268 results found
Su J, Simonsen U, Mellemkjaer S, et al., 2021, Limited value of pulse wave analysis in assessing arterial wave reflection and stiffness in the pulmonary artery., Physiol Rep, Vol: 9
We explored the use of the augmentation index (AI) based on pulse wave analysis (PWA) in the pulmonary circulation as a measure of wave reflection and arterial stiffness in individuals with and without pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in 10 controls, 11 PAH patients, and 11 CTEPH patients. PWA was applied to the measured pressure, while wave intensity analysis (WIA) and wave separation analysis (WSA) were performed using both the pressure and velocity to determine the magnitudes and timings of reflected waves. Type C (AI < 0) pressure waveform dominated in controls and type A (AI > 12%) waveform dominated in PAH patients, while there was a mixture of types A, B, and C among CTEPH patients. AI was greater and the inflection time shorter in CTEPH compared to PAH patients. There was a poor correlation between AI and arterial wave speed as well as measures of wave reflection derived from WIA and WSA. The infection point did not match the timing of the backward compression wave in ~50% of the cases. In patients with type C waveforms, the inflection time correlated well to the timing of the late systolic forward decompression wave caused by ventricular relaxation. In conclusion quantifying pulmonary arterial wave reflection and stiffness using AI based on PWA may be inaccurate and should therefore be discouraged.
Errington N, Iremonger J, Pickworth JA, et al., 2021, A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach, EBioMedicine, Vol: 69, ISSN: 2352-3964
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models. METHODS: Plasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis. FINDINGS: 20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells. INTERPRETATION: This consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets.
Kotecha T, Knight DS, Razvi Y, et al., 2021, Patterns ofmyocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 1866-1878, ISSN: 0195-668X
Frantz RP, Highland KB, McConnell JW, et al., 2021, A Phase 1b, Multi-Center, Randomized, Placebo-Controlled Trial of Inhaled Seralutinib in Subjects with WHO Group 1 Pulmonary Arterial Hypertension, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Seligman H, Zaman S, Pitcher DS, et al., 2021, Reusable snorkel masks adapted as particulate respirators, PLOS ONE, Vol: 16, ISSN: 1932-6203
Frantz R, Howard LS, McLaughlin VV, et al., 2021, Phase 2 Clinical Study to Evaluate the Efficacy and Safety of Inhaled GB002 for the Treatment of World Health Organization Group 1 Pulmonary Arterial Hypertension, Publisher: ELSEVIER SCIENCE INC, Pages: S107-S107, ISSN: 1053-2498
Price LC, Martinez G, Brame A, et al., 2021, Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement, BRITISH JOURNAL OF ANAESTHESIA, Vol: 126, Pages: 774-790, ISSN: 0007-0912
Howard LSGE, He J, Watson GMJ, et al., 2021, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials., Ann Am Thorac Soc
RATIONALE: Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES: To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS: In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS: Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION: Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
Mikhail G, Khawaja SA, Mohan P, et al., 2021, COVID-19 and its impact on the cardiovascular system, Open Heart, Vol: 8, Pages: 1-9, ISSN: 2053-3624
Objectives: The clinical impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare NHS Trust, United Kingdom.Methods: We retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7th March to 7th April 2020. Patient data was collected for baseline demographics, co-morbidities and in-hospital outcomes, especially relating to cardiovascular intervention.Results:Mean age was 67.4±16.1 years and 62.2%(n=310) were male. 64.1%(n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4%(n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%,p<0.001). Only 4 COVID-19 patients had invasive coronary angiography,2 underwent percutaneous coronary intervention and 1 required a permanent pacemaker implantation. 7.0%(n=35) of patients had an inpatient echocardiogram. Acute myocardial injury (OR 2.39,1.31-4.40,p=0.005) and history of hypertension (OR 1.88 ,1.01-3.55,p=0.049) approximately doubled the odds of in-hospital mortality in patients admitted with COVID-19 after other variables had been controlled for.Conclusion:Hypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.
Lewis RA, Armstrong I, Bergbaum C, et al., 2021, EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study, EUROPEAN RESPIRATORY JOURNAL, Vol: 57, ISSN: 0903-1936
Swietlik EM, Greene D, Zhu N, et al., 2021, Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension., Circulation: Genomic and Precision Medicine, Vol: 14, Pages: 57-70, ISSN: 2574-8300
Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Dhawan RT, Gopalan D, Howard L, et al., 2021, Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19, LANCET RESPIRATORY MEDICINE, Vol: 9, Pages: 107-116, ISSN: 2213-2600
Afoke J, Kanaganayagam GS, Casula R, et al., 2020, Cardiopulmonary exercise testing as a guideline indicator for mitral valve intervention, Publisher: OXFORD UNIV PRESS, Pages: 2003-2003, ISSN: 0195-668X
Stolfo D, Albani S, Biondi F, et al., 2020, Global Right Heart Assessment with Speckle-Tracking Imaging Improves the Risk Prediction of a Validated Scoring System in Pulmonary Arterial Hypertension, JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY, Vol: 33, Pages: 1334-+, ISSN: 0894-7317
Swietlik EM, Ghataorhe P, Zalewska K, et al., 2020, Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension, European Respiratory Journal, Vol: 57, Pages: 1-14, ISSN: 0903-1936
Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations.We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated.We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by ROC analysis to distinguish CTEPH and both healthy (AUCs 0.64–0.94, all p<2×10−5) and disease controls (AUCs 0.58–0.77, all p<0.05. Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15–100% of perturbation) in response to PEA were observed in some but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine, and Krebs cycle metabolites . Metabolites associated with CTEPH and gradients also showed significant associations with clinical measures of disease severity.We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with PH and metabolites t
Rinaldo RF, Vigo B, Davies R, et al., 2020, Cardiopulmonary exercise testing responses to initial treatment in Group 1 pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Vigo B, Rinaldo RF, Davies R, et al., 2020, Cardiopulmonary exercise test unveils abnormal exercise physiology in patients affected by pulmonary arterial hypertension with a low-risk profile 6 minute walk distance, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Howard L, Chin K, Fong Y-L, et al., 2020, CIPHER: a prospective, multicentre study for the identification of biomarker signatures for early detection of pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Otero-Nunez P, Rhodes C, Wharton J, et al., 2020, Multi-omic profiling in pulmonary arterial hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Swietlik E, Ghataorhe P, Zalewska K, et al., 2020, Plasma metabolomics in chronic thromboembolic pulmonary hypertension, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Price L, Brame A, Martinez G, et al., 2020, Perioperative management of patients with Pulmonary Hypertension undergoing Non-Cardiac Surgery: A Systemic Review and UK Consensus Statement, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Lewis R, Armstrong I, Bergbaum C, et al., 2020, EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multi-centre study, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Rhodes C, Otero-Núñez P, Wharton J, et al., 2020, Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 586-594, ISSN: 1073-449X
Rationale: Idiopathic and hereditary pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA-sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signalling pathways and stratify patients more robustly according to clinical risk. Objectives: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (MR) analysis. Methods: RNA-sequencing was performed on whole blood samples from 359 patients with idiopathic, heritable and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known eQTL and summary statistics from a PAH GWAS. Measurements and Main Results: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). Conclusions: A whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.
Sofianopoulou E, Church C, Coghlan G, et al., 2020, Deprivation and prognosis in patients with pulmonary arterial hypertension: missing the effect of deprivation on a rare disease?, European Respiratory Journal, Vol: 56, ISSN: 0903-1936
Alikhan R, Church C, Shapiro S, et al., 2020, Final results from the apixaban length-of-stay pulmonary embolism study - Hospital Admissions (ALPHA-PE), 60th Annual Scientific Meeting of the British-Society-for-Haematology (BSH), Publisher: WILEY, Pages: 71-72, ISSN: 0007-1048
Grapsa J, Tan TC, Nunes MCP, et al., 2020, Prognostic impact of right ventricular mass change in patients with idiopathic pulmonary arterial hypertension, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 304, Pages: 172-174, ISSN: 0167-5273
Rothman AMK, Vachiery J-L, Howard LS, et al., 2020, Intravascular ultrasound pulmonary artery denervation to treat pulmonary arterial hypertension (TROPHY1), JACC: Cardiovascular Interventions, Vol: 13, Pages: 989-999, ISSN: 1936-8798
ObjectivesThe aim of this study was to investigate whether therapeutic intravascular ultrasound pulmonary artery denervation (PDN) is safe and reduces pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) on a minimum of dual oral therapy.BackgroundEarly studies have suggested that PDN can reduce PVR in patients with PAH.MethodsTROPHY1 (Treatment of Pulmonary Hypertension 1) was a multicenter, international, open-label trial undertaken at 8 specialist centers. Patients 18 to 75 years of age with PAH were eligible if taking dual oral or triple nonparenteral therapy and not responsive to acute vasodilator testing. Eligible patients underwent PDN (TIVUS System). The primary safety endpoint was procedure-related adverse events at 30 days. Secondary endpoints included procedure-related adverse events, disease worsening and death to 12 months, and efficacy endpoints that included change in pulmonary hemodynamic status, 6-min walk distance, and quality of life from baseline to 4 or 6 months. Patients were to remain on disease-specific medication for the duration of the study.ResultsTwenty-three patients underwent PDN, with no procedure-related serious adverse events reported. The reduction in PVR at 4- or 6-month follow-up was 94 ± 151 dyn·s·cm−5 (p = 0.001) or 17.8%, which was associated with a 42 ± 63 m (p = 0.02) increase in 6-min walk distance and a 671 ± 1,555 step (p = 0.04) increase in daily activity.ConclusionsIn this multicenter early feasibility study, PDN with an intravascular ultrasound catheter was performed without procedure-related adverse events and was associated with a reduction in PVR and increases in 6-min walk distance and daily activity in patients with PAH on background dual or triple therapy.
Peacock AJ, Ling Y, Johnson MK, et al., 2020, Idiopathic pulmonary arterial hypertension and co-existing lung disease: is this a new phenotype?, Pulmonary Circulation, Vol: 10, Pages: 1-8, ISSN: 2045-8940
Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease). Patients with ‘IPAH lung disease’ have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ‘IPAH no lung disease’. We described the outcome of the cohort of patients with ‘IPAH no lung disease’ in a previous paper. Here, we have compared incident ‘IPAH lung disease’ patients with ‘IPAH no lung disease’ patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001–2009. Compared with ‘IPAH no lung disease’ (n = 355), ‘IPAH lung disease’ patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ‘IPAH lung disease’ and ‘IPAH no lung disease’. However, survival of ‘IPAH lung disease’ was lower than ‘IPAH no lung disease’ (one year survival: 72% compared with 93%). This survival was significantly w
Hodgson J, Swietlik EM, Salmon RM, et al., 2020, Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 575-585, ISSN: 1073-449X
OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised plasma BMP9 and BMP10 levels in patients with idiopathic PAH. METHODS: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. CONCLUSIONS: Our findings demonstrate that GDF2 mutations result in BMP9 loss-of-function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH.
Rosenkranz S, Howard LS, Gomberg-Maitland M, et al., 2020, Systemic consequences of pulmonary hypertension and right-sided heart failure., Circulation, Vol: 141, Pages: 678-693, ISSN: 0009-7322
Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.
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