−4) and IS of undetermined cause (OR, 3.44; 95% CI, 1.79–6.60; P=2×10−4) but not large artery atherosclerosis (OR, 2.73; 95% CI, 1.15–6.45; P=0.02) or small artery occlusion (OR, 1.19; 95% CI, 0.50–2.82; P=0.69). However, the statistically significant result for IS of undetermined cause was not replicated in all sensitivity analyses.Conclusions—We find Mendelian randomization evidence supporting FXI as a possible t
Westbury SK, Downes K, Burney C, et al., 2018, Phenotype description and response to thrombopoietin receptor agonist in DIAPH1-related disorder, Blood Advances, Vol: 2, Pages: 2341-2346, ISSN: 2473-9529
Laffan MA, Curry N, Davenport R, et al., 2018, The use of viscoelastic haemostatic assays in the management of major bleeding. A British Society for Haematology Guideline, British Journal of Haematology, Vol: 182, Pages: 789-806, ISSN: 1365-2141
Vandenbriele C, Bhudia N, Dhillon E, et al., 2018, Heparin anti-Xa assay versus Activated Partial Thromboplastin Time to monitor unfractionated heparin during Extra-Corporeal-Membrane-Oxygenation, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 358-358, ISSN: 0195-668X
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Ito Y, Carss KJ, Duarte ST, et al., 2018, De Novo truncating mutations in WASF1 cause intellectual disability with seizures, American Journal of Human Genetics, Vol: 103, Pages: 144-153, ISSN: 0002-9297
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.
Bell R, Kozlowski R, O'Brien H, et al., 2018, Large transgene strategies for von Willebrand disease, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy, Publisher: Mary Ann Liebert, Pages: A9-A9, ISSN: 1043-0342
Stanworth SJ, Desborough MJR, Simons G, et al., 2018, Clinical bleeding and thrombin generation in admissions to critical care with prolonged prothrombin time: an exploratory study, TRANSFUSION, Vol: 58, Pages: 1388-1398, ISSN: 0041-1132
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Jennings I, Perry D, Watson H, et al., 2018, Quality assurance and tests of platelet function, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 181, Pages: 560-561, ISSN: 0007-1048
Rangarajan S, Kim B, Lester W, et al., 2018, Achievement of normal factor VIII activity following gene transfer with valoctocogene roxaparvovec (BMN 270): Long-term efficacy and safety results in patients with severe hemophilia A, Publisher: WILEY, Pages: 65-65, ISSN: 1351-8216
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Dhillon E, Laffan M, Arachchillage DJ, 2018, Comparing Activated Partial Thromboplastin Time and Heparin anti-Xa levels to monitor anticoagulant intensity of unfractionated heparin in Extracorporeal Membrane Oxygenation, 58th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 138-138, ISSN: 0007-1048
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Arachchillage DJ, Kamani F, Fox S, et al., 2018, Does one size fit for everyone? Pre-test probability of heparin induced thrombocytopenia (4-T's score), 58th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 137-138, ISSN: 0007-1048
Thomas N, Lee K, Laffan M, et al., 2018, Variability of anti-beta2 glycoprotein I antibody measurement by commercial assays, 58th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 136-137, ISSN: 0007-1048
Arachchillage DJ, Faloye S, Daniel R, et al., 2018, Validation of Functional fibrinogen in thromboelastography during cardiopulmonary bypass, 58th Annual Scientific Meeting of the British-Society-for-Haematology, Publisher: WILEY, Pages: 136-136, ISSN: 0007-1048
Arachchillage DRJ, Passariello M, Laffan M, et al., 2018, Intracranial haemorrhage and early mortality in patients receiving extracorporeal membrane oxygenation for severe respiratory failure, Seminars in Thrombosis and Hemostasis, Vol: 44, Pages: 276-286, ISSN: 0094-6176
Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6–99.5), and 10.8 (5.6–16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.
Farmery JHR, Smith ML, Lynch AG, et al., 2018, Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data, Scientific Reports, Vol: 8, ISSN: 2045-2322
Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.
Rangarajan S, Walsh L, Lester W, et al., 2017, AAV5-factor VIII gene transfer in severe hemophilia A, New England Journal of Medicine, Vol: 377, Pages: 2519-2530, ISSN: 0028-4793
BackgroundPatients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A.MethodsWe infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain–deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks.ResultsFactor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected.ConclusionsThe infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants
Newnham M, South K, Bleda M, et al., 2017, ADAMTS13 PROTEIN LEVELS ARE DECREASED IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION AND IMPLICATED IN ITS PATHOBIOLOGY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A67-A67, ISSN: 0040-6376
Laffan M, 2017, Can you grow out of von Willebrand disease?, Haemophilia, Vol: 23, Pages: 807-809, ISSN: 1351-8216
Westbury SK, Canault M, Greene D, et al., 2017, Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding, Blood, Vol: 130, Pages: 1026-1030, ISSN: 1528-0020
Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls. Eleven cases harboured 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included five high-impact variants predicted to prevent CalDAG-GEFI expression and six missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signalling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical and dental bleeding from childhood, requiring at least one blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to ADP and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a non-syndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.
Millar CM, Laffan MA, 2017, Corrigendum: Drug therapy in anticoagulation: which drug for which patient?, Clinical Medicine, Vol: 17, Pages: 347-349, ISSN: 1470-2118
Gill D, Del Greco M F, Walker AP, et al., 2017, The effect of iron status on risk of coronary artery disease: a Mendelian randomization study, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 37, Pages: 1788-1792, ISSN: 1079-5642
Objective—Iron status is a modifiable trait that has been implicated in cardiovascular disease. This study uses the Mendelian randomization technique to investigate whether there is any causal effect of iron status on risk of coronary artery disease (CAD).Approach and Results—A 2-sample Mendelian randomization approach is used to estimate the effect of iron status on CAD risk. Three loci (rs1800562 and rs1799945 in the HFE gene and rs855791 in TMPRSS6) that are each associated with serum iron, transferrin saturation, ferritin, and transferrin in a pattern suggestive of an association with systemic iron status are used as instruments. SNP (single-nucleotide polymorphism)-iron status association estimates are based on a genome-wide association study meta-analysis of 48 972 individuals. SNP-CAD estimates are derived by combining the results of a genome-wide association study meta-analysis of 60 801 CAD cases and 123 504 controls with those of a meta-analysis of 63 746 CAD cases and 130 681 controls obtained from Metabochip and genome-wide association studies. Combined Mendelian randomization estimates are obtained for each marker by pooling results across the 3 instruments. We find evidence of a protective effect of higher iron status on CAD risk (iron odds ratio, 0.94 per SD unit increase; 95% confidence interval, 0.88–1.00; P=0.039; transferrin saturation odds ratio, 0.95 per SD unit increase; 95% confidence interval, 0.91–0.99; P=0.027; log-transformed ferritin odds ratio, 0.85 per SD unit increase; 95% confidence interval, 0.73–0.98; P=0.024; and transferrin odds ratio, 1.08 per SD unit increase; 95% confidence interval, 1.01–1.16; P=0.034).Conclusions—This Mendelian randomization study supports the hypothesis that higher iron status reduces CAD risk. These findings may highlight a therapeutic target.
Arachchillage DRJ, Kamani F, Deplano S, et al., 2017, Should we abandon the APTT for monitoring unfractionated heparin?, Thrombosis Research, Vol: 157, Pages: 157-161, ISSN: 0049-3848
INTRODUCTION: The activated partial thromboplastin time (APTT) is commonly used to monitor unfractionated heparin (UFH) but may not accurately measure the amount of heparin present. The anti-Xa assay is less susceptible to confounding factors and may be a better assay for this purpose. MATERIALS AND METHODS: The validity of the APTT for monitoring UFH was assessed by comparing with an anti-Xa assay on 3543 samples from 475 patients (infants [n=165], children 1-15years [n=60] and adults [n=250]) receiving treatment dose UFH. RESULTS: Overall concordance was poor. The highest concordance (66%; 168/254) was seen in children. Concordance (51.8%) or discordance (48.4%) was almost equal in adult patients. Among adult patients whose anti-Xa level was within 0.3-0.7IU/mL, only 38% had an APTT in the therapeutic range whilst 56% were below and 6% were above therapeutic range. Children and adult patients with anti-Xa of 0.3-0.7IU/mL but sub- therapeutic APTT had significantly higher fibrinogen levels compared to those with therapeutic or supra-therapeutic APTT. CONCLUSIONS: When the anti-Xa level was 0.3-0.7IU/mL, the majority of samples from infants demonstrated a supra-therapeutic APTT, whilst adults tended to have a sub-therapeutic APTT. This may lead to under anticoagulation in infants or over anticoagulation in adults with risk of bleeding if APTT is used to monitor UFH. These results further strengthen existing evidence of the limitation of APTT in monitoring UFH. Discordance of APTT and anti-Xa level in adults and children may be due to elevation of fibrinogen level.
Arachchillage DRJ, Laffan M, 2017, Can Mean Platelet Volume Be Used as a Predictor of Vascular Disease? Problems and Pitfalls., Seminars in Thrombosis and Hemostasis, Vol: 43, Pages: 599-608, ISSN: 0094-6176
Platelets play a pivotal role in both hemostasis and thrombosis. Increased platelet volume has several etiologies and may be secondary to a genetic variant, platelet activation, increased platelet turnover, or in response to inflammatory stimuli. There are several hereditary syndromes in which an increased mean platelet volume (MPV) occurs in association with a reduction in platelet number and function. An acquired increase in platelet size is often associated with increased platelet reactivity, shortened bleeding time, and increased platelet aggregation. Many studies have shown that high MPV is associated with increased risk of venous and arterial thrombosis, but genome-wide association analyses found a weak inverse association between the risk of coronary heart disease and MPV. The disease associations of MPV suggest that it could provide a useful contribution to risk assessment algorithms for both venous thromboembolism and arterial thrombosis. However, owing to the problems associated with reliably assessing MPV, it does not yet constitute a practically useful biomarker for this purpose. Before MPV can be adopted for wider clinical use, the methodological problems involved in obtaining accurate and interlaboratory comparable results must be resolved. In particular, a major degree of standardization is required, as are local reference ranges calculated with respect to specified time intervals from venipuncture to laboratory analysis. We discuss here the potential role of MPV in predicting the risk of acquired thrombotic disorders in addition to roles in congenital thrombocytopenic disorders, as well as the problems and pitfalls associated with use of MPV in these settings.
Millar CM, Laffan MA, 2017, Drug therapy in anticoagulation: which drug for which patient?, CLINICAL MEDICINE, Vol: 17, Pages: 233-244, ISSN: 1470-2118
Four non-vitamin K oral anticoagulants (NOACs) are now licensed and available in the UK, offering unprecedented choices in anticoagulant therapy for clinicians and patients. NOACs have many clear benefits over warfarin, the most striking being the reduction in intracranial haemorrhage. However, a number of uncertainties remain: their efficacy in certain situations, utility of drug assays, significance of drug interactions and management of bleeding. In the absence of any direct comparative trials, it is not clear that any of the NOACs is significantly better than the others in any of the licensed indications. The differential activities, pharmacokinetics, metabolism, excretion and side effects of the agents should be considered when selecting the most appropriate anticoagulant. In this article, we discuss how, with careful selection for the relevant indication, NOACs can simplify therapy while improving outcomes. We aim to provide clinicians with the information needed to select the most suitable anticoagulant drug for an individual patient in a given situation.
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