arthritis, natural arthritis remedies, Supplements

Micronutrient Therapy For Osteoarthritis

Osteoarthritis (OA) is considered a degenerative disease of the joints with progressive destruction of articular cartilage. According to current evidence, the disease affects not just the articular cartilage, but in fact the whole joint. Often, this can be treated with arthritis supplements.

The effects of OA can be observed in the subchondral bone, the menisci, the periarticular muscles, the joint capsule, and the synovial membrane1. These changes are detectable even before radiographic evidence of osteoarthritis23.

They may possibly represent the causative factor in the development of cartilage changes45. The symptoms of this progressive breakdown of the joints are pain, swelling, effusion, and aggravating functional and mobility problems6.

SUMMARY

Ostearthritis affects approximately every 5th person in our society. Fortunately, hundreds of clinical decades studies have found that widely-available nutrients from foods can prevent its onset and slow or stop its progress. We have taken a look at 12 different nutrients, explained its mechanism of action, listed clinical studies and recommended sensible products to buy.

How Common is OA?

Estimates suggest that up to 8.5 million people in the UK are affected by joint pain that may be attributed to osteoarthritis7 and 2 million adults per year visit their GP due to osteoarthritis8.

At least 4.4 million people in the UK have X-ray evidence of moderate to severe osteoarthritis of their hands, over 0.5 million have moderate to severe osteoarthritis of the knees and 210,000 have moderate to severe osteoarthritis of the hips910.

In Germany, it is estimated that 35 million people have radiologically detectable osteoarthritis. 5-15 million of them experience symptoms11.

Due to demographic development and the increasing prevalence of obesity it is expected that the number of patients suffering from osteoarthritis will double by year 202012.

Therapy

Since there is currently no cure for osteoarthritis, the applied treatment is only symptomatic. Non-steroidal anti-inflammatory drugs (NSAIDs) used in pharmacological treatment of osteoarthritis have analgesic and anti-inflammatory effect, but have no effect on the control of residual cartilage degradation.

Side effects affecting ​​the gastrointestinal tract, the cardiovascular system, the kidneys, and the liver should be taken into consideration during long-term use. This is recommended not only in older osteoarthritis patients with frequent comorbidities, but also in athletes131415.

Therefore, the ideal pharmacological therapy should be capable not only to reduce pain and inflammation, but also to slow down and stop the pathological catabolic process. In addition, the medication should promote cartilage regeneration, combined with low potential to produce side effects1617.

Glucosamine sulphate

Glucosamine sulphate is an amino monosaccharide. It serves as the main substrate for the formation of hyaluronic acid, chondroitin sulphate, and keratan sulphate in the articular cartilage.

Glucosamine sulphate is obtained from the biopolymer chitin, which is found in the exoskeletons of marine crustaceans (crabs, lobsters), and in fungal cell walls1819. Resorption rate of orally administered glucosamine sulphate is 90%20.

  • In vitro studies show specific mechanisms of action of glucosamine sulphate, such as improvement of cartilage synthesis, inhibition of cartilage degradation, and anti-inflammatory effect.

  • In the cartilage culture, Glucosamine sulphate improves the synthesis of aggrecan and type II collagen21. In addition, glucosamine sulphate promotes hyaluronic acid formation in cultures of synovial cells22.

  • Glucosamine sulphate affects the formation of enzymes responsible for degradation of proteoglycans (matrix metalloproteinase and aggrecanase)2324 and prevents the degeneration of collagen in chondrocytes by inhibiting lipid peroxidation and protein oxidation 25.

  • Glucosamine sulphate reduces the formation of COX-2 and prostaglandin E2. In addition, it inhibits DNA binding of the transcription factor NFκB, resulting in reduced formation of proinflammatory cytokines IL-1β and TNF-α, as well as the proinflammatory enzymes COX-2 and NOS-226272829.

  • Glucosamine sulphate also shows antioxidant effects with a distinct reduction of iNOS activity, thus reducing the NO-mediated apoptosis of chondrocytes30,31.
  • In a randomized, placebo-controlled double-blind study with 212 patients with knee osteoarthritis, patients treated with 1500 mg glucosamine sulphate/ day showed no significant narrowing of joint space after 3 years: -0.06 mm (95% CI – 0.48 to 0.09).

    In the placebo group, a significant joint space narrowing was detected: -0.31 mm (-0.48 to 0.13). At the same time, a slight worsening of the symptoms was measured by the WOMAC score in patients in the placebo group. The group treated with glucosamine sulphate showed improvement of the symptoms32.

  • Another randomized, placebo-controlled double-blind trial with 202 patients who suffered mild to moderate gonarthrosis, also showed marked narrowing of joint space in placebo group. Patients treated with 1500 mg glucosamine sulphate / day had no narrowing of the joint space after three years, with a significant difference when comparing the groups (p = 0.001).

    The symptoms improved slightly in the placebo group. Among patients treated with glucosamine sulphate, significant improvements of 20-25% were recorded, as measured by the Lequesne index and the WOMAC score. Tolerability was good, with no significant differences between the two groups33.

  • Postmenopausal women are most frequently affected by gonarthrosis. In a randomized placebo-controlled double-blind study with 319 postmenopausal women, the results of the two studies cited above were confirmed.

    After 3 years, in the group treated with 1,500 mg glucosamine sulphate there was no narrowing of joint space. The narrowing was detected in the placebo group (p <0.0001 in group comparison). The WOMAC score improved in Glucosamine sulphate group, while there was a slight deterioration in the placebo group (p = 0.003 in group comparison)34.

  • In a randomized double-blind trial with 318 patients with moderate symptomatic gonarthrosis, the effect of 1,500 mg glucosamine / day over 3 g paracetamol / day and placebo were compared over a period of 6 months.

    Glucosamine sulphate significantly improved the symptoms, as measured by the Lequesne index compared to placebo (p = 0.032). However, there was no significant difference between paracetamol and placebo (p = 0.18). Measured by the WOMAC score, there were significantly more responders with glucosamine sulphate (39.6%) and paracetamol (33.3%), compared with placebo (21.2%). Tolerability was good in all groups with no significant differences35.

  • In a controlled, observational study with 340 patients with gonarthrosis, the incidence of implantation of a total knee endoprosthesis was first determined after 3 years.

    During the 5-years follow-up, patients treated with 1,500 g glucosamine sulphate for at least 12 months, underwent surgery significantly less frequently compared with placebo (6.3% vs. 14.5%, p <0.0024)36.

  • The anti-catabolic effect of glucosamine sulphate on cartilage was demonstrated in a study with footballers by determining biomarkers of collagen degradation (CTX-II) collagen synthesis (CPII). Compared to non-athletes, football players had significantly higher degradation of collagen type II.

    The degradation could be significantly reduced by daily dose of 1,500 mg or 3,000 mg glucosamine sulphate. The effect could be detected only after ingestion the Glucosamine sulphate37.

We selected three products for you here, which offer daily glucosamine quantities above 1,000 mg per day – the amount, which has been clinically shown beneficial for joints.

COMPARISON OF THE BEST JOINT SUPPLEMENTS

Chondroitin sulfate

Chondroitin sulphate is an unbranched glycosaminoglycan and it consists of repeating non-sulphated or sulphated disaccharide units (N-acetylgalactosamine and glucuronic acid).

Due to the pronounced negative charge, chondroitin sulphate is responsible for water-binding properties of the articular cartilage. It can be extracted from different tissues (e.g. shark cartilage, tracheal cartilage from beef or calf)38. In animal models, absorption rate of Chondoitin sulphate is > 70% after oral administration39.

  • Reduction of proinflammatory cytokines and enzymes can be demonstrated in vitro, both for glucosamine sulphate and chondroitin sulphate. There is also antioxidant effect with reduction of NO-mediated apoptosis of chondrocytes4041.

  • Chondroitin sulphate increases the synthesis of hyaluronic acid in synovial cells. It also stimulates chondrocyte metabolism by promoting collagen and proteoglycan synthesis.

  • In addition, chondroitin sulphate inhibits enzymes called leukocyte elastase and hyaluronidase42434445.
  • In a randomized, placebo-controlled double-blind trial with 120 patients with gonarthrosis, the intermittent administration of 800 mg chondroitin sulphate over 2-3 months led to a significant decrease in the Lequesne index, compared to placebo.

    In the treatment group, no joint space narrowing could be measured. There was a significant narrowing of the joint space in the placebo group 46.

  • In another randomized, placebo-controlled double-blind trial with 300 patients with gonarthrosis, the daily intake of 800 mg chondroitin sulphate / day for 2 years, resulted in no narrowing of the joint space.

    In contrast, a significant joint space narrowing was observed in the placebo group (p = 0.001) compared with baseline. Despite the structure-preserving effect of chondroitin sulfate, there was no difference in impact compared with the placebo group47.

  • A randomized, placebo-controlled double-blind trial with 822 patients with gonarthrosis for more than 2 years was performed with the intent-to-treat analysis of patients. The patients who had been taking 800 mg of chondroitin sulphate daily for 2 years, had a significant reduction in joint space narrowing compared to placebo (p <0.0001 ).

    There was also a significantly lower number of patients with radiological progression in the chondroitin sulphate group (p <0.0005). Pain reduction was significantly faster compared to placebo (p <0.01) 48.

  • In a randomized double-blind study of 69 patients with active gonarthrosis, the volume loss of cartilage tissue and accompanying subchondral bone marrow oedema were measured using MRI. In the first 6 months, patients were given 800 mg of chondroitin sulphate / day or placebo. Afterwards, all study participants received 800 mg of chondroitin sulphate for 6 more months.

    After 6 months, the chondroitin sulphate group showed significantly lower volume loss of cartilage as compared to placebo (p = 0.03), with persistent significant difference after 12 months. After 12 months under chondroitin sulphate, the score for the subchondral bone marrow oedema was significantly lower in the ​​lateral compartment of the joints (p = 0.035) and the lateral femoral condyle (P = 0.044). The relief of symptoms was similar in both groups49.

  • In a randomized, placebo-controlled double-blind trial in 162 patients with osteoarthritis of finger joints, the subjects were given 800 mg chondroitin sulphate / day for 6 months.

    Treated patients showed a significantly greater pain reduction compared to placebo (p = 0.02).  They also experienced significantly improved function, as measured by the “Functional Index for Hand Osteoarthritis” (p = 0.008) 50.

  • Several meta-analyses confirmed the symptom and structure modifying effect of chondroitin sulphate on gonarthrosis and finger joint osteoarthritis515253.

Chondroitin is usually sold in combination with glucosamine. Here are three good products, which include both nutrients.

Glucosamine and chondroitin sulphate in combination

Experimental evidence for combined use of glucosamine sulphate and chondroitin sulphate result from a study that could show their differential effects on the proteome of chondrocytes. Glucosamine sulphate modulates proteins in terms of the signal transduction, redox response, stress response, and protein synthesis.

On the other hand, chondroitin sulphate affects energy production and metabolic pathways. Glucosamine sulphate alone and in combination with chondroitin sulphate increases the formation of the GRP78 protein, as a possible mechanism for the supposed anti-inflammatory action of both substances.

In addition, glucosamine sulphate and / or chondroitin sulphate influence the intracellular activity of the enzyme superoxide dismutase 2 (SOD-2)54.

  • In an animal model of osteoarthritis, the effect of glucosamine sulphate was compared to the combined effect of glucosamine sulphate and chondroitin sulphate. Rats with severed anterior cruciate ligament received either normal food, or food supplemented with glucosamine sulphate or with combination of glucosamine sulphate and chondroitin sulphate.

    After 70 days, the effect on pain and the histological changes of the articular cartilage were analysed. Only in combination therapy, there was a significant pain control compared to the control (-44.6%). In addition, cartilage damage was significantly less severe in comparison to the control group. The values ​​for glucosamine sulphate alone were also lower, but did not reach the level of statistical significance [63].[/note]55.

  • In a 6-month blinded multicentre study, the effects of placebo vs. Glucosamine sulphate hydrochloride (3×500 mg / day) vs. Chondroitin sulphate (3×400 mg / day) vs. combination of glucosamine sulphate and chondroitin sulphate vs. Celecoxib (200 mg / day) were examined in gonarthrosis. Efficacy was defined as an improvement of knee pain for 20% and more compared to the initial value. Glucosamine sulphate hydrochloride and chondroitin sulphate were not more effective than placebo (at very high response rate of 60.1% with placebo).

    In the subgroup of patients with moderate to severe knee pain at baseline, the effectiveness of the combination of glucosamine sulphate hydrochloride and chondroitin sulphate was significantly higher than placebo (79.2% vs. 54.3%, p = 0.002)56.

Hyaluronic acid

Hyaluronic acid is a hydrophilic amino sugar, composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine sulphate. It belongs to the group of glycosaminoglycans.

Hyaluronic acid is responsible for the viscoelastic quality of the synovial fluid. Integrated in cartilage tissue with collagen type II, hyaluronic acid is responsible for the elasticity of the articular cartilage due to the pronounced water binding capacity.

Exogenously supplied hyaluronic acid increases concentration of hyaluronic acid and synthesis of proteoglycan in chondrocytes. It also reduces the formation of proinflammatory cytokines and matrix metalloproteinase. In addition, reduced hyaluronic acid decreases NO formation, thus decreasing NO-mediated apoptosis of chondrocytes in osteoarthritis animal model 5758.

Besides previously intra-articular injection of hyaluronic acid as an established treatment method for osteoarthritis, oral administration of hyaluronic acid is now available 59.

  • In horses, the formation of joint effusion was measured after surgical intervention of osteochondrosis. In animals receiving food mixed with 100 mg hyaluronic acid / day, the ultrasound imaging showed significantly lower effusion 30 days postoperatively than in animals in the control group (0.67 vs. 2.05 effusion score, p <0.0001 )60.
  • In a randomized, placebo-controlled double-blind study with 20 patients with gonarthrosis, oral administration of 80 mg of hyaluronic acid for 8 weeks resulted in significant improvement in quality of life (determined by SF36) compared to placebo. There was no significant difference in the WOMAC score compared to placebo61.

Collagen hydrolysate

Collagen hydrolysate is derived enzymatically from natural collagen. It contains essential amino acids glycine and proline in three fold higher concentration than other protein sources. These amino acids are important for the development of cartilage proteins.

Orally administered collagen hydrolysate is well absorbed and accumulated in joint cartilage. It significantly increases the formation of macromolecules of the extracellular matrix by chondrocytes in comparison to untreated controls (p <0.05)62.

  • A prospective, randomized, placebo-controlled double-blind study of 147 athletes, examined the effect of 10 g collagen hydrolysate / day over a period of 24 weeks on activity-related joint pain. For all parameters (joint pain at rest, standing, walking, running) a significant improvement compared to placebo was found (p = 0.02)63.

  • In a randomized, placebo-controlled double-blind trial of 250 patients with gonarthrosis, the daily intake of 10 grams of collagen hydrolysate for 6 months led to significant improvement in pain (VAS and WOMAC pain scale) compared to placebo64.

  • A randomized, placebo-controlled double-blind pilot study included 30 patients with mild gonarthrosis, taking 10 g of collagen hydrolysate for 24 weeks. Improved dGEMRIC (delayed gadolinium-enhanced Magnetic Resonance Imaging of Cartilage) score was noted in the area of ​​the medial and lateral tibial plateau, while the score in the placebo group was decreased.

    This suggests that collagen hydrolysate supplementation indirectly increases the formation of proteoglycans in articular cartilage65.

Antioxidants

Free radicals can affect negatively the pathological process of osteoarthritis. They activate the phospholipase A2, causing the release of arachidonic acid from membrane phospholipids, and subsequently amplify the formation of proinflammatory eicosanoids.

They damage different biomolecules of the joints and the adjacent bones. In particular, proteoglycans, hyaluronic acid, and collagen are affected.

They induce the transcription factor NF-κB, thus maximizing the formation of proinflammatory cytokines. Free radicals increase the rate of apoptosis of chondrocytes.

By increased consumption, they decrease concentration of antioxidants locally in the affected tissues. That way, the oxidative stress is strengthened further, which in turn potentiates the inflammation and long term damage of cartilage tissue 6667.

In patients with osteoarthritis, the antioxidant capacity was reduced as compared to healthy controls. Therefore, oxidative stress was increased.

A connection between oxidative stress and metabolic activity of the cartilage can be measured by the marker of collagen synthesis (prolidase). Increased oxidative stress, leads to greater restriction of the cartilage metabolism68.

Among the herbal antioxidative supplements, Pine Bark Extract has proven beneficial effects on symptoms of osteoarthritis. It is able to lower pain and stiffness and improv symptoms of knee osteoarthritis (flexibility of osteoarthritic joints).

  • A study published in 2008 tested the efficacy of 100 mg Pine Bark Extract daily (oral capsules) in a 3 month study in patients with osteoarthritis (OA). OA symptoms were evaluated by WOMAC scores, mobility by recording their walking performance (treadmill).

    The use of drugs decreased by 58% in the treatment group (p < 0.05) versus 1% under placebo. Gastrointestinal complications decreased by 63% in the treatment group, but only 3% under placebo.

    Overall, treatment costs were reduced significantly compared with placebo. Foot edema was present in 76% of the patients of the treatment group at inclusion and in 79% of the controls. After 3 months edema decreased in 79% of Pine Bark Extract patients (p < 0.05) vs 1% in controls. In conclusion, Pine Bark Extract offers an option for reduction of treatment costs and side effects by sparing antiinflammatory drugs69.

  • Another study published in 2008 evaluated whether Pine Bark Extract reduced the symptoms of OA in a double-blind, placebo-controlled, randomly allocated trial with patients suffering from knee osteoarthritis stages I and II.

    100 patients were treated for 3 months either by 150 mg Pine Bark Extract per day at meals or by placebo. Patients had to report any change of use of previously prescribed antiinflammatory medication during the study period.

    Following treatment with Pine Bark Extract patients reported an improvement of WOMAC index (p < 0.05), and a significant alleviation of pain by visual analogue scale (p < 0.04), the placebo had no effect. The use of analgesics diminished in the verum group but increased under the placebo. Treatment with Pine Bark Extract was well tolerated.

    Results show that Pine Bark Extract in patients with mild to moderate OA improves symptoms and is able to spare NSAIDs70.

  • A 2007 study on knee-osteoarthritis investigated the potential effect of Pine Bark Extract, a flavonoid-rich dietary supplement, on the symptoms of knee OA. Thirty-seven osteoarthritic patients were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Patients received either placebo or Pine Bark Extract pills (50 mg, three times daily) in a blinded fashion for 3 months.

    In the Pine Bark Extract group, there was a significant improvement in total WOMAC score and WOMAC subscale score of pain and physical function at 60 and 90 days of treatment. At 90 days, significant reduction of 43%, 35%, 52%, and 49% in self-reported pain, stiffness, physical function, and composite WOMAC score, respectively, were reported in Pine Bark Extract group, whereas the placebo group showed no significant changes.

    The dosage and frequency of NSAIDs or COX-2 inhibitors usage were increased in placebo group, which were significantly less in Pine Bark Extract group. The results of this study indicate the efficacy of Pine Bark Extract in alleviating osteoarthritis symptoms and reducing the need for NSAIDs or COX-2 inhibitors administration.

    This beneficial effect of Pine Bark Extract might be due to its antioxidant and anti-inflammatory properties. Further research is warranted to determine the underlying mechanism associated with this apparent effect71.

Vitamin A

Besides having an antioxidant effect, vitamin A also affects the interleukin-1-mediated formation of matrix metalloproteinase in chondrocytes 72. Relevant studies on the impact of vitamin A on osteoarthritis are not available.

Vitamin C

Vitamin C supports the regeneration of vitamin E, which is self-inactivated by the inactivation of oxygen free radicals. In addition, vitamin C is an essential cofactor in the synthesis of collagenous connective tissues73.

  • The longitudinal Framingham Knee Cohort Study showed that people taking 120-200 mg of vitamin C daily had a 3-fold lower risk of progressive osteoarthritis. They also had lower risk of knee pain than people with lower vitamin C consumption during the 9-year observation period74.

  • In a prospective cohort study, the risk of new onset of gonarthrosis was lowered by 11% under the vitamin C substitution, compared to individuals without substitution. Progression of the disease was not decreased in patients with already existing osteoarthritis75.

  • In a randomized, placebo-controlled study of 133 patients with gonarthrosis and coxarthrosis the daily intake of 1 g calcium ascorbate (898 mg vitamin C) led to significant reduction in pain (p = 0.0078) and improvement in the Lequesne index (p = 0.036) compared to placebo76.

Vitamin E

Vitamin E is a lipophilic oxygen-radical scavenger. In addition to its antioxidant effect, vitamin E stimulates growth of chondrocytes and reduces inflammation by reducing the release of arachidonic acid. It also inhibits the activity of cyclooxygenase and lipoxygenase77.

  • In a study of 53 patients with gonarthrosis and coxarthrosis, the effects of 3 x 400 mg of vitamin E and 150 mg diclofenac were compared. Reduction of pain during rest, pressure, and movement was similar in both groups.

    A significant decrease in knee joint circumference (p = 0.001), an improvement of joint mobility (p = 0.002), and an increase in walk distance (p <0.001 ) were noted compared to baseline78.

  • In a double blind placebo controlled study of 136 patients with gonarthrosis, no difference in the progression of joint space narrowing or symptoms was found compared to placebo. The follow-up period was 2 years.

Selenium

Selenium is a cofactor of glutathione peroxidase of endogenous antioxidant defence system. In a study of human chondrocytes, selenomethionine inhibited the transcription of the IL-1β-mediated enzymes iNOS and COX-2. This in turn inhibited the formation of NO and PGE279.

Vitamin D

In addition to positive effects on bone metabolism, vitamin D also stimulates the synthesis of proteoglycan in chondrocyte cultures80. Metabolites of vitamin D3 affect the proliferation and differentiation of chondrocytes81.

  • One study proved significant association of low serum levels of 25-hydroxyvitamin D and gonarthrosis in patients aged < 60 years82.
  • A prospective study with 237 participants was able to demonstrate that low 25-hydroxyvitamin D levels were associated with a 3-fold higher risk of developing coxarthrosis over a period of 8 years 83.

Vitamin K

An observational study with 672 participants proved a direct correlation with low plasma levels of vitamin K and and increased prevalence of osteoarthritis in the joints of the hand and knee84.

In a controlled, randomized study, 378 participants supplemented with vitamin K have been observed for the development osteoarthritis of the hand. Only a subset of participants with low vitamin K levels at study entry showed narrowing of joint space by 47% (p = 0.02)85.

Omega-3

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are long-chain omega-3 fatty acids. They are able to inhibit the formation of thromboxane A2, prostaglandin E2, leukotriene B4, aggrecanase, and collagenases 8687.

In a randomized study of 177 patients with moderate to severe gonarthrosis and coxarthrosis, the effect 1500 mg glucosamine sulphate plus omega-3 fatty acids (EPA and DHA) plus vitamin A, D, and E, were compared using the WOMAC score to the combination of active ingredients without omega-3 fatty acids, over a period of 26 weeks.

By defining the therapeutic success as improvement of the WOMAC score by 20%, there were no significant differences between the two treatment groups. By defining the therapeutic success as improvement of the WOMAC score by 80% or more, significantly more patients in the Glucosamine sulphate / omega-3 FS group achieved the therapeutic success compared with the control group (52.2% vs. 37.9%, p = 0.044) 88.

MSM

MSM has a pain-relieving and detoxicating89 effect. The sulfur contained in MSM is an important building block for cartilage tissue. Cartilage tissue should therefore be positively affected by an increased consumption of MSM, although such effects are yet to be conclusively proven.

Selenium and Zinc

The trace elements selenium, manganese, iodine, iron, copper and zinc can inhibit inflammation90 and reduce cartilage destruction91. There is little clinical research on humans, but supplementation does make sense to avoid undersupply and prevent onset or development of both osteoarthritis as well as rheumatoid arthritis.

Micronutrient combinations

In a multicentre observational study, 450 patients with gonarthrosis stage I-IV by Kellgren u. Lawrence received a combination of micronutrients for 4 months. The combination included glucosamine sulphate, chondroitin sulphate, hyaluronic acid, collagen, vitamin A, C, E, D, K, B complex vitamins, Omega-3 fatty acids, minerals, as well as trace elements and phytochemicals. Pain intensity, joint stiffness, and global WOMAC score improved significantly compared to baseline in patients with all stages of osteoarthritis. In addition, significantly fewer patients required analgesics 92.

Conclusion

In conclusion, micronutrients in arthritis supplements have symptom-relieving, anti-inflammatory and structure-modifying effect. By synergistic enhancement of action and different mechanisms of action, micronutrient combinations should replace monotherapy as soon as possible, and should be used sufficiently long.

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