Site icon Preventive Health Advisor

Why Vitamin D is Important

why vitamin d is important preventive health advisor

New research on vitamin D supports lower chances of dying if you need to be hospitalized in the intensive care unit. Don’t overlook why vitamin D is important and optimize your vitamin D levels!

Why Vitamin D is Important

Michaëlsson K et al (10) performed research which found higher rates of death in vitamin D deficient individuals and lower rates of death as the vitamin D level increased to a higher range (above 26 ng/ml). Putzu et al (22) took the data from 7 randomized trials which tested the mortality rate of critically ill patients. Those who took vitamin D were compared to those who used a placebo were found to have an 8% lower chance of dying. The authors concluded that “In critically ill patients, vitamin D administration might be associated with a reduction in mortality without significant adverse events.”

Introduction

Finding out why vitamin D is important starts with the rediscovery by extensive research in the past decade. Vitamin D has been established as a necessary nutrient for widespread human health processes. Vitamin D is required for calcium absorption by the body and bone health. People who get too little vitamin D may develop soft, thin, and brittle bones, a condition known as rickets in children and osteomalacia in adults. Furthermore, optimal vitamin D levels may protect against cancer and may offer benefits in conditions such as diabetes, high blood pressure, and autoimmune conditions such as multiple sclerosis. Vitamin D supplementation taken during pregnancy may also prevent birth defects. Controversy surrounds the dilemma on whether to obtain vitamin D from sun exposure which increases the risk of skin cancer verses obtaining vitamin D through supplements. A fair skin person in a bathing suit going outside for 10 minutes in the sun will allow the skin to produce about 10,000 IUs of vitamin D, but a person would need to be north of Atlanta, GA in the winter in order for this to occur. An insufficient intake of vitamin D, as well as an excessive intake may result in harmful effects. Receiving the optimal amount of vitamin D has been proven in research to have many important health benefits. Don’t overlook why vitamin D is important and optimizing your vitamin D levels!

How to Measure Vitamin D Levels:

A vitamin D level is most commonly measured by physicians using a blood test for the concentration of the compound 25(OH)D in the body.

Many are Insufficient or Deficient in Vitamin D:

Among the U.S. population, vitamin D intake is poor and sun exposure is inadequate throughout the United States in order for the majority of the population to reach optimal levels.

Moore et al found that neither children nor adults in the US are obtaining the new RDA for vitamin D, and among women vitamin D intake from food was 156–208 IU/d and with supplements 244–324 IU/d. For men, corresponding values were 208–320 IU/d and 308–392 IU/d. (20)

Vitamin D Dosage Guidelines:

Vitamin D dosage recommendations were increased in 2012 as part of a report by the Institute of Medicine (IOM) and the Endocrine Society’s Clinical Practice Guidelines. The report defined vitamin D deficiency as a 25(OH)D < 20 ng/ml, insufficiency as a 25(OH)D of 21–29 ng/ml and sufficiency as a 25(OH)D of 30–100 ng/ml. This report also tripled the amount of vitamin D required for most children and adults. (4)

The 25-hydroxy vitamin D level should be checked every 3 months and vitamin D3 dose should be adjusted up or down until optimal.

More on Recent Increase of Vitamin D Dose Recommendations:

Institute of Medicine and the World Health Organization vitamin D dose recommendation and rationale for  new guidelines: Bosomworth NJ determined in 2011 that the Institute of Medicine and the World Health Organization vitamin D dose recommendation appears extremely conservative, supporting the recommendation for increase in vitamin D doses. Recent guidelines reflect a gradually increasing acceptance of enhanced vitamin D supplementation. As noted above, the Institute of Medicine (IOM) recommendations for vitamin D intake suggested that most adults up to age 70 needed no more than 600 IU of vitamin D daily to maintain health, and those 71 years of age and older might need 800 IU. These doses are considered very conservative. Bosomworth NJ made several points and observations as noted below regarding vitamin D dosing and expressed that the intervention of vitamin D supplementation has a wide margin of safety, and the potential for individual health improvement may be substantial. (3):

Ideal Dosage of Vitamin D and Levels of Vitamin D:

Evidence from studies was used to evaluate thresholds of vitamin D, 25-hydroxyvitamin [25(OH)D] on multiple health outcomes including bone mineral density (BMD), lower-extremity function, dental health, and risk of falls, fractures, and colorectal cancer. The researchers found the optimal level of vitamin D for all the health factors examined to start at 75 nmol/L (30 ng/mL), and the best was between 90 and 100 nmol/L (36-40 ng/mL). Based on this literature review, the authors suggest that the current intake of vitamin D for adults (200 to 600 IU) is insufficient to achieve optimal health outcomes. Among adults an intake of 1000 IU or greater is need to achieve the optimal level of vitamin D. (6) Vieth reported that the ideal level of vitamin D intake should be 50 mg (2000 IU) per day. In a separate study, an analysis of submarine sailors was done to determine the level of vitamin D supplementation that would sustain the sailors initial 25(OH)D (the precursor to active vitamin D) concentration of 78 nmol/L. It was shown that sailors taking 2000 IU/d of vitamin D increased their 25(OH)D from values of 15 nmol/L to more healthy levels of 81 nmol/L. Vieth also looked at other levels of vitamin D intake. To ensure that 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D dose of 4000 IU/d is required. While a toxic dose of vitamin D has yet to be determined, published cases of toxicity, for which levels and dose are known, all involve intake of ≥ 40000 IU per day. Vieth found that vitamin D3 doses up to 10,000 IU per day to be safe but increases in mortality risk was seen in other studies. (2)

Why Vitamin D is Important to take with Calcium

Vitamin D and Risk of Falling:

USPSTF Recommendation for Fall Risk:

To prevent falls in community-dwelling adults aged 65 years or older who are at increased risk for falls, the U.S. Preventive Services Task Force (USPSTF) recommends exercise or physical therapy and vitamin D supplementation. This was recommended by USPSTF as a result of determining that each these interventions have a moderate net benefit. The USPSTF stated that the risk of falls, and morbidity after falls is greater than the risk associated with taking vitamin D, exercising, or participating in physical therapy. (7)

Vitamin D and Fall Prevention:

Bischoff-Ferrari HA, et al conducted a comprehensive literature review of studies involving double blind randomized controlled trials where study participants received oral supplemental vitamin D for fall prevention. Eight trials were included in this study with a total of 2,426 individuals aged 65 years or older. Trials were required to have a minimum of three months follow up and to define and assess fall incidence as a primary or secondary endpoint over the entire trial period. Included studies used a range of doses and types of vitamin D supplementation with or without supplemental calcium. The results showed that overall pooled relative risk (RR) for vitamin D’s effect on fall prevention was statistically significant at 0.87. Falling was found to be less likely in individuals taking supplemental vitamin D compared to those that do not take the supplement. The study concluded that vitamin D at a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19%. Less than 700 IU of vitamin D per day or concentrations of vitamin D under 60 nmol/L may not reduce the risk of falling among older individuals. (8)

Vitamin D and Multiple Sclerosis:

In a review study, von Geldern and Mowry discussed the potential effects of vitamin D and other dietary components on the disease course of multiple sclerosis (MS). They looked at the effects of nutrition on relapse rate and/or disease progression in MS. The authors reviewed research which showed that vitamin D supplements have shown mixed results ranging from reduction of relapse rates and fewer new brain lesions on MRI, to no effect. Concentration of vitamin D in the body has been shown to influence the incidence and the course of MS in some research. Although the effectiveness of vitamin D in slowing the progression of MS has not yet been established, the authors of this study did conclude that sufficient vitamin D levels are likely protective against the development of MS and reduces progression of the disease, but vitamin D supplements have not yet been directly proven to change the course of MS. (9)

Vitamin D Dose and Mortality Rate of Adult Men:

Michaëlsson K et al followed a total of 1,194 men over a median duration of 12.7 years in this longitudinal study looking at the link between blood levels of vitamin D and mortality. They looked at vitamin D levels and three different rates of mortality—cardiovascular-related, cancer-related, and all-cause mortality. There was a clear U-shaped curve when looking at the relationship between vitamin D levels and all-cause mortality along with cancer-related mortality, meaning the risk of mortality was significantly increased at both low and high blood levels of vitamin D. Michaëlsson K et al found that the range with the lowest cardiovascular-related, cancer-related, and all-cause mortality corresponded to a vitamin D concentration of 24 to 34 ng/ml (60 to 85 nMol/L), which approximately translates to a vitamin D dose of 2000 IU/d. In general, the biggest drop in overall death rates were seen when subjects went from being vitamin D deficient to reaching adequate levels. However, too much vitamin D translated into a gradual increase of mortality rate with cancer deaths rising significantly for the highest levels of vitamin D intake. Cardiovascular related mortality painted a different picture. There was a sharp drop in death rates as study participants went from being vitamin D deficient to approaching the magic number of 26 ng/ml. At this point there was a leveling off with no added benefit or increase in mortality seen with higher vitamin D levels. Men with low concentrations of vitamin D had a higher cardiovascular mortality. Overall mortality was increased by 50–60% among subjects in the lowest 10% and highest 5% of the vitamin D distribution, whereas cardiovascular mortality was increased only in the bottom 10%. The ideal vitamin D dose for adult men according to findings in this study is 2000 IU/d. (10)

Vitamin D and Race:

The relationship between vitamin D status and the impact of race on sustaining necessary levels of vitamin D was examined in a longitudinal study. Between August 2006 and September 2008, 140 healthy African American (AA; n=94) and Caucasian (C; n=46) children aged 6-12 years old residing in Pittsburgh, Pennsylvania were examined. There were no differences between racial groups in the usage of multivitamins, vitamin D and/or calcium supplements. All children were found to suffer from vitamin D insufficiency during the summer (AA vs C, 17.2% vs 14.3%) and the winter (34.1% vs 32.5%) despite having a mean daily intake of vitamin D above the current American Academy of Pediatrics (AAP) recommended intake of 400 IU/day (AA vs C, summer: 421 vs 456 IU/d; winter: 507 vs 432 IU/d).  Race/season, skin type, sunscreen use, and dietary vitamin D (only in Caucasians during winter) were significant predictors of circulating concentration of 25(OH)D, the precursor to active vitamin D. African American children have a significantly lower concentration of 25(OH)D during summer when compared with Caucasian children. Dietary vitamin D was positively associated with 25(OH)D only in Caucasian children during winter. The racial differences in the relationship between dietary vitamin D and 25(OH)D during winter suggests that African American children may need higher oral inputs of vitamin D compared to Caucasian children. These findings highlight the relevance of season and skin color on vitamin D status. Additionally, the data suggests that the current AAP recommended dietary allowance for vitamin D might be inadequate for 6–12 yr old children throughout the year. (11)

Vitamin D and Heart Disease:

Sun and colleagues evaluated the associations between both dietary and supplemental vitamin D and cardiovascular disease risk. Researchers evaluated data on 74,272 women and 44,592 men who were initially heart disease and cancer-free from the Nurses’ Health Study (1984-2006) and the Health Professionals Follow-Up Study (1986-2006). After about a 20 year follow-up period, 9,886 cases of coronary heart disease and stroke were documented. Sun and colleagues found a 16% reduction in heart disease among men who met the Dietary Reference Intake (DRI) of vitamin D of at least 600 IU per day, as compared to men with daily intakes of less than 100 IU. The researchers found that men who consumed larger amounts of vitamin D had a decreased risk of heart disease. There was no association between vitamin D intake and heart disease risk for women. (12)

Vitamin D Supplements and Blood Pressure:

Goel, RK et al found that Vitamin D supplements lowered blood pressure in patients diagnosed with hypertension. Participants in a study received either standard antihypertensive drugs (n=100) or vitamin D(3) (33,000 IU, every 2 weeks, for 3 months) in addition to standard therapy (n=100). After 3 months, results showed a reduction in systolic blood pressure (BP) of 7.5 mmHG with Vitamin D supplementation compared to a 3.6 mmHg reduction in the standard therapy group. Diastolic BP in both the Vitamin D group and non-Vitamin D group increased by 2.1 mmHg and 1.3 mmHg, respectively. Additionally, Vitamin D supplementation showed a significant increase in blood calcium levels as well as albumin-corrected calcium with a decrease in phosphorous. (13)

Pfeifer M, et al performed a double-blind randomized controlled trial of 148 women with a mean age of 74 years tested the effect of calcium plus vitamin D on blood pressure compared to calcium alone. Participants received either 1200 mg calcium plus 800 IU vitamin D(3) or 1200 mg calcium/day. Vitamin D level, blood pressure, and heart rate were measured before and after treatment. Results indicate that supplementation with vitamin D and calcium resulted in a significant increase in vitamin D (25-D) levels by 72% and decreased PTH levels by 17% along with significant decreases in systolic blood pressure (SBP) by 9,3% and heart rate by 5.4% compared with calcium supplementation alone. Sixty subjects (81%) in the vitamin D(3) and calcium group compared with 35 (47%) subjects in the calcium group showed a decrease in SBP of 5 mm Hg or more (p = 0.04). The authors conclude that a short-term vitamin D plus calcium regimen is more reduced SBP better than calcium alone. (14)

Vitamin D and pregnancy:

Supplementation with vitamin D is important especially during the 3rd trimester of pregnancy unless subject to adequate sun exposure (15). Wagner, CL et al stated that pregnant women who take an adequate amount of vitamin D during pregnancy, may positively impact their own and their unborn baby’s health. The authors expressed that during pregnancy, the body will convert twice the normal amount of active 1,25(OH) vitamin D by the end of the first trimester, and over three times the normal amount by birth, while calcium levels remain normal. This is believed to represent a need for more vitamin D during pregnancy than at any other time, especially since the authors observed 80% of pregnant women to be well below this level. Wagner et al suggested that a daily dose of 4000 IU of vitamin D3 per day, starting at 12-16 weeks gestation, was effective in raising the mother’s 25(OH) D levels provides sufficient levels of vitamin D during pregnancy. (16)

Vitamin D and cancer:

A population-based randomized 4-year study conducted in Nebraska enrolled 1179 women aged 55 years and older, with no known cancer. Participants were randomly assigned to 3 groups: 1) Placebo (calcium placebo plus vitamin D placebo, n=266); 2) calcium-only (1400 mg calcium citrate or 1500 mg calcium carbonate plus vitamin D placebo, n=416); and Calcium + D (1000 IU [25 mcg] vitamin D plus calcium [as above], n=403). Serum samples were analyzed for levels of 25(OH)D, vitamin D, at baseline and then yearly. Study results found 50 women developed non-skin cancer during the study: 13 in the first year, and 37 during the second to fourth years. The relative risk reduction (RRR) for the calcium + D group after 12months of the treatment was 0.232 (confidence interval [CI], 0.09–0.60; P<.005), and the RRR for the calcium-only group was 0.587 (95% CI, 0.29–1.21; P=.147) compared with the placebo group. Increasing the dose of vitamin D from the current standard of 400–600 IU per day to 1000 IU per day lowers future risk of cancer in women older than age 55 who do not get adequate vitamin D from sun exposure or diet. (17)

Vitamin D and diabetes mellitus type 2:

A study looked at the relationship between vitamin D level and diabetes mellitus type 2 (T2DM). The study included 276 Korean patients with T2DM whose 25(OH)D levels were considered “deficient” and “insufficient”.  The authors defined vitamin D deficiency as a 25(OH)D level of less than 20 ng/ml and vitamin D insufficiency as a level of 20-29 ng/ml. Blood and urine tests were performed after at least 9 hours of fasting, and serum 25(OH)D was measured in a central laboratory in Seoul, Korea. To compare their results, 160 non-diabetic Koreans were selected as control subjects. The results of the study found that T2DM patients were significantly more likely than their non-diabetic counterparts to be taller, have higher body weight, higher body mass index, and bigger waist circumference. Compared with control subjects, patients with T2DM had a lower 25(OH)D level (15.4±0.5 vs. 12.9±0.4 ng/ml, p<0.01).  The incidence of vitamin D insufficiency was found to be higher among type 2 diabetics than controls by this study in Korea which found that 87% of type 2 diabetics were deficient in vitamin D (<20 ng/ml), and 11% were insufficient (20-29 ng/ml). Healthy subjects were 20% insufficient and 70% deficient. The study also found that high levels of triglycerides, LDL, and hemoglobin A1C were associated with vitamin D deficiency in type 2 diabetes patients. (18)

Vitamin D and type I diabetes:

In a study done in an area with a high prevalence of vitamin D deficiency, the incidence of type 1 diabetes in young children was reduced by vitamin D at a dose 2000 IU/d (21). This dose exceeds the safe upper limit of vitamin D daily intake for this age group and is not recommended.

Common Highest Vitamin D Containing Foods:

Fish, salmon, sockeye, cooked, dry heat, 1/2 fillet 812 IU
Fish, salmon, pink, canned, total can contents, 3 oz 464 IU
Malted drink mix, chocolate, with added nutrients, mixed with whole milk, 1 cup 328 IU
Fish, tuna, light, canned in oil, drained solids, 3 oz 228 IU
Milk shakes, thick vanilla, 11 fl oz 152 IU
Milk, nonfat, fluid, with added vitamin A and vitamin D (fat free or skim), 1 cup 116 IU
Milk, lowfat, fluid, 1% milkfat, with added vitamin A and vitamin D, 1 cup 116 IU
Milk, reduced fat, fluid, 2% milkfat, with added vitamin A and vitamin D, 1 cup 116 IU
Cereals ready-to-eat, GENERAL MILLS, Whole Grain TOTAL, 3/4 cup 100 IU
Cereals ready-to-eat, KELLOGG, KELLOGG’S RAISIN BRAN, 1 cup 96 IU
Cheese, pasteurized process, American, fortified with vitamin D 28.35, 1 oz 84 IU
Cereals ready-to-eat, KELLOGG, KELLOGG’S RICE KRISPIES 33 1-1/4 cup 80 IU
Soup, cream of mushroom, canned, prepared with low fat (2%) milk, 1 cup 68 IU
Fish, tuna, white, canned in water, drained solids, 3 oz 68 IU

Adapted from: USDA food list with vitamin D

Summary: Vitamin D

References:
1.Ross CA, Taylor CL, Yaktine AL, Del Valle HB, eds; Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2011. Accessed at http://www.nap.edu/catalog.php?record_id=13050 on 31 May 2012 and World Health Organization and Food and Agriculture Organization of the United Nations. Vitamin and Mineral Requirements in Human Nutrition. 2nd ed. Geneva, Switzerland: World Health Organization; 2004. Accessed at http://www.who.int/nutrition/publications/micronutrients/9241546123/en/index.html on 31 May 2012.
2.Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May; 69:842–856. http://ajcn.nutrition.org/content/69/5/842.long
3.Bosomworth NJ. Mitigating epidemic vitamin D deficiency: The agony of evidence. Can Fam Physician. 2011 Jan;57(1):16-20. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024150/
4.Holick MF. Evidence-based D-bate on health benefits of vitamin D revisited. Dermatoendocrin. 2012;4(2):183-190. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427198/
5.Report Brief, Dietary Reference Intakes for Calcium and Vitamin D, Food and Nutrition Board, Institute of Medicine, National Academy Press, Washington, D.C., November 30, 2010. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/DRI-Values.aspx
6.Bischoff-Ferrari HA,Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B 2006 Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84:18–28. http://www.ncbi.nlm.nih.gov/pubmed/16825677
7.Prevention of Falls in Community-Dwelling Older Adults, Topic Page. U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/uspstf/uspsfalls.htm
8.Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJOpens in New Window. 2009; 339:b3692. http://www.ncbi.nlm.nih.gov/pubmed/19797342
9.Von Geldern G, Mowry EM. The influence of nutritional factors on the prognosis of multiple sclerosis. Nat Rev Neurol 2012 Oct 2. http://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2012.194.html#B153
10.Michaëlsson K, Baron JA, Snellman G, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010 Oct;92(4):841-8. http://ajcn.nutrition.org/content/92/4/841.long
11.Rajakumar K, Holick MF, Jeong K, Moore CG, Chen TC, Olabopo F, Haralam MA, Nucci A, Thomas SB, Greenspan SL. Impact of season and diet on vitamin D status of African American and Caucasian children. Clin Pediatr (Phila). 2011; Jun;50(6):493-502. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296802/
12.Sun Q, Shi L, Rimm EB, et al. Vitamin D intake and risk of cardiovascular disease in US men and women. Am J Clin Nutr. 2011 Jun 8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142728/
13.Goel RK, Lal H. Role of vitamin d supplementation in hypertension.Indian J Clin Biochem. 2011 Jan;26(1):88-90. http://www.ncbi.nlm.nih.gov/pubmed/22211023
14.Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86:1633–1637. http://www.ncbi.nlm.nih.gov/pubmed/11297596
15.Hovdenak N, Haram K. Influence of mineral and vitamin supplements on pregnancy outcome. Eur J Obstet Gynecol Reprod Biol. 2012 Oct;164(2):127-32. http://www.ncbi.nlm.nih.gov/pubmed/22771225
16.Wagner CL, Taylor SN, Dawodu A, Johnson DD, Hollis BW. Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus. Nutrients 2012; 4: 208-203. http://www.mdpi.com/2072-6643/4/3/208
17.Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D Supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:1586–1591. http://www.ncbi.nlm.nih.gov/pubmed/17556697
18.Jung Re Yu, Sang Ah Lee, Jae-Geun Lee, Gil Myeong Seong, Seong Joo Ko, Gwanpyo Koh, Mi-Hee Kong, Keun-Young Park, Byung-Joon Kim, Dong-Mee Lim, and Dae Ho Lee. Serum Vitamin D Status and Its Relationship to Metabolic Parameters in Patients with Type 2 Diabetes Mellitus. Chonnam Med J. 2012 August; 48(2): 108–115. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434790/
19.Nutritive Value of Foods, United States Department of Agriculture, Agricultural Research Service, Home and Garden Bulletin Number 72. May be accessed at: https://www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR25/nutrlist/sr25w324.pdf and http://www.nal.usda.gov/fnic/foodcomp/Data/HG72/hg72_2002.pdf
20.Moore NL, Kiebzak GM. Suboptimal vitamin D status is a highly prevalent but treatable condition in both hospitalized patients and the general population. J Am Acad Nurse Pract. 2007 Dec;19(12):642-51. http://www.ncbi.nlm.nih.gov/pubmed/18042130
21.Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001 Nov 3;358(9292):1500-3. http://www.ncbi.nlm.nih.gov/pubmed/11705562
22.Putzu A, Belletti A, Cassina T, Clivio S, Monti G, Zangrillo A, Landoni G. Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials. J Crit Care. 2016 Nov 9;38:109-114. https://www.ncbi.nlm.nih.gov/pubmed/27883968
Exit mobile version