Predictive value of brain perfusion SPECT for ketamine response in hyperalgesic fibromyalgia

Service Central de Biophysique et de Médecine Nucléaire, Assistance Publique des Hôpitaux de Marseille, Centre Hospitalo-Universitaire de la Timone, 264 rue Saint Pierre, 13385 Marseille Cedex 5, France.
European journal of nuclear medicine and molecular imaging (Impact Factor: 5.38). 09/2007; 34(8):1274-9. DOI: 10.1007/s00259-007-0392-7
Source: PubMed

ABSTRACT

Ketamine has been used successfully in various proportions of fibromyalgia (FM) patients. However, the response to this specific treatment remains largely unpredictable. We evaluated brain SPECT perfusion before treatment with ketamine, using voxel-based analysis. The objective was to determine the predictive value of brain SPECT for ketamine response.
Seventeen women with FM (48 +/- 11 years; ACR criteria) were enrolled in the study. Brain SPECT was performed before any change was made in therapy in the pain care unit. We considered that a patient was a good responder to ketamine if the VAS score for pain decreased by at least 50% after treatment. A voxel-by-voxel group analysis was performed using SPM2, in comparison to a group of ten healthy women matched for age.
The VAS score for pain was 81.8 +/- 4.2 before ketamine and 31.8 +/- 27.1 after ketamine. Eleven patients were considered "good responders" to ketamine. Responder and non-responder subgroups were similar in terms of pain intensity before ketamine. In comparison to responding patients and healthy subjects, non-responding patients exhibited a significant reduction in bilateral perfusion of the medial frontal gyrus. This cluster of hypoperfusion was highly predictive of non-response to ketamine (positive predictive value 100%, negative predictive value 91%).
Brain perfusion SPECT may predict response to ketamine in hyperalgesic FM patients.

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SHORT COMMUNICATION
Predictive value of brain perfusion SPECT for ketamine
response in hyperalgesic fibromyalgia
Eric Guedj & Serge Cammilleri & Cecile Colavolpe &
David Taieb & Catherine de Laforte & Jean Niboyet &
Olivier Mundler
Received: 20 July 2006 / Accepted: 29 January 2007
#
Springer-Verlag 2007
Abstract
Purpose Ketamine has been used successfully in various
proportions of fibromyalgia (FM) patients. However, the
response to this specific treatment remains largely unpre-
dictable. We evaluated brain S PECT perfusion before
treatment with ketamine, using voxel-based analysis. The
objective was to deter mine the predictive value of brain
SPECT for ketamine response.
Methods Seventeen women with FM (48±11 years; ACR
criteria) were enrolled in the study. Brain SPECT was
performed before any change was made in therapy in the
pain care unit. We considered that a patient was a good
responder to ketamine if the VAS score for pain decreased
by at least 50% after treatment. A voxel-by-voxel group
analysis was performed using SPM2, in comparison to a
group of ten healthy women matched for age.
Results The VAS score for pain was 81.8±4.2 before
ketamine and 31.8±27.1 after ketamine. Eleven patients
were considered good responders to ketamine. Responder
and non-responder subgroups were similar in terms of pain
intensity before ketamine. In comparison to responding
patients and healthy subjects, non-responding patients
exhibited a significant reduction in bilateral perfusion of
the medial frontal gyrus. This cluster of hypoperfusion was
highly predictive of non-response to ketamine (positive
predictive value 100%, negative predictive value 91%).
Conclusion Brain perfusion SPECT may predict response
to ketamine in hyperalgesic FM patients.
Keywords Brain SPECT
.
Voxel-based analysis
.
Pain
.
Fibromyalgia
.
Ketamine
Introduction
Fibromyalgia (FM) syndrome is a chronic pain condition
without a clinically demonstrable peripheral nociceptive
cause [1]. We recently demonstrated that these patients
exhibit significant perfusion abnormalities in regions of the
brain known to be involved in sensory and affective
attentional dimensions of pain processing [2]. These results,
in agreement with previous functional magnetic resonance
imaging reports [3], confirm the hypothesis of central
sensitisation [4], which provides the rationale for prescrip-
tion of centrally acting analgesic agents in patients with
severe FM [5]. The N-methyl-
D-aspartate (NMDA) receptor
antagonist ketamine, in particular, has been successfully
used in various proportions of hyperalgesic FM patients.
However, the response to this specific treatment, usually
administered during a short hospital stay and not devoid of
side-effects, remains largely unpredictable.
In the present study we evaluated brain SPECT
perfusion before treatment with ketamine, using voxel-
based analysis in the same cohort of hyperalgesic FM
patients who had been enrolled in our previous study [2].
The objective of this prospective study was to determine the
predictive value of brain SPECT for ketamine response.
Eur J Nucl Med Mol Imaging
DOI 10.1007/s00259-007-0392-7
E. Guedj (*)
:
S. Cammilleri
:
C. Colavolpe
:
D. Taieb
:
C. de Laforte
:
O. Mundler
Service Central de Biophysique et de Médecine Nucléaire,
Assistance Publique des Hôpitaux de Marseille,
Centre Hospitalo-Universitaire de la Timone,
264 rue Saint Pierre,
13385 Marseille Cedex 5, France
e-mail: eric.guedj@ap-hm.fr
J. Niboyet
Unité dEtude et de Traitement de la Douleur,
Clinique La Phocéanne,
Marseille, France
Page 1
Materials and methods
Subjects
We enrolled the same cohort of hyperalgesic FM patients as
was previously included in our first study [2], except for
one patient who withdrew her consent (patient no. 2). These
17 women (48±11 years, range 2563) met the American
College of Rheumatology criteria for FM [6]. All patients
underwent a general medical a ssessme nt by the same
investigator to confirm the diagnosis. They had failed to
respond optimally to non-opioid analgesics or weak opioids
and had to be managed in a pain care unit. Patients with a
psychiatric disease wer e excluded. No patient had any other
significant medical illness. No change was made in
treatment during the month preceding inclusion. No patient
was receiving treatment with a potent opioid, a tricyclic
antidepressant, a selective serotonin reuptake inhibitor,
benzodiazepine or anti-convulsant agents. Patients were
treated in the pain care unit with rising doses of subcuta-
neous ketamine for 10 days (average maximum dose
100 mg). We considered that a patient was a good responder
to ketamine if the Visual Analogue Scale (VAS) score for
pain decreased by at least 50% after treatment. For
comparison of imaging findings, a control group of ten
women matched for age was also included (52±7 years,
p=0.21, using the Mann-Whitney U test). All subjects pro-
vided informed consent according to institutional guidelines.
SPECT protocol and statistical analysis
A brain SPECT was performed at baseline before any
change was made in therapy in the pain care unit. Patients
received an injection of 740 MBq of
99m
Tc-ECD (Neurolite,
BMS) and were placed at rest for 1 h, in quiet surroundings
with their eyes closed. SPECT image acquisition was
performed using a double-headed rotating gamma camera
(ECAM, Siemens) equipped with a fan-beam collimator.
Thirty-two 40-s projections per patient were collected in a
128×128 format. Tomographic 3D reconstr uction was
performed using a filtered back projection algorithm (Butter-
worth filter of order 4 with a cut-off frequency of 0.4 cm
1
)
and Changs attenuation correction. A voxel-by-voxel group
study was then performed using SPM2 (Welcome Depart-
ment of Cognitive Neurology, University College, London),
running on Matlab 6.0 Mathworks Inc, Sherborn, MA). We
compared brain SPECT perfusion between responders and
non-responders before ketamine, and healthy subjects, in
order to search for the predictive value of SPECT for ketamine
response. Images were initially converted from the DICOM to
the Analyze format using MRIcro (http://www.mricro.com),
and transferred to SPM2. Data were then standardised with
the Montreal Neurological Institute (MNI) atlas by using a
12-parameter affine transformation, followed by non-linear
transformations and trilinear interpolation. The dimensions
of the resulting voxels were 2×2×2 m m. Standardised
data were then smoothed with a Gaussian filter (FWHM=
12 mm). Subgroup analyses were performed using the
compare-populations one scan/subject routine, which car-
ries out a fixed-effects simple t test for each voxel, and
considering age as a nuisance variable. The proportional
scaling routine was used to control for individual variation
in global brain perfusion; these data will be referred to as
normalised regional cerebral blood flow (rCBF). The SPM
{T} maps were initially obtained at a height threshold of
p<0.005, and then an extent threshold was applied to obtain
a statistical threshold corrected for multiple comparisons for
the cluster (p<0.05). Using SPM2, the plot of adjusted
normalised rCBF (i.e. rCBF normalised by and adjusted to
the subjects global perfusion) in the maximum voxel value
of each eligible cluster (to be referred to as the peak)was
obtained, and the predictive values to discriminate the two
subgroups of FM patients according to the ketamine
response calculated.
Normalised perfusion values of significant clusters were
then extracted, and MNI coordinates finally converted into
Talairach coordinates using the Talairach Daemon database
(http://ric.uthscsa.e du/projects/talairachdaemon.html). A
Mann-Whitney U test was used to compare age and VAS
for pain in responder and non-responder subgro ups, and
adjusted normalised rCBF between subgroups of patients
and healthy subjects.
Table 1 Characteristics of 17 FM patients
Patient no. Age (yrs) Pain (VAS) before
ketamine
Pain (VAS) after
ketamine
16085 5
25690 80
35280 20
43480 80
56390 25
65575 45
74985 5
83175 30
95080 15
10 49 80 50
11 52 85 50
12 44 80 0
13 62 80 15
14 25 80 5
15 30 80 5
16 58 85 80
17 47 80 30
VAS Visual Analogue Scale
Eur J Nucl Med Mol Imaging
Page 2
Results
Pain intensity before and after ketamine
Clinical characteristics of each FM patient are listed in
Table 1. Mean VAS for pain was 81.8±4.2 (7590) before
ketamine and 31.8±27.1 (080) after ketamine (p<0.0001).
Eleven patients were considered good responders to
ketamine, with a pain intensity decrease of more than 50%
after treatment. In this subgroup, mean VAS for pain was
81.4±3.7 (7590) before ketamine and 14.1±10.4 (030)
after ketamine (p<0.0001). On the other hand, six patients
Fig. 1 Anatomical localisation
of the peak of significant rCBF
difference in responding and
non-responding patients, before
ketamine, in comparison to
healthy subjects, on 3D render
of the SPM template. In
comparison to healthy subjects,
responding and non-responding
patients exhibited hyperperfu-
sion of the somatosensory cortex
(in red) and hypoperfusion of
the frontal, cingulate, temporal
and cerebellar cortices
(in green). (P voxel value
<0.005, uncorrected; P cluster
level <0.05 corrected for
multiple comparison)
Table 2 Significant perfusion abnormalities in FM subgroups
Brain SPECT comparisons Contrast Cluster
p(cor)
k Vo x e l
p(cor)
Voxel T Vo x e l
p(unc)
x,y,z (mm) BA Localisation
Responding patients
vs healthy subjects
Hypoperfusion 0.001 10,105 0.001 8.60 0.001 32, 48, 16 R BA10 R middle frontal gyrus
0.008 6.82 0.001 24, 54, 4 R BA10 R superior frontal gyrus
0.017 6.41 0.001 10, 46, 26 R BA11 R rectal gyrus
0.001 3,185 0.003 7.37 0.001 20, 34, 32 R cerebellum
0.008 6.77 0.001 22, 40, 42 R cerebellum
0.087 5.56 0.001 20, 2, 26 Amygdala
0.037 1,115 0.008 6.80 0.001 30, 40, 34 L cerebellum
0.188 5.15 0.001 40, 52, 44 L cerebellum
Hyperperfusion 0.001 9,584 0.001 8.02 0.001 16, 44, 64 R BA3 R post-central gyrus
0.004 7.10 0.001 30, 56, 68 R BA7 R superior parietal lobule
0.007 6.88 0.001 58, 64, 20 R BA39 L inferior parietal lobule
Non-responding patients
vs healthy subjects
Hypoperfusion 0.001 3,695 0.001 8.24 0.001 18, 34, 32 Pons
0.009 6.74 0.001 36, 48, 32 R cerebellum
0.011 6.63 0.001 28, 40, 34 L cerebellum
0.001 8,122 0.001 7.74 0.001 6, 56, 2 R BA10 R medial frontal gyrus
0.002 7.53 0.001 2, 46, 0 L BA32 L anterior cingulum
Hyperperfusion 0.001 17,747 0.004 7.22 0.001 16, 48, 64 R BA7 R superior parietal lobule
0.010 6.68 0.001 58, 64, 18 L BA39 L superior temporal gyrus
0.033 6.07 0.001
60, 60, 26 L BA39 L superior temporal gyrus
Significant hypoperfusion
in non-responding patients,
masked by significant hypo-
perfusion in responding patients
0.016 1,371 0.030 6.12 0.001 2, 44, 24 L BA9 L medial frontal gyrus
0.062 5.74 0.001 6, 46, 22 R BA9 R medial frontal gyrus
0.183 5.16 0.001 4, 52, 14 L BA10 L medial frontal gyrus
Eur J Nucl Med Mol Imaging
Page 3
were considered poor responders to ketamine, with a pain
intensity decrease of less than 50% after treatment. In this
subgroup, mean VAS for pain was 82.5±4.8 (7590) before
ketamine and 64.2±15.9 (4580) after ketamine (p=0.0307).
These two subgroups were similar in terms of age (p=
0.5131) and pain intensity before ketamine (p=0.6192).
Brain SPECT comparisons
In comparison to healthy controls, FM patients exhibited
hyperperfusion of the somatosensory cortex and hypoper-
fusion of the frontal, cingulate, temporal and cerebellar
cortices, in accordance with results reported previously [2].
In particular, frontal hypoperfusion included medial areas.
Qualitative patterns similar to those obt ained in the whole
group were found when comparing responders versus
healthy subjects and non-responders versus healthy sub-
jects (Fig. 1,Table2). However, direct comparison
between responding and non-responding patients showed
a more significan t decrease in medio fronta l rCBF in the
non-responder group (left BA9; Talairach coordinates: 0,
44, 18; k=292, T-score=3.71, P voxel<0.005; Fig. 2). In
the same way, comparison of maps of significant hypo-
perfusion in responders and non-responders revealed more
extensive hypoperfusion of the bilateral mediofrontal cortex
in non-responders (left BA9; Talairach coordinates: 2, 44,
24; k=1,371, T-score=6.12, P voxel=0.001; Fig. 3, Table 2).
These maps of significant hypoperfusion were obtained by
comparing each group of patients with the healthy subjects.
In fact, in comparison to healthy subjects, both groups of
patients exhibited significant hypoperfusion of the medial
frontal cortex (Figs. 3, 4). This hypoperfusion was,
however, more severe in non-responders than in responders
(p=0.0067). In addition, this cluster of hypoperfusion was
highly predictive of non-response to ketamine. The
positive predictive val ue (PPV) and the negative predic-
tive value (NPV) were 100% and 91%, respectively. No
other differences were found between responding and non-
responding patients; i n particular, the non-responder group
did not exhibit m ore severe hyperperfusion.
Fig. 2 Anatomical localisation
of significant hypoperfusion in
non-responding patients, in
comparison to responding
patients (P voxel value <0.005,
uncorrected), projected onto
sections of a normal MRI set
spatially normalised into the
standard SPM2 template. In
comparison to responding
patients, non-responding
patients exhibited more severe
hypoperfusion of the medial
frontal gyrus (BA9)
Eur J Nucl Med Mol Imaging
Page 4
Discussion
Based on animal models and clinical studies, ketamine has
been widely used during the past 10 years for analgesia, in
particular to attenuate chronic hypersensitivity [5]. Indeed,
much evidence points to the involvement of NMDA
receptors in persisting nociceptive and neuropathic pain. In
FM patients, ketamine has been compared with morphine,
lidocaine, naloxone, and placebo in two randomised con-
trolled trials [7, 8]. These studies showed that ketamine
increased endurance and reduced pain intensity, tenderness at
trigger points, referred pain, temporal summation, muscular
hyperalgesia and muscle pain at rest. Both studies suggested
that tender points represent areas of secondary hyperalgesia
Fig. 4 rCBF values extracted,
for each FM patient, from the
cluster of significant hypoperfu-
sion in non-responding patients,
in comparison to significant
hypoperfusion in responding
patients (BA9). The rCBF of
this cluster was highly
predictive of non-response to
ketamine: PPV=100% and
NPV=91%. In comparison to
healthy subjects, both groups of
patients exhibited significant
hypoperfusion of the medial
frontal cortex. This hypoperfu-
sion was, however, more severe
in non-responders than in
responders (p=0.0067)
Fig. 3 Anatomical localisation of the peak of significant hypoperfu-
sion in responding patients in comparison to healthy subjects (a), and
in non-responding patients in comparison to healthy subjects (b),
projected onto sections of a normal MRI set spatially normalised into
the standard SPM2 template. (c) Anatomical localisation of significant
hypoperfusion in non-responding patients, masked by significant
hypoperfusion in responding patients (exclusive mask, P voxel value
<0.005, uncorrected; P cluster level <0.05 corrected for multiple
comparison). In comparison to responding patients, non-responding
patients exhibited more extensive bilateral hyp operfusion of the
medial frontal gyrus (BA9)
Eur J Nucl Med Mol Imaging
Page 5
and concluded that relief from these symptoms with keta-
mine indicates a reduction in central sensitisation. However,
not all patients with nociceptive and/or neuropathic pain
respond to ketamine. In some studies, barely 30% had a
beneficial effect [5]. Although several reports have suggested
that the likelihood of response is increased in younger
patients with a shorter history of pain [9], in fact this
response remains largely unpredictable. For example, the
best results in one study were obtained in two patients with a
prolonged (1220 year) history of disease [10]. For many
authors, this might suggest that only a subset of FM patients
has symptoms mediated by NMDA receptor mechanisms
[5]. Moreover, since intolerable psychotomimetic side-
effects are frequently reported [5], it is important to identify
within a population of hyperalgesic FM patients those who
might respond to ketamine.
In the present study conducted in hyperalgesic FM
patients at rest, we showed that hypoperfusion of the medial
frontal and anterior cingulate cortex was highly predictive
of non-response to ketamine (PPV=100% and NPV=91%),
and independent of initial pain intensity. Decreased synaptic
activity in this area, assumed to be related to apathy, has also
been observed in chronic pain conditions. Gracely et al.
found that, compared with healthy patients, painful stimu-
lation in FM patients induced smaller activations in the
anterior cingulate cortex [3]. The authors suggested that FM
patients develop a central processing of pain adapta tion that
reduces affective appraisal and responsiveness to pain. This
adaptative mechanism may in fact maintain pain, probably
induces treatment resistance and thus accounts for the
varying likelihood of response to ketamine. FM patients
with frontocingulate hypoperfusion would therefore proba-
bly benefit from cognitive therapy before ketamine, in order
to adjust their responsiveness to pain.
This prospective study showed that brain perfusion
SPECT may predict response to ketamine in hyperalgesic
FM patients. Larger studies and follow-up data, however,
will be necessary to determine the long-term predictive
value of these results.
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  • Source
    • "In this study, pronounced pretreatment hyperperfusion in the right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive appeared to be predictive of poor response to gabapentin given the high positive likelihood ratios obtained for these regions. These findings are not consistent with a previous finding for non-responders to ketamine, in which hypoperfusion in the medial frontal area was observed [18]. As noted above, subjects in the study of Guedj and colleagues were hospitalized because of treatment failure whereas our subjects were CNS drug-naive outpatients without major depressive disorder, and our findings were correspondingly not affected by CNS drugs. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the present study was to determine the brain areas associated with fibromyalgia, and whether pretreatment regional cerebral blood flow (rCBF) can predict response to gabapentin treatment. A total of 29 women with fibromyalgia and 10 healthy women (without pain) matched for age were finally enrolled in the study. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography ((99m)Tc-ECD SPECT) was performed in the fibromyalgia patients and controls. A voxel-by-voxel group analysis was performed using Statistic Parametric Mapping 5 (SPM5). After treatment with gabapentin, 16 patients were considered 'responders', with decrease in pain of greater than 50% as evaluated by visual analogue scale (VAS). The remaining 13 patients were considered 'poor responders'. We observed rCBF abnormalities, compared to control subjects, in fibromyalgia including hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. Compared to responders, poor responders exhibited hyperperfusion in the right middle temporal gyrus, left middle frontal gyrus, left superior frontal gyrus, right postcentral gyrus, right precuneus, right cingulate, left middle occipital gyrus, and left declive. The right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive exhibited high positive likelihood ratios. The present study revealed brain regions with significant hyperperfusion associated with the default-mode network, in addition to abnormalities in the sensory dimension of pain processing and affective-attentional areas in fibromyalgia patients. Furthermore, hyperperfusion in these areas was strongly predictive of poor response to gabapentin.
    Full-text · Article · Apr 2010 · Arthritis research & therapy
  • Source
    • "The fi ndings by Mountz and colleagues (1995) were largely replicated in a second SPECT study by Kwiatek and colleagues (2000). In a third SPECT trial, Guedj and colleagues (2007a, 2007b) reported a study using a more sensitive radioligand (99mTc-ECD) in fibromyalgia patients and pain free controls. Guedj and colleagues found hyperperfusion in fi bromyalgia patients within the somatosensory cortex and hypoperfusion in the anterior and posterior cingulate, the amygdala, medial frontal and parahippocampal gyrus, and the cerebellum. "
    [Show abstract] [Hide abstract] ABSTRACT: Fibromyalgia syndrome is a common chronic pain disorder of unknown etiology. The lack of understanding of the pathophysiology of fibromyalgia has made this condition frustrating for patients and clinicians alike. The most common symptoms of this disorder are chronic widespread pain, fatigue, sleep disturbances, difficulty with memory, and morning stiffness. Emerging evidence points towards augmented pain processing within the central nervous system (CNS) as having a primary role in the pathophysiology of this disorder. Currently the two drugs that are approved by the United States Food and Drug Administration (FDA) for the management of fibromyalgia are pregabalin and duloxetine. Newer data suggests that milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, may be promising for the treatment of fibromyalgia. A double-blind, placebo-controlled trial of milnacipran in 125 fibromyalgia patients showed significant improvements relative to placebo. Milnacipran given either once or twice daily at doses up to 200 mg/day was generally well tolerated and yielded significant improvements relative to placebo on measures of pain, patient's global impression of change in their disease state, physical function, and fatigue. Future studies are needed to validate the efficacy of milnacipran in fibromyalgia.
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  • Source
    • "The status of neural activity in the patients with FM was related to physiological and not psychological stimuli as mood states, such as depression, did not appear to influence the outcome. Data from SPECT neuroimaging studies have also been predictive of therapeutic responsiveness of treatment of patients with FM with amitriptyline and ketamine (Adiguzel et al 2004; Guedj et al 2007b). It is important to recognize that such neuroimaging techniques do not measure neural activity directly, but infer activity from localized changes in regional cerebral blood flow occurring in response to neural metabolic demand. "
    [Show abstract] [Hide abstract] ABSTRACT: Fibromyalgia (FM) is a common, complex, and difficult to treat chronic widespread pain disorder, which usually requires a multidisciplinary approach using both pharmacological and non-pharmacological (education and exercise) interventions. It is a condition of heightened generalized sensitization to sensory input presenting as a complex of symptoms including pain, sleep dysfunction, and fatigue, where the pathophysiology could include dysfunction of the central nervous system pain modulatory systems, dysfunction of the neuroendocrine system, and dysautonomia. A cyclic model of the pathophysiological processes is compatible with the interrelationship of primary symptoms and the array of postulated triggers associated with FM. Many of the molecular targets of current and emerging drugs used to treat FM have been focused to the management of discrete symptoms rather than the condition. Recently, drugs (eg, pregabalin, duloxetine, milnacipran, sodium oxybate) have been identified that demonstrate a multidimensional efficacy in this condition. Although the complexity of FM suggests that monotherapy, non-pharmacological or pharmacological, will not adequately address the condition, the outcomes from recent clinical trials are providing important clues for treatment guidelines, improved diagnosis, and condition-focused therapies.
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