Publications by authors named "Anitra C Carr"

71 Publications

Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence.

Life (Basel) 2021 Nov 1;11(11). Epub 2021 Nov 1.

Faculty of Medicine, Imperial College, London SW7 2AZ, UK.

Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin. Administration of intravenous vitamin C to patients with pneumonia and sepsis appears to decrease the severity of the disease and potentially improve survival rate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes pneumonia, sepsis and acute respiratory distress syndrome (ARDS) in severe cases, and is referred to as coronavirus disease 2019 (COVID-19). Patients with COVID-19 infection also appear to have depleted vitamin C status and require additional supplementation of vitamin C during the acute phase of the disease. To date there have been 12 vitamin C and COVID-19 trials published, including five randomised controlled trials (RCTs) and seven retrospective cohort studies. The current level of evidence from the RCTs suggests that intravenous vitamin C intervention may improve oxygenation parameters, reduce inflammatory markers, decrease days in hospital and reduce mortality, particularly in the more severely ill patients. High doses of oral vitamin C supplementation may also improve the rate of recovery in less severe cases. No adverse events have been reported in published vitamin C clinical trials in COVID-19 patients. Upcoming findings from larger RCTs will provide additional evidence on vitamin supplementation in COVID-19 patients.
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http://dx.doi.org/10.3390/life11111166DOI Listing
November 2021

Circulating protein carbonyls are specifically elevated in critically ill patients with pneumonia relative to other sources of sepsis.

Free Radic Biol Med 2021 Nov 21. Epub 2021 Nov 21.

Department of Pathology and Biomedical Science, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand. Electronic address:

Background: Septic shock is a life-threatening dysregulated response to severe infection and is associated with elevated oxidative stress. We aimed to assess protein carbonyls in critically ill patients with different sources of sepsis and determine the effect of vitamin C intervention on protein carbonyl concentrations.

Methods: Critically ill patients with septic shock (n = 40) were recruited, and sources of sepsis and ICU severity scores were recorded. The patients were randomised to receive either intravenous vitamin C (100 mg/kg body weight/day) or placebo infusions. Blood samples were collected at baseline and daily for up to three days for measurement of cell counts, vitamin C concentrations, protein carbonyls, C-reactive protein, and myeloperoxidase concentrations.

Results: Protein carbonyl concentrations increased 2.2-fold in the cohort over the duration of the study (from 169 to 369 pmol/mg protein; p = 0.03). There were significant correlations between protein carbonyl concentrations and ICU severity scores (APACHE III r = 0.47 and SOFA r = 0.37; p < 0.05) at baseline. At study admission, the patients with pneumonia had nearly 3-fold higher protein carbonyl concentrations relative to the patients with other sources of sepsis (435 vs 157 pmol/mg protein, p < 0.0001). The septic patients had deficient vitamin C status at baseline (9.8 ± 1.4 μmol/L). This increased to 456 ± 90 μmol/L following three days of intravenous vitamin C intervention. Vitamin C intervention did not attenuate the increase in protein carbonyl concentrations.

Conclusions: Circulating protein carbonyls are specifically elevated in critically ill patients with pneumonia relative to other sources of sepsis. The reasons for this are currently unclear and may indicate a mechanism unique to pulmonary sources of sepsis. Intravenous vitamin C administration did not attenuate the increase in protein carbonyls over time.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.11.029DOI Listing
November 2021

Neutrophils Isolated from Septic Patients Exhibit Elevated Uptake of Vitamin C and Normal Intracellular Concentrations despite a Low Vitamin C Milieu.

Antioxidants (Basel) 2021 Oct 13;10(10). Epub 2021 Oct 13.

Department of Intensive Care Medicine, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand.

Vitamin C (ascorbate) plays an important role in neutrophil function and is accumulated by the cells either directly via vitamin C transporters (SVCT) or indirectly following oxidation to dehydroascorbic acid. Septic patients are known to have significantly depleted plasma ascorbate status, but little is known about the ascorbate content of their circulating cells. Therefore, we assessed the ascorbate concentrations of plasma, leukocytes and erythrocytes from septic patients and compared these to healthy controls. Non-fasting blood samples were collected from healthy volunteers ( = 20) and critically ill patients with sepsis ( = 18). The ascorbate content of the plasma and isolated neutrophils and erythrocytes was measured using HPLC and plasma myeloperoxidase concentrations were determined using ELISA. Ex vivo uptake of ascorbate and dehydroascorbic acid by neutrophils from septic patients was also assessed. Neutrophils isolated from septic patients had comparable intracellular ascorbate content to healthy volunteers (0.33 vs. 0.35 nmol/10 cells, > 0.05), despite significantly lower plasma concentrations than the healthy controls (14 vs. 88 µmol/L, < 0.001). In contrast, erythrocytes from septic patients had significantly lower intracellular ascorbate content than healthy controls (30 vs. 69 µmol/L, = 0.002), although this was 2.2-fold higher than the matched plasma concentrations in the patients ( = 0.008). Higher concentrations of myeloperoxidase, a source of reactive oxygen species, were observed in the septic patients relative to healthy controls (194 vs. 14 mg/mL, < 0.0001). In contrast to neutrophils from healthy volunteers, the neutrophils from septic patients demonstrated elevated uptake of extracellular ascorbate. Overall, neutrophils from septic patients exhibited comparable intracellular ascorbate content to those from healthy controls, despite the patients presenting with hypovitaminosis C. The mechanisms involved are currently uncertain, but could include increased generation of dehydroascorbic acid in septic patients, enhanced basal activation of their neutrophils or upregulation of their vitamin C transporters.
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http://dx.doi.org/10.3390/antiox10101607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533547PMC
October 2021

Micronutrients and respiratory infections: the biological rationale and current state of clinical evaluation.

Br J Hosp Med (Lond) 2021 Apr 27;82(4):1-8. Epub 2021 Apr 27.

Nutrition in Medicine Research Group, University of Otago, Christchurch, New Zealand.

A range of nutrients has been studied or proposed for use in preventing respiratory tract infections and reducing their severity. This article gives a narrative review of the existing literature, biological rationales and current state of clinical evaluation for micronutrient therapies. The importance of vitamin A, the B vitamins, vitamin C, vitamin D, eicosapentaenoic acid, vitamin E, selenium, zinc and a range of combination therapies are discussed, looking at their effects on reducing rates of infection, reducing severity of infection and improved recovery from infection. Further discussion regarding the level of evidence required for nutritional interventions is included.
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http://dx.doi.org/10.12968/hmed.2020.0730DOI Listing
April 2021

Peroxiredoxin 2 oxidation reveals hydrogen peroxide generation within erythrocytes during high-dose vitamin C administration.

Redox Biol 2021 07 17;43:101980. Epub 2021 Apr 17.

Centre for Free Radical Research, Department of Pathology & Biomedical Science, University of Otago, Christchurch, New Zealand. Electronic address:

Intravenous infusion of high dose (>10 g) vitamin C (IVC) is a common alternative cancer therapy. IVC results in millimolar levels of circulating ascorbate, which is proposed to generate cytotoxic quantities of HO in the presence of transition metal ions. In this study we report on the in vitro and in vivo effects of millimolar ascorbate on erythrocytes. Addition of ascorbate to whole blood increased erythrocyte intracellular ascorbate approximately 35-fold. Within 10 min of ascorbate addition, we detected increased oxidation of erythrocyte peroxiredoxin 2 (Prx2), a major thiol antioxidant protein and a sensitive marker of HO production. Up to 50% of Prx2 was present in the oxidised form after 60 min. The presence of extracellular catalase, removal of plasma or the addition of a metal chelator did not prevent ascorbate-induced Prx2 oxidation, suggesting that the HO responsible for Prx2 oxidation was generated within the erythrocyte. Ascorbate is known to increase the rate of haemoglobin autoxidation and HO production. Through spectral monitoring of oxidised haemoglobin we estimated a generation rate of 15 μM HO/min inside erythrocytes. We also investigated changes in erythrocyte ascorbate concentration and Prx2 oxidation following IVC infusion in a cohort of patients with cancer. Plasma ascorbate levels ranged from 7.8 to 35 mM immediately post infusion, while erythrocyte ascorbate levels reached 1.5-3.4 mM 4 h after beginning infusion. Transient oxidation of erythrocyte Prx2 was observed. We conclude that erythrocytes accumulate ascorbate during IVC infusion, providing a significant reservoir of ascorbate, and this ascorbate increases HO generation within the cells. The consequence of increased erythrocyte Prx2 oxidation warrants further investigation.
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http://dx.doi.org/10.1016/j.redox.2021.101980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099772PMC
July 2021

Vitamin C: From Bench to Bedside.

Nutrients 2021 Mar 27;13(4). Epub 2021 Mar 27.

Faculty of Health & Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.

Vitamin C (ascorbic acid) is a normal liver metabolite in most animals, with humans being a notable exception due to random genetic mutations that have occurred during our evolution [...].
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http://dx.doi.org/10.3390/nu13041102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066298PMC
March 2021

Is "Mega-Dose" IV Vitamin C Required for Septic and Critical Coronavirus Disease 2019 Patients?

Authors:
Anitra C Carr

Crit Care Med 2021 04;49(4):e477-e478

Nutrition in Medicine Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.

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http://dx.doi.org/10.1097/CCM.0000000000004873DOI Listing
April 2021

Vitamin C Administration by Intravenous Infusion Increases Tumor Ascorbate Content in Patients With Colon Cancer: A Clinical Intervention Study.

Front Oncol 2020 11;10:600715. Epub 2021 Jan 11.

Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago Christchurch, Christchurch, New Zealand.

The use of high dose ascorbate infusions in cancer patients is widespread, but without evidence of efficacy. Several mechanisms whereby ascorbate could affect tumor progression have been proposed, including: (i) the localized generation of cytotoxic quantities of HO; (ii) ascorbate-dependent activation of the 2-oxoglutarate-dependent dioxygenases that control the hypoxia-inducible factors (HIFs) and that are responsible for the demethylation of DNA and histones; (iii) increased oxidative stress induced by dehydroascorbic acid. We hypothesize that the dysfunctional vasculature of solid tumors results in compromised delivery of ascorbate to poorly perfused regions of the tumor and that this ascorbate deficit acts as an additional driver of the hypoxic response via upregulation of HIFs. Using a randomized "therapeutic window of opportunity" clinical study design we aimed to determine whether ascorbate infusions affected tumor ascorbate content and tumor biology. Patients with colon cancer were randomized to receive infusions of up to 1 g/kg ascorbate for 4 days before surgical resection ( = 9) or to not receive infusions ( = 6). Ascorbate was measured in plasma, erythrocytes, tumor and histologically normal mucosa at diagnostic colonoscopy and at surgery. Protein markers of tumor hypoxia or DNA damage were monitored in resected tissue. Plasma ascorbate reached millimolar levels following infusion and returned to micromolar levels over 24 h. Pre-infusion plasma ascorbate increased from 38 ± 10 µM to 241 ± 33 µM (p < 0.0001) over 4 days and erythrocyte ascorbate from 18 ± 20 µM to 2509 ± 1016 µM (p < 0.005). Tumor ascorbate increased from 15 ± 6 to 28 ± 6 mg/100 g tissue (p < 0.0001) and normal tissue from 14 ± 6 to 21 ± 4 mg/100 g (p < 0.001). A gradient of lower ascorbate was evident towards the tumor centre in both control and infusion samples. Lower expression of hypoxia-associated proteins was seen in post-infusion tumors compared with controls. There were no significant adverse events and quality of life was unaffected by ascorbate infusion. This is the first clinical study to demonstrate that tumor ascorbate levels increase following infusion, even in regions of poor diffusion, and that this could modify tumor biology.

Clinical Trial Registration: ANZCTR Trial ID ACTRN12615001277538 (https://www.anzctr.org.au/).
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http://dx.doi.org/10.3389/fonc.2020.600715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830882PMC
January 2021

Vitamin C-An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19.

Nutrients 2020 Dec 7;12(12). Epub 2020 Dec 7.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

There are limited proven therapies for COVID-19. Vitamin C's antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8 g/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6-24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients' vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.
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http://dx.doi.org/10.3390/nu12123760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762433PMC
December 2020

The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19.

Nutrients 2020 Oct 27;12(11). Epub 2020 Oct 27.

Intensive Care Department, Newham University Hospital, Barts NHS Trust, London E13 8SL, UK.

Investigation into the role of vitamin C in the prevention and treatment of pneumonia and sepsis has been underway for many decades. This research has laid a strong foundation for translation of these findings into patients with severe coronavirus disease (COVID-19). Research has indicated that patients with pneumonia and sepsis have low vitamin C status and elevated oxidative stress. Administration of vitamin C to patients with pneumonia can decrease the severity and duration of the disease. Critically ill patients with sepsis require intravenous administration of gram amounts of the vitamin to normalize plasma levels, an intervention that some studies suggest reduces mortality. The vitamin has pleiotropic physiological functions, many of which are relevant to COVID-19. These include its antioxidant, anti-inflammatory, antithrombotic and immuno-modulatory functions. Preliminary observational studies indicate low vitamin C status in critically ill patients with COVID-19. There are currently a number of randomized controlled trials (RCTs) registered globally that are assessing intravenous vitamin C monotherapy in patients with COVID-19. Since hypovitaminosis C and deficiency are common in low-middle-income settings, and many of the risk factors for vitamin C deficiency overlap with COVID-19 risk factors, it is possible that trials carried out in populations with chronic hypovitaminosis C may show greater efficacy. This is particularly relevant for the global research effort since COVID-19 is disproportionately affecting low-middle-income countries and low-income groups globally. One small trial from China has finished early and the findings are currently under peer review. There was significantly decreased mortality in the more severely ill patients who received vitamin C intervention. The upcoming findings from the larger RCTs currently underway will provide more definitive evidence. Optimization of the intervention protocols in future trials, e.g., earlier and sustained administration, is warranted to potentially improve its efficacy. Due to the excellent safety profile, low cost, and potential for rapid upscaling of production, administration of vitamin C to patients with hypovitaminosis C and severe respiratory infections, e.g., COVID-19, appears warranted.
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http://dx.doi.org/10.3390/nu12113286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693980PMC
October 2020

Positive Association of Ascorbate and Inverse Association of Urate with Cognitive Function in People with Parkinson's Disease.

Antioxidants (Basel) 2020 Sep 23;9(10). Epub 2020 Sep 23.

Nutrition in Medicine Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8011, New Zealand.

Oxidative stress is thought to contribute to the aetiology of neurological disorders such as Parkinson's disease. Ascorbate (vitamin C) is a potent antioxidant and is associated with neurological and cognitive function. In this study we assessed the ascorbate status of a cohort of people with Parkinson's disease ( = 215), aged 50-90 years, compared with a cohort of age matched healthy controls ( = 48). The study sample's cognitive status ranged from normal to mild cognitive impairment and dementia. There was no difference between the Parkinson's disease and healthy control groups with respect to mean ascorbate status, however, a higher proportion of participants with Parkinson's disease had hypovitaminosis C (i.e., <23 μmol/L) compared with healthy controls (20% vs. 8%, respectively). Within the Parkinson's disease group, Montreal Cognitive Assessment (MoCA) scores correlated positively with ascorbate concentrations, with higher ascorbate status associated with better cognitive function ( = 0.14, = 0.045). Participants with hypovitaminosis C had significantly lower MoCA scores relative to participants with ascorbate concentrations >23 µmol/L ( = 0.014). Ascorbate concentrations were significantly lower in the cognitively impaired subgroup compared with the normal cognition subgroup in the Parkinson's disease cohort ( = 0.03). In contrast, urate showed an inverse correlation with cognitive function ( = -0.19, = 0.007), with higher urate concentrations observed in the cognitively impaired subgroup compared with the normal cognition subgroup ( = 0.015). There was an inverse association between ascorbate status and urate concentrations ( = -0.15, = 0.017). Plasma protein carbonyls, a measure of systemic oxidative stress, were not significantly different between the Parkinson's disease cohort and healthy controls, and there was no association with cognitive function ( = 0.09, = 0.19) or with ascorbate status ( = -0.05, = 0.45). Overall, our study showed ascorbate status was positively associated with cognitive function in Parkinson's disease, suggesting that longitudinal studies investigating the temporal sequence of cognitive decline and ascorbate status are warranted.
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http://dx.doi.org/10.3390/antiox9100906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598173PMC
September 2020

The effect of conservative oxygen therapy on systemic biomarkers of oxidative stress in critically ill patients.

Free Radic Biol Med 2020 11 5;160:13-18. Epub 2020 Aug 5.

Medical Research Institute of New Zealand, Wellington, New Zealand; Wellington Hospital Intensive Care Unit, Wellington, New Zealand.

Background: Supplemental oxygen is delivered to critically ill patients who require mechanical ventilation. Oxidative stress is a potential complication of oxygen therapy, resulting in damage to essential biomolecules such as proteins, lipids, and nucleic acids. Whether plasma levels of oxidative stress biomarkers vary based on how liberally oxygen therapy is applied during mechanical ventilation is unknown.

Methods: We carried out an oxidative stress substudy nested within a large multi-centre randomized controlled trial in which critically ill adults were randomized to receive either conservative oxygen therapy or standard oxygen therapy. Blood samples were collected at enrolment, and daily thereafter for up to three days. The antioxidant ascorbate (vitamin C) was assessed using HPLC with electrochemical detection and protein oxidation using a sensitive protein carbonyl ELISA. We also assessed whether critically ill patients with different disease states exhibited varying levels of oxidative stress biomarkers.

Results: A total of 125 patients were included. Mean ascorbate concentrations decreased over time (from 25 ± 9 μmol/L to 14 ± 2 μmol/L, p < 0.001), however, there was no significant difference between the conservative oxygen group and standard care (p = 0.2), despite a significantly lower partial pressure of oxygen (PaO) in the conservative oxygen group (p = 0.03). Protein carbonyl concentrations increased over time (from 208 ± 30 μmol/L to 249 ± 29 μmol/L; p = 0.016), however, there was no significant difference between the conservative and standard oxygen groups (p = 0.3). Patients with sepsis had significantly higher protein carbonyl concentrations than the other critically ill patients (293 ± 92 μmol/L vs 184 ± 24 μmol/L, p = 0.03). Within the septic subgroup, there were no significant differences in protein carbonyl concentrations between the two interventions (p = 0.4).

Conclusions: Conservative oxygen therapy does not alter systemic markers of oxidative stress in critically ill ventilated patients compared with standard oxygen therapy. Patients with sepsis exhibited elevated protein carbonyls compared with the other critically ill patients implying increased oxidative stress in this patient subgroup.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.06.018DOI Listing
November 2020

Reply to "Comment on: Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. 2020, , 1181".

Nutrients 2020 Aug 3;12(8). Epub 2020 Aug 3.

Department Internal Medicine, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

We thank Tsoupras and Zabetakis for their interest in our recent publication [...].
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http://dx.doi.org/10.3390/nu12082326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469053PMC
August 2020

Global Vitamin C Status and Prevalence of Deficiency: A Cause for Concern?

Nutrients 2020 Jul 6;12(7). Epub 2020 Jul 6.

Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch 8011, New Zealand.

Vitamin C is an essential nutrient that must be obtained through the diet in adequate amounts to prevent hypovitaminosis C, deficiency and its consequences-including the potentially fatal deficiency disease scurvy. Global vitamin C status and prevalence of deficiency has not previously been reported, despite vitamin C's pleiotropic roles in both non-communicable and communicable disease. This review highlights the global literature on vitamin C status and the prevalence of hypovitaminosis C and deficiency. Related dietary intake is reported if assessed in the studies. Overall, the review illustrates the shortage of high quality epidemiological studies of vitamin C status in many countries, particularly low- and middle-income countries. The available evidence indicates that vitamin C hypovitaminosis and deficiency is common in low- and middle-income countries and not uncommon in high income settings. Further epidemiological studies are required to confirm these findings, to fully assess the extent of global vitamin C insufficiency, and to understand associations with a range of disease processes. Our findings suggest a need for interventions to prevent deficiency in a range of at risk groups and regions of the world.
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http://dx.doi.org/10.3390/nu12072008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400810PMC
July 2020

Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective.

Nutrients 2020 Jul 1;12(7). Epub 2020 Jul 1.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L35QA, UK.

A recent review of global vitamin C status has indicated a high prevalence of deficiency, particularly in low- and middle-income countries, as well as in specific subgroups within high-income countries. Here, we provide a narrative review of potential factors influencing vitamin C status globally. The in vivo status of vitamin C is primarily affected by dietary intake and supplement use, with those who supplement having a higher mean status and a lower prevalence of deficiency. Dietary intake can be influenced by cultural aspects such as traditional cooking practices and staple foods, with many staple foods, such as grains, contributing negligible vitamin C to the diet. Environmental factors can also affect vitamin C intake and status; these include geographic region, season, and climate, as well as pollution, the latter partly due to enhanced oxidative stress. Demographic factors such as sex, age, and race are known to affect vitamin C status, as do socioeconomic factors such as deprivation, education and social class, and institutionalization. Various health aspects can affect vitamin C status; these include body weight, pregnancy and lactation, genetic variants, smoking, and disease states, including severe infections as well as various noncommunicable diseases such as cardiovascular disease and cancer. Some of these factors have changed over time; therefore, we also explore if vitamin C status has shown temporal changes. Overall, there are numerous factors that can affect vitamin C status to different extents in various regions of the world. Many of these factors are not taken into consideration during the setting of global dietary intake recommendations for vitamin C.
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http://dx.doi.org/10.3390/nu12071963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400679PMC
July 2020

Patients Undergoing Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation Exhibit Depleted Vitamin C Status in Association with Febrile Neutropenia.

Nutrients 2020 Jun 24;12(6). Epub 2020 Jun 24.

The Infection Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8011, New Zealand.

Patients undergoing myeloablative chemotherapy and hematopoietic stem cell transplantation (HSCT) experience profound neutropenia and vulnerability to infection. Previous research has indicated that patients with infections have depleted vitamin C status. In this study, we recruited 38 patients with hematopoietic cancer who were undergoing conditioning chemotherapy and HSCT. Blood samples were collected prior to transplantation, at one week, two weeks and four weeks following transplantation. Vitamin C status and biomarkers of inflammation (C-reactive protein) and oxidative stress (protein carbonyls and thiobarbituric acid reactive substances) were assessed in association with febrile neutropenia. The vitamin C status of the study participants decreased from 44 ± 7 µmol/L to 29 ± 5 µmol/L by week one ( = 0.001) and 19 ± 6 µmol/L by week two ( < 0.001), by which time all of the participants had undergone a febrile episode. By week four, vitamin C status had increased to 37 ± 10 µmol/L ( = 0.1). Pre-transplantation, the cohort comprised 19% with hypovitaminosis C (i.e., <23 µmol/L) and 8% with deficiency (i.e., <11 µmol/L). At week one, those with hypovitaminosis C had increased to 38%, and at week two, 72% had hypovitaminosis C, and 34% had outright deficiency. C-reactive protein concentrations increased from 3.5 ± 1.8 mg/L to 20 ± 11 mg/L at week one ( = 0.002), and 119 ± 25 mg/L at week two ( < 0.001), corresponding to the development of febrile neutropenia in the patients. By week four, these values had dropped to 17 ± 8 mg/L ( < 0.001). There was a significant inverse correlation between C-reactive protein concentrations and vitamin C status ( = -0.424, < 0.001). Lipid oxidation (thiobarbituric acid reactive substances (TBARS)) increased significantly from 2.0 ± 0.3 µmol/L at baseline to 3.3 ± 0.6 µmol/L by week one ( < 0.001), and remained elevated at week two ( = 0.003), returning to baseline concentrations by week four ( = 0.3). Overall, the lowest mean vitamin C values (recorded at week two) corresponded with the highest mean C-reactive protein values and lowest mean neutrophil counts. Thus, depleted vitamin C status in the HSCT patients coincides with febrile neutropenia and elevated inflammation and oxidative stress.
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http://dx.doi.org/10.3390/nu12061879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353216PMC
June 2020

Micronutrient status of COVID-19 patients: a critical consideration.

Authors:
Anitra C Carr

Crit Care 2020 06 16;24(1):349. Epub 2020 Jun 16.

Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand.

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http://dx.doi.org/10.1186/s13054-020-03085-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296900PMC
June 2020

Harm of IV High-Dose Vitamin C Therapy in Adult Patients: A Scoping Review.

Crit Care Med 2020 07;48(7):e620-e628

Department of Intensive Care, Austin Hospital, Heidelberg, VIC, Australia.

Objectives: The potential harm associated with the use of IV vitamin C has not been systematically assessed. We aimed to review the available evidence on harm related to such treatment.

Data Sources: We searched MEDLINE, EMBASE, Cochrane Library, National Institute of Health Clinical Trials Register, and World Health Organization International Clinical Trials Registry Platform.

Study Selection: We included studies in adult population that reported harm related to IV high-dose vitamin C which we defined as greater than or equal to 6 g/d, greater than or equal to 75 mg/kg/d, or greater than or equal to 3 g/m/d.

Data Extraction: Two independent investigators screened records and extracted data.

Data Synthesis: We identified 8,149 reports, of which 650 full text were assessed for eligibility, leaving 74 eligible studies. In these studies, 2,801 participants received high-dose vitamin C at a median (interquartile range) dose of 22.5 g/d (8.25-63.75 g/d), 455 mg/kg/d (260-925 mg/kg/d), or 70 g/m/d (50-90 g/m/d); and 932 or more adverse events were reported. Among nine double-blind randomized controlled trials (2,310 patients), adverse events were reported in three studies with an event rate per patient for high-dose vitamin C identical to placebo group in one study (0.1 [1/10] vs 0.1 [1/10]), numerically lower in one study (0.80 [672/839] vs 0.82 [709/869]), and numerically higher in one study (0.33 [24/73] vs 0.23 [17/74]). Six double-blind randomized controlled trials reported no adverse event in either group. Five cases of oxalate nephropathy, five cases of hypernatremia, three cases of hemolysis in glucose-6-phosphate dehydrogenase deficiency patients, two cases of glucometer error, and one case of kidney stones were also reported overall.

Conclusions: There is no consistent evidence that IV high-dose vitamin C therapy is more harmful than placebo in double-blind randomized controlled trials. However, reports of oxalate nephropathy, hypernatremia, glucometer error, and hemolysis in glucose-6-phosphate dehydrogenase deficiency patients warrant specific monitoring.
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http://dx.doi.org/10.1097/CCM.0000000000004396DOI Listing
July 2020

Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress.

Nutrients 2020 May 6;12(5). Epub 2020 May 6.

The Infection Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8011, New Zealand.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the Intensive Care Unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and hematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, an established marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs. 56 ± 24 µmol/L, < 0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs. 24 ± 14 µmol/L, = 0.02). The pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls ( < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples from 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values ( = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease excessive oxidative stress and aid in their recovery.
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http://dx.doi.org/10.3390/nu12051318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284353PMC
May 2020

Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections.

Nutrients 2020 Apr 23;12(4). Epub 2020 Apr 23.

Department of Internal Medicine, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B, B, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.
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http://dx.doi.org/10.3390/nu12041181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230749PMC
April 2020

A new clinical trial to test high-dose vitamin C in patients with COVID-19.

Authors:
Anitra C Carr

Crit Care 2020 04 7;24(1):133. Epub 2020 Apr 7.

Department of Pathology & Biomedical Science, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand.

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http://dx.doi.org/10.1186/s13054-020-02851-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137406PMC
April 2020

Is the VITAMINS RCT indicating potential redundancy between corticosteroids and vitamin C?

Authors:
Anitra C Carr

Crit Care 2020 04 6;24(1):129. Epub 2020 Apr 6.

Department of Pathology & Biomedical Science, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand.

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http://dx.doi.org/10.1186/s13054-020-02853-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137516PMC
April 2020

Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives.

Crit Rev Food Sci Nutr 2021 30;61(5):742-755. Epub 2020 Mar 30.

Faculty of Health & Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The concept of a 'recommended dietary allowance' (RDA) and similar terms describing the daily intake of essential nutrients recommended for healthy individuals is widely used by various health authorities around the world. For vitamin C, however, there remain significant discrepancies in the criteria used to establish dietary recommendations and consequently, global recommendations for daily vitamin C intake vary by more than five fold. While it appears that the scientific data underlying the recommendations are more or less the same, the interpretation differs considerably. Moreover, although a number of the assumptions used in e.g. the body pool estimates of the 1960s and 1970s have later been proven wrong and give rise to significant underestimations, these data are still used as the main support of several recommendations. Aspects that modify vitamin C requirements, such as gender, age, pregnancy, lactation, and smoking, have been taken into consideration by many but not all regulatory authorities, and are thus subject of debate. In contrast, body weight, a significant predictor of vitamin C status and requirement, has not been taken into consideration with respect to vitamin C recommendations, even in the face of the looming global obesity pandemic. The present review examines the discrepancies in vitamin C dietary recommendations of international authorities and critically discusses representative examples of criteria and the underlying health perspectives used to derive current recommended intakes of vitamin C. New biological signatures of vitamin C nutriture are also explored with regard to their potential use for future updates of dietary recommendations.
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http://dx.doi.org/10.1080/10408398.2020.1744513DOI Listing
February 2021

Erythrocyte Ascorbate Is a Potential Indicator of Steady-State Plasma Ascorbate Concentrations in Healthy Non-Fasting Individuals.

Nutrients 2020 02 6;12(2). Epub 2020 Feb 6.

Nutrition in Medicine Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch, PO Box 4345, 8140 Christchurch, New Zealand.

Plasma vitamin C concentrations fluctuate in response to recent dietary intake; therefore levels are typically determined in the fasting state. Erythrocyte ascorbate concentrations have been shown to be similar to plasma levels, but little is known about the kinetics of ascorbate accumulation in these cells. In this study, we investigated ascorbate uptake into erythrocytes after dietary supplementation with vitamin C and compared it to changes in plasma ascorbate concentrations. Seven individuals with baseline fasting plasma vitamin C concentrations ≥ 50 µmol/L were depleted of vitamin C-containing foods and drinks for one week, and then supplemented with 250 mg vitamin C/day in addition to resuming their normal diet. Fasting or steady-state plasma ascorbate concentrations declined to almost half of their baseline concentration over the week of vitamin C depletion, and then returned to saturation within two days of beginning supplementation. Erythrocyte ascorbate concentrations exhibited a very similar profile to plasma levels, with values ~76% of plasma, and a strong linear correlation (r = 0.89, < 0.0001). Using a pharmacokinetic study design in six individuals with baseline fasting plasma vitamin C concentrations ≥50 µmol/L, we also showed that, unlike plasma, which peaked between 2 and 4 h following ingestion of 200 mg of vitamin C, erythrocyte ascorbate concentrations did not change in the six hours after supplementation. The data from these two intervention studies indicate that erythrocyte ascorbate concentration provides a stable measure of steady-state plasma ascorbate status and could be used to monitor ascorbate status in healthy non-fasting individuals.
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http://dx.doi.org/10.3390/nu12020418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071312PMC
February 2020

Circulating myeloperoxidase is elevated in septic shock and is associated with systemic organ failure and mortality in critically ill patients.

Free Radic Biol Med 2020 05 5;152:462-468. Epub 2019 Nov 5.

Department of Intensive Care, Christchurch Hospital, Christchurch, New Zealand.

Background: Neutrophils are elevated in critically ill patients during the systemic inflammatory response to trauma and sepsis. The neutrophil-derived enzyme myeloperoxidase generates reactive oxygen species which can react with host tissue resulting in cell damage and dysfunction. Thus, elevated myeloperoxidase in the circulation may be associated with adverse patient outcomes.

Methods: Circulating myeloperoxidase concentrations were measured in a cohort of 44 critically ill patients, 55% of whom were diagnosed with septic shock, and 44 healthy controls. Intensive care mortality prediction scores (SOFA, SAPS, APACHE) and ICU and hospital mortality were obtained from the patients' clinical notes. Hematological and biochemical assessments included blood cell counts, lactate, alanine transaminase, creatinine, bilirubin, C-reactive protein, and PaO. Myeloperoxidase was measured using a commercial ELISA kit and cell free DNA was detected using SytoxGreen™ fluorescence staining.

Results: Myeloperoxidase concentrations were significantly higher in critically ill patients than control samples (234 ± 30 ng/ml versus 15 ± 4 ng/ml, p < 0.001), and were elevated in septic shock relative to non-septic patients (302 ± 42 ng/ml versus 156 ± 38 ng/ml, p = 0.02), despite neutrophil counts being comparable between the two subgroups (p = 0.6). Myeloperoxidase correlated with SOFA scores in the critically ill patients (r = 0.395, p = 0.02), and with markers of tissue dysfunction and injury such as lactate (r = 0.572, p < 0.001), log alanine transferase (r = 0.392, p = 0.016) and log cell free DNA (r = 0.371, p = 0.03). The subgroup of patients with higher than mean APACHE III scores (i.e. >78, n = 16) exhibited significantly elevated myeloperoxidase concentrations in the non-survivors compared with survivors (416 ± 59 ng/ml versus 140 ± 33 ng/mL, p = 0.001). Hospital mortality for the whole cohort was 27%; mortality in the high APACHE III subgroup was 38%, and when combined with higher than mean myeloperoxidase (i.e. >234 ng/mL), mortality increased to 71%.

Conclusions: Myeloperoxidase is associated with markers of tissue injury and systemic organ failure, particularly in septic patients. The enzyme is also associated with mortality in patients with higher APACHE III scores, and thus has potential as an additional diagnostic marker to improve mortality prediction.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.11.004DOI Listing
May 2020

Vitamin C and Neutrophil Function: Findings from Randomized Controlled Trials.

Nutrients 2019 Sep 4;11(9). Epub 2019 Sep 4.

Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch 8011, New Zealand.

Vitamin C is known to support immune function and is accumulated by neutrophils to millimolar intracellular concentrations suggesting an important role for the vitamin in these cells. In this review, the effects of vitamin C, as a mono- or multi-supplement therapy, on neutrophil function were assessed by conducting a systematic review of randomized controlled trials (RCTs). Specifically, trials which assessed neutrophil migration (chemotaxis), phagocytosis, oxidative burst, enzyme activity, or cell death (apoptosis) as primary or secondary outcomes were assessed. A systematic literature search was conducted using the Cochrane Central Register of Controlled Trials, EMBASE, Embase Classic, Joanna Briggs Institute EBP, Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid Nursing Database, CINAHL and PubMed database, which identified 16 eligible RCTs. Quality appraisal of the included studies was carried out using the Cochrane Risk of Bias tool. Three of the studies assessed neutrophil chemotaxis in hospitalised patients or outpatients, two of which showed improved neutrophil function following intravenous vitamin C administration. Ten RCTs assessed neutrophil phagocytosis and/or oxidative burst activity; five were exercise studies, one in smokers, one in myocardial infarction patients and three in healthy volunteers. Two of the multi-supplement studies showed a difference between the intervention and control groups: increased oxidative burst activity in athletes post-exercise and decreased oxidant generation in myocardial infarction patients. Two studies assessed neutrophil enzyme activity; one showed deceased antioxidant enzyme activity in divers and the other showed increased antioxidant enzyme activity in athletes. One final study showed decreased neutrophil apoptosis in septic surgical patients following intravenous vitamin C administration. Overall, 44% of the RCTs assessed in this review showed effects of vitamin C supplementation on neutrophil functions. However, the studies were very heterogeneous, comprising different participant cohorts and different dosing regimens. There were also a number of limitations inherent in the design of many of these RCTs. Future RCTs should incorporate prescreening of potential participants for low vitamin C status or utilize cohorts known to have low vitamin status, such as hospitalized patients, and should also comprise appropriate vitamin C dosing for the cohort under investigation.
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http://dx.doi.org/10.3390/nu11092102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770220PMC
September 2019

Formulation of Broccoli Sprout Powder in Gastro-Resistant Capsules Protects against the Acidic pH of the Stomach In Vitro but Does Not Increase Isothiocyanate Bioavailability In Vivo.

Antioxidants (Basel) 2019 Sep 1;8(9). Epub 2019 Sep 1.

Department of Pathology and Biomedical Science, University of Otago, Christchurch, P.O. Box 4345, Christchurch 8140, New Zealand.

Broccoli sprout powder is a rich source of glucosinolates, which are hydrolysed to isothiocyanates in the presence of the enzyme myrosinase. We showed that in vitro incubation of broccoli sprout powder extract with isolated lymphocytes resulted in the upregulation of transcription factor Nrf2, however, there was no increase in Nrf2 protein levels in lymphocytes isolated 3 h following the ingestion of broccoli sprout powder by healthy volunteers. This highlights the general issue that potential health benefits of food-derived compounds can be compromised by limitations in bioavailability. In vitro experiments showed that the generation of isothiocyanates was reduced when the powder was first exposed to the low pH (1.2) of the stomach and then transferred to the higher pH (6.8) of the intestine. The loss of activity due to pre-exposure to the low stomach pH indicates that formulating the broccoli sprout powder in gastro-resistant formulations should increase that amount of isothiocyanate generated in the intestine for absorption. Gelatin capsules were hand-coated with either Eudragit L100 or Eudragit L100-55 and were assessed for their gastro-resistant properties using paracetamol as a model active for dissolution studies. Disintegration and dissolution studies showed that Eudragit L100-55 coated capsules and DRcaps (Capsugel) failed the United States Pharmacopeia (USP) requirements for gastro-resistant capsules, whereas the Eudragit L100 coated capsules passed. Five healthy participants were administered 1 g of broccoli sprout powder, ingested either with water or encapsulated in uncoated or gastro-resistant capsules. Urinary excretion of isothiocyanate metabolites over the 24 h period post ingestion was assessed by HPLC. Broccoli sprout powder and uncoated gelatin-encapsulated powder showed comparable excretion of isothiocyanate metabolites (18.4 ± 2.3 and 23.9 ± 2.7 µmol, respectively). The enteric coated capsules provided a significantly longer T than the uncoated gelatin capsules (15.4 ± 2.3 versus 3.7 ± 0.7 h, respectively), indicating protection from disintegration in the stomach, however, the excretion of isothiocyanate metabolites was significantly decreased compared with uncoated capsules (i.e., 8.5 ± 1.1 µmol). The lower in vivo formation or absorption of isothiocyanates observed for the gastro-resistant capsules may be due to participant variation in intestinal pH or transit times, resulting in inappropriate pH conditions or insufficient time for the complete disintegration and dissolution of the capsules.
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http://dx.doi.org/10.3390/antiox8090359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770740PMC
September 2019

Duration of intravenous vitamin C therapy is a critical consideration.

Authors:
Anitra C Carr

Crit Care Resusc 2019 Sep;21(3):220-221

Nutrition in Medicine Research Group, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.

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September 2019
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