Calcium-Alkali Syndrome: When Calcium and Antacids Raise Blood Calcium and Alkalinity

Table of Contents

1. The Three Findings That Define the Syndrome
2. From the Sippy Ulcer Diet to Burnett's Syndrome
3. How the Cause Moved From Milk to Calcium Carbonate
4. How Often Hospitals Find It Among High-Calcium Patients
5. How Kidney Injury and Alkalosis Feed Each Other
6. The Calcium Amounts the Reports Describe
7. Who Appears in the Published Reports
8. Symptoms and Complications in Published Cases
9. Why the Diagnosis Is Easy to Miss
10. What Reports Describe in Recovery
11. What Remains Uncertain
12. Key Research Papers
13. Connections
14. Featured Videos

The Three Findings That Define the Syndrome

Reviews and case reports use the same three-part definition, often called a triad (Patel, Adeseun and Goldfarb 2013; Medarov 2009):

• High blood calcium, called hypercalcemia. Laboratories place normal calcium at about 8.8 to 10.8 mg/dL (Rehan 2020). Published cases of this syndrome reach far beyond that: 15.9 mg/dL in a 46-year-old man (Ulett 2010), 22 mg/dL in a man brought in with reduced consciousness (Jenkins 1987) and in a pregnant woman of 32 (Picolos 2004), and 23 mg/dL in a woman who had recently had parathyroid surgery (Rehan 2020).
• Metabolic alkalosis. This means the blood is too alkaline because bicarbonate has risen, with a higher arterial pH and slower breathing as the body tries to compensate (Do 2022). A blood pH of 7.46 with a bicarbonate of 40 mmol/L was recorded in one 2020 case (Wang 2020), and a pH of 7.59 in another (Rehan 2020).
• Kidney injury. The damage ranges from a mild, temporary dip to failure severe enough to need dialysis. In a Louisiana series of five patients with six episodes, all three findings were present and two patients needed dialysis (Abreo 1993).

The name matters to the people who study it. A 2010 review in the Journal of the American Society of Nephrology argued for dropping "milk-alkali" because the new term better reflects who gets the illness and why (Patel and Goldfarb 2010). A 2021 review traces the proposal for the name back to 2000 and states that the old term, tied to a historic ulcer treatment, may lead to missed or delayed diagnoses (Zayed 2021). The two names describe the same illness, and much of the research still uses the older one.

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From the Sippy Ulcer Diet to Burnett's Syndrome

In 1915 the American physician Bertram Sippy introduced a treatment for peptic ulcers built on the idea of neutralizing stomach acid. Patients took milk and cream every hour along with "Sippy powders," mixtures of sodium bicarbonate with calcined magnesia or bismuth subcarbonate. A daily regimen could deliver about 32 grams of sodium bicarbonate and 10 to 32 grams of calcium carbonate, which works out to 4 to 13 grams of elemental calcium (Patel, Adeseun and Goldfarb 2013). It became the standard treatment for ulcers (Zayed 2021).

Trouble was noticed within a few years.

• 1923. Hardt and Rivers described irritability, headache, dizziness, nausea, vomiting, muscle pain, weakness and apathy in 16 of 32 patients on the Sippy regimen, along with raised blood urea nitrogen and bicarbonate. Most recovered quickly after stopping, and one died of what the authors called subacute nephritis (Fiorino 1996). A later review gives 1923 as the year the syndrome was first identified (Orwoll 1982).
• 1920s and 1930s. Reports from these decades put the frequency of toxic reactions on the regimen between 2% and 18%, with a mortality rate of 4.4%, according to a 2021 review of that era's papers. In one study of 1,350 ulcer patients, 8% developed the syndrome (Zayed 2021).
• 1930s. Cope linked the regimen to high calcium, alkalosis and kidney injury, and found that the imbalances could clear completely when treatment stopped. Reviews date this work differently, to 1934 and to 1936 (Fiorino 1996; Zayed 2021).
• 1949. Burnett, Commons, Albright and Howard reported six men who had taken large amounts of milk and absorbable alkali for 2 to 30 years. They had high calcium, alkalosis, kidney insufficiency and calcium deposits in the cornea, lungs, lymph nodes and other soft tissues. Stopping brought blood calcium back to normal and improved kidney function only partly, and four of the six died (Burnett 1949, as summarized in Fiorino 1996 and Zayed 2021).
• 1965. McMillan and Freeman randomly assigned 40 men, most with a history of ulcers, to milk with either calcium carbonate or an aluminum or magnesium antacid. On average the men took about 1.5 liters of milk a day, and those in the carbonate group took about 28 grams of calcium carbonate a day. Blood calcium, phosphate, creatinine and bicarbonate rose significantly more in the calcium carbonate group, and one man developed the syndrome, which subsided after the regimen stopped (McMillan and Freeman 1965, as summarized in Fiorino 1996).

From this era come the three classic forms still quoted today. The acute or "toxemic" form could begin within days to a month of starting and cleared on withdrawal. The intermediate form, Cope's syndrome, came from longer, intermittent use and improved gradually, sometimes leaving mild kidney impairment. The chronic form, Burnett's syndrome, followed years of intake, with calcium deposits in the eye and other tissues, and its kidney damage usually persisted (Orwoll 1982; Patel, Adeseun and Goldfarb 2013; Zayed 2021).

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How the Cause Moved From Milk to Calcium Carbonate

The illness nearly disappeared as ulcer care changed. Antacids that are not absorbed came first, followed by histamine-2 blockers and proton pump inhibitors, which lower stomach acid instead of neutralizing it (Zayed 2021; Medarov 2009; Arroyo 2013). A 1975 report found the syndrome in fewer than 1% of cases of high calcium, and rates stayed under 2% through the 1970s and 1980s (Zayed 2021).

Then it returned in a different form. Calcium carbonate came to be promoted for both indigestion and osteoporosis, and in the early 1990s clinicians in Oklahoma, Louisiana and elsewhere began reporting a rise (Beall and Scofield 1995; Abreo 1993). Heart and heart-lung transplant recipients at one California center gave an early warning in 1986: they were routinely prescribed calcium carbonate at 4 to more than 10 grams of elemental calcium a day to protect against ulcers and bone loss. Of 297 recipients, 65 developed significant high calcium, 31 of them were alkalotic at the time, and 37 had impaired kidney function (Kapsner 1986).

The modern version differs from the old one in several ways (Beall 2006; Zayed 2021; Patel, Adeseun and Goldfarb 2013):

• The source. Pooled data from 53 cases reported between 1983 and 2004 showed all of them taking calcium carbonate, with only a minority consuming large quantities of milk.
• The patients. The classic patient was a younger man with an ulcer. Modern reports describe mainly postmenopausal women, pregnant women, people with bulimia, transplant recipients and people on dialysis.
• The phosphate level. Milk and cream are rich in phosphate, and the classic syndrome featured normal or raised blood phosphate. Calcium carbonate binds phosphate in the gut, so modern cases tend to show low or low-normal levels.
• The way it comes to light. Classic cases usually had obvious symptoms. Many modern cases are found by chance when blood work is done for another reason.

Calcium carbonate is about 40% elemental calcium, so the amount of "calcium carbonate" and the amount of "calcium" are two different numbers (Patel, Adeseun and Goldfarb 2013). The figures below say which one is meant.

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How Often Hospitals Find It Among High-Calcium Patients

The true incidence is unknown (Patel, Adeseun and Goldfarb 2013). What exists are single-center chart reviews, each counting a slightly different group of patients:

• Oklahoma, published 1995. The syndrome accounted for less than 2% of admissions for high calcium before 1990 and over 12% from 1990 through 1993. Only primary hyperparathyroidism and cancer-related high calcium, excluding multiple myeloma, were more common (Beall and Scofield 1995).
• Texas, November 1998 to October 2003. Among 125 inpatients with high calcium and without end-stage kidney disease, 11 (8.8%) had the syndrome, compared with 42 (33.6%) with cancer and 37 (29.6%) with hyperparathyroidism. Among the 35 with severe high calcium, defined as a corrected calcium of 3.5 mmol/L (about 14 mg/dL), cancer accounted for 13 (37.1%) and milk-alkali syndrome for nine (25.7%). That made it the third most common cause overall and the second most common cause of severe cases (Picolos 2005).
• South Carolina, published 2015. Over three years, 15 of 72 patients (20.8%) whose high calcium was not driven by parathyroid hormone met all the criteria. The authors called it "calcium supplement syndrome" (Machado 2015).

These figures use different denominators, and the 20.8% applies only to patients in whom parathyroid disease had been set aside, so they cannot be lined up as a trend. The statement that the syndrome is the third most common cause of hospital admission for high calcium is repeated across later reviews and case reports (Patel and Goldfarb 2010; Wang 2020), and the studies counted here are small. In parts of Asia and the South Pacific where betel nut is chewed with a lime paste, one review reports a prevalence of 9% to 12% and the same third-place ranking (Zayed 2021).

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How Kidney Injury and Alkalosis Feed Each Other

A healthy body has defenses against a calcium load. Rising blood calcium switches off parathyroid hormone, which slows the release of calcium from bone and lowers active vitamin D, which in turn reduces calcium absorption from the gut. The kidneys also dump excess bicarbonate with great efficiency (Patel, Adeseun and Goldfarb 2013; Do 2022). The syndrome develops when these defenses are overwhelmed, and a 2009 review describes what follows as "a self-reinforcing cycle" between high calcium and alkalosis in the kidneys, while noting that the exact mechanism remains uncertain (Medarov 2009).

The steps described in the reviews run roughly like this (Patel, Adeseun and Goldfarb 2013; Zayed 2021; Patel and Goldfarb 2010; Do 2022):

1. High calcium narrows the kidney's blood vessels. Less blood is filtered, so less calcium is filtered out and removed in the urine.
2. High calcium makes the kidneys waste salt and water. Calcium acts on sensing receptors in the kidney tubule with an effect the 2013 review compares to the diuretic furosemide. It also blocks the action of the water-retaining hormone vasopressin. The result is heavy urination, thirst and shrinking blood volume.
3. Low blood volume holds on to bicarbonate. Volume contraction, low filtration, low potassium and low chloride are among the factors that stop the kidney from getting rid of bicarbonate (Do 2022). The alkali from the calcium carbonate therefore stays in the blood.
4. Low blood volume also holds on to calcium. The kidney's early segments reabsorb more calcium along with salt and water, returning it to the blood.
5. Alkalosis pushes calcium back in as well. A more alkaline fluid in the tubules sensitizes the TRPV5 calcium channel in the distal kidney, enhancing reabsorption of calcium there. Alkalosis also makes the calcium-sensing receptor more sensitive, which worsens the salt and water loss.
6. The loop closes. Each round raises calcium, lowers filtration and deepens the alkalosis.

Continued calcium and alkali intake keeps feeding the loop from outside. Over time, long-standing reduced blood flow can cause permanent damage, and calcium can settle in the kidney itself, a finding called nephrocalcinosis (Patel, Adeseun and Goldfarb 2013). A small 1976 biopsy report of three patients related the degree of kidney impairment to the structural changes seen under the microscope (Junor and Catto 1976).

This loop also explains why other things can tip someone over. Vomiting, for example, causes fluid loss and alkalosis, and reports link it to bulimia and to pregnancy (Patel, Adeseun and Goldfarb 2013). Thiazide diuretics promote volume loss and alkalosis, and the 2013 review lists medicines that lower filtration, such as blockers of the renin-angiotensin system and non-steroidal anti-inflammatory drugs, as predisposing factors (Patel, Adeseun and Goldfarb 2013). One group proposed the name "calcium alkali thiazide syndrome" for the subset of patients also taking a thiazide (Rehan 2020).

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The Calcium Amounts the Reports Describe

The old threshold was high. Intake above 4 grams of calcium a day was generally considered the amount that predisposes someone to the syndrome, and one review says that when intake reaches 10 to 15 grams a day, the body's calcitriol suppression can no longer keep the blood level normal (Patel, Adeseun and Goldfarb 2013; Zayed 2021).

Later reports describe much lower amounts in susceptible people:

• Reports of the syndrome at 1 to 1.5 grams of calcium supplementation a day, within the range of many dietary guidelines (Patel, Adeseun and Goldfarb 2013; Wang 2020).
• Three Texas patients with blood calcium of 14 mg/dL or more, two of whom were taking 1 gram and 2 grams of elemental calcium a day as calcium carbonate (Picolos and Orlander 2005).
• A woman taking about 1,800 mg of elemental calcium a day from antacids over a long period, along with a blood pressure medicine, who had severe high calcium, kidney impairment and a staghorn kidney stone (Maarouf and Jones 2020).

These figures come with a stated caveat. Calcium intake in these reports is self-reported and may be inaccurate, and the lower threshold may partly reflect higher vitamin D use, which increases calcium absorption (Patel, Adeseun and Goldfarb 2013). Case reports also cannot show how many people take the same amount without any problem.

For comparison, the 2013 review reports the US Institute of Medicine's view that the risk of harm rises when calcium intake passes 2,000 mg a day and vitamin D intake passes 4,000 IU a day. The same review gives total intake from food and supplements below 1.2 to 1.5 grams a day as the figure generally cited for preventing the syndrome, together with leaving out absorbable alkali. It also reports that equal doses of calcium from dairy products raise blood calcium less than supplements do (Patel, Adeseun and Goldfarb 2013).

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Who Appears in the Published Reports

The Texas hospital series found that women predominated, and that high blood pressure, chronic kidney disease, osteoporosis, upper digestive disease, diuretic treatment and vitamin D use were common among those affected (Picolos 2005). Beyond that, the case literature groups into several patterns.

• Heartburn self-treatment. A 78-year-old woman using large amounts of calcium carbonate tablets for recent heartburn (Arroyo 2013), a 74-year-old woman using excess antacid for worsening heartburn (Timilsina 2018), and a 65-year-old woman after two weeks of heavy antacid use for abdominal discomfort (Wang 2020).
• Bone-health supplements. The modern syndrome has been described in women taking calcium carbonate to prevent osteoporosis, and a 2010 review places postmenopausal and pregnant women at greatest risk (Waked 2009; Patel and Goldfarb 2010).
• Pregnancy. Absorption of calcium rises in pregnancy, and vomiting adds alkalosis and fluid loss (Patel, Adeseun and Goldfarb 2013). Reported cases include a 26-year-old in her second trimester taking milk, calcium carbonate antacid and calcium-containing prenatal vitamins (Kolnick 2011); a 28-year-old, 14 weeks pregnant with twins, who needed intensive care and dialysis (Beamish 2024); and a patient treated with dialysis whose baby was born a month later with an uncomplicated newborn course (Kleinman 1991).
• Betel nut chewing. Two patients in Taiwan were estimated to have taken in 9 grams and 6 grams of calcium carbonate a day from the oyster-shell paste used to prepare the nut (Wu 1996).
• Prescribed combinations. A 73-year-old man taking the active vitamin D drug alfacalcidol and a thiazide diuretic developed the same picture without taking calcium or alkali (Satoh 2010). An 85-year-old woman on 14 drugs, including a calcium salt, the vitamin D drug eldecalcitol, a thiazide and then furosemide, developed it without any absorbable alkali preparation (Mizutani 2023).
• Unexpected sources. A 64-year-old woman's recurrent high calcium was eventually traced to nicotine-replacement gum and carbonated water (Swanson 2013). An 83-year-old man had been drinking 1.5 to 2.0 liters of calcium-rich thermal water a day for years, and all his values returned to normal after he stopped (Czirok 2025).

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Symptoms and Complications in Published Cases

Many of the complaints are those of high calcium in general, which are covered on the fatigue and confusion, thirst and bone pain and constipation and digestive pages. In the reports specific to this syndrome the following recur: weakness, malaise and confusion (Arroyo 2013); lethargy, poor appetite and abdominal pain (Timilsina 2018); muscle aches (Wang 2020); nausea, vomiting, numbness and difficulty walking (Rehan 2020); flank pain, headache and lightheadedness (Kolnick 2011); and, in some people, nothing at all until blood work is done (Zayed 2021).

Less common and more serious events in the reports include:

• Seizures. Two patients with no epilepsy risk factors had prolonged seizures, called status epilepticus, probably induced by high calcium, and later developed persistent seizures with scarring on brain scans. The authors note that the link to the scarring may be a coincidence (Dinnerstein 2008).
• Heart rhythm changes. A man at 22 mg/dL had J waves, a broad T wave and a U wave on his electrocardiogram, along with a longer QT interval rather than the usual shorter one. All of it reverted to normal when the calcium was corrected (Jenkins 1987).
• Pancreatitis. Inflammation of the pancreas has been reported with this syndrome, though the link between high calcium and pancreatitis is described as controversial (Brandwein and Sigman 1994; George and Clark 2000).
• Calcium in soft tissues. A 45-year-old woman with long-term use of alkaline medicines and furosemide had calcium deposits in her lungs and stomach, presenting with cough and breathlessness (Yamagami 2013).
• Pregnancy emergencies. Severe high calcium in pregnancy is described as a potentially life-threatening medical emergency (Picolos 2004).

Hospitals treat severe high calcium as urgent, particularly with confusion, drowsiness, seizures, heart rhythm changes or failing kidneys. In metabolic alkalosis generally, a blood pH of 7.55 or higher in critically ill patients is associated with a significantly increased death rate (Do 2022).

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Why the Diagnosis Is Easy to Miss

Nearly every paper on the subject makes the same point: the diagnosis depends on the history. A 1995 report says it is made "almost entirely" from what the patient has been taking, and that this requires asking about diet and over-the-counter products, since many contain calcium carbonate (Beall and Scofield 1995). A Louisiana series noted that patients and physicians alike are often unaware of the calcium and alkali content of nonprescription medicines (Abreo 1993).

The reports show what happens when that question goes unasked. A 50-year-old man was admitted twice with severe high calcium, and extensive tests on the first admission found no cause. A thorough history on the second admission supplied the answer (Swaminathan 2011). A 74-year-old woman had an extensive workup, which was unrevealing, before further questioning turned up the antacid (Timilsina 2018).

The chief confusion is with primary hyperparathyroidism, a much more common cause of high calcium. The usual dividing line is parathyroid hormone: in calcium-alkali syndrome it is typically suppressed, in hyperparathyroidism high. Modern assays show that expected suppression, but timing matters, since within hours or days of treatment the hormone can rebound and read high (Beall and Scofield 1995; Zayed 2021). Older assays could also mislead, particularly with kidney failure (Abreo 1993; Patel, Adeseun and Goldfarb 2013). About 10% of reported cases went through unnecessary parathyroid exploration or testing, according to the 2013 and 2021 reviews. In a 1983 surgical report, two of four patients had neck exploration and four normal glands were found in each (Carroll and Clark 1983). That report lists high calcium, alkalosis alongside kidney impairment, a history of calcium and alkali intake, and a response to lowering dietary calcium as the features that help separate the two. The lab tests involved are covered on the parathyroid hormone and serum calcium pages.

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What Reports Describe in Recovery

Treatment in the reports is mostly supportive. A 2010 review lists restoring blood volume, raising kidney filtration and calcium excretion, and stopping calcium supplements as the best treatment (Patel and Goldfarb 2010). A 1982 review states that conservative treatment is usually effective, and a 2009 review calls it supportive, with fluids and withdrawal of the offending products (Orwoll 1982; Medarov 2009). The speed of recovery in the reports can be striking:

• Calcium, bicarbonate and kidney function all back to baseline after 5 days of intravenous saline in a 78-year-old woman (Arroyo 2013).
• Discharge on hospital day 5 with normal calcium and creatinine after a blood calcium of 23 mg/dL, treated with intravenous fluids and furosemide (Rehan 2020).
• In the South Carolina series, all 15 patients received intravenous fluids and six (40%) received calcium-lowering drugs. Calcium was normal at discharge in 12 (80%). Mean creatinine fell from 2.4 to 1.6 mg/dL, and mean bicarbonate from 35 to 25.6 (Machado 2015).

Two parts of the recovery stand out as unusual.

The calcium can overshoot downward. Once the calcium source is gone, the suppressed parathyroid glands can take time to catch up, and calcium can drop too low. Saline alone may be enough to cause low calcium with a rebound rise in parathyroid hormone, a pattern a 1995 report considered probably unique to this syndrome (Beall and Scofield 1995). Bone-targeting drugs make this more likely: in the Texas series, all five patients given bisphosphonates developed low calcium, compared with one of five given conventional treatment (Picolos 2005). Pamidronate at 60 and 30 mg caused severe low calcium in two other patients (Picolos and Orlander 2005), and a single intravenous dose led to symptomatic low calcium requiring calcium replacement in a 2020 case (Wang 2020).

Recovery is not always complete. A 1985 report contrasted one patient with an acute, reversible illness and another with a chronic course and only partly reversible kidney disease, and it stated that early identification could prevent progression to irreversible failure (Schuman and Jones 1985). The 2013 review states that about one-third of patients develop permanent impairment of kidney function, and the 2021 review gives a similar figure, over a third, from the pooled 53 cases (Patel, Adeseun and Goldfarb 2013; Zayed 2021). Those pooled cases come from published reports, which may lean toward the more severe. In a 2013 case, kidney values improved with saline, but the calcium deposits in the lungs did not shrink (Yamagami 2013). In a 1996 report, a 66-year-old man's calcium of 17.8 mg/dL returned to normal within days, while his creatinine fell from 5.7 mg/dL only into a range of 1.8 to 2.2 mg/dL. He then died three weeks after admission from later complications including sepsis (Fiorino 1996).

Calcium usually settles over several days, though the reviews note that it can take up to six months (Patel, Adeseun and Goldfarb 2013; Zayed 2021). In the 1983 surgical report, high calcium eventually resolved in all patients on a low-calcium diet, with some taking as long as six months (Carroll and Clark 1983). Dialysis is reported for the most severe cases, including during pregnancy, where calcium and kidney function then quickly normalized and stayed normal after calcium carbonate was stopped (Beamish 2024; Kleinman 1991).

Recurrence also appears in the reports when the source was not identified the first time (Swaminathan 2011; Swanson 2013).

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What Remains Uncertain

• How common it really is. The true incidence is unknown, and the frequency figures come from a few single-hospital chart reviews (Patel, Adeseun and Goldfarb 2013).
• Why some people and not others. Individual differences in calcium absorption, bone buffering and vitamin D handling are proposed, and some patients are described as "hyper-absorbers" (Zayed 2021).
• The exact mechanism. A 2009 review states that the mechanism remains uncertain, and a 2010 review points to calcium-sensing receptors and TRPV5 channels as the newer focus (Medarov 2009; Patel and Goldfarb 2010).
• The best treatment in older people. A 2015 review of the geriatric literature found few observational or randomized studies, and drew on four case-based studies (Malcolm 2015). Almost everything on this page rests on case reports and retrospective chart reviews. The only randomized study described in the reviews read for this page is the 1965 trial of milk with antacids.

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Key Research Papers

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PubMed Topic Searches

1. PubMed: calcium-alkali syndrome
2. PubMed: milk-alkali syndrome
3. PubMed: calcium carbonate antacids and high blood calcium
4. PubMed: how metabolic alkalosis develops

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Connections

• Hypercalcemia (High Calcium) — the parent page on all causes of high blood calcium
• Hypercalcemia: Kidney Stones — another kidney consequence of excess calcium
• Low Chloride: Metabolic Alkalosis — alkalosis driven by chloride loss
• Baking Soda (Sodium Bicarbonate) — the other classic absorbable alkali
• Peptic Ulcer Disease: History and Discovery — the era of the Sippy diet
• Acute Kidney Injury — the kidney side of the triad
• Primary Hyperparathyroidism — the condition this syndrome is most often mistaken for
• Vitamin D Toxicity: Hypercalcemia — a related route to high calcium

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