Cardiovascular disease (CVD) is the leading cause of mortality, and accounts for 16% of all deaths worldwide within the past two decades. Since 2000, estimated annual number of cardiovascular deaths has increased by >2 million to approximately 8.9 million in 2019. Based on the most recent report, estimated number of the people with CVD is as high as 330 million in China. Epidemiological studies suggest regular consumption of fish oil could improve the health of cardiovascular system, but evidence that supports the use of fish oil supplements as either primary or secondary CVD prevention remains controversial. Another important question that remains to be answered is the specific indications and criteria for initiating fish oil supplementation and how much fish oil should be supplemented. This review summarizes the evidence that supports versus argues against omega-3 polyunsaturated fatty acids (PUFAs) supplementation, and discusses the use of Omega-3 Index.
The Omega-3 Index: biomarker and risk factor
As early as 1944, Sinclair described very low prevalence of coronary heart disease (CHD) among Greenland Eskimos, whose diet was rich in fish, seals, and whales. This and other similar observations sparked wide interest in the potential benefits of increasing dietary fish intake, most notably, the cardiovascular health benefits of omega-3 (also known as ω-3 or n-3) PUFAs.
Omega-3 fatty acids (FAs) mainly include eicosapentaenoic acid (EPA; C20:5 ω-3) and docosahexaenoic acid (DHA; C22:6 ω-3) and linolenic acid (LA; C18:3 ω-3). EPA and DHA mainly come from deep-sea fish, so they are also called fish oil. In addition to being essential components of cell membranes, omega-3 FAs possess important biological functions. Low intake and low blood levels of omega-3 FAs are independently associated with higher risk of death from CHD. In 2004, Harris and von Schacky proposed the use of Omega-3 Index (percentage of EPA + DHA to total FAs in red blood cell membrane) as a risk factor for death from CHD as Omega-3 Index is able to reflect long-term omega-3 FAs intake rather than merely blood level of omega-3 FAs.
In 2016, Stark et al. conducted a survey on the global Omega-3 Index by taking circulating EPA+DHA levels from 24,129 subjects from 398 datasets in 54 countries, and converting them into equivalent Omega-3 Index[5,6]. The results showed that Americans, Canadians, Indians and Brazilians had an Omega-3 Index of <4%, Russians, Chinese, Australians, and Western Europeans had an Omega-3 Index at 4% to 8%, Greenlanders, Norwegians, Japanese and Koreans had an Omega-3 Index of >8%.
The Omega-3 Index has been proposed as an indicator of the increase of CHD risk when <4%. An individual is at low risk when his Omega-3 Index is >8%.
Epidemiology: THE OMEGA-3 INDEX AND CVD MORTALITY
Association between higher Omega-3 Index and the reduction of risk for death from any cause has been established in three large-scale prospective cohorts studies[7–9] (Table 1). A meta-analysis of global studies of omega-3 FAs in 45,637 patients without CHD at the baseline revealed a strong correlation between higher omega-3 FAs levels and lower incidence of fatal CHD. In a recent study that pooled data of over 27,000 participants from 10 studies, people with >8% Omega-3 Index had a lower 35% risk of death from CHD than those with an Index <4%. In a de novo pooled analysis that included 42,466 participants from 17 prospective cohort studies with a median follow-up time of 16 years, subjects with 90th percentile of blood omega-3 FAs had 13% lower risk of death from all causes, 15% lower risk of death from CVD, and 11% lower risk of death from cancer in comparison to the 10th percentile.
Table 1 -
Epidemiological studies of the Omega-3 Index
on disease outcomes
||Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality
||8% reduction in risk for death from any cause per 1 SD increase in the Omega-3 Index
||3,259/screening by angiography
||11% reduction in risk for death from any cause per 1 SD increase in the Omega-3 Index
CVD: cardiovascular decease; LURIC: the Ludwigshafen Risk and Cardiovascular Health Study; SD: standard deviation; WHIMS: the Women's Health Initiative.
Erythrocyte EPA + DHA expressed as percentage of total erythrocyte fatty acids
Overall, these findings demonstrated that an Omega-3 Index in the 8%–12% range was independently associated with a lower risk of premature death.
Randomized controlled trials (RCTs) of primary prevention of CVD and Omega-3 Index
Two recent RCTs have tested omega-3 FAs as primary prevention of CVD (Table 2)[13,14].
Table 2 -
Major RCTs of omega-3 FAs as primary prevention of CVD
||15,480/patients with diabetes
||No reduction in composite endpoint, but 19% reduction in vascular death
||25,871/subjects without CVD or cancer at baseline
||2,000 IU vitamin D3
||No reduction in composite endpoint, but 28% reduction in heart attack; African Americans appeared to benefit more than Caucasians
||14,981/patients with hypercholesterolemia
||No significant reduction in major coronary events, coronary death or MI
||2,394/patients with diabetes and at least one additional risk factor
||12% reduction in primary endpoint and 19% reduction in key secondary endpoint
||5,762/statin-treated patients with CV risk
||No reduction in composite endpoint
ASCEND: a study of cardiovascular events in diabetes; CA: carboxylic acid formulation; CV: cardiovascular; CVD: cardiovascular decease; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; FAs: fatty acids; JELIS: Japan EPA Lipid Intervention Study; MI: myocardial infarction; RCT: randomized controlled trials; REDUCE-IT: the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; STRENGTH: the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; VITAL: the vitamin D and omega-3 trial.
The ASCEND trial randomized a total of 15,480 diabetic patients without evidence of atherosclerotic lesions to receive either 840 mg/day EPA+DHA or placebo. At a median follow-up of 7.4 years, the Omega-3 Index increased from 7.1% to 9.1% in the omega-3 FAs group, whereas there was little change in the placebo group (6.6% at baseline and 6.5% at follow-up). The Omega-3 Index increased by 32.5% relative to the placebo group. But the primary endpoint of serious vascular events (ie, non-fatal myocardial infarction [MI], stroke or transient ischemic attack, or vascular death, excluding confirmed hemorrhagic stroke) did not differ between the two groups (9.2% and 8.9% in the control and EPA+DHA groups, respectively; P = 0.55). The relative risk of vascular death, defined as death from CHD, stroke or other vascular causes, however, was 18% lower in the EPA+DHA group.
The VITAL trial randomized a total of 25,871 subjects without known CVD or cancer at the baseline using a 2 × 2 factorial design of omega-3 FAs (1,000 mg/day) and vitamin D3 (2,000 IU/day). The Omega-3 Index was (2.7±0.9)% in each group Among the 15,535 participants (60.0%) at baseline. After 1 year, the Omega-3 Index rose to 4.1% (increase of 54.7%) in the Omega-3 FAs group and changed by <2% in the placebo group among 1,583 participants. At a median follow-up of 5.3 years, the primary endpoint of major cardiovascular events did not differ between the omega-3 FAs and control groups. However, there was 19% reduction in MACE and 40% reduction in MI in the omega-3 FAs group in the subgroup analysis that included subjects who consumed fewer than 1.5 fish meals per week only. Notably, African American subjects in the omega-3 FAs group had a 77% reduction in heart attacks.
Neither of these two RCTs of primary prevention found significant cardiovascular benefits, possibly because the increase in the Omega-3 Index (ASCEND increased by 32.5% vs. VITAL increased by 54.7%) from fish oil supplementation at 840 mg/day was not sufficient to achieve health outcomes in people with lower baseline levels of Omega-3 Index (ASCEND based in UK vs. VITAL based in USA). Americans and Brits have this typical western diet with low seafood intake and need more supplement of fish oil.
The following three RCTs all included some primary prevention populations:
The JELIS trial randomized 14,981 patients (80.3%) with hypercholesterolemia (total cholesterol of 6.5 mmol/L or higher) to receive either statin only (control group) or 1,800 mg/day EPA plus statin (EPA group) . At a median follow-up of 4.6 years, there was no significant reduction in cardiovascular events, coronary death or MI in the EFA group.
In REDUCE-IT trial, 2,394 patients (29.3%) were on the basis of primary prevention (ie, patients with diabetes and other risk factors but not established cardiovascular disease at the baseline). They underwent randomization to receive either 4,000 mg/day EPA or mineral oil placebo. At the completion of the study, the risk of the primary endpoint was reduced by 12% in the EPA group, and the risk of key secondary endpoint was reduced by 19%.
In STRENGTH trial, 5,762 patients (44.1) were on the basis of primary prevention (ie, patients had diabetes and an additional risk factor), they were randomized to receive either 4,000 mg/day EPA + DHA or corn oil placebo in addition to standard medical therapy. The interim analysis showed that the primary end point of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization occurred in 12% patients in the omega-3 FAs group and 12.2% in the control group (P = 0.84).
RCTs of secondary prevention of CVD and Omega-3 Index
Six major RCTs have tested omega-3 FAs as secondary prevention of CVD (Table 3)[18–20].
Table 3 -
Major RCTs of omega-3 FAs as secondary prevention of CVD
||11,324/patients with recent MI
||14% reduction in the primary endpoint and 20% reduction in fatal events
||3,851/patients with acute MI
||No reduction in composite endpoint
||1,027/patients with acute MI
||No reduction in either composite endpoint or all-cause death
||3,664/patients with documented CVD
||19% and 28% reduction in major coronary events and the incidence of unstable angina, but not in vascular death
||5,785/patients with established CVD
||27% reduction in primary endpoint and 28% reduction in key secondary endpoint
||7,316/ patients with established CVD
||No reduction in composite endpoint, but 15% reduction in coronary events
CA: carboxylic acid formulation; CVD: cardiovascular decease; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; GISSI-P: the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico Prevenzione trial; JELIS: Japan EPA Lipid Intervention Study; MI: myocardial infarction; OMEMI: the Omega-3 Fatty acids in Elderly with Myocardial Infarction Trial; RCT: randomized controlled trials; REDUCE-IT: the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; STRENGTH: the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia.
The initial landmark trial of omega-3 supplementation, GISSI-P, randomized a total of 11,324 subjects with recent myocardial infarction (3 months or less) to receive 1,000 mg/day EPA + DHA, 300 mg/day vitamin E, both, or none. It suggested that intakes of about 1,000 mg/day of EPA + DHA would produce an Omega-3 Index of about 9.5%. After nearly 4 years of follow-up, there was a 14% reduction in the risk of primary endpoint (composite of death, non-fatal myocardial infarction, and stroke) as well as 20% reduction in fatal events in the EPA + DHA group.
The OMEGA trial randomized a total of 3,851 patients with acute MI to receive either 1,000 mg/day omega-3 PUFAs (EPA:DHA = 1.2:1) or placebo. At the 1-year follow-up, the primary endpoint of sudden cardiac death did not differ between the two groups (1.5% in both groups). There was also no difference in total mortality, major adverse cerebrovascular and cardiovascular events, and revascularization.
The OMEMI trial randomized a total of 1,027 elderly patients (70–82 years of age) with recent acute MI (2–8 weeks) to receive either 1,800 mg omega-3 PUFAs (930 mg EPA + 660 mg DHA) or corn oil placebo. After 1-year follow up, patients in omega-3 FAs group experienced a median increase of 87% in plasma level of EPA and 16% increase in DHA, while in the placebo group changes were −13% and −8% in EPA and DHA, respectively. The primary endpoint (ie, composite of non-fatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure requiring hospitalization) within 2 years was 20.2% and 21.4% in the control and omega-3 PUFAs groups, respectively (P = 0.60).
Unlike the above two failed trials, OMEGA and OMEMI, GISSI-P recruited Italian subjects with higher baseline Omega-3 Index levels, whose control group was not given any type of oil as a placebo, and had a longer follow-up period, for 3.5 years. The reasons for OMEGA's failure may be the low baseline level of the Omega-3 Index in the Germans, the small fish oil supplement dose of only 1,000 mg/day, and the short follow-up period of only 1 year. However, OMEMI, which included Norwegians with high baseline Omega-3 Index levels and a daily supplement of 1,800 mg EPA + DHA, also failed. The reason may be the fact that the study population was older (70–82 years old) and only 2–8 weeks after MI. Omega-3 FAs treatment increased plasma EPA levels by only 87%, which is not enough.
The following three RCTs all included some secondary prevention populations:
The JELIS trial randomized 3,664 patients (19.7%) with documented CVD to receive either statin only (control group) or 1,800 mg/day EPA plus statin (EPA group). At a median follow-up of 4.6 years, there was a 19% reduction in major coronary events and a 28% reduction in unstable angina in EPA group. Sudden cardiac death did not differ between the EPA group and control group.
The REDUCE-IT trial randomized 5785 patients (70.7%) with established CVD to receive either 4,000 mg/day EPA or mineral oil placebo. After 4.9-year follow up, the risk of the primary endpoint was reduced by 27% in the EPA group, and the risk of key secondary endpoint was reduced by 28%.
The STRENGTH trial randomized 7,316 patients (55.9%) with established CVD to receive either 4,000 mg/day EPA + DHA or corn oil placebo in addition to standard medical therapy. Although the trial was terminated prematurely based on the interim analysis that indicated no benefit in the omega-3 FAs group of total population, prespecified subgroup analyses revealed a reduction of 15% in coronary events in the secondary prevention population.
The cardiovascular benefits of fish oil supplements may be related to plasma/serum EPA levels reached after treatment
The following three RCTs had measured plasma or serum EPA levels before and after treatment of omega-3 FAs (Table 4)[15–17].
Table 4 -
Changes in plasma/serum EPA levels before and after fish oil supplements treatment in RCTs
||Follow -up (year)
||Medium change (%)
||Medium change (%)
CA: carboxylic acid formulation; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; JELIS: Japan EPA Lipid Intervention Study; RCT: randomized controlled trials; REDUCE-IT: the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; STRENGTH: the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia.
The JELIS trial randomized a total of 18,645 patients with hypercholesterolemia in Japan to receive either statin only (control group) or 1,800 mg/day EPA plus statin (EPA group). Plasma EPA at baseline was 2.9% of total molecules of fatty acids (mol %), which were the average values for all patients who gave informed consent in the control group (n = 8,076) and the EPA group (n = 8,321). Plasma EPA level at baseline were 93 μg/mL in controls, and 97 μg/mL in the EPA group, respectively. At a median follow-up of 4.6 years, the plasma EPA level of the EFA group increased to 169 μg/mL, a 70% increase from baseline, while the plasma EPA level in controls was still 93 μg/mL.
The REDUCE-IT trial randomized a total of 8,179 patients to receive either 4,000 mg/day EPA or mineral oil placebo. EPA was measured in serum samples at baseline and yearly follow up using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After 1 year, the serum EPA level in EPA group increased from baseline 26.1 to 144.0 μg/mL, with a median change of 393.5% from baseline; After 4.9-year follow up, the serum EPA level had increased 158.0 μg/mL, with a median change of 463.6% from baseline, while reduced to 25.3 μg/mL in control, with a median change of −2% from baseline.
The STRENGTH trial randomized a total of 13,078 patients with dyslipidemia, high TG and low levels of high-density lipoprotein cholesterol to receive either 4,000 mg/day EPA + DHA or corn oil placebo in addition to standard medical therapy. Plasma level of EPA were determined by OmegaQuant. After 1-year follow up, the plasma EPA level increased from baseline 21.0 to 89.6 μg/mL, which was a 268.8% increase from baseline, while reduced from baseline 21.3 to 19.0 μg/mL in control, with a median change of −10.5% from baseline.
Due to dietary habit of Japanese, subjects in JELIS had higher baseline levels of EPA compared with REDUCE-IT and STRENTH due to the high consumption of fish (baseline levels of EPA, JELIS vs. EDUCE-IT vs. STRENTH: 97.0 vs. 26.1 vs. 21.0 μg/mL). Therefore, in JELIS, only 1,800 mg/day omega-3 FAs had increased EPA level to 169.0 μg/mL, whereas 4,000 mg/day omega-3 FAs only increased EPA levels to 158.0 μg/mL in REDUCE-IT and 89.6 μg/mL in STRENTH. The EPA level after fish oil supplementation in STRENTH was much lower than in JELIS and REDUCE-IT. This might explain why JELIS and REDUCE-IT had cardiovascular benefit, while STRENTH did not. These results indicate that elevated EPA levels might be associated with cardiovascular benefits.
In REDUCE-IT trial, the triglyceride (TG) level was reduced by an average of 40 mg/dL (0.45 mmol/L), with a reduction of 19%, which is difficult to explain the 25% reduction of the primary endpoint[16,21]. There was no difference in the primary and key secondary endpoints between TG < 150 mg/dL and TG ≥ 150 mg/dL by 1-year achievement of TG levels. Cardiovascular benefit was dependent on elevated plasma EPA levels after fish oil supplementation, not TG levels.
It implies that the detection of plasma/serum EPA level or the Omega-3 Index has indispensable guiding significance.
Inspirations from comparing REDUCE-IT and STRENTH: the type of oil in placebo and the purity of EPA might play an important role
In addition to the increasing EPA level, the possible reasons for the heterogeneity in the results of REDUCE-IT and STRENTH were as follows:
On one hand, the type of oil as placebo used in the control group may have played a role. Both REDUCE-IT and STRENGTH had omega-3 FAs doses of 4,000 mg/day, but why did REDUCE-IT have cardiovascular benefit results and STRENGTH did not? The contrasting results may be partially explained by placebo differences (mineral oil vs. corn oil). A cohort study mimicking trial designs provided an alternative explanation for the discrepancy based on differences in the effect of comparators (mineral oil vs. corn oil) on lipid traits and C-reactive protein. In comparison to corn oil in this study, mineral oils increased low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B) and C-reactive protein levels as well as the risk of ASCVD. The unexplained additional 13% risk reduction in the REDUCE-IT trial probably reflects the effects mineral oil vehicle.
On the other hand, the purity of EPA supplements also matters. REDUCE-IT and STRENGTH had provided different omega-3 FAs supplements (4,000 mg/day EPA vs. 4,000 mg/day EPA + DHA). Both EPA and DHA are important structural components of the membrane phospholipid bilayer, maintaining the liquid properties of the membrane. DHA is abundant in nerve tissue and has obvious effects on neurons and retinal membrane tissue. EPA has the ability to reduce inflammation, cholesterol crystal formation, endothelial dysfunction and markers of oxidative modification of various ApoB-containing lipoprotein particles and to increase high-density lipoprotein[24–26]. The EVAPORATE trial compared the effects of high-dose purified EPA with mineral oil plus statin versus statin alone on coronary plaque and claimed a slight “regression” of coronary plaque in the EPA plus statin group. Together, these observations support the possibility that, in addition to lowering lipid markers and C-reactive protein, EPA reduces ASCVD risk through other actions . This indicates that high purity EPA may be another key to cardiovascular benefits.
The value, accessibility and cost of the Omega-3 Index detection
Canada was the first country to conduct a formal nationwide survey of the Omega-3 Index[28,29]. The mean Omega-3 Index reported by NHANES 2003–2004 was 4.5%, which falls in the intermediate range. Slightly higher Omega-3 Index has been associated with older age, likely reflecting higher fish intake and non-smoking status. Global Omega-3 Index data revealed that, genetic, geographic, and dietary differences result in different baseline levels of the Oega-3 Index in different ethnic groups. Most of the populations have very low fish intake and low Omega-3 Index. Also, the Omega-3 Index at >8% is rare in countries with low fish diets. The Omega-3 Index is a superior method for evaluating long-term Omega-3 status and can be used as a baseline reference. But to date, most studies have not consider the individuals’ initial or final levels of Omega-3 Index.
Feasibility and practical value of achieving the >8% Omega-3 Index target with public health effort is a difficult issue. The evidence for the low risk with >8% Omega-3 Index is strong[32,33]. Interventional studies have also shown that achieving >8% Omega-3 Index can reduce the risk of fatal CHD by approximately 35%[11,34,35]. However, at least a daily dose of ∼1,500 mg EPA+DHA is needed to increase the Omega-3 Index from 4% to 8%. This dose translates to consuming ≥1 serving of oily fish or taking a relatively potent supplement (>1,000 mg) daily, which is much higher than the 1–2 servings of seafood per week recommendation by the American Heart Association. A more conservative but realistic public health goal of >4% Omega-3 Index in 98% of the population could be achieved by eating 2 servings of oily fish per week. In people with a low Omega-3 Index, especially those at higher risk of CVD, healthcare professionals could test for omega-3 status regularly and titrate patients that require intervention to ≥8% Omega-3 Index through dietary change and supplements.
Determining the Omega-3 Index can help guide how much EPA+DHA you need in your diet to reach your Omega-3 Index goals. Based on research by Walker et al. in 2019, up to 3,000 mg/day of EPA and DHA is considered safe. They developed a model that can be used by researchers to help estimate the Omega-3 Index response to a given EPA + DHA dose and chemical form. Patients are recommended to retest after 3–4 months to see if the diet changes are working. In 2021, Andrew et al. has concluded the hypothetical omega-3 supplementation dose and threshold effect. Low baseline omega-3 levels (Omega-3 Index ≤ 4%) required a daily supplement of 4,000 mg Omega-3 FAs to reach 8%, while 1,000 mg Omega-3 FAs may be ineffective. High baseline omega-3 levels (Omega-3 Index ≥ 6%) needed only 1,000 mg/day Omega-3 FAs to increase the Omega-3 Index to >8%, while 4,000 mg Omega-3 FAs increased Omega-3 Index to even higher levels.
The Omega-3 Index, as percentage of EPA + DHA to total FAs in red blood cell membrane, compared to JELIS using 2.9% of total molecules of fatty acids (mol %) as plasma EPA levels, and REDUCE-IT and STRENTH using LC-MS/MS methods for serum/plasma EPA concentrations, can be measured by simply taking blood from a fingertip, which is more accurate, convenient, and valuable in clinical practice. Adequate diagnostics of the Omega-3 Index for indicating fish oil supplements dose is critical to ensure a personalized approach to prescribing omega-3 FAs for an individual to achieve health outcomes. The Omega-3 Index helps clinicians to determine a patient's risk stratification, to identify whether omega-3 FAs are deficient, to determine what supplemental dose should be, and to monitor whether the treatment is effective.
Commercial Omega-3 Index testing is available from OmegaQuant at $49.95. After sending in small amount of blood samples obtained with finger prick, the results become available within 2–4 weeks. Evidence suggested that simple dietary change or supplements for as short as a few weeks could increase Omega-3 Index.
Accurate detection of Omega-3 Index, individualized formulation of EPA + DHA supplements, and effective use of Omega-3 Index are needed. For clear reasons, this index can also be used as a target in clinical trials to reduce heterogeneity in trial design. First, the use of Omega-3 Index should be encouraged in clinical setting to help identify people with high CVD risk. This includes the acquisition of patent licensing from OMEGA Quant, the establishment of laboratories, and staff training. Second, the cost of testing must be brought down for use in a wider setting. Also, awareness by healthcare professionals and the general public must be promoted. Overall, effective use of the Omega-3 Index as a clinical diagnostic and research tool may be the key to resolving the controversy surrounding Omega-3 therapy.
Low Omega-3 Index (<4%) is a validated and modifiable risk for CVD as well as total mortality. First, ample epidemiological evidence demonstrated an association between low Omega-3 Index with CV risk. Second, RCTs showed that given at sufficient dosage, fish oil supplements (EPA+DHA) could reduce CVD risk, in the setting of both primary and secondary preventions. This is an inverse relationship whereby higher Omega-3 levels are associated with lower risk of CVD, the Omega-3 Index is a superior method for evaluating long-term Omega-3 status, it helps clinicians identity individual's CV risk, indicates Omega-3 intake and helps ensure fish oil supplements are effective.
CL wrote the original draft preparation. CL and ZYC conceived, reviewed and edited the manuscript.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this manuscript.
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