Immune System disorder

Prevention

Twinning is a naturally occurring phenomenon and
cannot be completely prevented. It occurs more often in
older mothers. Multiple births due to ART are a concern
because a multiple pregnancy represents a complication of
pregnancy. Efforts within the ART community are being
made to minimize the incidence of high-order multiples.
Efforts to prevent or minimize maternal and fetal
complications will result in closer monitoring. More
frequent ultrasounds, biophysical profile, and/or nonstress
tests may be ordered. Cervical length and change may be
monitored as an indicator of preterm delivery. If both
twins are vertex and vaginal delivery is attempted, both
fetal heart rates will be monitored. Caesarean deliveries of
twins are more common than for singletons; the rate of
cesarean delivery for twins in the United States has
increased by 22% since 1995, purely apart from the
presentation positions of the twins at the time of birth. This
increase is especially true for higher-order multiples. The
overall cesarean delivery rate tends to be about 75% for
multiple pregnancies as of 2012.

See also Fertility treatments; High-risk pregnancy.

Resources

BOOKS
Hanretty, Kevin P. Obstetrics Illustrated, 7th ed. New York:

Churchill Livingstone, 2010.

Jauniaux, Eric, and Botros Rizk. Pregnncy after Assisted
Reproductive Technology. New York: Cambridge Univer-
sity Press, 2012.

Luke, Barbara, Tamara Eberlein, and Roger Newman. When
You’re Expecting Twins, Triplets, or Quads: Proven
Guidelines for a Healthy Multiple Pregnancy, 4th ed.
New York: William Morrow, 2017.

PERIODICALS
Breborowicz, G.H., et al. “Variable Outcome in Quintuplets

Pregnancy Based on Obstetric Care.” Twin Research and
Human Genetics 14 (December 2011): 580–585.

Fisher, S.L., et al. “Sextuplet Heterotopic Pregnancy Presenting
as Ovarian Hyperstimulation Syndrome and Hemoperito-
neum. Fertility and Sterility 95 (June 2011): 2431: e1–e3.

Hasson, J., et al. “Reduction of Twin Pregnancy to Singleton:
Does It Improve Pregnancy Outcome?” Journal of Mater-
nal-Fetal and Neonatal Medicine 24 (November 2011):
1362–1366.

Klipstein, S. “Ethical Considerations Arising from the Use of
Assisted Reproductive Technologies.” Seminars in
Reproductive Medicine 30 (April 2012): 146–151.

Lee, H.C., et al. “Trends in Cesarean Delivery for Twin Births in
the United States: 1995-2008.” Obstetrics and Gynecology
118 (November 2011): 1095–1101.

Memmo, A., et al. “Prediction of Selective Fetal Growth
Restriction and Twin-to-twin Transfusion Syndrome in
Monochorionic Twins.” BJOG 119 (March 2012): 417–421.

Moragianni, V.A., et al. “Biweekly Ultrasound Assessment of
Cervical Shortening in Triplet Pregnancies and the Effect of
Cerclage Placement.” Ultrasound in Obstetrics and
Gynecology 37 (May 2011): 617–618.

Stock, S., and J. Norman. “Preterm and Term Labour in Multiple
Pregnancies.” Seminars in Fetal and Neonatal Medicine
15 (December 2010): 336–341.

ORGANIZATIONS
Association of Women’s Health, Obstetric and Neonatal Nurses ,

1800 M St. NW, Ste. 740 S, Washington, DC 20036, (202)
261-2400, (800) 673-8499, Fax: (202) 728-0575,
[email protected], http://www.awhonn.org.

American Congress of Obstetricians and Gynecologists, 409
12th St. SW, Washington, DC 20024, (202) 638-5577,
(800) 673-8444, [email protected], http://www.acog
.org.

National Institute of Child Health and Human Development, PO
Box 3006, Rockville, MD 20847, (800) 370-2943, Fax:
(866) 760-5947, NICHDInformationResourceCenter@
mail.nih.gov, http://www.nichd.nih.gov.

Society for Maternal-Fetal Medicine, 409 12th St. SW, 6th Fl,
Washington, DC 20024, (202) 863-2476, smfm@smfm
.org, https://www.smfm.org.

American Society for Reproductive Medicine, 1209
Montgomery Hwy., Birmingham, AL 35216-2809,
(205) 978-5000, Fax: (205) 978-5005, [email protected],
http://www.reproductivefacts.org.

Esther Csapo Rastegari, RN, BSN, EdM
Revised by Rebecca J. Frey, PhD

Multiple sclerosis
Definition

Multiple sclerosis (MS) is a chronic autoimmune
disorder affecting movement, sensation, and bodily
functions. It is caused by destruction of the myelin sheath
(insulation) covering nerve fibers (neurons) in the central
nervous system (brain and spinal cord).

Demographics

As of 2012, approximately 400,000 people in the
United States had been diagnosed with MS, with 10,000
new cases being diagnosed each year. Worldwide, MS
affects between 1.5 and 2.5 million people. Most people
have their first symptoms between the ages of 20 and 40;
symptoms rarely begin before age 15 or after age 60. The
mean age range is 29–33 years. Women are almost twice
as likely to get MS as men, especially in their early years.
People of northern European ancestry are more likely to be
affected than people of other racial backgrounds, and MS
rates are higher in the United States, Canada, and Northern
Europe than other parts of the world. The disorder is

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unknown among certain native peoples such as the Inuit
(native people of the Arctic) and Maori (Native people of
New Zealand).

Description

Multiple sclerosis is a slowly progressive disease of
the central nervous system (CNS), which is comprised of
the brain and spinal cord. In 1868, French physician Jean-
Martin Charcot (1825–1893) provided the first detailed
clinical description of the disease. Today researchers
know that MS is an autoimmune disorder that causes the
destruction of myelin, the insulating material that
surrounds nerve fibers (neurons). Myelin helps electrical
signals pass quickly and smoothly between the brain and
the rest of the body. When the myelin layer is destroyed,
nerve messages are sent more slowly and less efficiently.
Patches of scar tissue, called plaques, form over the
affected areas, further disrupting nerve communication.
The symptoms of MS occur when the brain and spinal
cord nerves no longer communicate properly with other
parts of the body. MS causes a wide variety of symptoms
and can affect vision, balance, strength, sensation,
coordination, and bodily functions.

Risk factors

The risk of developing MS is slightly higher if
another family member is affected, suggesting the
influence of genetic factors. If one person in a family
has MS, then that person’s close family relatives (parents,
children, siblings) have about a 5% greater chance of
developing MS than people who do not have family
members with the disorder. In addition, the higher
prevalence of MS among people of northern European
background suggests some genetic susceptibility.

Causes and symptoms

Causes

Multiple sclerosis is an autoimmune disease, meaning
its cause is due to an attack by the body’s own immune
system. For unknown reasons immune cells attack and
destroy the myelin sheath that insulates neurons in the
brain and spinal cord. This myelin sheath, created by other
brain cells called glia, speeds transmission and prevents
electrical activity in one cell from short-circuiting to
another cell. Disruption of communication between the
brain and other parts of the body prevents normal passage
of sensations and control messages, leading to the
symptoms of MS. The demyelinated areas appear as
plaques, small round areas of gray neurons without the
white myelin covering. The progression of symptoms is
correlated with development of new plaques in the portion
of the brain or spinal cord controlling the affected areas.

Because there appears to be no pattern in the appearance
of new plaques, the progression of MS is unpredictable.

Despite considerable research the trigger for this
autoimmune destruction is still unknown. At various times
evidence has pointed to genes, environmental factors,
viruses, or a combination of these factors.

The fact that the risk of developing MS is slightly
higher if another family member is affected suggests that
there is a genetic susceptibility to the disease.

The role of an environmental factor is suggested by
studies of the effect of migration on the risk of developing
MS. Age plays an important role in determining this
change in risk—young people in low-risk groups who
move into countries with higher MS rates display the risk
rates of their new surroundings, while older migrants
retain the risk rate of their original home country. One
interpretation of these studies is that an environmental
factor, either protective or harmful, is acquired in early
life; the risk of disorder later in life reflects the effects of
the early environment.

These same data can be used to support the
involvement of a slow-acting virus, one that is acquired
early in life but begins its destructive effects much later.
Slow viruses are known to cause other disorders,
including Creutzfeldt-Jakob disease, bovine spongiform
encephalopathy (“mad cow” disease), and AIDS. In
addition, viruses have been implicated in other autoim-
mune disorders. Many claims have been made for the role
of viruses, slow or otherwise, as the trigger for MS, but as
of 2012 no strong candidate had emerged.

How a virus could trigger the autoimmune reaction is
also unclear. There are two main models of virally induced
autoimmunity. The first suggests the immune system is
actually attacking a virus (one too well hidden for
detection in the laboratory), and the myelin damage is
an unintentional consequence of fighting the infection.
The second model suggests the immune system mistakes
myelin for a viral protein encountered during a prior
infection. Primed for the attack, the immune system
destroys myelin because it resembles the previously
recognized viral invader.

Either of these models allows a role for genetic
factors, since certain genes can increase the likelihood of
autoimmunity, and it seems likely that more than one gene
is involved in a person’s susceptibility to MS. Environ-
mental factors as well might change the sensitivity of the
immune system or interact with myelin to provide the
trigger for the secondary immune response. Possible
environmental triggers that have been invoked in MS
include viral infection, trauma, electrical injury, and
chemical exposure, although controlled studies do not
support a causative role.

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Symptoms

MS is a diverse disease. No two affected persons are
the same and each will experience different combinations
of symptoms with differing severity. The symptoms of
MS may occur in one of three patterns:

• The most common pattern is the relapsing-remitting
pattern, in which there are clearly defined symptomatic
attacks lasting 24 hours or more, followed by complete
or almost complete improvement. The period between
attacks may be a year or more at the beginning of the
disorder, but may shrink to several months later on.
About three-quarters of all people diagnosed with MS
have this version of the disorder. This pattern is
especially common in younger people who develop MS.

• In the primary progressive pattern, the disorder pro-
gresses without remission or with only occasional
plateaus or slight improvements. This pattern is more
common in older people. About 10% of people with the
disorder have this pattern.

• In the secondary progressive pattern, the person with MS
begins with relapses and remissions, followed by more
steady progression of symptoms. In some people, what
begins as a relapsing-remitting pattern develops into a
secondary progressive pattern.

Between 10%–20% of people have a benign type of
MS, meaning their symptoms progress very little over the
course of their lives.

Because plaques may form in any part of the central
nervous system, the symptoms of MS vary widely from
person-to-person and from stage-to-stage of the disease.
Initial symptoms often include:

• muscle weakness causing difficulty walking

• loss of coordination or balance

• numbness, “pins and needles,” or other abnormal
sensations

• visual disturbances, including blurred or double vision

Later symptoms may include:

• fatigue

• muscle spasticity and stiffness

• tremors

• paralysis

• pain

• vertigo

• speech or swallowing difficulty

• loss of bowel and bladder control

• sexual dysfunction

• changes in cognitive ability

Weakness in one or both legs is common, and may be
the first symptom noticed by a person with MS. Muscle
spasticity, or excessive tightness, is also common and may
be more disabling than weakness.

Double vision (diplopia) or eye tremor (nystagmus)
may result from involvement of the nerve pathways
controlling movement of the eye muscles. Visual
disturbances result from involvement of the optic nerves
(optic neuritis) and may include development of blind
spots in one or both eyes, changes in color vision, or
blindness. Optic neuritis usually involves only one eye at
a time and is often associated with movement of the
effected eye.

More than half of all people affected by MS have pain
during the course of their disease. Many experience
chronic pain, including pain from spasticity. Acute pain
occurs in about 10% of cases. This pain may be a sharp,
stabbing pain especially in the face, neck, or down the
back. Facial numbness and weakness are also common.

Cognitive changes, including memory disturbances,
depression, and personality changes, are found in people
affected by MS, although it is not entirely clear whether
these changes are due primarily to the disorder or to the
psychological reaction to it. Depression may be severe
enough to require treatment in up to 25% of those with
MS. A smaller number of people experience disorder–
related euphoria, or abnormally elevated mood, usually
after a long disorder duration and in combination with
other psychological changes.

Symptoms of MS may be worsened by heat or
increased body temperature, including fever, intense
physical activity, or exposure to sun, hot baths, or
showers.

Diagnosis

There is no single test that confirms the diagnosis of
multiple sclerosis and there are a number of other diseases
with similar symptoms. While one person’s diagnosis may
be immediately suggested by symptoms and history,
another’s may not be confirmed without multiple tests and
prolonged observation. The distribution of symptoms is
important, as MS affects multiple areas of the body over
time. The pattern of symptoms is also critical, especially
evidence of the relapsing-remitting pattern. Thus, a
detailed medical history is one of the most important
parts of the diagnostic process. A thorough search to
exclude other causes of a person’s symptoms is especially
important if the following features are present: 1) family
history of neurologic disease, 2) symptoms and findings
attributable to a single anatomic location, 3) persistent
back pain, 4) age of onset over 60 or under 15 years of age,
or 5) progressively worsening disease.

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Tests

In addition to a medical history and a standard
neurological exam, several lab tests are used to help
confirm or rule out a diagnosis of MS:

• Magnetic resonance imaging (MRI) can reveal plaques
on the brain and spinal cord. Gadolinium enhancement
can distinguish between old and new plaques, allowing a
correlation of new plaques with new symptoms. Plaques
may be seen in several other diseases as well, including
encephalomyelitis, neurosarcoidosis, and cerebral lupus.
Plaques seen on an MRI may, however, be difficult to
distinguish from damage caused by small strokes, areas
of decreased blood flow, or changes seen with trauma or
normal aging.

• A lumbar puncture, or spinal tap, is done to measure levels
of immune proteins, which are usually elevated in the
cerebrospinal fluid of a person with MS. This test may not
be necessary if other diagnostic tests are positive.

• Evoked potential tests, electrical tests of conduction
speed in the neurons, can reveal reduced speeds
consistent with the damage caused by plaques. These
tests may be done with small electrical charges applied to
the skin (somatosensory evoked potential), with light
patterns flashed on the eyes (visual evoked potential), or
with sounds presented to the ears (auditory evoked
potential).

The clinician making the diagnosis, usually a
neurologist, may classify the disorder as “definite MS,”
meaning the symptoms and test results all point toward
MS as the cause. “Probable MS” and “possible MS”
reflect less certainty and may require more time to pass to
observe the progression of the disorder and the distribu-
tion of symptoms.

Treatment

As of 2017, there was no known cure for MS.
Nevertheless, several drugs may slow progression of the
disorder and moderate some symptoms in many patients,
especially if started early.

Multiple sclerosis causes a wide variety of symptoms,
and the treatments for these are equally diverse. Most
symptoms can be treated and complications avoided with
good care and attention from medical professionals. Good
health and nutrition remain important preventive mea-
sures. Vaccination against influenza can prevent respira-
tory complications. Preventing complications such as
pneumonia, bedsores, injuries from falls, or urinary
infection requires attention to the primary problems that
may cause them. Shortened life spans with MS are almost
always due to complications rather than primary symp-
toms themselves.

Drugs

Drug treatment must be individualized. Not all drugs
are appropriate for all patients. In the United States as of
2011, MS was most often treated with four drugs known
as the ABCR drugs. These drugs are interferon beta-1a
(Avonex), interferon beta-1b (Betaseron and Rebif), and
glatiramer acetate (Copaxone). These drugs, on average,
reduce relapses in the relapsing-remitting form of MS by
about one-third. Different measurements from tests of
each have demonstrated other benefits as well: Avonex
may slow the progress of physical impairment, Betaseron
and Rebif may reduce the severity of symptoms, and
Copaxone may decrease disability. All four drugs are
administered by injection, some into muscle (IM), and
some under the skin (SC). Some controversy exists on the
most effective dose and the frequency with which these
drugs should be administered.

Although the ABCR drugs reduce relapses and may
keep patients in relatively good health for the short-
term, their long-term success has not been proven and
they do not work well for patients who have reached a
steadily progressive stage of MS. Individuals with
progressive forms of MS may be treated with mitoxan-
trone (Novantrone), cyclophosphamide (Cytoxan, Neo-
sar), azathioprine (Imuran), or methotrexate (Rheuma-
trex). All these drugs suppress the immune system.
None are ideal, and all have potentially serious side
effects. Corticosteroid drugs such as methylpredniso-
lone (Medrol) also may be used to reduce inflammation.
Long-term use of corticosteroids also causes serious
side effects.

Two disease modifying agents, fingolimod (Gilenya)
and natalizumab (Tysabri), are effective in keeping white
blood cells in the lymph system, thus preventing these
cells from crossing the blood-brain barrier into the central
nervous system, which in turn reduces inflammation and
damage to nerve cells.

Training in bowel and bladder care may be needed to
prevent or compensate for incontinence. If the urge to
urinate becomes great before the bladder is full, some
drugs may be helpful, including propantheline bromide
(Probanthine), oxybutynin chloride (Ditropan), or imipra-
mine (Tofranil). Baclofen (Lioresal) may relax the
sphincter muscle, allowing full emptying. Intermittent
catheterization is effective in controlling bladder dysfunc-
tion. In this technique, a catheter is used to periodically
empty the bladder.

Spasticity can be treated with oral medications,
including baclofen and diazepam (Valium), or by
injection with botulinum toxin (Botox). Spasticity relief
may also bring relief from chronic pain. More acute types
of pain may respond to carbamazepine (Tegretol) or
diphenylhydantoin (Dilantin). Low back pain is common

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from increased use of the back muscles to compensate for
weakened legs. Physical therapy and over-the-counter
pain relievers may help.

Fatigue may be partially avoidable with changes in
the daily routine to allow more frequent rests. Amantadine
(Symmetrel) and Modafinil (Provigil), although not
specifically approved for use with MS, are often used to
treat fatigue and improve alertness. Pemoline (Cylert), a
drug formerly used to treat fatigue in MS patients, was
withdrawn from sale in the United States in October 2005
because of potentially fatal liver complications. Visual
disturbances often respond to corticosteroids. Other
symptoms that may be treated with drugs include seizures,
vertigo, and tremor.

Treatment for significant acute exacerbations include
the use of steroids such as methyl-prednisolone (Medrol),
administered in high doses for a number of days, then
tapering to lower doses for a number of weeks.

Clinical trials of new drugs and drug combinations to
treat MS are ongoing. Individuals with MS who wish to
participate in the trial of an experimental therapy can find
a list of clinical trials currently enrolling volunteers at
http://clinicaltrials.gov. There is no cost to the patient to
participate in a clinical trial.

Other drugs used for the treatment or management of
symptoms associated with MS include:

Bladder dysfunction:

• tolterodine (Detrol)

• darifenacin (Enablex)

• tamsulosin (Flomax)

• terazosin (Hytrin)

• prazosin (Minipress)

• oxybutynin (Oxytrol)

• trospium chloride (Sanctura)

• solifenacin succinate (Vesicare)

Constipation:

• docusate (Colace)

• bisacodyl (Dulcolax)

• sodium phosphate (Fleet Enema)

• psyllium (Metamucil)

Depression and fatigue:

• venlafaxine (Effexor)

• paroxetine (Paxil)

• bupropion (Wellbutrin)

• sertraline (Zoloft)

• duloxetine hydrochloride (Cymbalta)

• fluoxetine (Prozac)

Dizziness:

• meclizine (Antivert)

Erectile dysfunction:

• tadalafil (Cialis)

• vardenafil (Levitra)

• alprostadil (Prostin VR)

• sildenafil (Viagra)

Itching:

• hydroxazyne (Atarax)

Pain:

• gabapentin (Neurontin)

• nortriptyline (Pamelor)

• amitriptyline (Elavil)

Spasticity:

• dantrolene (Dantrium)

• tizanidine (Zanaflex)

Urinary frequency:

• desmopressin (DDAVP)

Urinary tract infections:

• sulfamethoxazole (Bacrim, Septra)

• ciprofloxacin (Cipro)

• nitrofurantoin (Macrodantin)

• methenamine (Hiprex)

• vphenazopyridine (Pyridium)

Tremor:

• isoniazid (Laniazid, Nydrazid)

• clonazepam (Klonopin)

Walking:

• dalfampride (Ampyra)

Rehabilitative therapy

Physical therapy helps the person with MS to strengthen
and retrain affected muscles, maintain range of motion,
prevent muscle stiffening, learn to use assistive devices such
as canes and walkers, and to learn safer and more energy-
efficient ways of moving, sitting, and transferring. Exercise
and stretching programs are usually designed by the physical
therapist and taught to the patient and caregivers for use at
home. Exercise is an important part of maintaining function
for the person with MS. Swimming is often recommended,
not only for its low-impact workout, but also because it
allows strenuous activity without overheating.

Occupational therapy helps the person with MS adapt
to her environment and adapt the environment to her. The

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occupational therapist suggests alternate strategies and
assistive devices for activities of daily living, such as
dressing, feeding, and washing, and evaluates the home
and work environment for safety and efficiency improve-
ments that may be made.

Alternative therapies

Bee venom has been suggested as a treatment for MS,
but no studies or objective reports support this claim.

In several studies, marijuana has been shown to have
variable effects on the symptoms of MS. Improvements
have been documented for tremor, pain, and spasticity,
and worsening for posture and balance. Side effects have
included weakness, dizziness, relaxation, and incoordina-
tion, as well as euphoria.

Some studies support the value of high doses of
vitamins, minerals, and other dietary supplements for
controlling disorder progression or improving symptoms.
Alpha-linoleic and linoleic acids, as well as selenium and
vitamin E, have shown effectiveness in the treatment of
MS. Selenium and vitamin E act as antioxidants. In
addition, a diet low in saturated fats, maintained over a
long period, may retard the disorder process.

Studies have also shown that t’ai chi can be an
effective therapy for MS because it works to improve
balance and increase strength.

There are conflicting views about the herb Echinacea
and its benefit to MS. Some alternative practitioners
recommend Echinacea for people with MS. However,
Echinacea appears to stimulate different parts of the
immune system, particularly immune cells known as
macrophages. In MS these cells are very active already
and further stimulation could worsen the disorder.

Prognosis

It is difficult to predict how MS will progress in any
one person. Most people with MS will be able to continue
to walk and function at their work for many years after
their diagnosis. The factors associated with the mildest
course of MS are being female, having the relapsing-
remitting form, having the first symptoms at a younger
age, having longer periods of remission between relapses,
and initial symptoms of decreased sensation or vision
rather than of weakness or incoordination.

Fewer than 5% of people with MS have a severe
progressive form, leading to death from complications
within five years. At the other extreme, 10%–20% have a
benign form, with a very slow or no progression of their
symptoms. Studies have shown that about seven out of
ten people with MS are still alive 25 years after their
diagnosis, compared to about nine out of ten people of

similar age without disorder. On average, MS shortens
the lives of affected women by about 6 years, and men by
11 years. Suicide is a significant cause of death in MS,
especially in younger patients. Suicide is completed
7.5 times more often in patients with MS than in those
without the disorder.

The degree of disability a person experiences five
years after onset is, on average, about three-quarters of the
expected disability at 10–15 years. A benign course for the
first five years usually indicates the disorder will not cause
marked disability.

Healthcare team roles

Physicians provide initial diagnoses. Neurologists may
support diagnoses and monitor disease progression. Physi-
cal and occupational therapists provide exercise and
environmental support for relief from muscle strains and
weakness. Radiologists are important in documenting
disease progression. Psychiatrists, psychologists, and other
therapists may be helpful in treating depression that may
accompany MS. Nurses provide bedside care, education for
the patient and caregiver, preparation for home manage-
ment of the disease, and home safety assessment.

KEY TERMS

Clinical trial—All new drugs undergo clinical trials
before approval. Clinical trials are carefully con-
ducted tests in which effectiveness and side effects
are studied, with the placebo effect eliminated.

Evoked potentials—Tests that measure the brain’s
electrical response to stimulation of sensory organs
(eyes or ears) or peripheral nerves (skin). These tests
may help confirm the diagnosis of MS.

Myelin—A layer of insulation that surrounds the
nerve fibers in the brain and spinal cord.

Plaque—Patches of scar tissue that form where the
layer of myelin covering the nerve fibers is
destroyed by the MS disorder process.

Primary progressive—A pattern of symptoms of MS
in which the disorder progresses without remission,
or with occasional plateaus or slight improvements.

Relapsing-remitting—A pattern of symptoms of MS
in which symptomatic attacks occur that last 24
hours or more, followed by complete or almost
complete improvement.

Secondary progressive—A pattern of symptoms of
MS in which there are relapses and remissions,
followed by more steady progression of symptoms.

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Prevention

There is no known way to prevent MS. Until the cause
of the disorder is discovered, this is unlikely to change. Good
nutrition; adequate rest; avoidance of stress, heat, and
extreme physical exertion; and good bladder hygiene may
improve quality of life and reduce symptoms.

Resources

BOOKS
Aminoff, Michael, David Greenberg, and Roger Simon. Clinical

Neurology, 9th ed. New York: …