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Purpose: Changes in voice and speech are characteristic symptoms of Huntington’s disease (HD). Objective methods for quantifying speech impairment that can be used across languages could facilitate assessment of disease progression and intervention strategies. The aim of this study was to analyze acoustic features to identify language-independent features that could be used to quantify speech dysfunction in English-, Spanish-, and Polish-speaking participants with HD. Method: Ninety participants with HD and 83 control participants performed sustained vowel, syllable repetition, and reading passage tasks recorded with previously validated methods using mobile devices. Language-independent features that differed between HD and controls were identified. Principal component analysis (PCA) and unsupervised clustering were applied to the language-independent features of the HD data set to identify subgroups within the HD data. Results: Forty-six language-independent acoustic features that were significantly different between control participants and participants with HD were identified. Following dimensionality reduction using PCA, four speech clusters were identified in the HD data set. Unified Huntington’s Disease Rating Scale (UHDRS) total motor score, total functional capacity, and composite UHDRS were significantly different for pairwise comparisons of subgroups. The percentage of HD participants with higher dysarthria score and disease stage also increased across clusters. Conclusion: The results support the application of acoustic features to objectively quantify speech impairment and disease severity in HD in multilanguage studies. [ABSTRACT FROM AUTHOR]

In Huntington’s disease (HD), wearable inertial sensors could capture subtle changes in motor function. However, disease-specific validation of methods is necessary. This study presents an algorithm for walking bout and gait event detection in HD using a leg-worn accelerometer, validated only in the clinic and deployed in free-living conditions. Seventeen HD participants wore shank- and thigh-worn tri-axial accelerometers, and a wrist-worn device during two-minute walk tests in the clinic, with video reference data for validation. Thirteen participants wore one of the thigh-worn tri-axial accelerometers (AP: ActivPAL4) and the wrist-worn device for 7 days under free-living conditions, with proprietary AP data used as reference. Gait events were detected from shank and thigh acceleration using the Teager-Kaiser energy operator combined with unsupervised clustering. Estimated step count (SC) and temporal gait parameters were compared with reference data. In the clinic, low mean absolute percentage errors were observed for stride (shank/thigh: 0.6/0.9%) and stance (shank/thigh: 3.3/7.1%) times, and SC (shank/thigh: 3.1%). Similar errors were observed for proprietary AP SC (3.2%), with higher errors observed for the wrist-worn device (10.9%). At home, excellent agreement was observed between the proposed algorithm and AP software for SC and time spent walking (ICC $_{{2},{1}}\gt 0.975$). The wrist-worn device overestimated SC by 34.2%. The presented algorithm additionally allowed stride and stance time estimation, whose variability correlated significantly with clinical motor scores. The results demonstrate a new method for accurate estimation of HD gait parameters in the clinic and free-living conditions, using a single accelerometer worn on either the thigh or shank. [ABSTRACT FROM AUTHOR]

Background: There are early indications that lifestyle behaviors, specifically physical activity and sleep, may be associated with the onset and progression of Huntington disease (HD). Wearable activity trackers offer an exciting opportunity to collect long-term activity data to further investigate the role of lifestyle, physical activity, and sleep in disease modification. Given how wearable devices rely on user acceptance and long-term adoption, it is important to understand users' perspectives on how acceptable any device might be and how users might engage over the longer term. Objective: This study aimed to explore the perceptions, motivators, and potential barriers relating to the adoption of wearable activity trackers by people with HD for monitoring and managing their lifestyle and sleep. This information intended to guide the selection of wearable activity trackers for use in a longitudinal observational clinical study. Methods: We conducted a mixed methods study; this allowed us to draw on the potential strengths of both quantitative and qualitative methods. Opportunistic participant recruitment occurred at 4 Huntington's Disease Association meetings, including 1 international meeting and 3 United Kingdom-based regional meetings. Individuals with HD, their family members, and carers were invited to complete a user acceptance questionnaire and participate in a focus group discussion. The questionnaire consisted of 35 items across 8 domains using a 0 to 4 Likert scale, along with some additional demographic questions. Average questionnaire responses were recorded as positive (score>2.5), negative (score<1.5), or neutral (score between 1.5 and 2.5) opinions for each domain. Differences owing to demographics were explored using the Kruskal-Wallis and Wilcoxon rank sum tests. Focus group discussions (conducted in English) were driven by a topic guide, a vignette scenario, and an item ranking exercise. The discussions were audio recorded and then analyzed using thematic analysis. Results: A total of 105 completed questionnaires were analyzed (47 people with HD and 58 family members or carers). All sections of the questionnaire produced median scores >2.5, indicating a tendency toward positive opinions on wearable activity trackers, such as the devices being advantageous, easy and enjoyable to use, and compatible with lifestyle and users being able to understand the information from trackers and willing to wear them. People with HD reported a more positive attitude toward wearable activity trackers than their family members or caregivers (P=.02). A total of 15 participants participated in 3 focus groups. Device compatibility and accuracy, data security, impact on relationships, and the ability to monitor and self-manage lifestyle behaviors have emerged as important considerations in device use and user preferences. Conclusions: Although wearable activity trackers were broadly recognized as acceptable for both monitoring and management, various aspects of device design and functionality must be considered to promote acceptance in this clinical cohort. [ABSTRACT FROM AUTHOR]

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease-specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington's disease as a specific example, and suggest potential strategies to address these challenges. Huntington's disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington's disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells for Huntington's Disease and the European Huntington's Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington's disease. [ABSTRACT FROM AUTHOR]

Around half of pregnant women in the United Kingdom are overweight or obese. The antenatal period provides an opportunity for encouraging women to adopt positive lifestyle changes, and in recent years, this has included development of strategies to support women in avoiding excessive gestational weight gain. The objective of this interventional cohort study was to incorporate individualised gestational weight monitoring charts supported by motivational interviewing (MI)‐based conversations into midwifery‐led antenatal care and assess potential of the intervention for further development and evaluation. The study setting was a community midwifery team within a large maternity unit. The study explored the facilitators and barriers to engagement with the intervention as experienced by women and midwives; 52 women were recruited, of whom 48 were included in the analysis. A single training session was found adequate to prepare midwives to use antenatal weight charts but was insufficient to result in the incorporation of motivational interview techniques into clinical practice. We did not find sufficient evidence to recommend effectiveness testing of this intervention, and there is currently insufficient evidence to support reintroducing regular weighing of pregnant women into UK antenatal care. Given the public health importance of reducing rates of obesity, future interventions aimed at controlling gestational weight gain should continue to be developed but need to include innovative strategies particularly for women who are already obese or gain weight above that recommended. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea (OSA) is highly prevalent in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The gold standard treatment for OSA is continuous positive airway pressure (CPAP). Long-term, well-powered efficacy trials are required to understand whether CPAP could slow cognitive decline in individuals with MCI/AD, but its tolerability in this group remains uncertain. The present review investigates CPAP adherence among individuals with OSA and MCI/AD. Electronic searches were performed on 8 databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Six independent studies and four secondary analyses included 278 unique participants (mean age = 72.1 years). In five of the retained studies, around half of participants (45% N = 85 MCI, 56% N = 22 AD) were adherent to CPAP, where ≥4 h use per night was considered adherent. Three of the retained studies also reported average CPAP use to range between 3.2 and 6.3 h/night. CPAP adherence in individuals with MCI and AD is low, albeit similar to the general elderly population. Reporting adherence in future studies as both average duration as well as using a binary cut-off would improve our understanding of the optimum CPAP use in dementia clinical trials and care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Trials of complex interventions are associated with high costs and burdens in terms of paperwork, management, data collection, validation, and intervention fidelity assessment occurring across multiple sites. Traditional data collection methods rely on paper-based forms, where processing can be time-consuming and error rates high. Electronic source data collection can potentially address many of these inefficiencies, but has not routinely been used in complex intervention trials. Here we present the use of an on-line system for managing all aspects of data handling and for the monitoring of trial processes in a multicentre trial of a complex intervention. We custom built a web-accessible software application for the delivery of ENGAGE-HD, a multicentre trial of a complex physical therapy intervention. The software incorporated functionality for participant randomisation, data collection and assessment of intervention fidelity. It was accessible to multiple users with differing levels of access depending on required usage or to maintain blinding. Each site was supplied with a 4G-enabled iPad for accessing the system. The impact of this system was quantified through review of data quality and collation of feedback from site coordinators and assessors through structured process interviews. Results: The custom-built system was an efficient tool for collecting data and managing trial processes. Although the set-up time required was significant, using the system resulted in an overall data completion rate of 98.5% with a data query rate of 0.1%, the majority of which were resolved in under a week. Feedback from research staff indicated that the system was highly acceptable for use in a research environment. This was a reflection of the portability and accessibility of the system when using the iPad and its usefulness in aiding accurate data collection, intervention fidelity and general administration. Conclusions: A combination of commercially available hardware and a bespoke online database designed to support data collection, intervention fidelity and trial progress provides a viable option for streamlining trial processes in a multicentre complex intervention trial. There is scope to further extend the system to cater for larger trials and add further functionality such as automatic reporting facilities and participant management support. [ABSTRACT FROM AUTHOR]

Background: Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers.Methods/design: We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36.Discussion: This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether larger-scale trials are indicated and to explore suitable outcome measures and analytical methods for neurocognitive trial design.Trial Registration: ISRCTN09739757 . Registered on 28 Dec 2011. [ABSTRACT FROM AUTHOR]

Abstract: Locomotor performance of transgenic R6/2 mice carrying the Huntington''s disease (HD) mutation was assessed using four different tasks, fixed speed rotarod, accelerating rotarod, Digigait and footprint test. The tasks were compared directly in age- and CAG repeat-matched R6/2 mice. Accelerating rotarod was more sensitive than fixed speed rotarod for detecting early motor deficits in R6/2 mice. The sensitivity of accelerating rotarod increased with the acceleration rate and/or the start speed from which the rod accelerated. Differences between tasks were not due to inability of R6/2 mice to maintain balance at high speeds or increased fatigue on accelerating rotarod, but to difficulties in coordinating gait changes required by the constant change in speed on accelerating rotarod. The footprint test was sensitive to gait disturbances. However, surprisingly, R6/2 mice did not show major gait abnormalities on an automated treadmill task (Digigait), even though they showed overt gait deficits in the home cage. The fact that the sensitivity for detecting motor deficits depended strongly on the individual task, and on the protocol used, suggests that non-motor factors were differentially engaged in the different paradigms. We thus recommend that more than one task should be used for detecting and tracking different aspects of motor decay in animal models of HD. Since deficits in non-motor factors such as executive function and motivation may differentially influence motor outcome in each task, our results call for a more thorough investigation of the importance of higher level control of locomotion in animal models of HD. [Copyright &y& Elsevier]

Introduction: While physical activity (PA) is recognized as important in Huntington's disease (HD) disease management, there has been no long-term evaluation undertaken. We aimed to evaluate the feasibility of a nested (within cohort) randomized controlled trial (RCT) of a physical therapist-led PA intervention.Methods: Participants were recruited from six HD specialist centers participating in the Enroll-HD cohort study in Germany, Spain and U.S. Assessments were completed at baseline and 12 months and linked to Enroll-HD cohort data. Participants at three sites (cohort) received no contact between baseline and 12 month assessments. Participants at three additional sites (RCT) were randomized to PA intervention or control group. The intervention consisted of 18 sessions delivered over 12 months; control group participants received no intervention, however both groups completed monthly exercise/falls diaries and 6-month assessments.Results: 274 participants were screened, 204 met inclusion criteria and 116 were enrolled (59 in cohort; 57 in RCT). Retention rates at 12-months were 84.7% (cohort) and 79.0% (RCT). Data completeness at baseline ranged from 42.3 to 100% and at 12-months 19.2-85.2%. In the RCT, there was 80.5% adherence, high intervention fidelity, and similar adverse events between groups. There were differences in fitness, walking endurance and self-reported PA at 12 months favoring the intervention group, with data completeness >60%. Participants in the cohort had motor and functional decline at rates comparable to previous studies.Conclusion: Predefined progression criteria indicating feasibility were met. PACE-HD lays the groundwork for a future, fully-powered within cohort trial, but approaches to ensure data completeness must be considered.Clinicaltrials: GOV: NCT03344601. [ABSTRACT FROM AUTHOR]

Introduction: Huntington's disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronisation skills and improve cognitive and motor abilities in people with HD. This paper outlines a randomised controlled unblinded trial protocol to determine the feasibility of a larger effectiveness trial for HD-DRUM. Additionally, the trial investigates cognitive and motor function measures, along with brain microstructure, aiming to advance our understanding of the neural mechanisms underlying training effects., Methods, Design and Analysis: 50 individuals with HD, confirmed by genetic testing, and a Total Functional Capacity (TFC) score of 9-13, will be recruited into a two-arm randomised controlled feasibility trial. Consenting individuals with HD will be randomised to the intervention group, which entails 8 weeks of at-home usage of HD-DRUM or a usual-activity control group. All participants will undergo cognitive and motor assessments, alongside ultra-strong gradient (300 mT/m) brain microstructural MRI before and after the 8-week period. The feasibility assessment will encompass recruitment, retention, adherence and acceptability of HD-DRUM following prespecified criteria. The study will also evaluate variations in cognitive and motor performance and brain microstructure changes resulting from the intervention to determine effect size estimates for future sample size calculations., Ethics and Dissemination: The study has received favourable ethical opinion from the Wales Research Ethics Committee 2 (REC reference: 22/WA/0147) and is sponsored by Cardiff University (SPON1895-22) (Research Integrity, Governance and Ethics Team, Research & Innovation Services, Cardiff University, second Floor, Lakeside Building, University Hospital of Wales, Cardiff, CF14 4XW). Findings will be disseminated to researchers and clinicians in peer-reviewed publications and conference presentations, and to participants, carers and the general public via newsletters and public engagement activities. Data will be shared with the research community via the Enroll-HD platform., Trial Registration Number: ISRCTN11906973., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Huntington disease (HD) is a neurodegenerative condition that leads to progressive loss of cognitive-executive and motor functions, largely due to basal ganglia (BG) atrophy. Currently, there are no therapeutic interventions tailored to address executive and motor dysfunction in people with HD. Music-based interventions may aid executive abilities by compensating for impaired BG-reliant timing and rhythm generation using external rhythmic beats. Here, we applied an integrated knowledge translation (IKT) framework to co-design a tablet-based rhythmic drumming training app (HD-DRUM) to stimulate executive and motor abilities in people with HD., Objective: The primary aim was to develop the HD-DRUM app for at-home use that addressed the accessibility needs of people with HD and allowed for the quantification of performance improvements and adherence for controlled clinical evaluation., Methods: The IKT framework was applied to iteratively refine the design of HD-DRUM. This process involved 3 phases of knowledge user engagement and co-design: a web-based survey of people with HD (n=29) to inform about their accessibility needs, usability testing of tablet-based touch screens as hardware solutions, and usability testing of the design and build of HD-DRUM to meet the identified accessibility needs of people affected by HD and their clinicians (n=12)., Results: The survey identified accessibility problems due to cognitive and motor control impairments such as difficulties in finding and navigating through information and using PC keyboards and mouses to interact with apps. Tablet-based touch screens were identified as feasible and accessible solutions for app delivery. Key elements to ensure that the app design and build met the needs of people with HD were identified and implemented. These included the facilitation of intuitive navigation through the app using large and visually distinctive buttons; the use of audio and visual cues as training guides; and gamification, positive feedback, and drumming to background music as a means to increase motivation and engagement. The co-design development process resulted in the proof-of-concept HD-DRUM app that is described here according to the Template for Intervention Description and Replication checklist. HD-DRUM can be used at home, allowing the quantification of performance improvements and adherence for clinical evaluation, matching of training difficulty to users' performance levels using gamification, and future scale-up to reach a wide range of interested users., Conclusions: Applying an IKT-based co-design framework involving knowledge user engagement allowed for the iterative refinement of the design and build of the tablet-based HD-DRUM app intervention, with the aim of stimulating BG-reliant cognitive and motor functions. Mapping the intervention against the Template for Intervention Description and Replication framework to describe complex interventions allowed for the detailed description of the HD-DRUM intervention and identification of areas that required refinement before finalizing the intervention protocol., (©Claudia Metzler-Baddeley, Monica Busse, Cheney Drew, Philip Pallmann, Jaime Cantera, Vasileios Ioakeimidis, Anne Rosser. Originally published in JMIR Formative Research (https://formative.jmir.org), 06.10.2023.)

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease-specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington's disease as a specific example, and suggest potential strategies to address these challenges. Huntington's disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington's disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells for Huntington's Disease and the European Huntington's Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Huntington's disease is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington's disease is characterized by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell-replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration is a phase I Trial Within a Cohort designed to assess safety and feasibility of transplanting human foetal striatal cells into the striatum of people with Huntington's disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) 4 weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline (6 and 12 months). Surgery will be performed 1 month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed ∼1 month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomized controlled trials aimed at evaluating efficacy and cost-effectiveness of cell-replacement therapy. TRIal DEsigns for delivery of Novel Therapies in neurodegeneration will enable the assessment of the safety, feasibility, acceptability and cost of foetal cell transplants in people with Huntington's disease. The data collected will inform trial designs for complex intra-cranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials. Trial Registration: ISRCTN52651778., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Fissure sealant (FS) and fluoride varnish (FV) have been shown to be effective in preventing dental caries when tested against a no-treatment control. However, the relative clinical effectiveness and cost-effectiveness of these interventions is unknown., Objective: To compare the clinical effectiveness and cost-effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- and 7-year-olds and to determine their acceptability., Design: A randomised controlled allocation-blinded clinical trial with two parallel arms., Setting: A targeted population programme using mobile dental clinics (MDCs) in schools located in areas of high social and economic deprivation in South Wales., Participants: In total, 1016 children were randomised, but one parent subsequently withdrew permission and so the analysis was based on 1015 children. The randomisation of participants was stratified by school and balanced for sex and primary dentition baseline caries levels using minimisation in a 1 : 1 ratio for treatments. A random component was added to the minimisation algorithm, such that it was not completely deterministic. Of the participants, 514 were randomised to receive FS and 502 were randomised to receive FV., Interventions: Resin-based FS was applied to caries-free FPMs and maintained at 6-monthly intervals. FV was applied at baseline and at 6-month intervals over the course of 3 years., Main Outcome Measures: The proportion of children developing caries into dentine (decayed, missing, filled teeth in permanent dentition, i.e. D 4-6 MFT) on any one of up to four treated FPMs after 36 months. The assessors were blinded to treatment allocation; however, the presence or absence of FS at assessment would obviously indicate the probable treatment received. Economic measures established the costs and budget impact of FS and FV and the relative cost-effectiveness of these technologies. Qualitative interviews determined the acceptability of the interventions., Results: At 36 months, 835 (82%) children remained in the trial: 417 in the FS arm and 418 in the FV arm. The proportion of children who developed caries into dentine on a least one FPM was lower in the FV arm (73; 17.5%) than in the FS arm (82, 19.6%) [odds ratio (OR) 0.84, 95% confidence interval (CI) 0.59 to 1.21; p  = 0.35] but the difference was not statistically significant. The results were similar when the numbers of newly decayed teeth (OR 0.86, 95% CI 0.60 to 1.22) and tooth surfaces (OR 0.85, 95% CI 0.59 to 1.21) were examined. Trial fidelity was high: 95% of participants received five or six of the six scheduled treatments. Between 74% and 93% of sealants (upper and lower teeth) were intact at 36 months. The costs of the two technologies showed a small but statistically significant difference; the mean cost to the NHS (including intervention costs) per child was £500 for FS, compared with £432 for FV, a difference of £68.13 (95% CI £5.63 to £130.63; p  = 0.033) in favour of FV. The budget impact analysis suggests that there is a cost saving of £68.13 (95% CI £5.63 to £130.63; p  = 0.033) per child treated if using FV compared with the application of FS over this time period. An acceptability score completed by the children immediately after treatment and subsequent interviews demonstrated that both interventions were acceptable to the children. No adverse effects were reported., Limitations: There are no important limitations to this study., Conclusions: In a community oral health programme utilising MDCs and targeted at children with high caries risk, the twice-yearly application of FV resulted in caries prevention that is not significantly different from that obtained by applying and maintaining FSs after 36 months. FV proved less expensive., Future Work: The clinical effectiveness and cost-effectiveness of FS and FV following the cessation of active intervention merits investigation., Trial Registration: EudraCT number 2010-023476-23, Current Controlled Trials ISRCTN17029222 and UKCRN reference 9273., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 21, No. 21. See the NIHR Journals Library website for further project information.

Background: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy., Methods: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation., Results: 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort., Conclusions: We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.

Background and Purpose: We studied the development and delivery of a 14-week complex physical activity intervention for people with Huntington disease, where detailed information about the intervention was fully embedded in the trial design process., Methods: Intervention Development: The intervention was developed through a series of focus groups. The findings from the focus groups informed the development of a logic model for the physical activity intervention that was broadly consistent with the framework of self-determination theory. Intervention Delivery: Key components underpinning the delivery of the intervention were implemented including a defined coach training program and intervention fidelity assessment methods. Training of coaches (physical therapists, occupational therapists, research nurses, and exercise trainers) was delivered via group and 1:1 training sessions using a detailed coach's manual, and with ongoing support via video calls, and e-mail communication as needed. Detailed documentation was provided to determine costs of intervention development and coach training., Results: Intervention delivery coaches at 8 sites across the United Kingdom participated in the face-to-face training. Self-report checklists completed by each of the coaches indicated that all components of the intervention were delivered in accordance with the protocol. Mean (standard deviation) intervention fidelity scores (n = 15), as measured using a purpose-developed rating scale, was 11 (2.4) (out of 16 possible points). Coaches' perceptions of intervention fidelity were similarly high. The total cost of developing the intervention and providing training was £30,773 ($47,042 USD)., Discussion and Conclusions: An important consideration in promoting translation of clinical research into practice is the ability to convey the detailed components of how the intervention was delivered to facilitate replication if the results are favorable. This report presents an illustrative example of a physical activity intervention, including the development and the training required to deliver it. This approach has the potential to facilitate reproducibility, evidence synthesis, and implementation in clinical practice.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A122).

Background: Spatial learning deficits are observed in R6/2 mice, a transgenic mouse model of Huntington's Disease (HD). Spatial learning is a hippocampal-dependent process, and impairment of memory is thought to be due, at least in part, to structural changes such as loss of dendritic spines., Objective: To analyse dendritic spines in the hippocampus of R6/2 mice to determine if there are changes that correlate with the hippocampal dysfunction observed in these mice., Methods: A double transgenic cross between R6/2 mice and a reporter line (YFP-H) of mice that express yellow fluorescent protein (YFP) in a subset of their neurons was used. This allowed us to visualise dendritic spines in the brains of R6/2 mice directly., Results: Clear differences were seen in the distribution of YFP in the hippocampal formation of wild-type (WT)-YFP-H and R6/2-YFP-H mice, particularly in the CA1 region. We quantified dendritic spine density and dendritic spine length in the apical dendrites of the CA1 hippocampal neurons. A significant reduction in dendritic spine density, and a concomitant increase in dendritic spine length was observed in R6/2-YFP-H mice compared to WT-YFP-H mice., Conclusion: The R6/2-YFP-H mouse is a useful tool for directly visualising dendritic spines in the brain of a Huntington's disease mouse model. The changes we observed in dendritic spine density and length in the hippocampus might contribute to the synaptic plasticity deficits and behavioural alteration of impaired spatial learning seen in R6/2 mice.

There has been an academic "gold rush" with researchers mining the deep seams of whole-exome and whole-genome sequencing since 2008. Although undoubtedly a major advance initially for identifying new disease-associated genes for rare monogenetic disorders--more recently, common and complex conditions have been successfully studied using these techniques. With great power comes great responsibility, however, and we must not forget that next generation sequencing produces unique ethical conundrums and validation challenges. We review the progression of published papers using whole-exome sequencing from a clinical and technical viewpoint before then reflecting on the key arguments that need to be fully understood before these tools can become a routine part of clinical practice and we ask what may be the role for the biomedical scientists?, (Copyright © 2012 Elsevier Inc. All rights reserved.)