A Qualitative Review of Patient Feedback for the OPAT (Outpatient Antimicrobial Therapy) Service in Bristol.

Outpatient parenteral antimicrobial therapy (OPAT) aims to deliver intravenous antimicrobials to medically stable patients with complex infections outside of a hospital setting. There is good evidence to demonstrate the safety and efficacy of OPAT in the literature. Anecdotally, the feedback from patients has been positive, but only a few studies evaluate this topic in detail. The aim of this qualitative study was to examine patients' experiences with and feedback on the OPAT service in Bristol, United Kingdom, which was established in 2021. A total of 92 patient feedback surveys were reviewed retrospectively, and thematic analysis was undertaken. Feedback from OPAT patients in our centre was overwhelmingly positive. The key themes identified were benefits to the patients, their friends, and family, and positive feedback about OPAT staff. The mean overall satisfaction score for OPAT was 9.6 out of 10. Areas to improve included communication between the OPAT and parent teams, improving OPAT capacity, and expansion of the service.

Genetic influences on epilepsy outcomes: A whole-exome sequencing and health care records data linkage study.

OBJECTIVE: This study was undertaken to develop a novel pathway linking genetic data with routinely collected data for people with epilepsy, and to analyze the influence of rare, deleterious genetic variants on epilepsy outcomes. METHODS: We linked whole-exome sequencing (WES) data with routinely collected primary and secondary care data and natural language processing (NLP)-derived seizure frequency information for people with epilepsy within the Secure Anonymised Information Linkage Databank. The study participants were adults who had consented to participate in the Swansea Neurology Biobank, Wales, between 2016 and 2018. DNA sequencing was carried out as part of the Epi25 collaboration. For each individual, we calculated the total number and cumulative burden of rare and predicted deleterious genetic variants and the total of rare and deleterious variants in epilepsy and drug metabolism genes. We compared these measures with the following outcomes: (1) no unscheduled hospital admissions versus unscheduled admissions for epilepsy, (2) antiseizure medication (ASM) monotherapy versus polytherapy, and (3) at least 1 year of seizure freedom versus <1 year of seizure freedom. RESULTS: We linked genetic data for 107 individuals with epilepsy (52% female) to electronic health records. Twenty-six percent had unscheduled hospital admissions, and 70% were prescribed ASM polytherapy. Seizure frequency information was linked for 100 individuals, and 10 were seizure-free. There was no significant difference between the outcome groups in terms of the exome-wide and gene-based burden of rare and deleterious genetic variants. SIGNIFICANCE: We successfully uploaded, annotated, and linked genetic sequence data and NLP-derived seizure frequency data to anonymized health care records in this proof-of-concept study. We did not detect a genetic influence on real-world epilepsy outcomes, but our study was limited by a small sample size. Future studies will require larger (WES) data to establish genetic variant contribution to epilepsy outcomes.

Protocol for a realist and social return on investment evaluation of the use of patient-reported outcomes in four value-based healthcare programmes.

INTRODUCTION: There is growing recognition that in order to remain sustainable, the UK's National Health Service must deliver the best patient outcomes within available resources. This focus on outcomes relative to cost is the basis of value-based healthcare (VBHC) and has led to interest in the recording of patient-reported outcome measures (PROMs) to measure patient perspectives on the impact of a health condition on their lives. Every health board in Wales is now required to collect PROMS as part of routine care. We will evaluate the VBHC programme implemented in a lead health board. The study aim is to understand what works about PROMs collection, for whom, in what contexts and why in a VBHC context. In addition, we will assess the social value of integrating PROMs collection into routine care. METHODS AND ANALYSIS: A three-stage mixed-methods study comprising a realist evaluation integrated with social return on investment (SROI) analysis across four conditions; Parkinson's disease, epilepsy, heart failure and cataract surgery. Workstream 1: Development of logic models, informed by a scoping review, documentary analysis, patient and public involvement (PPI), staff and key stakeholder engagement. Workstream 2: Realist evaluation building on multiple data sources from stages 1 to 3 to test and refine the programme theories that arise from the logic model development. Workstream 3: SROI analysis using interview data with patients, staff and carers, stakeholder and PPI engagement, anonymised routinely collected data, and questionnaires to populate a model that will explore the social value generated by the implementation of PROMs. Findings across stages will be validated with key stakeholders. ETHICS AND DISSEMINATION: The study is approved by Wales Research Ethics Committee #5 (22/WA/0044). Outcomes will be shared with key stakeholders, published in peer-reviewed journals and presented at national and international conferences.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) licence, which permits others to distribute, remix, adapt, build on this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.

'It was just - everything was normal': outcomes for people living with dementia, their unpaid carers, and paid carers in a Shared Lives day support service.

OBJECTIVES: Short breaks support the wellbeing of people living with dementia (PLWD) and their unpaid carers. However, little is known about the benefits of community-based short breaks. The objective of this study was to conduct interviews with stakeholders of a Shared Lives (SL) day support service to explore mechanisms and outcomes for the service. The aim of the study was to refine a logic model for a SL day support service for PLWD, their unpaid carers, and paid carers. This logic model shall form the basis for a Social Return on Investment evaluation to identify the social value contributed by the service. METHODS: Thirteen interviews were conducted with service stakeholders including PLWD, unpaid carers and paid carers. Framework analysis assisted in the synthesis of the findings into a logic model. RESULTS: The logic model refined through the interviews, detailed service mechanisms (inputs, activities, outputs) and outcomes. An overarching theme from the interviews concerned the importance of triadic caring relationships, which conferred benefits for those involved in the service. CONCLUSION: SL day support fosters triadic caring relationships, and interview data suggests that these relationships are associated with meaningful outcomes for PLWD, their unpaid carers, and paid carers. We highlight the implications for policy, practice, and future research.

Effects of an e-health intervention 'iSupport' for reducing distress of dementia carers: protocol for a randomised controlled trial and feasibility study.

INTRODUCTION: In the UK, National Health Service (NHS) guidelines recommend that informal carers of people living with dementia should be offered training to help them develop care skills and manage their own physical and mental health. The WHO recommends access to affordable, proven, well-designed, online technologies for education, skills training and support for dementia carers. In response to these recommendations, this multisite randomised controlled trial (RCT) is the first study in the UK to evaluate the clinical and cost-effectiveness of an online support programme developed by the WHO called 'iSupport for dementia carers'. METHODS AND ANALYSIS: 350 informal carers (age 18+ years) living in Britain who self-identify as experiencing stress and depression will be recruited. They will be randomised to receive 'iSupport', or standardised information about caring for someone with dementia (control-comparison). Data will be collected via videoconferencing (eg, Zoom) or telephone interview at baseline, 3 months and 6 months. Intention-to-treat analysis will ascertain effectiveness in the primary outcomes (distress and depression) and combined cost, and quality-adjusted life-year data will be used to assess cost-effectiveness compared with usual care from a public sector and wider societal perspective. A mixed-methods process evaluation with a subgroup of carers in the intervention (~N=50) will explore the barriers and facilitators to implementing 'iSupport'. A non-randomised feasibility study will adapt 'iSupport' for young carers (n=38 participants, age 11-17 years). ETHICS AND DISSEMINATION: The research plan was scrutinised by National Institute for Health Research reviewers ahead of funding being awarded. Ethical approval was granted by Bangor University's School of Health and Medical Sciences Academic Ethics Committee, reference number 2021-16915. Dissemination plans include delivering events for stakeholders, social media, a project website, developing policy briefings, presenting at conferences and producing articles for open access publications. TRIAL REGISTRATION NUMBER: ISRCTN17420703.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

Markup: A Web-Based Annotation Tool Powered by Active Learning.

Across various domains, such as health and social care, law, news, and social media, there are increasing quantities of unstructured texts being produced. These potential data sources often contain rich information that could be used for domain-specific and research purposes. However, the unstructured nature of free-text data poses a significant challenge for its utilisation due to the necessity of substantial manual intervention from domain-experts to label embedded information. Annotation tools can assist with this process by providing functionality that enables the accurate capture and transformation of unstructured texts into structured annotations, which can be used individually, or as part of larger Natural Language Processing (NLP) pipelines. We present Markup (https://www.getmarkup.com/) an open-source, web-based annotation tool that is undergoing continued development for use across all domains. Markup incorporates NLP and Active Learning (AL) technologies to enable rapid and accurate annotation using custom user configurations, predictive annotation suggestions, and automated mapping suggestions to both domain-specific ontologies, such as the Unified Medical Language System (UMLS), and custom, user-defined ontologies. We demonstrate a real-world use case of how Markup has been used in a healthcare setting to annotate structured information from unstructured clinic letters, where captured annotations were used to build and test NLP applications.

Mechanism of Staphylococcus aureus peptidoglycan O-acetyltransferase A as an O-acyltransferase.

The O-acetylation of exopolysaccharides, including the essential bacterial cell wall polymer peptidoglycan, confers resistance to their lysis by exogenous hydrolases. Like the enzymes catalyzing the O-acetylation of exopolysaccharides in the Golgi of animals and fungi, peptidoglycan O-acetyltransferase A (OatA) is predicted to be an integral membrane protein comprised of a membrane-spanning acyltransferase-3 (AT-3) domain and an extracytoplasmic domain; for OatA, these domains are located in the N- and C-terminal regions of the enzyme, respectively. The recombinant C-terminal domain (OatAC) has been characterized as an SGNH acetyltransferase, but nothing was known about the function of the N-terminal AT-3 domain (OatAN) or its homologs associated with other acyltransferases. We report herein the experimental determination of the topology of Staphylococcus aureus OatAN, which differs markedly from that predicted in silico. We present the biochemical characterization of OatAN as part of recombinant OatA and demonstrate that acetyl-CoA serves as the substrate for OatAN Using in situ and in vitro assays, we characterized 35 engineered OatA variants which identified a catalytic triad of Tyr-His-Glu residues. We trapped an acetyl group from acetyl-CoA on the catalytic Tyr residue that is located on an extracytoplasmic loop of OatAN Further enzymatic characterization revealed that O-acetyl-Tyr represents the substrate for OatAC We propose a model for OatA action involving the translocation of acetyl groups from acetyl-CoA across the cytoplasmic membrane by OatAN and their subsequent intramolecular transfer to OatAC for the O-acetylation of peptidoglycan via the concerted action of catalytic Tyr and Ser residues.

Social Return on Investment Analysis of the Health Precinct Community Hub for Chronic Conditions.

Local governments and Health Boards are seeking to develop integrated services to promote well-being. Social participation and physical activity are key in promoting well-being for older people. The Health Precinct is a community hub in North Wales that people with chronic conditions are referred to through social prescribing. To improve community-based assets there is a need to understand and evidence the social value they generate. Data collection took place October 2017-September 2019. Social Return on Investment (SROI) analysis was used to evaluate the Health Precinct. Stakeholders included participants aged 55+, participants' families, staff, the National Health Service and local government. Participants' health and well-being data were collected upon referral and four months later using the EQ-5D-5L, Campaign to End Loneliness Scale and the Rosenberg Self-Esteem Scale. Family members completed questionnaires at four months. Baseline data were collected for 159 participants. Follow-up data were available for 66 participants and 38 family members. The value of inputs was £55,389 (attendance fees, staffing, equipment, overheads), and the value of resulting benefits was £281,010; leading to a base case SROI ratio of £5.07 of social value generated for every £1 invested. Sensitivity analysis yielded estimates of between 2.60:1 and 5.16:1.

Structural basis for the O-acetyltransferase function of the extracytoplasmic domain of OatA from Staphylococcus aureus.

Many bacteria possess enzymes that modify the essential cell-wall polymer peptidoglycan by O-acetylation. This modification occurs in numerous Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, a common cause of human infections. O-Acetylation of peptidoglycan protects bacteria from the lytic activity of lysozyme, a mammalian innate immune enzyme, and as such is important for bacterial virulence. The O-acetylating enzyme in Gram-positive bacteria, O-acetyltransferase A (OatA), is a two-domain protein consisting of an N-terminal integral membrane domain and a C-terminal extracytoplasmic domain. Here, we present the X-ray crystal structure at 1.71 Å resolution and the biochemical characterization of the C-terminal domain of S. aureus OatA. The structure revealed that this OatA domain adopts an SGNH-hydrolase fold and possesses a canonical catalytic triad. Site-specific replacement of active-site amino acids revealed the presence of a water-coordinating aspartate residue that limits esterase activity. This residue, although conserved in staphyloccocal OatA and most other homologs, is not present in the previously characterized streptococcal OatA. These results provide insights into the mechanism of acetyl transfer in the SGNH/GDSL hydrolase family and highlight important evolutionary differences between homologous OatA enzymes. Furthermore, this study enhances our understanding of PG O-acetyltransferases, which could guide the development of novel antibacterial drugs to combat infections with multidrug-resistant bacterial pathogens.

Dementia and Imagination: A Social Return on Investment Analysis Framework for Art Activities for People Living With Dementia.

BACKGROUND AND OBJECTIVES: Arts activities may benefit people living with dementia. Social return on investment (SROI) analysis, a form of cost-benefit analysis, has the potential to capture the value of arts interventions, but few rigorous SROI analyses exist. This article presents a framework for an SROI analysis. RESEARCH DESIGN AND METHODS: One hundred twenty-five people with mild to severe dementia and 146 caregivers were recruited to the Dementia and Imagination study across residential care homes, a hospital and community venues in England and Wales for a 12-week visual arts program. Quantitative and qualitative data on quality of life, support, and program perceptions were obtained through interviews. SROI was undertaken to explore the wider social value of the arts activities. RESULTS: An input of £189,498 ($279,320/€257,338) to deliver the groups created a social value of £980,717 ($1,445,577/€1,331,814). This equates to a base case scenario of £/$/€5.18 of social value generated for every £/$/€1 invested. Sensitivity analysis produced a range from £/$/€3.20 to £/$/€6.62 per £/$/€1, depending on assumptions about benefit materialization; financial value of participants' time; and length of sustained benefit. DISCUSSION: To our knowledge, this is the first study applying SROI to an arts intervention for people with dementia. Arts-based activities appear to provide a positive SROI under a range of assumptions. IMPLICATIONS: Decision makers are increasingly seeking wider forms of economic evidence surrounding the costs and benefits of activities. This analysis is useful for service providers at all levels, from local government to care homes.

Rapid Detection and Quantification of Novel Psychoactive Substances (NPS) Using Raman Spectroscopy and Surface-Enhanced Raman Scattering.

With more than a million seizures of illegal drugs reported annually across Europe, the variety of psychoactive compounds available is vast and ever-growing. The multitude of risks associated with these compounds are well-known and can be life threatening. Hence the need for the development of new analytical techniques and approaches that allow for the rapid, sensitive, and specific quantitative detection and discrimination of such illicit materials, ultimately with portability for field testing, is of paramount importance. The aim of this study was to demonstrate the application of Raman spectroscopy and surface-enhanced Raman scattering (SERS) combined with chemometrics approaches, as rapid and portable techniques for the quantitative detection and discrimination of a wide range of novel psychoactive substances (methcathinone and aminoindane derivatives), both in powder form and in solution. The Raman spectra of the psychoactive compounds provided clear separation and classification of the compounds based on their core chemical structures; viz. methcathinones, aminoindanes, diphenidines, and synthetic cannabinoids. The SERS results also displayed similar clustering patterns, with improved limits of detections down to ~2 mM (0.41 g L-1). As mephedrone is currently very popular for recreational use we performed multiplexed quantitative detection of mephedrone (4-methylmethcathinone), and its two major metabolites (nor-mephedrone and 4-methylephedrine), as tertiary mixtures in water and healthy human urine. These findings readily illustrate the potential application of SERS for simultaneous detection of multiple NPS as mixtures without the need for lengthy prior chromatographic separation or enrichment methods.

Development of a High Throughput Screen for the Identification of Inhibitors of Peptidoglycan O-Acetyltransferases, New Potential Antibacterial Targets.

The O-acetylation of peptidoglycan occurs in many Gram-negative and most Gram-positive pathogens and this modification to the essential wall polymer controls the lytic activity of the autolysins, particularly the lytic transglycosylases, and inhibits that of the lysozymes of innate immunity systems. As such, the peptidoglycan O-acetyltransferases PatA/B and OatA are recognized as virulence factors. In this study, we present the high throughput screening of small compound libraries to identify the first known inhibitors of these enzymes. The fluorometric screening assay developed involved monitoring the respective O-acetyltransferases as esterases using 4-methylumbelliferylacetate as substrate. Pilot screens of 3921 compounds validated the usefulness of the HTS protocol. A number of potential inhibitors were identified amongst a total of 145,000 low molecular-weight compounds, some of which were common to both enzymes, while others were unique to each. After eliminating a number of false positives in secondary screens, dose response curves confirmed the apparent specificity of a benzothiazolyl-pyrazolo-pyridine as an inhibitor of Neisseria gonorrhoeae PatB, and several coumarin-based compounds as inhibitors of both this PatB and OatA from Staphylococcus aureus. The benzothiazolyl-pyrazolo-pyridine was determined to be a non-competitive inhibitor of PatB with a Ki of 126 µM. At 177 µg/mL and close to its solubility limit, this compound caused a 90% reduction in growth of N. gonorrhoeae, while growth of Escherichia coli, a bacterium that lacks PatB and, hence, does not produce O-acetylated peptidoglycan, was unaffected. These data provide preliminary proof of concept that peptidoglycan O-acetyltransferases would serve as useful antibacterial targets.

Effects of defined gut microbial ecosystem components on virulence determinants of Clostridioides difficile.

Many cases of Clostridioides difficile infection (CDI) are poorly responsive to standard antibiotic treatment strategies, and often patients suffer from recurrent infections characterized by severe diarrhea. Our group previously reported the successful cure of two patients with recurrent CDI using a standardized stool-derived microbial ecosystem therapeutic (MET-1). Using an in vitro model of the distal gut to support bacterial communities, we characterized the metabolite profiles of two defined microbial ecosystems derived from healthy donor stool (DEC58, and a subset community, MET-1), as well as an ecosystem representative of a dysbiotic state (ciprofloxacin-treated DEC58). The growth and virulence determinants of two C. difficile strains were then assessed in response to components derived from the ecosystems. CD186 (ribotype 027) and CD973 (ribotype 078) growth was decreased upon treatment with DEC58 metabolites compared to ciprofloxacin-treated DEC58 metabolites. Furthermore, CD186 TcdA and TcdB secretion was increased following treatment with ciprofloxacin-treated DEC58 spent medium compared to DEC58 spent medium alone. The net metabolic output of C. difficile was also modulated in response to spent media from defined microbial ecosystems, although several metabolite levels were divergent across the two strains examined. Further investigation of these antagonistic properties will guide the development of microbiota-based therapeutics for CDI.

A randomised controlled trial of an exercise intervention promoting activity, independence and stability in older adults with mild cognitive impairment and early dementia (PrAISED) - A Protocol.

BACKGROUND: People with dementia progressively lose cognitive and functional abilities. Interventions promoting exercise and activity may slow decline. We developed a novel intervention to promote activity and independence and prevent falls in people with mild cognitive impairment (MCI) or early dementia. We successfully undertook a feasibility randomised controlled trial (RCT) to refine the intervention and research delivery. We are now delivering a multi-centred RCT to evaluate its clinical and cost-effectiveness. METHODS: We will recruit 368 people with MCI or early dementia (Montreal Cognitive Assessment score 13-25) and a family member or carer from memory assessment clinics, other community health or social care venues or an online register (the National Institute for Health Research Join Dementia Research). Participants will be randomised to an individually tailored activity and exercise programme delivered using motivational theory to promote adherence and continued engagement, with up to 50 supervised sessions over one year, or a brief falls prevention assessment (control). The intervention will be delivered in participants' homes by trained physiotherapists, occupational therapists and therapy assistants. We will measure disabilities in activities of daily living, physical activity, balance, cognition, mood, quality of life, falls, carer strain and healthcare and social care use. We will use a mixed methods approach to conduct a process evaluation to assess staff training and delivery of the intervention, and to identify individual- and context-level mechanisms affecting intervention engagement and activity maintenance. We will undertake a health economic evaluation to determine if the intervention is cost-effective. DISCUSSION: We describe the protocol for a multi-centre RCT that will evaluate the clinical and cost-effectiveness of a therapy programme designed to promote activity and independence amongst people living with dementia. TRIAL REGISTRATION: ISRCTN, ISRCTN15320670. Registered on 4 September 2018.

Facilitating Implementation of Research Evidence (FIRE): an international cluster randomised controlled trial to evaluate two models of facilitation informed by the Promoting Action on Research Implementation in Health Services (PARIHS) framework.

BACKGROUND: Health care practice needs to be underpinned by high quality research evidence, so that the best possible care can be delivered. However, evidence from research is not always utilised in practice. This study used the Promoting Action on Research Implementation in Health Services (PARIHS) framework as its theoretical underpinning to test whether two different approaches to facilitating implementation could affect the use of research evidence in practice. METHODS: A pragmatic clustered randomised controlled trial with embedded process and economic evaluation was used. The study took place in four European countries across 24 long-term nursing care sites, for people aged 60 years or more with documented urinary incontinence. In each country, sites were randomly allocated to standard dissemination, or one of two different types of facilitation. The primary outcome was the documented percentage compliance with the continence recommendations, assessed at baseline, then at 6, 12, 18, and 24 months after the intervention. Data were analysed using STATA15, multi-level mixed-effects linear regression models were fitted to scores for compliance with the continence recommendations, adjusting for clustering. RESULTS: Quantitative data were obtained from reviews of 2313 records. There were no significant differences in the primary outcome (documented compliance with continence recommendations) between study arms and all study arms improved over time. CONCLUSIONS: This was the first cross European randomised controlled trial with embedded process evaluation that sought to test different methods of facilitation. There were no statistically significant differences in compliance with continence recommendations between the groups. It was not possible to identify whether different types and "doses" of facilitation were influential within very diverse contextual conditions. The process evaluation (Rycroft-Malone et al., Implementation Science. doi: 10.1186/s13012-018-0811-0) revealed the models of facilitation used were limited in their ability to overcome the influence of contextual factors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11598502 . Date 4/2/10. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 223646.

Mechanistic Pathways for Peptidoglycan O-Acetylation and De-O-Acetylation.

The post-synthetic O-acetylation of the essential component of bacterial cell walls, peptidoglycan (PG), is performed by many pathogenic bacteria to help them evade the lytic action of innate immunity responses. Occurring at the C-6 hydroxyl of N-acetylmuramoyl residues, this modification to the glycan backbone of PG sterically blocks the activity of lysozymes. As such, the enzyme responsible for this modification in Gram-positive bacteria is recognized as a virulence factor. With Gram-negative bacteria, the O-acetylation of PG provides a means of control of their autolysins at the substrate level. In this review, we discuss the pathways for PG O-acetylation and de-O-acetylation and the structure and function relationship of the O-acetyltransferases and O-acetylesterases that catalyze these reactions. The current understanding of their mechanisms of action is presented and the prospects of targeting these systems for the development of novel therapeutics are explored.

A development study and randomised feasibility trial of a tailored intervention to improve activity and reduce falls in older adults with mild cognitive impairment and mild dementia.

BACKGROUND: People with dementia progressively lose abilities and are prone to falling. Exercise- and activity-based interventions hold the prospect of increasing abilities, reducing falls, and slowing decline in cognition. Current falls prevention approaches are poorly suited to people with dementia, however, and are of uncertain effectiveness. We used multiple sources, and a co-production approach, to develop a new intervention, which we will evaluate in a feasibility randomised controlled trial (RCT), with embedded adherence, process and economic analyses. METHODS: We will recruit people with mild cognitive impairment or mild dementia from memory assessment clinics, and a family member or carer. We will randomise participants between a therapy programme with high intensity supervision over 12 months, a therapy programme with moderate intensity supervision over 3 months, and brief falls assessment and advice as a control intervention. The therapy programmes will be delivered at home by mental health specialist therapists and therapy assistants. We will measure activities of daily living, falls and a battery of intermediate and distal health status outcomes, including activity, balance, cognition, mood and quality of life. The main aim is to test recruitment and retention, intervention delivery, data collection and other trial processes in advance of a planned definitive RCT. We will also study motivation and adherence, and conduct a process evaluation to help understand why results occurred using mixed methods, including a qualitative interview study and scales measuring psychological, motivation and communication variables. We will undertake an economic study, including modelling of future impact and cost to end-of-life, and a social return on investment analysis. DISCUSSION: In this study, we aim to better understand the practicalities of both intervention and research delivery, and to generate substantial new knowledge on motivation, adherence and the approach to economic analysis. This will enable us to refine a novel intervention to promote activity and safety after a diagnosis of dementia, which will be evaluated in a definitive randomised controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02874300; ISRCTN 10550694.