Summary
Background
We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder.
Methods
12
children (mean age 6 years [range 3–10], 11 boys) were referred to a
paediatric gastroenterology unit with a history of normal development
followed by loss of acquired skills, including language, together with
diarrhoea and abdominal pain. Children underwent gastroenterological,
neurological, and developmental assessment and review of developmental
records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging
(MRI), electroencephalography (EEG), and lumbar puncture were done
under sedation. Barium follow-through radiography was done where
possible. Biochemical, haematological, and immunological profiles were
examined.
Findings
Onset of
behavioural symptoms was associated, by the parents, with measles,
mumps, and rubella vaccination in eight of the 12 children, with measles
infection in one child, and otitis media in another. All 12 children
had intestinal abnormalities, ranging from lymphoid nodular hyperplasia
to aphthoid ulceration. Histology showed patchy chronic inflammation in
the colon in 11 children and reactive ileal lymphoid hyperplasia in
seven, but no granulomas. Behavioural disorders included autism (nine),
disintegrative psychosis (one), and possible postviral or vaccinal
encephalitis (two). There were no focal neurological abnormalities and
MRI and EEG tests were normal. Abnormal laboratory results were
significantly raised urinary methylmalonic acid compared with agematched
controls (p=0·003), low haemoglobin in four children, and a low serum
IgA in four children.
Interpretation
We
identified associated gastrointestinal disease and developmental
regression in a group of previously normal children, which was generally
associated in time with possible environmental triggers.
Introduction
We
saw several children who, after a period of apparent normality, lost
acquired skills, including communication. They all had gastrointestinal
symptoms, including abdominal pain, diarrhoea, and bloating and, in some
cases, food intolerance. We describe the clinical findings, and
gastrointestinal features of these children.
Patients and methods
12
children, consecutively referred to the department of paediatric
gastroenterology with a history of a pervasive developmental disorder
with loss of acquired skills and intestinal symptoms (diarrhoea,
abdominal pain, bloating and food intolerance), were investigated. All
children were admitted to the ward for 1 week, accompanied by their
parents.
Clinical investigations
We
took histories, including details of immunisations and exposure to
infectious diseases, and assessed the children. In 11 cases the history
was obtained by the senior clinician (JW-S). Neurological and
psychiatric assessments were done by consultant staff (PH, MB) with
HMS-4 criteria.
Developmental histories included a review of prospective developmental records from parents, health visitors, and general practitioners. Four children did not undergo psychiatric assessment in hospital; all had been assessed professionally elsewhere, so these assessments were used as the basis for their behavioural diagnosis.
Developmental histories included a review of prospective developmental records from parents, health visitors, and general practitioners. Four children did not undergo psychiatric assessment in hospital; all had been assessed professionally elsewhere, so these assessments were used as the basis for their behavioural diagnosis.
After
bowel preparation, ileocolonoscopy was performed by SHM or MAT under
sedation with midazolam and pethidine. Paired frozen and formalin-fixed
mucosal biopsy samples were taken from the terminal ileum; ascending,
transverse, descending, and sigmoid colons, and from the rectum. The
procedure was recorded by video or still images, and were compared with
images of the previous seven consecutive paediatric colonoscopies (four
normal colonoscopies and three on children with ulcerative colitis), in
which the physician reported normal appearances in the terminal ileum.
Barium follow-through radiography was possible in some cases.
Also
under sedation, cerebral magnetic-resonance imaging (MRI),
electroencephalography (EEG) including visual, brain stem auditory, and
sensory evoked potentials (where compliance made these possible), and
lumbar puncture were done.
Laboratory investigations
Thyroid
function, serum long-chain fatty acids, and cerebrospinal-fluid lactate
were measured to exclude known causes of childhood neurodegenerative
disease. Urinary methylmalonic acid was measured in random urine samples
from eight of the 12 children and 14 age-matched and sex-matched normal
controls, by a modification of a technique described previously.
Chromatograms were scanned digitally on computer, to analyse the methylmalonic-acid zones from cases and controls. Urinary methylmalonic-acid concentrations in patients and controls were compared by a two-sample t test. Urinary creatinine was estimated by routine spectrophotometric assay.
Chromatograms were scanned digitally on computer, to analyse the methylmalonic-acid zones from cases and controls. Urinary methylmalonic-acid concentrations in patients and controls were compared by a two-sample t test. Urinary creatinine was estimated by routine spectrophotometric assay.
Children
were screened for antiendomyseal antibodies and boys were screened for
fragile-X if this had not been done before. Stool samples were cultured
for Campylobacter spp, Salmonella spp, and Shigella spp and assessed by microscopy for ova and parasites. Sera were screened for antibodies to Yersinia enterocolitica.
Histology
Formalin-fixed
biopsy samples of ileum and colon were assessed and reported by a
pathologist (SED). Five ileocolonic biopsy series from age-matched and
site-matched controls whose reports showed histologically normal mucosa
were obtained for comparison. All tissues were assessed by three other
clinical and experimental pathologists (APD, AA, AJW).
Ethical approval and consent
Investigations
were approved by the Ethical Practices Committee of the Royal Free
Hospital NHS Trust, and parents gave informed consent.
Results
Clinical details of the children are shown in Table 1, Table 2.
None had neurological abnormalities on clinical examination; MRI scans,
EEGs, and cerebrospinal-fluid profiles were normal; and fragile × was
negative. Prospective developmental records showed satisfactory
achievement of early milestones in all children. The only girl (child
number eight) was noted to be a slow developer compared with her older
sister. She was subsequently found to have coarctation of the aorta.
After surgical repair of the aorta at the age of 14 months, she
progressed rapidly, and learnt to talk. Speech was lost later. Child
four was kept under review for the first year of life because of wide
bridging of the nose. He was discharged from follow-up as
developmentally normal at age 1 year.
Table 1Clinical details and laboratory, endoscopic, and histological findings
| Child | Age (years) | Sex | Abnormal laboratory tests | Endoscopic findings | Histological findings |
|---|---|---|---|---|---|
| 1 | 4 | M | Hb 10·8, PCV 0·36, WBC 16·6 (neutrophilia), lymphocytes 1·8, ALP 166 | Ileum not intubated; aphthoid ulcer in rectum | Acute caecal cryptitis and chronic non-specific colitis |
| 2 | 9·5 | M | Hb 10·7 | LNH of T ileum and colon; patchy loss of vascular pattern; caecal aphthoid ulcer | Acute and chronic non-specific colitis: reactive ileal lymphoid hyperplasia |
| 3 | 7 | M | MCV 74, platelets 474, eosinophils 2·68, IgE 114, IgG1, 8·4 | LNH of T ileum | Acute and chronic non-specific colitis: reactive ileal and colonic lymphoid hyperplasia |
| 4 | 10 | M | IgE 69, IgG1 8·25, IgG4 1·006, ALP 474, AST 50 | LNH of T ileum; loss of vascular pattern in rectum | Chronic non-specific colitis: reactive ileal and colonic lymphoid hyperplasia |
| 5 | 8 | M | LNH of T lieum; proctitis with loss of vascular pattern | Chronic non-specific colitis: reactive ileal lymphoid hyperplasia | |
| 6 | 5 | M | Platelets 480, ALP 207 | LNH of T ileum; loss of colonic vascular pattern | Acute and chronic non-specific colitis: reactive ileal lymphoid hyperplasia |
| 7 | 3 | M | Hb 9·4, WBC 17·2 (neutrophilia), ESR 16, IgA 0·7 | LNH of T ileum | Normal |
| 8 | 3·5 | F | IgA 0·5, IgG 7 | Prominent ileal lymph nodes | Acute and chronic non-specific colitis: reactive ileal lymphoid hyperplasia |
| 9 | 6 | M | LNH of T ileum; patchy erythema at hepatic flexure | Chronic non-specific colitis: reactive ileal and colonic lymphoid hyperplasia | |
| 10 | 4 | M | IgG2 9-0 | LNH of T ileum and colon | Chronic non-specific colitis: reactive ileal lymphoid hyperplasia |
| 11 | 6 | M | Hb 11·2, IgA 0·26, IgM 3·4 | LNH of T ileum | Chronic non-specific colitis |
| 12 | 7 | M | IgA 0·7 | LNH on barium follow-through; colonoscopy normal; ileum not intubated | Chronic non-specific colitis: reactive colonic lymphoid hyperplasia |
LNH=lymphoid
nodular hyperplasia; T ileum=terminal ileum. Normal ranges and units:
Hb=haemoglobin 11·5–14·5 g/dL; PCV=packed cell volume 0·37–0·45;
MCV=mean cell volume 76–100 pg/dL; platelets 140–400 109/L; WBC=white cell count 5·0–15·5 109/L; lymphocytes 2·2–8·6 109/L; eosinophils 0–0·4 109/L; ESR=erythrocyte sedimentation rate transaminase 5–40 U/L.
Table 2Neuropsychiatric diagnosis
| Child | Behavioural diagnosis | Exposure identified by parents or doctor | Interval from exposure to first behavioural symptom | Features associated with exposure | Age at onset of first symptom | |
|---|---|---|---|---|---|---|
| Behaviour | Bowel | |||||
| 1 | Autism | MMR | 1 week | Fever/delirium | 12 months | Not known |
| 2 | Autism | MMR | 2 weeks | Self injury | 13 months | 20 months |
| 3 | Autism | MMR | 48 h | Rash and fever | 14 months | Not known |
| 4 | Autism? Disintegrative disorder? | MMR | Measles vaccine at 15 months followed by slowing in development. Dramatic deterioration in behaviour immediately after MMR at 4·5 years | Repetitive behaviour, self injury, loss of self-help | 4·5 years | 18 months |
| 5 | Autism | None—MMR at 16 months | Self-injurious behaviour started at 18 months | 4 years | ||
| 6 | Autism | MMR | 1 week | Rash & convulsion; gaze avoidance & self injury | 15 months | 18 months |
| 7 | Autism | MMR | 24 h | Convulsion, gaze avoidance | 21 months | 2 years |
| 8 | Post-vaccinial encephalitis? | MMR | 2 weeks | Fever, convulsion, rash & diarrhoea | 19 months | 19 months |
| 9 | Autistic spectrum disorder | Recurrent otitis media | 1 week (MMR 2 months previously) | Disinterest; lack of play | 18 months | 2·5 years |
| 10 | Post-viral encephalitis? | Measles (previously vaccinated with MMR) | 24 h | Fever, rash & vomiting | 15 months | Not known |
| 11 | Autism | MMR | 1 week | Recurrent “viral pneumonia” for 8 weeks following MMR | 15 months | Not known |
| 12 | Autism | None—MMR at 15 months | Loss of speech development and deterioration in language skills noted at 16 months | Not known | ||
MMR=measles, mumps, and rubella vaccine.
In
eight children, the onset of behavioural problems had been linked,
either by the parents or by the child's physician, with measles, mumps,
and rubella vaccination. Five had had an early adverse reaction to
immunisation (rash, fever, delirium; and, in three cases, convulsions).
In these eight children the average interval from exposure to first
behavioural symptoms was 6·3 days (range 1–14). Parents were less clear
about the timing of onset of abdominal symptoms because children were
not toilet trained at the time or because behavioural features made
children unable to communicate symptoms.
One
child (child four) had received monovalent measles vaccine at 15
months, after which his development slowed (confirmed by professional
assessors). No association was made with the vaccine at this time. He
received a dose of measles, mumps, and rubella vaccine at age 4·5 years,
the day after which his mother described a striking deterioration in
his behaviour that she did link with the immunisation. Child nine
received measles, mumps, and rubella vaccine at 16 months. At 18 months
he developed recurrent antibioticresistant otitis media and the first
behavioural symptoms, including disinterest in his sibling and lack of
play.
table 2
summarises the neuropsychiatric diagnoses; the apparent precipitating
events; onset of behavioural features; and age of onset of both
behaviour and bowel symptoms.
Laboratory tests
All
children were antiendomyseal-antibody negative and common enteric
pathogens were not identified by culture, microscopy, or serology.
Urinary methylmalonic-acid excretion was significantly raised in all
eight children who were tested, compared with age-matched controls
(p=0·003; figure 1). Abnormal laboratory tests are shown in table 1.
Figure 1Urinary methylmalonic-acid excretion in patients and controls
Endoscopic findings
The caecum was seen in all cases, and the ileum in all but two cases. Endoscopic findings are shown in table 1.
Macroscopic colonic appearances were reported as normal in four
children. The remaining eight had colonic and rectal mucosal
abnormalities including granularity, loss of vascular pattern, patchy
erythema, lymphoid nodular hyperplasia, and in two cases, aphthoid
ulceration. Four cases showed the “red halo” sign around swollen caecal
lymphoid follicles, an early endoscopic feature of Crohn's disease.
The most striking and consistent feature was lymphoid nodular hyperplasia of the terminal ileum which was seen in nine children (figure 2), and identified by barium follow-through in one other child in whom the ileum was not reached at endoscopy. The normal endoscopic appearance of the terminal ileum (figure 2) was seen in the seven children whose images were available for comparison.
The most striking and consistent feature was lymphoid nodular hyperplasia of the terminal ileum which was seen in nine children (figure 2), and identified by barium follow-through in one other child in whom the ileum was not reached at endoscopy. The normal endoscopic appearance of the terminal ileum (figure 2) was seen in the seven children whose images were available for comparison.
Figure 2Endoscopic view of terminal ilium in child three and in a child with endoscopically and histologically normal ileum and colon
Histological findings
Histological findings are summarised in table 1.
Terminal ileum
A
reactive lymphoid follicular hyperplasia was present in the ileal
biopsies of seven children. In each case, more than three expanded and
confluent lymphoid follicles with reactive germinal centres were
identified within the tissue section (figure 3). There was no neutrophil infiltrate and granulomas were not present.
Figure 3Biopsy sample from terminal ileum (top) and from colon (bottom)
Colon
The
lamina propria was infiltrated by mononuclear cells (mainly lymphocytes
and macrophages) in the colonic-biopsy samples. The extent ranged in
severity from scattered focal collections of cells beneath the surface
epithelium (five cases) to diffuse infiltration of the mucosa (six
cases). There was no increase in intraepithelial lymphocytes, except in
one case, in which numerous lymphocytes had infiltrated the surface
epithelium in the proximal colonic biopsies. Lymphoid follicles in the
vicinity of mononuclear-cell infiltrates showed enlarged germinal
centres with reactive changes that included an excess of tingible body
macrophages.
There was no clear
correlation between the endoscopic appearances and the histological
findings; chronic inflammatory changes were apparent histologically in
endoscopically normal areas of the colon. In five cases there was focal
acute inflammation with infiltration of the lamina propria by
neutrophils; in three of these, neutrophils infiltrated the caecal (figure 3)
and rectal-crypt epithelium. There were no crypt abscesses. Occasional
bifid crypts were noted but overall crypt architecture was normal. There
was no goblet-cell depletion but occasional collections of eosinophils
were seen in the mucosa. There were no granulomata. Parasites and
organisms were not seen. None of the changes described above were seen
in any of the normal biopsy specimens.
Discussion
We
describe a pattern of colitis and ileal-lymphoidnodular hyperplasia in
children with developmental disorders. Intestinal and behavioural
pathologies may have occurred together by chance, reflecting a selection
bias in a self-referred group; however, the uniformity of the
intestinal pathological changes and the fact that previous studies have
found intestinal dysfunction in children with autistic-spectrum
disorders, suggests that the connection is real and reflects a unique
disease process.
Asperger first recorded the link between coeliac disease and behavioural psychoses.
Walker-Smith and colleagues
detected low concentrations of alpha-1 antitrypsin in children with typical autism, and D'Eufemia and colleagues
identified abnormal intestinal permeability, a feature of small intestinal enteropathy, in 43% of a group of autistic children with no gastrointestinal symptoms, but not in matched controls. These studies, together with our own, including evidence of anaemia and IgA deficiency in some children, would support the hypothesis that the consequences of an inflamed or dysfunctional intestine may play a part in behavioural changes in some children.
Walker-Smith and colleagues
detected low concentrations of alpha-1 antitrypsin in children with typical autism, and D'Eufemia and colleagues
identified abnormal intestinal permeability, a feature of small intestinal enteropathy, in 43% of a group of autistic children with no gastrointestinal symptoms, but not in matched controls. These studies, together with our own, including evidence of anaemia and IgA deficiency in some children, would support the hypothesis that the consequences of an inflamed or dysfunctional intestine may play a part in behavioural changes in some children.
The “opioid excess” theory of autism, put forward first by Panksepp and colleagues
and later by Reichelt and colleagues
and Shattock and colleagues
proposes that autistic disorders result from the incomplete breakdown and excessive absorption of gut-derived peptides from foods, including barley, rye, oats, and caesin from milk and dairy produce. These peptides may exert central-opioid effects, directly or through the formation of ligands with peptidase enzymes required for breakdown of endogenous central-nervous-system opioids,
leading to disruption of normal neuroregulation and brain development by endogenous encephalins and endorphins.
and later by Reichelt and colleagues
and Shattock and colleagues
proposes that autistic disorders result from the incomplete breakdown and excessive absorption of gut-derived peptides from foods, including barley, rye, oats, and caesin from milk and dairy produce. These peptides may exert central-opioid effects, directly or through the formation of ligands with peptidase enzymes required for breakdown of endogenous central-nervous-system opioids,
leading to disruption of normal neuroregulation and brain development by endogenous encephalins and endorphins.
One
aspect of impaired intestinal function that could permit increased
permeability to exogenous peptides is deficiency of the
phenyl-sulphur-transferase systems, as described by Waring.
The normally sulphated glycoprotein matrix of the gut wall acts to regulate cell and molecular trafficking.
Disruption of this matrix and increased intestinal permeability, both features of inflammatory bowel disease,
may cause both intestinal and neuropsychiatric dysfunction. Impaired enterohepatic sulphation and consequent detoxification of compounds such as the phenolic amines (dopamine, tyramine, and serotonin)
may also contribute. Both the presence of intestinal inflammation and absence of detectable neurological abnormality in our children are consistent with an exogenous influence upon cerebral function. Lucarelli's observation that after removal of a provocative enteric antigen children achieved symptomatic behavioural improvement, suggests a reversible element in this condition.
The normally sulphated glycoprotein matrix of the gut wall acts to regulate cell and molecular trafficking.
Disruption of this matrix and increased intestinal permeability, both features of inflammatory bowel disease,
may cause both intestinal and neuropsychiatric dysfunction. Impaired enterohepatic sulphation and consequent detoxification of compounds such as the phenolic amines (dopamine, tyramine, and serotonin)
may also contribute. Both the presence of intestinal inflammation and absence of detectable neurological abnormality in our children are consistent with an exogenous influence upon cerebral function. Lucarelli's observation that after removal of a provocative enteric antigen children achieved symptomatic behavioural improvement, suggests a reversible element in this condition.
Despite
consistent gastrointestinal findings, behavioural changes in these
children were more heterogeneous. In some cases the onset and course of
behavioural regression was precipitous, with children losing all
communication skills over a few weeks to months. This regression is
consistent with a disintegrative psychosis (Heller's disease), which
typically occurs when normally developing children show striking
behaviour changes and developmental regression, commonly in association
with some loss of coordination and bowel or bladder function.
Disintegrative psychosis is typically described as occurring in children after at least 2–3 years of apparently normal development.
Disintegrative psychosis is typically described as occurring in children after at least 2–3 years of apparently normal development.
Disintegrative psychosis is recognised as a sequel to measles encephalitis, although in most cases no cause is ever identified.
Viral encephalitis can give rise to autistic disorders, particularly when it occurs early in life.
Rubella virus is associated with autism and the combined measles, mumps, and rubella vaccine (rather than monovalent measles vaccine) has also been implicated. Fudenberg
noted that for 15 of 20 autistic children, the first symptoms developed within a week of vaccination. Gupta
commented on the striking association between measles, mumps, and rubella vaccination and the onset of behavioural symptoms in all the children that he had investigated for regressive autism. Measles virus
,
and measles vaccination
have both been implicated as risk factors for Crohn's disease and persistent measles vaccine-strain virus infection has been found in children with autoimmune hepatitis.
Viral encephalitis can give rise to autistic disorders, particularly when it occurs early in life.
Rubella virus is associated with autism and the combined measles, mumps, and rubella vaccine (rather than monovalent measles vaccine) has also been implicated. Fudenberg
noted that for 15 of 20 autistic children, the first symptoms developed within a week of vaccination. Gupta
commented on the striking association between measles, mumps, and rubella vaccination and the onset of behavioural symptoms in all the children that he had investigated for regressive autism. Measles virus
,
and measles vaccination
have both been implicated as risk factors for Crohn's disease and persistent measles vaccine-strain virus infection has been found in children with autoimmune hepatitis.
We
did not prove an association between measles, mumps, and rubella
vaccine and the syndrome described. Virological studies are underway
that may help to resolve this issue.
If
there is a causal link between measles, mumps, and rubella vaccine and
this syndrome, a rising incidence might be anticipated after the
introduction of this vaccine in the UK in 1988. Published evidence is
inadequate to show whether there is a change in incidence
or a link with measles, mumps, and rubella vaccine.
A genetic predisposition to autistic-spectrum disorders is suggested by over-representation in boys and a greater concordance rate in monozygotic than in dizygotic twins.
In the context of susceptibility to infection, a genetic association with autism, linked to a null allele of the complement (C) 4B gene located in the class III region of the major-histocompatibility complex, has been recorded by Warren and colleagues.
C4B-gene products are crucial for the activation of the complement pathway and protection against infection: individuals inheriting one or two C4B null alleles may not handle certain viruses appropriately, possibly including attenuated strains.
or a link with measles, mumps, and rubella vaccine.
A genetic predisposition to autistic-spectrum disorders is suggested by over-representation in boys and a greater concordance rate in monozygotic than in dizygotic twins.
In the context of susceptibility to infection, a genetic association with autism, linked to a null allele of the complement (C) 4B gene located in the class III region of the major-histocompatibility complex, has been recorded by Warren and colleagues.
C4B-gene products are crucial for the activation of the complement pathway and protection against infection: individuals inheriting one or two C4B null alleles may not handle certain viruses appropriately, possibly including attenuated strains.
Urinary
methylmalonic-acid concentrations were raised in most of the children, a
finding indicative of a functional vitamin B12 deficiency. Although
vitamin B12 concentrations were normal, serum B12 is not a good measure
of functional B12 status.
Urinary methylmalonic-acid excretion is increased in disorders such as Crohn's disease, in which cobalamin excreted in bile is not reabsorbed. A similar problem may have occurred in the children in our study. Vitamin B12 is essential for myelinogenesis in the developing central nervous system, a process that is not complete until around the age of 10 years. B12 deficiency may, therefore, be a contributory factor in the developmental regression.
Urinary methylmalonic-acid excretion is increased in disorders such as Crohn's disease, in which cobalamin excreted in bile is not reabsorbed. A similar problem may have occurred in the children in our study. Vitamin B12 is essential for myelinogenesis in the developing central nervous system, a process that is not complete until around the age of 10 years. B12 deficiency may, therefore, be a contributory factor in the developmental regression.
We
have identified a chronic enterocolitis in children that may be related
to neuropsychiatric dysfunction. In most cases, onset of symptoms was
after measles, mumps, and rubella immunisation. Further investigations
are needed to examine this syndrome and its possible relation to this
vaccine.
Addendum:
Up to Jan 28, a further 40 patients have been assessed; 39 with the syndrome.
Contributors
A
J Wakefield was the senior scientific investigator. S H Murch and M A
Thomson did the colonoscopies. A Anthony, A P Dhillon, and S E Davies
carried out the histopathology. J Linnell did the B12 studies. D M
Casson and M Malik did the clinical assessment. M Berelowitz did the
psychiatric assessment. P Harvey did the neurological assessment. A
Valentine did the radiological assessment. JW-S was the senior clinical
investigator.
Acknowledgements
This
study was supported by the Special Trustees of Royal Free Hampstead NHS
Trust and the Children's Medical Charity. We thank Francis Moll and the
nursing staff of Malcolm Ward for their patience and expertise; the
parents for providing the impetus for these studies; and Paula Domizo,
Royal London NHS Trust, for providing control tissue samples.
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Article Info
Publication History
Published: 28 February 1998
Identification
DOI: https://doi.org/10.1016/S0140-6736(97)11096-0Copyright
© 1998 Elsevier Ltd. All rights reserved.
ScienceDirect
Access this article on ScienceDirectFigures
- Figure 1Urinary methylmalonic-acid excretion in patients and controls
- Figure 2Endoscopic view of terminal ilium in child three and in a child with endoscopically and histologically normal ileum and colon
- Figure 3Biopsy sample from terminal ileum (top) and from colon (bottom)
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