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FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, January 9, 2022
Top Vitamin D Papers in 2021
Benefits ignored at a time they are most needed
by William B. Grant, PhD.
OMNS (Jan. 9, 2022) The total number of publications that mention vitamin D is more than 93,600. A simple search at pubmed.gov shows there were 5484 publications in 2021 with vitamin D in the title or abstract. That is up from 4548 in 2020. In 2021, 609 of the publications with vitamin D in the title or abstract in 2021 were about COVID-19, and 279 about SARS-CoV-2.
The dominant health concern in 2020 has been COVID-19. According to data posted at
https://www.worldometers.info/coronavirus/#countries, there have been over 288 million cases of SARS-CoV-2 infection or COVID-19 as well as over 5.4 million deaths attributed to COVID-19 by December 31, 2021. In addition, there have been tremendous disruptions in business, education, food production, social life, and travel. RNA vaccinations have been developed and used to reduce the risk of SARS-CoV-2 infection and incidence and severity of COVID-19. But as we are now learning, the protection from vaccination wanes with time and may not be as useful for new variants such as Omicron. One of the understandings when the U.S. Food and Drug Administration gave the emergency use authorization for the RNA vaccines in December 2020 was that there were no simple methods to prevent the infection or treat the disease. As a result, there has been a near-total mass media blockade on information regarding vitamin D in that regard, and a partial social media blockade. Several of the top vitamin D papers for 2021 were related to COVID-19.
Evidence that vitamin D fights COVID-19
There have been many observational studies of serum 25-hydroxyvitamin D [25(OH)D] and incidence of SARS-CoV-2 infection and/or COVID-19 as well as the severity of and death from COVID-19. The most complete meta-analysis study included data from 76 observational studies.
 In that study, Figure 3 included 19 studies and found an odds ratio (OR) for low vs. high 25(OH)D levels of 1.48 (95% confidence interval (CI) 1.28 to 1.65). However, there has been a concern that measurements near the time of diagnosis may cause a reduction in the measured 25(OH)D level due to the acute inflammatory response. Those data were used to estimate the size of this effect.
 The 19 studies can be divided into four categories: 25(OH)D at time of diagnosis (7 studies); within the prior year (8); preceding 10 years (1); and 10-15 years prior (3). The mean weighted ORs for each time are 2.08, 1.76, 1.27, and 1.04, respectively. Those values are consistent with a longer interval between blood draw and health outcome being associated with worse health outcomes due to changes in 25(OH)D levels. If we assume that the OR for the period less than one year is correct, then the OR at time of diagnosis may be somewhat too high. Even if so, that still means that observational studies with 25(OH)D measured near time of diagnosis are useful and imply that an adequate vitamin D level significantly lowers the risk of COVID-19.
There are a number of factors that increase risk of COVID-19 including obesity, older age, and comorbid diseases. Obesity is an important risk factor since it increases systemic inflammation and leads to storage of vitamin D in the adipose tissue, which tends to lower the vitamin D level in other organs of the body. A study conducted in Boston, MA found that while patients with 25(OH)D > 30 ng/ml and BMI < 30 kg/m2 had a significantly reduced risk of death from COVID-19 [OR = 0.18], a 25(OH)D level > 30 ng/ml was not associated with reduced risk of death for patients with BMI > 30 kg/m2.
 Evidently a level significantly higher than 30 ng/ml is needed to lower risk in obese patients.
How it works
The innate immune system mechanisms by which vitamin D reduces risk of SARS-CoV-2 infection and COVID-19 appear to include reduced viral viability and replication by inducing cathelicidin and defensins as well as reduced production of proinflammatory cytokines and the risk of the cytokine storm. The innate immune system is not sensitive to the variant of SARS-CoV-2 involved. That is important because the virus readily mutates, thereby reducing the adaptive immune system's ability to respond effectively. Thus, vitamin D can serve as an extra measure of protection as vaccine effectiveness wanes. The recommended serum 25(OH)D level for prevention is 40 to 60+ ng/ml, which could be achieved with the safe dose range of 5000 to 10,000 IU/d vitamin D3.
In all the studies, vitamin D was unfortunately tested in the same fashion as drugs are tested. That is, one vitamin was tested to the exclusion of all other nutrients necessary for optimum health. Such a "scientific" endeavor offers at best a picture of one nutrient in a vacuum. But unlike drugs, nutrients in the human body work together as a team and therefore should be tested accordingly. For example, magnesium plays important roles in activating vitamin D as well as other health benefits
. The beneficial effects include reducing oxidative stress, reducing risk of the cytokine storm, maintaining endothelial integrity, increasing fibrinolysis, reducing coagulation, and strengthening the immune system. Thus, magnesium should be taken along with vitamin D3 supplements, perhaps 400 mg/d.
Observational studies that look at the results of vitamin D supplementation can be used to help determine whether the effects related to 25(OH)D level are due to vitamin D rather than something else such as non-vitamin D effects of solar UVB exposure. An article from Barcelona has done this for COVID-19.
 Many people in Barcelona receive prescriptions for vitamin D3 or calcifediol [25(OH)D] from their physicians, making it easy to do observational studies on the effect of supplementation. Records were available for 108,343 patients prescribed vitamin D3 and 134,703 patients prescribed calcifeciol. Those prescribed vitamin D3 had a 5% lower risk of SARS-CoV-2 infection than controls [multivariate hazard ratio (HR) = 0.95 (95% CI, 0.91 to 0.98)], but no significant difference for severe COVID-19 or COVID-19 mortality. However, comparing 9474 treated with vitamin D3 who achieved > 30 ng/ml with 7616 untreated controls with 25(OH)D < 20 ng/ml, the multivariate HRs were near 0.7 for SARS-CoV-2 infection, severe COVID-19 and COVID-19 mortality. The same comparisons for 16,276 treated with calcifediol vs. 7616 untreated controls found multivariate HRs or 0.69 (95% CI, 0.61 to 0.79) for infection, 0.61 (0.46 to 0.81) for severe COVID-19, and 0.56 (0.42 to 0.76) for mortality. Evidently it is the level of 25(OH)D actually achieved that reduces risk of infection.
The most recent article on vitamin D and risk of COVID-19 hospitalization and mortality was published on January 1, 2022.
 It presented an analysis of 4599 veteran patients receiving care in the US Department of Veterans Affairs health care facilities who tested positive SARS-CoV-2 during the period February 20 to November 8, 2020 and had data on serum 25(OH)D levels from the previous 15 to 90 days on file. Twenty one percent of the patients were hospitalized and 7.4% died within 60 days of their index SARS-CoV-2 test. Hospitalization rates decreased from 25% at 15 ng/ml to 18% at 60 ng/ml (adjusted relative risk ratio = 1.29), while mortality rates decreased from 11% for vitamin D level = 15 ng/ml to 6% at 60 ng/ml (adjusted relative risk ratio = 1.82). This provides excellent evidence for the efficacy of an adequate level of vitamin D in lowering risk of serious complications and mortality from COVID-19.
Making sense of the research
The observational studies suggest that treating COVID-19 patients with vitamin D might be beneficial. Unfortunately, in some studies, treatment with high-dose vitamin D3 was found to be ineffective. A study in Turkey involved the supplementation of 163 COVID-19 patients with between 254,000 to 500,000 IU in three to seven days to increase 25(OH)D level to above 30 ng/ml.
 The mean 25(OH)D for the treated patients reached only 31±12 ng/ml on day 7 and 35±11 ng/ml on day 14. The rate of mortality was 11.19% (97 out of 867) in the whole cohort, including patients with comorbidities. The mortality rate of prospective cases who also had comorbidities but received vitamin D treatment was 5.5% (9 out of 162). Having vitamin D treatment decreased the mortality rate by a factor of 2.14.
Calcifediol treatment of COVID-19 patients in Spain is fairly common. An article reported results of treating 79 of 537 COVID-19 patients between February 5 and May 5, 2020.
 The treatment used 0.266-mg calcifediol capsules (equivalent to 34,000 IU of vitamin D3), two on day 1, then one each on days 3, 7, 14, 21, and 28. Four (5%) treated patients died vs. 90 (20%) untreated patients. The multivariate OR for death by day 30 was 0.16 (95% CI, 0.03 to 0.80). The reason calcifediol in this type of study obtains much better results than vitamin D3 it that it raises serum 25(OH)D in a few hours rather than in a few days. That rapidly activates the important mechanisms of vitamin D such as reducing survival and replication of the SARS-CoV-2 virus as well as reducing the production of proinflammatory cytokines and the cytokine storm that damages the epithelial layer of many organs.
Sunlight and the seasons
It is well known from existing virus variants that SARS-CoV-2 infection and COVID-19 rates are lower in summer than in winter. There are now three hypothesized reasons for lower rates in summer: (1), higher 25(OH)D levels; (2), inactivation of SARS-CoV-2 by solar UV; (3), higher serum nitric oxide levels from ultraviolet-A (320-400 nm) exposure. Solar UVA exposure increases serum nitric oxide by liberating it from subcutaneous nitrogen compounds, which has been found to reduce blood pressure.
 Nitric oxide also has antiviral effects. All three reasons may be important.
For those who do not get adequate supplements of vitamin D, the blood level drops continually during the winter months in high-latitude countries. An analysis of COVID-19 deaths during January to April 17, 2020 was conducted with respect to sunlight doses at latitudes in three countries, England, Italy, and the U.S. where winter solar UVB doses are too low to produce adequate vitamin D, i.e., north of Florida
. The adjusted mortality risk factors were worst for England, and slightly less but still serious for the USA and Italy.
The effect of UV radiation in inactivating SARS-CoV-2 was outlined in a modeling study.
 Laboratory studies of the UV inactivation action spectrum for SARS-CoV-2 were used with data for the spectral components of solar UV radiation at the earth's surface between 70º S and 70º N to generate midday sun exposure inactivation times for viruses. Solar UVA in the range of 366 to 405 nm was found to be most important, because UVA intensity remains strong throughout the day, varying much less than UVB intensity. However, virus inactivation due to sunlight exposure is several times faster in summer than winter. For example, at 40º N, virus inactivation times varied from two minutes in July to six minutes in December. Also, the fact that people spend more time in the sun in summer than in winter further adds to the summer-winter differences in virus inactivation.
It may well be that all three factors affect seasonal variations in SARS-CoV-2 infection and COVID-19 rates. The implications are that people could spend more time in the sun in summer and take more vitamin D supplements in winter to achieve 25(OH)D levels in the 40-60 ng/ml (100-150 nmol/L) range. To do so could require 5000 to 10,000 IU/d for most adults, and would have many other health benefits as well.
There were important advances in understanding the role of vitamin D in reducing risk of cardiovascular disease (CVD) in 2021. For over a decade it has been known that serum 25(OH)D levels are inversely correlated with risk of CVD. However, since randomized controlled trials (RCTs) had not supported those findings, the medical treatment system elected to ignore that evidence. This year saw more observational studies that support vitamin D's role in preventing disease, including one with respect to vitamin D supplementation, and others on Mendelian randomization (MR) studies. MR studies use genetic scores based on several single nucleotide polymorphisms (SNPs) that affect the serum 25(OH)D level. The idea is that if people are exposed to the same sources of vitamin D, those with a set of SNPs that predict the highest increase in genetically-predicted 25(OH)D levels will have better outcomes than those with sets of SNPs that predict the lowest levels. The problem with most MR studies to date is that they have lumped all results together irrespective of the genetically-predicted 25(OH)D levels. Instead, the most recent MR studies stratify the data by genetically-predicted serum 25(OH)D levels.
The first stratified MR study on vitamin D and risk of CVD used data from several European studies with four strata: <10 ng/ml, 10-25 ng/ml, 20-30 ng/ml, and >30 ng/ml.
 For the participants with vitamin D deficiency [25(OH)D level < 10 ng/ml], genetic analyses provided strong evidence for an inverse association with all-cause mortality OR per 4 ng/ml increase in genetically-predicted 25(OH)D level (0.69) and nonsignificant inverse associations for stroke (0.85) and coronary heart disease (0.89). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D levels and all-cause mortality up to around 16 ng/ml. This article also reported observational results with respect to measured serum 25(OH)D levels. They showed significantly increased HRs for coronary heart disease below 10 ng/ml, stroke below 16 ng/ml, all-cause mortality rate below 16 ng/ml, CVD, cancer, and all-cause mortality rates below 20 ng/ml. These findings help explain why most RCTs have failed to find a beneficial effect of vitamin D supplementation on CVD outcomes: they enroll people with baseline 25(OH)D rates with a mean value often above 30 ng/ml, e.g. The VITamin D and OmegA-3 TriaL (VITAL).
A second MR study used data from the UK Biobank dataset with 100 genetically-predicted 25(OH)D strata.
 There was an L-shaped association between genetically-predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing levels and plateaued at around 20 ng/ml. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) blood pressure. The observational analysis of serum 25(OH)D levels indicated that risk of all three outcomes was reduced up to 50 ng/ml.
An observational study compared risk of myocardial infarction and all-cause mortality rate.
 This study used data from patients who received care at the Veterans Health Administration from 1999 to 2018. Comparing risk for those with baseline 25(OH)D < 20 ng/ml supplemented with vitamin D and achieving > 30 ng/ml (N = 2942) with those who did not supplement and remained with 25(OH)D < 20 ng/ml (N = 10014), the HR for myocardial infarction was 0.73 and the all-cause mortality rate HR was 0.61.
A study from Stockholm investigated the role of developmental vitamin D status and risk of autism spectrum disorder (ASD) for participants born in Sweden between 1996 and 2000.
 The study involved 947 ASD cases without intellectual disability (ID) and 452 with ID, based on maternal 25(OH)D measured near 10 weeks of gestation and neonatal 25(OH)D measured at birth. Based on maternal 25(OH)D, the OR of ASD for 25(OH)D between 10 and 20 ng/ml was 1.58 while the OR for a 25(OH)D increase of 10 ng/ml was 0.65. Based on neonatal 25(OH)D, the OR for an increase of 10 ng/ml was 0.86. For ASD with ID, based on maternal 25(OH)D, the OR for an increase of 10 ng/ml was 0.52 while based on neonatal 25(OH)D, the OR for an increase of 10 ng/ml was 0.87. These results indicate that 25(OH)D levels early and throughout pregnancy are more important than at the end of pregnancy.
A modeling study estimated the reduction in cancer deaths and costs of supplementing all inhabitants over the age of 50 years in Germany.
 They used the value of 13% reduction obtained from meta-analysis of vitamin D supplementation RCTs. They noted that 247,000 cancer deaths occurred Germany in 2018. They assumed end-of-life costs per cancer death to be 40,000 € (Euros) and 25 € per person for 1000 IU/d vitamin D. The net savings was estimated to be 254 million €. Supplementing with 2000 IU/d vitamin D was estimated to achieve a cancer mortality reduction of 17%, albeit at twice the cost of 1000 IU/d vitamin D, while supplementing with 400 IU/d would reduce cancer death rates by 11% at 40% of the cost.
A meta-analysis was published regarding observational studies of colorectal cancer risk with respect to serum 25(OH)D level.
 There were 15,542 cases and 22,376 controls from case-control studies [serum 25(OH)D levels measured at time of diagnosis] and 1402 incident cases analyzed from a total population of 68,701. The OR for high vs. low 25(OH)D from case-control studies was 0.60 and 0.80 from prospective studies. The general reason why the ORs are better for case-control studies is that 25(OH) varies with time, and the longer the follow-up time, the lower the correlation with health outcomes. Some people are concerned that having undiagnosed cancer can lower serum 25(OH)D levels. However, that effect seems to apply to acute inflammatory diseases, such as viral infections, not cancer.
Why isn't vitamin D being recommended?
Despite the recent advances in understanding the health benefits of higher 25(OH)D levels and vitamin D supplementation, the U.S. Preventive Service Task Force concluded in a review published in JAMA: "No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection."
 Table 1 in that review presented results for benefits and harms from 45 vitamin D RCTs. No benefits or harms were found.
The reasons why randomized controlled studies have shown little beneficial effect are straightforward. As is now well known, traditional vitamin D randomized controlled studies are based on guidelines for pharmaceutical drugs. Participants are enrolled, generally with 25(OH)D levels above the population mean and given small vitamin D doses, generally no more than 2000 IU/d. The results are judged on the basis of treatment vs. placebo. As is now well known, such RCTs are doomed to failure since it is 25(OH)D that is correlated with health outcomes, not vitamin D dose.
 The researchers who conducted the Vitamin D and Type 2 diabetes (D2d) study understood this after completing and reporting the results, and subsequently reported that risk of progression from prediabetes to type 2 diabetes was reduced by 25% for each 10 ng/ml from 20-30 ng/ml to > 50 ng/ml.
If the lungs' defense systems do not protect the lungs from damage from various irritants, permanent damage can develop, making the lungs more susceptible to various respiratory diseases. A review of the therapeutic potential of vitamin D in inflammatory lung diseases was published recently.
 The actions of vitamin D on inflammatory cells are dissected in this review, as well as their clinical significance in respiratory illnesses.
A recent study reviewed trends in vitamin D status around the world. Some regions such as the Middle East and some countries in Asia have low vitamin D status.
 A large improvement was seen in Finland after mandatory fortification of dairy products with vitamin D was introduced. Determinants of decline in vitamin D status are less sun exposure, increased use of sunscreen, increase of body mass index (BMI), less physical activity, and poor socioeconomic status. Determinants of increase in vitamin D status are food fortification with vitamin D and vitamin D supplements. As shown by the Finnish example, food fortification can lead to a population-wide increase in vitamin D status.
The evidence that vitamin D has important health benefits continued to increase in 2021. In particular, the benefits in reducing risk of SARS-CoV-2 infection and COVID-19 became more robust, as did those for CVD. The evidence clearly points to the healthy range of 25(OH)D as being 30-40 ng/ml, with additional evidence for the optimal range being 40-60 ng/ml. Due to modern lifestyles, it is very difficult to achieve those levels from solar UVB exposure and diet. The most efficient way to raise serum 25(OH)D is to supplement with vitamin D3, of at least 5000 IU/d, and up to 10,000 IU/d. After taking a supplement for 4 months, a blood test for vitamin D level (suggested level 40-60 ng/ml) along with a doctor's advice can assist in setting the dose.
Adequate amounts of magnesium in the diet or in supplements (400-600 mg/d in malate, citrate, or chloride form) are necessary to aid the action of vitamin D.
[24-27] Supplements of other essential nutrients are beneficial in empowering the immune system, including zinc (50 mg/d with 2 mg/d copper), and selenium (100 mcg/d, included in many multivitamins).
Disclosure: The author's non-profit organization, Sunlight, Nutrition and Health Research Center (www.sunarc.org), receives funding from Bio-Tech Pharmacal, a vitamin D supplement manufacturer. He has 291 publications regarding vitamin D listed at pubmed.gov dating from 1999.
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2. Grant, W.B. (2022) Vitamin D's Role in Reducing Risk of SARS-CoV-2 and COVID-19 Incidence, Severity, and Death. Nutrients 14:183.
3. Charoenngam N, Shirvani A, Reddy N, et al. (2021) Association of Vitamin D Status With Hospital Morbidity and Mortality in Adult Hospitalized Patients With COVID-19. Endocr Pract 27:271-278.
4. DiNicolantonio JJ, O'Keefe JH (2021) Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients. Mo Med. 118: 68-73.
5. Oristrell J, Oliva JC, Casado E, et al. (2021) Vitamin D supplementation and COVID-19 risk: a population-based, cohort study. J Endocrinol Invest 2021:1-13.
6. Seal KH, Bertenthal D, Carey E, et al (2022) Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. J Gen Intern Med. 2022 Jan 1.
7. Gonen MS, Alaylioglu M, Durcan E, et al. (2021) Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1. Nutrients 13:4047.
8. Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, et al. (2021) Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients 13:1760.
9. Grant WB, Lahore H, McDonnell SL, et al. (2020) Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020;12:988.
10. Cherrie M, Clemens T, Colandrea C, et al. (2021) Ultraviolet A radiation and COVID-19 deaths in the USA with replication studies in England and Italy. Br J Dermatol 185:363-370.
11. Nicastro F, Sironi G, Antonello E, et al. (2021) Solar UV-B/A radiation is highly effective in inactivating SARS-CoV-2. Sci Rep 11:14805.
12. Emerging Risk Factors Collaboration E-CVD/VDSC. (2021) Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses. Lancet Diabetes Endocrinol 9:837-846.
13. Manson JE, Cook NR, Lee IM, et al. (2019) Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med 380:33-44.
14. Zhou A, Selvanayagam JB, Hypponen E. (2021) Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. Eur Heart J 2021:ehab809.
15. Acharya P, Dalia T, Ranka S, et al. (2021) The Effects of Vitamin D Supplementation and 25-Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality. J Endocr Soc 5:bvab124.
16. Lee BK, Eyles DW, Magnusson C, et al. (2021) Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort. Mol Psychiatry 26:1578-1588.
17. Niedermaier T, Gredner T, Kuznia S, et al. (2021) Vitamin D supplementation to the older adult population in Germany has the cost-saving potential of preventing almost 30 000 cancer deaths per year. Mol Oncol 2021;15:1986-1994.
18. Hernandez-Alonso P, Boughanem H, Canudas S, et al. (2021) Circulating vitamin D levels and colorectal cancer risk: A meta-analysis and systematic review of case-control and prospective cohort studies. Crit Rev Food Sci Nutr 2021:1-17.
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20. Grant WB, Boucher BJ, Bhattoa HP, et al. (2018) Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol 177:266-269.
21. Dawson-Hughes B, Staten MA, Knowler WC, et al. (2020) Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care 43:2916-2922.
22. Afzal M, Kazmi I, Al-Abbasi FA, et al., (2021) Current Overview on Therapeutic Potential of Vitamin D in Inflammatory Lung Diseases. Biomedicines.9:1843.
23. Lips P, de Jongh RT, van Schoor NM (2021) Trends in Vitamin D Status Around the World. JBMR Plus. 5:e10585.
24. Deng X, Song Y, Manson JE, et al. (2013) BMC Medicine, 11:187. doi.org/10.1186/1741-7015-11-187. Figure 1: Magnesium is needed by Vitamin D in 8 places:
25. Web search for vitamin D and magnesium. The whole list (576,000 !):
26. Web search for vitamin D, magnesium, and Covid-19 in 2021 (21,000 !):
27. Dean, C (2017) The Magnesium Miracle, 2nd Ed., Ballantine Books, ISBN-13: 978-0399594441.
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