The dark side of the hypoxia response


Brain cell dysfunction in low oxygen is, surprisingly, caused by the very same responder system that is intended to be protective, according to a new published study by a team of researchers at the Case Western Reserve University School of Medicine.

“These powerful protein responders initially protect brain cells from low oxygen as expected, but we find that their prolonged activity leads to unintended collateral damage that ultimately impairs brain cell function,” said the study’s principal investigator Paul Tesar, a professor in the Department of Genetics and Genome Sciences at the Case Western Reserve School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics.

Defining the mechanism of brain-cell damage in low oxygen conditions provides an opportunity to develop effective therapies, including a class of drugs studied in their research that could inform future clinical approaches for many neurological diseases caused by low oxygen.

The work also clarifies how the response to low oxygen causes disease in other tissues outside the brain.

Their research was published online Oct. 21 in the journal Cell Stem Cell.

The body’s response to low oxygen

With the dawn of an oxygenated atmosphere, a burst of multicellular life was possible, as oxygen could be used to produce the energy needed to support complex life functions.

Given the requirement of oxygen for life, nearly all organisms evolved a mechanism to rapidly respond to low oxygen—a condition called hypoxia. The Noble Prize in Physiology or Medicine was awarded in 2019 for discoveries of how cells in our body sense low oxygen levels and respond to stay alive.

At the core of this ancient response are proteins called hypoxia-inducible factors (HIFs), which instruct the cell to minimize oxygen consumption and maximize their access to oxygen.

In this way, HIFs can be thought of as valiant heroes attempting to protect and resuscitate cells in the immediate response to low oxygen.

Prolonged hypoxia causes dysfunction in many tissues. In particular, stem cells in the brain are impaired by hypoxia in many diseases, including stroke, cerebral palsy related to premature birth, respiratory distress syndromes, multiple sclerosis and vascular dementia. Even the significant neurological damage caused by COVID-19 is attributed to hypoxia.

Until now, the precise causes of cell malfunction due to low oxygen were unknown.

The dark side of the hypoxia response

In this study, researchers developed a new approach to closely study how the hypoxia responder proteins function.

By comparing how they work in brain-stem cells with other tissues, such as heart and skin, the scientists confirmed that the hypoxia responder proteins perform a beneficial function to promote cell survival in low oxygen in all tissues.

However, these same hypoxia responder proteins had a previously unappreciated dark side, as they also switched on other cellular processes outside of the core beneficial response.

The team then demonstrated that this additional – and previously unknown – response is what impaired brain-stem cell function. This suggests that, while hypoxia responder proteins evolved to promote cell survival in all tissues of the body in low-oxygen conditions, their powerful effects can also have unintended consequences to disrupt cell function.

New opportunities for treating hypoxia damage

The authors tested thousands of drugs to try to restore brain-stem cell function to overcome the damaging effects of the hypoxia responder proteins. They discovered a group of drugs that specifically overcome the damage-inducing response, while leaving the beneficial response intact.

“One of the exciting avenues that stems from this work is identifying drugs that specifically target the damaging side of the hypoxia response while sparing the beneficial side,” said first author Kevin Allan, a graduate student in Case Western’s Medical Scientist Training Program. “This offers a new perspective on combating tissue damage due to hypoxia.”

“Whether the damaging side of the hypoxia response is solely an unintended pathological effect or potentially a previously undiscovered normal process that goes awry in disease remains unknown,” Tesar said. “Our work opens the door to a new way of thinking about how cells respond to low oxygen in health and disease.”

Hypoxia is a state in which oxygen is not available in sufficient amounts at tissue level to maintain adequate homeostasis; this can result from inadequate oxygen delivery to the tissues either due to low blood supply or low oxygen content in blood (hypoxemia).

Hypoxia can vary in intensity from mild to severe and can present in acute, chronic, or acute and chronic forms. The response to hypoxia is variable; while some tissues can tolerate some forms of hypoxia/ischemia for a longer duration, other tissues are severely damaged by low oxygen levels.[1][2][3]


There are 2 major causes of hypoxia at the tissue level, low blood flow to the tissue, or low oxygen content in blood (hypoxemia).[4][5][6]

In order to understand the mechanism of hypoxia, we have to know that in order to have the oxygen carried by hemoglobin, direct interaction between red blood cells in pulmonary capillaries and the air in the alveoli is needed. This process can be compromised at any 1 of the following 3 points: blood flow to the lung (perfusion), airflow to the alveoli (ventilation), and the gas exchange through the interstitial tissue (diffusion).

Reduced Oxygen Tension

As in cases of high altitude.


  1. Airway obstruction which can be proximal as in laryngeal edema or foreign body inhalation, or distal as in bronchial asthma or chronic obstructive pulmonary disease (COPD)
  2. Impaired respiratory drive as in cases of deep sedation or coma
  3. Restricted movement of chest wall as in obesity hypoventilation syndrome, circumferential burns, massive ascites or ankylosing spondylitis
  4. Neuromuscular diseases, such as myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis or phrenic nerve injuries

Ventilation-perfusion Mismatch (V/Q Mismatch)

  1. Decreased V/Q ratio: (Impaired ventilation) or high perfusion, e.g., chronic bronchitis, obstructive airway disease, mucus plugs, pulmonary edema all impair the ventilation and therefore decrease the ratio of ventilation to perfusion
  2. Increased V/Q ratio: (Impaired perfusion) in cases of pulmonary embolism or increased ventilation as in emphysema (large bullae in the lungs, decreased the surface area available for gas exchange, this causes higher ventilation in comparison to perfusion leading to a high V/Q ratio

Right to Left Shunt

The blood crosses from the right to the left side of the heart without being oxygenated. Causes include:

  1. Anatomic shunts: Blood bypasses the alveoli; e.g., intracardiac shunts (ASD, VSD, PDA, among others), pulmonary arteriovenous malformations, fistulas, and hepato-pulmonary syndrome
  2. Physiologic shunting: Blood passes through non-ventilated alveoli, for example, pneumonia, atelectasis, and ARDS

Impaired Diffusion of Oxygen

Oxygen diffusion is impaired between the alveolus and the pulmonary capillaries. Causes are usually interstitial edema, interstitial inflammation or fibrosis. Clinical examples include pulmonary edema and interstitial lung disease.


Hypoxia is a common disorder that we encounter every day in the hospital. However, the causes of hypoxia are multiple, and its prevalence is variable. Some of these causes are very common like pneumonia or chronic obstructive pulmonary disease (COPD); others are quite rare like the hypoxia due to reduced oxygen tension as in high altitude or due to cyanide poisoning.



This includes the factors that decrease the percentage of oxygen in the alveoli, either due to obstruction of the airways or increase in partial pressure of alveolar gases other than oxygen. Carbon dioxide is one of the examples. Hypoventilation can also occur due to impaired respiratory drive as in cases of deep sedation or because of restricted movement of chest wall as in obesity hypoventilation syndrome or ankylosing spondylitis. In this setting, the A-a gradient will be normal as the oxygen is deficient in both alveoli and bloodstream.

In alveoli, an increase in partial pressure of one gas will be on the cost of the other gases composing the air, e.g., an increase in carbon dioxide partial pressure results in a decrease of partial pressure of oxygen, both at alveolar as well as the arterial level. This type of hypoxemia is easily corrected with supplemental oxygen.

Ventilation-Perfusion Mismatch (V/Q Mismatch)

In which there is an imbalance between lung ventilation and blood flow. Even in the normal lung, there is V/Q mismatch. In an upright individual, V/Q ratio is higher in the apices than at the lung base. This difference is responsible for the normal A-a gradient. V/Q mismatch increases in pulmonary vascular disease, thromboembolic disease or atelectasis to name a few. Such process ultimately results in hypoxemia which is more difficult to correct with supplemental oxygen.

Right to Left Shunt

Occurs when blood passes from the right to the left side of the heart without being oxygenated. Anatomic abnormalities, such as atrial or ventricular septal defects as well as pulmonary arteriovenous malformations can cause hypoxemia that is notoriously difficult to correct with supplemental oxygen. Similar physiology is observed in hepato-pulmonary syndrome. Physiologic right-to-left shunt exists when the blood passes through non-ventilated alveoli in cases of atelectasis, pneumonia, and acute respiratory distress syndrome (ARDS).

Impaired Diffusion of Oxygen Across the Alveoli into Blood

The usual causes are interstitial edema, lung tissue inflammation or fibrosis. Depending on disease extent, moderate to a large amount of supplemental oxygen may be required to correct this type of hypoxemia. Exercise can worsen hypoxemia resulting from impaired diffusion. Increase in cardiac output with exercise results in accelerated blood flow through alveoli, reducing the time available for gas exchange. In case of the abnormal pulmonary interstitium, gas exchange time becomes insufficient, and hypoxemia ensues.

History and Physical

Hypoxia presentation can be acute or chronic; acutely the hypoxia may present with dyspnea and tachypnea. Symptom severity usually depends on the severity of hypoxia. Sufficiently severe hypoxia can result in tachycardia to provide sufficient oxygen to the tissues. Some of the signs are very evident on physical exam; stridor can be heard once the patient arrives in cases of upper airway obstruction. Skin can be cyanotic, which might indicate severe hypoxia.

When oxygen delivery is severely compromised, organ function will start to deteriorate. Neurologic manifestations include restlessness, headache, and confusion with moderate hypoxia. In severe cases, altered mentation and coma can occur, and if not corrected quickly may lead to death.

The chronic presentation is usually less dramatic, with dyspnea on exertion as the most common complaint. Symptoms of the underlying condition that induced the hypoxia can help in narrowing the differential diagnosis. For instance, productive cough and fever will be seen in cases of lung infection, leg edema, and orthopnea in cases of heart failure, and chest pain and unilateral leg swelling may point to pulmonary embolism as a cause of hypoxia.

The physical exam may show tachycardia, tachypnea, and low oxygen saturation. Fever may point to infection as the cause of hypoxia.

Lung auscultation can yield a lot of useful information. Bilateral basilar crackles may indicate pulmonary edema or volume overload, other signs of that includes jugular venous distention and lower limb edema. Wheezing and rhonchi can be found in obstructive lung disease. Absent unilateral air entry can be caused by either massive pleural effusion or pneumothorax. Chest percussion can help differentiate the two and will reveal dullness in cases of pleural effusion and hyper-resonance in cases of pneumothorax. Clear lung fields in a setting of hypoxia should raise suspicion of pulmonary embolism, especially if the patient is tachycardic and has evidence of deep vein thrombosis (DVT).


Evaluation of Acute Hypoxia

Pulse oximetry to evaluate arterial oxygen saturation (SaO2)

The arterial oxygen saturation (SaO2) refers to the amount of oxygen bound to hemoglobin in arterial blood. The measurement is given as a percentage. Resting SaO2 less than or equal to 95% or exercise desaturation greater than or equal to 5% is considered abnormal. However, clinical correlation is always necessary as the exact cutoff below which tissue hypoxia ensues has not been defined.[7][8][9]

Arterial Blood Gas

It is a useful tool to evaluate hypoxemia. Aside from diagnosis of hypoxemia, additional information obtained, such as PCO2, can shed light on etiology of the process.

  1. Arterial oxygen tension (PaO2): Partial pressure of oxygen is the amount of oxygen dissolved in the plasma. A PaO2 less than 80 mm Hg is considered abnormal. However, this should be in line with the clinical situation.
  2. The partial pressure of CO2: it is an indirect measure of exchange of CO2 with the air via the alveoli, its level is related to minute ventilation. PCO2 is elevated in hypoventilation like in obesity hypoventilation, deep sedation, or may be low in the setting of acute hypoxia secondary to tachypnea and washout of CO2.

N.B. PaO2: FiO2 ratio (Normal ratio is 300 to 500), if this ratio drops this may indicate a deterioration in gas exchange, this is particularly important in defining ARDS.


Imaging studies of the chest, such as chest x-rays or CT help in identifying the cause of the hypoxia, e.g., pneumonia, pulmonary edema, hyperinflated lungs in COPD and other conditions. CT chest can give more detailed images that outline the exact pathology, CT angiogram of the chest is of particular importance in detecting the pulmonary embolism. Another modality is the VQ scan which can detect the ventilation-perfusion mismatch, which is helpful in diagnostics of acute or chronic pulmonary embolism. VQ scan can be particularly useful when renal failure or allergy to iodinated contrast increases risks of CT angiography.

The first step in evaluating the hypoxia is to calculate the A-a gradient of oxygen. This is the difference in the amount of oxygen between the Alveoli “A” and the amount of oxygen in the blood “a.” In other terms, the A-a oxygen gradient = PAO2 – PaO2.

PaO2 can be obtained from the arterial blood gas; however, PAO2 is calculated using the alveolar gas equation:

PAO2 = (FiO2 x [760-47]) – PaCO2/0.8)

N.B.1: 760 is the atmospheric pressure at the sea level in mm Hg, 47 is the partial pressure of water at a temperature of 37 C, and 0.8 is the steady-state respiratory quotient.

N.B.2: the A-a gradient changes with age, and thus it is corrected for age using this equation; A-a gradient = (age/4+4).

If the A-a gradient is normal, then the cause of hypoxia is low oxygen content in the alveoli, either due to low O2 content in the air (low FiO2, as in the high altitude) or more commonly due to hypoventilation like central nervous system (CNS) depression, OHS, or obstructed airways as in COPD exacerbation.

If the gradient is height then the cause of hypoxia is either due to a diffusion defect or perfusion defect (VQ mismatch), an alternative explanation is shunting of blood flow around the alveolar circulation, administering 1.0 FiO2 may help differentiate the 2, as the oxygenation will improve in VQ mismatch, however, barely will when shunt physiology is present.

PaO2: FiO2 Ratio

This ratio is another way to measure the degree of hypoxia. A normal PaO2/FiO2 ratio is about 300 to 500 mm Hg. If the ration is less than 300, this indicates abnormal gas exchange, and values less than 200 mm Hg indicates severe hypoxemia. The PaO2/FiO2 ratio is used mostly as a definition of acute respiratory distress syndrome severity.

Evaluation of Chronic Hypoxia

Pulmonary Function Test

Provide a direct measure of the lung volumes, bronchodilator response and diffusion capacity, which can help in establishing the diagnosis and guiding the treatment of the lung disorders. Aiding the history and physical exam, PFTs can be used to differentiate between the obstructive (bronchial asthma, COPD, upper airway obstruction) versus restrictive lung diseases (interstitial lung diseases, chest wall abnormalities). PFTs play a role in the assessment of airway obstruction severity as well as a response to therapy. One has to keep in mind that PFTs are effort dependent and require patient ability to cooperate and understand instructions.

Nocturnal (overnight) Trend Oximetry

Provides information about oxyhemoglobin saturation over a period (usually overnight). This test is primarily used to assess adequacy or need for oxygen supplementation at night. Use of overnight trend oximetry as a surrogate for a diagnostic sleep study is possible, however, is discouraged. A formal sleep study should be used whenever possible.

Six-Minute Walk Test

Provides information on oxyhemoglobin saturation response to exercise as well as the total distance a patient can walk in 6 minutes on a ground level. This information can be used to titrate oxygen supplementation as well as evaluate the response to therapy. The 6-minutes walk test is frequently used in the preoperative pulmonary evaluation, pulmonary hypertension treatment and assessment of supplemental oxygen need with exercise.


Secondary polycythemia can be an indicator of chronic hypoxia.

Treatment / Management

Management of hypoxia falls under 3 categories: maintaining patent airways, increasing the oxygen content of the inspired air, and improving the diffusion capacity.[10][11][12]

Maintaining Patent Airways

Ensure patency of the upper airways with good suctioning, maneuvers that prevent occlusion of the throat (head tilt and jaw trust if necessary), sometimes the placement of an endotracheal tube or tracheostomy is necessary.

In chronic conditions like OSA, maintaining patent airways can be achieved with positive pressure ventilation like CPAP or BiPAP.

Bronchodilators and aggressive pulmonary hygiene, such as chest physiotherapy, flutter valve, and incentive spirometry can be used to maintain patency of the lower airways.

Increase Fraction of the Inspired O2 (FiO2)

This is indicated for low PaO2 less than 60 or SaO2 less than 90, and this can be achieved by increasing the percentage of oxygen in the inspired air that reach the alveoli.

Low-Flow Devices

  • Nasal cannula
  1. Use: mild hypoxia (with FiO2 approximately 92%)
  2. Flow rate: up to 6 L per minute
  3. FiO2 delivered: up to 45% (0.45)
  4. Advantage: Easy to use and more convenient to the patient (can be used during eating, drinking, talking)
  5. Disadvantage: Dry nasal mucosa (humidify if the flow is greater than or equal to 4 L per minute), FiO2 being delivered varies greatly. Mouth breathers derive less benefit from using a nasal cannula.
  6. The following formula can be used to approximate the percentage of FiO2; FiO2 = 20% + (4 times oxygen flow liters) For example, oxygen flow 2L/min would deliver approximately FiO2 of 0.3, 6 L per minute would deliver approximately FiO2 of 0.45 (more commonly known as 45%).
  • Simple face mask
  1. Use: Moderate to severe hypoxia, initial treatment.
  2. Flow rate: up to 10 L per minute
  3. FiO2 delivered: 35% to 50%
  4. Advantage: provides higher FiO2, no pressures involved, well tolerated by patients
  5. Disadvantage: Dry oral mucosa (needs humidification), the flow must be at least 5 L per minute to flush CO2, not high flow. Also, the mask itself can interfere with activities of daily living
  •  Reservoir cannulas (Oxymizer)
  1. The device uses a reservoir space, which stores O2 during expiration, making it available as a bolus during the next inspiration. This way the patient gets a higher oxygen delivery without increasing flow. 
  2. Flow rate: up to 16 L per minute.
  3. FiO2 = up to 90% (0.9)
  4. Reservoir cannulas are available as mustache configuration (Oxymizer), where the  reservoir is located directly beneath the nose, pendant configuration (Oxymizer Pendant) which is connected to a plastic reservoir on the anterior chest
  • Partial-rebreather mask
  1. Has a 300 to 500 mL reservoir bag and 2 one-way valves to prevent exhaling into the reservoir
  2. Use: Moderate to severe hypoxia, initial treatment
  3. Flow rate: 6 to 10 L per minute (flow must be sufficient to keep reservoir bag from collapse during inspiration)
  4. FiO2 delivered: 50% to 70%
  5. Advantage: Higher FiO2 can be delivered
  6. Disadvantage: Interferes with activities of daily living. 
  • Non-rebreather mask
  1. Has a 300 to 500 mL reservoir bag and 2 one-way valves
  2. Use: Moderate to severe acute hypoxia, initial treatment
  3. Flow rate: 10 to 15 (at least 10 L per minute to avoid bag collapse during inspiration)
  4. FiO2 delivered: 85% to 90%
  5. Advantage: even higher FiO2 can be achieved
  6. Disadvantage: Interferes with activities of daily living

High-Flow Devices 

Usually, this requires oxygen blender, humidifier, and heated tubing.

  • Venturi mask
  1. Mask attached an air entrainment valve
  2. Use: Moderate to severe hypoxia, initial treatment
  3. The flow rate and FiO2: (depends on the color). (Blue = 2 to 4 L per minute = 24% O2, White = 4 to 6 L per minute = 28% O2, Yellow = 8 to 10 L per minute = 35% O2, Red = 10 to 12 L per minute = 40% O2, Green = 12 to 15 L per minute = 60% O2)
  4. Advantage: provides the most accurate O2 delivery, high flow
  5. Disadvantage: need to be removed for eating. Less accurate at high flow rates
  6. Does not guarantee the total flow with O2 percentages above 35% in patients with high inspiratory flow demands; the problem with air entrainment systems is that as this is increased, the air to oxygen ratio decreases
  • High-flow nasal cannula
  1. High-flow oxygen (HFO) consists of a heated, humidified O2
  2. Flow rate: 10 to 60 L per minute
  3. FiO2 delivered: Up to 100%
  4. Advantages: More convenient, Can deliver up to 100% heated and humidified oxygen at a maximum flow of 60 LPM
  5. Disadvantages: Fairly large cannula, can be a source of (although usually rather minimal) discomfort
  • Air/oxygen blender
  1. Provides accurate oxygen delivery independent of the patient’s inspiratory flow demands
  2. Positive end-expiratory pressure may be generated
  3. For approximately every 10 liters of flow delivered, about 1 cm/HO of positive pressure is obtained

Positive Pressure Ventilation

Allows for accurate delivery of any necessary FiO2

Non-Invasive Ventilation usually used as the last resort to avoid the intubation

  • Continuous Positive Airways Pressure Mask (CPAP)
  1. Mainly used in patients with obstructive sleep apnea or in acute pulmonary edema
  2. Delivers oxygen (or air) under pre-determined high pressure via a tightly fitting face mask
  3. Positive pressure is continuous, to ensure that the airways are open (split them)
  • Bilevel Positive Airways Pressure (BiPAP)
  1. Mainly used in patients with acute Hypercarbia as in patients with COPD exacerbation and ARDS patients
  2. High positive pressure on inspiration and lower positive pressure on expiration
  3. Pressure delivery is variable throughout the respiratory cycle, with high positive pressure on inspiration and lower positive pressure on expiration

Invasive Ventilation

  1. Positive pressure ventilator attached to (usually) endotracheal tube. 
  2. Allows for accurate delivery of predetermined minute ventilation as well as accurate FiO2 and positive end-expiratory pressure.
  3. Can be used electively during surgery

Improve the Diffusion of Oxygen through the Alveolar Interstitial Tissue

The overall idea s to treat the underlying cause of respiratory failure:

  1. Diuretics can be used in cases of pulmonary edema
  2. Steroids in certain cases of interstitial lung disease
  3. Extracorporeal membrane oxygenation (ECMO) can be used as an ultimate method of increasing oxygenation.

Differential Diagnosis

Hypoxemic Hypoxia

Low oxygen tension in the arterial blood (PaO2); due to the inability of the lungs to properly oxygenate the blood. Causes include hypoventilation, impaired alveolar diffusion, and pulmonary shunting.

Circulatory Hypoxia

Due to pump failure (heart is unable to pump enough blood, and therefore oxygen delivery is impaired).

Anemic Hypoxia

Decrease in oxygen carrying capacity due to low hemoglobin leading to inadequate oxygen delivery.

Histotoxic Hypoxia (Dysoxia)

Cells are unable to utilize oxygen effectively, the best example for this is Cyanide poisoning; which inhibits the enzyme cytochrome C oxidase in the mitochondria, blocking the use of oxygen to make ATP.

Pearls and Other Issues

  • The characteristics of each category of hypoxemia are as follows: 1) hypoventilation presents with an elevated PaCO2 with a normal A-a gradient, 2) low-inspired oxygen presents with a normal PaC02 plus normal A-a gradient, 3) shunting presents with a normal PaC02 and elevated A-a gradient that does not correct with administration of 100% oxygen, and 4) V/Q mismatch presents with a normal PaC02 and elevated A-a gradient that does correctly with 100% oxygen.
  • Oxygen supplementation varies between FiO2 of 0.21 and 1.00. Variety of low and high flow devices exist to facilitate this process, each with unique advantages and disadvantages. 
  • Delivery of oxygen depends on 2 variables: FiO2 and flow rate. There are several devices which designed to deliver oxygen at different rates and concentrations as described above.
  • Oxygen toxicity may result if oxygen is delivered at a higher concentration for the long duration of time.
  •  Decreased body temperature decreases metabolic rate, this lowers the oxygen consumption and minimize the adverse effects of tissue hypoxia (especially brain) Therapeutic hypothermia is based on this principle. 
  • Long-term oxygen therapy can reduce the mortality, and it is indicated in these patient populations:
  1. Group I (Absolute): PaO2 55 mm Hg or SaO2  88%
  2. Group II (In the presence of cor pulmonale): PaO2 55 to 59 mm Hg or SaO2 89%, ECG evidence of right atrial enlargement, hematocrit greater than  55%, congestive heart failure

Enhancing Healthcare Team Outcomes

Hypoxia is low oxygen content at tissue level to meet the metabolic needs of the cells. The condition can occur in a patient for a variety of reasons and healthcare workers including nurses must be aware of the work up of such a patient. Classic causes of hypoxia include hypoventilation, ventilation-perfusion mismatch, the low oxygen content in the air, right to left shunting or impaired diffusion. By analyzing the arterial blood gas (ABG), calculating the alveolar-arterial oxygen gradient (A-a gradient), and determining whether administration of 100% oxygen leads to improvement, one can determine the specific type of hypoxemia plaguing a particular patient. Leaving hypoxia untreated for prolonged periods leads to permanent organ injury including death.


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Journal information:Cell Stem Cell


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