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Burstedt, Marie
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Publications (10 of 26) Show all publications
Jonsson, F., Boström, I. M., Österman, L., Sandgren, O., Burstedt, M., Holmberg, M. & Golovleva, I. (2018). ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing. Acta Ophthalmologica, 96(7), 737-743
Open this publication in new window or tab >>ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing
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2018 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 7, p. 737-743Article in journal (Refereed) Published
Abstract [en]

Purpose

Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP‐binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing.

Methods

The splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE‐19, using a minigene system containing variants c.4773+3A>G and c.5461‐10T>C.

Results

We showed that both ABCA4 variants, c.4773+3A>G and c.5461‐10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type.

Conclusion

Two intronic variants c.4773+3A>G and c.5461‐10T>C, both predicted to affect splicing, are indeed disease‐causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
ABCA4, intronic variants, mutation, splicing, Stargardt disease
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-154068 (URN)10.1111/aos.13676 (DOI)000451035500011 ()29461686 (PubMedID)
Funder
Västerbotten County Council
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Weisschuh, N., Stingl, K., Audo, I., Biskup, S., Bocquet, B., Branham, K., . . . Kohl, S. (2018). Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Human Mutation, 39(10), 1366-1371
Open this publication in new window or tab >>Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia
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2018 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 10, p. 1366-1371Article in journal (Refereed) Published
Abstract [en]

Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
achromatopsia, cone phosphodiesterase, mutation spectrum and prevalence, PDE6C
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-152387 (URN)10.1002/humu.23606 (DOI)000444948000008 ()30080950 (PubMedID)
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-05Bibliographically approved
Jonsson, F., Burstedt, M., Kellgren, T. & Golovleva, I. (2018). Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa. Molecular Vision, 24, 667-678
Open this publication in new window or tab >>Non-homologous recombination between Alu and LINE-1 repeats results in a 91 kb deletion in MERTK causing severe retinitis pigmentosa
2018 (English)In: Molecular Vision, ISSN 1090-0535, E-ISSN 1090-0535, Vol. 24, p. 667-678Article in journal (Refereed) Published
Abstract [en]

Purpose: Retinitis pigmentosa (RP) represents a large group of inherited retinal diseases characterized by clinical and genetic heterogeneity. Among patients with RP in northern Sweden, we identified two severely affected siblings and aimed to reveal a genetic cause underlying their disease.

Methods: Whole exome sequencing (WES) was performed on both affected individuals. Sequence variants were filtered using a custom pipeline to find a rare or novel variant predicted to affect protein function. Genome-wide genotyping was used to identify copy number variants (CNVs) and homozygous regions with potential disease causative genes.

Results: WES uncovered a novel heterozygous variant in the MER proto-oncogene, tyrosine kinase (MERTK) gene, c.2309A>G, p.Glu770Gly located in the tyrosine kinase domain and predicted to be likely pathogenic. The second variant, a large heterozygous deletion encompassing exons 1 to 7 of the MERTK gene, was revealed with genome-wide genotyping. The CNV analysis suggested breakpoints of the deletion, in the 5′-untranslated region and in intron 7. We identified genomic sequences at the site of the deletion as part of L1ME4b (LINE/L1) and AluSx3 that indicated a non-homologous recombination as a mechanism of the deletion evolvement.

Conclusions: Patients with RP in this study were carriers of two novel allelic mutations in the MERTK gene, a missense variant in exon 17 and an approximate 91 kb genomic deletion. Mapping of the deletion breakpoints allowed molecular testing of a cohort of patients with RP with allele-specific PCR. These findings provide additional information about mutations in MERTK for molecular testing of unsolved recessive RP cases and highlight the necessity for analysis of large genomic deletions.

National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-153121 (URN)000447627900001 ()2-s2.0-85055736745 (Scopus ID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Burstedt, M., Jonsson, F., Boström, I. M. & Golovleva, I. (2018). Phenotypic expression of EYS mutations in patients with autosomal recessive retinitis pigmentosa in northern Sweden. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI. Investigative Ophthalmology and Visual Science, 59(9)
Open this publication in new window or tab >>Phenotypic expression of EYS mutations in patients with autosomal recessive retinitis pigmentosa in northern Sweden
2018 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 59, no 9Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Purpose : To describe clinical phenotype in patients of northern Sweden affected by recessive retinitis pigmentosa (ARRP) caused by mutations in Eyes Shut Homolog (Drosophila) (EYS) gene.

Methods : Whole exome sequencing (WES) and multiple ligation dependent prode amplification (MLPA) were used for identification of EYS sequence variants in a cohort of ARRP patients (n=148) from northern Sweden. The patients with EYS mutations were ophthalmologically examined over time using visual acuity (ETDRS), visual fields, slit lamp and fundus examination and ocular coherence tomography (OCT). Dark adaptometry and full-field electroretionograms (ERG) was performed.

Results : Phenotype characterization was done in 13 ARRP cases with EYS mutations representing five bi-allelic sequence variants, three of which were novel. Only one variant was detected in two cases. The phenotypic outcome was predominately presented as classical RP aggravating in young adulthood. However, among these patients we observed a variation of phenotypic expression with initial paracentral to central macular affection of the retina and areolar retinal degeneration with electrophysiological outcome of only slightly subnormal responses of both rods and cones in late adulthood (60 y/o), clinically defined as areolar atrophy.

Conclusions : The EYS mutations account for 10% of ARRP in northern Sweden. The phenotype presents both typical classical RP and chorioretinal degenerative retinal disease, areolar dystrophy. This suggests that molecular genetic testing of the EYS is crucial when both RP and pattern macular diseases are clinically diagnosed.

Place, publisher, year, edition, pages
The Association for Research in Vision and Ophthalmology, Inc., 2018
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-152275 (URN)000442912500004 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), APR 29-MAY 03, 2018, Honolulu, HI
Available from: 2018-10-02 Created: 2018-10-02 Last updated: 2018-10-02Bibliographically approved
Tolley, C., Mullins, A., Kilgariff, S., Arbuckle, R., Green, J., Burstedt, M., . . . Sloesen, B. (2017). Qualitative interviews to inform development of a patient reported outcome (PRO) strategy in RLBP1 retinitis pigmentosa (RLBP1 RP). Paper presented at ISPOR 20th Annual European Congress, 4–8 November 2017, Glasgow, Scotland. Value in Health, 20(9), A761-A761
Open this publication in new window or tab >>Qualitative interviews to inform development of a patient reported outcome (PRO) strategy in RLBP1 retinitis pigmentosa (RLBP1 RP)
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2017 (English)In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 9, p. A761-A761Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Objectives: RLBP1 RP is a rare autosomal recessive form of retinitis pigmentosa (RP), characterized by night blindness, prolonged dark adaptation, constricted visual fields and reduced macular function. This study aimed to better understand the patient experience of RLBP1 RP and to evaluate the content validity of existing patient reported outcome (PRO) instruments in this condition. Methods: This qualitative study involved 90 minute, semi-structured, concept elicitation and cognitive debriefing interviews with patients with RLBP1 RP in Canada (n=10) and Sweden (n=11). Qualitative analysis of anonymized, verbatim transcripts was performed using Atlas.Ti software and thematic analysis methods. Participants were cognitively debriefed on The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25), Low Luminance Questionnaire (LLQ) and four items of the Visual Activities Questionnaire (VAQ). Results: Fourteen visual symptoms were reported. The symptoms most frequently reported were night blindness (n=21), difficulty adapting to changes in lighting (n=21) and difficulties seeing in bright lighting (n=18). Impacts on daily activities (n=21) and physical functioning (n=17) were important to participants. Other domains of quality of life affected included social functioning (n=21), emotional functioning (n=19), work and education (n=18), and psychological functioning (n=17). Participant understanding and interpretation of the NEI VFQ-25 and LLQ was mixed. Patients reported that examples in single items represented different levels of functional impairment. In addition, some items did not specify what lighting conditions should be considered when responding. LLQ items were more relevant to RLBP1 RP than NEI VFQ-25 items. The four VAQ items assessing light/dark adaptation were well understood and relevant to participants. There were both gaps and overlaps in conceptual coverage of the instruments. Conclusions: The symptoms of RLBP1 RP have a substantial impact on patients’ daily lives and physical functioning. Issues have been identified with conceptual coverage, rel- evance and patient understanding of the NEI VFQ-25, LLQ and VAQ in RLBP1 RP.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2017
National Category
Health Care Service and Management, Health Policy and Services and Health Economy
Identifiers
urn:nbn:se:umu:diva-143153 (URN)10.1016/j.jval.2017.08.2157 (DOI)000413599903004 ()
Conference
ISPOR 20th Annual European Congress, 4–8 November 2017, Glasgow, Scotland
Available from: 2017-12-20 Created: 2017-12-20 Last updated: 2018-06-09Bibliographically approved
Golovleva, I., Jonsson, F. & Burstedt, M. (2016). Heterogeneity and complexity of EYS mutations in autosomal recessive retinitis pigmentosa in northern Sweden. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA. Investigative Ophthalmology and Visual Science, 57(12)
Open this publication in new window or tab >>Heterogeneity and complexity of EYS mutations in autosomal recessive retinitis pigmentosa in northern Sweden
2016 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 12Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-132853 (URN)000394210202022 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 01-05, 2016, Seattle, WA
Note

Meeting Abstract: 3136

Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2018-06-09Bibliographically approved
Wang, L., el Azazi, M., Eklund, A., Burstedt, M. & Wachtmeister, L. (2015). The response of the neuronal adaptive system to background illumination and readaptation to dark in the immature retina. Acta Ophthalmologica, 93(2), 146-153
Open this publication in new window or tab >>The response of the neuronal adaptive system to background illumination and readaptation to dark in the immature retina
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2015 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 93, no 2, p. 146-153Article in journal (Refereed) Published
Abstract [en]

Purpose: Developmental characteristics of the neuronal adaptive system of the retina, focusing on background light (BGL) adaptation and readaptation functions, were studied by measuring the oscillatory response (SOP) of the electroretinogram (ERG).

Methods: Digitally filtered and conventional ERGs were simultaneously recorded. Rats aged 15 and 17 days were studied during exposure to BGLs of two mesopic intensities and during readaptation to dark.

Results: Results were compared to adult rats. In ‘low mesopic’ BGL SOP instantly dropped significantly to about half of its dark-adapted (DA) value contrary to mature rats, in which the SOP significantly increased. In ‘high mesopic’ BGL SOP decreased to about 20% and 30% of DA values in immature and adult rats, respectively. The process of recovery of SOP in darkness lacked the transient enhancement immediately as BGL was turned off, characteristic of adult rats. There were no major age differences in adaptive behaviour of a-wave. In young rats, recovery of b-wave was relatively slower.

Conclusions: Properties of BGL adaptation and readaptation functions of the neuronal adaptive system in baby retina differed compared to the adult one by being less forceful and more restrained. Handling of mesopic illumination and recovery in the dark was immature. Development of these functions of the neuronal adaptive system progresses postnatally and lags behind that of the photoreceptor response and seems to be delayed also compared to that of the bipolar response.

Keywords
background light adaptation, electroretinogram, immature neuronal adaptive system, oscillatory tentials, readaptation to dark
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-101387 (URN)10.1111/aos.12456 (DOI)000349900200032 ()24924739 (PubMedID)
Available from: 2015-07-07 Created: 2015-03-30 Last updated: 2018-06-07Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2014). Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes. In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy. Paper presented at 15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012 (pp. 177-183). Springer Berlin/Heidelberg, 801
Open this publication in new window or tab >>Genetic heterogeneity and clinical outcome in a Swedish family with retinal degeneration caused by mutations in CRB1 and ABCA4 genes
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2014 (English)In: Retinal Degenerative Diseases: Mechanisms and Experimental Therapy, Springer Berlin/Heidelberg, 2014, Vol. 801, p. 177-183Conference paper, Published paper (Refereed)
Abstract [en]

Genetic mechanisms underlying severe retinal dystrophy in a large Swedish family presenting two distinct phenotypes, Leber congenital amaurosis and Stargardt disease were investigated. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was a compound heterozygous for c.5461-10T>C and a novel ABCA4 mutation c.4773+3 A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants.Our results provide evidence of genetic complexity causative of different clinical features present in the same family, which is an obvious challenge for ophthalmologists, molecular geneticists and genetic counsellors.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2014
Series
Advances in Experimental Medicine and Biology, ISSN 0065-2598 ; 801
Keywords
applanation resonance tonometry, ART, glaucoma, intraocular pressure, ISO standard, tonometry
National Category
Ophthalmology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-101488 (URN)10.1007/978-1-4614-3209-8_23 (DOI)000350418200024 ()24664696 (PubMedID)978-1-4614-3209-8 (ISBN)978-1-4614-3208-1 (ISBN)
Conference
15th International Symposium on Retinal Degeneration (RD) Location: GERMANY Date: JUL 16-21, 2012
Available from: 2015-03-31 Created: 2015-03-31 Last updated: 2018-06-07Bibliographically approved
Burstedt, M., Jonsson, F., Köhn, L., Burstedt, M., Kivitalo, M. & Golovleva, I. (2013). Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations. Acta Ophthalmologica, 91(5), 437-444
Open this publication in new window or tab >>Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations
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2013 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 91, no 5, p. 437-444Article in journal (Refereed) Published
Abstract [en]

Purpose: To evaluate phenotypes caused by different RLBP1 mutations in autosomal recessive retinitis pigmentosa of Bothnia type. Methods: Compound heterozygotes for mutations in the RLBP1 gene [c.677T>A]+[c.700C>T] (p.M226K+p.R234W), n=10, aged 7-84years, and homozygotes c.677T>A (p.M226K), n=2, aged 63 and 73years, were studied using visual acuity (VA), low-contrast VA, visual fields (VFs) and optical coherence tomography (OCT). Retrospective VA and VFs, standardized dark adaptation and full-field electroretinograms (ERGs) were analysed and prolonged dark adaptometry and ERG (at 24hr) were performed. Results: Progressive decline of VA and VF areas was age-dependent. Retinal degenerative maculopathy, peripheral degenerative changes and retinitis punctata albescens (RPA) were present. Early retinal thinning in the central foveal, foveal (O 1mm), and inner ring (O 3mm) in the macular region, with homogenous, high-reflectance RPA changes, was visualized in and adjacent to the retinal pigment epithelium/choriocapillaris using OCT. Reduced dark adaptation and affected ERGs were present in all ages. Prolonged dark adaptation and ERG (at 24hr), an increase in final threshold, and ERG rod and mixed rod/cone responses were found. Conclusions: The two RLBP1 genotypes presented a phenotypical and electrophysiological expression of progressive retinal disease similar to that previously described in homozygotes for the c.700C>T (p.R234W) RLBP1 mutation. The uniform phenotypical expression of RLBP1 mutations is relevant information for the disease and of importance in planning future treatment strategies.

Keywords
electroretinogram, optical coherence tomography, prolonged dark adaptation, retinitis pigmentosa, retinitis punctata albescens, RLBP1
National Category
General Practice
Identifiers
urn:nbn:se:umu:diva-79415 (URN)10.1111/j.1755-3768.2012.02431.x (DOI)000321626000031 ()
Available from: 2013-09-04 Created: 2013-08-19 Last updated: 2018-06-08Bibliographically approved
Jonsson, F., Burstedt, M. S., Sandgren, O., Norberg, A. & Golovleva, I. (2013). Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family. European Journal of Human Genetics, 21(11), 1266-1271
Open this publication in new window or tab >>Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family
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2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1266-1271Article in journal (Refereed) Published
Abstract [en]

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
Keywords
CRB1, ABCA4, SNP-array, Stargardt disease, Leber congenital amaurosis
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-82275 (URN)10.1038/ejhg.2013.23 (DOI)000325861500015 ()23443024 (PubMedID)
Available from: 2013-10-29 Created: 2013-10-29 Last updated: 2018-06-08Bibliographically approved
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