Functional imaging in asthma and COPD: design of the NOVELTY ADPro substudy

Helen Marshall, Jim M. Wild, Laurie J. Smith, Latife Hardaker, Titti Fihn-Wikander, Hana Müllerová, Rod Hughes for the NOVELTY study investigators
ERJ Open Research 2023 9: 00344-2022; DOI: 10.1183/23120541.00344-2022

Abstract

The NOVEL observational longiTudinal studY (NOVELTY; ClinicalTrials.gov identifier NCT02760329) is a global, prospective, observational study of ∼12 000 patients with a diagnosis of asthma and/or COPD. Here, we describe the design of the Advanced Diagnostic Profiling (ADPro) substudy of NOVELTY being conducted in a subset of ∼180 patients recruited from two primary care sites in York, UK. ADPro is employing a combination of novel functional imaging and physiological and metabolic modalities to explore structural and functional changes in the lungs, and their association with different phenotypes and endotypes.

Patients participating in the ADPro substudy will attend two visits at the University of Sheffield, UK, 12±2 months apart, at which they will undergo imaging and physiological lung function testing. The primary end-points are the distributions of whole lung functional and morphological measurements assessed with xenon-129 magnetic resonance imaging, including ventilation, gas transfer and airway microstructural indices. Physiological assessments of pulmonary function include spirometry, bronchodilator reversibility, static lung volumes via body plethysmography, transfer factor of the lung for carbon monoxide, multiple-breath nitrogen washout and airway oscillometry. Fractional exhaled nitric oxide will be measured as a marker of type-2 airways inflammation.

Regional and global assessment of lung function using these techniques will enable more precise phenotyping of patients with physician-assigned asthma and/or COPD. These techniques will be assessed for their sensitivity to markers of early disease progression.

Abstract

The NOVELTY ADPro substudy will use functional imaging and physiological and metabolic measures to examine patterns of ventilation, gas transfer, acinar dimensions and small airway dysfunction to phenotype patients with asthma and/or COPD more precisely. https://bit.ly/3GfmN4S

Introduction

Background

Asthma and COPD are highly prevalent lung diseases, affecting >600 million individuals globally [1]. They are often regarded as separate clinical disorders; however, they are heterogeneous diseases with similar symptoms, and patients may have features of both [2, 3]. In addition, there is significant overlap in the diagnostic criteria and clinical presentation for asthma and COPD, including symptoms, airflow obstruction, increased expiratory time, hyperinflation and response to bronchodilators [2, 3].

Spirometry is an important method of pulmonary function testing for diagnosing and stratifying obstructive lung disease; however, it is largely insensitive to changes involving the small airways, and substantial small airways disease often exists before spirometry appears to be abnormal [4]. Patients with normal spirometry can also exhibit other characteristics of disease, such as ventilation heterogeneity, gas trapping and impaired gas exchange [4, 5].

Therefore, there is a need for additional diagnostic procedures to gain a better understanding of the nature of the structural and functional changes in the airways and alveoli that may be associated with different clinical phenotypes, endotypes, exposure to tobacco smoke or other harmful particles, and inflammatory patterns seen in patients with asthma and/or COPD.

Hyperpolarised xenon-129 (129Xe) magnetic resonance imaging (MRI) is a highly sensitive imaging technique that has gained traction in recent years for examining lung function and structure. Previous studies have used hyperpolarised helium-3 (3He) MRI to assess lung ventilation in patients with asthma and/or COPD [6–10], with some including measurements of longitudinal change [6, 7] and alveolar microstructure [6]. Due to the additional ability of 129Xe to measure gas exchange, and a shortage of 3He, recent studies have used 129Xe MRI to assess lung ventilation [5, 11–15], alveolar microstructure [11–13, 16] and gas exchange [17, 18] in patients with asthma and/or COPD. However, study protocols that use 129Xe MRI to identify and characterise damage to the lungs in asthma and/or COPD across the spectrum of disease stage, severity and diagnosis, are lacking. Additionally, these studies have not used 129Xe MRI to investigate ventilation, acinar microstructure and gas exchange simultaneously, or to assess longitudinal change.

Advanced Diagnostic Profiling

The NOVEL observational longiTudinal studY (NOVELTY; ClinicalTrials.gov identifier: NCT02760329) is a large, global, prospective, cohort study enrolling patients with a suspected or confirmed physician diagnosis of asthma and/or COPD [1]. Analyses have demonstrated heterogeneity within physician-assigned diagnosis groups and overlap between patients with asthma and/or COPD in the cohort [19].

The Advanced Diagnostic Profiling (ADPro) study is a substudy of NOVELTY recruiting patients from two primary care sites in York, UK. It is designed to examine patterns of ventilation, gas transfer, acinar dimensions and small airways dysfunction in patients with asthma and/or COPD using novel imaging, advanced pulmonary function tests and metabolic modalities. Procedures include hyperpolarised gas MRI, multiple-breath nitrogen washout (MBW) and airwave oscillometry (AOS). The ADPro substudy will use these modalities to assess early markers and phenotypes of lung disease, with the aim of understanding which techniques are most sensitive to initial changes in lung morphology during disease progression.

Ventilation patterns

Hyperpolarised 129Xe MRI can provide detailed, three-dimensional (3D) imaging of ventilation patterns, which allows measurement of the proportion of unventilated lung (ventilation defect percentage) and ventilation heterogeneity [11]. MBW allows calculation of the lung clearance index (LCI), which quantifies the overall degree of global ventilation heterogeneity and is sensitive enough to assess small airways abnormalities [20, 21]. 129Xe MRI treatment response mapping can provide regional information on ventilation changes between imaging time points [22].

Small airways disease and inflammation

Small airways obstruction frequently occurs during the earliest stages of disease for both asthma and COPD [4]. However, clinical assessment of the small airways is challenging, due to their small size and inaccessibility [20], and finding new methods and markers to facilitate the earlier detection of small airways disease may enable the delivery of targeted therapy to slow or alter the course of disease [20, 23]. Small airways obstruction can be assessed using AOS, MBW and body plethysmography [21, 24, 25]. 129Xe MRI can also be used to gain information about the alveolar and acinar size and microstructure, and potentially detect early emphysema [26, 27]. Additionally, fractional exhaled nitric oxide (FENO) indicates the level of type-2 airways inflammation [4]. Examining these measures of small airways disease may help to determine markers of early lung disease and identify patients at risk of rapid progression.

Mucous plugging and gas trapping

Mucous plugs in patients with obstructive pulmonary disease are thought to contribute to the pathophysiology of airflow obstruction and gas trapping in severe asthma and COPD [28, 29]. Body plethysmography can be used to identify gas trapping and lung hyperinflation [4]. Structural proton (1H) MRI images can also be used to visualise air trapping and larger mucous plugs [30].

Gas exchange

Gas exchange can be impaired due to inflammatory thickening of the lung parenchyma, or breakdown of alveolar walls in emphysema [4, 31], which can cause large air-filled spaces to form in the lung parenchyma [4, 32]. 129Xe MRI is uniquely capable of imaging the transfer of gas from the airspaces across the alveolar–capillary barrier and into the red blood cells (RBCs), enabling the assessment of all three of the components of gas exchange: airspace, alveolar–capillary membrane and RBCs. This allows impairments in gas transfer that can arise with disease to be identified [17, 31]. The transfer factor of the lungs for carbon monoxide (TLCO) provides information about the surface area and integrity of the alveolar membrane, and impairments in gas exchange [33].

Aims

To describe the design and rationale of the ADPro substudy of NOVELTY, which will allow detailed assessments of exploratory and pre-defined phenotypes in patients with physician-assigned asthma and/or COPD. Phenotypes being assessed include small airways disease, emphysematous disease and inflammatory phenotypes, and these will be compared between asthma and COPD. The study also aims to identify methods that will allow the earlier detection of asthma and COPD in the future, and to explore patients at risk of progression.

Materials and methods

Study design

The ADPro substudy aims to recruit ∼180 patients enrolled in NOVELTY. NOVELTY is a global, prospective, observational study enrolling ∼12 000 patients with asthma and/or COPD (suspected or confirmed); the study design and patient eligibility criteria have been described previously [1]. Given the observational nature of NOVELTY, patients will receive standard medical care as determined by their physician; no experimental intervention or treatment will be given as part of NOVELTY. All patients enrolled in NOVELTY will attend a baseline visit in which patient demographics, characteristics, risk factors for development of obstructive lung disease and patient-reported outcomes (including the Chronic Airways Assessment Test (CAAT) and the Respiratory Symptoms Questionnaire (RSQ)) will be recorded. Patients will complete the CAAT and RSQ every 3 months after the baseline visit. Patients participating in the ADPro substudy will attend two additional visits accompanied by a study nurse for lung imaging and lung function assessments at the POLARIS lung imaging centre, University of Sheffield (Sheffield, UK) (figure 1). Imaging will be performed at the Royal Hallamshire Hospital and Northern General Hospital sites, under the governance of Sheffield Teaching Hospitals National Health Trust.

FIGURE 1
FIGURE 1

Advanced Diagnostic Profiling (ADPro) substudy design. NOVELTY: NOVEL observational longiTudinal studY; BMI: body mass index; BD: bronchodilator; 129Xe: xenon-129; MRI: magnetic resonance imaging; 1H: proton; MBW: multiple-breath nitrogen washout; AOS: airwave oscillometry; R5–R20: resistance between 5 and 20 Hz; TLCO: transfer factor of the lung for carbon monoxide; FENO: fractional exhaled nitric oxide.

ADPro substudy protocol-based objectives

The primary objective is to assess global and regional lung functional and morphological measurements with 129Xe MRI, including ventilation, gas transfer and airway microstructural indices. The procedures and variables used to assess the primary, secondary and exploratory objectives are given in table 1.

View this table:
TABLE 1

Overview of Advanced Diagnostic Profiling (ADPro) substudy assessments

Secondary and exploratory objectives are to:

  1. evaluate relationships between 129Xe MRI measurements of ventilation and airway microstructural indices, and pulmonary function markers of small airways dysfunction;

  2. evaluate relationships between 129Xe MRI gas transfer and airway microstructural indices, and pulmonary function markers of gas transfer and gas trapping;

  3. describe heterogeneity of regional ventilation, gas transfer and alveolar microstructure;

  4. describe the progression of 129Xe MRI and pulmonary function indices between substudy visits 1 and 2, and compare the sensitivity of the measures to longitudinal change;

  5. assess bronchodilator reversibility using pulmonary function tests and 129Xe MRI;

  6. assess MRI-derived mucous plugging and air trapping scores;

  7. describe associations between FENO and markers of ventilation heterogeneity, small airways dysfunction and clinical descriptors;

  8. assess the relationship between the progression of 129Xe MRI and pulmonary function indices between substudy visits 1 and 2, and disease progression (assessed by change in forced expiratory volume in 1 s (FEV1) and CAAT scores).

Patients

Patients enrolled in NOVELTY will be recruited from two primary care sites in York, UK. Patients with physician-identified suspected or confirmed asthma and/or COPD (no specified diagnostic criteria) recruited to the ADPro substudy will be a representative spread across physician-assigned diagnostic groups and physician-assessed categories of severity. Patients will be aged ≥16 years and be enrolled from an active clinical practice. Patients will not have participated in any respiratory interventional trial in the previous 12 months.

Substudy procedures

At each substudy visit, patient smoking activity and concomitant medication within the past 24 h, asthma or COPD exacerbations within the past 6 weeks, physiological data (e.g. height, weight and body mass index) and contraindications to MRI will be recorded by the study nurse using a designated electronic case report form (eCRF). At substudy visit 1, imaging and pulmonary function testing will be undertaken post-bronchodilator (figure 1). At visit 2, 129Xe ventilation MRI at end-inspiratory tidal volume and 129Xe gas exchange MRI will be obtained pre- and post-bronchodilator, and 129Xe MRI microstructural imaging will be obtained post-bronchodilator. Post-bronchodilator imaging will be conducted ≥20 min after the administration of 400 µg salbutamol. Post-bronchodilator, MRI will be performed before pulmonary function tests to avoid any changes in lung physiology that might be induced by performing the forced manoeuvres required for spirometry and plethysmography. Patients will be asked to withhold their bronchodilator medications for ≥24 h prior to visit 2, during which time any reliever medication use will be recorded. The imaging and pulmonary function tests that will be conducted at each visit, and their component measures, are shown in figures 1 and 2, and table 1, respectively.

FIGURE 2
FIGURE 2

Lung structure and variables assessed in the Advanced Diagnostic Profiling (ADPro) substudy. TLC: total lung capacity; RV: residual volume; FRC: functional residual capacity; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; LCI: lung clearance index; VDP: ventilation defect percentage; CV: coefficient of variation of signal intensity; ΔR: regional treatment response; FENO: fractional exhaled nitric oxide; t1: longitudinal relaxation time; ADC: apparent diffusion coefficient; LmD: diffusive length scale; M0: proton spin density; IC: inspiratory capacity; PEF: peak expiratory flow; FEF25–75%: forced expiratory flow at 25–75% of FVC; R5: resistance at 5 Hz; R5–R20: resistance between 5 and 20 Hz; AX: airway reactance; fres: resonance frequency; RBC: red blood cell; M: membrane; TLCO: transfer factor of the lung for carbon monoxide; KCO: transfer coefficient for carbon monoxide.

Imaging

MRI is noninvasive and ionising radiation-free. 129Xe MRI involves the inhalation of hyperpolarised 129Xe and imaging during a short breath-hold. Patients will be scanned supine using a whole-body 1.5-T MRI scanner equipped with a 129Xe transmit/receive vest coil (GE Signa HDx; Milwaukee, USA). The 129Xe gas will be generated onsite [42] under the Medicines and Healthcare Products Regulatory Agency regulatory specials licence and administered via inhalation from a Tedlar plastic bag.

We are assessing markers of ventilation heterogeneity to investigate whether they might explain some of the variability of symptoms in patients with similar levels of airflow impairment. We will compare the regional ventilation imaging patterns and LCI with patient-reported outcomes to determine if these measures can predict symptoms, such as breathlessness. 129Xe breath-hold ventilation imaging of the lung will be performed at end-inspiratory tidal volume and at total lung capacity (TLC) using a 3D steady-state free precession sequence, with co-registered 1H anatomical imaging [11]. 129Xe 3D dissolved phase imaging will be used to assess gas exchange by assessing 129Xe in the capillary RBCs and lung tissue, and gaseous 129Xe in the alveolar compartments [34]. 129Xe 3D diffusion-weighted MRI will be used to assess alveolar microstructure [26]. Structural proton (1H) MRI of the lung using a 3D gradient echo sequence, at approximate lung volumes of end-inspiratory tidal volume, residual volume (RV) and TLC, and an ultra-short echo time sequence [43] will be used to qualitatively assess air trapping. Mucous plugging will be assessed by radiological review of the images; structural proton (1H) MRI will be co-registered with larger ventilation defects to determine to what extent the ventilation defects are due to mucous plugs or bronchial tapering. 129Xe MRI treatment response mapping will enable the evaluation of regional lung ventilation longitudinally over the 12-month period, and between pre-bronchodilator and post-bronchodilator imaging. Longitudinal relaxation time and proton spin density mapping will be performed using 3D gradient echo sequences with variable flip angles [35, 36].

Pulmonary function tests

Spirometry to calculate FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow, forced expiratory flow at 25–75% of the FVC and inspiratory capacity will be performed according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria [44]. Static lung volumes (to calculate TLC, RV, functional residual capacity (FRC), RV/TLC and FRC/TLC) will be measured via body plethysmography according to international guidelines [37] using a Vyaire PFT Pro (Vyaire Medical, Inc., Basingstoke, UK). TLCO will also be performed on a Vyaire PFT Pro and according to international guidelines [45]. Spirometry, static lung volume and gas transfer measurements will be expressed as both z-scores and % predicted. Measurements will be converted to z-scores using recommended reference equations [44, 46, 47]; a z-score of <−1.64 will be defined as the lower limit of normal.

MBW to calculate the LCI will be performed using an Eco Medics Exhalyzer D and according to international guidelines at visit 1 only [21]. AOS will be performed using a Thorasys TremoFlo C-100, according to manufacturer guidelines and in keeping with international guidance [48], to calculate the resistance at 5 Hz and the difference between the resistance at 5 and 20 Hz, the reactance at 5 Hz, the resonance frequency and the area of the reactance curve. The results will be expressed as % predicted and z-scores [49]. Reversibility of airway obstruction will be assessed at visit 2 only. At visit 2, patients will withhold their short-acting bronchodilator medication for ≥6 h prior to reversibility testing and their long-acting bronchodilators, with or without inhaled corticosteroids, for 12–24 h, depending on whether the patient is using twice- or once-daily therapy.

Metabolic measures

FENO will be performed using a Niox Vero according to the equipment manufacturer recommendations and ATS/ERS guidelines [50]. All FENO data will be entered into the eCRF.

Statistical analysis

The sample size calculation used in NOVELTY has been described previously [1]; given the observational nature of the ADPro substudy, no formal size calculation was performed. However, we aimed to recruit ∼30 patients within each disease severity for patients with a clinical primary diagnosis of asthma or COPD (with or without features of the other diagnosis). This projected sample size was selected based on previous MRI studies that have identified clinically meaningful correlations [5, 12, 13, 15]. Disease progression will be defined by relative changes to FEV1 and CAAT between visits 1 and 2. Spearman's correlations will be performed to assess relationships between imaging, pulmonary function tests and clinical metrics. Data will be divided into three groups based on physician-assigned diagnosis: asthma, asthma and COPD, and COPD. For each metric, differences between groups will be assessed using either a one-way ANOVA test with Tukey correction for multiple comparisons (for normally distributed data), or a Kruskal–Wallis test with Dunn's correction for multiple comparisons (for non-normally distributed data). To assess change in metrics between visit 1 and visit 2, and change in metrics in response to bronchodilator administration, paired t-tests (for normally distributed data) or Wilcoxon matched pairs tests (for non-normally distributed data) will be performed. A p-value <0.05 will be considered statistically significant. Treatment changes will be considered as a covariant when assessing imaging or physiological changes between visit 1 and visit 2.

Ethics approval and consent

The ADPro substudy will be conducted following the principles of the Declaration of Helsinki, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practices, Good Pharmacoepidemiology Practices and applicable legislation for observational studies. The ADPro substudy has been approved by the Leicester Central Research Ethics Committee (reference no. 16/EM/0439). Written informed consent will be obtained by trained study staff from all patients who wish to participate in the ADPro substudy prior to any procedure being performed.

Discussion

By examining a range of functional, morphological, physiological and metabolic markers, the ADPro substudy will allow evaluation of the varying patterns of ventilation heterogeneity, gas exchange, acinar dimensions and small airways dysfunction in patients with asthma and/or COPD, as well as their relationship to important clinical features. These evaluations could allow us to profile patients based on the presence of small airways disease, airways inflammation, lung parenchymal distortion and disease progression. We hope that by more precisely phenotyping and endotyping patients with physician-diagnosed asthma and/or COPD, we will identify clinically meaningful profiles that may help to inform a precision medicine-based approach to asthma and COPD care in future. In addition, this comprehensive approach within a single cohort may highlight where differences exist between patients with guideline-determined diagnoses of asthma or COPD and patients with physician-diagnosed asthma and/or COPD in the real world, and where they overlap. Furthermore, given the broad inclusion criteria, patients included will be representative of both early and late disease stages. Analysing the longitudinal changes in patients with preserved spirometry will be of particular importance when determining which methods are the most sensitive to early changes to the lungs in disease and which may enable the earlier detection of disease in future.

Until recently, phenotyping of patients with obstructive lung disease has been reliant on nonspecific clinical risk factors and exposures, poorly differentiating symptoms and overlapping lung function measures [2, 3]. The addition of functional imaging, such as 129Xe MRI, may facilitate more specific and earlier detection of significant airways and lung parenchymal disease. Compared with FEV1, 129Xe MRI has increased sensitivity to lung abnormalities and bronchodilator response, and can depict regional heterogeneity of ventilation, as opposed to providing a whole-lung average. It is also more effective than computed tomography (CT) in evaluating the alveolar microstructure and distinguishing patients with COPD from healthy controls [27]. The high sensitivity of 129Xe MRI provides a means to detect and characterise early emphysematous and obstructive lung disease, and to identify patients suitable for early interventions. 129Xe MRI can provide information to aid the identification of structural and functional phenotypes, particularly in regions of air trapping and mucous plugging [27]. Therefore, the clinical use of 129Xe MRI in future may allow us to identify more discrete phenotypes across diagnostic categories and predict those at risk of more rapidly progressive disease.

Given the observational design of the NOVELTY study, patients will receive standard medical care. The ADPro substudy will analyse markers of disease progression irrespective of treatment changes; however, changes to treatment will be considered as a co-variant when assessing any imaging or physiological changes.

The strengths of the ADPro substudy reflect those of the NOVELTY study [1]; patients with asthma and/or COPD have been recruited from primary care and are not limited by many of the eligibility criteria restrictions associated with randomised controlled trials. Containing a diverse patient population within the same study protocol will enable comparisons between patients across the spectrum of asthma and COPD, including those with features of both diagnoses and those with early disease. Furthermore, this study will evaluate 129Xe MRI ventilation, microstructural and gas exchange indices in this patient population, whereas previous studies using 129Xe in patients with asthma or COPD have only reported on one or two aspects of lung function and have not assessed longitudinal change [5, 11–18].

One limitation of the ADPro substudy may be that recruitment through clinical practice could bias the study population towards those with more frequent healthcare utilisation. The substudy population are recruited from one area of the UK, so may not be representative of patients in other parts of the world. Travelling to the study site and receiving the tests required at both study visits is likely to be time-consuming and could constitute a substantial burden for the patient. It is possible that patients who are willing to travel and undergo extensive imaging procedures, particularly during the coronavirus disease 2019 (COVID-19) pandemic, have mild disease. In order to reduce the time burden of each visit, not all tests are conducted at both visits. Finally, the 12-month time period between visit 1 and visit 2 will not be long enough to capture all patients with disease progression; a longer trial would be needed to explore long-term disease progression.

As the primary purpose of this study was to evaluate functional ventilatory assessment, clinical and physiological measurements, it was not deemed necessary to include detailed anatomical structure. Given the sensitivity of MRI ventilation imaging, CT imaging is unlikely to have added to the understanding of these relationships, and the utilisation of ionising radiation would add risk and inconvenience to participants. In future, larger studies comparing the relative utility of MRI and CT for the assessment of functional markers in specific disease areas may be necessary.

Overall, this longitudinal study employs novel imaging techniques, as well as physiological and metabolic testing to more precisely phenotype patients with asthma and COPD by identifying small airways disease, emphysematous disease and inflammation. These techniques will be assessed for their sensitivity to changes in lung function and morphology during disease progression, and in response to bronchodilator administration. This study is being conducted during the COVID-19 pandemic despite the associated challenges. These findings should increase our understanding of the phenotypes and endotypes of patients with asthma and COPD, and help to inform a precision-based medicine approach to patient care in future.

Acknowledgements

The authors thank the patients and NOVELTY study investigators for their contribution to the study. Medical writing support, under the direction of the authors, was provided by Katie Webster of Core Medica, London, UK, and was funded by AstraZeneca, Cambridge, UK, in accordance with Good Publication Practice guidelines.

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Conflict of interest: H. Marshall, J. Wild and L. Smith are employees of the University of Sheffield, who received funding to conduct the study. H. Marshall has received support for attending meetings from AstraZeneca. T. Fihn-Wikander and H. Müllerová are employees of AstraZeneca. R. Hughes has received personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis outside of the submitted work, and is an employee of AstraZeneca. L. Hardaker has no conflicts to disclose.

  • Support statement: The NOVELTY ADPro substudy is funded by AstraZeneca. The sponsor participated in the design of the study and preparation of the manuscript. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received July 12, 2022.
  • Accepted December 17, 2022.
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Functional imaging in asthma and COPD: design of the NOVELTY ADPro substudy
Helen Marshall, Jim M. Wild, Laurie J. Smith, Latife Hardaker, Titti Fihn-Wikander, Hana Müllerová, Rod Hughes
ERJ Open Research Mar 2023, 9 (2) 00344-2022; DOI: 10.1183/23120541.00344-2022
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