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Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Kathy M. Tran, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Emily K. McDonald, Tara Corpuz, Production Editors

Case 15-2023: A 33-Year-Old Man

with Paresthesia of the Arms and Legs
William P. Schmitt, M.D., Saurabh Rohatgi, M.D., and Marcelo Matiello, M.D.​​

Pr e sen tat ion of C a se

Dr. Priyanka Pullarkat (Medicine): A 33-year-old man was evaluated in the emer- From the Departments of Medicine
gency department of this hospital because of progressively worsening paresthesia. (W.P.S.), Radiology (S.R.), and Neurology
(M.M.), Massachusetts General Hospi‑
The patient had been in his usual state of health until 8 weeks before the cur- tal, and the Departments of Medicine
rent evaluation, when he began to have an abnormal tingling sensation in the toes (W.P.S.), Radiology (S.R.), and Neurology
that he described as “pins and needles.” Over the course of several days, the par- (M.M.), Harvard Medical School — both
in Boston.
esthesia extended to the feet.
Six weeks before the current presentation, episodes of headache that lasted ap- N Engl J Med 2023;388:1893-900.
DOI: 10.1056/NEJMcpc2300895
proximately 5 minutes and affected the left periorbital region began to occur on Copyright © 2023 Massachusetts Medical Society.
a daily basis. The headaches became less severe after the patient took acetamino-
phen. He had no associated nausea, vomiting, or neck pain.
Two weeks before the current presentation, paresthesia developed in the finger-
tips and, over the course of several days, extended to the hands and then the
forearms. One week before the current presentation, the patient was evaluated
by his primary care physician. The temporal temperature was 36.9°C, the blood
pressure 134/82 mm Hg, the heart rate 92 beats per minute, the respiratory rate
18 breaths per minute, and the oxygen saturation 100% while he was breathing
ambient air. The body-mass index (the weight in kilograms divided by the square
of the height in meters) was 25.9. He had no rash. Sensation to light touch and
pinprick was absent from the toes to the midfoot.
Screening tests for human immunodeficiency virus (HIV), hepatitis B and C
viruses, and Lyme disease were negative. The blood level of folate was greater
than 20 ng per milliliter (45 nmol per liter; reference value, >4.6 ng per milliliter
[>10 nmol per liter]), the vitamin B1 (thiamine) level 149.1 nmol per liter (reference
range, 66.5 to 200), and the vitamin B12 (cobalamin) level 235 pg per milliliter
(173 pmol per liter; reference range, 232 to 1245 pg per milliliter [171 to 919 pmol
per liter]). Testing for anti–myelin-associated glycoprotein antibodies was negative.
Imaging studies were obtained.
Dr. Saurabh Rohatgi: Magnetic resonance imaging (MRI) of the head (Fig. 1) was
performed. T2-weighted and fluid-attenuated inversion recovery images, obtained
before the administration of intravenous contrast material, showed mild, nonspe-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C

Figure 1. MRI of the Head.

MRI of the head was performed 5 days before the current presentation. An axial T2‑weighted image (Panel A) and fluid‑attenuated in‑
version recovery (FLAIR) images (Panels B and C) show mild, nonspecific, scattered foci of hyperintensity involving the supratentorial
white matter (Panel C, arrow), with a dominant lesion in the right frontal centrum semiovale and corona radiata (Panels A and B, arrows).
There was no associated abnormal enhancement.

cific, scattered foci of hyperintensity involving years before quitting 4 years before the current
the supratentorial white matter; the dominant presentation. He had consumed three alcoholic
lesion, which was located in the right frontal drinks daily for many years, but 1 month before
centrum semiovale and corona radiata, measured the current presentation, he had reduced con-
1.4 cm in diameter. No associated abnormal sumption to two drinks one or two times per
enhancement was seen on images obtained after week. He used intranasal cocaine three or four
the administration of contrast material. times per week and inhaled nitrous oxide once
Dr. Pullarkat: The patient was referred to a neu- per week. He had last used lysergic acid diethyl-
rology clinic. One week later, while the patient amide and ketamine 10 weeks before the current
was awaiting an appointment in the neurology presentation during a camping trip in rural New
clinic, paresthesia extended into the thighs and England; there were ticks in the area where he
torso. The patient was advised by his primary had camped, but he had not found any ticks on
care physician to present to the emergency de- his body. The patient had a normal diet with no
partment of this hospital for further evaluation. dietary restrictions, and there was no history of
In the emergency department, the patient re- diarrhea or unintentional weight loss. His ma-
ported worsening paresthesia and loss of dexter- ternal grandfather had diabetes, and his pater-
ity in his hands. He was no longer able to play nal grandfather had gastric cancer.
guitar. He had no motor weakness, bowel or The patient was alert and interactive and fol-
bladder incontinence, or double vision. There was lowed commands. The temporal temperature
no change in sensation in his face or in articula- was 36.5°C, the blood pressure 131/82 mm Hg,
tion of his speech, and he had no dysphonia, the heart rate 88 beats per minute, the respira-
dysphagia, or shortness of breath. tory rate 16 breaths per minute, and the oxygen
Other medical history included depression saturation 96% while he was breathing ambient
and chronic knee and ankle pain after trauma. air. He had a flat affect but was oriented to time,
Medications included bupropion and mirtazapine. place, and person. Speech was fluent with intact
There were no known allergies. The patient was naming, repetition, and comprehension. Cranial
a graduate student and lived with several room- nerve examination was normal. Muscle tone and
mates. He was sexually active with women. He strength were normal. In the legs, there was
had smoked one pack of cigarettes per day for 11 reduced sensation to pinprick and to tempera-

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 Case Records of the Massachuset ts Gener al Hospital

ture that extended from the toes to the hips and in the legs suggests involvement of the periph-
flanks, with sparing of the anterior trunk and eral nerves as well. He appeared to have a sub-
the back. In the arms, there was reduced sensa- acute, progressively worsening myeloneuropathy
tion to pinprick and to temperature that extended involving both the posterior columns of the spi-
from the fingers to the shoulders. The reduced nal cord and the peripheral nerves of the legs.1
sensation was most pronounced in the fingers What could cause this?
and toes. Vibratory sensation and proprioception
were decreased below the shins. The reflexes Infection
were 2+ in the arms but were absent in the legs. Tickborne illness is a consideration in this case,
The patient was able to touch the tip of his nose owing to the patient’s recent camping trip. The
with his index finger when his eyes were open most common neurologic manifestations of Lyme
but was unable to do so when his eyes were disease are cranial neuropathies and meningo-
closed. His gait was unsteady, and the Romberg encephalitis; patients with Lyme disease can
test was positive. also have polyradiculopathies and, very rarely,
A diagnostic test was performed. transverse myelitis. However, this patient had no
prodromal symptoms, such as rash or fever, and
serologic tests for Lyme disease were negative.
Differ en t i a l Di agnosis
Other tickborne illnesses are unlikely in the ab-
Dr. William P. Schmitt: This 33-year-old graduate sence of systemic symptoms, and myelopathy
student — who had a history of use of alcohol, would be unusual with these illnesses.
cocaine, nitrous oxide, lysergic acid diethylamide, Poliovirus and enteroviruses can cause trans-
and ketamine — presented with progressively verse myelitis. However, patients with viral myeli-
worsening, painless, symmetric sensory deficits tis typically present with weakness that pro-
that had begun 8 weeks earlier, with eventual gresses over a period of 2 weeks. The absence of
gait and hand ataxia. Because the patient’s pre- weakness during this patient’s steady progres-
sentation is most consistent with a neurologic sion of symptoms over the course of 8 weeks
process, I will begin by localizing the lesion be- makes viral myelitis very unlikely.1 Infection with
fore considering the possible causes of his illness. varicella–zoster virus (VZV), herpes simplex virus
(HSV), or HIV can cause myelopathy. However,
Localization this patient did not have evidence of either acute
Although imaging of the head in this patient VZV or HSV infection or reactivation of VZV or
showed a 1.4-cm lesion in the right frontal cen- HSV replication, and the slow pace of illness is
trum ovale and corona radiata, his symptoms not consistent with these infections. HIV infec-
and examination findings are not consistent tion is unlikely, given the negative screening
with a process involving the central nervous test. Syphilis should also be considered in any
system. He appeared to have a pure sensory patient with suspected disease in the posterior
deficit that started in the toes and progressed columns of the spinal cord. However, classic ta-
proximally to the legs and eventually to the hands bes dorsalis (the form of neurosyphilis in which
and arms; strength was fully preserved, and nerves of the posterior columns of the spinal
there were no signs of cranial nerve involvement. cord degenerate) usually occurs 10 to 20 years
The symmetric, progressive nature of the pa- after initial untreated infection with Treponema
tient’s sensory deficit is suggestive of a process pallidum. Although tabes dorsalis is unlikely in
involving the peripheral nerves, the spinal cord, this relatively young patient, I would still recom-
or both. Paresthesia of the arms in conjunction mend testing for syphilis.
with normal reflexes in the arms may indicate a
myelopathic process rather than neuropathy. The Mechanical Disruption
patient’s normal results on the strength exami- Mechanical disruption of the cervical spinal cord
nation are consistent with a process that is se- by a mass, cervical stenosis, or cervical disk
lectively affecting the posterior columns of the disease can produce myelopathic features. How-
spinal cord; weakness would be expected if ever, it would be unusual for a mechanical pro-
there was involvement of the lateral columns of cess to affect only the posterior columns of the
the spinal cord. However, the absence of reflexes spinal cord, and I would expect the leg reflexes

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 The n e w e ng l a n d j o u r na l of m e dic i n e

to be brisk as opposed to absent. This patient’s tion. Multiple sclerosis can cause myeloneu-
steady progression of symptoms also makes a ropathy, although the pace of this patient’s
mass, cervical stenosis, or cervical disk disease progression is atypical for either the relapsing–
unlikely. However, imaging would be necessary remitting or primary progressive form of mul-
to rule out a mechanical process that disrupts tiple sclerosis. The relapsing–remitting form of
the cervical spinal cord. multiple sclerosis, which is the most common
form, is characterized by symptoms that occur
Inflammatory Demyelinating acutely, over a period of days, before remitting;
Polyneuropathies the pace of this process is too fast to have been
Acute inflammatory demyelinating polyneurop- present in this case. The primary progressive
athy (AIDP) and chronic inflammatory demye- form of multiple sclerosis progresses slowly in
linating polyneuropathy (CIDP) can both cause a linear fashion over a period of years, and mo-
sensory symptoms such as those seen in this pa- tor symptoms predominate; the pace of this
tient. However, the course of illness in patients process is too slow to have been present in this
with AIDP usually peaks within 2 to 4 weeks case.5 In addition, patients with multiple scle-
after the onset of symptoms. Although the time rosis typically have asymmetric sensory loss,
course of this patient’s presentation could be which reflects the patchy distribution of neuro-
consistent with CIDP, both AIDP and CIDP usu- logic lesions. This patient had no cranial nerve
ally affect the motor nerves, which results in abnormalities, eye-movement abnormalities, or
weakness. Uncommon variants of CIDP that spasticity that would support the diagnosis of
cause purely sensory effects have been reported; multiple sclerosis, and the absence of distal leg
however, the symptoms tend to progress more reflexes would be atypical. Other forms of auto-
slowly than those seen in this patient, and loss immune transverse myelitis, such as systemic
of reflexes in the arms would be expected.2 In lupus erythematosus and systemic sclerosis, can
contrast, this patient had paresthesia involving also cause symmetric sensory changes; how­
the arms but had normal reflexes in the arms. ever, such changes are almost always accompa-
The negative test for anti–myelin-associated gly- nied by motor findings, and the pace of evolu-
coprotein antibodies also argues against a sen- tion is often much faster than that seen in this
sory-predominant variant of CIDP.3 patient.6-8
Patients with Sjögren’s syndrome can present
with peripheral neuropathy, but myelopathy is Cancer
rare. Patients with Behçet’s disease can have Patients with paraneoplastic subacute sensory
myelitis, although the presence of myelitis in neuronopathy can present with neuropathy that
such patients is usually associated with other precedes the diagnosis of cancer.9 However, such
central nervous system findings. This patient did neuropathy is usually painful, and this patient’s
not have dry mouth, dry eyes, or enlargement of relatively young age and modest smoking history
the salivary glands — features that would sug- make this diagnosis unlikely.
gest Sjögren’s syndrome — nor did he have
features that would be consistent with Behçet’s Toxic Metabolic Process
disease, such as oral or urogenital lesions. Sar-
This patient had several toxic exposures, includ-
coidosis can also cause neuropathy and myelitis,
ing the frequent use of alcohol, cocaine, and
which develop over a period of hours to days nitrous oxide. Alcohol use can lead to peripheral
until a maximum level of myelopathy symptoms neuropathy, although this outcome is more typi-
is present; the pace of this patient’s illness and
cal in patients who consume larger amounts of
the absence of pulmonary symptoms make sar- alcohol than this patient described. Also, the
coidosis an unlikely diagnosis.4 progression of symptoms in this patient is more
rapid than would be expected for peripheral
Multiple Sclerosis and Other Autoimmune neuropathy associated with alcohol use. The use
Diseases of cocaine can cause strokes and nerve infarcts,
The first manifestation of multiple sclerosis and a stroke could explain the brain lesion seen
commonly includes sensory symptoms that on MRI, but cocaine use is not commonly asso-
range from mild paresthesia to loss of sensa- ciated with myelopathy or neuropathy.

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 Case Records of the Massachuset ts Gener al Hospital

A Mechanism of Functional Vitamin B12 Deficiency B Normal C Vitamin B12 Deficiency

with Nitrous Oxide Use
Shorter,
Myelin
thinner,
sheath
Methylmalonic acid and damaged
Methylmalonyl segments
coenzyme A mutase of myelin
Methylmalonyl Succinyl
coenzyme A Adenosylcobalamin coenzyme A
(cofactor B12)

Nitrous
oxide
Cob(I)alamin
(active monovalent B12)

Cob(II)alamin Nodes of Additional

5-Methyltetrahydrofolate
(inactive bivalent B12) Ranvier nodes of
Tetrahydrofolate Ranvier
Methylcobalamin
(cofactor B12)
Homocysteine Methionine Myelin
sheath
Methionine
synthase

Figure 2. Mechanism of Functional Vitamin B12 Deficiency with Nitrous Oxide Use.
Panel A shows the mechanism of functional vitamin B12 deficiency in a patient with nitrous oxide use. Nitrous oxide
irreversibly inhibits the catalytic functions of vitamin B12 by transforming it from the active monovalent form to the
inactive bivalent form through the oxidation of the cobalt portion of methylcobalamin. Vitamin B12 acts as a critical
enzyme that converts methylmalonic acid to succinyl coenzyme A and converts homocysteine to methionine (with
folate as a cofactor). Increased levels methylmalonic acid can be neurotoxic. Decreased levels of methionine impair
the production and maintenance of the myelin sheaths of sensory neurons. The red X indicates a blocked pathway,
and the green arrow an increased concentration. Panels B and C show the features of a normal axon and an axon in
a patient with vitamin B12 deficiency, respectively.

Patients with vitamin B12 deficiency can have This patient’s clinical picture is most consis-
myeloneuropathy that is caused by dysfunction tent with vitamin B12 deficiency, even though his
in the posterior columns of the spinal cord that vitamin B12 level was normal. Risk factors for
leads to progressive symmetric loss of sensation vitamin B12 deficiency include poor nutrition,
in the legs, accompanied by ataxia.10 The condi- impaired absorption of vitamin B12 (e.g., due to
tion can progress to involve the arms and, if left pernicious anemia or previous bariatric surgery),
untreated, can result in distal neuropathy. Vita- or inactivation of vitamin B12 as a result of inter-
min B12 acts as a critical enzyme that converts ference with its catalytic activity. This patient’s
homocysteine to methionine (with folate as a frequent use of nitrous oxide (also known as
cofactor) and converts methylmalonic acid to “laughing gas” or “whippets”) may provide the
succinyl coenzyme A. Functional vitamin B12 explanation for his presentation. Nitrous oxide
deficiency causes decreased levels of methio- irreversibly inhibits the catalytic functions of
nine, which in turn impair the production and vitamin B12 by transforming it from the active
maintenance of the myelin sheaths of sensory monovalent form to the inactive bivalent form
neurons. In addition, functional vitamin B12 de- (Fig. 2).12 Despite the presence of a normal blood
ficiency results in an increase in the level of level of vitamin B12 in this patient, the vitamin
methylmalonic acid, which can be neurotoxic. may not have been in a functional form and
Patients with copper deficiency can have a simi- therefore may have caused the same pathologi-
lar presentation.11 Although this patient did not cal process as that which occurs in patients who
have typical risk factors for copper deficiency, are deficient in vitamin B12.
such as previous bariatric surgery, malnutrition, To establish the diagnosis of functional vita-
or overuse of zinc-containing denture cream, I min B12 deficiency in the context of nitrous oxide
would still measure the blood level of copper. use, I would obtain an MRI of the spine to look

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

Figure 3. MRI of the Spine.

MRI of the cervical and thoracic spine was performed after admission. A sagittal T2‑weighted image of the cervical
spine (Panel A) and a short‑tau inversion recovery (STIR) image of the thoracic spine (Panel B) show a long segment
of hyperintensity involving the cervical and thoracic spine (at C2–C6 and T1–T5) (Panels A and B, arrows). There
was no associated abnormal enhancement. An axial T2‑weighted image of the cervical spine (Panel C) shows hyper‑
intensity involving the posterior columns of the cervical spine in an inverted‑V pattern (arrow).

for enhancement of the posterior columns of the No signs of impairment of the lateral columns
cervical and thoracic spinal cord, a finding that (e.g., muscle weakness, diffuse hyperreflexia,
would be highly suggestive of vitamin B12 defi- or spasticity) were present at the time of diag-
ciency or copper deficiency. I would expect the nosis.13
blood levels of methylmalonic acid and homo- The patient’s subacute course over a period of
cysteine to be elevated. weeks to months and his history of substance
use strongly pointed to a metabolic process or a
direct effect of drugs or toxins. His history of
Dr . W il l i a m P. Schmi t t ’s
Di agnosis nitrous oxide use made a functional vitamin B12
deficiency most likely.
Functional vitamin B12 deficiency from use of
nitrous oxide. Cl inic a l Di agnosis
Functional vitamin B12 deficiency from use of
Cl inic a l Impr e ssion
nitrous oxide.
Dr. Marcelo Matiello: This patient’s progression of
symptoms fit the clinical presentation of sub- Im aging S t udie s
acute combined degeneration of the spinal cord.
His symptoms were related to degeneration of Dr. Rohatgi: MRI of the cervical and thoracic
the posterior columns of the spinal cord, includ- spine was performed (Fig. 3). T2-weighted and
ing paresthesia (observed in the form of tingling short-tau inversion recovery images showed a long
and burning) followed by impaired propriocep- segment of hyperintensity involving the cervical
tion and vibratory sensation (leading to ataxia). and thoracic spine (at C2–C6 and T1–T5) with no

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 Case Records of the Massachuset ts Gener al Hospital

associated enhancement. An axial T2-weighted

image showed hyperintensity involving the pos- Anterior median fissure Anterior root
terior columns of the cervical spine in an invert-
ed-V pattern. The differential diagnosis of signal Central canal
change within the cord is broad. After a com- White matter Posterior root
pressive myelopathy or cancer is ruled out, the
differential diagnosis can be further narrowed Gray matter
Posterior median sulcus
on the basis of the pattern of cord involvement
(Fig. 4).14-16 In this patient, the posterior columns
of the spinal cord were involved; this pattern is A Central B Central Gray Matter
commonly seen in patients with deficiencies of
vitamin B12 or copper, in patients with toxic ef-
fects from excess ingestion of zinc or from the
use of nitrous oxide, or in patients with tertiary
syphilis.

C Peripheral Short Segment D Posterior Columns

L a bor at or y Te s t ing
Dr. Matiello: The blood levels of copper and zinc
were normal, and a screening test for T. pallidum
IgG and IgM was negative. The blood methylma-
lonic acid level was 6.41 nmol per milliliter
(reference value, <0.40) and the blood homocys-
teine level 63.9 μmol per liter (reference range, E Centripetal F Anterior Horns
0 to 14.2). Taken together with the patient’s his-
tory of nitrous oxide use and the findings on
MRI of the spine, a diagnosis of functional vita-
min B12 deficiency from the use of nitrous oxide
was made.
Figure 4. Cross-Sectional Patterns of Spinal Cord Involvement.
Im aging a nd L a bor at or y A central pattern of cord involvement (Panel A) is characteristic of neuro‑
Di agnosis myelitis optica spectrum disorder, acute disseminated encephalomyelitis,
and spinal dural arteriovenous fistula. This pattern can also be seen with
Functional vitamin B12 deficiency from use of systemic inflammatory or infectious diseases. A central gray‑matter pattern
of cord involvement (Panel B) is more common in patients with infarction
nitrous oxide.
or cord compression. A peripheral short‑segment pattern of cord involve‑
ment (Panel C) is more common in patients with multiple sclerosis. In‑
Discussion of Neurol o gy volvement of the posterior columns of the cord (Panel D) can be seen in
M a nagemen t patients with vitamin B12 or copper deficiency, in patients with toxic effects
from excess ingestion of zinc or from the use of nitrous oxide, or in patients
with tertiary syphilis. A centripetal pattern of cord involvement (Panel E)
Dr. Matiello: Recreational exposure to nitrous ox-
is typical in patients with sarcoidosis. Involvement of the anterior horns of
ide causes irreversible inactivation of vitamin B12 the cord (Panel F) is characteristic of infarction or viral infections such as
through the oxidation of the cobalt portion of enterovirus or poliovirus.
methylcobalamin. Inactivation of vitamin B12
leads to the impairment of myelin production
and maintenance.17,18 Moreover, inactivation of effects of nitrous oxide was provided to this
vitamin B12 results in elevated levels of methyl- patient, and his cessation efforts were further
malonic acid, which can be neurotoxic and can supported by consultation with the addiction
cause further damage. medicine service. The second step is supplemen-
Two main treatment steps are simple yet ef- tation with vitamin B12, which in this patient
ficacious in stopping further nervous system was achieved by the administration of intramus-
damage. The first step is cessation of the use cular injections of cyanocobalamin once daily
of nitrous oxide. Education regarding the toxic for 5 days. In patients with normal absorption,

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 Case Records of the Massachuset ts Gener al Hospital

oral and intramuscular cyanocobalamin treat- transferred to the psychiatry floor, and treat-
ments result in similar serum vitamin B12 levels; ment included electroconvulsive therapy.
therefore, oral supplementation with cyanoco- On follow-up, 3 months after the diagnosis,
balamin once daily can be used after initial the patient had mild improvement in the dexter-
parenteral replacement. Although the most im- ity of his hands, although he continued to have
portant management step is the cessation of difficulty with fine movements including playing
nitrous oxide use, oral cyanocobalamin supple- guitar. He continued to have numbness and tin-
mentation is planned to be continued indefi- gling in the fingertips and feet, along with gait
nitely, given that this patient also had low-normal instability. There was no recurrence of suicidal
vitamin B12 levels.19 ideation, and he had stopped using nitrous oxide.
Vitamin B12 deficiency can lead to many neu-
ropsychiatric manifestations, including apathy, Fina l Di agnosis
decreased memory, personality changes, emo-
tional lability, and, in more severe cases, psycho- Functional vitamin B12 deficiency from use of
sis and auditory and visual hallucinations.20 nitrous oxide.
Later in this patient’s hospitalization, he began
This case was presented at the Medicine Case Conference.
to have severe symptoms, including depression, Disclosure forms provided by the authors are available with
suicidal ideation, and signs of catatonia. He was the full text of the article at NEJM.org.

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