Low Levels of Serum and Intracellular Vitamin C in Hospitalized COVID-19 Patients

{ 'indexed': {'date-parts': [[2023, 8, 22]], 'date-time': '2023-08-22T05:04:06Z', 'timestamp': 1692680646109}, 'reference-count': 49, 'publisher': 'MDPI AG', 'issue': '16', 'license': [ { 'start': { 'date-parts': [[2023, 8, 20]], 'date-time': '2023-08-20T00:00:00Z', 'timestamp': 1692489600000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': '<jats:p>Vitamin C is a crucial micronutrient for human immune cell function and has potent ' 'antioxidant properties. It is hypothesized that vitamin C serum levels decline during ' 'infection. However, the precise mechanisms remain unknown. To gain deeper insights into the ' 'true role of vitamin C during infections, we aimed to evaluate the body’s vitamin C storage ' 'during a SARS-CoV-2 infection. In this single-center study, we examined serum and ' 'intracellular vitamin C levels in peripheral blood mononuclear cells (PBMCs) of 70 ' 'hospitalized COVID-19 patients on the first and fifth days of hospitalization. Also, clinical ' 'COVID-19 severity was evaluated at these timepoints. Our findings revealed a high prevalence ' 'of hypovitaminosis C and vitamin C deficiency in hospitalized COVID-19 patients (36% and ' '15%). Moreover, patients with severe or critical disease exhibited a higher prevalence of low ' 'serum vitamin C levels than those with moderate illness. Serum vitamin C levels had a weak ' 'negative correlation with clinical COVID-19 severity classification on the day of ' 'hospitalization; however, there was no correlation with intracellular vitamin C. ' 'Intracellular vitamin C levels were decreased in this cohort as compared to a healthy cohort ' 'and showed further decline during hospitalization, while serum levels showed no relevant ' 'change. Based on this observation, it can be suggested that the reduction of intracellular ' 'vitamin C may be attributed to its antioxidative function, the need for replenishing serum ' 'levels, or enhanced turnover by immune cells. These data give an incentive to further ' 'investigate the role of intracellular vitamin C in a larger and more heterogeneous cohort as ' 'well as the underlying mechanisms.</jats:p>', 'DOI': '10.3390/nu15163653', 'type': 'journal-article', 'created': {'date-parts': [[2023, 8, 21]], 'date-time': '2023-08-21T05:46:56Z', 'timestamp': 1692596816000}, 'page': '3653', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Low Levels of Serum and Intracellular Vitamin C in Hospitalized COVID-19 Patients', 'prefix': '10.3390', 'volume': '15', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-6870-1992', 'authenticated-orcid': False, 'given': 'Lara S.', 'family': 'Boerenkamp', 'sequence': 'first', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Birgit L. M. G.', 'family': 'Gijsbers', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Erik-Jan', 'family': 'Ververs', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Eva M. S.', 'family': 'Pijpers', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Internal Medicine, Maastricht University Medical ' 'Center, 6229 HX Maastricht, The Netherlands'}]}, { 'ORCID': 'http://orcid.org/0000-0003-3062-2612', 'authenticated-orcid': False, 'given': 'Bart', 'family': 'Spaetgens', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Internal Medicine, Maastricht University Medical ' 'Center, 6229 HX Maastricht, The Netherlands'}]}, { 'given': 'Aniek', 'family': 'de Coninck', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Wilfred T. V.', 'family': 'Germeraad', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Will K. W. H.', 'family': 'Wodzig', 'sequence': 'additional', 'affiliation': [ { 'name': 'Central Diagnostic Laboratory, Department of Clinical Chemistry, ' 'Maastricht University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'given': 'Lotte', 'family': 'Wieten', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Transplantation Immunology, Maastricht University ' 'Medical Center, 6229 HX Maastricht, The Netherlands'}]}, { 'ORCID': 'http://orcid.org/0000-0001-7327-7834', 'authenticated-orcid': False, 'given': 'Gwendolyn N. Y.', 'family': 'van Gorkom', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}, { 'ORCID': 'http://orcid.org/0000-0003-1784-1765', 'authenticated-orcid': False, 'given': 'Catharina H. M. J.', 'family': 'van Elssen', 'sequence': 'additional', 'affiliation': [ { 'name': 'Division of Hematology, Department of Internal Medicine, GROW ' 'School for Oncology and Developmental Biology, Maastricht ' 'University Medical Center, 6229 HX Maastricht, The ' 'Netherlands'}]}], 'member': '1968', 'published-online': {'date-parts': [[2023, 8, 20]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '419', 'DOI': '10.1016/S8755-9668(86)80021-7', 'article-title': 'The antioxidant role of vitamin C', 'volume': '2', 'author': 'Bendich', 'year': '1986', 'journal-title': 'Adv. Free Radic. Biol. Med.'}, { 'key': 'ref_2', 'doi-asserted-by': 'crossref', 'first-page': '52', 'DOI': '10.5492/wjccm.v7.i5.52', 'article-title': 'Vitamin C in the critically ill—Indications and controversies', 'volume': '7', 'author': 'Nabzdyk', 'year': '2018', 'journal-title': 'World J. Crit. Care Med.'}, { 'key': 'ref_3', 'doi-asserted-by': 'crossref', 'first-page': '49', 'DOI': '10.1177/1533210110392951', 'article-title': 'Vitamin C: Overview and update', 'volume': '16', 'author': 'Schlueter', 'year': '2011', 'journal-title': 'J. Evid. Based Complement. Altern. Med.'}, { 'key': 'ref_4', 'doi-asserted-by': 'crossref', 'first-page': '100190', 'DOI': '10.1016/j.phanu.2020.100190', 'article-title': 'Intravenous vitamin C for reduction of cytokines storm in acute ' 'respiratory distress syndrome', 'volume': '12', 'author': 'Boretti', 'year': '2020', 'journal-title': 'PharmaNutrition'}, { 'key': 'ref_5', 'doi-asserted-by': 'crossref', 'unstructured': 'Bozonet, S.M., and Carr, A.C. (2019). The Role of Physiological Vitamin ' 'C Concentrations on Key Functions of Neutrophils Isolated from Healthy ' 'Individuals. Nutrients, 11.', 'DOI': '10.3390/nu11061363'}, { 'key': 'ref_6', 'doi-asserted-by': 'crossref', 'first-page': '2574', 'DOI': '10.3390/nu7042574', 'article-title': 'Enhanced human neutrophil vitamin C status, chemotaxis and oxidant ' 'genera-tion following dietary supplementation with vitamin C-rich ' 'SunGold kiwifruit', 'volume': '7', 'author': 'Bozonet', 'year': '2015', 'journal-title': 'Nutrients'}, { 'key': 'ref_7', 'doi-asserted-by': 'crossref', 'first-page': '463', 'DOI': '10.1111/odi.12446', 'article-title': 'Vitamin C: The known and the unknown and Goldilocks', 'volume': '22', 'author': 'Padayatty', 'year': '2016', 'journal-title': 'Oral Dis.'}, { 'key': 'ref_8', 'doi-asserted-by': 'crossref', 'first-page': '1165', 'DOI': '10.1189/jlb.1TA0214-121RR', 'article-title': 'Technical Advance: Ascorbic acid induces development of double-positive ' 'T cells from human hematopoietic stem cells in the absence of stromal ' 'cells', 'volume': '96', 'author': 'Huijskens', 'year': '2014', 'journal-title': 'J. Leukoc. Biol.'}, { 'key': 'ref_9', 'doi-asserted-by': 'crossref', 'first-page': '2054', 'DOI': '10.1089/ars.2012.4988', 'article-title': 'Vitamin C Promotes Maturation of T-Cells', 'volume': '19', 'author': 'Manning', 'year': '2013', 'journal-title': 'Antioxid. Redox Signal'}, { 'key': 'ref_10', 'doi-asserted-by': 'crossref', 'unstructured': 'Carr, A.C., and Maggini, S. (2017). Vitamin C and Immune Function. ' 'Nutrients, 9.', 'DOI': '10.3390/nu9111211'}, { 'key': 'ref_11', 'doi-asserted-by': 'crossref', 'first-page': '613', 'DOI': '10.1016/j.jcyt.2015.01.004', 'article-title': 'Ascorbic acid promotes proliferation of natural killer cell populations ' 'in culture systems applicable for natural killer cell therapy', 'volume': '17', 'author': 'Huijskens', 'year': '2015', 'journal-title': 'Cytotherapy'}, { 'key': 'ref_12', 'doi-asserted-by': 'crossref', 'first-page': '389', 'DOI': '10.1111/j.1749-6632.1987.tb23776.x', 'article-title': 'Measurement of vitamin C in blood components by high-performance ' 'liq-uid chromatography. Implication in assessing vitamin C status', 'volume': '498', 'author': 'Omaye', 'year': '1987', 'journal-title': 'Ann. N. Y. Acad Sci.'}, { 'key': 'ref_13', 'doi-asserted-by': 'crossref', 'unstructured': 'Van Gorkom, G.N.Y., Klein Wolterink, R.G.J., Van Elssen, C.H.M.J., ' 'Wieten, L., Germeraad, W.T.V., and Bos, G.M.J. (2018). Influence of ' 'Vitamin C on Lymphocytes: An Overview. Antioxidants, 7.', 'DOI': '10.3390/antiox7030041'}, { 'key': 'ref_14', 'doi-asserted-by': 'crossref', 'first-page': '88', 'DOI': '10.5115/acb.2016.49.2.88', 'article-title': 'Vitamin C is taken up by human T cells via sodium-dependent vitamin C ' 'transporter 2 (SVCT2) and exerts inhibitory effects on the activation ' 'of these cells in vitro', 'volume': '49', 'author': 'Hong', 'year': '2016', 'journal-title': 'Anat. Cell Biol.'}, { 'key': 'ref_15', 'doi-asserted-by': 'crossref', 'first-page': '2584', 'DOI': '10.1016/S0021-9258(19)39841-2', 'article-title': 'Millimolar concentrations of ascorbic acid in purified human ' 'mononuclear leukocytes. Depletion and reaccumulation', 'volume': '265', 'author': 'Bergsten', 'year': '1990', 'journal-title': 'J. Biol. Chem.'}, { 'key': 'ref_16', 'doi-asserted-by': 'crossref', 'first-page': '347', 'DOI': '10.1007/s00726-007-0555-7', 'article-title': 'SVCT1 and SVCT2: Key proteins for vitamin C uptake', 'volume': '34', 'author': 'Savini', 'year': '2007', 'journal-title': 'Amino Acids'}, { 'key': 'ref_17', 'doi-asserted-by': 'crossref', 'first-page': '1539', 'DOI': '10.1017/S0007114515000690', 'article-title': 'Distribution of vitamin C is tissue specific with early saturation of ' 'the brain and adrenal glands following differential oral dose regimens ' 'in guinea pigs', 'volume': '113', 'author': 'Hasselholt', 'year': '2015', 'journal-title': 'Br. J. Nutr.'}, { 'key': 'ref_18', 'doi-asserted-by': 'crossref', 'first-page': '3704', 'DOI': '10.1073/pnas.93.8.3704', 'article-title': 'Vitamin C pharmacokinetics in healthy volunteers: Evidence for a ' 'recommended dietary allowance', 'volume': '93', 'author': 'Levine', 'year': '1996', 'journal-title': 'Proc. Natl. Acad. Sci. USA'}, { 'key': 'ref_19', 'doi-asserted-by': 'crossref', 'first-page': '1203', 'DOI': '10.1093/ajcn/82.6.1203', 'article-title': 'Plasma ascorbic acid concentrations and fat distribution in 19 068 ' 'British men and women in the European Prospective Investigation into ' 'Cancer and Nutrition Norfolk cohort study', 'volume': '82', 'author': 'Canoy', 'year': '2005', 'journal-title': 'Am. J. Clin. Nutr.'}, { 'key': 'ref_20', 'doi-asserted-by': 'crossref', 'unstructured': 'Rowe, S., and Carr, A.C. (2020). Global Vitamin C Status and Prevalence ' 'of Deficiency: A Cause for Concern?. Nutrients, 12.', 'DOI': '10.3390/nu12072008'}, { 'key': 'ref_21', 'doi-asserted-by': 'crossref', 'first-page': '419', 'DOI': '10.1016/j.ejim.2003.08.006', 'article-title': 'Hypovitaminosis C in hospitalized patients', 'volume': '14', 'author': 'Fain', 'year': '2003', 'journal-title': 'Eur. J. Intern. Med.'}, { 'key': 'ref_22', 'doi-asserted-by': 'crossref', 'unstructured': 'Hemilä, H. (2017). Vitamin C and Infections. Nutrients, 9.', 'DOI': '10.3390/nu9040339'}, { 'key': 'ref_23', 'doi-asserted-by': 'crossref', 'first-page': '300', 'DOI': '10.1186/s13054-017-1891-y', 'article-title': 'Hypovitaminosis C and vitamin C deficiency in criti-cally ill patients ' 'despite recommended enteral and parenteral intakes', 'volume': '21', 'author': 'Carr', 'year': '2017', 'journal-title': 'Crit. Care'}, { 'key': 'ref_24', 'doi-asserted-by': 'crossref', 'first-page': '180', 'DOI': '10.1007/s001340050813', 'article-title': 'Antioxidant status in patients with acute respiratory dis-tress ' 'syndrome', 'volume': '25', 'author': 'Metnitz', 'year': '1999', 'journal-title': 'Intensive Care Med.'}, { 'key': 'ref_25', 'doi-asserted-by': 'crossref', 'first-page': '760', 'DOI': '10.1093/ajcn/63.5.760', 'article-title': 'Total vitamin C, ascorbic acid, and dehy-droascorbic acid ' 'concentrations in plasma of critically ill patients', 'volume': '63', 'author': 'Schorah', 'year': '1996', 'journal-title': 'Am. J. Clin. Nutr.'}, { 'key': 'ref_26', 'doi-asserted-by': 'crossref', 'first-page': '679', 'DOI': '10.1080/00365513.2021.2000635', 'article-title': 'CRP, SAA, LDH, and DD predict poor prognosis of coronavirus disease ' '(COVID-19): A meta-analysis from 7739 patients', 'volume': '81', 'author': 'Wang', 'year': '2021', 'journal-title': 'Scand. J. Clin. Lab. Investig.'}, { 'key': 'ref_27', 'doi-asserted-by': 'crossref', 'first-page': '774', 'DOI': '10.1097/CCM.0000000000003700', 'article-title': 'The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: ' 'A Systematic Review With Meta-Analysis of Randomized Controlled Trials', 'volume': '47', 'author': 'Putzu', 'year': '2019', 'journal-title': 'Crit. Care Med.'}, { 'key': 'ref_28', 'doi-asserted-by': 'crossref', 'first-page': '2050312118807615', 'DOI': '10.1177/2050312118807615', 'article-title': 'Vitamin C supplementation in the critically ill: A systematic review ' 'and meta-analysis', 'volume': '6', 'author': 'Zhang', 'year': '2018', 'journal-title': 'SAGE Open Med.'}, { 'key': 'ref_29', 'doi-asserted-by': 'crossref', 'first-page': '94', 'DOI': '10.4103/2279-042X.179569', 'article-title': 'Effect of high-dose Ascorbic acid on vasopressor′s requirement in ' 'septic shock', 'volume': '5', 'author': 'Zabet', 'year': '2016', 'journal-title': 'J. Res. Pharm. Pract.'}, { 'key': 'ref_30', 'first-page': 'CD000980', 'article-title': 'Vitamin C for preventing and treating the common cold', 'volume': '2013', 'author': 'Chalker', 'year': '2013', 'journal-title': 'Cochrane Database Syst. Rev.'}, { 'key': 'ref_31', 'doi-asserted-by': 'crossref', 'first-page': '1033', 'DOI': '10.1016/S0140-6736(20)30628-0', 'article-title': 'COVID-19: Consider cytokine storm syndromes and immunosuppression', 'volume': '395', 'author': 'Mehta', 'year': '2020', 'journal-title': 'Lancet'}, { 'key': 'ref_32', 'doi-asserted-by': 'crossref', 'first-page': '54', 'DOI': '10.2174/187152811794352105', 'article-title': 'Micronutrients at the interface between inflammation and infection ' 'ascorbic acid and calciferol. Part 1: General overview with a focus on ' 'ascorbic acid', 'volume': '10', 'author': 'Wolters', 'year': '2011', 'journal-title': 'Inflamm. Allergy-Drug Targets'}, { 'key': 'ref_33', 'doi-asserted-by': 'crossref', 'unstructured': 'Carr, A.C., Bozonet, S., Pullar, J., Spencer, E., Rosengrave, P., and ' 'Shaw, G. (2021). Neutrophils Isolated from Septic Patients Exhibit ' 'Elevated Uptake of Vitamin C and Normal Intracellular Concentrations ' 'despite a Low Vitamin C Milieu. Antioxidants, 10.', 'DOI': '10.3390/antiox10101607'}, { 'key': 'ref_34', 'unstructured': 'NHCotPsRo (2021, November 01). Chinese Clinical Guidance for COVID-19 ' 'Pneumonia Diagnosis and Treatment, 7th Edition 2020. China, Available ' 'online: ' 'http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml.'}, { 'key': 'ref_35', 'doi-asserted-by': 'crossref', 'first-page': 'e26900', 'DOI': '10.1097/MD.0000000000026900', 'article-title': 'The prognostic value of the SOFA score in patients with COVID-19: A ' 'retrospective, observational study', 'volume': '100', 'author': 'Yang', 'year': '2021', 'journal-title': 'Medicine'}, { 'key': 'ref_36', 'doi-asserted-by': 'crossref', 'unstructured': 'van Gorkom, G., Gijsbers, B., Ververs, E.-J., El Molla, A., Sarodnik, ' 'C., Riess, C., Wodzig, W., Bos, G., and Van Elssen, C. (2022). ' 'Easy-to-Use HPLC Method to Measure Intra-cellular Ascorbic Acid Levels ' 'in Human Peripheral Blood Mononuclear Cells and in Plasma. Antioxidants, ' '11.', 'DOI': '10.3390/antiox11010134'}, { 'key': 'ref_37', 'doi-asserted-by': 'crossref', 'unstructured': 'German Nutrition Society (2015). New Reference Values for Vitamin C ' 'Intake. Ann. Nutr. Metab., 67, 13–20.', 'DOI': '10.1159/000434757'}, { 'key': 'ref_38', 'doi-asserted-by': 'crossref', 'first-page': '100064', 'DOI': '10.1016/j.medidd.2020.100064', 'article-title': 'Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill ' 'COVID-19 Patients of a North American Community Hospital Intensive Care ' 'Unit in May 2020: A Pilot Study', 'volume': '8', 'author': 'Arvinte', 'year': '2020', 'journal-title': 'Med. Drug Discov.'}, { 'key': 'ref_39', 'doi-asserted-by': 'crossref', 'first-page': '14', 'DOI': '10.14336/AD.2020.0918', 'article-title': 'Low level of Vitamin C and dysregulation of Vitamin C transporter might ' 'be involved in the severity of COVID-19 Infection', 'volume': '12', 'author': 'Patterson', 'year': '2021', 'journal-title': 'Aging Dis.'}, { 'key': 'ref_40', 'doi-asserted-by': 'crossref', 'first-page': '66', 'DOI': '10.1186/s12937-021-00727-z', 'article-title': 'COVID-19: Up to 82% critically ill patients had low Vitamin C values', 'volume': '20', 'year': '2021', 'journal-title': 'Nutr. J.'}, { 'key': 'ref_41', 'doi-asserted-by': 'crossref', 'first-page': '1181', 'DOI': '10.1038/sj.ejcn.1602230', 'article-title': 'Serum concentrations of β-carotene, vitamins C and E, zinc and selenium ' 'are influenced by sex, age, diet, smoking status, alcohol consumption ' 'and corpulence in a general French adult population', 'volume': '59', 'author': 'Galan', 'year': '2005', 'journal-title': 'Eur. J. Clin. Nutr.'}, { 'key': 'ref_42', 'doi-asserted-by': 'crossref', 'unstructured': 'McCall, S.J., Clark, A.B., Luben, R.N., Wareham, N.J., Khaw, K.-T., and ' 'Myint, P.K. (2019). Plasma Vitamin C Levels: Risk Factors for Deficiency ' 'and Association with Self-Reported Functional Health in the European ' 'Prospective Investigation into Cancer-Norfolk. Nutrients, 11.', 'DOI': '10.3390/nu11071552'}, { 'key': 'ref_43', 'doi-asserted-by': 'crossref', 'first-page': '173', 'DOI': '10.1016/j.jsps.2020.12.018', 'article-title': 'Immune system re-sponse during viral Infections: Immunomodulators, ' 'cytokine storm (CS) and Immunotherapeutics in COVID-19', 'volume': '29', 'author': 'AlHajri', 'year': '2021', 'journal-title': 'Saudi. Pharm. J.'}, { 'key': 'ref_44', 'doi-asserted-by': 'crossref', 'unstructured': 'Mueller, S.N., and Rouse, B.T. (2008). Immune responses to viruses. ' 'Clin. Immunol., 421–431.', 'DOI': '10.1016/B978-0-323-04404-2.10027-2'}, { 'key': 'ref_45', 'doi-asserted-by': 'crossref', 'first-page': '30', 'DOI': '10.1186/s43094-020-00040-2', 'article-title': 'Association of vitamin C status in diabetes mellitus: Prevalence and ' 'predictors of vitamin C defi-ciency', 'volume': '6', 'author': 'Praveen', 'year': '2020', 'journal-title': 'Future J. Pharm. Sci.'}, { 'key': 'ref_46', 'doi-asserted-by': 'crossref', 'first-page': '1252', 'DOI': '10.3945/ajcn.2008.27016', 'article-title': 'Serum vitamin C and the prevalence of vitamin C deficiency in the ' 'United States: 2003–2004 National Health and Nutrition Examination ' 'Survey (NHANES)', 'volume': '90', 'author': 'Schleicher', 'year': '2009', 'journal-title': 'Am. J. Clin. Nutr.'}, { 'key': 'ref_47', 'doi-asserted-by': 'crossref', 'first-page': 'e33989', 'DOI': '10.1056/EVIDoa2200105', 'article-title': 'Parenteral Vitamin C in Patients with Severe Infection: A Systematic ' 'Review', 'volume': '1', 'author': 'Agarwal', 'year': '2022', 'journal-title': 'NEJM Evid.'}, { 'key': 'ref_48', 'doi-asserted-by': 'crossref', 'first-page': '102324', 'DOI': '10.1016/j.dsx.2021.102324', 'article-title': 'Vitamin C and COVID-19 treatment: A systematic review and ' 'me-ta-analysis of randomized controlled trials', 'volume': '15', 'author': 'Rawat', 'year': '2021', 'journal-title': 'Diabetes Metab. Syndr. Clin. Res. Rev.'}, { 'key': 'ref_49', 'doi-asserted-by': 'crossref', 'first-page': '1837634', 'DOI': '10.1155/2018/1837634', 'article-title': 'Extra Dose of Vitamin C Based on a Daily Supplementation Shortens the ' 'Common Cold: A Meta-Analysis of 9 Randomized Controlled Trials', 'volume': '2018', 'author': 'Ran', 'year': '2018', 'journal-title': 'BioMed Res. Int.'}], 'container-title': 'Nutrients', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.mdpi.com/2072-6643/15/16/3653/pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 8, 21]], 'date-time': '2023-08-21T06:54:54Z', 'timestamp': 1692600894000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.mdpi.com/2072-6643/15/16/3653'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 8, 20]]}, 'references-count': 49, 'journal-issue': {'issue': '16', 'published-online': {'date-parts': [[2023, 8]]}}, 'alternative-id': ['nu15163653'], 'URL': 'http://dx.doi.org/10.3390/nu15163653', 'relation': {}, 'ISSN': ['2072-6643'], 'subject': ['Food Science', 'Nutrition and Dietetics'], 'container-title-short': 'Nutrients', 'published': {'date-parts': [[2023, 8, 20]]}}