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Stuttering Priapism
Introduction
Stuttering priapism, a rare but potentially serious condition, involves recurrent, self-limiting penile erections lasting less than 3 to 4 hours per episode. Though transient, it can progress to ischemic priapism, necessitating immediate intervention to prevent complications like erectile dysfunction. Most commonly seen in sickle cell disease (SCD) patients, stuttering priapism has varied treatment approaches.
Priapism is a prolonged and sustained penile erection, usually lasting more than 3 to 4 hours without the presence of a stimulus.[1] This condition has been classified into 3 types:
- Low-flow or ischemic priapism is the most common type.
- High-flow or oxygenated priapism is often the result of a penile injury.
- Recurrent or stuttering priapism is the least common type.[2]
Stuttering priapism is generally self-limiting and lasts less than 3 to 4 hours per episode. However, this condition has the potential to develop into complete ischemic priapism in one-third of the cases, requiring urgent intervention.[3] Ischemic priapism can cause many morbidities, including erectile dysfunction; therefore, patients should be treated within 4 hours to minimize the chance of developing long-term complications and permanent damage to the erection bodies or corpora.[4]
Three parts compose the body of the penis—the corpora cavernosa, corpus spongiosum, and urethra. The penile corpora are vascular beds and sinusoidal spaces supported by smooth muscles, nerves, and capillaries. The common penile artery and cavernosal arteries, branches of the internal pudendal artery, actively supply blood to the penile region. Venous drainage is through the superficial, intermediate, and deep venous systems, which drain into the cavernous and the deep dorsal veins. The parasympathetic nerve supply to the penis is through the cavernosal nerves, which arise from the pelvic ganglionic plexus.
When sexual excitement occurs, the parasympathetic nerves stimulate the release of vasodilating neurotransmitters, which relax the intracorporal trabecular smooth muscles, increasing sinusoidal compliance—resulting in substantial dilation of the arterioles and arteries. This dramatic and substantial increase in blood flow expands the corpora cavernosa until pressure and compression of the subtonic venular plexus decrease venous outflow, trapping the blood at maximum capacity inside.
The venous outflow stops as the compression builds. The increased hydrostatic pressure inside the inelastic corporal space results in rigidity and a full erection.[5][6][7] The process is similar to filling a car tire with 200 lbs per square inch of air pressure. The steel belts in the tire are inelastic, so as the tire pressure increases, it becomes stiffer and more rigid without stretching or enlarging.
Etiology
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Etiology
Similar to ischemic priapism, stuttering priapism causes hematological, pharmacological, neurological, and malignancy, classifying them as such. Sickle cell disease (SCD) is the most common cause of stuttering priapism. Although stuttering priapism is not common in the general population, it is relatively frequent amongst men with SCD, affecting between 30% and 45% of all adult males with SCD.[8] Most patients with sickle cell disease with priapism have stuttering priapism. Most will be homozygous for hemoglobin S, although this can occur in the sickle cell trait. Other hematologic causes include leukemia, thalassemia, and platelet abnormalities.
Medications most closely linked to priapism are psychoactive agents and the use of erectile dysfunction (ED) drugs in non-prescribed combinations or at higher than recommended dosages.[9][10] Testosterone supplementation does not appear to play a significant role in causing priapism, and neither does urination or having a full bladder.
Epidemiology
Results from several studies have reported significantly different rates of priapism in the general population and specific populations, which means that there is a lack of accurate information on the prevalence of different types of priapism.[11] In one study, the reported incidence of stuttering priapism in men with SCD was 42%. However, results from another study reported the incidence in adolescents and children with SCD to be 65%.[12] The vast majority (82%) of all patients with SCD who have had any priapism reported a history of stuttering variety. Moreover, 49% of patients who have experienced stuttering priapism had an acute episode.
The frequency of episodes generally ranges from 4 per week to 3 a year, with a median of 3 episodes per month.[13] The occurrence of priapism typically follows a bimodal distribution, with the first peak being between 5 to 10 years in children and 20 to 50 years in adults.[14] The probability of experiencing priapism in males with SCD is 12% in the first 10 years of life, up to 50% when they reach 15 years old, and almost 90% by the time they are 20 years of age. The mean age to have the first episode is 15 years.[15] Results from another study revealed that virtually all patients with SCD reported having their first episode of priapism before the age of 30.[13] In children, about two-thirds of all those who demonstrate priapism will also have SCD. Thus, among children with SCD, the rate of pediatric priapism is about 25% to 30%.
Pathophysiology
The mechanism for normal erectile function initially involves the activation of cyclic guanosine monophosphate (GMP) by nitric oxide, which causes relaxation of the cavernosal smooth muscle tissue, resulting in increased blood flow into the corpora and inducing an erection. The action of the phosphodiesterase type 5 enzyme, which converts cyclic GMP back to its inactive state, limits this process.[16]
Adrenergic mediators stimulate the RhoA/Rho kinase pathway, leading to cavernosal vasoconstriction and penile flaccidity.[17] A natural balance between these 2 functions allows normal penile flaccidity with intermittent, limited erectile rigidity. Disruption of this balance results in priapism.[18]
Although the pathophysiology of stuttering priapism is not fully understood, it appears to result from dysregulated dynamics of the normal erection process, leading to venous stasis, compartment syndrome, and diminished blood flow. This process eventually leads to tissue damage and, ultimately, corporal fibrosis with permanent loss of erectile ability.
Researchers believe the mechanism underlying stuttering priapism closely resembles ischemic priapism.[12] The most commonly reported precipitants of priapism are sexual arousal, fever, and sleep.[13]
The molecular mechanism thought to cause stuttering priapism involves reduced cavernosal nitric oxide in the endothelial cells, which downregulates phosphodiesterase type 5 (PDE-5) and reduces RhoA/Rho-kinase activity while increasing adenosine and opiorphin levels.
Downregulation of nitric oxide-cyclic GMP-PDE-5 signaling occurs within the corporal cavernosal tissue, accompanied by increased oxidative stress and disruptions in the usual vasoconstrictive mechanisms. All these effects, taken together, cause a reduced cavernosal smooth muscle tone, leading to enhanced tissue relaxation and an exaggerated response to normal stimuli, resulting in prolonged erections.[19]
The conventional explanation for priapism related to SCD is based on the principles of increased blood viscosity and venous congestion. Normal erections reduce the oxygen saturation in the corpora cavernosa.
In patients with SCD, this predisposes the red blood cells to sickle inside the corpora cavernosa, creating a higher viscosity. This increase in viscosity induces venous stasis—leading to increased congestion and priapism. The priapism further reduces blood flow, causing acidosis, damage to the smooth muscle tissue, and an inflammatory reaction, eventually resulting in penile corporal fibrosis and permanent ED.[20]
History and Physical
History
In the emergency department, it is imperative to know what type of priapism the patient is presenting with to initiate prompt treatment. Ischemic priapism presents as progressive penile pain with the duration of the erection. Risk factors include a past medical history of SCD, other hematological disorders, or a known neurological condition. In high-flow priapism, the patient usually presents with a history of a prolonged erection but no pain. This condition usually follows a perineal or penile trauma, penile injections or procedures, or pelvic surgery.
When a patient presents with stuttering priapism, it is important to know the number and frequency of episodes, their average duration, and what the precipitating factors were. These episodes usually occur as a non-resolving morning erection or after sexual stimulation. A history of high-risk or underlying causative factors such as SCD and other hematological diseases and a complete medication history is essential. Psychoactive medications or a history of mental health issues can also be critically important. Many patients will have learned how to resolve this at home, such as hot or cold packs, cold baths, or exercise. Establish whether this ever progressed to an acute ischemic attack and, if so, how often. As this has the potential to cause permanent erectile dysfunction and difficulties in the patient's sex life, it is pertinent and reasonable to establish its effect on their life.[21]
Physical Examination
The aim of the physical examination in the acute attack is also to determine the type of priapism the patient is presenting with. In ischemic attacks, the corpora cavernosa is fully rigid and somewhat tender. In high-flow priapism, it is the opposite: full but relatively soft and painless. Clinicians must inspect and palpate the perineum to identify signs of trauma, including discoloration and tenderness, as this is one of the leading causes of high-flow priapism.
In cases of recurrent priapism, healthcare providers should conduct thorough examinations of the testicles, abdomen, perineum, rectum, and prostate to identify any masses. While masses are rarely a cause of priapism, it is advisable to thoroughly examine the patient, as there is a possibility of identifying the causative factors.[22] Since priapism does not cause an increase in body temperature, any fever would likely be from some other cause.
Evaluation
Laboratory Testing
Evaluation in the emergency department aims to find the cause of priapism. A complete blood count (CBC) and a clotting profile assess for anemia and infection and detect any hematological abnormality. Request urine and plasma toxicology if recreational narcotics use is suspected. If the patient has a history of psychological issues, healthcare providers should actively seek tests for psychoactive medication levels in the blood.
Additionally, a corporal blood aspirate should be analyzed in the acute phase to rule out ischemic priapism. In ischemic priapism, the first aspirate will show acidity (pH <7.25), high PCO2 (>60 mm Hg), and low PO2 (<30 mm Hg).
A sickle cell screen should be considered and performed selectively in all patients presenting with stuttering priapism to rule out SCD as an underlying problem. Other hematologic causes, like leukemia, thalassemia, and platelet abnormalities, should also be investigated.[22][23]
Imaging
In the acute phase, color duplex Doppler ultrasonography can be used to measure the blood flow in the penis and perineum. Ischemic priapism will not show any significant blood flow in the cavernous arteries.[23] A peak systolic velocity (PSV) of < 50 cm/s and a mean velocity of < 6.5 cm/sec highly suggest ischemic priapism.[24] Some patients with ischemia priapism will show a PSV of >22 cm/s together with no diastolic flow or diastolic flow reversal, resulting in tissue hypoperfusion.[24][25]
Selectively perform CT scans to rule out suspected malignancy as an underlying etiology of the priapism if clinically indicated. MRI of the penis can be useful in determining the viability of cavernosal smooth muscle and the likelihood of ED in patients who present with priapism.[26] Penile arteriography is seldom necessary, except when there is suspicion of high-flow priapism and consideration of embolization. High-flow priapism does not typically cause frequent recurrences.
Treatment / Management
The primary goal in treating stuttering priapism is preventing future episodes. Managing an acute episode of prolonged ischemic priapism lasting over four hours is imperative as an emergency. Healthcare providers must perform the aspiration of penile blood and intracorporal infusion of diluted α-adrenergic agents within 24 hours. However, presenting with such episodes carries a high risk of developing complications, which is why the treatment aim in stuttering priapism is preventative.
The advances in understanding the mechanism of stuttering priapism have led to the trial of new medications with the aim of prevention. The specific medical management of stuttering priapism options are grouped into hormonal agents, drugs that change the corporal muscle tone, and others.[27] Treatments for acute episodes of priapism are described elsewhere.[1][28]
In general, treat acute priapism in patients with frequent recurrences is the same as those without such recurrences. This report will focus on treatment and prophylactic therapies for stuttering priapism.
Hormonal Manipulation
There are multiple options for hormone treatment for patients with stuttering priapism, but they all aim to reduce the circulating testosterone levels. Results from a study suggest that reducing testosterone level to 10% of its normal level will reduce libido and nocturnal erections, which will reduce the number of priapism episodes. The treatment lasted from 2 weeks to 2 months and ended with sustained treatment results.
Options for hormonal manipulation include gonadotropin-releasing hormones (GnRH) agonists/antagonists (downregulate the pituitary gland), antiandrogens (block androgen receptors), ketoconazole (reduces testosterone production as a side effect), and finasteride (5α-reductase inhibitor). However, these agents will affect sperm production, growth, and sexual maturation; this is why they are contraindicated in males who are still in their growth phase and relatively contraindicated in those who want to conceive.
Other treatment options can be used cautiously in this patient group where possible, such as self-administering α-adrenergic agonists in acute attacks[29][30](A1)
A suggested treatment regimen for ketoconazole involves an initial dose of 200 mg 3 times per day, with prednisone 5 mg daily for 2 weeks, followed by a reduced dose of 200 mg of ketoconazole nightly for an additional 6 months.[31] Results from a small study showed this regimen resolved the stuttering priapism in 94% of patients while on treatment and in 79% of patients after completing the ketoconazole therapy.[31](B2)
Increasing the Cavernosal Smooth Muscle Tone
The first option of these medications is the intracavernosal injection of diluted pseudoephedrine. This treatment is usually an injection directly into the cavernosal tissue, making this more of a treatment option for acute attacks rather than prevention. The standard recommended dilution is from 100 to 500 mcg/mL, and treatment involves the injection of 1 ml roughly every 5 minutes until either resolution or 1 hour of treatment.[28] This injection exerts its effect as an α-agonist acting on the α-adrenergic receptors in the cavernosal smooth muscles, causing contraction and detumescence. Using this as an oral agent for prevention has been suggested, but there are no studies yet.
Digoxin inhibits the sodium-potassium pump and leads to increased intracellular calcium, which causes smooth muscle contraction and detumescence. However, researchers have conducted only a small study on this agent.
Terbutaline, a β2 adrenergic agonist, has long been recommended for preventing recurrent episodes of stuttering priapism. The dosage of oral terbutaline is 5 mg immediately, with another 5 mg taken 15 minutes later. The proposed prophylactic dose of terbutaline is 5 to 10 mg daily. Recent questioning of the role of terbutaline due to the lack of proven efficacy in acute priapism has led to its current non-recommendation.
Other Agents
Gabapentin is used for the treatment of convulsions and as an anxiolytic. This medication can reduce calcium influx into smooth muscle cells and inhibit muscle contraction; this may explain why it has sometimes been effective in treating refractory priapism.[18]
Healthcare providers have used hydroxyurea with some success in patients with SCD.[32] Originally designed as an anti-cancer drug, hydroxyurea affects the bone marrow and reduces the overall hemoglobin S (Hb S) concentration. This drug also reduces hemolysis and causes vasodilation through increased nitric oxide production. Healthcare providers have used hydroxyurea with some success in treating patients with SCD,[32][33][34] as these patients generally have decreased nitric oxide levels in the blood due to chronic hemolysis. Free hemoglobin in the blood acts as a nitric oxide sink;[35][36][37] there are also other mechanisms involved.(B3)
Patients with SCD and stuttering priapism tend to have more severe disease, a higher incidence of stroke, an increased rate of acute chest syndrome, and lower average Hgb levels.[38] The initial dose of hydroxyurea is 20 mg/kg daily. Healthcare providers can incrementally increase this dosage until it reaches clinical success or the maximum tolerable dose, guided by periodic laboratory complete blood count testing.
Other agents found to be effective against stuttering priapism are hydralazine, baclofen, and procyclidine. Also, conventional treatment of SCD has been found effective in the prevention of priapism in the patient group (including analgesia, fluids, oxygen, alkalinization, and transfusions). However, these treatments are useful only after the initial management of the acute priapism episode.[27]
Researchers have investigated using a low daily dose (25-50 mg) of sildenafil to aid in moderating nitric oxide signaling and normalizing/reprogramming phosphodiesterase type 5 activity. Results from some limited studies have suggested a benefit in stuttering priapism in men both with and without SCD.[39][40][41][42] This can be combined with 5-alpha reductase inhibitors such as finasteride.[43][44][45](B2)
Some patients can prepare, mix, and perform intracavernosal self-administration of diluted α-agonist medication.[30][46] While this is often effective, it is not a cure and requires substantial patient skills, motivation, and abilities.[30] This therapy is rarely associated with thromboembolic events such as intracerebral hemorrhages and myocardial infarctions.[47][48][49](B3)
Special Considerations for Patients with SCD, Including Automated Red Cell Exchange Transfusions
Initial therapy for patients with SCD and presenting with priapism generally includes alkalinization, adequate analgesia, IV hydration, and supplemental oxygen to prevent more sickling. The American Urological Association Guidelines on the Management of Priapism recommends intracavernosal therapy together with systemic treatment of SCD. Consider surgical shunts after intracavernosal therapy has failed. Initial shunting should be between the glans (corpora spongiosa) and the corpora cavernosa. Tunneling, where a dilator is passed through the corpora from the tip to the tail to provide additional drainage, may also help in some cases but is more invasive than the shunt alone.[28]
Sildenafil can be used as an additional therapeutic option for those who continue to have episodes of priapism despite hydroxyurea therapy. This drug has shown some efficacy in resolving priapism in SCD patients.[40][50](A1)
Finasteride blocks the enzymatic conversion of testosterone to the more active dihydrotestosterone. There is some limited evidence of reducing the frequency of priapism episodes in patients with SCD and stuttering priapism, but it can also cause gynecomastia, decreased libido, and ED in some individuals.[43]
There are also limited studies on using GnRH agonists for stuttering priapism in patients with SCD. However, this has been used anecdotally with success.[51] Theoretically, a GnRH antagonist should also be effective, but there is no reliable data to confirm this. More studies on this type of therapy are needed.(B3)
Standard transfusions can improve tissue oxygenation and reduce the percentage of sickled erythrocytes in the circulation for patients with SCD suffering from stuttering priapism. They also have the advantage of not requiring any special staffing or equipment. Unfortunately, standard transfusions are also associated with iron overloads, are relatively slow, and are substantially less effective than exchange transfusions in reducing the Hb S level. Healthcare providers can manually perform exchange transfusions using donor red blood cells and normal saline, but this process is lengthy and laborious. In addition, exchange transfusions are not as rapid or effective as automated red cell exchanges and can still cause an iron overload.
Healthcare providers perform automated red cell exchanges using an apheresis system. The process involves removing the patient's blood, replacing the red cells with donor erythrocytes, and returning the blood to the original patient. While this process requires special staffing and equipment, it can rapidly reduce the Hb S level and avoid excessive iron loading. Therefore, this is the recommended method of exchange transfusion in patients with SCD.[52][53][54] Automated red cell exchange transfusions have successfully managed stuttering priapism in patients with SCD.[52][55][56] (B3)
Target post-transfusion Hb S is usually 10% or less, but a clinical response may begin at just 30%. This technique has been successful in patients with SCD who otherwise suffer intractable, recurrent episodes of stuttering priapism. Treating patients with SCD with severe, intractable stuttering priapism who do not otherwise respond to or tolerate pharmacotherapy or hormonal manipulation has been recommended.[8][52] Negatives include the need for specialized equipment and staffing, traveling to treatment locations, the requirement for ongoing therapy, limited studies proving efficacy, and the cost.
Crizanlizumab is a monoclonal antibody used to reduce the frequency of sickle cell crises. It has reduced priapism events in a small number of patients, suggesting a possible prophylactic role in stuttering priapism in patients with SCD.[57](B2)
Prophylactically, most patients with SCD do not develop additional episodes of priapism as long as their Hb S levels are at 30% or less. Despite some favorable evidence of efficacy, automated red cell exchange transfusions for acute priapism are not officially recommended by the Guidelines from the American Society of Apheresis or by the 2014 NIH Guidelines on SCD. Nevertheless, several experts recommend consideration of this therapy when all other treatments have been unsuccessful and as an alternative to proceeding to a penile prosthesis with its irreversible sequelae.
Insertion of a Penile Prosthesis
When all other reasonable means fail, complete corporal dilation can resolve the priapism but will also destroy the patient's natural erectile function. Consider a prosthesis when the patient presents with an acute, low flow, ischemic priapism > 36 hours duration or in those who have failed surgical shunting procedures.[58] Inserting a penile prosthesis at the time of the corporal dilation can resolve the ED problem if a suitable implant is available and if the tunica has not been overly weakened, especially at the tip, by attempts at creating a shunt.(B3)
If any prior shunt procedures have weakened a portion of the tunica albuginea, the probability of extrusion increases. Waiting too long after a complete corporal dilation can lead to scarring and fibrosis, making inserting a prosthesis much more difficult. Hence, it is advisable to implant the penile prosthesis either during corporal dilation surgery or shortly after, preferably within a few weeks.
There are typically higher failure rates with penile prosthesis implantation for priapism than with routine, elective placement.[59] The consensus recommends earlier penile prosthesis placement to prevent fibrosis, decrease the infection rate, and minimize penile shortening; malleable prostheses are usually recommended in these cases.[60] A reduced rate of device erosion may also be associated with earlier prosthesis placement as long as the tunica is intact after shunting.[28][60] (B2)
Unfortunately, there are no clear guidelines on managing and preventing stuttering priapism, and this is a topic that requires more research. In the absence of clear guidelines, the following is suggested:[44]
- Any testosterone abnormalities should be corrected
- There is good evidence that stuttering priapism patients with SCD will benefit from hydroxyurea
- Terbutaline is no longer recommended
- There is reasonable evidence of a prophylactic benefit to sildenafil and finasteride, alone or taken together
- Use third-line agents such as digoxin and baclofen if previous measures fail. However, digoxin can cause weakness or undesirable cardiac effects, while baclofen may lead to drowsiness
- Hormonal manipulation with GnRH therapy or ketoconazole appears reasonably effective prophylactically but may have side effects, particularly concerning fertility
- Patients can give themselves diluted α-agonist medication intracavernosal injections at home, although there is a small risk of thromboembolic complications
- Patients with SCD can benefit from prophylactic automated red cell exchanges
- Consider the early insertion of a penile prosthesis in complex or intractable cases that do not respond to standard therapies; this will eliminate the recurrent priapism problem but at the cost of a surgical implant
Differential Diagnosis
The most important thing is to differentiate stuttering priapism from acute ischemic priapism and initiate management immediately to avoid complications.
Prognosis
Stuttering priapism in itself causes ED in only one-quarter of patients. However, as about half of all patients who have stuttering priapism develop acute ischemic priapism, it can cause ED if not treated properly.[13]
Complications
Complications arise not from stuttering priapism itself but from acute ischemic episodes if they arise. If not treated within 24 hours, ischemic priapism can lead to fibrosis of the corpus cavernosum and eventually to significant ED. Half or more patients with even one episode of prolonged priapism will develop ED. This rate increases with the repeated episodes found in stuttering priapism. Liability exposure to the treating physicians is relatively high as patients may become upset with a poor outcome (ED) or repeated episodes of priapism despite correct treatment and counseling on presentation. Meticulous documentation is recommended. Several psychological issues arise from stuttering priapism, like sadness (70%), embarrassment (62%), fear (44%), and exhaustion (39%), which should be recognized and addressed appropriately.[61]
Deterrence and Patient Education
Results from one survey showed that only 7% of patients with SCD who have never experienced priapism were familiar with priapism as a possible complication of the disease.[13] In addition, only 50% of patients who have experienced priapism related to SCD have sought medical advice for this condition, meaning priapism may be more common than previously thought.[61]
Educating patients recognized to have a disease putting them at higher risk of developing priapism (like SCD, other hematological diseases, and various cancers) is of paramount importance. Education should include some techniques done at home to relieve the episode and when to seek medical advice to avoid or minimize complications. In addition, counseling patients about the impact on the patient's future sexual life might help mitigate the effects on their mental health and family.
Pearls and Other Issues
For more detailed information on the management of acute priapism, see the companion StatPearls reference article on "Priapism."[1] Also, review the 2021 American Urological Association/Sexual Medicine Society of North America Guideline on Acute Ischemic Priapism.[28]
Enhancing Healthcare Team Outcomes
Stuttering priapism, a rare but potentially serious condition, involves recurrent, self-limiting penile erections lasting less than 3 to 4 hours per episode. Though transient, it can progress to ischemic priapism, necessitating immediate intervention to prevent complications like erectile dysfunction. Most commonly seen in SCD patients, stuttering priapism has varied treatment approaches. Hormonal manipulation via GnRH agents, antiandrogens, or ketoconazole aims to lower testosterone levels, reducing episodes but may affect fertility. Medications altering cavernosal muscle tone (pseudoephedrine, digoxin, terbutaline) show mixed efficacy. Other agents like gabapentin, hydroxyurea, and sildenafil have demonstrated promise, especially in SCD-related cases. Additionally, automated red cell exchanges or penile prosthesis implantation serve as alternate therapies for intractable cases. Standardized management guidelines and further research are warranted for effective stuttering priapism care.
A multidisciplinary approach to managing this condition is fundamental. Once a patient has been diagnosed with any disease that is associated with priapism, the clinician should counsel them about the relative risk of development, how to treat it at home initially, and when to seek medical advice. Counseling can help reduce the anxiety associated with this disease and the number of patients who present to the emergency department late with acute ischemic attacks and complications; this also applies to counseling when starting medications with priapism as a potential adverse effect.
Having the hospital pharmacy ready to prepare a diluted phenylephrine treatment pack for intracavernosal injections in patients with priapism can speed up the process and minimize delays in therapy. Quick recognition and prompt treatment of acute attacks in the emergency department will help reduce the incidence of complications like erectile dysfunction and improve treatment outcomes.
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