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- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
- van Kuilenburg, Andre B. P., et al.
(författare)
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Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:15, s. 1433-1441
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Tidskriftsartikel (refereegranskat)abstract
- We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5′ untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.
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| 6. |
- Geraghty, A., et al.
(författare)
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Internet-based vestibular rehabilitation for older adults with chronic dizziness : A randomised controlled trial in primary care
- 2017
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Konferensbidrag (refereegranskat)abstract
- Introduction: Vestibular dysfunction occurs in 50% of those over age 60, and with an ageing population the health burden will increase. Vestibular Rehabilitation (VR) has been shown to be effective for dizziness caused by vestibular dysfunction, but it is seldom provided in primary care. The rapid growth in internet access provides a promising vehicle for VR to achieve widespread health impact. We aimed to determine the effectiveness of internet-based VR on chronic dizziness in older adults in primary care.Method: We conducted a single centre randomised controlled trial comparing an internet-based VR intervention with usual primary care. 296 primary care patients aged 50 years and over with current dizziness exacerbated by head movements were recruited from 54 primary care practices from southern England. Patients in the intervention arm accessed an automated internet-based intervention that taught VR exercises and suggested cognitive behavioural management strategies. Dizziness was measured by the Vertigo Symptom Short-Form (VSS-SF) at baseline, 3 and 6 months. The primary outcome was VSS-SF score at 6 months (ISRCTN: 86912968).Results: The VSS-SF was completed by 250 (84%) at 3 months and 230 (78%) at 6 months. Dizziness symptoms were significantly lower in the internet-based VR group compared to usual care at 3 (2.75, 95% CI:1.39, 4.12; p<0.001 and 6 months (2.26, 95% CI: 0.39, 4.12; p=0.018). Dizziness-related disability was also significantly lower in the internet-based VR condition, at 3 (5.33, 95% CI: 1.41, 9.26; p=0.008) and 6 month (5.58 95% CI: 1.19, 10.0; p=0.013).Discussion: Internet-based VR improves dizziness and reduces dizziness-based disability in older primary care patients without requiring structured guidance. The effectiveness without the need for health professional support indicates that this intervention could be made rapidly available to GPs for provision to their patients and wider dissemination in the community.
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| 7. |
- Lines, Matthew A, et al.
(författare)
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Infantile Sialic Acid Storage Disease : Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation
- 2014
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Ingår i: JIMD Reports. - Cham : Springer. - 9783319034614 - 9783319034607 ; , s. 79-84
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Bokkapitel (refereegranskat)abstract
- Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.
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| 8. |
- Alshiekh, S., et al.
(författare)
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Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease
- 2017
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Ingår i: Hla. - : Wiley. - 2059-2302. ; 90:2, s. 95-101
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Tidskriftsartikel (refereegranskat)abstract
- Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4-DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non-HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value < .0001). In a subpopulation analysis, DRB3*01:01:02-DQA1*05:01-DQB1*02:01 remained the most significant in patients with Scandinavian ethnicity (RR = 4.63; P < .0001) whereas DRB1*07:01:01-DRB4*01:03:01-DQA1*02:01-DQB1*02:02:01 presented the highest risk of celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02-DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity.
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| 10. |
- Bowers, Hannah M, et al.
(författare)
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Supporting antidepressant discontinuation : the development and optimisation of a digital intervention for patients in UK primary care using a theory, evidence and person-based approach
- 2020
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We aimed to develop a digital intervention to support antidepressant discontinuation in UK primary care that is scalable, accessible, safe and feasible. In this paper, we describe the development using a theory, evidence and person-based approach.DESIGN: Intervention development using a theory, evidence and person-based approach.SETTING: Primary Care in the South of England.PARTICIPANTS: Fifteen participants with a range of antidepressant experience took part in 'think aloud' interviews for intervention optimisation.INTERVENTION: Our digital intervention prototype (called 'ADvisor') was developed on the basis of a planning phase consisting of qualitative and quantitative reviews, an in-depth qualitative study, the development of guiding principles and a theory-based behavioural analysis. Our optimisation phase consisted of 'think aloud' interviews where the intervention was iteratively refined.RESULTS: The qualitative systematic review and in-depth qualitative study highlighted the centrality of fear of depression relapse as a key barrier to discontinuation. The quantitative systematic review showed that psychologically informed approaches such as cognitive-behavioural therapy were associated with greater rates of discontinuation than simple advice to reduce. Following a behavioural diagnosis based on the behaviour change wheel, social cognitive theory provided a theoretical basis for the intervention. The intervention was optimised on the basis of think aloud interviews, where participants suggested they like the flexibility of the system and found it reassuring. Changes were made to the tone of the material and the structure was adjusted based on this qualitative feedback.CONCLUSIONS: 'ADvisor' is a theory, evidence and person-based digital intervention designed to support antidepressant discontinuation. The intervention was perceived as helpful and reassuring in optimisation interviews. Trials are now needed to determine the feasibility, clinical and cost-effectiveness of this approach.
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