Using co-design methods to develop new personalised support for people living with Long Covid: The 'LISTEN' intervention.

INTRODUCTION: Many Covid-19 survivors are living with unresolved, relapsing and remitting symptoms and no 'one size' of treatment is likely to be effective for everyone. Supported self-management for the varied symptoms of Long Covid (LC) is recommended by the National Institute for Health and Care Excellence in the United Kingdom. We aimed to develop a new personalised support intervention for people living with LC using a structured co-design framework to guide replication and evaluation. METHODS: We used the improvement methodology, Experience-Based Co-Design, in an accelerated form to harness the collective experiences of people with LC. Incorporating evidence from 'Bridges Self-Management' (Bridges) an approach in which healthcare professionals (HCPs)are trained to support knowledge, confidence and skills of individuals living with long term conditions. Co-designed resources are also central to Bridges. Adults who self-identified as living with or recovered from LC, from England or Wales, aged 18 years and over were recruited, and HCPs, with experience of supporting people with LC. Participants took part in a series of small co-design group meetings and larger mixed meetings to agree priorities, core principles and generate resources and intervention content. RESULTS: People with LC (n = 28), and HCPs (n = 9) supported co-design of a book (hard-copy and digital form) to be used in 1:1 support sessions with a trained HCP. Co-design stages prioritised stories about physical symptoms first, and psychological and social challenges which followed, nonlinear journeys and reconceptualising stability as progress, rich descriptions of strategies and links to reputable advice and support for navigating healthcare services. Co-design enabled formulation of eight core intervention principles which underpinned the training and language used by HCPs and fidelity assessments. CONCLUSION: We have developed a new personalised support intervention, with core principles to be used in one-to-one sessions delivered by trained HCPs, with a new co-designed book as a prompt to build personalised strategies and plans using narratives, ideas, and solutions from other people with LC. Effectiveness and cost effectiveness of the 'LISTEN' intervention will be evaluated in a randomised controlled trial set within the context of the updated Framework for Developing and Evaluating Complex Interventions. PATIENT AND PUBLIC CONTRIBUTION: The LISTEN Public and Patient Involvement (PPI) group comprised seven people living with LC. They all contributed to the design of this study and five members were part of a larger co-design community described in this paper. They have contributed to this paper by interpreting stages of intervention design and analysis of results. Three members of our PPI group are co-authors of this paper.

Translating cell therapies for neurodegenerative diseases: Huntington's disease as a model disorder.

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.

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

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. TRIAL REGISTRATION: ClinicalTrials.gov, Registry number NCT02990676.

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

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. TRIAL REGISTRATION: The study is registered on clinicaltrials.gov and has the unique identifier NCT02990676.

Using Actiwatch to monitor circadian rhythm disturbance in Huntington' disease: A cautionary note.

Huntington's disease (HD) is an inherited neurodegenerative disorder that is well recognised as producing progressive deterioration of motor function, including dyskinetic movements, as well as deterioration of cognition and ability to carry out activities of daily living. However, individuals with HD commonly suffer from a wide range of additional symptoms, including weight loss and sleep disturbance, possibly due to disruption of circadian rhythmicity. Disrupted circadian rhythms have been reported in mice models of HD and in humans with HD. One way of assessing an individual's circadian rhythmicity in a community setting is to monitor their sleep/wake cycles, and a convenient method for recording periods of wakefulness and sleep is to use accelerometers to discriminate between varied activity levels (including sleep) during daily life. Here we used Actiwatch(®) Activity monitors alongside ambulatory EEG and sleep diaries to record wake/sleep patterns in people with HD and normal volunteers. We report that periods of wakefulness during the night, as detected by activity monitors, agreed poorly with EEG recordings in HD subjects, and unsurprisingly sleep diary findings showed poor agreement with both EEG recordings and activity monitor derived sleep periods. One explanation for this is the occurrence of 'break through' involuntary movements during sleep in the HD patients, which are incorrectly assessed as wakeful periods by the activity monitor algorithms. Thus, care needs to be taken when using activity monitors to assess circadian activity in individuals with movement disorders.

Use of hand-held dynamometry in the evaluation of lower limb muscle strength in people with Huntington's disease.

PURPOSE: Sub-clinical muscle involvement, including myopathic changes and mitochondrial dysfunction of skeletal muscle, has been reported in people with Huntington's disease (HD). Muscle strength was evaluated using a hand-held dynamometer. Reliability and validity in people with HD were determined. METHOD: Isometric muscle strength of 6 lower limb muscle groups was measured in 20 people with HD and matched healthy controls. People with HD were evaluated with the Unified Huntington's Disease Rating Scales (UHDRS). Within session reliability using intra-class correlation coefficients (ICC) was calculated. Discriminant and convergent validity was also evaluated. RESULTS: UHDRS motor scores of people with HD ranged from 28 to 80. Reliability of strength testing was excellent (ICC 0.86 to 0.98). People with HD had on average about half the strength of healthy matched controls. UHDRS motor scores and strength scores were significantly correlated (convergent) providing a further indication of validity of strength testing. CONCLUSIONS: The hand-held dynamometer is a reliable and valid measurement tool to detect strength differences between people with HD and a matched control group. There is significant reduction in lower limb muscle strength in HD which does not appear to have been described previously.

Physical therapy intervention for people with Huntington disease.

BACKGROUND AND PURPOSE: The clinical symptoms of Huntington disease (HD) include progressive movement disorders, cognitive deficits, and behavioral changes, all of which affect an individual's ability to participate in activities of daily living. To date, very few quantitative or qualitative studies have been conducted to guide physical therapists working with people with HD. The objective of this study was to characterize current physical therapist practice for people with HD, thus informing the development of standardized clinical care and future research studies. SUBJECTS AND METHODS: Consultation with physical therapists working with people with HD was undertaken in the form of mailed questionnaires (n=49) and semistructured interviews (n=8). The development of the interview schedule was aided by consideration of the data obtained from the questionnaires. Themes identified from the interviews were considered in light of published literature and questionnaire responses. RESULTS: The main issues that emerged from the interviews were classified into 3 subthemes: (1) there is insufficient use of routine physical therapy-related outcome measures at different stages of HD, (2) there is underutilization of physical therapy services in managing HD (particularly in the early stages), and (3) the management of falls and mobility deficit progression is a key treatment aim for people with HD. DISCUSSION AND CONCLUSION: A conceptual framework for physical therapy intervention in HD was developed on the basis of the themes that emerged from the data in this study. Such a framework has utility for complex, progressive conditions such as HD and may facilitate clinical decision making and standardization of practice and affect the development of future physical therapy trials.

Co-activation: its association with weakness and specific neurological pathology.

BACKGROUND: Net agonist muscle strength is in part determined by the degree of antagonist co-activation. The level of co-activation might vary in different neurological disorders causing weakness or might vary with agonist strength. AIM: This study investigated whether antagonist co-activation changed a) with the degree of muscle weakness and b) with the nature of the neurological lesion causing weakness. METHODS: Measures of isometric quadriceps and hamstrings strength were obtained. Antagonist (hamstring) co-activation during knee extension was calculated as a ratio of hamstrings over quadriceps activity both during an isometric and during a functional sit to stand (STS) task (using kinematics) in groups of patients with extrapyramidal (n = 15), upper motor neuron (UMN) (n = 12), lower motor neuron (LMN) with (n = 18) or without (n = 12) sensory loss, primary muscle or neuromuscular junction disorder (n = 17) and in healthy matched controls (n = 32). Independent t-tests or Mann Witney U tests were used to compare between the groups. Correlations between variables were also investigated. RESULTS: In healthy subjects mean (SD) co-activation of hamstrings during isometric knee extension was 11.8 (6.2)% and during STS was 20.5 (12.9)%. In patients, co-activation ranged from 7 to 17% during isometric knee extension and 15 to 25% during STS. Only the extrapyramidal group had lower co-activation levels than healthy matched controls (p < 0.05). Agonist isometric muscle strength and co-activation correlated only in muscle disease (r = (-)0.6, p < 0.05) and during STS in UMN disorders (r = (-)0.7, p < 0.5). CONCLUSION: It is concluded that antagonist co-activation does not systematically vary with the site of neurological pathology when compared to healthy matched controls or, in most patient groups, with strength. The lower co-activation levels found in the extrapyramidal group require confirmation and further investigation. Co-activation may be relevant to individuals with muscle weakness. Within patient serial studies in the presence of changing muscle strength may help to understand these relationships more clearly.