37 research outputs found

    Exploring computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD): protocol for a randomised feasibility study

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    Background Cognitive impairments, especially deficits of executive function, have been well documented as a core and early feature in Huntington’s disease (HD). Cognitive impairments represent considerable burden and can be devastating for people and families affected by HD. Computerised cognitive training interventions that focus on improving executive function present a possible non-pharmacological treatment option. We propose to determine the feasibility, acceptability, and appropriate outcome measures for use in a randomised controlled feasibility study. Methods/design Participants will be randomised into either a computerised cognitive training group or a control group. Those randomised to the training group will be asked to complete a cognitive training intervention based on the HappyNeuron Pro software tasks of executive function, for a minimum of 30 min, three times a week for the 12-week study duration. Participants in the control group will not receive computerised cognitive training but will receive a similar degree of social interaction via equivalent study and home visits. We will explore quantitative outcome measures, including measures of cognitive performance, motor function, questionnaires and semi-structured interviews, as well as magnetic resonance imaging (MRI) measures in a subset of participants. Feasibility will be determined through assessment of recruitment, retention, adherence and acceptability of the intervention. Discussion The results of this study will provide crucial guidance and information regarding the feasibility of conducting a randomised controlled study into computerised cognitive training in HD. This study is crucial for the development of larger definitive randomised controlled trials which are powered to determine efficacy and for the development of future cognitive training programmes for people affected by HD

    A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington's disease (CogTrainHD)

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    Background Huntington’s disease (HD) is associated with a range of cognitive deficits including problems with executive function. In the absence of a disease modifying treatment, cognitive training has been proposed as a means of slowing cognitive decline; however, the impact of cognitive training in HD patient populations remains unclear. The CogTrainHD study assessed the feasibility and acceptability of home-based computerised executive function training, for people impacted by HD. Methods Thirty HD gene carriers were recruited and randomised to either executive function training or non-intervention control groups. Participants allocated to the intervention group were asked to complete executive function training three times a week for 30 min for 12 weeks in their own homes. Semi-structured interviews were conducted with participants and friends, family or carers, to determine their views on the study. Results 26 out of 30 participants completed the baseline assessments and were subsequently randomised: 13 to the control group and 13 to the intervention group. 23 of the 30 participants were retained until study completion: 10/13 in the intervention group and 13/13 in the control group. 4/10 participants fully adhered to the executive function training. All participants in the control group 13/13 completed the study as intended. Interview data suggested several key facilitators including participant determination, motivation, incorporation of the intervention into routine and support from friends and family members. Practical limitations, including lack of time, difficulty and frustration in completing the intervention, were identified as barriers to study completion. Conclusions The CogTrainHD feasibility study provides important evidence regarding the feasibility and acceptability of a home-based cognitive training intervention for people with HD. Variable adherence to the cognitive training implies that the intervention is not feasible to all participants in its current form. The study has highlighted important aspects in relation to both the study and intervention design that require consideration, and these include the design of games in the executive function training software, logistical considerations such as lack of time, the limited time participants had to complete the intervention and the number of study visits required. Further studies are necessary before computerised executive function training can be recommended routinely for people with HD

    Successful stabilisation of nephropathy in a patient with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, skin changes) syndrome on treatment with mycophenolate and steroids: a case report

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    <p>Abstract</p> <p>Introduction</p> <p>Renal involvement in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-band, skin changes) syndrome is considered to be an under-diagnosed phenomenon with no clear treatment path. The limited literature suggests steroids to be the drug of choice, although improvements are limited and usually reverse on withdrawal of the drug.</p> <p>Case presentation</p> <p>A 52-year-old Caucasian woman presenting with features consistent with POEMS syndrome developed progressive renal impairment with proteinuria. Renal biopsy revealed a membranoproliferative glomerulonephritis. She was treated with relatively low dose oral mycophenolate mofetil and prednisolone which stabilised her nephropathy and neuropathy.</p> <p>Conclusion</p> <p>We describe an alternative therapeutic option in patients with this serious but poorly understood condition.</p

    Proceedings of the 6th National Patient Reported Outcome Measures (PROMs) Annual UK Research Virtual Conference, Bridgend, Wales 2022

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    The 6th UK Patient Reported Outcome Measures (PROMs) Research Conference was held on the 14th and 15th of June 2022. Hosted online, it attracted an international audience from locations including Europe, the USA, Australia, New Zealand, and the Caribbean, and was attended by 381 people with representatives from academia, healthcare, patients, and industry. Previously hosted by the Universities of Sheffield, Oxford, Birmingham and Leeds Beckett, for the first time it was hosted by a non-academic organisation, making its inaugural visit to Wales, and was hosted by The Welsh Value in Health Centre. Welcoming abstracts on any topics, focused themes included: Methods; Implementation; Palliative Care; COVID-19; Patient and Public Involvement; Mental Health; and Social Care

    Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset

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    The age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with complete FAN1 knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD

    Prevalence and architecture of de novo mutations in developmental disorders.

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    The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

    Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

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    Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre

    Diplomazia creativa al servizio di strategie di nicchia di una piccola potenza

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    In the year marking the centenary since the foundation of the Azerbaijani Diplomatic Service, Baku’s foreign policy is increasingly characterised by a broader understanding of diplomacy, shaped by the gradual yet steady expansion of both areas and the tools for intervention. Guided by the attempt to develop a ‘niche strategy’ aiming at safeguarding and promoting Azerbaijani national interest, the Humanitarian Diplomacy emerges as a privileged field for Baku to adopt a pro-active and creative foreign policy. Building upon the debate around the interests behind the aid-providing activities of traditional and emerging donors, the article aims at introducing the motivations and the aims behind Azerbaijani aid policy. In particular, it aims at demonstrating that Baku’s Humanitarian Diplomacy aims chiefly at achieving immaterial benefits, having to do with international prestige and with the construction and international projection of a Good International Citizenship

    Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation

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    Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS

    Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

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    We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities
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