Health state utility estimates for value assessments of novel treatments in Huntington's disease: a systematic literature review.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease with a devastating impact on patients and their families. Quantifying how treatments affect patient outcomes is critical for informing reimbursement decisions. Many countries mandate a formal value assessment in which the treatment benefit is measured as quality-adjusted life-years, calculated with the use of utility estimates that reflect respondents' preferences for health states. OBJECTIVE: To summarize published health state utility data in HD and identify gaps and uncertainties in the data available that could be used to inform value assessments. METHODS: We conducted a systematic literature review of studies that used preference-based instruments (e.g., EQ-5D and SF-6D) to estimate utility values for people with HD. The studies were published between January 2012 and December 2022. RESULTS: Of 383 articles screened, 16 articles reported utility values estimated in 11 distinct studies. The utility measure most frequently reported was EQ-5D (9/11 studies). Two studies reported SF-6D data; one used time trade-off methods to value health state descriptions (vignettes). Although utility scores generally worsened to a lower value with increased HD severity, the estimates varied considerably across studies. The EQ-5D index range was 0.89 - 0.72 for mild/prodromal HD and 0.71 - 0.37 for severe/late-stage disease. CONCLUSIONS: This study uncovered high variability in published utility estimates, indicating substantial uncertainty in existing data. Further research is needed to better understand preferences and valuation across all stages and domains of HD symptoms and the degree to which generic utility measures capture the impact of cognitive changes on quality of life.

Targeting Huntingtin Expression in Patients with Huntington's Disease.

BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. RESULTS: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONS: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI.

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these.

Understanding Psychiatric Disorders in Idiopathic and Inherited (Monogenic) Forms of Isolated and Combined Dystonia: A Systematic Review.

OBJECTIVE: The relationship between idiopathic and inherited (monogenic) forms of isolated and combined dystonia and psychiatric disorders remains unclear. In the present review, the authors aimed to provide increased clarity on this association through a systematic review of all controlled quantitative studies using a structured or semi-structured psychiatric interview to diagnose psychiatric disorders in individuals with these conditions. METHODS: Three databases were searched to identify 20 eligible studies, with a total of 1,275 participants fulfilling inclusion criteria. Eligible articles were quality appraised and divided into four sections (idiopathic forms of dystonia [N=11], early-onset torsion dystonia [N=2], gene mutation positive myoclonus dystonia; DYT-SGCE [N=6], and rapid-onset dystonia-parkinsonism [N=1]). RESULTS: For each study, results were grouped into subcategories (overall psychiatric comorbidity, anxiety disorders, mood disorders, substance misuse, and other [personality disorder and cognitive impairment]). For idiopathic dystonia, higher rates of psychiatric comorbidity, including mood and anxiety disorders, were noted when cases were compared with both healthy control subjects and control groups with a medical comorbidity. However, for major depressive disorder and obsessive-compulsive disorder (OCD) specifically, no differences were seen between groups. Study subjects with DYT-SGCE appeared to be at higher risk of psychiatric comorbidity, major depressive disorder, OCD, and alcohol dependence than control populations. CONCLUSIONS: Overall, the prevalence of psychiatric comorbidity appears to be increased in individuals with idiopathic and inherited (monogenic) forms of isolated and combined dystonia compared with control subjects. This finding is not consistent for all comparisons, and further research is required to understand the nature of these associations and the underlying causative etiologies.

Through your eyes or mine? The neural correlates of mental state recognition in Huntington's disease.

Huntington's disease (HD) can impair social cognition. This study investigated whether patients with HD exhibit neural differences to healthy controls when they are considering mental and physical states relating to the static expressions of human eyes. Thirty-two patients with HD and 28 age-matched controls were scanned with fMRI during two versions of the Reading the Mind in the Eyes Task: The standard version requiring mental state judgments, and a comparison version requiring judgments about age. HD was associated with behavioral deficits on only the mental state eyes task. Contrasting the two versions of the eyes task (mental state > age judgment) revealed hypoactivation within left middle frontal gyrus and supramarginal gyrus in HD. Subgroup analyses comparing premanifest HD patients to age-matched controls revealed reduced activity in right supramarginal gyrus and increased activity in anterior cingulate during mental state recognition in these patients, while manifest HD was associated with hypoactivity in left insula and left supramarginal gyrus. When controlling for the effects of healthy aging, manifest patients exhibited declining activation within areas including right temporal pole. Our findings provide compelling evidence for a selective impairment of internal emotional status when patients with HD appraise facial features in order to make social judgements. Differential activity in temporal and anterior cingulate cortices may suggest that poor emotion regulation and emotional egocentricity underlie impaired mental state recognition in premanifest patients, while more extensive mental state recognition impairments in manifest disease reflect dysfunction in neural substrates underlying executive functions, and the experience and interpretation of emotion.

Practitioner Review: Treatments for Tourette syndrome in children and young people - a systematic review.

BACKGROUND: Tourette syndrome (TS) and chronic tic disorder (CTD) affect 1-2% of children and young people, but the most effective treatment is unclear. To establish the current evidence base, we conducted a systematic review of interventions for children and young people. METHODS: Databases were searched from inception to 1 October 2014 for placebo-controlled trials of pharmacological, behavioural, physical or alternative interventions for tics in children and young people with TS or CTD. Certainty in the evidence was assessed with the GRADE approach. RESULTS: Forty trials were included [pharmacological (32), behavioural (5), physical (2), dietary (1)]. For tics/global score there was evidence favouring the intervention from four trials of α2-adrenergic receptor agonists [clonidine and guanfacine, standardised mean difference (SMD) = -0.71; 95% CI -1.03, -0.40; N = 164] and two trials of habit reversal training (HRT)/comprehensive behavioural intervention (CBIT) (SMD = -0.64; 95% CI -0.99, -0.29; N = 133). Certainty in the effect estimates was moderate. A post hoc analysis combining oral clonidine/guanfacine trials with a clonidine patch trial continued to demonstrate benefit (SMD = -0.54; 95% CI -0.92, -0.16), but statistical heterogeneity was high. Evidence from four trials suggested that antipsychotic drugs improved tic scores (SMD = -0.74; 95% CI -1.08, -0.40; N = 76), but certainty in the effect estimate was low. The evidence for other interventions was categorised as low or very low quality, or showed no conclusive benefit. CONCLUSIONS: When medication is considered appropriate for the treatment of tics, the balance of clinical benefits to harm favours α2-adrenergic receptor agonists (clonidine and guanfacine) as first-line agents. Antipsychotics are likely to be useful but carry the risk of harm and so should be reserved for when α2-adrenergic receptor agonists are either ineffective or poorly tolerated. There is evidence that HRT/CBIT is effective, but there is no evidence for HRT/CBIT alone relative to combining medication and HRT/CBIT. There is currently no evidence to suggest that the physical and dietary interventions reviewed are sufficiently effective and safe to be considered as treatments.

Exploring the Structural Relationship Between Interviewer and Self-Rated Affective Symptoms in Huntington's Disease.

This study explores the structural relationship between self-report and interview measures of affect in Huntington's disease. The findings suggest continued use of both to recognize the multidimensionality within a single common consideration of distress.

A randomized, placebo-controlled trial of AFQ056 for the treatment of chorea in Huntington's disease.

BACKGROUND: This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). METHODS: This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. RESULTS: Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. CONCLUSIONS: AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.

Perceptions of treatment for tics among young people with Tourette syndrome and their parents: a mixed methods study.

BACKGROUND: Tourette syndrome (TS) among young people is associated with psychosocial difficulties and parents play an important role in the management of the condition. Clinical guidelines have been developed for the treatment of TS and tics, but little is known about how young people and their parents perceive their treatment options or their desired outcomes of treatment. The aim of this study is to explore perceptions of treatments for tics among young people with TS and their parents. METHODS: In-depth interviews with 42 young people with TS and a mixed-methods, online survey of 295 parents of young people with TS. Participant recruitment was conducted through Tourettes Action (TA): a non-profit UK organisation for the support of people with TS. Interview transcripts were analysed using thematic analysis and responses to survey open-ended questions were analysed using content analysis. Triangulation of qualitative and quantitative data from the parents' survey and qualitative data from the interviews with young people was used to increase the validity and depth of the findings. RESULTS: A strong theme was the perception that health professionals have limited knowledge of TS and its treatment. Medication was a common treatment for tics and both young people and parents described benefits of medication. However, adverse effects were frequently described and these were a common reason for stopping medication among young people. Aripiprazole was viewed most positively. Access to behavioural interventions for tics was limited and 76% of parents wanted this treatment to be available for their child. Some young people had reservations about the effectiveness or practicality of behavioural interventions. Reduction and abolition of tics were desired outcomes of treatment, but both parents and young people also identified the importance of increasing control over tics and reducing anxiety-related symptoms. For young people, managing the urge to tic was an important outcome of treatment. CONCLUSIONS: The results suggest a need for more training in the identification and management of TS and wider availability of behavioural treatments. Clinical trials could explore the effectiveness of Aripiprazole used in combination with psycho-educational interventions to reduce anxiety and promote a sense of control.

Neuropsychiatric symptoms in a European Huntington's disease cohort (REGISTRY).

BACKGROUND: The majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods. METHODS: The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis. RESULTS: Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association. CONCLUSIONS: A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.

Putting things into perspective: the nature and impact of theory of mind impairment in Huntington's disease.

In Huntington's disease (HD), frontostriatal dysfunction may lead to deficits in theory of mind (ToM), in addition to broader cognitive impairment. We investigated relationships between patients' spatial and social perspective taking performance and executive deficits, self-reported everyday perspective taking, motor symptoms, functional capacity and quality of life. Thirty patients with symptomatic HD and twenty-three healthy controls of similar age and education completed two ToM tasks, a scale assessing everyday interpersonal perspective taking, a novel object-based spatial perspective taking task (SPT) and executive measures. Ratings of quality of life, psychiatric symptoms, motor symptom severity and functional capacity were also taken for patients. When compared to controls, patients exhibited significant deficits in ToM and spatial perspective taking and lower everyday perspective taking scores. Executive deficits were linked to poor understanding of socially inappropriate remarks and errors in mental state attribution. This may be the first study to show that aspects of ToM performance are linked to spatial perspective taking, motor symptom severity and functional capacity in HD. Our findings indicate that patients with HD exhibit evidence of reduced perspective taking in everyday life in addition to poor performance on social and SPTs. They also emphasise the need to better specify the precise cognitive and neural bases for ToM deficits in neurodegenerative conditions. Further research exploring the impact of striatal degeneration on perspective taking abilities will make a valuable contribution to the continued development of functional models of frontostriatal circuitry.

A controlled study of personality and affect in Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) can increase the likelihood of social and emotional difficulties which may shape an individual's personality and self-perception. We investigated personality and affect in patients with TS. METHODS: Twenty-five adults with TS (2 with co-morbid obsessive compulsive disorder, 4 with co-morbid attention-deficit hyperactivity disorder and 4 with both co-morbidities), who were not clinically depressed, and 25 matched controls participated in the study. They completed the Ten-Item Personality Index, the Positive and Negative Affect Scale and the Beck Depression Inventory. RESULTS: Adults with TS exhibited no differences from controls in reported emotional experience or depressive symptoms but did differ for four of the five assessed personality dimensions; extraversion, conscientiousness, openness and emotional stability. Individuals with pure TS (who had no co-morbid conditions) exhibited reduced extraversion and emotional stability compared to controls. Personality scores were not related to tic severity, yet lower emotional stability scores were associated with higher ratings of negative affect. CONCLUSIONS: This study is limited by a restricted sample in terms of size and source. However, our findings indicate that in the absence of depression and common co-morbidities, people with TS differ from controls in indices of personality, which are linked to negative affectivity.

What does social cognition look like in everyday social functioning in Huntington's disease? A protocol for a scoping review to explore and synthesise knowledge about social cognition alongside day-to-day social functioning of people with Huntington's disease.

INTRODUCTION: Social cognition is problematic in Huntington's disease (HD). Despite the observations of clinicians and families, there is minimal empirical literature about how it presents in daily life and the impact on social functioning. This protocol forms the basis of a scoping review to synthesise both the quantitative knowledge and qualitative experiences of the HD community so that a visual and narrative map can address what is known and what is not known for the benefit of the community and clinicians and academics alike. METHODS AND ANALYSES: An umbrella scoping review of previous work and a scoping review of newer studies of social cognition and social functioning will be undertaken. The electronic databases PubMed, Medline, PsycINFO, Web of Science, Scopus, Embase and CINAHL will be searched to identify eligible studies from starting from 2003 to June 2023. A grey literature search and grey data search will also be undertaken. Quality appraisal of the included documents will use the Critical Appraisal Skills Programme and Authority, Accuracy, Coverage, Objectivity, Date, Significance checklists. A data charting table will be used for data extraction, with analysis of qualitative data using the framework method. The review findings will be presented in a visual form and in a narrative summary. ETHICS AND DISSEMINATION: Ethical review is not usually required as scoping reviews are produced via secondary data analysis, however, this protocol includes the use of grey data from a charity web forum and so in line with best practice for internet mediated research ethical review was sought and approved (STEM Ethical Review Committee, University of Birmingham-ERN_21-1028A). Review findings will be shared with service users and disseminated through a peer-reviewed publications, conference presentations and hosted via the website of the patient association charity the HD Association.

An Overview of Specialist Services for Huntington's Disease in the United Kingdom.

BACKGROUND: Huntington's disease (HD) is a rare inherited neurodegenerative disorder characterized by complex evolving needs that change as the condition progresses. There is limited understanding about the organization of HD clinical services and their resourcing in the United Kingdom (UK). OBJECTIVE: To understand the organization and resourcing of specialist HD services for people with HD (PwHD) in the UKMethods:This cross-sectional study collected quantitative data via on online survey, and qualitative data via telephone semi-structured interviews. Descriptive statistics were used to describe quantitative outcomes, and qualitative results were analyzed using content analysis. RESULTS: A total of 31 specialist services for HD were identified. Of the 27 services that completed the online survey, 23 had an active multidisciplinary team of healthcare professionals (HCPs) and were led primarily by a mental health trust (26%) or tertiary referral hospital (26%). Specialist services offered outpatient clinics (96%), outreach in the community (74%), telemedicine (70%), inpatient beds (26%) and satellite clinics (26%). Many services indicated that their capacity (ability to see patients as often as needed with current resources) was difficult, with some services reporting more difficulty at the early or later stages of HD. Key resourcing gaps were identified with access to facilities, HCPs and referral networks. CONCLUSIONS: This research highlights the variation in organization and capacity within individual HD services as well as current resourcing and gaps in access that influence this capacity. Further research should be done to understand the impact of service organization and current resourcing gaps in access on the quality of care provided for PwHD in the UK.

Behavioral adverse effects of antiepileptic drugs in epilepsy.

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.

Impulse-control disorders in gilles de la tourette syndrome.

Impulse-control disorders (ICDs) are more common in clinic populations with Gilles de la Tourette syndrome (GTS) than in the general population. The clinical phenomenology of ICDs differ between men with GTS (who tend to be externally impulsive) and women with GTS (who tend to be internally impulsive). This article reviews the relevant literature to-date on impulsivity in GTS, with special focus on intermittent, explosive disorder, self-injurious behavior, trichotillomania, and impulsive-compulsive sexual behavior. The medical and legal community should be aware of the full spectrum of organically-based behaviors that may predispose patients with GTS to unwanted legal disciplinary action.

The assessment of consciousness during partial seizures.

A wide range of controversial definitions and dynamic components surround the multi-dimensional concept of consciousness, with important reflections on the phenomenological description of ictal states relevant to epileptic seizures. The inadequacies of terminology, the insufficient emphasis on the subjective nature of consciousness, as well as the intrinsic limitations of the simple versus complex dichotomy for partial seizures, are to be considered in view of a modern definition of consciousness. In this paper, we review the difficulties encountered by clinicians in assessing the ictal conscious state in patients with epilepsy, and illustrate how a more sophisticated bi-dimensional model of consciousness can prove a valuable conceptual tool for the clinical assessment of ictal consciousness and the categorization of seizures.

The evolving discipline and services of neuropsychiatry in the United Kingdom.

BACKGROUND: The last few decades have seen a renaissance in the development of neuropsychiatric services on a global scale. METHODS: This paper reviews the existing literature on the changing role of the clinical neuropsychiatrist and discusses the evolving theory and practice of neuropsychiatry in the United Kingdom. RESULTS: The rapidly evolving specialty of neuropsychiatry is currently facing a number of challenges. These include, but are not limited to, uncertainties about the curricular requirements for clinical neuropsychiatrists and the changing roles within the wider scenario of health-care service provision. DISCUSSION: An informed historical perspective on this multifaceted discipline allows key insights into its future development.

Social cognition and quality of life in Huntington's disease.

Individuals with Huntington's disease (HD) and their close others report difficulties with social interaction, and previous studies have shown that the areas of quality of life detrimentally impacted by HD include social and emotional domains. However, despite the finding that people with HD often exhibit difficulties on standard tests of social cognition, the relationship between such impairments and patients' everyday life has remained largely unexplored. We used a range of tasks assessing empathy, emotion recognition and Theory of Mind, to investigate whether patients' performance may predict quality of life within the social and emotional domains, while also accounting for broader cognitive function, behavioural changes, motor symptoms, disease stage and functional capacity. Poorer social functioning was predicted specifically by a reduced tendency to attribute intentionality while viewing social animations, in addition to emotional blunting and apathy, while role limitations due to emotional problems were predicted by personal distress, irritability and aspects of executive function. These findings highlight the potential impact of Theory of Mind impairment on quality of life in HD, and suggest that enhanced assessment of social cognition will offer unique insight into patients' social function and related wellbeing.

Enhancing the health of NHS staff: eTHOS - protocol for a randomised controlled pilot trial of an employee health screening clinic for NHS staff to reduce absenteeism and presenteeism, compared with usual care.

BACKGROUND: Staff absenteeism and presenteeism incur high costs to the NHS and are associated with adverse health outcomes. The main causes are musculoskeletal complaints and mental ill-health, which are potentially modifiable, and cardiovascular risk factors are also common. We will test the feasibility of an RCT to evaluate the clinical and cost-effectiveness of an employee health screening clinic on reducing sickness absenteeism and presenteeism. METHODS: This is an individually randomised controlled pilot trial aiming to recruit 480 participants. All previously unscreened employees from four hospitals within three UK NHS hospital Trusts will be eligible. Those randomised to the intervention arm will be invited to attend an employee health screening clinic consisting of a screening assessment for musculoskeletal (STarT MSK and STarT Back), mental (PHQ-9 and GAD-7) and cardiovascular (NHS Health Check if aged ≥ 40, lifestyle check if < 40 years) health. Screen positives will be given advice and/or referral to recommended services. Those randomised to the control arm will receive usual care. Participants will complete a questionnaire at baseline and 26 weeks; anonymised absenteeism and staff demographics will also be collected from personnel records. The co-primary outcomes are as follows: recruitment, referrals and uptake of recommended services in the intervention arm. Secondary outcomes include the following: results of screening assessments, uptake of individual referrals, reported changes in health behaviours, acceptability and feasibility of intervention, indication of contamination and costs. Outcomes related to the definitive trial include self-reported and employee records of absenteeism with reasons. Process evaluation to inform a future trial includes interviews with participants, intervention delivery staff and service providers receiving referrals. Analyses will include presentation of descriptive statistics, framework analysis for qualitative data and costs and consequences presented for health economics. DISCUSSION: The study will provide data to inform the design of a definitive RCT which aims to find an effective and cost-effective method of reducing absenteeism and presenteeism amongst NHS staff. The feasibility study will test trial procedures, and process outcomes, including the success of strategies for including underserved groups, and provide information and data to help inform the design and sample size for a definitive trial. TRIAL REGISTRATION: ISRCTN reference number 10237475 .