Whilst Pharmaceutical drugs can be life-saving in some cases, it is well-known that they can cause side-effects which can impede on your quality of life. A number of these side effects can be linked to nutrient deficiencies caused by the medications, but as medical doctors have limited training in nutrition, these deficiencies can go undiagnosed.
My late grandfather was one of those people who almost rattled when he walked from all the medications. His maladies included GORD, Barrett’s Oesophagus, leukaemia, haemochromatosis & arthritis (rheumatoid & osteo) to name a few. His skin was paper-thin & in his later years, he gained a lot of weight due to the steroids. His breakfast consisted of 20+ pills, with many of the medications given to counter the side effects of others. Although he did take some supplements & saw his chiropractor regularly, he was a creature of habit & was not one to make the dietary changes I suggested.
I know he was not alone in this regard. Sometimes, we just want to take a pill to make the symptoms disappear rather than treating the underlying cause, but a review published in ‘Pharmaceutics’ this week looks at links between medications & nutrient deficiencies. If you do need to take certain medications, you may want to consider specific supplementation to reduce side-effects & other unintended consequences.
Abstract:The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is quite limited. A comprehensive, updated review of the potential drug–nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care.
Proton Pump Inhibitors (PPIs)
The main action of PPIs is to reduce gastric acid production. Thus, decreased absorption of micronutrients that depend on low pH for uptake into intestinal cells may occur with PPI use.
- PPI use has been observed to decrease protein-bound B12 absorption and may lead to B12 deficiency in some individuals, although the results are mixed.
- Certain PPI users including the elderly, individuals with atrophic gastritis and/or H. pylori infection, and slow metabolizers of omeprazole may be at a higher risk of B12 deficiency.
- Additionally, certain dietary choices may influence risk of deficiency. Evidence suggests the effects of omeprazole on B12 status are due solely to impaired gastric acid secretion and not impaired intrinsic factors. Therefore, drinking acidic fruit juice concurrently with B12 may improve absorption in PPI users, as demonstrated in a small absorption study in hypochlorhydric older adults taking omeprazole.
- Vitamin C is highly concentrated in gastric juice, where it is predominantly found in its biologically active antioxidant form, ascorbic acid (AA). In addition to acting as an antioxidant, AA in gastric juice functions to eliminate potentially carcinogenic nitrites from saliva. In this process, AA is converted into its inactive form, dehydroascorbic acid (DHAA), which cannot be absorbed in the intestine. However, it may be converted back to AA through a pH-dependent process for reabsorption.
- In one observational study, patients with H. pylori infection had plasma vitamin C levels that were at least 30% less than H. pylori-negative patients. However, the dietary intake of vitamin C in infected patients was also lower than in non-infected volunteers.
- Two short-term (four weeks) intervention studies found reduced circulating vitamin C levels in H. pylori-infected patients taking omeprazole independent of dietary intake.
- Given the evidence that omeprazole increases the ratio of DHAA to total vitamin C in the gastrointestinal tract, lower circulating vitamin C levels with PPI use in H. pylori-infected patients may be due to decreased intestinal bioavailability of vitamin C.
- There is some evidence to indicate PPI use may negatively impact iron absorption. PPI users already at elevated risk for iron-deficiency or those with pre-existing iron deficiency may be at greater risk for impaired iron absorption during PPI therapy.
- The collective evidence indicates that chronic PPI use is associated with increased fracture risk, particularly in individuals who may already be at risk of fractures, such as older adults, and is considered a contributing factor to osteoporosis and fracture risk by the National Osteoporosis Foundation.
- Case reports of hypomagnesemia with chronic PPI use have been widely documented. In some, but not all cases, magnesium supplementation alone was not completely successful in reversing hypomagnesemia until PPI therapy was discontinued. Among ~30 cases of hypomagnesemia, more than half of these patients received PPI therapy for ≥5 years and 30% for ≥10 years. All of these reported cases were in older adults (age 51–82 years) and occurred more frequently in women than men.
- Gastric acid secretion may play a role in intestinal zinc absorption in humans, reflecting the need for dietary zinc to be in the reduced state. In one study, omeprazole administration at 60 mg/d for one week in healthy adults almost doubled the pH of fasting gastric juice and decreased plasma zinc levels by ~40%. These results suggest omeprazole may decrease zinc absorption by increasing gastric pH, however there was no control group and the sample size was small. A more recent study found that in healthy control subjects the plasma zinc increased 126% in response to supplementation with 26.2 mg zinc twice daily for 14 days, compared with only a 37% increase in those on long-term PPI therapy. In this study, baseline plasma zinc levels were also negatively associated with long-term PPI use.
- Thus far, only one study has investigated the effect of PPI therapy on the absorption of the provitamin A carotenoid, β-carotene. In a crossover study of 12 healthy volunteers, plasma β-carotene levels at 6 and 24 h after supplementation with 120 mg were significantly lower following seven-day treatment with 40 mg/d omeprazole compared with no omeprazole treatment.
- Acute and short-term doses of aspirin taken concurrently with vitamin C may alter vitamin C absorption in leukocytes, and its antioxidant activity in gastric mucosa may protect mucosal cells from damage. However, the effects of long-term, low-dose aspirin on vitamin C status, and its clinical implications, are unclear. Given the evidence that vitamin C may help prevent aspirin-induced gastric lesions, patients suffering from gastric mucosal injury due to an aspirin regimen may benefit from vitamin C supplementation.
- Collectively, the associations between aspirin, anemia, and Hb were inconsistent, and it is unclear whether low-dose aspirin causes iron deficiency anemia. However, among older adults the association between low dose aspirin use and decreased Hb was notable.
- One limitation to using Hb as a marker of iron status is that it is generally considered to be the last parameter to change. That is, early stages of iron deficiency occur well before measurable changes in Hb are observed.
- Older adults on a low-dose regimen, particularly those with H. pylori infection, may be at risk of decreased Hb and serum ferritin.
Calcium and Loop Diuretics
- Loop diuretics (especially furosemide) negatively affect calcium homeostasis, which may lead to secondary hyperparathyroidism.
- Loop diuretics increase urinary calcium excretion, although calcium balance may possibly be maintained by increased intestinal calcium absorption. Despite this potential compensatory mechanism, some individuals, particularly older adults and the elderly who absorb intestinal calcium less efficiently with age, may be at higher risk of decreased BMD and increased fracture risk with chronic use. Other risk factors for this association include the dose, duration, and form of loop diuretic.
Calcium and Thiazides
- Chronic thiazide use leads to reabsorption of renal calcium and may increase serum calcium levels above the normal range in certain individuals, particularly older women. Although observational studies indicate thiazide diuretics may protect against hip fractures, RCTs are needed to confirm these findings.
- Extensive evidence indicates that mild magnesium depletion is relatively common with loop and thiazide diuretic use. Loop diuretics directly inhibit magnesium reabsorption in the kidney, thus, both short and long-term treatment can lead to depletion. Conversely, thiazides induce magnesium excretion indirectly through multiple mechanisms, including suppression of PTH. Therefore, long-term therapy with thiazides is more likely to cause magnesium depletion than acute thiazide exposure.
- Population studies that investigated risk factors for hypomagnesaemia with diuretic use have determined patients with congestive heart failure who receive high doses of loop diuretics on a chronic basis, elderly patients, and individuals with poor dietary magnesium intake, or high alcohol intake may be at increased risk.
- Oral magnesium supplementation has been shown to be effective in increasing muscle concentrations of magnesium. In patients with arterial hypertension or congestive heart failure, magnesium concentrations were restored to normal after six months of supplementation.
Thiamin (Vit B1)
- Evidence from both animal and human studies has demonstrated that acute doses of loop diuretics increase urinary loss of thiamin.
- The effect of diuretics on thiamin is of particular concern for the elderly, who are at an increased risk of thiamin deficiency due to low dietary intake of this vitamin.
- Diuretic users were 2.3 and 4.2 times more likely to have intakes below the recommended dietary allowance and estimated average requirement for thiamin, respectively, compared to nonusers, even after adjusting for sociodemographic and meal pattern variables.
- Urinary zinc depletion with thiazide diuretic use may lead to tissue depletion, although it is unclear to what extent diuretics alone lead to clinical zinc deficiency. It is also possible the loss of zinc from thiazide diuretic use may be additive to other risk factors for zinc deficiency, such as inadequate intake, hepatic cirrhosis, diabetes mellitus, gastrointestinal disorders, or renal disease.
- Although both loop and thiazide diuretics increase urinary potassium excretion with chronic use, most research has focused on the latter since they generate hypokalemia more frequently than the former.
- While potassium supplements may not fully restore serum or body tissue potassium levels to normal, they appear to be effective in preventing hypokalemia.
- However, potassium supplementation may further decrease blood pressure in addition to the effects of the diuretic itself, potentially resulting in low blood pressure.
- In an observational study conducted after the implementation of folate fortification (1998), long-term use of diuretics was associated with lower red blood cell folate in hypertensive patients.
- A short trial of hypertensive patients found decreased folate levels with hydrochlorothiazide use after six weeks.
- Diuretics other than triamterene, namely thiazides, may negatively influence folate status, even in the age of folate fortification. However, the clinical significance of this drug–nutrient association is unknown.
Anti-Hypertensives: Angiotensin-Converting Enzyme (ACE) Inhibitors
- ACE inhibitors, as a drug class, may increase the risk of zinc deficiency. However, this effect is more pronounced with captopril than other ACE inhibitors. The underlying mechanism may be due to the thiol-radical group present in captopril that can chelate serum zinc and enhance its excretion.
- Patients on chronic ACE inhibitor treatment, especially captopril, may be at higher risk of impaired zinc status, particularly when other factors associated with impaired zinc status—such as heart failure, renal disease, older age, malabsorption and diarrhea—are present.
- ACE inhibitors can cause retention of potassium in the kidney via their inhibitory effect on aldosterone secretion.
- Certain factors may contribute to increased risk of hyperkalemia with ACE inhibitor use, including older age, renal disease, diabetes, congestive heart failure, use of potassium-sparing diuretics, potassium supplements or consumption of potassium-rich diets.
Anti-Hypertensives: Calcium Channel Blockers (CCBs)
- Gingival hyperplasia may develop in response to CCB treatment, mostly in men, but also in women. Although likely a drug class effect, the largest number of case reports have been documented with the use of nifedipine. A case–control study from The Netherlands showed current use of CCBs doubled the risk of gingival hyperplasia in a dose-dependent manner. The association between CCB use and gingival hyperplasia has been confirmed in other studies that investigated the incidence of this condition in users of amlodipine and nifedipine when compared with controls.
- In addition to the presence of dental plaque and poor oral hygiene, a major contributing factor to the development of gingival hyperplasia is impaired uptake of folate into gingival fibroblasts. Folic acid supplementation has been shown to decrease the incidence, reduce the severity, or delay the onset of gingival hyperplasia.
- Patients taking CCBs should be counselled on how to meet their recommended folate intake.
- Very limited data indicates that CCB monotherapy does not appear to influence potassium status, while the concomitant use of beta-blockers may be of concern in some older adults.
Coenzyme Q10 (CoQ10)
- CoQ10 is a naturally occurring, fat-soluble, vitamin-like compound obtained from the diet and, to a lesser extent, from endogenous synthesis. CoQ10 functions in the electron transport chain in the mitochondria and, thus, plays an important role in energy metabolism. CoQ10 is an intermediate in the mevalonate pathway, which is inhibited by statins.
- Statin use may lower serum CoQ10 levels in a dose-dependent manner but the clinical implications are unclear, and it is unknown whether decreases in serum CoQ10 result in significant depletions in muscle. The risk of CoQ10 depletion in muscle may be greater in older adults, as well as patients who develop myopathy while taking statins. The efficacy of CoQ10 supplementation on statin-induced myopathy symptoms is still under debate.
- There is a higher prevalence of suboptimal 25-hydroxyvitamin D levels in patients experiencing myopathic symptoms from statin use compared to those who do not. Furthermore, supplementation with vitamin D regressed myopathic symptoms in >90% of patients.
- The relationship between statins and vitamin D status remains controversial, and it appears that the nature of this particular drug–nutrient interaction is complex. Some studies indicate that some hyperlipidemic or vitamin-D-deficient individuals may improve their vitamin D status while taking statins. Conversely, vitamin D levels may be lower in patients with statin-induced myopathy.
Vitamin E and β-Carotene
- Vitamin E and β-carotene are transported in the circulation, in part, by low density lipoprotein (LDL) cholesterol, and a few studies investigating whether statins influence the status of these nutrients have been conducted.
- Statins are very commonly prescribed and may be associated with changes in circulating β-carotene and vitamin E levels. However, the effect of statins on these compounds is unclear. Additional, high-quality, controlled studies are needed to better understand potential interactions.
Oral Hypoglycemics: Metformin
- Cross-sectional analyses of adult populations with T2D from the U.S., Korea, the Netherlands and Brazil have consistently reported lower serum or plasma B12 in those taking metformin when compared to either healthy controls or T2D patients not taking metformin, after adjusting for covariates.
- Serum folate levels also decreased by 7% with metformin use, raising the concern that elevated Hcy in response to metformin may be attributable to decreased folate status, and not solely to decreased vitamin B12 status. Similar observations were made in another RCT investigating the long-term effect (~4 years) of 850 mg/d metformin on vitamin B12 and folate status in T2D patients receiving insulin treatment.
- Data from survey and case-report studies indicate that metformin use may reduce the intestinal absorption of dietary B12. Other studies have observed clinical symptoms of B12 deficiency with long-term metformin use, including megaloblastic anemia and peripheral neuropathy.
- Observational and intervention studies have shown that metformin use may negatively affect vitamin B12 status in a duration- and dose-dependent manner through impaired intestinal absorption. Individuals already at risk of low B12 status, including the elderly and vegetarians, may be at greater risk during drug therapy. Although more studies that include functional markers of B12 status are needed, the current evidence is sufficient to recommend periodic assessment of vitamin B12 in patients taking metformin. Furthermore, the concomitant use of a multivitamin with metformin appears to protect against B12 deficiency.
Oral Hypoglycemics: Thiazolidinediones (TZD)
Calcium and Vitamin D
- There is consistent evidence that T2D patients have a higher incidence of bone fractures compared to non-diabetic patients, despite no significant differences in BMD between the two groups.
- Long-term TZD use has been shown to increase the risk of bone fracture in women, who are already at a higher risk for osteoporosis, bone loss, and bone fracture than men . Furthermore, the intake of nutrients critical for bone health, including calcium, vitamin D, and magnesium, was reported to be insufficient in T2D patients on antidiabetic therapies.
- Although evidence indicates that TZD increase the risk for bone fracture and osteoporosis, in particular among older women, no studies have examined the potential protective effect of concurrent supplementation with calcium and vitamin D on bone health. Considering the dietary intake of these nutrients is likely insufficient in this population, supplementation may be warranted in some cases.
Calcium and Vitamin D
- Extensive evidence from cross-sectional and longitudinal studies indicates that prior and current exposure to glucocorticoids increases the risk for bone loss and fractures.
- In a meta-analysis of five RCTs, supplementation with calcium plus vitamin D had a significant effect on preventing bone loss at the lumbar spine and forearm, but not on femoral neck bone mass, fracture incidence, or bone resorption. The combination of calcium plus vitamin D was also found to be more effective than calcium supplementation alone. While it is likely that calcium plus vitamin D supplementation does protect against bone loss in patients taking glucocorticoids, it may be insufficient to protect against bone fracture and osteoporosis.
- Glucocorticoids have a negative effect on bone loss and fracture and are a leading cause of secondary osteoporosis, particularly in individuals who cannot achieve the recommended intake of calcium and vitamin D from diet alone, and in those who are otherwise at high risk of bone fractures and osteoporosis, e.g., advanced age or postmenopausal females. Concurrent supplementation with calcium and vitamin D may be appropriate for some patients.
Sodium and Potassium
- Corticosteroid use has been reported to cause sodium and water retention as well as increased potassium excretion, potentially leading to hypertension.
- In general, it is recommended that patients on chronic corticosteroid therapy limit their sodium intake and monitor their potassium intake. A diet rich in potassium is likely sufficient to maintain normal levels during corticosteroid treatment, but potassium supplements may be recommended for individuals who are unable to obtain the recommended amount through diet alone.
- A study investigating the effect of corticosteroid treatment on chromium status in 13 patients reported increased excretion of this essential mineral after three days of treatment, although the clinical significance is unclear . In this same study, chromium supplementation of three patients with steroid-induced diabetes was found to improve fasting blood glucose levels. To date, no additional RCTs have been performed to validate these preliminary findings.
Bronchodilators: Beta2-Agonists and Inhaled Corticosteroids [ICS]
Calcium and Vitamin D
- The effect of long-term ICS use may negatively influence bone metabolism and BMD in certain patients. The association appears to be stronger in COPD compared to asthmatic patients since the former are already at an increased risk of impaired bone health. No studies have tested the effect of calcium and vitamin D supplementation in ICS users on markers of bone health, and such studies are needed.
Calcium and Vitamin D
- Numerous studies have reported a significant association between the use of selective serotonin reuptake inhibitors (SSRIs) and risk of osteoporosis, with considerable evidence indicating these drugs increase the risk of fracture in a dose- and duration-dependent manner. Additional evidence indicates SSRIs may also decrease BMD. However, collective findings from cohort and case–control studies report the increased risk of fracture from SSRIs may be independent of BMD.
Oral Contraceptives (OC)
- Tryptophan metabolism, an indirect measure of vitamin B6 status, is abnormal in OC users compared to controls and can be corrected with supplemental doses of vitamin B6.
- Intervention studies with vitamin B6 supplementation have reported improvements in clinical symptoms of B6 deficiency and fewer side effects in OC users who may be deficient in this vitamin.
- Several studies have consistently reported serum B12 levels are lower in OC users compared to nonusers. While most of these studies adjusted for confounders, not all adjusted for dietary intake.
- Although there is consistent evidence that OC use is related to lower serum B12 levels, it is not clear whether this is actually indicative of a biochemical B12 deficiency. For populations already at risk for B12 deficiency, such as vegetarians, it is unclear how a potential change in serum B12 binding capacity due to OC use may affect them.
- A recent meta-analysis that included case–control, cohort studies, and clinical trials from 1970–2013 concluded that OC use is, indeed, associated with lower blood folate status, though other studies conducted during the same time period found no difference in folate status between OC users and controls. This discrepancy may be due to confounding issues, including lack of adjustment for dietary folate intake, supplement use, smoking, and alcohol consumption. Even in studies that considered dietary intake of folate, results varied. It is possible inter-individual genetic differences in folate handling may contribute to the variation.
- The collective scientific evidence, at present, is too inconsistent to support the conclusion that OC use causes folate deficiency. However, maintaining normal folate status is critical among women of child-bearing age, regardless of OC use. In 2010, the Food and Drug Administration approved a folate-containing OC for use. Two recent clinical trials tested the effects of this folate-fortified product, and both reported clinically significant increases in markers of folate status when compared to women given an OC absent folate.
- Several studies have reported that OC use may increase BMD in women ranging in age from young adulthood to perimenopause.
- In contrast, others have reported a detrimental effect of OC use on BMD.
- The effect of OC use on TBBMC and BMD at specific sites may depend on a number of factors, including type and level of physical activity as well as calcium intake. Women on long-term OC therapy and high physical activity may be at highest risk.
- Most cross-sectional studies have shown serum magnesium levels are lower in OC users compared to both nonusers and women on other forms of contraception, with one exception. An increase in the blood calcium to magnesium ratio due to low magnesium levels can influence blood coagulation processes. Indeed, a systematic review and network meta-analysis of 26 observational studies that investigated the risk of venous thrombosis for different combined OCs concluded OC use increased the risk of venous thrombosis, and effect size depended on the combination used.
Vitamin C and E
- While some studies indicate circulating vitamin C levels are lower in OC users compared to nonusers, others indicate little threat to individuals who live a healthy lifestyle and consume a diet adequate in vitamin C. Then again, several studies show chronic OC use leads to increased oxidative stress, in particular lipid peroxidation, and lower circulating vitamin E. Enhanced oxidative stress and lipid peroxidation may represent a potential risk for cardiovascular disease.
Not only can some medications affect nutritional status, but poor nutrition or poor metabolism of nutrients, such as with leaky gut or MTHFR mutations, can affect the efficacy of some medications:
Antidepressants and Folate
- Several observational studies report lower folate status, as measured by serum, plasma, and red blood cell folate concentrations or plasma Hcy, in patients with major depressive disorder (MDD) compared to healthy controls. Additionally, genotyping analysis determined gene variants of methyltetrahydrofolate (MTHFR) are associated with risk of being diagnosed with depression, findings that were confirmed in a meta-analysis of similar studies.
- The relationship between folate status and depressive symptoms is of interest because, despite the widespread use of antidepressants among patients with MDD, 31–49% of patients are either partial- or non-responders (this is around the same percentage of the population estimated to have MTHFR variants).
- Additionally, about one-third of patients classified as responders to antidepressants were reported to have cognitive or physical symptoms, likely to be residual symptoms of depression, side effects of medication, or both. Furthermore, observational studies of middle aged and older adults found low blood folate levels were associated with greater resistance to improvement following antidepressant therapy.
- The evidence suggests low folate status may be associated with depression and adjunctive treatment with folate may benefit individuals on antidepressant therapy, including patients with MDD who are nonresponsive to antidepressant medication. Currently there are no official guidelines regarding the most effective form, dose, or duration of folate supplementation in this capacity.
ACE Inhibitors and Iron
- The most common side effect of chronic ACE inhibitor use is a dry cough, which occurs in 5–39% of patients. Given the evidence that nitric oxide synthesis is down-regulated in the presence of iron, it has been hypothesized that nitric oxide generation in bronchial epithelial cells may contribute to the ACE-inhibitor-induced cough.
- Following iron supplementation, the reduction in mean score of daily cough severity was significantly greater when compared with the placebo group, and three subjects in the iron group reported complete cough resolution. No changes in iron status were observed in either group. These findings suggest that iron supplementation may ameliorate ACE-inhibitor-induced cough, although additional research is needed to confirm.
There is no doubt the use of commonly prescribed medications that can adversely impact nutritional status is on the rise. Given the increasing prevalence of conditions that require long term medication use, and an inadequately nourished adult population, the potential public health implications are profound. While young and middle-aged adults are certainly affected, there is particular concern for older adults who are more likely to use multiple concurrent medications. Aging adults also undergo physiological changes that affect nutrient needs, and their ability to meet these needs, which may further compound the issue.
Ideally, clinicians should recommend their patients consume a sufficient quantity and variety of nutrient-dense foods in their daily diet. Unfortunately, health professionals are not routinely trained to provide dietary advice, nor do they have time to provide effective counseling during an office visit.
Many adults are aware of potential shortfalls in their diet and take a dietary supplement, most often a multivitamin/mineral (MVM) preparation, to compensate. Indeed, observational data indicates adults who take a full spectrum MVM supplement are less likely than nonusers to be deficient in any micronutrient (14% vs. 40%, p < 0.02). Intervention studies confirm MVM supplementation helps fulfill micronutrient requirements and improve nutritional status even in healthy adults. A growing body of evidence also supports the use of MVM in preventing certain chronic conditions, especially with long term use. Historically, physicians have been hesitant to recommend a MVM, despite little evidence of harm. Current evidence indicates age- and gender-appropriate MVM supplements, formulated at or near 100% of the daily value for most micronutrients, are generally well tolerated and do not appear to increase the risk of mortality or disease.
In conjunction with an overall healthy diet, a single daily MVM may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. Practitioners should be aware that a single dose MVM will not provide sufficient calcium, CoQ10, or fish oil. Depending on the medication in use, as well as the patient’s baseline status, usual dietary intake, and current condition, a separate supplement may be warranted.
This article is a summary of a Review published 20th March, 2018 at http://www.mdpi.com/1999-4923/10/1/36/htm. All References can be viewed there.
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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