- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03203512
Fish Oil-derived N-3 Polyunsaturated Fatty Acids and Extracellular Vesicles (HI-FIVE)
November 4, 2022 updated by: Professor Parveen Yaqoob, MA, DPhil, RNutr, FAfN, University of Reading
Effects of Fish Oil-derived N-3 Polyunsaturated Fatty Acids on the Generation and Functional Activities of Extracellular Vesicles
N-3 polyunsaturated fatty acids (n-3 PUFA), which are abundant in oily fish and fish oils, have been suggested to play a role in reducing the risk of cardiovascular diseases (CVDs) by modifying a wide range of risk factors, such as blood fats, blood clotting, blood vessel function and inflammation.
Extracellular vesicles (EVs) are small particles released from various cells when they are activated or damaged.
High numbers of EVs in the blood have been associated with a higher risk of CVDs, and it is thought that this is because they carry 'bioactive' components which can affect many processes involved in CVDs.
However, very few clinical trials have investigated the relationships between the consumption of n-3 PUFA and circulating EVs.
This study aims to investigate the effects of dietary n-3 PUFA on the generation and functional activities of EVs, which would provide new insight into the benefits of n-3 PUFA on cardiovascular health.
Study Overview
Status
Completed
Intervention / Treatment
Detailed Description
The proposed study will be a randomised, double-blind, placebo-controlled crossover intervention.
Subjects (40-70y) at moderate CVDs risk will be supplemented with either fish oil (1.8 g/d n-3 PUFA) or placebo (high-oleic safflower oil) for 12 weeks.
After a 12-week washout and then cross-over to the other intervention for another 12 weeks.
Blood samples will be collected before and after each intervention.
A food frequency questionnaire will be administered to assess the subject's habitual intake of n-3 PUFA.
Subjects will also be expected to maintain a low consumption of n-3 fatty acids, refrain from the use of all supplements, and maintain their body weight during the study.
The dose is based on our previous work, which demonstrated a reduction in numbers of endothelial-derived EVs (EEVs) and a trend for reduced numbers of platelet-derived EVs (PEVs), and a dose at which beneficial effects of n-3 PUFA on plaque stability are reported.
The experimental work will follow two main strands.
The first strand will examine the influence of n-3 PUFA supplementation on the characteristics and functional activities of total EVs from plasma.
The second strand will examine the influence of n-3 PUFA on the generation of PEVs from platelets taken from subjects and stimulated in vitro; the PEVs generated will subsequently be assessed for their composition and functional activity.
This experimental design will allow simultaneous investigation of both the composition and activity of total EVs taken directly from blood, and the generation and activity of PEVs.
Based on our previous work, 27 subjects are required to detect a 10% reduction in numbers of EVs following fish oil supplementation with a two-sided significance level of 5% and a power of 90%, and 34 subjects are required for a power of 95%.
Also based on previous data, 22 subjects would give 95% power to detect 10% differences in thrombus formation and 30 subjects are required to detect a significant effect of n-3 PUFA on platelet aggregation and phosphatidylserine (PS) exposure.
Allowing for a 15% dropout rate, and aiming for 95% power based on a 10% reduction in EVs numbers, we will therefore recruit 40 subjects in total.
Study Type
Interventional
Enrollment (Actual)
42
Phase
- Not Applicable
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
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Reading, United Kingdom, RG6 6AP
- University of Reading
-
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
40 years to 70 years (ADULT, OLDER_ADULT)
Accepts Healthy Volunteers
Yes
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Aged 40-70 years
- Non-smoker
At moderate risk of cardiovascular diseases
- The risk will be evaluated by an online calculator called "QRISK2". This online calculator (https://qrisk.org/2016/), which use traditional risk factors (age, systolic blood pressure, smoking status and ratio of total serum cholesterol to high-density lipoprotein cholesterol) together with body mass index, ethnicity, measures of deprivation, family history, will provide a percentage of risk of having a heart attack or stroke within the next 10 years.
- Subjects with 10%-20% will be regarded as being at moderate risk
Exclusion Criteria:
- BMI: <18.5 kg/m2
- Anaemia (haemoglobin concentration <12.5 g/L in men and<11.5 g/L in women)
- Hyperlipidaemia (total cholesterol concentration >8 mmol/L)
- Diabetes (diagnosed or fasting glucose concentration >7 mmol/L) or other endocrine disorders
- Angina, stroke, or any vascular disease in the past 12 months
- Renal, gastrointestinal, respiratory, liver or bowel disease
- Inflammatory disease
- Take drug treatment for hypertension, hyperlipidaemia, inflammation, depression or thyropathy.
- Take aspirin, ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs) > 4 times per month, or once in the week preceding the study
- Take any other anti-platelet or anti-coagulant drugs, like triflusal, clopidogrel and warfarin.
- Have allergies
- Smoking (including e-cigarettes and nicotine products)
- Alcohol misuse or intakes >21 units/wk for men and >15 units/wk for women or have a history of alcohol misuse
- Regularly consume oily fish and/or dietary supplements
- Planning to start or on a weight reducing regimen
- Intense aerobic exercise (>20 min, three times a week)
- Females who are pregnant, lactating, or if of reproductive age and not using a reliable form of contraception (including abstinence)
- Have participated in another clinical trial within the last three months
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: TRIPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: Intervention
Fish oil capsules
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Each serving contains 360mg eicosapentaenoic acid (EPA), 270mg docosahexaenoic acid (DHA) and total supplement is 1.8 g per day n-3 PUFA for 12 weeks
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PLACEBO_COMPARATOR: Placebo
High-oleic safflower oil capsules
|
High-oleic safflower oil capsules for 12 weeks
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Numbers of Circulating Total EVs in Platelet-free Plasma (PFP) Detected by Nanoparticle Tracking Analysis (NTA)
Time Frame: Change of circulating total EV numbers in PFP detected by NTA after intake period of 12 weeks
|
Circulating EVs were first isolated to obtain fractions 7~9 by size exclusion chromatography (SEC) using Izon qEV columns (Izon Science Ltd, Oxford, United Kingdom).
Fractions were then diluted with PBS to maintain the recommended concentration range of particles (1~10*10^8 vesicles/ml) before being analysed on NanoSight 300 (Malvern, Amesbury, United Kingdom).
For each analysis, five videos, each of 60 seconds duration, were captured with the camera level at 13. Data were analysed using the instrument software NTA 3.20, which can identify individual particles and estimate their sizes based on the Stokes-Einstein Equation.
Finally, a threshold of 70nm was set for NTA to ensure minimal interference by small lipoproteins.
|
Change of circulating total EV numbers in PFP detected by NTA after intake period of 12 weeks
|
Numbers of Total Phosphatidylserine Positive EVs (PS+EVs) in Platelet-free Plasma (PFP) Detected by Flow Cytometry (FCM)
Time Frame: Change of total PS+EV numbers in PFP detected by FCM after intake period of 12 weeks
|
A 5μl of PFP was added into nonsticky microcentrifuge tubes (Alpha Laboratories Ltd, Hampshire, United Kingdom), which contained 5μl FcR blocking reagent (Miltenyi Biotec Ltd, Surrey, United Kingdom) and Annexin V buffer and incubated for 15 minutes in the dark at room temperature.
Antibodies and isotype-matched controls were then added and samples incubated for another 15 minutes in the dark at room temperature.
After incubation, samples were diluted with 200μl Annexin V buffer and transferred into FACS flow tubes (BD Biosciences, Wokingham, United Kingdom), ready to be analysed by FCM.
PS+EVs were identified as Annexin V+EVs when triggering on APC fluorescence.
|
Change of total PS+EV numbers in PFP detected by FCM after intake period of 12 weeks
|
Characterisation of Circulating EVs Subpopulation in PFP Detected by Fluorescence FCM
Time Frame: Change in the numbers of circulating EVs subpopulation in PFP by fluorescence FCM after intake period of 12 weeks
|
A 5μl of PFP was added into nonsticky microcentrifuge tubes (Alpha Laboratories Ltd, Hampshire, United Kingdom), which contained 5μl FcR blocking reagent (Miltenyi Biotec Ltd, Surrey, United Kingdom) and Annexin V buffer and incubated for 15 minutes in the dark at room temperature.
Antibodies and isotype-matched controls were then added and samples incubated for another 15 minutes in the dark at room temperature.
After incubation, samples were diluted with 200μl Annexin V buffer and transferred into FACS flow tubes (BD Biosciences, Wokingham, United Kingdom), ready to be analysed by FCM.
Platelet-derived EVs (PDEVs) were identified as Annexin V+EVs which also stained positive for CD41-PE in APC vs PE quadrant plot, and endothelial-derived EVs (EDEVs) were identified as Annexin V+EVs which also stained positive for CD105- eFluor450 in APC vs PB quadrant plot.
|
Change in the numbers of circulating EVs subpopulation in PFP by fluorescence FCM after intake period of 12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pro-thrombotic Activities of Circulating EVs in PFP (Lag Time for Thrombin Generation)
Time Frame: Change of pro-thrombotic activities (lag time for thrombin generation)of circulating EVs in PFP after intake period of 12 weeks
|
A commercially available, plate-based thrombin generation assay was used to measure thrombin generation in either a standard, pooled vesicle and platelet-free plasma (termed vesicle-free plasma or VFP) or in the same VFP but with added circulating EVs from subjects in the intervention study.
This enabled the assessment of TF-dependent thrombin generation specifically attributed to circulating EVs in samples from the intervention study.
Results were presented as five variables: (i) lag-phase for initiation of thrombin generation after addition of the trigger (time to 1/6 of the peak height) (min); (ii) peak thrombin concentration (nM); (iii) time to reach the peak (min); (iv) velocity index, defined as = [peak height/(time to peak - lag time)] and (v) area under the curve, defined as endogenous thrombin potential (ETP) (expressed as nM thrombin × min)
|
Change of pro-thrombotic activities (lag time for thrombin generation)of circulating EVs in PFP after intake period of 12 weeks
|
Pro-thrombotic Activities of Circulating EVs in PFP (Peak Thrombin Concentration)
Time Frame: Change of pro-thrombotic activities (peak thrombin concentration) of circulating EVs in PFP after intake period of 12 weeks
|
A commercially available, plate-based thrombin generation assay was used to measure thrombin generation in either a standard, pooled vesicle and platelet-free plasma (termed vesicle-free plasma or VFP) or in the same VFP but with added circulating EVs from subjects in the intervention study.
This enabled the assessment of TF-dependent thrombin generation specifically attributed to circulating EVs in samples from the intervention study.
Results were presented as five variables: (i) lag-phase for initiation of thrombin generation after addition of the trigger (time to 1/6 of the peak height) (min); (ii) peak thrombin concentration (nM); (iii) time to reach the peak (min); (iv) velocity index, defined as = [peak height/(time to peak - lag time)] and (v) area under the curve, defined as endogenous thrombin potential (ETP) (expressed as nM thrombin × min)
|
Change of pro-thrombotic activities (peak thrombin concentration) of circulating EVs in PFP after intake period of 12 weeks
|
Pro-thrombotic Activities of Circulating EVs in PFP (Time to Peak Thrombin Concentration)
Time Frame: Change of pro-thrombotic activities (time to peak thrombin concentration) of circulating EVs in PFP after intake period of 12 weeks
|
A commercially available, plate-based thrombin generation assay was used to measure thrombin generation in either a standard, pooled vesicle and platelet-free plasma (termed vesicle-free plasma or VFP) or in the same VFP but with added circulating EVs from subjects in the intervention study.
This enabled the assessment of TF-dependent thrombin generation specifically attributed to circulating EVs in samples from the intervention study.
Results were presented as five variables: (i) lag-phase for initiation of thrombin generation after addition of the trigger (time to 1/6 of the peak height) (min); (ii) peak thrombin concentration (nM); (iii) time to reach the peak (min); (iv) velocity index, defined as = [peak height/(time to peak - lag time)] and (v) area under the curve, defined as endogenous thrombin potential (ETP) (expressed as nM thrombin × min)
|
Change of pro-thrombotic activities (time to peak thrombin concentration) of circulating EVs in PFP after intake period of 12 weeks
|
Pro-thrombotic Activities of Circulating EVs in PFP (Velocity Index)
Time Frame: Change of pro-thrombotic activities (velocity index) of circulating EVs in PFP after intake period of 12 weeks
|
A commercially available, plate-based thrombin generation assay was used to measure thrombin generation in either a standard, pooled vesicle and platelet-free plasma (termed vesicle-free plasma or VFP) or in the same VFP but with added circulating EVs from subjects in the intervention study.
This enabled the assessment of TF-dependent thrombin generation specifically attributed to circulating EVs in samples from the intervention study.
Results were presented as five variables: (i) lag-phase for initiation of thrombin generation after addition of the trigger (time to 1/6 of the peak height) (min); (ii) peak thrombin concentration (nM); (iii) time to reach the peak (min); (iv) velocity index, defined as = [peak height/(time to peak - lag time)] and (v) area under the curve, defined as endogenous thrombin potential (ETP) (expressed as nM thrombin × min)
|
Change of pro-thrombotic activities (velocity index) of circulating EVs in PFP after intake period of 12 weeks
|
Pro-thrombotic Activities of Circulating EVs in PFP (Endogenous Thrombin Potential)
Time Frame: Change of pro-thrombotic activities (endogenous thrombin potential) of circulating EVs in PFP after intake period of 12 weeks
|
A commercially available, plate-based thrombin generation assay was used to measure thrombin generation in either a standard, pooled vesicle and platelet-free plasma (termed vesicle-free plasma or VFP) or in the same VFP but with added circulating EVs from subjects in the intervention study.
This enabled the assessment of TF-dependent thrombin generation specifically attributed to circulating EVs in samples from the intervention study.
Results were presented as five variables: (i) lag-phase for initiation of thrombin generation after addition of the trigger (time to 1/6 of the peak height) (min); (ii) peak thrombin concentration (nM); (iii) time to reach the peak (min); (iv) velocity index, defined as = [peak height/(time to peak - lag time)] and (v) area under the curve, defined as endogenous thrombin potential (ETP) (expressed as nM thrombin × min)
|
Change of pro-thrombotic activities (endogenous thrombin potential) of circulating EVs in PFP after intake period of 12 weeks
|
Ex Vivo Agonist-stimulated Platelet Activation Detected by Plate-based Platelet Aggregation Assay
Time Frame: Change in ex vivo platelet activation after intake period of 12 weeks
|
96-well high-throughput aggregometry technique, allowing testing of a wide range of concentrations of different agonists, was used to examine the influence of n-3 PUFA supplementation on platelet function.
Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) from each study visit was used in the platelet aggregation assay using pre-prepared 96-well microplates, containing the agonists (ADP, EPI, TRAP-6 and U46619).
Dose-response curves in response to each agonist were obtained and results were represented as a LogEC50 (log concentration of agonist, M, giving a response halfway between maximum and minimum aggregation).
|
Change in ex vivo platelet activation after intake period of 12 weeks
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Ex Vivo Agonist-stimulated Platelet Activation Detected by Plate-based Platelet Aggregation Assay (CRP-XL Log EC50)
Time Frame: Change in ex vivo platelet activation after intake period of 12 weeks
|
96-well high-throughput aggregometry technique, allowing testing of a wide range of concentrations of different agonists, was used to examine the influence of n-3 PUFA supplementation on platelet function.
Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) from each study visit was used in the platelet aggregation assay using pre-prepared 96-well microplates, containing the agonists (CRP-XL).
Dose-response curves in response to each agonist were obtained and results were represented as a LogEC50 (log concentration of agonist, mg/ml, giving a response halfway between maximum and minimum aggregation).
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Change in ex vivo platelet activation after intake period of 12 weeks
|
Pro-thrombotic Activities of Platelet-derived Extracellular Vesicles (PDEVs) Prepared From the Supernatants of Stimulated Platelets (Endpoint and Maximum of Thrombus Formation)
Time Frame: Change in pro-thrombotic activities (endpoint and maximum of thrombus formation)of PEVs prepared from the supernatants of stimulated platelets after intake period of 12 weeks
|
Ex vivo thrombus formation was measured by the addition of in vitro-generated PDEVs from stimulated platelets into whole blood under flow.
Results were presented as three variables: (i) endpoint for ex vivo thrombus formation (FU); (ii) endpoint for ex vivo thrombus formation (FU); (iii) area under curve.
|
Change in pro-thrombotic activities (endpoint and maximum of thrombus formation)of PEVs prepared from the supernatants of stimulated platelets after intake period of 12 weeks
|
Pro-thrombotic Activities of Platelet-derived Extracellular Vesicles (PDEVs) Prepared From the Supernatants of Stimulated Platelets (Area Under Curve)
Time Frame: Change in pro-thrombotic activities (area under curve) of PEVs prepared from the supernatants of stimulated platelets after intake period of 12 weeks
|
Ex vivo thrombus formation was measured by the addition of in vitro-generated PDEVs from stimulated platelets into whole blood under flow.
Results were presented as three variables: (i) endpoint for ex vivo thrombus formation (FU); (ii) endpoint for ex vivo thrombus formation (FU); (iii) area under curve.
|
Change in pro-thrombotic activities (area under curve) of PEVs prepared from the supernatants of stimulated platelets after intake period of 12 weeks
|
Circulating EV Total Lipids Analysis
Time Frame: Change in total lipids of EVs after intake period of 12 weeks
|
A 500μl aliquot of frozen PFP was defrosted at room temperature using a roller mixer and subjected to SEC for the isolation and purification of EVs.
The fractions 7~9 were pooled together, and 800μl of pooled fractions was prepared for total lipid extraction and methyl esterification.
The EV total lipid methyl esters were then analysed by gas chromatography on a Hewlett-Packard 6890 series GC (Hewlett-Packard, California, United States), with the following protocol: split ratio was set as 30:1 for plasma and EV analysis.
The injection volume was 1μl for plasma and 5μl for EVs, respectively.
The temperature of both injector and detector were kept at 300°C and the temperature program was initial temperature 115°C for 2 minutes, increased at 10 °C/min to 200°C and hold at this temperature for 16 minutes, and finally increased at 60°C/min to 240°C for 2 minutes (total run time: 29.2 minutes).
Samples were analysed by using ChemStation software and Microsoft Excel.
|
Change in total lipids of EVs after intake period of 12 weeks
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Plasma Total Phospholipids Analysis
Time Frame: Change of plasma total phospholipids after intake period of 12 weeks
|
A 400μl aliquot of frozen PFP was defrosted and centrifuged to remove denatured protein.
The 400μl of 0.9% NaCl was added to the PFP sample to make up 800μl in total, and 30μg of phosphatidylcholine (PC) and 15μg of phosphatidylethanolamine (PE) internal standards were then added for the quantitative analysis.
After lipid extraction, separation of PC and PE, and methyl esterification of plasma phospholipid extracts, samples were analysed by GC.
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Change of plasma total phospholipids after intake period of 12 weeks
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Concentrations of Lipid Profile in Plasma
Time Frame: Change in concentrations of plasma lipid profile after intake period of 12 weeks
|
A 250μl aliquot of frozen PFP was defrosted at room temperature using a roller mixer and centrifuged at 500xg for 5 minutes at room temperature (Eppendorf Centrifuge 5415 R, DJBlabcare, United Kingdom).
Then the sample was analysed by a RANDOX clinical analyser (RANDOX Daytona+ Analyser, Randox Laboratories Ltd, United Kingdom) for the concentration of TC, TAG, HDL-C, LDL-C and TC/HDL-C ratio.
|
Change in concentrations of plasma lipid profile after intake period of 12 weeks
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Concentrations of TC/HDL-C Ratio in Plasma
Time Frame: Change in concentrations of plasma TC/HDL-C ratio after intake period of 12 weeks
|
A 250μl aliquot of frozen PFP was defrosted at room temperature using a roller mixer and centrifuged at 500xg for 5 minutes at room temperature (Eppendorf Centrifuge 5415 R, DJBlabcare, United Kingdom).
Then the sample was analysed by a RANDOX clinical analyser (RANDOX Daytona+ Analyser, Randox Laboratories Ltd, United Kingdom) for TC/HDL-C ratio.
|
Change in concentrations of plasma TC/HDL-C ratio after intake period of 12 weeks
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Blood Pressure
Time Frame: Change in blood pressure after intake period of 12 weeks
|
Subjects were asked to have a rest for 10 mins before blood pressure detection, and then blood pressure cuff was placed firmly on their upper left arms approximately 2 cm above the elbow with the indicator mark on the cuff over the brachial artery to start measurement.
Subjects should put their arms at the level of the heart and should not speak and cross their legs during the measurement.
Measurement was performed three times and waited for 2 mins between each reading ((Omron M2 Upper Arm Blood Pressure Monitor, OMRON Healthcare Europe BV, United Kingdom).
The average of the three readings was taken to obtain the final result.
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Change in blood pressure after intake period of 12 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Parveen Yaqoob, MA, DPhil, RNutr, University of Reading
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (ACTUAL)
February 16, 2018
Primary Completion (ACTUAL)
November 30, 2019
Study Completion (ACTUAL)
March 30, 2021
Study Registration Dates
First Submitted
June 23, 2017
First Submitted That Met QC Criteria
June 27, 2017
First Posted (ACTUAL)
June 29, 2017
Study Record Updates
Last Update Posted (ACTUAL)
November 7, 2022
Last Update Submitted That Met QC Criteria
November 4, 2022
Last Verified
November 1, 2022
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- UREC 17/18
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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