2009497.323_339.tp

Clin Chem Lab Med 2010;48(3):323–327 ᮊ 2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2010.077 The underestimated problem of using serum magnesium
measurements to exclude magnesium deficiency in adults;
a health warning is needed for ‘‘normal’’ results
Yasmin Ismail1, Abbas A. Ismail2 and Adel
warning is therefore warranted regarding potential misuse A.A. Ismail3,*
of ‘‘normal’’ serum magnesium because restoration of mag- nesium stores in deficient patients is simple, tolerable, inex- Severn and Wessex Deanery, Bristol, Avon, UK pensive and can be clinically beneficial.
Stepping Hill Hospital, Stockport, Cheshire, UK Chevet Lane, Wakefield, West Yorkshire, UK Keywords: deficiency; diagnosis; life-style; limitation;
Abstract
Background: A major use of serum magnesium measure-
ments in clinical practice is to identify patients with defi-
Introduction
ciency. However, numerous studies have shown that mag-nesium deficiency is common and may be present in over Magnesium is the fourth most abundant mineral in the body 10% of hospitalized patients, as well as in the general pop- after calcium, potassium and sodium. It is biochemically ulation. An important cause for under diagnosis of deficiency regarded as a ‘‘chronic regulator’’ and physiologically as a is that serum magnesium, the most commonly used test, can ‘‘forgotten electrolyte’’ (1–5). Adequate magnesium stores be normal despite negative body stores. This article focuses are necessary for the function of hundreds of widely distrib- on the limitations of ‘‘normal’’ magnesium results and high- uted kinases, a group of magnesium-dependent enzymes that lights the importance of lifestyle or ‘‘modus vivendi’’ as a catalyzes the transfer of a phosphate group to a recipient pragmatic means of identifying those individuals potentially molecule in the process of phosphorylation. The underlying at risk for negative body magnesium stores.
mechanism seems to be the same for all known kinases and Methods: Researched peer reviewed articles on magne-
necessitates the presence of magnesium. Kinases can only sium published between 1990 and 2008 in MEDLINE and bind ‘‘ATP-Mg’’ molecules, cleaving the g phosphate group EMBASE, using database keywords ‘‘magnesium, deficien- which is subsequently transferred to the recipient molecule.
cy, diagnosis, treatment and hypomagnesaemia’’. Bibliogra- Phosphorylation transforms (switches on) an inactive mole- phies of retrieved articles have been searched and followed.
cule into an active or ‘‘functional’’ one, which can then per- We have also performed a manual search of each individual form specific biological/biochemical tasks (or vice versa). In issue in which most of these reports have appeared.
addition to the phosphorylation of small organic molecules, Results: In 183 peer reviewed studies published from 1990
up to 30% of body proteins are activated by magnesium- to 2008, magnesium deficiency was associated with increased prevalence and risk in 11 major conditions. Simi- Magnesium-dependent kinases are paramount in regulat- larly, in 68 studies performed over the same period, mag- ing the cell-cycle and growth, as well as apoptosis. It has nesium deficiency was found to predict adverse events and also a vital role in signal transduction and the production and a decreased risk of pathology was noted when supplemen- actions of second messengers, such as c-AMP, diacylglyce- rol, calmodulin and c-GMP. Central to all these intracellular Conclusions: The perception that ‘‘normal’’ serum magne-
functions is that each protein must be at the right place and sium excludes deficiency is common among clinicians. This work at the right time. Individual kinases regulate and con- perception is probably enforced by the common laboratory trol a particular subset of proteins in these highly complex practice of highlighting only abnormal results. A health Magnesium plays an important role in electrolyte home- ostasis; being necessary for the activation of ATP/ATPase *Corresponding author: Adel A.A. Ismail, BPharm, PhD, pumps, such as Naq/Kq, Naq/Ca2q, Naq/Mg2q and Mg2q/ FRCPath, Retired Consultant in Clinical Biochemistry and Ca2q pumps. If deficient, this can result in a reduction in Chemical Endocrinology, Wakefield, West Yorkshire, UK their efficacy and activities. Chronic magnesium deficiency Phone/Fax: q44-1924-254359E-mail: adelaaismail@aol.com with time may eventually lead to overt pathology and elec- Received September 9, 2009; accepted November 11, 2009 trolyte disturbances, such as ‘‘refractory’’ hypokalaemia and/ 2010/497
324 Ismail et al.: Limitation of serum magnesium measurement or hypocalcaemia. Neither the former nor the latter can be Although deficiency of other major minerals, such as cal- corrected by potassium or calcium treatment alone, and mag- cium, sodium and potassium are commonly reflected in their nesium replacement becomes essential for restoration of cel- serum concentrations, significant deficiency of body mag- lular function (6). It is essential to note that magnesium itself nesium may not be associated with low serum concentra- is an electrolyte and plays a major role in the homeostasis tions. Since an alternative biomarker for magnesium, which of other major electrolytes, namely Naq, Kq and Ca2q. Fur- is both practicable and accurate, is currently unavailable. It thermore, magnesium is necessary for bone mineral density may be prudent that the patient’s lifestyle or ‘‘modus viven- and strength, protein, carbohydrate and fat metabolism, ener- di’’ is taken into account as a pragmatic means for identi- gy transfer, storage and use. About 150 magnesium-depend- fying patients with potential risk of negative body mag- ent kinases are linked to a wide variety of diseases.
nesium stores, despite normal serum magnesium, and for Therefore, it is not surprising that magnesium deficiency can whom further testing and/or supplementation may be potentially cause or exacerbate a wide range of disorders Role of ‘‘modus vivendi’’ in identifying patients
Diagnosis of magnesium deficiency
with potential magnesium deficiency
The diagnosis of magnesium deficiency is biochemical.
The main causes of magnesium deficiency are shown in However, even when magnesium deficiency is suspected, the Table 1. It may not be difficult to surmise potential magne- diagnosis can still be missed since the routine practice is to sium deficiency from an individual’s ‘‘modus vivendi’’ as assess serum magnesium concentrations, which can be nor- body stores are dependent on the balance between daily mal despite whole body deficiency. This is not surprising intake and renal loss. Approximately 30%–70% of dietary because magnesium in the circulation does not represent total magnesium intake is absorbed by a healthy gut with a neg- body magnesium, being only 1% or less of total body con- ative magnesium store, with high gastric acidity enhancing tent. In addition, magnesium in serum is subdivided into absorption (13, 14). The commonly recommended daily three heterogeneous fractions: magnesium-bound to albumin intake for adults is 320–400 mg/day or 6 mg/kg/body weight (;30%), a fraction loosely complexed with anions, such as for both genders (13–15). An average healthy daily diet sup- phosphate, citrate and bicarbonate (;20%) and a free ion- plies ;250 mg of magnesium (120 mg per 1000 calories) ised fraction. The latter represents ;50% of total serum with green vegetables, cereals, fish and nuts being a rich magnesium and is mistakenly regarded by some to be the source (Table 2). Refined grains and white flour are generally biologically active moiety i.e., analogous to ionised calcium.
However, unlike calcium the bulk of magnesium is intracel- Another important source is water (16), with some hard lular, bound to numerous subcellular components, and these tap water containing 5–25 times more magnesium than soft are the moieties which account for its biological role. Thus, water, averaging ;6 mg/L. Local water suppliers can pro- it is intracellular bound magnesium which accounts for its vide information regarding magnesium concentration in tap primary biological role, and normal serum magnesium, total water in each location (e.g., postcode area in the UK). The or ionised, must be interpreted with caution (7).
content of magnesium in bottled water also varies greatly, Dynamic studies involving the intravenous administration from 0 to 126 mg/L (17). Carbonated tonic and soda water of an elemental magnesium load (as sulphate or chloride), contain little or no magnesium. One gram of instant coffee followed by assessment of the amount of elemental magne- granules release ;5 mg of magnesium in hot water; the cor- sium excreted in the urine in the following 24 h, are valuable responding figure for tea is ;0.6 mg (18). Unrefined sea salt (8–12). Deficiency is present if -90% of the administered is very rich in magnesium, present at ;12% of the mass of magnesium load is excreted in the urine. This is because a sodium. However, because this makes raw sea-salt bitter, larger fraction of the given magnesium load is retained and magnesium, as well as calcium, are removed, making puri- therefore a smaller amount of the given dose appears in the fied table salt essentially ;99% sodium chloride.
urine. Such a procedure, though valuable, accurate and Significant magnesium deficiency has been reported in informative, is time consuming and rarely used in clinical both self-caring elderly individuals, as well as in hospitalised practice. Also, it is contraindicated in individuals with renalimpairment.
Factors contributing to chronic magnesium deficiency.
Low serum magnesium, with normal albumin in a fasting or random sample indicates deficiency and warrants supple- Age; elderly absorb less and lose more magnesium mentation. However, normal magnesium concentrations must not be used to exclude deficiency. In cases with a high index Soft drinking water, bottled or hard water low in magnesium of suspicion, the only reliable biochemical test is the mag- nesium loading test, performed in patients with normal renal Regular alcohol intake esp. spiritsMalabsorption (also short bowel syndrome/intestinal surgery) function, as it is the only physiological ‘‘gold standard test’’ within the capability of all routine hospital laboratories.
Ismail et al.: Limitation of serum magnesium measurement Clinical Features of magnesium deficiency
Magnesium-rich food contains )100 mg per measure. A measure We reviewed peer reviewed articles on magnesium published is a cup of vegetables, grains, legumes or 2 oz (or 56 g) of nutsand seeds.
in English between 1990 and 2008 in MEDLINE and Vegetables: Green and leafy e.g., spinach, seaweed and artichoke EMBASE using database keywords ‘‘magnesium, deficiency, diagnosis, treatment and hypomagnesaemia’’. The biblio- Grains: Barley, wheat, oat, bran (whole grain bread) graphies of retrieved articles were searched and reviewed. In addition, we also performed a manual search of each indi- Nuts: Almond, Brazil, cashews, pine, peanuts (peanut butter) vidual issue of the major clinical and biochemical journals Seeds: (Dried) Pumpkin, sunflower, watermelon in which most of these reports have appeared.
Clinically, magnesium deficiency may present acutely or Intermediate values of magnesium are present in other vegetables, with chronic latent manifestations. Clinical presentation of fruits, meats, dairy products and fish.
chronic magnesium deficiency may vary from vague andnon-specific symptoms to causing and/or exacerbating theprogression of wide range of diseases, such as cardiovascularpathology (CVS), primary hypertension and diabetes type 2.
Norwegians (19). In a survey involving 37,000 Americans, Magnesium is a physiological calcium antagonist in skel- 39% were found to ingest -70% of the recommended daily etal and smooth muscle, promoting relaxation whereas cal- magnesium intake (20) and 10% of women over the age of70 years consume -42% of the recommended dietary cium stimulates contraction. A high calcium/magnesium requirement. When dietary magnesium intake is poor, the ratio caused by magnesium deficiency and/or high calcium kidney can compensate by increasing fractional reabsorption.
intake may affect this finely regulated homeostatic balance However, prolonged periods of poor dietary intake will even- and may be a factor in the increased risk of cardiovascular tually lead to a decline in intracellular magnesium con- events in patients receiving calcium supplementation (25, 26). Magnesium deficiency is present in almost all patients Another common cause of negative magnesium stores is with hypokalaemia and those with magnesium-dependent excessive renal loss. Alcohol is a known cause, being a mag- nesium diuretic; even moderate amounts can produce magne- A growing body of literature has demonstrated a wide siuresis. Alcohol increases urinary magnesium loss above pathological role for magnesium deficiency. In 183 peer baseline by an average of 167% (range 90%–357%). This reviewed studies published from 1990 to 2008, magnesium effect is rapid (21–23) and even occurs in individuals who deficiency was associated with increased risk and prevalence already have a negative magnesium balance (22). Alcohol for the 11 conditions listed in Table 3 (irrespective of the consumption has increased due to its being readily available nature, design, parameters, size and statistical approach of and with low cost (24). Taken in moderate amounts, alcohol these studies). Such an inverse relationship was also demon- consumption is considered socially and culturally acceptable strable irrespective of the wide range of methods used to (taken as 2–4 units’ i.e., 16–32 g of alcohol a day, though assess magnesium body stores. Because it would be difficult there is no standard definition). It may be of interest to point to be prescriptive (being outside the scope of this review), out that spirits, such as gin, rum, brandy, cognac, vodka and these references are indicated in Table 3 for each of these whisky contain little or no magnesium; fermented apple ciders have 10–50 mg/L of magnesium, while beer and wine Similarly, in 68 studies over the same period, magnesium have concentrations ranging from ;30–250 mg/L. Although deficiency was found to predict adverse events and a reduced drinks, such as some ciders, beer and wine may be consid- risk of pathology was noted when supplementation or treat- ered ‘‘magnesium-rich’’, they cannot be recommended as a ment was instituted. In a recent study (28), a direct aetiolo- reliable source of magnesium. In addition, consumption of gical link between magnesium deficiency, impaired glucose large volumes of magnesium rich beer and wine can have a tolerance and CVS was demonstrated. In this study, 13 post- significant laxative effect, potentially impeding bioavailabil- menopausal American women (12 Caucasian and 1 African- American) volunteered to reduce their dietary magnesium Therefore, it seems reasonable to suggest that a lifestyle intake to approximately one-third of the recommended daily associated with low dietary magnesium intake in food and requirement (average 101 mg/day). In -3 months, five sub- drinking water, purified table salt for cooking and in food, jects had cardiac rhythm abnormalities and three exhibited coupled with moderate and regular consumption of alcoholic atrial fibrillation or flutter that responded quickly to mag- drinks that cause net renal magnesium loss, can lead to neg- nesium supplementation (28). Furthermore, impaired glucose ative balance over time. Potential magnesium deficiency can homeostasis was found in 10 volunteers who underwent an further be compounded with malabsorption; medications, intravenous glucose tolerance test (IV GTT). The clinical such as diuretics (loop and thiazide), proton pump inhibitors manifestation in these patients was reflected in reduced con- (omeprazole), tacrolimus, chemotherapeutic agents, such as centrations in red cell membranes, although serum concen- cisplatin, cyclosporin and some phosphate-based drugs.
trations remained within the reference range (28). This study, 326 Ismail et al.: Limitation of serum magnesium measurement Conditions associated with magnesium deficiency.
Electrolytes (1–23): Hypocalcaemia
CVS (24–152):
The commonly used serum magnesium is potentially flawed Treatment is straightforward and clinically beneficial superventricular tachycardias (SVTs),Abnormal vascular tone, congestivecardiac failure supplement when renal function is normal. This is because Ischaemic heart disease, cardiac surgery, magnesium excretion can exceed 100% of the filtered load when the intake is above normal, achieved by reduced Hypertension (153–200): Pre-eclampsia/eclampsia, primary
absorption from the gut plus minimal or no renal re-absorp- Diabetes (201–262): Type 2 diabetes mellitus
It is of interest that net magnesium absorption rises with Metabolic syndrome (263–269): The Metabolic syndrome
increasing intake. However, fractional absorption falls as Osteoporosis (270–309): Bone mineral density and osteoporosis
magnesium intake increases (e.g., from 65% at 40 mg intake Musculoskeletal (310–326): Muscle weakness, fatigue,
to 11% at 960 mg). Magnesium absorption from the gut is numbness, tingling, spasms/cramps/tetany, fibromyalgia slow, with ;80% of oral magnesium being absorbed within Neurological (327–352): Irritability, depression, migraines,
strokes, vertical and horizontal nystagmus
Cancer (353–361): Colorectal
Alcoholics (362–383): Exhibiting any of the described
manifestations
Conclusions
Respiratory (384–431): Asthma
The numbers between brackets are additional references published Serum magnesium is a useful test because low serum con- from 1990 to 2008 for each entity, see Supplemental data.
centrations indicate significant deficiency warranting re-placement. However, normal magnesium concentrationsmust not be used to exclude negative body stores. Modus though small, is consistent with epidemiological surveys, vivendi has an important role in identifying at risk patients, supplementation trials and animal studies (29, 30).
such as adults living in areas with soft drinking water orhard water with low magnesium content, plus the other fac- Biochemical monitoring of magnesium therapy
tors listed in Table 1, notably diet and diuretics. Magnesiumstatus should always be considered in cases such as electro- Magnesium supplementation has low toxicity in people with lyte disturbances (hypocalcaemia and/or hypokalaemia), normal renal function. However, deficiency may not be cor- arrhythmias, especially Torsades de Pointes, regular or exces- rected through nutritional supplementation only. The most sive alcohol intake and muscular spasms/cramps in both nor- common therapeutic modalities are intravenous infusion in mocalcaemic and hypocalcaemic patients. However, for the patients with depletion manifesting as significant hypomag- other conditions listed in Table 3, it is important that patients nesaemia; and orally (occasionally subcutaneously) for indi- at risk in each category are identified.
viduals requiring long-term supplementation.
The inaccuracy of serum magnesium as a biomarker of Intravenous magnesium (up to ;30 mmol of elemental negative body stores, although well known among labora- magnesium; 1 mmols24 mg) is given over a period of torians, is not widely disseminated nor emphasised to clini- hours. A slow rate infusion is important because plasma cians. The perception that ‘‘normal’’ serum magnesium magnesium concentrations affect the renal reabsorption excludes deficiency is not uncommon among clinicians, and threshold, and abrupt increases in plasma concentrations this has contributed to under-diagnosis of chronic deficiency above the normal range would reduce magnesium retention (Table 4). Based on literature in the last two decades, mag- and increases urinary excretion with its potential misinter- nesium deficiency remains common and undervalued, war- pretation. Magnesium body stores are considered repleted ranting a proactive approach by the laboratory because when )90% of an elemental magnesium load is excreted in restoration of magnesium stores is simple, tolerable, inex- a 24-h urine. Other analytes which may be associated with pensive and can be clinically beneficial.
magnesium deficiency are calcium, potassium, phosphateand vitamin D (31).
Supplementary data associated with this article can be found in the online version at: http://www.reference-global.com/doi/suppl/ Common oral magnesium supplements exist in two forms: chelated and non-chelated. In the chelated form, magnesiumis attached to organic radicals. In the non-chelated form,magnesium is in the form of sulphate, chloride or oxide.
Acknowledgements
Magnesium attached to aminoacid radicals appears to be bet-ter tolerated. Generally, toxic concentrations are unlikely to We are grateful to the following colleagues with whom we discussed occur in patients receiving the recommended oral magnesium the contents of this review and made a number of pertinent com- Ismail et al.: Limitation of serum magnesium measurement ments and advice; Prof. A. Al-Din (Neurology), Dr. M. Galvin (Hae- trients and other dietary constituents: United States 1988–94.
matology), Dr. P. Gajjar (General practice and Palliative medicine); Vital Health Stat 11. 2002;245:1–158.
Dr. N. Haboubi (Chemical Pathology); Mr. D. Hutchinson (Sur- 15. Nielsen FH, Lukaski HC. Update on the relationship between gery); Dr. T. Lench (General Practice); Dr. R. MacFaul (Paediatric); magnesium and exercise. Magnesium Res 2006;19:180–9.
Mr. Y. Mashhour (Cardio-thoracic surgery); Dr. S. Smellie (Chem- 16. Rubenowitz E, Axelsson G, Rylander R. Magnesium in drink- ical pathology); Dr. D. Walls (Gastroenterology).
ing water and body magnesium status measured by an oralloading test. Scand J Clin Lab Invest 1998;58:423–8.
17. Garzon P, Mark J, Eisenberg MJ. Variation in the mineral Conflict of interest statement
content of commercially available bottled waters: implicationsfor health and disease. Am J Med 1998;105:125–30.
18. Gillies ME, Birbeck JA. Tea and coffee as source of some Authors’ conflict of interest disclosure: The authors stated that
minerals in the New Zealand diet. Am J Clin Nutr 1983;38: there are no conflicts of interest regarding the publication of this 19. Gullestad L, Nes M, Ronneberg R, Midtvedt K, Falch D, Research funding: None declared.
Kjekshus J. Magnesium status in healthy free-living elderly Employment or leadership: None declared.
Norwegians. J Am Coll Nutr 1994;13:45–50.
Honorarium: None declared.
20. Costello RB, Moser-Veillon PB. A review of magnesium intake in the elderly. A cause for concern? Magnesium Res1992;5:61–7.
References
21. Rylander R, Megevand Y, Lasserre B, Granbom AS. Moderate alcohol consumption and urinary excretion of magnesium andcalcium. Scand J Clin Lab Invest 2001;61:401–5.
1. Touyz RM. Transient receptor potential melastatin 6 and 7 22. Rivlin RS. Magnesium deficiency and alcohol intake: mech- channels magnesium transport and vascular biology: impli- anisms, clinical significance. J Am Coll Nutr 1994;13:416– cations in hypertension. Am J Physiol Heart Circ Physiol 23. Kalbfleisch JM, Linderman RD, Ginn HE, Smith WO. Effects 2. Laires MJ, Monteiro CP, Bicho M. Role of cellular magne- of ethanol administration on urinary excretion of magnesium sium in health and human disease. Front Biosci 2004;9: and other electrolytes in alcoholics and normal subjects. J Clin 3. Alexander RT, Hoenderop JG, Bindels R. Molecular deter- minants of magnesium homeostasis: insights from human dis- 24. Sheron N. Alcohol in Europe: the EU alcohol forum. Clin ease. J Am Soc Nephrol 2008;19:1451–8.
4. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in rela- 25. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, tion to risk of colorectal cancer in women. J Am Med Assoc Ames R, et al. Vascular events in healthy older women receiv- ing calcium supplementation: randomised controlled trial. Br 5. Rude RK. Magnesium deficiency: a cause of heterogeneous disease in humans. J Bone Miner Res 1998;13:749–58.
26. Rowe WJ. Calcium-magnesium-ratio and cardiovascular risk.
6. Huang CL, Kuo E. Mechanism of hypokalaemia in magne- sium deficiency. J Am Soc Nephrol 2007;18:2649–52.
27. Loughrey C. Serum magnesium must also be known in pro- 7. Franz KB. A functional biomarker is needed for diagnosing found hypokalaemia. Br Med J 2002;324:1039.
magnesium deficiency. J Am Coll Nutr 2004;23:738S–41S.
28. Forrest H, Nielson DB, Milne LM, Klevay SG, LuAnn J. Die- 8. Ismail AAA. Disorders of parathyroid hormone, calcitonin tary magnesium deficiency induces heart rhythm changes, and vitamin D metabolism. In: Biochemical investigation in impairs glucose tolerance and decrease serum cholesterol in post-menopausal women. J Am Coll Nutr 2007;26:121–32.
9. Goto K, Yasue H, Okumura K, Matsuyama K, Kugiyama K, 29. Fung TT, Manson JE, Solomon CG, Liu S, Willett WC, Hu Miyagi H, et al. Magnesium deficiency detected by iv loading FB. The association between magnesium intake and fasting test in varient angina pect. Am J Cardiol 1990;65:709–12.
insulin concentration in healthy middle-aged women. J Am 10. Seyfert T, Dick K, Renner F, Rob PM. Simplification of the magnesium loading test for use in outpatients. Trace metals 30. Rumawas ME, McKeown NM, Rogers G, Meigs JB, Wilson PW, Jacques PF. Magnesium intake in relation to improved 11. Gullestad L, Midtvedt K, Dolva LO, Narseth J, Kjekshus J.
insulin homeostasis in the Framingham offspring cohort. J Am The magnesium loading test: reference value in healthy sub- jects. Scand J Clin Lab Invest 1994;54:23–31.
31. Bringhurst FR, Demay MB, Krane SM, Kronenberg HM.
12. Gullestad L, Dolva LO, Waage A, Falch D, Fagerthun H, Bone and mineral metabolism in health and disease. In: Fauci Kjekshus J. Magnesium deficiency diagnosed by an intrave- AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jame- nous loading test. Scand J Clin Lab Invest 1992;52:245–53.
son JL, Loscalzo J, editors. Harrison’s principles of internal 13. Ford ES, Mokdad AH. Dietary magnesium intake in a national medicine, 17th ed. Publ McGraw Hill Medical, 2008:2372–3.
sample of U.S. adults. J Nutr 2003;133:2879–82.
32. Graham LA, Caesae JJ, Burgen AS. Gastrointestinal absorp- 14. Bialostosky K, Wright JD, Kennedy-Stephenson J, McDowell tion and excretion of magnesium in man. Metabolism 1960; M, Johnson CL. Dietary intake of macronutrients, micronu- Copyright of Clinical Chemistry & Laboratory Medicine is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

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