Pediatr Radiol (1998) 28: 805±814 Ó Springer-Verlag 1998
Gregory J. Moore
Received: 14 April 1998 Accepted: 7 July 1998 This work was supported in part by a NARSAD Young Investigator Award Grant and a grant from the Children's Research Center of Michigan.
G.J. Moore Departments of Psychiatry and Behavioral Neurosciences, and Radiology, Children's Hospital of Michigan Wayne State University School of Medicine, 4201 St. Antoine, UHC-9B, Detroit, MI 48201, USA
Proton magnetic resonance spectroscopy in pediatric neuroradiology
Abstract This review reports on recent developments in proton magnetic resonance spectroscopy (MRS) and its potential clinical application in pediatric neuroradiology. An overview of the essential principles of the methodology including pulse sequences and their practical application is provided. Each of the major neurochemical compounds found in the pediatric brain and its potential clinical significance is reviewed. Special consideration is given to issues of quantitation and maturational changes in neurochemistry which are un-
Introduction Over the past decade there have been rapid advances in neuroimaging which have had a major impact on the diagnosis and treatment of children. This review reports on recent developments in the application of proton magnetic resonance spectroscopy (MRS). Proton MRS is a tool which provides a noninvasive window to brain biochemistry. In the past this has been solely a clinical research technique, however with recent technological advancements and FDA approval, proton MRS has now become a valuable clinical tool useful for diagnosis and/or monitoring of treatment in multiple conditions affecting the pediatric central nervous system. This report is specifically not intended to be a comprehensive review of the rapidly expanding clinical neuroscience MRS research literature. For this, the reader is referred to several excellent recent review articles [1±9]. Rather, the purpose of this review is to outline the essential principles of proton MRS, to provide an overview of the major neurochemical compounds ob-
ique to the developing brain. Examples of potential clinical applications of proton MRS are given in a brief case report format. Finally, the direction of likely future developments and the need for further investigation of proton MRS in pediatric populations is discussed. This review will provide the reader with a basic foundation for deciding when a proton MRS exam may be helpful for diagnosis and for the interpretation of proton MRS findings in the pediatric neuroradiology setting.
served in the pediatric brain and their potential significance, and to cover some of the practical clinical applications of this emerging technology in the pediatric neuroradiology setting. This information should help to provide a foundation for deciding when a proton MRS exam may be helpful for diagnosis and for the interpretation of proton MRS findings in the pediatric neuroradiology setting.
Noninvasive brain biochemistry Unlike MRI, which provides high-resolution images of brain anatomy primarily using signals from brain water and lipids, proton MRS actually suppresses these high background signals in order to measure the concentration of the major brain neurotransmitters and metabolites. Compounds which can be measured include Nacetyl-aspartate (NA), creatine/phosphocreatine (Cr), choline compounds (Cho), myo-inositol (mI), glutamate/glutamine/GABA(Glx), and lactate (Lac). Figure
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Fig. 1 Proton MR spectra from brain white and gray matter regions in a normal 8-year-old child, TE = 30/TR = 2000. (NA) N-acetyl-aspartate, (Cr) creatine/phosphocreatine, (Cho) choline compounds, (mI) myo-inositol, (Glx) glutamate/ glutamine
1 shows proton MR spectra from white and gray matter brain regions in a normal 8-year-old child. Each of the individual compounds is identified by its peak position (or chemical shift) on the x-axis, which is a frequency scale measured in parts-per-million (ppm). The area under each of the peaks (sometimes referred to as resonances) is proportional to the concentration of the neurochemical compound within the particular volume of the brain being investigated. Note that there are differences between the proton MRS spectral profiles of the volumes containing predominately gray matter and predominantly white matter in Fig. 1; most apparent is the change in the ratios of Cho to Cr with Cho greater in white matter. The major MRS visible neurochemical compounds in the human brain and their potential significance are briefly reviewed below. N-acetyl-aspartate (NA) 2.02 ppm. This resonance is usually the most predominant peak in the normal brain and consists mostly of NA but also contains smaller contributions from other N-acetyl compounds including Nacetyl-aspartyl-glutamate [10]. While the functional role of this amino acid has not been determined, NA is a putative neuronal marker [11], localized to neurons and not found in mature glial cells, CSF, or blood. A relative decrease in this compound may reflect decreased neuronal viability, neuronal function, or neuronal loss. Glutamate/glutamine/g-aminobutyric acid (Glx) 2.3 ppm. The broad resonance centered at approximately 2.3 ppm contains several overlapping resonances, predominantly glutamate and glutamine, which are both involved in a glutamatergic pathway [12]. g-aminobutyric acid (GABA) is visible on MR to a lesser extent due to its strong coupling properties. Glutamate is a neurotransmitter and is the most abundant amino acid in the human brain, and glutamine is believed to be local-
ized primarily to cerebral astrocytes and is the primary derivative for glutamate. Elevated levels of the Glx region of the spectrum (particularly glutamate) are thought to be deleterious to neuronal tissue. Creatine/phosphocreatine (Cr) 3.02 ppm. This single resonance contains both creatine and phosphocreatine. Creatine is converted to phosphocreatine through the enzyme creatine kinase. Phosphocreatine is a high-energy phosphate which is critical for maintaining cellular energy dependent systems. The Cr peak has been used by a number of investigators as an internal standard for interpretation of qualitative changes in the concentration of the other MR-visible neurochemical compounds and as such one often will see various references containing proton MRS data with Cr in the denominator (i. e., NA/Cr or Cho/Cr). This reflects the assumption that the Cr resonance is relatively unaffected by various pathologies. This has yet to be definitively established and in several studies has in fact been reported not to be a good assumption. Choline compounds (Cho) 3.23 ppm. The Cho resonance contains contributions from a number of mobile choline compounds, but predominantly from phosphorylcholine (PC) and glycerophosphorylcholine (GPC). Membrane-bound compounds are generally not MRvisible which in this case means that the high concentration of membrane bound phospatidylcholine does not contribute to the normal proton brain spectrum. However, in disease processes which result in membrane breakdown, this formerly bound choline is released into the free choline pool and becomes MR-visible, which is thought to contribute to an increase of this resonance in neurodegenerative states. In addition, pathological specimens of various tumors have been shown to contain highly elevated concentrations of PC and
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Fig. 2 Proton MRS gray matter spectra obtained from an infant of 45 weeks' gestational age (GA) compared to a 4-year-old child, TE = 30/TR = 2000
GPC which is believed to be the rationale behind the observed relative increased levels of Cho seen in various brain tumors examined by proton MRS. Myo-inositol (mI) 3.56 ppm. The mI resonance contains predominantly myo-inositol with minor contributions ( < 5 %) from glycine and inositol ±1-phosphate. Myoinositol is involved in osmoregulation of the brain and the metabolism of membrane-bound phospholipids. It is also directly involved in a number of important neuronal signaling systems including the phosphoinositide pathway. Perturbations in brain mI concentrations can have significant clinical effects on each of these systems. Lactate (Lac) 1.33 ppm. The lactate resonance appears in a region of the spectrum which often contains overlapping signals from lipids and macromolecules. Lactate is a product of anaerobic glycolysis and has a doublet peak structure centered at 1.33 ppm with a 7-Hz peak splitting. This compound is usually not present at MRS-detectable concentrations ( < 0.7 mM) in the normal brain. The presence of lactate in a region of the brain is often associated with pathology and poor prognosis for the brain tissue involved. As such, extra care should be taken in identifying lactate (see Essentials of clinical proton MRS below) in this sometimes difficultto-interpret region of the spectrum. Neurochemical considerations in the developing brain Maturational changes in brain content and structure can be readily identified at different developmental stages utilizing MRI. Not surprising then, are findings that the brain also undergoes developmentally associated neurochemical changes [13]. Figure 2 shows proton MRS gray matter spectra obtained from an infant of 45 weeks' gestational age compared to a 4-year-old child. Note that
there are several striking differences including increased mI in infancy, and a reversal of the Cho/Cr and a dramatic increase in NA/Cr with increasing age. These latter 2 changes are thought to be associated with myelination of the developing brain. Maturational curves for changes in the absolute concentrations of neurochemicals in the normal pediatric brain have been established [13]. This study indicates that NA, Cr, and Glx all increase in concentration with brain development, and Cho and mI decrease in concentration with brain development. Each of the neurochemicals appear to reach approximately adult levels by age 4 years, with the most rapid changes occurring within the first 2 years of life. These data suggest that special caution should be used in the interpretation of data from young infants as there appear to be very significant neurochemical changes occurring in the developing brain. Interpretation of ratios in very young patients can be particularly problematic, as several of the neurochemical compounds are increasing with maturation while others are decreasing (also see Essentials of clinical proton MRS below for discussion on quantitation). Finally, it should be noted that the literature reveals that developmental curves describing the time course of these neurochemical changes have relatively few data points in the adolescent age range, with the majority of the data points falling at the extremes of age (infancy/early childhood or adulthood). The significance and association of these neurochemical changes with development have yet to be fully elucidated.
Essentials of clinical proton MRS Pulse sequences The two most common pulse sequences used for the acquisition of clinical proton MRS studies are Stimulat-
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ed-Echo Acquisition Mode (STEAM) [14] and Point Resolved Spectroscopy (PRESS) [15]. The STEAM sequence is based on a stimulated-echo methodology which uses 3 consecutive 90 degree radiofrequency (rf) pulses. The PRESS sequence is based on a double spinecho rf scheme (90 ±180 ±180 ). Both of these methods are most typically applied in single-voxel (volume element) mode, however spectroscopic imaging methods based on these and similar techniques are likely to gain more widespread clinical application in the future (see Conclusions and future directions below). Both methods utilize the gradients to define a particular volume of interest within the brain and acquire a profile of the major biochemicals within the selected region while suppressing the background (and much more abundant) water signal as well as signals from the surrounding brain regions. In the not-too-distant past, if one wanted a to perform a short echo time (TE) study, the choice was always STEAM, as this sequence is technically much easier for a scanner's gradients to perform at short TE compared to the more demanding PRESS technique. The PRESS sequence was then reserved for relatively longer TE studies as it has the advantage of giving twice the signal to noise per unit time compared to STEAM at equal TE. However, with recent improvements in scanner gradient performance, if one has a system with these enhanced gradient capabilities the preferred choice for short TE studies is now PRESS due to its inherent signal to noise advantage. Relaxation times and the choice of TE and TR Similar to MRI, the choice of TE and repetition time (TR) can have a dramatic effect on the appearance of the information obtained in a proton MRS study. The most common values utilized for TE in clinical studies are 30 ms and 144 ms. The effect of TE on the visibility of the various neurochemical compounds is illustrated in Fig. 3. With increasing TE, those neurochemical compounds with the shorter spin-spin (T2) relaxation times (mI and Glx) disappear, while those with longer T2 values (NA, Cr, Cho) become more prominent. As one goes to TEs shorter than 30 ms, the mI and Glx region of the spectrum become even more prominent; however, water and lipids become more difficult to suppress adequately and the pulse sequences become more prone to artifacts. Note that lactate has the property of inverting at a TE of 144 ms due to its coupling properties. This characteristic can be utilized to identify this compound definitively in a region of the spectrum which is often overlapped with lipids and macromolecules. The choice of TR affects the spin-lattice relaxation time (T1) weighting of the spectrum. Compounds with a shorter T1 will appear more prominent in the spectrum
Fig. 3 The effect of TE on the visibility of the various neurochemical compounds is illustrated
with decreasing TR; conversely, at longer TRs the spectrum will more accurately reflect the concentration of all the compounds without T1 weighting. Again, as in MRI studies, the choice of TE and TR in clinical proton MRS studies reflects a compromise between a number of factors including scanner time, patient tolerance, and obtaining optimal information. The current consensus is the use of a TE of 30 ms and a TR of 2000 ms for most routine clinical exams. These parameters consistently produce a high-quality spectrum containing all the major MR-visible compounds within the brain in an examination time of approximately 5 minutes (assuming a typical 8 cc voxel and 128 averages). Situations where one might want to use a longer echo time ( 144 ms) would include difficult regions of the brain where water and/or lipid contamination of the voxel from nearby tissues is an issue or for the positive identification of lactate. Practical issues Although proton MRS has undergone many technological advances and is now highly automated and robust on many of the manufacturer's scanners, it does not always provide readily interpretable biochemical data. Proton MRS is susceptible to the same types of artifacts as MRI: the two most common in the pediatric setting are due to patient motion in the scanner and metal-containing orthodontic braces, both of which can render a proton MRS exam uninterpretable. Perhaps the single most important factor in determining the quality of a proton MR spectrum is obtaining
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optimal magnetic field homogeneity (e. g., shimming) over the volume of interest to be investigated. Fortunately, most clinical scanners have automated shimming features which greatly simply this task. A general rule of thumb is that a water linewidth of £ 3 Hz in the region investigated is required to obtain data which are of diagnostic quality. After shimming is completed, optimal adjustment of water suppression parameters is necessary as the signal from water is five orders of magnitude larger than the signals from the various neurochemical compounds of interest in proton MRS. Again, most scanners have automated features to accomplish this task and in fact on some scanners, both the shimming and water suppression adjustments are invisible to the user as they are simply performed during an automated prescan feature prior to the acquisition of the proton MRS data. In some areas of the brain it may be particularly difficult to obtain acceptable shim and water suppression parameters due to magnetic susceptibility artifacts from air-brain tissue interfaces. This can be particularly problematic in the inferior frontal and temporal lobes where there exist large sinuses proximal to these brain structures. When this problem arises it may be necessary to adjust the size and/or location of the voxel until acceptable shim and water suppression parameters can be obtained. Alternatively, some scanners allow the users to quickly adjust the gradient order of the pulse sequence timing such that the gradient in the direction of the largest magnetic susceptibility change is played out first in the pulse sequence, thus positioning it furthest away from the refocusing pulse and making the proton MRS data less prone to artifact. Finally, large peaks in the lipid region of the proton MRS spectrum can most often be attributed to contamination of the signals from the desired voxel within the brain, by signal from scalp lipids. Contamination from scalp lipids occurs most often due to patient motion during the MRS acquisition. Alternatively, contamination can result from placing the voxel too close to the edge of the brain surface, which often results in unintentional volume averaging of a portion of scalp or marrow into the voxel. Neurochemical quantitation There are several approaches that may be utilized for quantitation of proton MRS spectral data. The first, and perhaps least practical, approach in the clinical setting is to normalize the brain neurochemical concentrations to an external standard of known concentration. This is often not practical in the routine clinical setting as it requires the patient to remain in the scanner for a significant amount of extra time while data is being collected from the external standard. The water-referencing approach uses brain water as an internal standard
and assumes constant brain water content. This method has been utilized for over a decade for quantitation of in vivo MRS data. The internal brain metabolite-referencing approach is similar to the water-referencing approach but instead assumes a constant compound concentration, most commonly Cr. The last approach is more qualitative in nature and makes use of metabolite ratios (usually with Cr in the denominator) and/or visual pattern recognition of spectral profiles to determine which profiles are normal versus abnormal. The most commonly used method is currently the latter; however, there is a consensus beginning to form that a more quantitative approach utilizing the brain waterreferencing method may ultimately prove to be more sensitive and specific for diagnosis than the qualitative ratio methodology. Nonetheless, it is clear that qualitative ratios do often provide clinically useful diagnostic information in a number of disorders, and it is likely that many if not most groups will continue to use this qualitative assessment of the proton MRS data for primary diagnostic interpretation for the foreseeable future. Most scanner software packages include a method for analyzing the quantitative data and peak ratios, and in some cases the scanner software packages will automatically calculate the numerical values for the various neurochemical compounds and output them on the display to be filmed with the corresponding proton MRS spectrum. These automated features have greatly increased the practical clinical utility of this modality.
Clinical applications As discussed at the outset of this review, proton MRS has been shown to be a valuable tool which may be of help in the diagnosis and treatment of a large number of disorders affecting the pediatric brain. Several studies will be briefly presented to illustrate selected cases in which proton MRS has been shown to be valuable for diagnosis and/or treatment. Seizure disorders Numerous proton MRS studies in epilepsy and other seizure disorders have consistently demonstrated decreased NA in the region of seizure focus [16±23]. This focal decrease in NA appears to be very sensitive for lateralization of the epileptic focus in children with intractable seizures who are candidates for surgery. This finding has particular significance as scalp EEG is often misleading and/or falsely lateralizing in this difficult patient population. An example of how proton MRS was used to lateralize a seizure focus prior to epilepsy surgery is shown in Fig. 4.
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Fig. 4 1H MR spectra from right (left) and left (right) medial temporal lobe regions as indicated on T2-W Coronal MRI (central top), from a 6year-old girl with left temporal lobe epilepsy. Note the decreased NA peak (indicative of neuronal dysfunction/loss) in the MR spectrum from the left voxel. TE = 30/TR = 2000
Fig. 5 In this spectrum the abnormally elevated lactate concentration and decreased NA concentration was helpful in diagnosing this young patient with mitochondrial encephalopathy with lactic acidosis syndrome (MELAS). TE = 30/ TR = 2000
The neurosurgical decision-making process for control of seizures ultimately depends on a consensus of several differing modalities (imaging and non-imaging). There is growing evidence that proton MRS measurement of NA concentration is a sensitive test for lateralization of seizure foci in children with intractable temporal lobe epilepsy and, as such, this modality can serve an important complementary role in this area. Metabolic and mitochondrial disorders Proton MRS is also a useful tool which may be useful for diagnosis of inborn errors in metabolism and mitochondrial disorders. There has been considerable work in this area [24±27], and the data obtained have direct clinical relevance. For example, Fig. 5 demonstrates a case in which MRS was helpful for diagnosing a mitochondrial disorder. In this case the proton MRS spectrum of the occipital region revealed an abnormally elevated lactate concentration and decreased NA concentration in this young patient. This proton MRS finding resulted in further testing which led to a proper diagnosis of mitochondrial encephalopathy with lactic acidosis syndrome (MELAS).
Neuro-oncology Some of the first clinical applications of proton MRS described were in pediatric brain tumors [9, 28±32]. As discussed briefly above, particularly high-grade brain tumors tend to have dramatically increased levels of Cho. In addition, large tumors will often have areas with increased lactate. There are several studies which have been successful at distinguishing tumor type with proton MRS and work in this area is ongoing. Perhaps the most useful clinical utilization of proton MRS is distinguishing between tumor necrosis as a result of therapeutic intervention and recurrent tumor. This is often a very difficult diagnosis even with Gd-enhanced MRI. In the example case shown in Fig. 6, proton MRS was utilized to investigate the suspicious region for recurrent tumor. The elevated choline observed in the proton MRS spectrum suggested that there was indeed recurrent tumor and that further treatment was warranted. Childhood neurodegenerative disorders Proton MRS has been found to be clinically useful for evaluating a number of childhood-onset neurodegenerative disorders including many of the various forms of
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Fig. 6 Proton MRS was utilized to investigate the suspicious region for recurrent tumor by looking for active metabolites in the region . Note the increased choline peak, consistent with recurrent tumor. TE = 144/TR = 2000
Fig. 7 Proton MRS findings in a child with metachromatic leukodystrophy. Note the decreased NA, increased Cho, and elevated lactate
leukodystrophy [33±35]. In particular, increased levels of choline appear to be an early marker of demyelination occurring prior to apparent changes on MRI . This increased choline is presumably due to membrane bound phosphatidyl choline being released into the free choline pool due to the demyelination process. This finding may have important implications for the optimal timing of proposed therapies such as bone marrow transplantation. An example of proton MRS findings in a child with metachromatic leukodystrophy is shown in Fig. 7. In addition to the elevated choline resonance, also note the relative decrease in NA and the abnormally elevated lactate. The decreased NA is thought to be a consequence of the demyelination process and the associated neuronal dysfunction. The increased lactate is often observed together with the increased choline in these disorders during active demyelination and may be reflective of the active gliosis and/or macrophage metabolism products.
Neuropsychiatric disorders Emerging clinical applications of proton MRS are being rapidly being developed in the often overlooked area of pediatric neuropsychiatric disorders [36]. Since proton MRS allows for the direct and noninvasive monitoring of brain neurochemistry, this is an ideal tool to monitor the efficacy of specific psychotropic agents in modulating neurochemical levels. In Fig. 8, we report a treatment-naive 9-year-old boy with recent-onset obsessivecompulsive disorder who had pretreatment and posttreatment proton (1H) MRS scans to monitor glutamatergic changes in neurochemistry in the caudate nucleus following effective treatment with the selective serotonin reuptake inhibitor (SSRI), paroxetine. A striking change can be seen in the Glx region of the spectrum, consistent with a serotonin-mediated glutamatergic pathway in this disorder. Similar studies in other neuropsychiatric disorders are also under investigation, so this promises to be an area of expanding clinical utility for proton MRS. Particularly exciting in this area of investigation is that early neurochemical markers (particularly Glx and mI) may be indicative of
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Fig. 8 A treatment-naive 9year-old boy with recent onset of obsessive-compulsive disorder who had pretreatment and posttreatment proton (1H) MRS scans (TE = 30/ TR = 2000) to monitor glutamatergic changes in neurochemistry in the caudate nucleus following effective treatment with the selective serotonin reuptake inhibitor (SSRI), paroxetine. (From [36] with author's permission)
Fig. 9 Proton MRS study (TE = 144/TR = 2000) from a child with sickle-cell disease with new-onset paralysis while being seen in the hospital clinic. In this spectrum acquired 75 min after the onset of symptoms, a small inverted lactate resonance in the hyperintense region of the brain is shown. Note that this region fared poorly as seen on follow-up MRI 19 days later
long-term treatment response for given psychotropic agents. Hypoxic/ischemic insults The final area of clinical application which will be explored is that pertaining to hypoxic/ischemic insults in the pediatric brain [37±39]. A number of investigations performed in this area focused on the measurement of cerebral lactate concentration in hypoxic neonates. Increased lactate and its longitudinal persistence was correlated with poor neurological outcome
in these infants. There has also been work done in the area of stroke [40]. Figure 9 shows a proton MRS study from a child with sickle-cell disease with newonset paralysis while being seen in the hospital clinic. The proton MRS scan revealed a locally acute increased level of lactate in the brain, predictive of a poor prognosis for recovery of this area of the involved brain tissue. As predicted, this area of the brain fared rather poorly as demonstrated by a follow-up MRI 19 days later. The recent advent of thrombolytic therapy for intervention in acute stroke may expand the clinical role of proton MRS in this important area.
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Fig. 10 Example of proton spectroscopic imaging study (TE = 280/ TR = 2300). A map of the distribution of NA throughout the brain in this normal subject is shown in this high-resolution study. The bright outer band represents contamination from scalp lipids. Individual spectra can also be extracted for quantitation from these data sets as illustrated
Conclusions and future directions It is now clear that proton MRS will play an increasingly important role in clinical pediatric neuroradiology. The technological advances and standardization of protocols in this modality have allowed it to gain critical footholds
in areas of clinical importance. In the pediatric environment, it shares many of the advantages of MRI in that it is a completely noninvasive modality without ionizing radiation. This feature allows for convenient and safe follow-up studies at regular intervals. It is also clear that proton MRS has not yet reached the technical maturity level of clinical MRI. Advances in the research arena involving MRS continue at a rapid pace and some of these developments are likely to be incorporated into widespread clinical use in the near future. One possible example of this may be the use of multislice spectroscopic imaging techniques (see Fig. 10) as an alternative to the single voxel mode methods [41]. Spectroscopic imaging offers an order of magnitude increase in spatial resolution compared to single-voxel schemes (0.8 cc vs 8 cc). Additional improvements likely to come include faster acquisition times to facilitate dynamic MRS studies and MR visibility for a growing list of neurochemical compounds. This is especially true as one goes to field strengths greater than 1.5 T. The future of clinical proton MRS does indeed appear to be bright; however, much of the proton MRS literature in pediatrics is currently based on case reports and studies with small numbers of patients. Real advances in the clinical applicability of this modality will come only with widespread experience and evaluation of the utility of this modality in much larger patients populations than those studied to date. Acknowledgements. The author thanks Dr. Thomas L. Slovis, MD for reading the manuscript and providing many thoughtful comments.
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