JOURNAL OF MAGNETIC RESONANCE IMAGING 13:560 –567 (2001)
Original Research
Proton MR Spectroscopy in Clinical Routine
Isabella M. Burtscher, MD, PhD* and Stig Holtås, MD, PhD
In vivo magnetic resonance spectroscopy (MRS) addresses
metabolic pathways and their steady states in different
tissue types. The brain has by tradition, and due to tech-
nical limitations in other organs, been one of the tissues
most studied by MRS, and both 1H- and 31P-MRS have been
used. Although 31P-MRS is outstanding for the evaluation
of sources of metabolic energy in the brain, 1H-MRS has
become the major clinically applied method in neurospec-
troscopy, as it provides information on markers of neuro-
nal function, myelin, cell membranes, and metabolic ac-
tive compounds. Furthermore, MR sensitivity is much
greater for protons than it is for phosphorus and 1H-MRS,
therefore allowing better spatial resolution. This review
focuses on neurospectroscopy and diagnostic insights into
diverse neurological problems provided by 1H-MRS applied
as a clinical tool. J. Magn. Reson. Imaging 2001;13:
560 –567. © 2001 Wiley-Liss, Inc.
Index terms: proton magnetic resonance spectroscopy; brain;
disease; in vivo; human
INTRODUCED TO MEDICINE in the early 1980s, mag-
netic resonance (MR) has proven to be a valuable tool in
the evaluation of anatomy, physiology, and biochemis-
try of the human body. In contrast to MR imaging (MRI)
and MR angiography (MRA), both focusing on human
morphology, in vivo MR spectroscopy (MRS) addresses
metabolic pathways and their steady states in different
tissue types (1– 6). The fields of application for MRI
expanded rapidly during the last decades and finally
cover all major tissues and organs of the body. Al-
though MRS can theoretically be applied to almost all
human organs, which is shown by the numerous re-
search publications in the field of MRS, the use of the
technique is, in clinical routine, still restricted to a few
organs and a selection of diseases represented in the
studied tissues. Restrictions are mainly of a technical
nature and will partly be overcome by the introduction
of more powerful magnets and software solutions ap-
plicable for clinical routine.
The introduction of MRS to clinical neurospectros-
copy went parallel to the tremendous development of
MRI applications in the field of neuroradiology. The
Department of Diagnostic Radiology, University Hospital Lund, Lund,
Sweden.
Part of the illustrations were presented in a lecture at the 6th Annual
Meeting of ISMRM, Sydney, 1998, morning categorical course, by I.M.B.
*Address reprint requests to: I.M.B., Department of Radiology, Univer-
sity Hospital, S-22185 Lund, Sweden.
E-mail: isabella.burtscher@drad.lu.se
Received July 28, 2000; Accepted December 28, 2000.
© 2001 Wiley-Liss, Inc.
brain has by tradition, and based on the well-suited
MRS properties of brain tissue, been one of the organs
most studied by MRS. Furthermore, a number of dis-
eases of the central nervous system (CNS) or systemic
diseases showing CNS involvement can often not be
diagnosed sufficiently by means of noninvasive imaging
techniques, due to lack of or simply uncharacteristic
structural abnormalities. As the discussion of all or-
gans possibly evaluated by MRS in clinical routine
would be beyond the scope of a single review, we focus
on neurospectroscopy and diagnostic insights into di-
verse neurological problems provided by MRS applied
as a clinical tool.
TECHNICAL BACKGROUND AND CHALLENGES
The results of an MRI examination are images repre-
senting the proton (1H) content of the examined tissue
displayed as slices of the body anatomy with a spatial
resolution as low as approximately 1 mm3 and the sig-
nal mainly arising from water and fat. In spectroscopy,
MR signals corresponding to biochemical compounds
investigated are presented as peaks (also called reso-
nances) in MR spectra illustrated in Fig. 1. Depending
on the addressed nucleus, different compounds can be
detected. 1H, also used in MRI, and 31P are the most
frequently used nuclei in clinical MRS; however, even
13
C, 15N, 19F, and 23Na are assessable by MRS. Giving
insights into the energetic pathways, including, e.g.,
ATP and phosphocreatine (PCr), 31P-MRS is outstand-
ing for the evaluation of sources of metabolic energy in
the brain. Nevertheless, 1H-MRS has become the main
clinically applied tool in neurospectroscopy, as it pro-
vides information on markers of neuronal function, my-
elin, cell membranes, and metabolic active compounds,
as well as the fact that the MR sensitivity is much
greater for protons than it is for phosphorus and allows
for better spatial resolution.
Spatial resolution in in vivo 1H-MRS is limited, and
spectra are usually acquired from a localized area ob-
taining single (single-voxel spectroscopy (SVS)) or mul-
tiple voxels (multivoxel spectroscopy, also referred to as
chemical shift imaging (CSI)) on the order of 1– 8 cm3.
The acquisition of localized spectra is of special impor-
tance in focal or heterogeneous lesions where it allows
the separate evaluation of morphologically normal and
pathologic-appearing parts in and adjacent to brain
lesions, as well as the comparison to the contralateral
hemisphere.
560

Proton MR Spectroscopy in Clinical Routine
Figure 1. Metabolic compounds de-
tected by proton MRS at different echo
times. A: TE ⫽ 270 msec (PRESS se-
quence); reading from right to left, the
three main resonances NAA (2.0 ppm),
Cr (3.0 ppm), and Cho (3.2 ppm) are ob-
served. B: TE ⫽ 20 msec (STEAM se-
quence); with main additional reso-
nances at 3.6 and 4.0 ppm (mI) and at
2.6 ppm (additional NAA peak) and a
cluster of small peaks at 2.2–2.4 ppm,
consistent of Glx, which is mainly de-
tected in pathologically altered tissue,
e.g., in hepatic encephalopathy (not
shown).
To be able to acquire signals representing metabolic
compounds of interest, the brain water resonance, the
main signal source in 1H-MRS, has to be suppressed,
as the water signal is much larger than the desired
signal of investigated brain compounds and their reso-
nances would literally drown in the water peak. Special
water suppression pulses are added to the pulse se-
quences.
Besides localization and water suppression, shim
procedures represent one of the major challenges in
clinical MRS, as the separation of interesting reso-
nances requires a field homogeneity exceeding stan-
dards known from conventional MRI. Although shim
procedures are often automated, manual shimming
might still be necessary in, e.g., short TE experiments,
which allow the detection of compounds with short T2
relaxation times, as discussed in the section below.
COMPOUNDS OBSERVABLE IN VIVO
Main resonances observed in a proton MR spectrum
(Fig. 1) are (5,7–12) N-acetyl-aspartate (NAA), and a
neuron marker observed at 2.02 ppm in the spectrum.
A decrease of the compound is seen in processes involv-
ing neuronal loss or damage, such as neoplasm, epi-
lepsy, multiple sclerosis (MS), stroke, hypoxia, and de-
mentia (13–16). Compared to the many diseases
leading to decreased NAA, cases with a pathologically
increased NAA resonance, such as Canavan’s disease
(17), occur rarely but are nonetheless well known.
Physiologically increasing NAA levels can be seen in
brain development and maturation in the infant
(18,19), and they can represent axonal recovery follow-
ing neuronal damage (14).
Choline (Cho), as well as choline-containing com-
pounds, has its main resonance at 3.2 ppm. It is often
referred to as a cell membrane and myelin marker. The
major cerebral choline compound, phosphatidylcho-
line, is partly MR invisible, and stored in cell mem-
branes, myelin, and other cerebral lipid pools. Its visi-
ble form is released from them under diverse
pathological conditions, such as acute myelin break-
down and increased cellular density (5,7,15).
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561
Total creatine (Cr), as well as phosphocreatine (PCr),
is a marker for brain energy metabolism and displayed
at 3.0 ppm in the proton spectrum. Cr concentrations
are comparable for different locations throughout the
brain and relatively resistant to changes. Therefore, Cr
is used as the internal standard to which resonance
intensities of other compounds are normalized. How-
ever, alterations in Cr levels occur, e.g., in trauma,
tumors, and hypoxia. Cr, PCr, Cho, and myo-inositol
(see below) are also recognized osmotically active me-
tabolites (7).
Lactate (Lac) is not seen in the spectrum of a healthy
human. Pathologic accumulation (resonance at 1.3
ppm) of this end product of anaerobe glycolysis indi-
cates that oxidative metabolism is unable to meet en-
ergy requirements. Neurological diseases accompanied
by positive lactate findings in MRS are, e.g., hypoxia,
ischemia, epilepsy, tumors, and mitochondrial diseases
(1,7,8,14,20).
Potentially MR-visible lipids in normal brain tissue
are bound to macromolecules in membranes and mye-
lin and therefore invisible. Due to severe pathologic
disruption of such structures, increased lipid turnover
leads to more mobile lipids, yielding detectable lipid
signals at 0.9 and 1.3 ppm (8).
The glutamate (Glu) and glutamine (Gln) resonances
are often summarized as a multiplet, Glx, at 2.2–2.4
ppm. The signal from normal brain tissue is weak, and
short echo time studies (10 –20 msec), studies at higher
field strength (ⱖ1.5 Tesla), or 13C or 15N studies are
preferable to achieve a closer look at Glx turnover. Glu
is a neurotransmitter, a redox marker, and, when oc-
curring in pathologically increased concentrations, a
neurotoxin. Gln is an astrocyte marker (5,7).
Myo-inositol (mI) is an astrocyte marker and os-
molyte, and its resonance, preferably evaluated with
short echo times, appears at 3.6 ppm in the proton
spectrum (5,7).
Further metabolites, such as amino acids and ace-
tate, will be referred to in the text below.
Although MR spectra, as any MR image, can be read
visually, quantitative information on concentrations of

562
observed compounds and metabolite (compound) ratios
permit a more precise and reproducible interpretation
of MRS data and should therefore be obtained (19,21–
23). Furthermore, clinical data and morphologic infor-
mation based on computer tomography (CT), MRI, sin-
gle-photon-emission computer tomography (SPECT),
and positron emission tomography (PET) have to be
taken into account when interpreting MR spectra, as
pathologic entities easily differentiated on clinical or
morphological bases can be impossible to differentiate
by MRS alone. Also, age differences and concentration
differences for the observed compounds throughout the
brain have to be considered (7,18,19).
MAIN CLINICAL APPLICATIONS OF PROTON MRS
OF THE HUMAN BRAIN
In Europe, a developed part of the world with a high
standard of health care, several CNS diseases and sys-
temic diseases with CNS involvement remain major
causes of disability or death. More sophisticated diag-
nostic methods are solicited to identify, characterize,
and classify these diseases to provide a diagnostic basis
for new and/or standardized therapy regimens.
MRS is one of these sophisticated methods adjusted
to the diagnostic challenges represented by diseases
like epilepsy, cerebral space-occupying lesions, MS, de-
generative diseases, and metabolic diseases. The im-
pact of these diseases on society both from economic
and humanitarian points of view can be imagined, con-
sidering some of the following incidence and prevalence
rates.
The mean incidence rate of epilepsy in Europe is
50/100,000; however, regional differences occur, and
the prevalence is 6 –7/1000. Among space-occupying
lesions, brain tumors have an incidence rate of 15/
100,000 (prevalence of 60/100,000). Although brain
tumors represent about 10% of neoplasm in adults
(higher percentage in children) and two-thirds of brain
tumors are benign, highly malignant astrocytomas are
the fourth leading cause of cancer mortality in men and
women between 15 and 34 years of age and the fifth
leading cause in men between 35 and 54 years of age.
Other space-occupying lesions, such as brain ab-
scesses, are rare in developed countries. MS shows
high regional differences in incidence (3/100,000) and
prevalence (between 50 –100/100,000; 70/100,000 in
central Europe) with the highest rates in the northern
parts of the United States, Canada, central and north-
ern Europe, southern Australia, and New Zealand. For
degenerative diseases, exact prevalence and incidence
rates are often unknown. A total of 5%–7% of the pop-
ulation over 65 years of age suffers from Alzheimer’s
disease (AD), the most common form of dementia in
Western industrialized countries. Parkinson’s disease
shows highest prevalence rates in northern parts of
America and Europe (200/100,000 in central Europe)
and incidence rates of 20/100,000.
Epilepsy
Spectroscopy findings in seizures illustrate that MRS
can provide valuable information that is different from
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Burtscher and Holtås
and complementary to that provided by MRI. Compared
to space-occupying brain lesions, many patients pre-
senting seizures do not show any MRI-detectable, mor-
phological alterations of brain parenchyma. Spectros-
copy provides the possibility of obtaining information
on cerebral metabolism based on the evaluation of
static metabolic abnormalities, primarily through the
NAA resonance, and on dynamic changes associated
with the activation of anaerobic glycolysis through the
lactate resonance (14,24,25).
Temporal lobe epilepsy (TLE) is well studied by MRS,
focusing on lateralization of the seizure (14,26 –29).
Measurements of NAA in epileptogenic regions have
consistently shown decreased NAA levels that represent
neuronal dysfunction and neuronal loss. MRS localizes
unilateral seizure foci in concordance with EEG and
clinical recordings with high precision. However, MRS
also demonstrates the presence of a high proportion of
bilateral abnormalities (28), which can be difficult to
observe with other techniques. MRS revealed both de-
creased NAA levels to be present even in the absence of
any MRI-visible abnormality and possible improvement
of NAA levels in the remaining temporal lobe after suc-
cessful resection of the epileptogenic temporal lobe (30).
Based on these findings, NAA decrease is thought to
partly reflect neuronal dysfunction associated with the
epileptic state rather than neuronal loss associated
with, e.g., hippocampal sclerosis. An increase in cho-
line-containing compounds in the epileptogenic region
might be associated with a reactive gliosis (24). In tissue
directly involved in seizure activity, the metabolic de-
mands may exceed the capacity of the tissue to provide
the required energy by oxidative metabolism, leading to
regional accumulation of lactate as a result of activated
anaerobic glycolysis. This local increase in lactate can
persist for several hours and may be used as a more
direct marker of seizure activity (7,25,31). Figure 2 il-
lustrates spectral abnormalities and asymmetries in a
patient presenting with partial status epilepticus and
electroencephalographically and clinically determined
unilateral epileptogenic focus.
Cerebral Space-Occupying Lesions
Cerebral space-occupying lesions can easily be de-
tected and visualized by means of diagnostic tools, such
as MRI, CT, and SPECT. However, as visualization itself
is often not sufficient for discrimination of different
lesion types, MRS can add another dimension to differ-
ential diagnosis by providing biochemical profiles of the
lesions.
Comparable to the diversity of tumor types, a variety
of different spectroscopic methods has been suggested
for differential diagnosis of brain tumors. Starting with
the interpretation of metabolite ratios and quantitative
MRS data acquired by means of single-volume spec-
troscopy measurements covering large and heteroge-
neous parts of the lesions, several spectral character-
istics could be associated to different tumor groups,
although large overlaps, questioning the specificity,
were observed (8,32– 41). Consistent findings were the
decrease and ultimately loss of NAA resonances in tu-
mors derived from other-than-neuronal tissue and an

Proton MR Spectroscopy in Clinical Routine
Figure 2. Partial status epilepticus. A: NAA is decreased and lactate slightly increased ipsilateral to the electroencephalographi-
cally determined epileptogenic focus (right, frontocentral) in an adult with partial status epilepticus. MRS localization scout
image (B) with measurement area and voxels represented by the spectra outlined in A and C. The contralateral brain tissue does
not show any spectral alterations (C).
increase in choline-containing compounds represent-
ing increased cell turnover, cell density, and gliosis (Fig.
3A). Lactate, mobile lipids, choline, and NAA levels were
furthermore used for malignancy staging (41– 44), and
the occurrence of alanine was associated with menin-
giomas (34). More sophisticated evaluation of spectral
data using neuronal networks and automated pattern
recognition showed promising results and, although
their clinical implication still is limited to a few research
centers, will certainly contribute to an increased repro-
ducibility of true differentiation of cerebral tumors in
the future (45–54). CSI allows the observation of spec-
tral alterations in heterogeneous parts of space-occu-
pying lesions based on increased resolution and more
efficient data acquisition regarding the number of vox-
els per examination time. The information provided
can, as illustrated in Fig. 3, be used for differential
diagnosis of focal vs. infiltrating tumors and ring-en-
hancing tumors vs. abscesses (55,56).
MS
Acute and chronic functional impairment in MS re-
sults from multiple mechanisms, including demyeli-
nation, conduction block, and axonal injury. The
main spectroscopic finding in MS lesions is decreased
NAA. However, early increase in Cho and lactate, as
well as early, transient decrease in Cr, can be ob-
served (15,25,35,57,58). In chronic lesions, Cr levels
normalize while NAA levels stay low, representing in-
complete recovery of axonal injury. Studies using
short echo times showed increased mI (59) and lipid
signals. Detecting decreased NAA levels even outside
lesions visualized using T2-weighted MRI, MRS
proved to be more sensitive in the detection of tissue
abnormalities in MS than conventional MRI. Consid-
ering the low percentage of white matter (WM) en-
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563
gaged by T2-weighted lesions in MS patients, changes
in normal-appearing WM might be more significant
for the chronic functional impairment of the patients
than abnormalities in the lesions. Fu et al (58)
showed that changes in NAA in normal-appearing
WM correlated better with functional impairment
than those in T2-weighted lesions. MRS may be used
for detection of axonal damage and demyelination in
MS and might be the only noninvasive method to
evaluate future treatment targeting axonal injury and
demyelination.
Degenerative Diseases
Although often diagnosed based on clinical findings,
several neurodegenerative diseases show MRS-detect-
able metabolic changes, which can contribute to the
differentiation of different groups and subtypes of these
diseases, as well as to the monitoring of progression in
certain diseases or their response to therapy.
AD shows, as other types of dementia, decreased NAA
levels (1,7,16,25). Differentiation might, however, be
possible when utilizing information from short TE ex-
aminations revealing, e.g., increased mI in AD, com-
pared to increased Cho in multi-infarct dementia (7).
Parkinson’s disease challenges MRS, due to technical
limitations in spatial resolution necessary for the as-
sessment of brain tissue involved in Parkinson’s dis-
ease (e.g., substantia nigra) and in management of sus-
ceptibility effects caused by excess of iron in these
regions. However, preliminary results from Holshouser
et al (60) indicate a decreased NAA/Cho ratio in the
striatum in a treatment subset of patients.
In Huntington’s disease (HD), MRS reveals reduced
NAA/Cho ratios and increased lactate in the cortex and
basal ganglia in symptomatic HD patients. Increased
lactate levels detected by MRS guided the choice of
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Figure 3. CSI can contribute to differential diagnosis of ring-enhancing lesions, such as infiltrating brain tumors (high-grade
glioma in AA), focal metastases (adenocarcinoma metastasis in BA), and abscesses (CA) by the detection of spectral alterations
in heterogeneous parts of the space-occupying lesions. The spectra representing the cystic parts of the lesions allow the
differentiation of the abscess (CB) from the glioma (AB) and the metastasis (BB) based on the combination of the detected
resonances of amino acids (2.4 ppm; 1.4 ppm, alanine; and 0.9 ppm), acetate (1.9 ppm), lactate (1.3 ppm), and mobile lipids (0.9
ppm) in the spectrum of the abscess. In comparison, the spectra representing the cystic necrosis of the glioma (AB) are
dominated by a lactate peak, and the cystic part of the metastasis shows lactate and an unassigned peak at 2.0 ppm, not
consistent with NAA. Spectra from the boarders of the cysts show, due to partial volume effects, a combination of the resonances
representing the cystic components and surrounding contrast-enhancing tissue with increased Cho/NAA (AC, BC, and CC).
Normal-appearing tissue outside the lesions in metastases (BD) and abscesses (CD) do not show any major spectral alterations.
However, normal-appearing tissue surrounding a glioma might show increased Cho and decreased NAA (AD), representing the
infiltrative growth of the glioma.

Proton MR Spectroscopy in Clinical Routine
Figure 4. Decreased NAA and a minor
lactate peak (inverted due to acquisition
with TE ⫽ 135 msec) following asphyxia
are seen in the MR spectrum (B) from a
voxel covering the basal ganglia (out-
lined in A) in a 2-day-old boy (gestational
age, 41 weeks).
treatment, and reversion of increased lactate following
coenzyme Q treatment can be monitored (61).
MRS utilized in other neurodegenerative diseases
showed decrease in NAA and increase in Cho and mI in
amyotrophic lateral sclerosis (ALS) (7,62) and strong
lipid-triglyceride signal in central pontine myelinolysis
(CPM) consistent with histological evidence of lipid-
filled macrophages at the site of myelinolysis (7).
Hypoxia
General biochemical reactions underlie the major spec-
tral alterations detected by 1H-MRS following hypoxia
based on, e.g., asphyxia (Fig. 4), near-drowning, car-
diac arrest, respiratory failure, stroke, TIA, or trauma
(5,7,63– 65). At the expense of accumulation of lactate,
anaerobic glycolysis meets energy requirements when
O2 is insufficient, which also leads to increased Glx in
short echo time studies. Decrease in NAA reflects neu-
ron dysfunction and axonal injury, and NAA levels can
continue to decline several days after the acute insult to
the CNS. Increased Cho levels can be observed in asso-
ciation with diffuse axonal injury and myelin and mem-
brane breakdown/turnover. Also, changes in Cr may
occur after hypoxia, as O2 is insufficient. MRS may be
used for prediction of impaired neurologic function
based on NAA and lactate levels and for monitoring
therapeutic intervention in, e.g., the acute phase of
stroke.
Metabolic Diseases
In metabolic diseases, inherited or acquired, the chal-
lenge for MRS is most often not the detection of the
primarily underlying metabolite, protein, enzyme, or
transmitter, but the visualization of the secondary
changes caused by the pathophysiological mechanisms
and expressed as neuronal dysfunction/damage, de-
myelination, gliosis, or accumulation of vast products.
Only a limited number among the variety of metabolic
diseases evaluated by MRS show specific spectral pat-
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565
terns, and spectral information always has to be inter-
preted in conjunction with clinical findings and case
history. Some of the specific changes recognized as
characteristic for a particular metabolic disease when
interpreted on the basis of the individual case are: ele-
vated lactate and sometimes decreased NAA in mito-
chondrial disorders (Fig. 5) (5,7); elevation of Glu, de-
pletion of mI, and reduction of Cho (in WM) in chronic
hepatic encephalopathy (66); reduced Cho and mI in
hypo-osmolar encephalopathy (7); increased NAA in
Canavan’s disease (17); increased glycine in nonketotic
hyperglycinemia; and elevated phenylalanine in phe-
nylketonuria (5). MRS may also be used for monitoring
the therapeutic intervention on the abnormal metabo-
lism in some of these disorders, as, e.g., in hepatic
encephalopathy with normalization of Glu, mI, and Cho
after liver transplantation (5,7).
CONCLUSIONS
MRS is an interesting and expanding branch of radiol-
ogy and neuroradiology in particular, and acquisition of
clinical MRS data has during the last decade become
convenient from a technical point of view. Interpreta-
tion of standard examinations has been made easier by
the accessibility of extensive research reports on MRS
and separate sessions focusing on clinical MRS at in-
ternational and clinical, as well as technical, MR meet-
ings.
MRS has already great clinical impact in localization
of foci and brain damage in epilepsy and represents a
valuable complement to conventional imaging tech-
niques, such as CT and MRI. MRS is superior to MRI in
the differential diagnosis of untreated bacterial ab-
scesses vs. other space-occupying lesions and in the
detection of tumor growth in morphologically normal
tissue. The possibility of a noninvasive evaluation of
metabolic abnormalities provided by MRS allows, in
comparison to MRI and CT, in many cases of metabolic
diseases, a more accurate differential diagnosis and

566
prediction of severity. MRS can also provide crucial
information for the evaluation of prognosis in asphyxia.
Neurospectroscopy, however, still provides more
challenges and can be expected to expand to other clin-
ical areas, such as therapy monitoring in, e.g., tumors,
metabolic and degenerative diseases, or MS. Whether
other diagnostic challenges can be found where MRS is
useful above and beyond MRI, SPECT, PET, and CT will
depend on further clinical studies and future develop-
ments. Main technical challenges are the optimization
of pulse sequences for clinical settings, e.g., multislice
sequences, the development of more user-friendly post-
processing protocols, and the introduction of neural
network analysis, automated pattern recognition, and
other mathematical or statistical methods for data
analysis.
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