Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Cultural adaptations of third-wave psychotherapies in Gulf Cooperation Council countries: A systematic review.

The effectiveness of third-wave psychotherapies has been demonstrated in a range of mental and physical health conditions in Western cultures. However, little is known about the cultural appropriateness and effectiveness of third-wave psychotherapies for Gulf Cooperation Council (GCC) populations. This review aimed to critically evaluate cultural adaptations to third-wave psychotherapies and explored the effectiveness of these interventions on physical and mental health outcomes in GCC populations. Five bibliographic databases and grey literature were searched; both English and Arabic studies conducted in the GCC were included. Mental and physical health-related outcomes were included. Eleven studies were identified. The overall degree of cultural adaptation ranged from 2 to 5, based on Bernal et al.'s cultural adaptation framework. Language and assessment tools were most frequently adapted. Several studies incorporated goal, method, and context adaptations, whereas metaphor and content were least frequently adapted. None of the studies incorporated person or concept adaptations. Culturally adapted third-wave psychotherapies were associated with improvement in numerous mental health outcomes, including psychological distress, well-being, and psychological traits. No physical health outcomes were identified. Although findings are promising with respect to the effectiveness of third-wave psychotherapies for GCC populations, they should be interpreted with caution due to the small number of studies conducted, cultural adaptation evaluations relying on explicit reporting in studies, and the weak methodological quality of studies. Future rigorous research is needed in the evaluation of culturally adapted third-wave psychotherapies in GCC populations, with more comprehensive reporting of cultural considerations.

Predictors and moderators of treatment outcome in late-life anxiety: A systematic review.

BACKGROUND: The aim of this review was to identify and critically appraise predictors and moderators of outcomes of psychological and pharmacological treatments for late-life anxiety disorders. Their identification may guide the development of personalised treatments for older people with anxiety disorders. METHODS: Web of Science, PsychINFO, CINAHL, Embase, and Pubmed were searched for studies published up to 12 May 2022. Randomised controlled trials and observational studies reporting treatment predictors and moderators were included. Participants with a diagnosis of any anxiety disorder who were aged over 60 years were included. Treatment outcomes included response, remission, and change in anxiety score. RESULTS: Thirteen studies met the inclusion criteria. Twenty-three out of 49 predictors or moderators assessed at post-treatment, and 14 out of 33 predictors or moderators assessed at follow-up were statistically significant. Only one predictor, baseline worry severity at post-treatment, was reported in at least three studies. Most studies were rated as having a low risk of bias in at least three areas and satisfied important quality criteria for predictor and moderator analyses. LIMITATIONS: Samples were predominantly white, female and highly educated, and most studies were secondary analyses. CONCLUSIONS: There is evidence that baseline worry severity appears to predict treatment outcome in late-life anxiety disorders. However, this was only explored in psychological intervention studies and therefore its predictive ability in pharmacotherapy remains unknown. Future research should explore predictors and moderators in a range of anxiety disorders and design methodologically-strong and adequately-powered studies with the primary aim of assessing predictors of treatment outcomes.

Acceptance and Commitment Therapy for people living with motor neuron disease: an uncontrolled feasibility study.

BACKGROUND: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. METHODS: PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. RESULTS: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. CONCLUSIONS: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. TRIAL REGISTRATION: The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

Impact of the covid-19 pandemic on amyotrophic lateral sclerosis care in the UK.

The Covid-19 pandemic has impacted healthcare. Our aim was to identify how amyotrophic lateral sclerosis (ALS) care in the UK has been affected by the pandemic by exploring the experiences of people living with ALS (plwALS), healthcare professionals (HCPs) working with plwALS, and ALS care centers. Three surveys were carried out to explore the experiences of plwALS, HCPs and ALS care centers during the pandemic. Quantitative data were analyzed using descriptive and inferential statistics and triangulated with the qualitative data which were analyzed thematically. Responses from 53 plwALS, 73 HCPs and 23 ALS care centers were analyzed. Five main themes were identified: keeping safe, losses, negative emotions, delivering care and alternative care delivery in a pandemic. PlwALS and HCPs felt that care was sub-optimal as a result of the pandemic. Changes to care included longer waiting times and face-to-face appointments being canceled or replaced by virtual consultations. While benefits of virtual consultations were reported, concerns were raised about incomplete clinical assessments and the disruption of provision of testing and interventions. ALS care has changed as a result of the pandemic. Patients have had a lack of face-to-face contact with HCPs and have experienced delays to investigations and treatments. PlwALS and HCPs were concerned about the impact of this change, but the long-term implications remain unclear. We propose recommendations for HCPs caring for plwALS, that will promote continuity of evidenced based care in the context of a pandemic.

A randomised controlled trial of acceptance and commitment therapy plus usual care compared to usual care alone for improving psychological health in people with motor neuron disease (COMMEND): study protocol.

BACKGROUND: Motor neuron disease (MND) is a rapidly progressive, fatal neurodegenerative disease that predominantly affects motor neurons from the motor cortex to the spinal cord and causes progressive wasting and weakening of bulbar, limb, abdominal and thoracic muscles. Prognosis is poor and median survival is 2-3 years following symptom onset. Psychological distress is relatively common in people living with MND. However, formal psychotherapy is not routinely part of standard care within MND Care Centres/clinics in the UK, and clear evidence-based guidance on improving the psychological health of people living with MND is lacking. Previous research suggests that Acceptance and Commitment Therapy (ACT) may be particularly suitable for people living with MND and may help improve their psychological health. AIMS: To assess the clinical and cost-effectiveness of ACT modified for MND plus usual multidisciplinary care (UC) in comparison to UC alone for improving psychological health in people living with MND. METHODS: The COMMEND trial is a multi-centre, assessor-blind, parallel, two-arm RCT with a 10-month internal pilot phase. 188 individuals aged ≥ 18 years with a diagnosis of definite, laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis, and additionally the progressive muscular atrophy and primary lateral sclerosis variants, will be recruited from approximately 14 UK-based MND Care Centres/clinics and via self-referral. Participants will be randomly allocated to receive up to eight 1:1 sessions of ACT plus UC or UC alone by an online randomisation system. Participants will complete outcome measures at baseline and at 6- and 9-months post-randomisation. The primary outcome will be quality of life at six months. Secondary outcomes will include depression, anxiety, psychological flexibility, health-related quality of life, adverse events, ALS functioning, survival at nine months, satisfaction with therapy, resource use and quality-adjusted life years. Primary analyses will be by intention to treat and data will be analysed using multi-level modelling. DISCUSSION: This trial will provide definitive evidence on the clinical and cost-effectiveness of ACT plus UC in comparison to UC alone for improving psychological health in people living with MND. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN12655391. Registered 17 July 2017, https://www.isrctn.com/ISRCTN12655391 . PROTOCOL VERSION: 3.1 (10/06/2020).

Clinical and cost-effectiveness of a personalised health promotion intervention enabling independence in older people with mild frailty ('HomeHealth') compared to treatment as usual: study protocol for a randomised controlled trial.

BACKGROUND: Frailty is clinically associated with multiple adverse outcomes, including reduced quality of life and functioning, falls, hospitalisations, moves to long-term care and mortality. Health services commonly focus on the frailest, with highest levels of need. However, evidence suggests that frailty is likely to be more reversible in people who are less frail. Evidence is emerging on what interventions may help prevent or reduce frailty, such as resistance exercises and multi-component interventions, but few interventions are based on behaviour change theory. There is little evidence of cost-effectiveness. Previously, we co-designed a new behaviour change health promotion intervention ("HomeHealth") to support people with mild frailty. HomeHealth is delivered by trained voluntary sector support workers over six months who support older people to work on self-identified goals to maintain their independence, such as strength and balance exercises, nutrition, mood and enhancing social engagement. The service was well received in our feasibility randomised controlled trial and showed promising effects upon outcomes. AIM: To test the clinical and cost-effectiveness of the HomeHealth intervention on maintaining independence in older people with mild frailty in comparison to treatment as usual (TAU). METHODS: Single-blind individually randomised controlled trial comparing the HomeHealth intervention to TAU. We will recruit 386 participants from general practices and the community across three English regions. Participants are included if they are community-dwelling, aged 65 + , with mild frailty according to the Clinical Frailty Scale. Participants will be randomised 1:1 to receive HomeHealth or TAU for 6 months. The primary outcome is independence in activities of daily living (modified Barthel Index) at 12 months. Secondary outcomes include instrumental activities of daily living, quality of life, frailty, wellbeing, psychological distress, loneliness, cognition, capability, falls, carer burden, service use, costs and mortality. Outcomes will be analysed using linear mixed models, controlling for baseline Barthel score and site. A health economic analysis and embedded mixed-methods process evaluation will be conducted. DISCUSSION: This trial will provide definitive evidence on the effectiveness and cost-effectiveness of a home-based, individualised intervention to maintain independence in older people with mild frailty in comparison to TAU, that could be implemented at scale if effective. TRIAL REGISTRATION: ISRCTN, ISRCTN54268283 . Registered 06/04/2020.

A Systematic Review and Meta-Analysis Exploring Effects of Third-Wave Psychological Therapies on Hearing-Related Distress, Depression, Anxiety, and Quality of Life in People With Audiological Problems.

PURPOSE: There is growing evidence supporting the use of third-wave psychological therapies, such as mindfulness-based interventions (MBIs) and acceptance and commitment therapy (ACT), for people with long-term or chronic physical health conditions. We conducted a systematic review and meta-analysis to critically evaluate the effectiveness of third-wave interventions for improving hearing-related distress and psychological well-being in people with audiological problems. METHOD: We searched online bibliographic databases and assessed study quality. We conducted random-effects meta-analyses if at least two randomized controlled trials (RCTs) examined hearing-related distress, depression, anxiety, or quality of life in people with audiological problems. Findings of pre-post studies were summarized narratively. RESULTS: We identified 15 studies: six RCTs and nine pre-post studies. The methodological quality of studies was mostly poor to moderate, and sample sizes were typically small (overall n = 750). Most studies focused on tinnitus (n = 12), MBIs (n = 8), and ACT (n = 6). Statistically significant improvements in hearing-related distress were found with ACT and MBIs versus controls and other treatments at post-intervention in people with tinnitus, while improvements in depression and anxiety were only found for ACT versus controls at post-intervention. However, gains were either not maintained or not examined at follow-up, and there was no evidence for improvements in quality of life. CONCLUSIONS: At present, there is insufficient evidence to recommend the use of third-wave interventions for improving hearing-related distress or psychological well-being in people with audiological problems. There is some evidence that ACT and MBIs may be useful in addressing hearing-related distress in people with tinnitus, but only in the short term. However, findings should be interpreted with caution given the small number of studies with generally small sample sizes and mostly poor-to-moderate methodological quality. More high-quality, adequately powered, double-blind RCTs, particularly in audiological problems other than tinnitus, are needed to draw firm conclusions and meaningful clinical recommendations. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19735975.

Internet-delivered guided self-help Acceptance and Commitment Therapy for family carers of people with dementia (iACT4CARERS): a qualitative study of carer views and acceptability.

PURPOSE: To explore carers' views and acceptability of internet-delivered, therapist-guided, self-help Acceptance and Commitment Therapy (ACT) for family carers of people with dementia (iACT4CARERS). METHODS: A qualitative approach with semi-structured interviews was employed with family carers (N = 23) taking part in a feasibility study of iACT4CARERS. The interviews were audio-recorded, transcribed and analysed using thematic analysis. RESULTS: Four overarching themes were identified: 1) usefulness and relevance of the content of the sessions, 2) sense of connectedness, 3) the impact of the intervention on participants and 4) acceptability of the online delivery. Positive carer experiences and intervention acceptability were facilitated by learning helpful ACT skills, perceiving the content of the session as relatable to the carers' needs, feeling connected to other carers and the therapist during the intervention, noticing the benefits of the intervention and the user-friendliness of the online platform. Recommendations for a full-scale trial were identified, such as the inclusion of some "face-to-face" interactions (e.g., via video call) between carers and therapists to facilitate a bidirectional interaction and the provision of an additional aide-memoire to improve the learning experiences. CONCLUSION: Overall, the intervention was acceptable to the family carers. The proposed recommendations should be considered in a full-scale trial.

Paranoid and misidentification subtypes of psychosis in dementia.

This study aimed to review the neurobiological and neuropsychological correlates of paranoid (persecutory delusions) and misidentification (misidentification delusions and/or hallucinations) subtypes of psychosis in dementia, to establish if they represent distinct subphenotypes. Nine studies were eligible, all included patients with Alzheimer's disease. Greater global cognitive deficits and an accelerated global cognitive decline were observed in the misidentification subtype. Neuroimaging studies showed more marked volume loss in multiple regions in patients with the misidentification subtype, including those involved in object recognition and the processing of information on spatial and temporal context. A single study found greater impairment in visual sustained attention and object recognition in the misidentification subtype. The small number of studies and methodological heterogeneity limit interpretation of the findings. Nevertheless, these findings would tentatively suggest that there may be additional or accelerated pathological change in functional networks involved in visuoperceptual processing in the misidentification subtype. This should be further explored in prospective studies and the investigation extended to other forms of dementia, to gain a transdiagnostic perspective.

Internet-delivered guided self-help acceptance and commitment therapy for family carers of people with dementia (iACT4CARERS): a feasibility study.

OBJECTIVES: The feasibility of research into internet-delivered guided self-help Acceptance and Commitment Therapy (ACT) for family carers of people with dementia is not known. This study assessed this in an uncontrolled feasibility study. METHOD: Family carers of people with dementia with mild to moderate anxiety or depression were recruited from primary and secondary healthcare services in the UK. Participants were offered eight, guided, self-help online ACT sessions adapted for the needs of family carers of people with dementia with optional online peer support groups. Pre-defined primary indicators of success included recruitment of 30 eligible carers over 6 months and ≥70% completing at least two online sessions. RESULTS: Thirty-three participants (110% of the target sample) were recruited over 6 months and 30 participants (91%) completed two or more sessions, and thus both indicators of success were met. Further, 70% of participants completed seven or all eight sessions, and 27% of participants were lost to follow-up, but none of the reasons for early withdrawal were related to the intervention. CONCLUSION: This study supports the feasibility, including recruitment and treatment completion. A full-scale trial to assess the clinical- and cost-effectiveness of the intervention including its long-term effects is warranted.

Assessing frailty indicators in the context of psychiatric disorder: A Delphi consensus study.

OBJECTIVES: Substantial construct overlap exists between indicators of frailty and symptoms of some psychiatric disorders. This study aimed to gain consensus of expert academic opinion on the potential impact of psychiatric illness on frailty assessment and how best to conceptualise and measure frailty indicators in the context of psychiatric symptoms. DESIGN: A classic Delphi approach was employed across two studies to achieve consensus: The first-round questionnaire consisted of open-ended questions, analysed through content analysis. The results informed the development of statements for participants to rate their agreement with in subsequent Delphi rounds. Statements with ≥66% agreement were accepted. Delphi Study 1 recruited experts in frailty assessment (n = 13) and Delphi Study 2 recruited experts in frailty and psychiatric disorder (n = 8). Experts were recruited globally. RESULTS: Overall, 40% of Delphi Study 1 statements and 43% of Delphi Study 2 statements were accepted. Primarily, consensus was reached for statements concerning the influence of depression/anxiety on frailty assessment and potential methods of conceptualising and measuring frailty indicators in the context of psychiatric symptoms. Little consensus was reached concerning the ease and importance of differentiating between frailty indicators and psychiatric assessment criteria with substantial overlap. CONCLUSIONS: The Delphi studies provide a novel exploration and consensus of expert academic opinions concerning the assessment of frailty indicators in the context of psychiatric symptoms. The results will inform future research into the adaptation or development of a frailty assessment tool specifically for use in older adult psychiatric populations.

Acceptance and commitment therapy for older people with treatment-resistant generalised anxiety disorder: the FACTOID feasibility study.

BACKGROUND: Generalised anxiety disorder, characterised by excessive anxiety and worry, is the most common anxiety disorder among older people. It is a condition that may persist for decades and is associated with numerous negative outcomes. Front-line treatments include pharmacological and psychological therapy, but many older people do not find these treatments effective. Guidance on managing treatment-resistant generalised anxiety disorder in older people is lacking. OBJECTIVES: To assess whether or not a study to examine the clinical effectiveness and cost-effectiveness of acceptance and commitment therapy for older people with treatment-resistant generalised anxiety disorder is feasible, we developed an intervention based on acceptance and commitment therapy for this population, assessed its acceptability and feasibility in an uncontrolled feasibility study and clarified key study design parameters. DESIGN: Phase 1 involved qualitative interviews to develop and optimise an intervention as well as a survey of service users and clinicians to clarify usual care. Phase 2 involved an uncontrolled feasibility study and qualitative interviews to refine the intervention. SETTING: Participants were recruited from general practices, Improving Access to Psychological Therapies services, Community Mental Health Teams and the community. PARTICIPANTS: Participants were people aged ≥ 65 years with treatment-resistant generalised anxiety disorder. INTERVENTION: Participants received up to 16 one-to-one sessions of acceptance and commitment therapy, adapted for older people with treatment-resistant generalised anxiety disorder, in addition to usual care. Sessions were delivered by therapists based in primary and secondary care services, either in the clinic or at participants' homes. Sessions were weekly for the first 14 sessions and fortnightly thereafter. MAIN OUTCOME MEASURES: The co-primary outcome measures for phase 2 were acceptability (session attendance and satisfaction with therapy) and feasibility (recruitment and retention). Secondary outcome measures included additional measures of acceptability and feasibility and self-reported measures of anxiety, worry, depression and psychological flexibility. Self-reported outcomes were assessed at 0 weeks (baseline) and 20 weeks (follow-up). Health economic outcomes included intervention and resource use costs and health-related quality of life. RESULTS: Fifteen older people with treatment-resistant generalised anxiety disorder participated in phase 1 and 37 participated in phase 2. A high level of feasibility was demonstrated by a recruitment rate of 93% and a retention rate of 81%. A high level of acceptability was found with respect to session attendance (70% of participants attended ≥ 10 sessions) and satisfaction with therapy was adequate (60% of participants scored ≥ 21 out of 30 points on the Satisfaction with Therapy subscale of the Satisfaction with Therapy and Therapist Scale-Revised, although 80% of participants had not finished receiving therapy at the time of rating). Secondary outcome measures and qualitative data further supported the feasibility and acceptability of the intervention. Health economic data supported the feasibility of examining cost-effectiveness in a future randomised controlled trial. Although the study was not powered to examine clinical effectiveness, there was indicative evidence of improvements in scores for anxiety, depression and psychological flexibility. LIMITATIONS: Non-specific therapeutic factors were not controlled for, and recruitment in phase 2 was limited to London. CONCLUSIONS: There was evidence of high levels of feasibility and acceptability and indicative evidence of improvements in symptoms of anxiety, depression and psychological flexibility. The results of this study suggest that a larger-scale randomised controlled trial would be feasible to conduct and is warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12268776. 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. 25, No. 54. See the NIHR Journals Library website for further project information.

Generalised anxiety disorder, characterised by a tendency to worry, is the most common anxiety disorder among older people. Those with this condition may experience other difficulties, including increased distress and disability, poorer coping and reduced quality of life. Medication and talking therapy are usually offered as forms of treatment, but many do not find them helpful. Guidance is lacking on how to help older people manage generalised anxiety disorder when it does not respond to such treatments. We developed a 16-session intervention specifically for older people with treatment-resistant generalised anxiety disorder. This was based on acceptance and commitment therapy: a form of talking therapy that helps people to learn how to best live with distressing experiences while still doing things that really matter to them. It may be particularly suited to older people because many older people experience difficulties with chronic ill health and other problems that cannot be easily improved with conventional talking therapies. We developed our intervention by asking 15 older people about their experiences of treatment-resistant generalised anxiety disorder and treatments they have received for it, as well as what might help or hinder their engagement with talking therapy. We combined their guidance with advice from 36 clinicians to ensure that our intervention was tailored to the needs of this population. We then asked the same 15 older people, our Service User Advisory Group and academic clinicians about how we could optimise our intervention. We also conducted an online survey of service users and clinicians to clarify what care older people with generalised anxiety disorder are typically offered and receive. We tested how acceptable our intervention was to 37 older people with treatment-resistant generalised anxiety disorder, and how feasible it was to deliver within the NHS. We found evidence that it was acceptable to participants, that it could be delivered within the NHS and that its value for money could be tested in a larger study. We also found evidence suggestive of improvements in anxiety, depression and coping. There were some limitations of our study. However, overall, our results suggest that we should conduct a larger study to find out whether or not our intervention is helpful for older people with treatment-resistant generalised anxiety disorder.

Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system.

The tripeptide glutathione (GSH) is instrumental to antioxidant protection and xenobiotic metabolism, and the ratio of its reduced and oxidized forms (GSH/GSSG) indicates the cellular redox environment and maintains key aspects of cellular signaling. Disruptions in GSH levels and GSH/GSSG have long been tied to various chronic diseases, and many studies have examined whether variant alleles in genes responsible for GSH synthesis and metabolism are associated with increased disease risk. However, past studies have been limited to established, canonical GSH genes, though emerging evidence suggests that novel loci and genes influence the GSH redox system in specific tissues. The present study marks the most comprehensive effort to date to directly identify genetic loci associated with the GSH redox system. We employed the Diversity Outbred (DO) mouse population, a model of human genetics, and measured GSH and the essential redox cofactor NADPH in liver, the organ with the highest levels of GSH in the body. Under normal physiological conditions, we observed substantial variation in hepatic GSH and NADPH levels and their redox balances, and discovered a novel, significant quantitative trait locus (QTL) on murine chromosome 16 underlying GSH/GSSG; bioinformatics analyses revealed Socs1 to be the most likely candidate gene. We also discovered novel QTL associated with hepatic NADP+ levels and NADP+/NADPH, as well as unique candidate genes behind each trait. Overall, these findings transform our understanding of the GSH redox system, revealing genetic loci that govern it and proposing new candidate genes to investigate in future mechanistic endeavors.

Genetic mapping of renal glutathione suggests a novel regulatory locus on the murine X chromosome and overlap with hepatic glutathione regulation.

Glutathione (GSH) is a critical cellular antioxidant that protects against byproducts of aerobic metabolism and other reactive electrophiles to prevent oxidative stress and cell death. Proper maintenance of its reduced form, GSH, in excess of its oxidized form, GSSG, prevents oxidative stress in the kidney and protects against the development of chronic kidney disease. Evidence has indicated that renal concentrations of GSH and GSSG, as well as their ratio GSH/GSSG, are moderately heritable, and past research has identified polymorphisms and candidate genes associated with these phenotypes in mice. Yet those discoveries were made with in silico mapping methods that are prone to false positives and power limitations, so the true loci and candidate genes that control renal glutathione remain unknown. The present study utilized high-resolution gene mapping with the Diversity Outbred mouse stock to identify causal loci underlying variation in renal GSH levels and redox status. Mapping output identified a suggestive locus associated with renal GSH on murine chromosome X at 51.602 Mbp, and bioinformatic analyses identified apoptosis-inducing factor mitochondria-associated 1 (Aifm1) as the most plausible candidate. Then, mapping outputs were compiled and compared against the genetic architecture of the hepatic GSH system, and we discovered a locus on murine chromosome 14 that overlaps between hepatic GSH concentrations and renal GSH redox potential. Overall, the results support our previously proposed model that the GSH redox system is regulated by both global and tissue-specific loci, vastly improving our understanding of GSH and its regulation and proposing new candidate genes for future mechanistic studies.

Acceptance and commitment therapy for late-life treatment-resistant generalised anxiety disorder: a feasibility study.

BACKGROUND: Generalised anxiety disorder (GAD) is the most common anxiety disorder in older people. First-line management includes pharmacological and psychological therapies, but many do not find these effective or acceptable. Little is known about how to manage treatment-resistant generalised anxiety disorder (TR-GAD) in older people. OBJECTIVES: To examine the acceptability, feasibility and preliminary estimates of the effectiveness of acceptance and commitment therapy (ACT) for older people with TR-GAD. PARTICIPANTS: People aged ≥65 years with TR-GAD (defined as not responding to GAD treatment, tolerate it or refused treatment) recruited from primary and secondary care services and the community. INTERVENTION: Participants received up to 16 one-to-one sessions of ACT, developed specifically for older people with TR-GAD, in addition to usual care. MEASUREMENTS: Co-primary outcomes were feasibility (defined as recruitment of ≥32 participants and retention of ≥60% at follow-up) and acceptability (defined as participants attending ≥10 sessions and scoring ≥21/30 on the satisfaction with therapy subscale). Secondary outcomes included measures of anxiety, worry, depression and psychological flexibility (assessed at 0 and 20 weeks). RESULTS: Thirty-seven participants were recruited, 30 (81%) were retained and 26 (70%) attended ≥10 sessions. A total of 18/30 (60%) participants scored ≥21/30 on the satisfaction with therapy subscale. There was preliminary evidence suggesting that ACT may improve anxiety, depression and psychological flexibility. CONCLUSIONS: There was evidence of good feasibility and acceptability, although satisfaction with therapy scores suggested that further refinement of the intervention may be necessary. Results indicate that a larger-scale randomised controlled trial of ACT for TR-GAD is feasible and warranted.

Adapting and Optimizing Problem Adaptation Therapy (PATH) for People With Mild-Moderate Dementia and Depression.

OBJECTIVE: To adapt and optimize problem adaptation therapy for depression in dementia by grounding it in the lives of people with dementia, caregivers and clinicians. METHODS: A person-centered qualitative approach was taken to elicit the unique cognitive, psychological and social needs of people with dementia relevant to the adaptation of the intervention. A two-stage design was used: the first involved interviews and focus groups to identify priorities and concerns surrounding depression in dementia, the second trialling of the adapted intervention. PARTICIPANTS: Ten people with dementia and nine caregivers participated in individual interviews, 35 healthcare practitioners and clinical academics with experience of working with dementia participated in focus groups. RESULTS: The findings highlight the importance of addressing key themes that typified the experience of depression among people with dementia including: a profound sense of isolation and role loss, the feeling of being both a burden and poorly understood, polarized thinking, interpersonal tensions, diverging views among carers and people with dementia about their capabilities, and changeability in cognitive ability and mood. These themes were used to inform adaptation of the intervention manual, ensuring that its content and delivery addressed the concerns of both people with depression and dementia and those who support them. CONCLUSION: Implications for PATH included a focus on facilitating open communication, supporting the continuation of valued roles, and improving confidence.

The effects of L-Arginine supplementation on growth performance and intestinal health of broiler chickens challenged with Eimeria spp.

This study evaluated the effects of varying levels of L-arginine (Arg) on performance and intestinal health of broilers challenged with Eimeria. Cobb 500 male chicks (n = 720) were randomly distributed in a 5 × 2 factorial arrangement (6 replicates/12 birds). The main factors were Arg levels (1.04, 1.14, 1.24, 1.34, 1.44%) and challenge or non-challenge with Eimeria. At day 12, in the challenge group, each bird received orally 12,500 Eimeria maxima, 12,500 Eimeria tenella, and 62,500 Eimeria acervulina sporulated oocysts. At 5 d postinfection (dpi), intestinal permeability was measured. At 6 and 14 dpi, performance, intestinal histomorphology, nutrient digestibility, tight junction protein (TJP) gene expression, and antioxidant markers were evaluated. Few interactions were found, and when significant, the supplementation of Arg did not counteract the negative effects of Eimeria challenge. Challenge, regardless of Arg level, increased intestinal permeability, although the expression of Claudin-1, a TJP, was upregulated. At 6 dpi, the antioxidant system was impaired by the challenge. Moreover, growth performance, intestinal histomorphology, and nutrient digestibility were negatively affected by challenge at 6 and 14 dpi. Regardless of challenge, from 0 to 14 dpi, birds fed 1.44% showed higher weight gain than 1.04% of Arg, and birds fed 1.34% showed lower feed conversion than 1.04% of Arg. At 5 dpi, intestinal permeability was improved in birds fed 1.34% than 1.04% of Arg. Moreover, 1.34% of Arg upregulated the expression of the TJP Zonula occludens-1 (ZO-1) as compared with 1.24 and 1.44% of Arg at 6 dpi. At 14 dpi, 1.44% of Arg upregulated the expression of ZO-1 and ZO-2 compared with 1.24 and 1.34% of Arg. The nutrient digestibility was quadratically influenced by Arg, whereas the antioxidant markers were unaffected. Thus, the challenge with Eimeria had a negative impact on growth and intestinal health. The dietary supplementation of levels ranging from 1.24 to 1.44% of Arg showed promising results, improving overall growth, intestinal integrity, and morphology in broilers subjected or not to Eimeria challenge.

Supporting frail older people with depression and anxiety: a qualitative study.

OBJECTIVES: Depression and anxiety are common in later life, particularly when people are frail. This leads to reduced quality of life, faster decline in physical health and increased health/social care use. Available treatments are commonly not tailored to people with frailty. We explored frail older peoples' experiences of depression and/or anxiety and how services could be adapted to their needs. METHODS: Semi-structured interviews with 28 older people in the UK purposively sampled for practice location and severity of frailty and anxiety/depression. We asked about symptoms, interactions with physical health, help-seeking, treatments and what might help in future. We audio-recorded and transcribed interviews, using thematic analysis to inductively derive themes. RESULTS: Frail older people had low expectations of their wellbeing at this point in life due to multiple physical health issues and so anxiety and mild depressive symptoms were normalised. There was a particular reluctance and uncertainty regarding help-seeking for anxiety. Treatments were considered appropriate where they aligned with coping skills developed over their lifetime, and facilitated independence and problem-solving skills. Most older people felt their knowledge of mental health was limited and relied upon information about and endorsement of therapies from an expert. This was usually their GP, but access was often problematic. Online methods of accessing information and therapies were not popular. CONCLUSION: Mental health support for frail older people needs to address late-life anxieties as well as depression, account for physical health issues, align with older people's need for independence and facilitate coping skills.