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Introduction
  • Mechanism  
    • stretching injury
      • 8% elongation will diminish nerve's microcirculation
      • 15% elongation will disrupt axons
      • examples
        • "stingers" refer to neurapraxia from brachial plexus stretch injury
        • suprascapular nerve stretching injuries in volley ball players
        • correction of valgus in TKA leading to peroneal nerve palsy
    • compression/crush
      • fibers are deformed
        • local ischemia
        • increased vascular permeability
      • endoneurial edema leads to poor axonal transport and nerve dysfunction
      • fibroblasts invade if compression persists
        • scar impairs fascicular gliding
      • 30mm Hg can cause paresthesias
        • increased latencies
      • 60 mm Hg can cause complete block of conduction
    • laceration
      • sharp transections have better prognosis than crush injuries
      • continuity of nerve disrupted
        • ends retract
        • nerve stops producing neurotransmitters
        • nerve starts producing proteins for axonal regeneration
  • Pathophysiology
    • regeneration process after transection  
      • distal segment undergoes Wallerian degeneration (axoplasm and myelin are degraded distally by phagocytes)
      • existing Schwann cells proliferate and line up on basement membrane
      • proximal budding (occurs after 1 month delay) leads to sprouting axons that migrate at 1mm/day to connect to the distal tube
    • variables affecting regeneration  
      • contact guidance with attraction to the basal lamina of the Schwann cell
      • neurotropism
      • neurotrophism
      • neurotrophic factors (factors enhancing growth and preferential attraction to other nerves rather than other tissues)
  • Prognosis  
    • factors affecting success of recovery following repair
      • age 
        • is single most important factor influencing success of nerve recovery
      • level of injury 
        • is second most important (the more distal the injury the better the chance of recovery)
      • sharp transections
        • have better prognosis than crush injuries
      • repair delay 
        • worsen prognosis of recovery (time limit for repair is 18 months)
    • return of function
      • pain is first modality to return
Anatomy
  • Highly organized structure consisting of nerve fibers, blood vessels, and connective tissue
  • Functional structures   
    • epineural sheath
      • surrounds peripheral nerve
    • epineurium
      • surrounds a group of fascicles to form peripheral nerve
      • functions to cushion fascicles against external pressure 
    • perineurium
      • connective tissue covering individual fascicles
      • primary source of tensile strength and elasticity of a peripheral nerve 
      • provides extension of the blood-brain barrier
      • provides a connective tissue sheath around each nerve fascicle
    • fascicles
      • a group of axons and surrounding endoneurium
    • endoneurium
      • fibrous tissue covering axons
      • participates in the formation of Schwann cell tube
    • myelin
      • made by Schwann cells
      • functions to increase conduction velocity
    • neuron cell
      • cell body - the metabolic center that makes up < 10% of cell mass
      • axon - primary conducting vehicle
      • dendrites - thin branching processes that receive input from surrounding nerve cells
  • Blood supply
    • extrinsic vessels
      • run in loose connective tissue surrounding nerve trunk
    • intrinsic vessels
      • plexus lies in epineurium, perineurium, and endoneurium 
  • Physiology
    • presynaptic terminal & depolarization
      • electrical impulse transmitted to other neurons or effector organs at presynaptic terminal
      • resting potential established from unequal distribution of ions on either side of the neuron membrane (lipid bilayer)
      • action potential transmitted by depolarization of resting potential
      • caused by influx of Na across membrane through three types of Na channels
        • voltage gate channels
        • mechanical gated channels
        • chemical-transmitter gated channels
    • nerve fiber types
Fiber Type
Diameter (uM)
Myelination
Speed
Example
A
10-20
heavy
fast
touch
B
< 3
moderate
medium
ANS
C
< 1.3
none
slow
pain
 
Classification
  • Seddon Classification
    • neurapraxia 
      • same as Sunderland 1st degree, "focal nerve compression"
      • nerve contusion leading to reversible conduction block without Wallerian degeneration
      • histology
        • histopathology shows focal demyelination of the axon sheath (all structures remain intact)
        • usually caused by local ischemia 
      • electrophysiologic studies
        • nerve conduction velocity slowing or a complete conduction block
        • no fibrillation potentials 
      • prognosis
        • recovery prognosis is excellent
    • axonotmesis 
      • same as Sunderland 2nd degree
      • axon and myelin sheath disruption leads to conduction block with Wallerian degeneration 
      • endoneurium remains intact
      • fibrillations and positive sharp waves on EMG
    • neurotmesis
      • complete nerve division with disruption of endoneurium
      • no recovery unless surgical repair performed 
      • fibrillations and positive sharp waves on EMG
Seddon Type
Degree
Myelin Intact
Axon Intact
Endoneurim Intact
Wallerian Degen.
Reversible
Neurapraxia
1st
No
Yes
Yes
No
reversible
Axonotmesis
2nd
No
No
Yes
Yes
reversible
Neurotmesis
3rd
No
No
No
Yes
irreversible
  • Sunderland Classification
    • 1st degree
      • same as Seddon's neurapraxia
    • 2nd degree
      • same as Seddon's axonotmesis
    • 3rd degree 
      • included within Seddon's neurotmesis
      • injury with endoneurial scarring
      • most variable degree of ultimate recovery
    • 4th degree
      • included within Seddon's neurotmesis
      • nerve in continuity but at the level of injury there is complete scarring across the nerve)
    • 5th degree
      • included within Seddon's neurotmesis

Sunderland Grade
Myelin Sheath
Axon
Endoneurim
Perineurium
Epineurium
I
Disrupted
Intact Intact
Intact
Intact
II
Disrupted
Disrupted
Intact
Intact
Intact
III
Disrupted
Disrupted
Disrupted
Intact
Intact
IV Disrupted
Disrupted Disrupted Disrupted Intact
V Disrupted Disrupted Disrupted Disrupted Disrupted
 
Evaluation
  • EMG
    • often the only objective evidence of a compressive neuropathy (valuable in workcomp patients with secondary gain issues)
    • characteristic findings
      • denervation of muscle
        • fibrillations
        • positive sharp waves (PSW)
        • fasiculations
      • neurogenic lesions
        • fasiculations
        • myokymic potentials
      • myopathies
        • complex repetitive discharges
        • myotonic discharges
  • NCV
    • focal compression / demyelination leads to
      • increase latencies (slowing) of NCV
        • distal sensory latency of > 3.2 ms are abnormal for CTS
        • motor latencies > 4.3 ms are abnormal for CTS
      • decreased conduction velocities less specific that latencies
        • velocity of < 52 m/sec is abnormal
      • motor action potential (MAP) decreases in amplitude
      • sensory nerve action potential (SNAP) decreases in amplitude
Treatment
  • Nonoperative
    • observation with sequential EMG
      • indications
        • neuropraxia (1st degree)
        • axonotmesis (2nd degree)
  • Operative
    • surgical repair
      • indications
        • neurotomesis (3rd degree)
    • nerve grafting
      • indications
        • defects > 2.5 cm
      • type of autograft (sural, saphenous, lateral antebrachial, etc)
        • no effect on functional recovery
Surgical Techniques
  • Direct muscular neurotization
    • insert proximal nerve stump into affected muscle belly
    • results in less than normal function but is indicated in certain cases
  • Epineural Repair
    • primary repair of the epineurium in a tension free fashion
    • first resect proximal neuroma and distal glioma
    • it is critical to properly align nerve ends during repair to maximize potential of recovery
  • Fasicular repair
    • indications
      • three indications exist for grouped fascicular repair
        • median nerve in distal third of forearm
        • ulnar nerve in distal third of forearm
        • sciatic nerve in thigh
    • technique
      • similar to epineural repair, but in addition repair the perineural sheaths (individual fascicles are approximated under a microscope)
    • outcomes
      • no improved results have been demonstrated over epineural repair
  • Nerve grafting
    • autologous graft
      • indications
        • ≥ 3cm gap
      • digital nerve defects
        • at wrist to common digital nerve bifurcation - use sural nerve
        • at MCP to DIP level - use lateral antebrachial cutaneous nerve
        • at DIP level - use AIN, PIN or medial antebrachial cutaneous nerve
      • outcomes
        • gold standard for segmental defects > 5cm    
    • collagen conduit
      • tensioned closures inhibit Schwann cell activation and axon regeneration, compromise perfusion and lead to scarring
      • collagen conduits allow nutrient exchange and accessibility to neurotrophic factors to the axonal growth zone during regeneration
      • indications
        • defects ≤ 2cm
      • outcomes
        • equal results to autologous grafting when gap ≤5mm 
        • quality of nerve recovery drops with gaps >5mm
    • allograft
      • off-the-shelf option for defects up to 5cm
 

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Questions (9)

(OBQ13.24) Which statement most accurately describes the physiology of peripheral nerve regeneration following an axonotmesic lesion? Review Topic

QID:4659
1

The proximal nerve segment undergoes Wallerian degeneration

14%

(425/3111)

2

Axon growth occurs from the distal segment to proximal segment

3%

(98/3111)

3

Neurotrophic factors direct phagocytic activity

7%

(212/3111)

4

Proximal axon budding allows for antegrade (or distal) axon migration

71%

(2208/3111)

5

Axoplasm and myelin are degraded distally predominantly by Schwann cells for the first 12 months following injury

5%

(151/3111)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

Axonomesis is a disruption of the nerve axon following injury. Repair/regeneration of the nerve occurs via proximal budding, followed by antegrade (or distal) axon migration.

The peripheral nerve regeneration process begins with the distal segment undergoing Wallerian degeneration (axoplasm and myelin are degraded distally by phagocytes). Existing Schwann cells proliferate and line-up along the basement membrane. Proximal budding occurs after a one-month delay. This is followed by sprouting axons that migrate in an antegrade fashion to connect to the distal tube. Repair of the nerve can take months, and often have poor outcomes.

Lee et al. reviewed peripheral never injury and repair. They commented that Wallerian degeneration (i.e., breakdown of the axon distal to the site of injury) is initiated 48 to 96 hours after transection. The Schwann cells then align themselves longitudinally, creating columns of cells called Büngner bands. At the tip of the regenerating axon is the growth cone.

Illustration A shows a chart of peripheral nerve injury. The two main classification systems are Seddon and Sunderland. Video V is a lecture discussing peripheral nerve injury and management.

Incorrect Answers:
Answer 1: The distal nerve segment undergoes Wallerian degeneration.
Answer 2: Axon growth occurs from the proximal to distal segment.
Answer 3: Neurotrophic factors do not direct phagocytic activity.
Answer 5: Schwann cells do not degrade axoplasm and myelin.

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(OBQ12.46) The patient sustains the injury seen in Figure A from a gunshot injury. The physical exam is notable for lack of sensation in his fourth and fifth digits as well as a positive Froment's sign. Which of the following factors has not been shown to be a significant prognostic indicator of functional recovery following nerve repair? Review Topic

QID:4406
FIGURES:
1

Duration to time of repair

12%

(416/3570)

2

Repair level

7%

(256/3570)

3

Length of repair

8%

(297/3570)

4

Postoperative physical rehabilitation

26%

(940/3570)

5

Type of autograft used

46%

(1648/3570)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

The clinical scenario describes an ulnar nerve laceration. Studies have shown that the ulnar nerve does not typically have good outcomes after nerve repair. (worse recovery than repairs of the tibial, radial, femoral, and musculocutaneous nerves)

Nerve injuries from gunshot injuries (GSWs) can cause both a direct injury to the nerve as well as surrounding structures (zone of injury). Many factors including age of patient, time to repair, repair level, and length of repair have been shown to be important determinants in nerve recovery following repair. The type of nerve graft (sural, saphenous, etc) used has not shown to be statistically significant in terms of functional recovery after nerve repair.

Secer et al.(J. Neurosurg) reviewed 2210 peripheral nerve lesions in 2106 patients which were injured by a GSW and who were treated surgically. Of the peripheral nerves repaired surgically, the tibial, median, and femoral nerve lesions showed the best recovery rate. The deep peroneal nerve, ulnar nerve, and brachial plexus lesions had the worst recovery.

Secer et al.(Surg. Neur.) found that of 455 patients with 462 ulnar nerve lesions only a good outcome was noted in 15.06% of patients who underwent high-level repair, 29.60% of patients who underwent intermediate-level repair, and 49.68% of patients after low-level repair. The authors also noted that a better functional recovery was noted in patients who were treated earlier.

Figure A shows a distal humerus fracture caused by a GSW.

Incorrect Answers
Answer 1: Earlier nerve repairs typically have better functional results.
Answer 2: The lower level of nerve repair (more distal), the better functional results.
Answer 3: Shorter length of the nerve repair typically leads to better functional results.
Answer 4: Pre and post operative physical rehabilitation after nerve repairs has been shown to have better results.


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(OBQ12.210) A 55-year-old male laborer comes in with a chief complaint of clumsiness with his right hand for the past 3 months including difficulty using a hammer while at work. He has had no injury to the right upper extremity. On physical examination, he has persistent small finger abduction/extension with finger extension and active adduction. An EMG is performed and demonstrates ulnar nerve conduction velocities of 31 m/sec (normal >52m/sec). The patient symptoms are most accurately described as Review Topic

QID:4570
1

Axonotmesis with ischemia origin

12%

(396/3364)

2

Axonotmesis with myelin disruption

17%

(567/3364)

3

Neurapraxia with ischemia origin

58%

(1941/3364)

4

Neurapraxia with endoneurium disruption

11%

(370/3364)

5

Neurotmesis

2%

(56/3364)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

The history and clinical presentation are consistent with ulnar entrapment neuropathy at the level of the cubital tunnel. This would be classified as a neuropraxia with ischemia origin.

Compression injuries to the peripheral nerves are often the result of micro-vascular dysfunction as the nerves traverse a high to low pressure gradient. Peripheral nerve injury can be classified as neuropraxia, axonotmesis and neurotmesis. Compressive neuropathies are typically neuropraxias, with local myelin damage but not compromise of the major components of the nerve. In axonotmesis, there is Wallerian degeneration and myelin loss distal to the site of injury. The most severe type is that of neurotmesis. Neurotmesis is composed of a spectrum of injury, in which all components are affected except for the perineurium or the endoneurium may be intact. The worst form of neurotmesis is that of nerve transection.

Elhassan et al. review the pathophysiology of cubital tunnel syndrome. They report nerve dysfunction results from ischemic changes secondary to compression. Compressive effects on the nerves can last greater than 24 hours, even after the source of compression has been removed.

Rempel et al. review the pathophysiology of peripheral nerve compression syndromes. The authors indicate that deforming pressures to nerves are often the result of stenotic soft tissue canal boundaries. This leads to interference with local microvasculature of the nerve itself.

Incorrect Answers:
Answer 1, 2: Axonotmesis is considered a second degree nerve injury, characterized by Wallerian degeneration of axons distal to site of injury. Compression neuropathies are more often neuropraxias (1st degree nerve injury)
Answer 4: Compression neuropathies result from ischemic insult to the nerve
Answer 5: Neurotmesis may be characterized by complete disruption of all components of nerve (as in transection) or with disruption of all components except for the perineurium or the endoneurium. This is not characteristic of a compression neuropathy such as cubital tunnel syndrome.

Illustration A demonstrates the Wartenberg sign, where the patient has persistent small finger abduction/extension resulting from weakness of the 3rd palmar interosseous/small finger lumbrical.
Illustration B reveals clawing which results from over powering of the intrinsic muscles by the extensors; a tenodesis effect results in flexion of the PIP/DIP joints. This is more severe in ulnar nerve compression at Guyon’s canal.
Illustration C shows the Froment sign, where the FPL attempts to compensate for a deficient pinch, because of weakness of the adductor pollicis. Illustration D demonstrates atrophy of the 1st dorsal webspace from chronic compressive changes.
Illustration E demonstrates atrophy of the thenar compartment which is consistent with carpal tunnel syndrome.

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(OBQ09.268) You are seeing a 24-year-old male in the emergency room after he was involved in a knife fight. He has severed the common digital nerve to the index finger on his dominant hand, with an 8mm gap between nerve ends. In counseling him about repair, which of the following options is as good as autologous nerve grafting? Review Topic

QID:3081
1

Glycolide trimethylene carbonate conduit

5%

(89/1751)

2

Collagen conduit

61%

(1075/1751)

3

Silicone sleeve

7%

(122/1751)

4

Primary end-to-end repair

13%

(235/1751)

5

Polyglycolic acid conduit

13%

(225/1751)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Repair of segmental nerve loss in the hand using collagen conduits allows for nutrient exchange and accessibility of neurotrophic factors to the axonal growth zone during regeneration. While the other listed answers have been used, none has shown the efficacy of collagen conduits or autograft.

Li et al. describe the repair of peripheral nerves with a tubular collagen conduit and review supporting data from in vitro and in vivo primate studies to this regard.

Bertleff et al. describe the recovery of sensory nerve function after treatment of traumatic peripheral nerve lesions with a biodegradable poly(DL-lactide-epsilon-caprolactone) neurolac nerve guide, compared to their control of end-to-end repair, no autologous grafting. They show equal results between primary end-to-end repair and their synthetic graft.

Waitayawinyu et al. compared 2 synthetic polyglycolic acid conduits to autogenous nerve grafting using histopathologic and neurophysiologic analyses in a segmental defect rat model. They found that collagen conduits and autografts produced comparable results, which were significantly better than polyglycolic acid conduits.

Video V is a lecture discussing peripheral nerve injury and management.

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(OBQ08.30) Which of the following nerves has the most favorable regenerative potential in restoring motor function after a graft repair within half a year after being injured? Review Topic

QID:416
1

Median

22%

(432/1983)

2

Ulnar

10%

(199/1983)

3

Radial

61%

(1204/1983)

4

Tibial

4%

(77/1983)

5

Peroneal

3%

(63/1983)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Of the choices listed, the radial nerve has the best opportunity for recovery.

Roganovic performed a prospective study of 393 graft repairs of the median, ulnar, radial, tibial, peroneal, femoral, and musculocutaneous nerves which showed that peripheral nerves differ significantly regarding the motor recovery potential, and the difference depends on the level of nerve repair. The following nerves had excellent recovery potential: the radial, musculocutaneous, and femoral nerves. The following nerves had moderate recovery potential: the median, ulnar, and tibial nerves. The following nerve had poor recovery potential: the peroneal nerve.

Mohler et al, recommends testing nerve action potentials at the time of nerve exploration to guide surgical treatment.


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(OBQ05.66) Axon regeneration almost always occurs following a Sunderland second-degree nerve injury because which anatomic structure is not injured? Review Topic

QID:952
1

Epineurium

23%

(216/932)

2

Endoneurium

52%

(481/932)

3

Perineurium

10%

(91/932)

4

Myelin sheath

11%

(103/932)

5

Schwann cell

4%

(34/932)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Following a Sunderland second-degree injury, axon regeneration is possible because the endoneurium is intact.

There are two classification schemes for peripheral nerve injuries, which include the Seddon and the Sunderland systems. Under the Sunderland classification, a second-degree injury is considered a part of the axonotmesis spectrum. The endoneurium, perineurium and epineurium are still intact. This enables complete functional recovery.

Lee et al. review the pathophysiology and evaluation of peripheral nerve injuries. They note that in Sunderland type two injuries, there is physiologic disruption of the axons. Because the endoneurium is still intact, axons are able to regenerate. This process takes months.

Illustration A is a schematic of the various stages of peripheral nerve injury.

Incorrect Answers
Answers 1, 3: Although the epineurium and perineurium are intact in a Sunderland type 2 injury, axon regeneration is possible because of an intact endoneurium.
Answers 4, 5: The myelin sheath and Schwann cells are disrupted in axonotmesis.

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(OBQ05.218) Vitamin B12 deficiency is a known cause of which the following? Review Topic

QID:1104
1

Inability to whistle

0%

(6/2361)

2

Peripheral sensory neuropathy

96%

(2277/2361)

3

Increased deep tendon reflexes

3%

(65/2361)

4

Urinary retention

0%

(4/2361)

5

Hydrophobia

0%

(3/2361)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Vitamin B12 deficiency is a known cause of peripheral sensory neuropathy and B12 levels should be evaluated in patients presenting with peripheral sensory neuropathy. It is associated with decreased deep tendon reflexes, pathologic reflexes like Babinski's sign, and fatigue/depression. The inability to whistle is associated with fascioscapular dystrophy. Hydrophobia is associated with rabies infection.

Smith and Singleton evaluated 138 patients referred with predominantly sensory symptoms to identify a standardized approach to diagnosis. They recommend that patients be tested for glucose tolerance and vitamin B(12) concentration in all cases, but that other tests should be performed only when the clinical scenario is suggestive.

Steiner et al. describe a case report of a patient with vitamin B12 sensory peripheral neuropathy and associated EMG evidence of nerve demyelination as the potential cause for the observed clinical symptoms.


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(OBQ04.248) Which of the following structures are slowly adapting skin receptors that detect pressure, texture, and low frequency vibration and are best evaluated by static two-point discrimination? Review Topic

QID:1353
1

Meissner's corpuscles

19%

(117/628)

2

Pacinian corpuscles

48%

(301/628)

3

Merkel's receptor

27%

(171/628)

4

Free nerve endings

2%

(10/628)

5

Ruffini corpuscles

4%

(22/628)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Merkel's skin receptors are slowly adapting skin receptors that detect pressure, texture, and low frequency vibration and can be appropriately evaluated by static two-point discrimination. Merkel's disk receptors adapt slowly and sense sustained pressure, texture, and low-frequency vibrations.

Szabo et al state in their review that static and moving two point discrimination are best to initially evaluate innervation density for both quickly and slowly adapting fibers. Vibratory moving 2 point discrimination is best for evaluation of quickly adapting fibers.

Meissner corpuscle, a rapidly adapting sensory receptor, is very sensitive to touch. Pacinian corpuscles are ovoid in shape, measuring approximately 1 mm in length. They respond to high-frequency vibration and rapid indentations of the skin. Ruffini corpuscles are slowly adapting receptors that detect stretching of the skin.

Illustration A demonstrates Meissner's corpuscles (A), Pacinian corpuscles (B), Merkel's receptor (C), free nerve ending (D), and Ruffini corpuscles (E). Illustration B displays the function and location of the receptors.

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(OBQ04.257) Which of the following peripheral nerve structures functions to cushion the nerve against external pressure? Review Topic

QID:1362
1

Endoneurium

9%

(38/442)

2

Fibronectin

2%

(9/442)

3

N-cadherin

1%

(3/442)

4

Epineurium

66%

(292/442)

5

Perineurium

22%

(99/442)

Select Answer to see Preferred Response

PREFERRED RESPONSE 4

The epineurium is a supportive sheath surrounding peripheral nerves that cushions fascicles against external pressure. It is comprised of a loose meshwork of collagen and elastin fibers that are aligned parallel with the nerve fibers.

Illustration A & B depicts the contents of a nerve including epineurium, perineurium, and endoneurium.

Incorrect Answers:
Answer 1: Endoneurium is a fibrous tissue that covers the axon, Schwann cell, and myelin of each nerve fiber.
Answer 2: Fibronectin and laminin are extracellular matrix glycoproteins that facilitate directional nerve fiber branching.
Answer 3: N-cadherin is an adhesive membrane glycoproteins on neural ectoderm and facilitate growing axons.
Answer 4: Perineurium is a dense connective tissue which surrounds nerve fascicles. It provides high tensile strength. The perineurium also limits diffusion within the intraneural environment and subsequently prevents injury from edema.




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