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Folate-Deficient Hypermobility Syndrome: A Proposed Mechanism and Diagnosis

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Hypermobility syndrome involves excessive flexibility and systemic manifestations of connective tissue fragility. Certain genetic polymorphisms involving the MTHFR gene result in elevated serum folate and low intracellular folate, resulting in a relative folate deficiency. We describe relationships between folate metabolism and key proteins in the extracellular matrix that can explain the signs and symptoms seen in hypermobility syndrome. The Fascia Institute and Treatment Center, Department of Orthopedics Tulane University School of Medicine @fasciainstitute
Folate-Deficient Hypermobility Syndrome: A Proposed Mechanism and 1
Diagnosis 2
Jacques Courseault, MD, CAQSM, FAAPMR1 Christiania Edstrom1 Catherine Kingry, MD1 5
Kelli Morrell, MSN, FNP-C1 Lisa Jaubert, MD1, CAQSM1 Gregory Bix, MD2 6
Abstract 8
Hypermobility syndrome involves excessive flexibility and systemic manifestations of connective tissue 10
fragility. Certain genetic polymorphisms involving the MTHFR gene result in elevated serum folate and 11
low intracellular folate, resulting in a relative folate deficiency. We describe relationships between folate 12
metabolism and key proteins in the extracellular matrix that can explain the signs and symptoms seen in 13
hypermobility syndrome. 14
1. Tulane University School of Medicine, Department of Orthopedics, 1430 Tulane Avenue, New 20
Orleans, LA 70112 21
2. Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical 22
Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112 23
Keywords: Hypermobility Spectrum Disorder, Ehlers-Danlos Syndrome, MTHFR Gene Polymorphism, 26
Folate Deficiency, Hypermobility Syndrome, Folate Hypermobility Syndrome 27
Corresponding Author: 34
Jacques Courseault, MD, CAQSM, FAAPMR 35 36
Tulane University School of Medicine 37
Department of Orthopedics 38
1430 Tulane Avenue 39
New Orleans, LA 70112 40
Declarations of interest: none. 42
Folate-Deficient Hypermobility Syndrome
Background 43
Hypermobility syndrome is becoming a better-recognized entity in the medical community, with a 45
suggested prevalence of 2-57% of the population [1,2]. The 2017 International Consortium of 46
hypermobile-type Ehlers-Danlos Syndrome (hEDS) is an assessment tool that differentiates 47
hypermobility syndrome (HS) from hEDS. However, clinicians and patients have raised concerns that the 48
diagnostic criteria for hEDS are research restrictive and minimize related associated conditions and 49
comorbidities of patients with HS. HS patients are disregarded as only having benign joint flexibility but 50
can present with systemic manifestations of connective tissue fragility. Systemic manifestations include 51
myofascial pain, joint pain, poor wound healing, gastrointestinal dysfunction, postural orthostatic 52
tachycardia syndrome, and mast cell activation disorders. Systemic manifestations overlap with many 53
features of hEDS but may not meet all of the criteria for diagnosing hEDS.  54
While physicians identify other subtypes of EDS with genetic testing, HS and hEDS do not have known 55
genetic correlates. HS and hEDS are not primarily collagen-based disorders, resulting in the inability to 56
be identified with genetic testing. Therefore, physicians use clinical criteria to reach a diagnosis, which 57
can be controversial.  58
In our clinic, we have identified a subset of HS patients with high serum folate levels and C677T or 60
A1298C methylenetetrahydrofolate (MTHFR) polymorphisms. These HS patients tend to have more 61
significant systemic symptoms. To identify a relationship between abnormally high serum folate and 62
connective tissue fragility, we have identified a pathway leading to decreased activation of decorin, a 63
proteoglycan necessary for tissue integrity. Because of this correlating pathway, we propose a mechanism 64
and diagnosis of Folate-Deficient Hypermobility Syndrome (FDHS). 65
Folate-Deficient Hypermobility Syndrome
Elevated Serum Folate Levels in Hypermobile Patients 69
In addition to an extensive interview and physical exam, lab evaluations have identified a pattern of 71
abnormal lab values. Many of our symptomatic HS patients have elevated serum folate and normal MCV 72
and homocysteine levels. Further testing revealed a pattern of patients with an MTHFR polymorphism, 73
resulting in unmetabolized folate. The correlation between high serum folate and MTHFR polymorphism 74
prompted further evaluation to identify a potential metabolic mechanism to explain hypermobility and 75
associated systemic complications. 76
MTHFR Polymorphisms 78
MTHFR polymorphisms affect an individual's ability to metabolize folate to the biologically active form 80
of 5-MTHF (Figure 1). Polymorphisms reduce enzyme function to 30-80% depending on the type of 81
polymorphism and whether the individual is heterozygous or homozygous for one or both of the 82
polymorphic alleles. Two of the common polymorphisms described most frequently in the literature are 83
the polymorphisms C677T and A1298C. The C677T allele results in a more severe decrease in folate 84
metabolism than the A1298C allele. Homozygous polymorphisms result in a more severe decrease in 85
folate metabolism. A patient can have polymorphisms in both alleles, but rarely if ever homozygous in 86
both alleles. 87
Because of a lack of MTHFR enzymes, folate builds up extracellularly as the MTHFR enzymes become 88
saturated [3]. Unavailable MTHFR enzymes result in unmetabolized serum folate and high folate lab 89
values [3]. Figure 2 describes the metabolism of folate through the one-carbon pathway. 90
Folate-Deficient Hypermobility Syndrome
Folate-Deficient Hypermobility Syndrome
Pseudo-MTHFR Deficiency 93
Folic acid (synthetic folate) supplementation has led to unmetabolized folic acid (UMFA), which is 95
gaining interest in the research community. High levels of folic acid supplementation in mice caused a 96
pseudo-MTHFR deficiency [4]. In the mouse model experiment, high levels of synthetic folic acid 97
supplementation decrease the amount of MTHFR protein and the activity level of the available MTHFR 98
enzyme [4]. Therefore, improperly adding synthetic folic acid to a patient's diet with an MTHFR 99
polymorphism may cause a further decrease in MTHFR efficiency. 100
The Role of Decorin Within the Extracellular Matrix 102
The extracellular matrix (ECM) is vital for cellular structure and functions as cytokine and growth factor 104
storage. The ECM comprises collagens, laminins, fibronectin, entactin/nidogen, heparan sulfate 105
Folate-Deficient Hypermobility Syndrome
proteoglycans (e.g., perlecan), and a proteoglycan termed decorin. Proteoglycans are glycosylated 106
proteins essential for cellular adhesion and growth factor binding. Decorin is one such proteoglycan 107
primarily responsible for tissue integrity of the tendon, skin, and cornea [5]. Recent evidence has found 108
that decorin is the glue that holds the ECM and collagen fibers together. It is vital for binding collagen 109
together and cell growth, differentiation, spread, migration, adhesion, inflammatory regulation, and 110
fibrillogenesis [6]. 111
Mouse model experiments have demonstrated that the mice lacking the decorin gene have more fragile 112
skin with reduced strength [7]). The collagen was also loosely packed with abnormal collagen fibers of 113
varying diameters [7]. Typically collagen fibrils are arranged in parallel; however, without decorin the 114
orientation is random with abnormal collagen patterns [8, 18]. Gordon et al. further report that mice 115
deficient in decorin had higher Achilles rupture rates [8]. It is postulated that decreased skin strength 116
observed in knock-out decorin mice directly relates to the composition and layout of the collagen fibril 117
network [17]. Similarly, Alshiri and Palmer report a greater gastrocnemius medius and Achilles tendon 118
complex elasticity in those with HS [9]. 119
Folate Is Necessary for the Activation of Decorin 121
Endopeptidases modify the structure and composition of the ECM. Endopeptidases called matrix 123
metalloproteinases (MMP), specifically MMP-2 and MMP-3 activate decorin [10,5]. Activation occurs 124
through the process of proteolysis and cleavage of decorin into seven active fragments (Figure 4)[10, 11, 125
5]. During proteolysis, MMPs release bioactive fragments, growth factors, cytokines, chemokines, 126
adhesion molecules, and cell surface proteoglycans [11, 5]. MMPs are also crucial in wound healing, 127
tissue remodeling, and angiogenesis.    128
Folate modulates MMP transcription via promoter methylation through epigenetic changes [12]. In 129
general, DNA methylation is essential for regulating the expression of genes throughout the body. One 130
experiment investigating spinal cord recovery in mice found that dietary folate supplementation caused 131
Folate-Deficient Hypermobility Syndrome
higher levels of methylation in specific CNS genes. Relevant to the discussion of HS is the gene that 132
encodes for MMP-2 expression [12]). In methylating the genes that code for MMP-2, the expression of 133
those genes decreases (Figure 3). Consequently, in those with elevated serum folate levels, the amount of 134
available MMP-2 within the body ECM is reduced [12]. 135
We hypothesize that elevated, unmetabolized folate levels cause decreased transcription of MMP-2. 136
Decorin is not activated when MMP-2 is not present. Without decorin, collagen becomes more loosely 137
associated, and a lack of adhesion between collagen and the ECM occurs. Mechanically, this presents in 138
HS patients as unstable joints and hyper-extensible skin, similar to characteristics in decorin deficient 139
mice.   140
Folate-Deficient Hypermobility Syndrome
hEDS, Decorin, and Myofascial Pain Secondary to Fibrosis 145
In our clinic, HS patients present with symptomatic complaints of myofascial pain. We have found that 147
these HS patients have increased symptomatic fascial fibrosis noted on ultrasound imaging. We propose 148
that the lack of active decorin also plays a role in developing adhesions, fibrosis, and hypertrophic 149
scarring in hEDS patients. 150
TGF-Beta is a cytokine required for fibrotic tissue growth and chemotactic for fibroblasts that stimulate 151
their proliferation [13]. Fibroblasts synthesize collagen within the ECM [14]. TGF-Beta both stimulates 152
and inhibits different aspects of the ECM, contributing to wound repair and fibrosis for wound healing 153
(Brandon). Persistent long-term secretion of TGF-Beta causes excessive fibrosis (13, 14). 154
Growing evidence has demonstrated the importance of decorin in regulating the cytokine TGF-Beta 155
regulation that occurs through the binding of active decorin to the TGF-Beta receptor [15]. Research has 156
also demonstrated the use of decorin in modulating TGF-Beta and fibrosis in experimental kidney disease 157
[16]. Järvinen and Ruoslahti have described the role of decorin as anti-inflammatory and KO mice 158
without decorin are used as pro-inflammatory and pro-fibrotic models[21]. 159
Two mechanisms of regulation have been proposed. The first suggests that in binding decorin to the 160
receptor, TGF-Beta is down-regulated, preventing excessive fibrosis from developing [15]. Another 161
mechanism describes decorin as trapping TGF-beta within the ECM before interaction with its receptor 162
[22]. 163
Decorin interacts directly with fibroblasts, and it has been demonstrated that fibroblasts treated with 164
decorin had significantly lower levels of TGF-Beta [6]. 165
Finally, Miura et al. have demonstrated that decorin also specifically binds and regulates myostatin, a 166
subset of the TGF-beta family [19]. Myostatin is responsible for inhibiting myoblast differentiation, and 167
upregulation of myostatin has been associated with muscle atrophy [20]. The role of decorin in 168
modulating fibrosis has more recently become recognized, and ongoing research for pharmaceutical 169
therapies with decorin is currently under investigation [21]. 170
Folate-Deficient Hypermobility Syndrome
Discussion 171
We suggest that MTHFR polymorphisms can be suspected when high serum folate levels are present in 173
HS patients. MTHFR polymorphisms result in high serum levels of unmetabolized folate leading to an 174
intracellular folate deficiency. The subsequent folate deficiency is ultimately responsible for decreased 175
active decorin and instability of the ECM. Instability of the ECM can be associated with myofascial pain, 176
tendon and ligament laxity, and joint instability. Inactive decorin may also correlate with systemic 177
inflammatory manifestations of hypermobility, such as POTS and mast cell activation disorders; however, 178
further research is needed.  179
Serum folate levels should be checked while evaluating a patient with hypermobility syndrome. If folate 180
levels are high, the physician should consider that the patient may have unmetabolized serum folate and 181
test for an MTHFR polymorphism. If confirmed, the treatment plan should consider supplementation with 182
an appropriate dose of methylated folate. 183
In addition to identifying genetic reasons for high serum folate levels secondary to poor folate 184
metabolism, physicians may consider a further analysis of synthetic folic acid intake. Decreasing 185
synthetic folic acid intake may restore balance to native methylation pathways, leading to further decorin 186
activation. 187
While the importance of folate supplementation to prevent neural tube defects is well researched, further 188
research must be dedicated to the importance of folate metabolism in the context of ECM disorders 189
involving decorin. Hypermobility syndrome, specifically hEDS, follows a trend toward poor folate 190
metabolism and connective tissue fragility. In addition, research should be dedicated to evaluating the role 191
of vitamin B12 methylation in connective tissue disorders. 192
Finally, it has been challenging to identify mechanisms and genetic correlates for HS. Based on clinical 193
observations and correlation with known metabolic pathways and genetic testing, we propose a new 194
diagnosis of folate-deficient hypermobility syndrome (FDHS). Specifying a folate deficient subtype will 195
allow clinicians to identify a subset of hypermobility spectrum disorders and begin treatment with vitamin 196
Folate-Deficient Hypermobility Syndrome
supplementation that may prove beneficial. Research can then be further directed towards this particular 197
sub-type. 198
List of Abbreviations 200
hEDS: Hypermobile-type Ehlers-Danlos Syndrome 201
HSD: Hypermobility Spectrum Disorder 202
MTHFR: Methylenetetrahydrofolate reductase 203
FDHS: Folate-Deficient Hypermobility Syndrome 204
ECM: Extracelluar Matrix 205
MMPs: Matrix Metalloproteinases 206
UMFA: Unmetabolized Folic Acid 207
Declarations 208
Not applicable. 209
Ethics approval and consent to participate 211
Not applicable. 212
Consent for publication 214
Not applicable. 215
Folate-Deficient Hypermobility Syndrome
Availability of data and materials 217
Not applicable. 218
Competing interests 220
The authors declare that they have no competing interests. 221
Funding 223
Not applicable. 224
Authors’ Information 226
Affiliations 227
Tulane University School of Medicine, Department of Orthopedics, 1430 Tulane Avenue, New Orleans, 228
LA 70112 229
Jacques Courseault, MD, CAQSM, FAAPMR, Christiania Edstrom, Catherine Kingry, MD, 231
Kelli Morrell, MSN, FNP-C1 Lisa Jaubert, MD, CAQSM,
Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical 233
Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112 234
Gregory Bix, MD 235
Contributions 236
Jacques Courseault, Christiania Edstrom, Catherine Kingry, – Original Draft 237
Kelli Morrell, Lisa Jaubert Review and Editing 238
Folate-Deficient Hypermobility Syndrome
Gregory Bix - Supervision 239
Correspondence to: Jacques Courseault, MD, CAQSM, FAAPMR 240
Acknowledgments 241
Andre Labbe, PT, MOMT, Felix Savoie, MD 242
Tulane University School of Medicine, Department of Orthopedics 243
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Folate-Deficient Hypermobility Syndrome
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Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells' metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.
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Extracellular matrix (ECM) molecules play important roles in regulating processes such as cell proliferation, migration, differentiation and survival. Decorin (DCN) is a proteoglycan that binds to (“decorates”) collagen fibrils in the ECM. DCN also interacts with multiple growth factors and their receptors, the most notable of these interactions being its inhibitory activity on transforming growth factor‐β (TGF‐β), the growth factor responsible for fibrosis formation. We have generated a recombinant, multi‐functional, fusion‐protein consisting of DCN as a therapeutic domain and vascular homing and cell penetrating peptide as a targeting vehicle. The recombinant DCN (CAR‐DCN) accumulates at the targeted disease at higher levels, and as a result, has substantially enhanced biological activity over native DCN. CAR‐DCN is an example how molecular engineering gives compound an ability to seek out the sites of disease and enhance its therapeutic potential. CAR‐DCN will hopefully be used one day pharmacologically to treat severe human diseases.
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Severity of lacerative skin injury depends on the applied load and the resistance of the tissue. At low (static) rates of loading there is a high degree of correlation between skin tensile strength and the degree of collagen crosslinking, with little added strength due to collagen interactions with the glycosaminoglycan matrix. We examined the effects of high (ballistic) rates of loading in order to determine the contributions to strength made by both the degree of collagen crosslinking and the collagen-matrix interaction. Tensile failure experiments were conducted using the dorsal skin of rats 1.5-6 months of age. Test specimen orientations were cut parallel and transverse to the body axis at cephalad and caudad locations on the dorsum. Tensile strength was measured at nominal strain rates of 30%/sec (low speed) and 6000%/sec (high speed) using both control and lathyrogen fed rats. Biochemical analyses were conducted to determine the amount of total and crosslinked (insoluble) collagen. In low-speed tests, there was a significant correlation (r > or = 0.900) between collagen content and skin tensile strength measured both transverse and parallel to the spine. The degree of correlation was higher with insoluble (r = 0.973) collagen content than with total (r = 0.901) collagen. The effect of a lathyrogen diet produced a significant (P < 0.001) reduction (two- to threefold) in tensile strength compared to control. In both high- and low-speed groups, tensile strength was greatest in the transverse samples with a significant correlation to collagen content (r > or = 0.858).(ABSTRACT TRUNCATED AT 250 WORDS)
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Decorin is a small leucine-rich proteoglycan that interacts with several matrix molecules, including various types of collagen and growth factors, and suppresses the growth of neoplastic cells by an epidermal growth factor (EGF) receptor-mediated pathway. Decorin is abundantly expressed in the periodontal connective tissues during development and tissue maintenance. In periodontal disease, which is one of the most common diseases in the human kind, the level of decorin is decreased in the periodontal connective tissue. Abnormal expression of decorin may also associate with certain inherited disorders that involve increased susceptibility to severe periodontal disease in the early childhood. Therefore, we investigated the periodontal tissues of mice with targeted disruption of the decorin gene. Gross and microscopic analyses showed that decorin-deficient mice appeared to have normal tooth development and eruption, and there were no signs of periodontal disease. However, electron microscopic analysis revealed abnormal morphology and organization of the collagen fibrils in the periodontal ligament. The number of periodontal ligament fibroblasts in the decorin-deficient mice was also increased about two-fold as compared with the wild-type mice. In cell culture, ectopic overexpression of decorin in NIH 3T3 fibroblasts or decorin added exogenously to periodontal fibroblasts suppressed cell growth. However, blocking the EGF receptor tyrosine kinase activity did not prevent the decorin-elicited growth suppression in periodontal fibroblasts. Additionally, decorin did not induce a marked increase in the relative expression of p21 mRNA in periodontal fibroblasts. Therefore, decorin appeared to regulate growth of normal periodontal fibroblasts by a mechanism distinct from that reported for neoplastic cells. The findings demonstrate that decorin plays a role in the organization of collagen fibrils and regulates cell proliferation in the periodontal ligament.
Matrix metalloproteinases (MMPs) are endopeptidases that contribute to growth, development and wound healing as well as to pathologies such as arthritis and cancer. Until recently, it has been thought that MMPs participate in these processes simply by degrading extracellular matrix (ECM) molecules. However, it is now clear that MMP activity is much more directed and causes the release of cryptic information from the ECM. By precisely cleaving large insoluble ECM components and ECM-associated molecules, MMPs liberate bioactive fragments and growth factors and change ECM architecture, all of which influence cellular behavior. Thus, MMPs have become a focal point for understanding matrix biology.
Myostatin, a member of TGF-beta superfamily of growth factors, acts as a negative regulator of skeletal muscle mass. The mechanism whereby myostatin controls the proliferation and differentiation of myogenic cells is mostly clarified. However, the regulation of myostatin activity to myogenic cells after its secretion in the extracellular matrix (ECM) is still unknown. Decorin, a small leucine-rich proteoglycan, binds TGF-beta and regulates its activity in the ECM. Thus, we hypothesized that decorin could also bind to myostatin and participate in modulation of its activity to myogenic cells. In order to test the hypothesis, we investigated the interaction between myostatin and decorin by surface plasmon assay. Decorin interacted with mature myostatin in the presence of concentrations of Zn(2+) greater than 10microM, but not in the absence of Zn(2+). Kinetic analysis with a 1:1 binding model resulted in dissociation constants (K(D)) of 2.02x10(-8)M and 9.36x10(-9)M for decorin and the core protein of decorin, respectively. Removal of the glycosaminoglycan chain by chondroitinase ABC digestion did not affect binding, suggesting that decorin could bind to myostatin with its core protein. Furthermore, we demonstrated that immobilized decorin could rescue the inhibitory effect of myostatin on myoblast proliferation in vitro. These results suggest that decorin could trap myostatin and modulate its activity to myogenic cells in the ECM.
This literature review of generalized joint hypermobility (GJH) syndromes discusses information regarding sex-, age-, and race-related factors from publications that specifically document validated GJH criteria. We present an analysis of criterion-referenced connections that identify similarities among major and minor clinical criteria that identify both GJH and benign joint hypermobility syndrome (BJHS). In our search, we found considerable empirical evidence that supports an increased prevalence of hypermobility among children, women, and certain racial groups. Two commonly used clinical assessment tools, the Carter and Wilkinson criteria (>or= 3 positive tests out of 5) and the Beighton method (>or= 4 positive tests out of 9), are the sources of these data. BJHS is diagnosed through a set of major and minor criteria - a combination of symptoms and objective findings -- that include arthralgia, back pain, spondylosis, spondylolysis/spondylolisthesis, joint dislocation/subluxation, soft tissue rheumatism, marfanoid habitus, abnormal skin, eye signs, varicose veins or hernia or uterine/rectal prolapse. Clinically, there is some evidence that arthralgia, the proposed BJHS major criterion, is a major component of alleged hypermobility-related problems. In contrasting, there is no clear evidence that proposed BJHS minor diagnostic criteria are associated with hypermobility-related problems. An empirical correlation between hypermobility and osteoarthritis is possible, but so far unproven. There are no randomized controlled studies regarding effects of existing treatments. Generalized hypermobility is both sex- and age-related. Racial differences are also identifiable. The existence of BJHS can be accepted using present criteria.
  • A Hakim
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