| 1. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
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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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| 11. |
- Conte, Michael S., et al.
(författare)
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Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia
- 2019
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Saunders Elsevier. - 1078-5884 .- 1532-2165. ; 58:1, s. S1-S109
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Tidskriftsartikel (refereegranskat)abstract
- Chronic limb-threatening ischemia (CLTI) is associated with mortality, amputation, and impaired quality of life. These Global Vascular Guidelines (GVG) are focused on definition, evaluation, and management of CLTI with the goals of improving evidence-based care and highlighting critical research needs. The term CLTI is preferred over critical limb ischemia, as the latter implies threshold values of impaired perfusion rather than a continuum. CLTI is a clinical syndrome defined by the presence of peripheral artery disease (PAD) in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration. Venous, traumatic, embolic, and nonatherosclerotic etiologies are excluded. All patients with suspected CLTI should be referred urgently to a vascular specialist. Accurately staging the severity of limb threat is fundamental, and the Society for Vascular Surgery Threatened Limb Classification system, based on grading of Wounds, Ischemia, and foot Infection (WIfI) is endorsed. Objective hemodynamic testing, including toe pressures as the preferred measure, is required to assess CLTI. Evidence-based revascularization (EBR) hinges on three independent axes: Patient risk, Limb severity, and ANatomic complexity (PLAN). Average-risk and high-risk patients are defined by estimated procedural and 2-year all-cause mortality. The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP), resulting in three stages of complexity for intervention. The optimal revascularization strategy is also influenced by the availability of autogenous vein for open bypass surgery. Recommendations for EBR are based on best available data, pending level 1 evidence from ongoing trials. Vein bypass may be preferred for average-risk patients with advanced limb threat and high complexity disease, while those with less complex anatomy, intermediate severity limb threat, or high patient risk may be favored for endovascular intervention. All patients with CLTI should be afforded best medical therapy including the use of antithrombotic, lipid-lowering, antihypertensive, and glycemic control agents, as well as counseling on smoking cessation, diet, exercise, and preventive foot care. Following EBR, long-term limb surveillance is advised. The effectiveness of nonrevascularization therapies (eg, spinal stimulation, pneumatic compression, prostanoids, and hyperbaric oxygen) has not been established. Regenerative medicine approaches (eg, cell, gene therapies) for CLTI should be restricted to rigorously conducted randomizsed clinical trials. The GVG promotes standardization of study designs and end points for clinical trials in CLTI. The importance of multidisciplinary teams and centers of excellence for amputation prevention is stressed as a key health system initiative.
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| 12. |
- Essery, Rosie, et al.
(författare)
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The Development of Balance Retraining : An Online Intervention for Dizziness in Adults Aged 50 Years and Older
- 2015
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Ingår i: American Journal of Audiology. - : AMER SPEECH-LANGUAGE-HEARING ASSOC. - 1059-0889 .- 1558-9137. ; 24:3, s. 276-279
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This article outlines the rationale and development process for an online intervention based on vestibular rehabilitation therapy (VRT). The intervention aims to assist adults aged 50 years and older to self-manage and reduce dizziness symptoms. Method: The intervention was developed according to the person-based approach to digital intervention design focused on accommodating perspectives of target users. A prototype version of the intervention was provided to 18 adults (11 women, 7 men) aged 50 years and older with dizziness. These adults were invited to use the intervention over a 6-week period and, during this time, took part in a think-aloud session. This session sought to understand users' perceptions of how acceptable, engaging, and easy to use they found the online intervention. Results: Users were extremely positive regarding how easy to navigate, visually appealing, and informative they found the intervention. Think-aloud sessions provided valuable data for informing small amendments to further enhance acceptability of the intervention for target users. Conclusions: Informed by these development-phase data, a finalized version of the intervention is now being investigated in a primary care–based randomized controlled trial. Results should provide an understanding of whether VRT can be effectively—especially, cost-effectively—delivered via an online intervention to adults aged 50 years and older.
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| 13. |
- Geraghty, Adam W. A., et al.
(författare)
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Internet-based vestibular rehabilitation for adults aged 50 years and over: a protocol for a randomised controlled trial
- 2014
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Ingår i: BMJ Open. - : BMJ Publishing Group: Open Access / BMJ Journals. - 2044-6055. ; 4:7, s. e005871-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Dizziness is highly prevalent in older adults and can lead to falls, fear of falling, loss of confidence, anxiety and depression. Vestibular rehabilitation (VR) exercises are effective in reducing dizziness due to vestibular dysfunction, but access to trained therapists is limited. Providing dizzy patients with booklets teaching them how to carry out VR exercises has been shown to be a cost-effective way of managing dizziness in primary care. Internet-based intervention delivery has many advantages over paper-based methods, including the provision of video instructions, automated tailoring and symptom-related feedback. This trial will examine whether an internet-based VR intervention is (1) effective in reducing dizziness and (2) a cost-effective primary care treatment option. Methods/analysis: This will be a single blind, randomised controlled trial carried out in UK primary care. A stand-alone internet-based VR intervention will be compared with routine care in 262 dizzy patients aged 50 years and over. Measures will be taken at baseline, 3 and 6 months. Our primary outcome measure will be the effectiveness of the intervention in reducing dizziness symptoms compared with routine care at 6 months. Cost-effectiveness will be examined along with the effect of the intervention on dizziness-related disability and symptoms of depression and anxiety. Psychological process variables including expectancy, self-efficacy and acceptance will be explored in relation to adherence and symptom reduction. Ethics/dissemination: This trial has undergone ethical scrutiny and been approved by an NHS Research Ethics Committee, Southampton A REC Reference: 13/SC/0119. The findings of this trial will be disseminated to the scientific community through presentations at national and international conferences, and by publishing in peer review journals. Findings will be disseminated to the public through targeted press releases. This trial will provide valuable information on the role of internet interventions in facilitating self-management in older adults.
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| 14. |
- Geraghty, Adam W. A., et al.
(författare)
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Internet-Based Vestibular Rehabilitation for Older Adults With Chronic Dizziness : A Randomized Controlled Trial in Primary Care
- 2017
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Ingår i: Annals of Family Medicine. - : Annals of Family Medicine. - 1544-1709 .- 1544-1717. ; 15:3, s. 209-216
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Vestibular rehabilitation is an effective intervention for dizziness due to vestibular dysfunction, but is seldom provided. We aimed to determine the effectiveness of an Internet-based vestibular rehabilitation program for older adults experiencing dizziness in primary care.METHODS: We undertook a single-center, single-blind randomized controlled trial comparing an Internet-based vestibular rehabilitation intervention (Balance Retraining, freely available from https://balance.lifeguidehealth.org) with usual primary care in patients from 54 primary care practices in southern England. Patients aged 50 years and older with current dizziness exacerbated by head movements were enrolled. Those in the intervention group accessed an automated Internet-based program that taught vestibular rehabilitation exercises and suggested cognitive behavioral management strategies. Dizziness was measured by the Vertigo Symptom Scale–Short Form (VSS-SF) at baseline, 3 months, and 6 months. The primary outcome was VSS-SF score at 6 months.RESULTS: A total of 296 patients were randomized in the trial; 66% were female, and the median age was 67 years. The VSS-SF was completed by 250 patients (84%) at 3 months and 230 patients (78%) at 6 months. Compared with the usual care group, the Internet-based vestibular rehabilitation group had less dizziness on the VSS-SF at 3 months (difference, 2.75 points; 95% CI, 1.39–4.12; P <.001) and at 6 months (difference, 2.26 points; 95% CI, 0.39–4.12; P = .02, respectively). Dizziness-related disability was also lower in the Internet-based vestibular rehabilitation group at 3 months (difference, 6.15 points; 95% CI, 2.81–9.49; P <.001) and 6 months (difference, 5.58 points; 95% CI, 1.19–10.0; P = .01).CONCLUSIONS: Internet-based vestibular rehabilitation reduces dizziness and dizziness-related disability in older primary care patients without requiring clinical support. This intervention has potential for wide application in community settings.
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| 15. |
- Johnstone, Devon L., et al.
(författare)
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Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ : Report of seven new subjects and review of the literature
- 2020
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 43:6, s. 1321-1332
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Tidskriftsartikel (refereegranskat)abstract
- We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
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| 16. |
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| 17. |
- Ping Zhao, Lue, et al.
(författare)
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Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes
- 2017
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Ingår i: Diabetes/Metabolism Research Reviews. - : WILEY. - 1520-7552 .- 1520-7560. ; 33:8
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Tidskriftsartikel (refereegranskat)abstract
- AimIt is of interest to predict possible lifetime risk of type 1 diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. MethodsUtilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing technology to genotype class II genes and applied an object-oriented regression to build and validate a prediction model for T1D. ResultsIn the training set, estimated risk scores were significantly different between patients and controls (P=8.12x10(-92)), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a biological validation by correlating risk scores with 6 islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score=3.628, Pamp;lt;0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying approximately 20 000 high-risk subjects after testing all newborns, and this calculation would identify approximately 80% of all patients expected to develop T1D in their lifetime. ConclusionThrough both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.
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