Indian food habit & food ingredients may have a role in lowering the severity & high death rate from COVID-19 in Indians: findings from the first nutrigenomic analysis : Indian Journal of Medical Research

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Indian food habit & food ingredients may have a role in lowering the severity & high death rate from COVID-19 in Indians: findings from the first nutrigenomic analysis

Barh, Debmalya1,3,; Aburjaile, Flávia Figueira5; Tavares, Thais Silva6,#; Silva, Miguel Etcheverria da3,#; Bretz, Gabriel Pissolati Mattos7,#; Rocha, Igor Fernando Martins8,#; Dey, Annesha1; Souza, Renan Pedra de4; Góes-Neto, Aristóteles3; Ribeiro, Sérvio Pontes9; Alzahrani, Khalid J.11; Alghamdi, Ahmad A.11; Alzahrani, Fuad M.11; Halawani, Ibrahim Faisal11; Tiwari, Sandeep10; Aljabali, Alaa A. A.12; Lundstrom, Kenneth13; Azevedo, Vasco3; Ganguly, Nirmal Kumar2

Author Information
Indian Journal of Medical Research 157(4):p 293-303, April 2023. | DOI: 10.4103/ijmr.ijmr_1701_22
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Background & objectives: 

During the COVID-19 pandemic, the death rate was reportedly 5-8 fold lower in India which is densely populated as compared to less populated western countries. The aim of this study was to investigate whether dietary habits were associated with the variations in COVID-19 severity and deaths between western and Indian population at the nutrigenomics level.


In this study nutrigenomics approach was applied. Blood transcriptome of severe COVID-19 patients from three western countries (showing high fatality) and two datasets from Indian patients were used. Gene set enrichment analyses were performed for pathways, metabolites, nutrients, etc., and compared for western and Indian samples to identify the food- and nutrient-related factors, which may be associated with COVID-19 severity. Data on the daily consumption of twelve key food components across four countries were collected and a correlation between nutrigenomics analyses and per capita daily dietary intake was investigated.


Distinct dietary habits of Indians were observed, which may be associated with low death rate from COVID-19. Increased consumption of red meat, dairy products and processed foods by western populations may increase the severity and death rate by activating cytokine storm-related pathways, intussusceptive angiogenesis, hypercapnia and enhancing blood glucose levels due to high contents of sphingolipids, palmitic acid and byproducts such as CO2 and lipopolysaccharide (LPS). Palmitic acid also induces ACE2 expression and increases the infection rate. Coffee and alcohol that are highly consumed in western countries may increase the severity and death rates from COVID-19 by deregulating blood iron, zinc and triglyceride levels. The components of Indian diets maintain high iron and zinc concentrations in blood and rich fibre in their foods may prevent CO2 and LPS-mediated COVID-19 severity. Regular consumption of tea by Indians maintains high high-density lipoprotein (HDL) and low triglyceride in blood as catechins in tea act as natural atorvastatin. Importantly, regular consumption of turmeric in daily food by Indians maintains strong immunity and curcumin in turmeric may prevent pathways and mechanisms associated with SARS-CoV-2 infection and COVID-19 severity and lowered the death rate.

Interpretation & conclusions: 

Our results suggest that Indian food components suppress cytokine storm and various other severity related pathways of COVID-19 and may have a role in lowering severity and death rates from COVID-19 in India as compared to western populations. However, large multi-centered case−control studies are required to support our current findings.

Variation in the rate of deaths due to COVID-19 has been detected in different countries (; accessed on May 30, 2022). Since COVID-19 is an infectious disease, presumably more cases and higher death rates should be found in densely populated countries. The population density varies between 36/km² to 92/km² in the USA, Spain and Greece, whereas, in India, it is 428/km2 (https//; accessed on May 18, 2022). Therefore, in principle, India should have had a higher number of COVID-19 cases and deaths. However, in reality, these western countries have shown five to eight times higher death rates compared to India (; accessed on May 30, 2022). Therefore, identifying factors that could explain such differences remain important.

Existing comorbid conditions and their risk related to COVID-19 severity and death have been well established1. Host genetic polymorphisms are also associated with severe symptoms and deaths from COVID-192. Plant-based foods, pescatarian and Mediterranean diets and low consumption of red and processed meat have been shown to lower the susceptibility to moderate-to-severe COVID-19 disease3,4. Reported diets supplemented with vitamins and zinc may reduce COVID-19 severity5. On the other hand, higher consumption of a western diet was found to be associated with increased COVID-19 risk and severity4,6.

Gene expression profiles of SARS-CoV-2-infected individuals have been used to identify susceptibility, symptoms, severity, disease pathways and drugs for COVID-19 patients7–10. In this study, we aimed to identify specific foods, diets, metabolites or nutrients associated with the observed differences in severity and death rates due to COVID-19 in the western and Indian populations using available transcriptome data and nutrigenome approaches.

Material &Methods

Selection of datasets: RNA sequencing (RNA-Seq) data from COVID-19 patients’ blood were obtained from public domain through Gene Expression Omnibus (GEO; and PubMed ( databases and were grouped into two categories based on the country-specific death rates (death/100,000 people) from COVID-19. The USA, Greece and Spain were the selected countries with high death rates representing western samples, whereas data from India was used for a country with a low COVID-19 death rate. For the USA, 29 severe COVID-19 samples and nine healthy controls were collected from Bioproject: PRJNA6344897 and GSE18999011. For Greece, the GSE152641 dataset of 62 cases and 24 controls were included12, and for Spain, the GSE180594 dataset (18 cases and 7 controls)13 was used. Two datasets were chosen for India; the south Indian (Karnataka) dataset (GSE196822) of 49 expression profiles of four distinct COVID-19 conditions including asymptomatic (n=8), mild (n=9), moderate (n=10), severe (n=7) and control (n=9) and the north Indian (Haryana) dataset (GSE181439) had asymptomatic (n=9) and severe (n=9) cases.

Obtaining differentially expressed genes (DEGs) from RNA-Seq data: The GO2R tool (; accessed on May 16, 2022) was used for differentially expressed gene (DEG) profiles of cases vs. control for GSE180594 and for the south Indian dataset GSE196822. The Limma-Voom package version 4.2 (Bioconductor, Victoria, Australia) was used in R Studio14 to analyze asymptomatic vs. control, mild vs. control, moderate vs. control and severe vs. control. Other DEGs were obtained from the corresponding publications7,11,12,15. In all cases, the fold change (Log2) >1 was considered upregulated and <1 was considered downregulated at adjusted P<0.05.

DEG analysisfor metabolites and pathways: A modified method of our previously established DEG analysis using only the upregulated gene sets was applied which gave us >90 per cent accuracy8–10. DEGs of each country sample were separately analyzed using Enrichr (release March 29, 2021; New York, USA)16. However, two USA samples and two Indian datasets were clubbed to make combined USA and Indian samples, respectively. Since for the other countries, only one sample was used, the two Indian samples were combined to make one combined sample for India and the two USA samples were combined to make one combined USA samples for our analysis. All western country samples were also combined for an integrated and comparative analysis with the combined Indian samples. Some analyses with the downregulated genes were also considered to cross verify the reliability of data sets. For example, while using the ‘COVID-19 Related Gene Sets 2021’ database in the Enrichr for upregulated gene sets, it required first to be enriched by giving n number of genes upregulated by SARS-CoV-2 infection. In our cross verification of data set reliability, it was found that all these DEGs were associated with SARS-CoV-2 infection and influenza. Therefore, we proceeded with our DEGs for further analysis.

In Enrichr, the ‘COVID-19 Related Gene Sets 2021’ database was first used to validate if our applied gene set was up or downregulated in COVID-19. In addition, ‘Disease perturbations from GEO up’ and ‘Disease perturbations from GEO down’ were also used to cross-verify the reliability of datasets. In the second step, the human metabolites database (HMDB) was used to identify the metabolites associated with the given gene set. Three pathway databases, WikiPathway 2021 Human, KEGG 2021 Human, and Reactome 2016 were used to identify pathways commonly enriched by at least two databases to interpret our results. The ‘Drug perturbations from GEO up’ and ‘Drug perturbations from GEO down’ databases were also used to correlate the results with identified pathways. In all enrichment analyses, top 10 enrichment results were only considered for interpretation.

Nutrigenomics analysis of DEG: NutriGenomeDB (release November 21, 2021; Madrid, Spain)17 and its phenotype-centered analysis was used for nutrigenomics analysis and selected Homo sapiens as organism. Each dataset was analyzed individually and in combination with complete DEGs (up + downregulated genes). Only the blood based gene expression signatures of different foods, nutrients and bioactive compounds from this database were considered. Furthermore, net enrichment score (NES) were used to predict the final results as NES typically gives better accuracy compared to the number of overlapping gene (NOS) calculations.

Analyses of western and Indian foods and diet: Data and literature mining approaches were used to understand the food consumption among western and Indian populations. Furthermore, various databases and corporate reports were used to understand the differences between dietary habits in the western and Indian populations (Supplementary Table I).

Supplementary Table I:
Dietary intakes of key foods and nutrients in adults aged 20 yr, national data, per capita g/day

A flow diagram of overall study design is given in Figure 1.

Fig. 1:
Schematic flow chart of overall methodology or study design.


Differences between Indian and western dietary intakes: Twelve key food components were found in the Indian diet, which were considerably different from that in the western populations (Supplementary Table I). At the national level (mean intake per capita, g/day), western populations consumed 10-25 times more red meat, 8-12 times more processed foods, 5-7 times more dairy products, 3-8 times more fish, 10-12 times more coffee and two times more alcohol than Indians. On the other hand, Indians used 1.5 times more legumes and vegetables and four times more whole grains than western populations. Most importantly, while western populations used nil or negligible amounts of tea and turmeric, Indians consumed an average 1.2 and 2.5 g tea and turmeric per person per day, respectively (Table I and Supplementary Figure). In south India, the main staple foods were Idli and Dosa (fermented food, rice and black gram 2:1 ratio) with Sambar (lentil-based stew) and rice with Rasam (spicy soup)18. Sambar and Rasam contain several spices including turmeric, chili pepper, cumin, curry leaves, mustard, coriander, asafoetida, sea salt, etc.19,20. Similarly, in north India, kidney bean (Rajma), chickpea, legumes, wheat, corn, rice and several spices such as turmeric, chili, cumin, mustard, coriander etc. were used as daily foods21. When the raw values of per capita daily consumptions of the identified twelve key food components were plotted against COVID-19-associated deaths to create a column chart, a distinct food habit of Indians was found which may be associated with low death rate in Indian populations (Fig. 2 and Supplementary Table I).

Supplementary Figure:
Differences between Indian and western food and spices. The figure is developed based on Supplementary Table 1, several web portals, following literature1–13.
Fig. 2:
Dietary habits in Indian and western populations. Per capita daily consumption of 12 key foods and nutrients (variables) along with the population density and death rates (person/100,000) in India and three western countries (Also shown in Supplementary Table 1).

Cytokine storm and complement related pathways are upregulated in western and Indian severe COVID-19 samples, respectively: Two pathway databases showed upregulation of interferon (IFN) (type I and II), tumour necrosis factor (TNF), cytokine, chemokine and NOD-like receptor signalling pathways in severe COVID-19 patients from Spain and Greece (Supplementary Table IIE and G). The USA samples displayed over expression of the VEGFA-VEGFR2 signaling pathway (Supplementary Table IIF). The up regulated DEG of combined western populations was associated with IFN, TNF, cytokine, chemokine, VEGFA-VEGFR2 and NOD-like receptor signalling pathways (Supplementary Table IIH). The upregulated genes of combined western countries were also associated with lipopolysaccharide (LPS) and IFN-beta responses (Supplementary Table IIE-H). In contrast, the cell cycle and vitamin D metabolism related pathways were over represented in north Indian severe and south Indian asymptomatic cases (Supplementary Table IIA and C). South Indian severe COVID-19 samples showed upregulation of complement and coagulation cascades (Supplementary Table IIB). The combined Indian severe cases showed similar results to those found for cases from south India (Supplementary Table IIB and D).

Supplementary Table IIA:
Gene set enrichment analysis of asymptomatic South Indian samples
Supplementary Table IIB:
Gene set enrichment analysis of severe South Indian samples
Supplementary Table IIC:
Gene set enrichment analysis of severe north Indian samples
Supplementary Table IID:
Gene set enrichment analysis of combined severe North and South Indian samples
Supplementary Table IIE:
Gene set enrichment analysis of severe Greece samples
Supplementary Table IIF:
Gene set enrichment analysis of severe USA samples
Supplementary Table IIG:
Gene set enrichment analysis of severe Spain samples
Supplementary Table IIH:
Gene set enrichment analysis of severe all western (combined) samples

Atorvastatin, lipopolysaccharide (LPS), and interferon (IFN)-β responsive genes are differentially upregulated in Indian and western populations: In Using Drug perturbations from GEO up analysis, it was found that the cholesterol lowering drug atorvastatin ranked at 3rd position among severe COVID-19 cases in the USA, 2nd amond severe Indian and 3rd asymptomatic Indian cases. Atorvastatin was not enriched in any other western country (Supplementary Table IIA-H). Therefore, atorvastatin itself, or metabolites or nutrients that act as atorvastatin may have a role in regulating the severity of COVID-19. In contrast, LPS and IFN-β-1a were enriched in all samples except in severe Indian cases. The ranks of LPS and INF-β in asymptomatic Indian cases and in severe USA cases were lower as compared to other severe cases from western countries (Supplementary Table IIA-H).

Palmitic acid (PA) and CO2 responsive genes upregulated in western severe COVID cases and zinc, iron and carbohydrate responsive genes are enriched in Indian patients: The HMDB-based metabolite analysis showed that carbon dioxide (CO2), hexadecanoyl-CoA, dermatan sulfate, arachidonic acid and palmitic acid (PA) were differentially enriched for individual western country samples (Supplementary Table IIE-G). However, for combined western samples, CO2, hexadecanoyl-CoA and PA were enriched (Supplementary Table IIH). In contrast, upregulation of zinc and glucose responsive genes (Supplementary Table IIB) was observed in severe south Indian samples and upregulation of iron, sodium, ammonia, folic acid, riboflavin etc. responsive genes in asymptomatic south Indian samples (Supplementary Table IIA). Importantly, the combined severe Indian samples gave a result similar to the south Indian samples. We found that zinc, iron and glucose responsive genes were over represented (Supplementary Table IIB and D). Based on the enrichment ranks, our results indicated that blood iron levels might be associated with COVID-19 severity22. Taken together, there were distinct metabolic processes and metabolites governing the severity of COVID-19 between western and Indian populations and they could potentially be linked to the dietary habits of these populations.

PA and CO2 responsive genes were associated with increased sphingolipid metabolism and PPAR signaling: In a separate Enrichr analysis, we found that the CO2 responsive genes were associated with the TCA cycle, sphingolipid metabolism, proximal tubule transport and O2/CO2 exchange in erythrocyte pathways in western samples. Upregulation of these genes was associated with chronic obstructive pulmonary disease (COPD)-like conditions and metabolic acidosis. In addition, we found curcumin and iron having some association with CO2 (Supplementary Table IIIA and B). On the other hand, a separate nutrigenomics analysis of the CO2 responsive genes showed that curcumin negatively regulated CO2 production (Supplementary Table IIIA and C). Conversely, the PA responsive genes were associated with fatty acid beta-oxidation, PPAR signalling and sphingolipid metabolism. Furthermore, the PA responsive genes also had indicative association with hypertension and obesity like comorbid conditions in COVID-19 (Supplementary Table IIIA and D).

Supplementary Table IIIA:
HMDB-based enriched genes for CO2, hexadecanoyl-CoA and palmitic acid responses from combined all severe Western samples
Supplementary Table IIIB:
Gene set enrichment of CO2 responsive genes from severe western samples (HMDB-based enriched) by Enrichr
Supplementary Table IIIC:
Nutrigenomics (blood transcriptome) analysis of CO2 responsive genes from severe western samples (HMDB-based enriched) using NutriGenomeDB
Supplementary Table IIID:
Gene set enrichment of palmitic acid responsive genes from severe western samples (HMDB-based enriched) by Enrichr
Supplementary Table IIIE:
Nutrigenomics (blood transcriptome) analysis of all Indian and western samples

Curcumin determines COVID-19 severity: In NutriGenome DB analyses, three datasets were found to be related to blood based gene expression in response to Lactobacillus rhamnosus, curcumin and docosahexaenoic acid. Based on NOG calculation, the number of response genes (RG) for these three nutrients were higher in severe cases as compared to asymptomatic COVID-19 in south Indian samples. The number of RGs was higher in severe western samples than in severe Indian cases (Fig. 3A and Supplementary Table IIIE). The NES analysis yielded positive scores for curcumin, which was higher in cases of asymptomatic Indian samples as compared to severe cases from both north and south India. The NES of curcumin RGs was negative for all western samples. Importantly, we found that the negative NES of curcumin RGs of all severe western samples was lower after treatment with curcumin for 4 h than 18 h (Fig. 3B and Supplementary Table IIIE).

Fig. 3:
Blood nutrigenomics profiles of samples from western and Indian populations. (A) Number of L. rhamnosus, curcumin, and DHA responsive genes increased with increased disease severity in India and the USA and Greece, but not in Spain. (B) The NES-based analysis shows that the curcumin response score is positive and highest in samples from asymptomatic cases in India compared to the severe cases in India. In contrast, the NES is negative for curcumin in all samples in western countries (Black arrow). NES, net enrichment score.

Diets and nutrients correlated with pathways and metabolites related to COVID-19 severity: A linear correlation was observed between diet or nutrients and molecular mechanisms of COVID-19 severity. The cytokine storm, intussusceptive angiogenesis and respiratory acidosis related pathways, which were exclusively upregulated in severe western samples, were positively associated with PA and CO2 but were negatively correlated with curcumin. The sources of the PA and CO2 were red meat, processed food and dairy products. PA also increased the expression of ACE2 leading to more severe COVID-19. The low iron and zinc levels in red meat and dairy products of western diets had the probability of increasing the severity and death from COVID-19. In contrast, south Indian Idli and other food components are high in iron and zinc content. Curcumin also reduces respiratory acidosis and blood glucose levels (Fig. 4)18,22,23–75. Therefore, regular intake of an Indian diet rich in zinc, iron, curcumin, fibre, catechins and EGCG have the potential to reduce the severity and death due to COVID-19. However, consumption of regular western diet, mainly red meat, processed food, dairy products, coffee and alcohol could activate the pathways and factors associated with COVID-19 severity, which may therefore contribute to the increased deaths observed in western countries.

Fig. 4:
Key dietary and nutrient interactions with COVID-19 pathways at molecular level that determines COVID-19 severity and fatality rates in Indian and Western populations. The figure is developed based on our results, available literature18 , 22–75.↑ and ▲ indicate upregulation or increase, ← is activation, and Tdenotes inhibition.


Low serum iron and zinc levels are associated with increased severity and death rates in COVID-1922 (Fig. 4). Zinc is used for treatment of COVID-1923. Dairy products are low in iron contents and alcohol consumption decreases plasma zinc levels. Notably, Idli (zinc 23.4 mg/g, iron 46.4 mg/g, 3-4% fibre)18 contains higher amount of zinc and iron than meat and its zinc content is twice the amount available from vitamin tablets containing zinc which were consumed (10 mg), commonly during the COVID-19 pandemic. Similarly, rice, legumes, wheat, chickpeas and Rajma, which are daily used ingredients in north Indian diet21, are rich in vitamins, minerals, zinc and iron. Hence, Indian foods, in contrast to the western diet are able to maintain high blood zinc and iron levels, which can lower the COVID-19 severity and death rates in India (Fig. 4)18,22–75.

Low plasma HDL-C and high triglyceride levels increase COVID-19 severity24. High alcohol consumption in western countries, increases plasma triglyceride and atorvastatin, a triglyceride lowering medicine and increases HDL-C in the blood is enriched in the Indian samples. Atorvastatin reduces COVID-19 severity, contributes to shortening hospitalization and reduction in COVID-19 mortality25. Catechins present in tea are the natural substitutes of statin. Catechin and EGCG in tea block SARS-CoV-2 Spike RBD and ACE2 interactions and prevent initiation of SARS-CoV-2 infection. India is the largest tea consumer (Supplementary Table I), where >64 per cent of Indians drink tea26. Furthermore, curcumin, consumed in India, enhances the permeability and lipid-lowering effect of EGCG. In contrast, caffeine in coffee reduces statin function, decreases zinc levels, and also inhibits iron absorption27 (Fig. 4). Coffee is the main source of caffeine and is consumed in large quantities per capita in western countries, whereas the consumption is negligible in India (Supplementary Table 1). Therefore, while coffee consumption contribute to COVID-19 severity in western countries; high consumption of tea is potentially associated with less severe form of COVID-19 and lower death rates in India.

Low zinc and high PA-containing western food induces pro-inflammatory activity of PPAR signalling and enhances SARS-CoV-2 pathogenesis by activating pro-inflammatory cytokines, chemokines, NF-κB and ACE228. Western foods also contain high amounts of sphingolipids which activate the SphK1/S1P/S1PR (S1P) hyperinflammatory response pathway and increased COVID-19 severity29 (Fig. 4). We found that PA and sphingolipids, the two key metabolites of western foods, were associated with the activation of COVID-19 severity pathways and higher death rates in western countries (Fig. 4)18,22–75.

Meat, fish, eggs, cheese and alcohol induce hypercapnia and respiratory acidosis30. Furthermore, high animal fat and protein diets, which are low in fibres, are known to cause gut microbiota dysbiosis leading to increased CO2 and hypercapnia and LPS-induced increased blood glucose levels31. Both the hypercapnia and increased blood glucose levels are associated with COVID-19 severity (Fig. 4)18,22–75. CO2 RGs are highly enriched in patients with severe COVID-19 in western countries, but not in India. Therefore, the western diet might be associated with hypercapnia and increased blood glucose levels contributing to increase the severity and death during COVID-19 in western populations.

Curcumin, the active compound of turmeric is a prophylactic agent9 and treatment with curcumin reduces the severity and mortality from COVID-1932. Curcumin increases serum zinc levels33 and it blocks the Spike RBD interaction with ACE2, decreases cholesterol and triglyceride levels, and inhibits hypercapnia, IFN, TNF, chemokine, cytokine, VEGFA-VEGFR2-mediated intussusceptive angiogenesis and NOD-like receptor signaling pathways, which are associated with cytokine storm leading to severity and deaths from COVID-1934,35 (Fig. 4).

We found that all these pathways were exclusively upregulated in western but not in Indian samples (Supplementary Table II). Further, we identified curcumin to be inversely associated with COVID-19 severity (Fig. 3 and Supplementary Table IIIE). Curcumin is the active compound of turmeric and turmeric is regularly consumed (>2 g/day/capita) spice/condiment in India, but not in western countries (Fig. 2 and Supplementary Table I). Therefore, daily intake of turmeric in India maintains high concentration of body curcumin that inhibits almost all molecular mechanisms associated with SARS-CoV-2 infection and COVID-19 severity, leading to less severe disease outcome and lower death rates in India as compared to western countries (Fig. 4)18,22,23–75.

Although our findings are significant from the nutrigenomics point of view, there are some limitations. Our study does not represent a precise case-control study where specific foods were used as treatment. Rather, we considered population-specific dietary habits and transcriptomes of patients. We also did not consider factors such as major clinical determinants of health outcomes, co-morbid conditions, age, gender, vaccination status, nutrition index, food habit diversity, smoking status and other biological and socio-economic factors. Our sample sizes were small and hence establishing statistically significant correlation is not possible.

In conclusion, our results suggested that Indian dietary habits and food ingredients could possibly be associated with reduced severity and death rates from COVID-19 in India. While the western diet and food components seemed to contribute to severity of COVID-19, Indian dietary habits and food ingredients might play a role in reduction of severity of COVID-19 disease. Regular consumption of plant-based foods, Idli, whole grains, legume, vegetables, tea and turmeric (curcumin) diets were probably the key elements behind reduced severity and lower death rates from COVID-19 in India, despite the much higher population density in the country as compared to western countries. However, additional large scale and intervention trial are required for drawing definitive inference in this direction.

Acknowledgment: Authors acknowledge the Omics Science Network (RECOM) and CNPq for their support. AAA acknowledges the Taif University Researchers Supporting Program and KJA would like to acknowledge the support from Deanship of Scientific Research, Taif University, Saudi Arabia.

Financial support & sponsorship: None.

Conflicts of Interest: None.


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Caffeine; COVID-19; death rate; diet; iron; palmitic acid; severity; sphingolipid; tea; transcriptome; turmeric; zinc

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