Tuesday Nov 15, 20059:30 – 11:00Lecture

Esophageal Physiology, Motility and Related Pathologic Conditions

Arnold Wald, M. D. (walda@upmc.edu)

Learning Objectives

1. Discuss the normal physiology of swallowing from the mouth to the stomach.2. Compare the normal and abnormal neuromuscular activity of the esophagus.3. Understand the symptoms of esophageal disorders with particular attention to

dysphagia and its evaluation.4. Understand the difference between dysphagia and odynophagia, including the

underlying causes of each.5. Distinguish the physiologic and clinical differences between structural and

functional causes of dysphagia.6. Explain the predominant pathophysiologic mechanisms underlying

gastroesophageal reflux.7. Discuss pathophysiology and management of achalasia.

Suggested Readings

Arora AS, Conklin JL. Practical approaches to dysphagia caused by esophageal motor disorders. Current Gastroenterology Reports, 2001;3:191-9.

Sontag SJ. Gastroesophageal reflux disease. In Clinical Practice of Gastroenterology. LJ Brandt Ed. Churchill Livingstone, Philadelphia 1999; pp 21-33.

Function of the Esophagus

The primary physiologic function of the esophagus is to transport a food bolus from the mouth to the stomach. This lecture reviews the process of swallowing and transportation via the esophagus to the stomach, beginning with the transfer of a bolus from the pharynx to the upper esophagus and continuing with the movement of material into the stomach.

Pathologic conditions of the esophagus will be reviewed here. These frequently involve disturbance of normal swallowing and of esophageal motility. Other disorders of the esophagus are covered in the pathology lectures for this course.

Physiology of Swallowing

Oropharyngeal PhaseThe initial stages of the act of swallowing – the so-called oropharyngeal phase, involve neuromotor function in the mouth and pharynx. After the ingested bolus is suitably prepared by chewing and mixing with saliva or liquid , it is moved voluntarily from the mouth into the pharynx on initiation of a swallow. The movement of the bolus through the pharynx (the pharyngeal stage of swallowing) is referred to as the

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transfer stage. This stage of swallowing is highly integrated and coordinated through a rapid series of events that occur less than 1 second after swallowing is initiated.

When the person decides to force a bolus from the oral cavity into the oropharynx;

1) the soft palate is elevated against the posterior pharyngeal wall, thereby sealing off the nasopharynx and preventing regurgitation into the nasal cavity, 2) the afferent nerve endings in the oropharynx and pharynx are stimulated on initiation of the swallowing act, and 3) the bolus is pushed into the proximal pharynx, initiating a reflex action that cannot be aborted; 4) the posterior pharyngeal constrictor muscles contract sequentially in a caudad direction, 5) forcing the food bolus into the hypopharynx (pyriform sinuses) and 6) through the receptively relaxed upper esophageal sphincter (cricopharyngeus). As swallowing begins, 7) the cricopharyngeus muscle relaxes at the same time 8) a pharyngeal peristaltic wave propels the bolus in a caudad direction.

Within 2 seconds of the initiation of the swallow, the bolus is completely cleared from the pharynx and hypopharynx, including the recesses of the pyriform sinuses, through the UES into the upper esophagus.

In the esophagus, an integrated mechanism transports material by peristaltic contractions into the stomach via coordinated relaxation of the lower esophageal sphincter (LES). The normal tone of the LES helps prevent reflux of gastric contents back into the esophagus. The esophagus has no storage capacity and there is no meaningful retention of food or liquids under normal circumstances.

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Normal Esophageal Motility

Figure 1:

Primary Peristalsis Secondary Peristalsis

At rest, the normal esophagus is quiescent, with no spontaneous contractions, and both sphincters are tonically contracted. Swallows trigger relaxation of the upper and lower esophageal sphincters and give rise to a peristaltic contraction traveling smoothly through the striated and then the smooth muscle portion of the esophagus (Figure 1, left). Each location along the esophageal axis contracts with a latency that increases gradually from the upper esophagus to the LES. The velocity of the peristaltic wave is slower in the striated muscle and faster in the smooth muscle. Contractions reach the striated muscle segment within 2 seconds after the onset of the swallow, traveling at a speed of about 3 cm per second; in the smooth muscle segment, the velocity of propagation may be as fast as 5 cm per second. Contractions in the distal one third of the esophagus are usually stronger (50-150 mmHg) than those in the upper third (40-120 mmHg), and both are stronger than those in the middle third where they are relatively weak (20-80 mmHg), probably occurring at the transition between the striated and smooth muscle esophagus.

If material is refluxed into the esophagus from the stomach, distension of the esophagus triggers peristaltic contractions which sweep the bolus into the stomach (Figure 1, right). This occurs in the absence of swallowing and is termed secondary peristalsis.

Manometric pressure waves can be correlated with movement of a bolus through the esophagus (Figure 2).

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Figure 2

The schematic above relates manometric pressure measurements to bolus movement as shown videographically. The tracings from the video images on the right show the distribution of the barium column at the times indicated above the individual tracings and by arrows on the manometric record. (Kahrilas, et al, Gastro 1988;94:73)

Esophageal Pathophysiology

Clinical symptomsFour symptoms are classically associated with diseases of the esophagus. These are dysphagia, odynophagia, heartburn, and chest pain. Other symptoms such as wheezing, cough, hoarseness, laryngitis and sore throat may be associated with gastro-esophageal reflux disease (GERD) but are not specific to the esophagus.

DysphagiaDysphagia is defined as difficulty in swallowing and is perhaps the most specific symptom of esophageal disease. When dysphagia is accompanied by painful swallowing, it is called odynophagia; these two conditions are distinct and should not be considered synonymous.

There are two types of dysphagia;

1. Oropharyngeal dysphagia - defined as the inability to initiate swallowing or transfer a bolus from the mouth to the esophagus. It is caused by neuromuscular disorders or structural abnormalities of the striated muscles of the oropharynx or upper esophageal sphincter (UES) (Table 1).

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Table 1: Common Causes of Oropharyngeal Dysphagia

Structural Abnormalities Neuromuscular Abnormalities

Zenker’s diverticulum

Cricopharyngeal bar

Postcricoid web

Tumor

Enlarged Thyroid

Cervical Osteophyte

Stroke

Multiple Sclerosis

Parkinson’s disease

Cerebral palsy

Myopathies and muscular

dystrophies

Motor neuron disease

Therapeutic options for oropharyngeal dysphagia include: Swallowing therapy

o Retrainingo Bolus size and consistency adjustmento Specific swallowing maneuvers

Esophageal dilation Surgical Myotomy of UES closure of Zenker’s diverticulum

Severe cases may require temporary or prolonged cessation of oral feeding together with nutrition support via a gastric or jejunal feeding tube (PEG, PEJ) or intravenously (TPN).

2. Esophageal dysphagia reflects difficulty in moving material through the esophagus and is caused by neuromuscular disorders of esophageal smooth muscle or by mechanical obstruction of the esophagus (Table 2).

Table 2: Common Causes of Esophageal Dysphagia

Structural Abnormalities Motility Abnormalities

Peptic stricture

Esophageal (Schatzki’s) ring

Carcinoma

Webs

Benign tumors

Osteophytes

Achalasia

Diffuse esophageal spasm

Ineffective esophageal motility

Gastroesophageal reflux (most likely

from ineffective esophageal motility)

Scleroderma or other collagen

vascular disorders

When esophageal dysphagia is clinically suspected, it is important to differentiate between dysphagia for solids or for liquids. This suggests diagnostic possibilities and directs the work-up (Table 3). Dysphagia for solid foods suggests a structural abnormality whereas dysphagia for both liquids and solids suggests a motility disorder. Many patients with a peptic stricture or a carcinoma initially have dysphagia for solids which progresses to liquids as the lumen narrows. Intermittent dysphagia for solid foods, which does not progress over time, is more characteristic of an esophageal ring or web.

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The presence of dysphagia for both solids and liquids suggests the presence of an esophageal motility disorder (Table 2). These disorders invariably affect esophageal smooth muscle function; often, the LES in involved as well.

Table 3: Esophageal Dysphagia: Symptoms Suggest Diagnosis

Diagnostic Evaluation of Dysphagia

The choice of available diagnostic tests is generally decided on the basis of the clinical question.

Question Best Diagnostic Test

What is the structure and function of the

esophagus?

Barium esophagogram using both liquids

and a solid bolus

What is the integrity of the mucosa

and/or the cause of luminal narrowing?

Endoscopy with biopsies

What is the motor function of the

esophagus and LES?

Esophageal manometry

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A suggested diagnostic approach to a patient with dysphagia is as follows

The following case histories serve to illustrate the more common clinical

conditions related to esophageal pathophysiology. Each case will be

discussed in greater detail in class.

Case History #1

A 67 year-old woman presents with dysphagia, choking and coughing for the past 15 months. She is a nonsmoker who has been well until the onset of these symptoms.

Her dysphagia is characterized by difficulty in swallowing, initially for solids but now equally for liquids and solids. Frequently, she coughs when trying to eat. In the last 15 months, she has noticed a gurgling sensation on swallowing. On occasion, she awakens from sleep because of forceful coughing and choking.

She denies heartburn, odynophagia, chest pain, shortness of breath or vomiting. She has no neck or chest pain and no hoarseness.

Her physical examination is unremarkable.

What is the mechanism behind her symptoms; structural? motility?

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Zenker’s Diverticulum: An example ofa disorder involving dysfunction of theupper esophageal sphincter

Epidemiology

Zenker’s diverticulum is an uncommondisorder affecting both men and women,most of whom are older. It is believed tobe a late manifestation of cricopharyngealdysfunction which may be idiopathic butis also thought to be associated withgastroesophageal reflux.

Pathophysiology

The primary abnormality concerns that of UES relaxation. Most recent studies suggest that the resistance of the UES to opening is increased associated with reduced muscle compliance. As a result, increased pharyngeal pressures are necessary to open the UES during swallowing. This results in protrusion of hypopharyngeal mucosa between the oblique fibers of the inferior pharyngeal constrictor and the transverse fibers of the cricopharyngeal muscle. With time, the protrusion elongates to produce the diverticulum.

In fully developed Zenker’s diverticulum, oropharyngeal dysphagia is the result of UES dysfunction whereas accumulation of food and fluid in the pouch can lead to aspiration with recurrent pulmonary infections. Other symptoms include halitosis, a gurgling sound while swallowing and coughing episodes.

Diagnostic Evaluation

The best study is a modified barium swallow using cineradiology to assess transfer of a bolus from mouth to esophagus. This may show a prominent cricopharyngeal bar, a diverticulum of various sizes and preferential filling of the diverticulum with contrast (see figure-arrow).

Treatment

The treatment is usually surgical myotomy to reduce UES pressure together with diverticulectomy or reduction of the pouch using a plication technique. UES myotomy alone is insufficient if the diverticulum is large; diverticulectomy without myotomy does not correct the underlying problem and will lead to recurrence of the pouch.

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Case History #2

A 78 year-old man presents with dysphagia and a 10 pound weight loss during the past 18 months. He is a former heavy smoker who had undergone a coronary bypass graft 10 years earlier.

His dysphagia began insidiously and he reports difficulty in both solids and liquids. On occasion, he regurgitates foamy white bland tasting material. Increasingly, eating became more deliberate and he often stands up during a meal to relieve the sensation of retrosternal fullness. Over the past 6 months, he has noted a steady weight loss that reached 10 pounds at the time he presented to the office

His physical examination is unremarkable except for a well-healed scar over the sternum.

What is the mechanism behind his symptoms; structural? motility?

Achalasia: An example of a disorder involving esophageal motility

Epidemiology

Achalasia is an uncommon but worldwide disorder affecting both genders and all ages. The etiology is unknown although an autoimmune mechanism is plausible.

An achalasia-like condition is Chagas disease which occurs in South America and is caused by an immune response to a parasite (Trypanosoma cruzi), which damages the myenteric plexus of the esophagus. A similar mechanism in response to an unknown agent(s) is hypothesized for achalasia.

Pathophysiology

Presumably, an inciting event produces damage or death to myenteric ganglia containing the inhibitory neurotransmitters, nitric oxide and vasoactive intestinal polypeptide (VIP) in the esophageal smooth muscle and LES. This results in loss of peristalsis as well as incomplete relaxation of the LES. The LES is not able to relax properly due to an unopposed cholinergic stimulation. This produces a functional mechanical obstruction at the LES and slowly progressive dilation of the esophagus. As the disease advances there is retention of ingested food and saliva and symptoms of regurgitation.

Diagnostic evaluation

A characteristic barium esophagram shows a dilated esophagus, a column of barium extending high into the chest and a characteristic “bird’s beak” narrowing at the region of the LES.

Esophageal manometry reveals 4 characteristic findings, only two of which are necessary for the diagnosis of achalasia.

Manometric criteria for achalasia Necessary

Absence of esophageal peristalsisIncomplete LES relaxation

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Not NecessaryIncreased LES pressureIntraesophageal pressures exceed intragastric pressures

Treatment

No treatment restores neuronal loss or peristalsis. Thus, efforts are directed towards decreasing LES pressure to reduce functional obstruction. This can be done by disrupting the LES mechanically or reducing LES tone pharmacologically.

Muscle Disruption: Pneumatic dilationLES myotomy (Heller myotomy)

Treatment Of Achalasia

Balloon Dilation Esophagogastric Myotomy

Muscle Relaxation: Botulinum toxin injectionNitratesCalcium channel blockers

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Mechanism by which botulinum toxin A blocks release of acetylcholine at neuromuscular junction.

From:   Arnon: JAMA, Volume 285(8).February 28, 2001.1059-1070

Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex (SNARE proteins) which fuses to allow release of Ach into the synaptic cleft. Botulinum A toxin cleaves SNAP-25 protein (a docking protein) to block the release. When injected into the LES, this release is blocked locally which decreases LES pressure. Best used as a temporary bridge to more definitive therapies or for patients who cannot tolerate the potential morbidity of muscle disruption.

Surgical myotomy is best for young patients and for those who do not respond to pneumatic dilation. Either results in good to excellent results with acceptable morbidity rates.

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SUGGESTED ALGORITHM FOR TREATMENT OF ACHALASIA

Low surgical risk High surgical risk/unwilling to have surgery

Laparoscopic myotomy Graded Pneumatic Botulinum Toxin (80-100 units) Dilation

Failure Success Failure Success Failure Success

Low surgical risk Repeat botulinum toxin

Failure Success Failure Success

Low surgical risk Nifedipine/Isordil

Case History #3

A 52 year-old woman presents with dysphagia over the past 3 months. She is a moderate smoker who underwent a cholecystectomy 13 years earlier and a hysterectomy 1 year later, both for benign diseases.

Her dysphagia began approximately 3 months ago when she began to notice that solid foods would stick in the region of the lower substernal area. Gradually, she began to eat semi-solid foods to avoid symptoms. Liquids passed without difficulty. Although she changed her diet, her appetite was maintained and she lost no weight.

Further history reveals that she has had intermittent heartburn for many years for which she used antacids and more recently over-the-counter Cimetidine. She reports no cold intolerance, tightening of skin or change in bowel habits.

Her physical examination is unremarkable except for well-healed surgical scars.

What is the mechanism behind her symptoms; structural? motility?

Peptic Stricture: An example of a complication of gastroesophageal (GE) reflux.

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Epidemiology of GERD

Gastroesophageal reflux disease (GERD) is the most common condition arising from the GI tract. The most characteristic symptom is heartburn. A small minority of affected persons seeks medical attention and even fewer have complications. Other common symptoms include regurgitation, belching and “water brash”, but patients may also have atypical presentations including chest pain, hoarseness, loss of dental enamel, chronic cough, and asthma. Slowly progressive dysphagia for solids suggests a peptic stricture in the esophagus whereas liquid and solid dysphasia suggests a reflux related motility disorder.

Pathophysiology

The primary abnormality in GERD is excessive ‘reflux’ of stomach contents into the esophagus at inappropriate times and for an inappropriately long duration and frequency. Damage caused by acid, enzymes and other gastric juice constituents may lead to esophageal mucosal damage and subsequent symptoms and complications.

Four major physiologic mechanisms act to prevent and protect the esophagus from the damaging effects of gastroesophageal reflux. These are, according to their degree of importance:

1. Lower esophageal sphincter (LES) competence,2. Esophageal clearance mechanisms,3. Gastric emptying, and4. Esophageal mucosal integrity.

The most important parameter in preventing gastric regurgitation is LES competence, which consists of LES pressure and the location of the sphincter adjacent to the diaphragmatic crus.

Normally, when gastric contents reflux into the esophagus during periods of transient LES relaxation, primary or secondary peristalsis clears the majority of refluxant while the alkaline saliva neutralizes residual acid. Gravity also promotes esophageal clearance, returning refluxed material to the stomach without peristalsis when the patient is in the upright position. The constant emptying of gastric contents ensures that gastric stasis and/or subsequent increase in gastric pressure with resulting GER is minimized. The esophagus also secretes bicarbonate, has a cellular mechanism to actively transport H+ out of epithelial cells, and secretes mucin and epidermal growth factor in response to acid and pepsin.

With respect to LES function in GE reflux, at least 3 mechanisms have been demonstrated:1. Transient LES (TLES) relaxations occur in all persons via a neural reflex

which is mediated through the brainstem. Gastric distrension, upright posture and meals high in fat increase the frequency of TLES which in turn can result in increased reflux into the lower esophagus.

2. Decreased LESP weakens the GE barrier to reflux and is associated with more severe esophageal changes.

3. Some patients have low normal LESP but do not increase pressures in response to increased abdominal pressure. This mechanisms are illustrated as follows:

Three Mechanisms of LESP Incompetence

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With respect to decreased esophageal clearance mechanisms, this can occur because of weak or absent peristaltic esophageal contractions or decreased production of saliva whose alkanility serves to neutralize acid in the esophagus

Delayed gastric emptying increases the risk of excessive reflux of gastric contents (see lecture on gastric physiology)

The final line of defense of the esophageal mucosa is its intrinsic resistance to acid, pepsin and bile acids. Such factors such as epidermal growth factor (EGF) and intracellular electrolyte movement helps to maintain esophageal epithelial integrity and may be inadequate in some patients with reflux esophagitis.

Hiatal hernias are noted in 42% of all patients with symptoms of reflux, but in 60% to 80% of patients with endoscopic esophagitis or peptic strictures. Patients with large hiatal hernias associated with relatively low LES pressures are susceptible to reflux episodes following sudden increases in intra-abdominal pressure. These reflux episodes probably occur because the LES does not tonically contract in response to intra-abdominal pressure events so that transmitted intragastric pressures easily overcome the LES, which is located in the negative atmosphere of the thoracic cavity. Once gastroesophageal reflux occurs, esophageal peristalsis clears the esophageal contents into the hiatal hernia, which then acts as a reservoir of gastric contents awaiting further intra-abdominal pressure events, transient LES relaxations, or free reflux events to repeat the reflux cycle.

Diagnostic Testing in suspected GERD

The choice of available diagnostic tests, as with dysphagia, is decided on the basis of the clinical question. Available tests include barium swallow, endoscopy, esophageal pH monitoring and esophageal manometry

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AMBULATORY pH STUDY

ESOPHAGEAL pH PROBE BRAVO (wireless pH probe)

pH RECORDING

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Question Best Diagnostic TestDoes patient have sigificant acid reflux? Esophageal pH with “DeMeester score”

Are symptoms due to acid reflux? Esophageal pH with “symptom index”

Why is patient having dysphagia? Barium esophagram with liquids and solids

Has acid reflux caused damge to esophageal mucosa?

Endoscopy with biopsy

Treatment of GERD

Treatment options for GERD include; Lifestyle modifications Acid suppression and promotility medications Surgical antireflux procedures

Phase 1 therapy, which involves life-style and dietary modifications, is the initial step for treatment of all patients with GERD. The head of the bed should be elevated 6” with bed blocks or a wedge under the shoulders. This practice uses gravity to decrease esophageal acid contact time when reflux occurs. An empty stomach before going to sleep reduces the stimulus for nocturnal reflux. Reduction in dietary fat decreases reflux frequency in patients with GERD. Patients should stop smoking and avoid esophageal irritants, such as citrus products and coffee. Potentially harmful medications should be avoided. For instance, nitrates, theophylline, and calcium channel blockers may reduce LES pressure, whereas doxycycline, quinidine, and NSAIDs may cause mucosal injury.

Acid suppression is the backbone of pharmacologic therapy for GERD. The two classes of drugs commonly used are H2 receptor antagonists (H2 RAs) and the proton pump inhibitors (PPIs). Promotility drugs improve esophageal and gastric emptying and may be useful in some patients. However, these drugs frequently are required indefinitely and are expensive..Otherwise healthy patients under the age of 50 may be more effectively treated and perhaps at reduced cost with anti-reflux surgery compared to a lifetime of medical therapy. Other indications for anti-reflux surgery include difficult to manage strictures, severe bleeding from esophagitis, and aspiration symptoms.

The principle of surgery is to restore an effective GE barrier to eliminate GE reflux. The most common operation is a fundoplication in which the hernia, if present, is reduced and the fundus of the stomach is wrapped around the GE junction at the level of the diaphragmatic crus. The fundoplication is then anchored to the upper portion of the esophageal hiatus.

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Total Fundoplication

Efficacy of Therapies for GE Reflux

Antacids Prokinetics H2RAs PPIs Surgery

Eliminate Symptoms

+ ++ +++ ++++ ++++

Heal Esophagitis 0 + +++ ++++ ++++

Manage or PreventComplications

0 0 ++ +++ +++

Maintain Remission 0 + ++ +++++ ++++

Esophageal stricture

This most often occurs in the distal esophagus where GERD does most of its damage and is typically less than 1 cm in length. Dysphagia is often insidious in onset, the typical patient has dysphagia for several years. Profound weight loss is uncommon, in contrast to patients with esophageal cancer.

The diagnosis is often made with barium contrast studies and/or endoscopy with biopsy and brush cytology specimens. Treatment using various dilating devices and with aggressive acid suppression therapy is often effective. In some patients, surgery may be required.

Barrett’s Esophagus (BE)

This is a condition in which columnar intestinal-like epithelium replaces the squamous epithelium which normally lines the distal esophagus. This develops when GE reflux damages the squamous mucosa and the injury heals through a metaplastic process. The abnormal epithelium that characterizes BE is an incomplete form of intestinal

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metaplasia (called specialized metaplasia) and its importance is that it predisposes patients to an increased risk of developing adenocarcinoma.

The diagnosis of BE is made by endoscopic recognition and confirmed by biopsies of the affected area. In essence, it is the recognition that the squamocolumnar junction (called the Z line) now lies proximal to the gastroesophageal junction.

If the segment is 3 cm, it is known as long-segment BE whereas if it is less than 3 cm, it is known as short-segment BE. Although it seems logical that the risk of developing adenocarcinoma is proportionate to the length of BE, this is unproven and both are managed in a similar fashion.

Management consists of periodic endoscopic surveillance with multiple biopsies. The finding of high grade dysplasia often prompts esophagectomy although nonsurgical means of treatment are currently under investigation. It is unproven as to whether aggressive antireflux therapy, either medical or surgical, reduces the risk of cancer.

NOTES

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NOTES

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