Identifying the Active Ingredients of a Computerized Speech and Language Therapy Intervention for Poststroke Aphasia: Multiple Methods Investigation Alongside a Randomized Controlled Trial.

BACKGROUND: Aphasia is a communication disorder affecting more than one-third of stroke survivors. Computerized Speech and Language Therapy (CSLT) is a complex intervention requiring computer software, speech and language therapists, volunteers, or therapy assistants, as well as self-managed practice from the person with aphasia. CSLT was found to improve word finding, a common symptom of aphasia, in a multicenter randomized controlled trial (Clinical and Cost Effectiveness of Computer Treatment for Aphasia Post Stroke [Big CACTUS]). OBJECTIVE: This study provides a detailed description of the CSLT intervention delivered in the Big CACTUS trial and identified the active ingredients of the intervention directly associated with improved word finding for people with aphasia. METHODS: We conducted a multiple methods study within the context of a randomized controlled trial. In study 1, qualitative interviews explored key informants' understanding of the CSLT intervention, how the components interacted, and how they could be measured. Qualitative data were transcribed verbatim and analyzed thematically. Qualitative findings informed the process measures collected as part of a process evaluation of the CSLT intervention delivered in the Big CACTUS trial. In study 2, quantitative analyses explored the relationship between intervention process measures (length of computer therapy access; therapists' knowledge of CSLT; degree of rationale for CSLT tailoring; and time spent using the software to practice cued confrontation naming, noncued naming, and using words in functional sentences) and change in word-finding ability over a 6-month intervention period. RESULTS: Qualitative interviews were conducted with 7 CSLT approach experts. Thematic analysis identified four overarching components of the CSLT approach: (1) the StepByStep software (version 5; Steps Consulting Ltd), (2) therapy setup: tailoring and personalizing, (3) regular independent practice, and (4) support and monitoring. Quantitative analyses included process and outcome data from 83 participants randomized to the intervention arm of the Big CACTUS trial. The process measures found to be directly associated with improved word-finding ability were therapists providing a thorough rationale for tailoring the computerized therapy exercises and the amount of time the person with aphasia spent using the computer software to practice using words in functional sentences. CONCLUSIONS: The qualitative exploration of the CSLT approach provided a detailed description of the components, theories, and mechanisms underpinning the intervention and facilitated the identification of process measures to be collected in the Big CACTUS trial. Quantitative analysis furthered our understanding of which components of the intervention are associated with clinical improvement. To optimize the benefits of using the CSLT approach for word finding, therapists are advised to pay particular attention to the active ingredients of the intervention: tailoring the therapy exercises based on the individual's specific language difficulties and encouraging people with aphasia to practice the exercises focused on saying words in functional sentences. TRIAL REGISTRATION: ISRCTN Registry ISRCTN68798818; https://www.isrctn.com/ISRCTN68798818.

Mesothelioma patient and carer experience research: A research prioritisation exercise.

OBJECTIVES: Incidence of mesothelioma worldwide is growing and the UK reports the highest global incidence. Mesothelioma is an incurable cancer with a high symptom burden. However, it is under researched when compared to other cancers. The aim of this exercise was to identify unanswered questions about the mesothelioma patient and carer experience in the UK and to prioritise research areas of most importance through consultation with patients, carers and professionals. MATERIALS AND METHODS: A virtual Research Prioritisation Exercise was conducted. This involved a review of mesothelioma patient and carer experience literature to identify research gaps and a national online survey to identify and rank research gaps. Following this, a modified consensus method with mesothelioma experts (patients, carers and professionals from healthcare, legal, academic and volunteer organisations) was undertaken to reach a consensus regarding mesothelioma patient and carer experience research priorities. RESULTS: Survey responses were received from 150 patients, carers and professionals and 29 research priorities were identified. During consensus meetings, 16 experts refined these into a list of 11 key priorities. The five most urgent priorities were symptom management, receiving a mesothelioma diagnosis, palliative and end of life care, treatment experiences, barriers and facilitators to joined up service provision. CONCLUSION: This novel priority setting exercise will shape the national research agenda, contribute knowledge to inform nursing and wider clinical practice and ultimately improve the experiences of mesothelioma patients and carers.

Clinical nurse specialist role in providing generalist and specialist palliative care: A qualitative study of mesothelioma clinical nurse specialists.

AIM: To explore perspectives of Mesothelioma UK clinical nurse specialists (CNSs) on their role in providing palliative care for patients with mesothelioma and their families. DESIGN: A qualitative descriptive approach using focus group and interview methods. METHODS: Focus groups and semi-structured interviews were conducted with 16 Mesothelioma UK clinical nurse specialists using the online software Google Meet. Data collection was carried out in Jan-Feb 2021 and data were analysed using thematic analysis. The consolidated criteria for reporting qualitative research (COREQ) was used as the reporting guideline for this paper. RESULTS: Four main themes were identified from the data: Mesothelioma UK clinical nurse specialist role in relation to palliative care; joint working with specialist palliative care and community services; patients and family carer's willingness to engage with palliative care services; and the impact of COVID-19 on palliative care for mesothelioma patients. CONCLUSION: This study provides valuable insights into palliative care needs in mesothelioma. Patients with mesothelioma and their families have significant palliative care needs throughout the course of their illness from diagnosis to the end of life. Mesothelioma UK CNS's play a crucial role in supporting patients' and families palliative care needs, and are highly skilled in providing this care. IMPACT: By acknowledging the role of Mesothelioma UK CNS's in palliative care provision, and supporting collaborative working between specialist and generalist palliative care providers, there is the capacity to significantly improve palliative care in mesothelioma and improve outcomes for patients and their families.

Patients' and informal carers' experience of living with mesothelioma: A systematic rapid review and synthesis of the literature.

PURPOSE: Mesothelioma is a rare and incurable cancer linked to asbestos exposure. It primarily affects the pleura. This systematic rapid review aimed to identify what is known about the experience of living with mesothelioma, from the perspective of patients and their informal carers. METHODS: Medline, PsycInfo, Scopus and the Cumulative Index to Nursing and Allied Health Literature were searched for empirical studies published between December 2008 and October 2020. Google Scholar was searched. The inclusion criteria stated that studies were peer-reviewed, reported the experience of living with mesothelioma from the perspective of patients and carers and written in English. The Mixed-Methods Appraisal Tool was used to assess quality. The review protocol is registered on PROSPERO: CRD42020204726. RESULTS: Twenty-five studies met the inclusion criteria. Following data extraction, a narrative synthesis identified three themes: the impact on the individual; the impact on informal carers and relationships; and interactions with professionals and systems. The physical and psychological symptom burden of mesothelioma on patients' lives was reported as high. Both the qualitative and quantitative literature highlighted that patients and carers may have different needs throughout the mesothelioma journey. Differences included psychological experiences and preferences regarding the timing of information and support provision. Patients and carers expected their health care professionals to be knowledgeable about mesothelioma or refer to those who were. Health care professionals that were compassionate, honest and supportive also positively influenced the experience of patients and carers living with mesothelioma. A lack of communication or misinformation was damaging to the patient-healthcare professional relationship. Continuity of care, coordinated care and good communication between treatment centres were widely reported as important in the literature. Fragmented care was identified as detrimental to the patient experience, increasing anxiety in patients. However, relationships with professionals were not only important in terms of co-ordinating care. There was also evidence that good relationships with healthcare professionals were beneficial to coping with the mesothelioma diagnosis. CONCLUSION: The volume of mesothelioma experience research has grown over the past decade. This has led to our growing understanding of the complex needs and experiences of mesothelioma patients and carers. However, this review identified several evidence gaps.

Understanding the Experiences of end of Life Care for Patients with Mesothelioma from the Perspective of Bereaved Family Caregivers in the UK: A Qualitative Analysis.

Objectives: Mesothelioma is a rare, progressive cancer with a short trajectory from diagnosis to the end of life. This study explores the experiences of palliative and end of life care for patients with mesothelioma from the perspective of bereaved family caregivers. Methods: A qualitative, descriptive approach was adopted comprising face-to-face, semi-structured interviews with bereaved caregivers of patients with mesothelioma in the UK. An inductive, thematic analysis was conducted using the 'Framework' approach. Results: Nine bereaved caregivers participated. Four themes emerged: understanding what lies ahead; carer support; care co-ordination; managing after death: practicalities, inquests and abandonment. Caregivers need to understand what lies ahead in order to emotionally and practically prepare themselves for supporting the patient at the end of life. Information and support needs of caregivers were often distinct from those of patients, including the importance of information about the coroner's involvement. The importance of care co-ordination was emphasised, with caregivers valuing on-going relationships and a named individual taking responsibility for co-ordinating the patients care. Feelings of abandonment arose when there was no contact with healthcare professionals following the death of the patient. Conclusions: Greater opportunity for open, one-to-one communication between family caregivers and healthcare professionals is vital to enable the caregiver to prepare for what lies ahead at the end of life and prevent feelings of abandonment after the death of the patient. Improved care co-ordination and partnership working are essential for supporting both patient and caregiver at the end of life.

What are the factors that may influence the implementation of self-managed computer therapy for people with long term aphasia following stroke? A qualitative study of speech and language therapists' experiences in the Big CACTUS trial.

PURPOSE: To explore speech and language therapists' (SLT) experiences of delivering therapy using a computerised self-management approach within a pragmatic trial, in order to identify and understand key factors that may influence the implementation of computerised approaches to rehabilitation for aphasia in routine practice. METHODS: Qualitative semi-structured telephone interviews were conducted with eleven SLTs delivering computer therapy in the multisite Big CACTUS trial. The interviews were recorded, transcribed verbatim and analysed using thematic analysis in NVivo11. RESULTS: Five themes with implications for implementation emerged: 1) characteristics of the intervention: complexity and adaptability 2) knowledge and beliefs about the intervention: familiarity with computers and the benefits of training; 3) patient needs and the service resource dilemma: "is there anything I can be doing on my computer at home?"; 4) networks and communications; 5) reflecting and evaluating: adaptations for sustainability. CONCLUSIONS: Personalisation, feedback and volunteer/assistant support were viewed as benefits of this complex intervention. However, the same benefits required resources including therapist time in learning to use software, procuring it, personalising it, working with volunteers/assistants, and building relationships with IT departments which formed barriers to implementation. The discussion highlights the need to consider integration of computer and face-to-face therapy to support implementation and potentially optimise patient outcomes.IMPLICATIONS FOR REHABILITATIONBenefits of the self-managed computer approach to word finding therapy evaluated in the Big CACTUS trial included the ability to personalise content, to provide feedback, and provide support with volunteers or assistants depending on availability in different clinical contexts to enable repetitive self-managed practice of word finding.Whilst use of computer therapy approaches can facilitate self-management of practice and increased therapy hours in an efficient manner, services need to consider the resources required to implement and support the approach: costs of software and hardware SLT time required to learn to use the software, tailor and personalise it and manage volunteers/assistants.Readiness for successful adoption of computer approaches requires building of relationships and mutual understanding of requirements between SLT and IT departments within an organisation.For time efficiency, it is recommended that SLTs providing self-managed computer therapy approaches pilot the approach with each individual to check patient ability and engagement before fully investing SLT time in personalisation and tailoring of software.

Service change and innovation in community end-of-life care during the COVID-19 pandemic: Qualitative analysis of a nationwide primary care survey.

BACKGROUND: Primary healthcare teams (general practice and community nursing services) within the United Kingdom provided the majority of community end-of-life care during COVID-19, alongside specialist palliative care services. As international healthcare systems move to a period of restoration following the first phases of the pandemic, the impact of rapidly-implemented service changes and innovations across primary and specialist palliative care services must be understood. AIM: To provide detailed insights and understanding into service changes and innovation that occurred in UK primary care to deliver end-of-life care during the first phase of the COVID-19 pandemic. DESIGN: Cross-sectional online survey. Responses were analysed using descriptive statistics and thematic analysis. SETTING/PARTICIPANTS: United Kingdom survey of general practitioners and community nurses, circulated via regional and national professional networks. RESULTS: A total of 559 valid responses were received from 387 community nurses, 156 general practitioners and 16 'other'. Over a third of respondents (n = 224; 40.8%) experienced changes in the organisation of their team in order to provide end-of-life care in response to the COVID-19 pandemic. Three qualitative themes were identified: COVID-19 as a catalyst for change in primary palliative care; new opportunities for more responsive and technological ways of working; and pandemic factors that improved and strengthened interprofessional collaboration. CONCLUSION: Opportunity has arisen to incorporate cross-boundary service changes and innovations, implemented rapidly at the time of crisis, into future service delivery. Future research should focus on which service changes and innovations provide the most benefits, who for and how, within the context of increased patient need and complexity.

Understanding the palliative care needs and experiences of people with mesothelioma and their family carers: An integrative systematic review.

BACKGROUND: People with mesothelioma and their families have palliative care needs throughout the relatively short trajectory of their illness. AIM: To describe the palliative care needs and experiences of people with mesothelioma and their family carers. DESIGN: Integrative systematic review with narrative synthesis (PROSPERO: CRD42020190115). DATA SOURCES: MEDLINE, CINAHL, PsycINFO and the Cochrane Library were searched for articles published between 01 January 2000 and 10 May 2020. Articles were included if they presented empirical studies or comprehensive reviews including information about the palliative care needs and experiences of people with mesothelioma and their family carers. RESULTS: The search yielded 508 articles, 14 were included in the analysis. A cross cutting theme of 'uncertainty' was identified encompassing five themes: (1) organisation and co-ordination of services, (2) communication and information needs, (3) management of care needs and high symptom burden, (4) consideration of the impact of seeking compensation and (5) family carer needs. Our findings demonstrate that people with mesothelioma want a co-ordinated, team-based approach to palliative care with a named point of contact. Whilst carers value and benefit from early referral to specialist palliative care, this does not necessarily reflect the outcomes and views of patients. CONCLUSION: The evidence base around the palliative care needs and experiences of people with mesothelioma and their carers needs to be strengthened. The results of this review support the need to develop a greater understanding about the role non-specialist palliative care clinicians' play in providing generalist palliative care for people with mesothelioma and their carers.

Self-managed, computerised word finding therapy as an add-on to usual care for chronic aphasia post-stroke: An economic evaluation.

OBJECTIVE: To examine the cost-effectiveness of self-managed computerised word finding therapy as an add-on to usual care for people with aphasia post-stroke. DESIGN: Cost-effectiveness modelling over a life-time period, taking a UK National Health Service (NHS) and personal social service perspective. SETTING: Based on the Big CACTUS randomised controlled trial, conducted in 21 UK NHS speech and language therapy departments. PARTICIPANTS: Big CACTUS included 278 people with long-standing aphasia post-stroke. INTERVENTIONS: Computerised word finding therapy plus usual care; usual care alone; usual care plus attention control. MAIN MEASURES: Incremental cost-effectiveness ratios (ICER) were calculated, comparing the cost per quality adjusted life year (QALY) gained for each intervention. Credible intervals (CrI) for costs and QALYs, and probabilities of cost-effectiveness, were obtained using probabilistic sensitivity analysis. Subgroup and scenario analyses investigated cost-effectiveness in different subsets of the population, and the sensitivity of results to key model inputs. RESULTS: Adding computerised word finding therapy to usual care had an ICER of £42,686 per QALY gained compared with usual care alone (incremental QALY gain: 0.02 per patient (95% CrI: -0.05 to 0.10); incremental costs: £732.73 per patient (95% CrI: £674.23 to £798.05)). ICERs for subgroups with mild or moderate word finding difficulties were £22,371 and £21,262 per QALY gained respectively. CONCLUSION: Computerised word finding therapy represents a low cost add-on to usual care, but QALY gains and estimates of cost-effectiveness are uncertain. Computerised therapy is more likely to be cost-effective for people with mild or moderate, as opposed to severe, word finding difficulties.

Factors Associated With Adherence to Self-Managed Aphasia Therapy Practice on a Computer-A Mixed Methods Study Alongside a Randomized Controlled Trial.

Background: Aphasia is a communication disorder often acquired after a stroke. Independent use of specialist aphasia software on a home computer is a form of asynchronous tele-rehabilitation that can provide increased opportunity for practice of rehabilitation exercises. This study aimed to explore the factors associated with adherence to self-managed aphasia computer therapy practice. Method: A mixed methods exploration of adherence was conducted alongside the Big CACTUS randomized controlled trial [ISRCTN: 68798818]. The trial evaluated the clinical effectiveness of self-managed aphasia computer therapy. This study reports secondary analysis of data from participants randomized to the computer therapy group to investigate whether any demographic, clinical or intervention variables were associated with adherence to therapy practice. A sub-sample of the same participants took part in qualitative interviews exploring the factors perceived to influence the amount of aphasia computer therapy practice undertaken. Interviews were analyzed thematically. A convergence-coding matrix was used to triangulate the two sets of findings. Results: Data from 85 participants randomized to the computer therapy group were included in the quantitative analyses. At a clinical level, a greater length of time post-stroke was associated with higher adherence to self-managed aphasia therapy practice on a computer. At an intervention level, length of computer therapy access and therapist time supporting the participant were associated with greater adherence to computer therapy practice. Interviews with 11 patients and 12 informal carers identified a multitude of factors perceived to influence engagement with tele-rehabilitation by people with aphasia. The factors grouped around three themes: capability to use the computer therapy, having the opportunity to practice (external influences and technological issues) and motivation (beliefs, goals and intentions vs. personality, emotions, habit and reinforcement). Triangulation demonstrated convergence for the finding that participants' practiced computer-based therapy exercises more when they received increased support from a speech and language therapist. Conclusion: Clinicians delivering asynchronous tele-rehabilitation involving self-management of aphasia therapy practice on a computer should consider the factors found to be associated with engagement when deciding which patients may be suited to this option, as well as how they can be supported to optimize the amount of practice they engage in.

Computerised speech and language therapy or attention control added to usual care for people with long-term post-stroke aphasia: the Big CACTUS three-arm RCT.

BACKGROUND: People with aphasia may improve their communication with speech and language therapy many months/years after stroke. However, NHS speech and language therapy reduces in availability over time post stroke. OBJECTIVE: This trial evaluated the clinical effectiveness and cost-effectiveness of self-managed computerised speech and language therapy to provide additional therapy. DESIGN: A pragmatic, superiority, single-blind, parallel-group, individually randomised (stratified block randomisation, stratified by word-finding severity and site) adjunct trial. SETTING: Twenty-one UK NHS speech and language therapy departments. PARTICIPANTS: People with post-stroke aphasia (diagnosed by a speech and language therapist) with long-standing (> 4 months) word-finding difficulties. INTERVENTIONS: The groups were (1) usual care; (2) daily self-managed computerised word-finding therapy tailored by speech and language therapists and supported by volunteers/speech and language therapy assistants for 6 months plus usual care (computerised speech and language therapy); and (3) activity/attention control (completion of puzzles and receipt of telephone calls from a researcher for 6 months) plus usual care. MAIN OUTCOME MEASURES: Co-primary outcomes - change in ability to find treated words of personal relevance in a bespoke naming test (impairment) and change in functional communication in conversation rated on the activity scale of the Therapy Outcome Measures (activity) 6 months after randomisation. A key secondary outcome was participant-rated perception of communication and quality of life using the Communication Outcomes After Stroke questionnaire at 6 months. Outcomes were assessed by speech and language therapists using standardised procedures. Cost-effectiveness was estimated using treatment costs and an accessible EuroQol-5 Dimensions, five-level version, measuring quality-adjusted life-years. RESULTS: A total of 818 patients were assessed for eligibility and 278 participants were randomised between October 2014 and August 2016. A total of 240 participants (86 usual care, 83 computerised speech and language therapy, 71 attention control) contributed to modified intention-to-treat analysis at 6 months. The mean improvements in word-finding were 1.1% (standard deviation 11.2%) for usual care, 16.4% (standard deviation 15.3%) for computerised speech and language therapy and 2.4% (standard deviation 8.8%) for attention control. Computerised speech and language therapy improved word-finding 16.2% more than usual care did (95% confidence interval 12.7% to 19.6%; p < 0.0001) and 14.4% more than attention control did (95% confidence interval 10.8% to 18.1%). Most of this effect was maintained at 12 months (n = 219); the mean differences in change in word-finding score were 12.7% (95% confidence interval 8.7% to 16.7%) higher in the computerised speech and language therapy group (n = 74) than in the usual-care group (n = 84) and 9.3% (95% confidence interval 4.8% to 13.7%) higher in the computerised speech and language therapy group than in the attention control group (n = 61). Computerised speech and language therapy did not show significant improvements on the Therapy Outcome Measures or Communication Outcomes After Stroke scale compared with usual care or attention control. Primary cost-effectiveness analysis estimated an incremental cost per participant of £732.73 (95% credible interval £674.23 to £798.05). The incremental quality-adjusted life-year gain was 0.017 for computerised speech and language therapy compared with usual care, but its direction was uncertain (95% credible interval -0.05 to 0.10), resulting in an incremental cost-effectiveness ratio of £42,686 per quality-adjusted life-year gained. For mild and moderate word-finding difficulty subgroups, incremental cost-effectiveness ratios were £22,371 and £28,898 per quality-adjusted life-year gained, respectively, for computerised speech and language therapy compared with usual care. LIMITATIONS: This trial excluded non-English-language speakers, the accessible EuroQol-5 Dimensions, five-level version, was not validated and the measurement of attention control fidelity was limited. CONCLUSIONS: Computerised speech and language therapy enabled additional self-managed speech and language therapy, contributing to significant improvement in finding personally relevant words (as specifically targeted by computerised speech and language therapy) long term post stroke. Gains did not lead to improvements in conversation or quality of life. Cost-effectiveness is uncertain owing to uncertainty around the quality-adjusted life-year gain, but computerised speech and language therapy may be more cost-effective for participants with mild and moderate word-finding difficulties. Exploring ways of helping people with aphasia to use new words in functional communication contexts is a priority. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68798818. 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. 24, No. 19. See the NIHR Journals Library website for further project information. The Tavistock Trust for Aphasia provided additional support to enable people in the control groups to experience the intervention after the trial had ended.

Aphasia is a communication disorder that can be caused by a stroke. It affects a person's understanding of spoken words and their talking, reading and writing abilities. Communication may improve months, or years, after a stroke with speech and language therapy. Many patients want more speech and language therapy than the NHS can provide. The Big CACTUS (clinical and cost-effectiveness of aphasia computer treatment versus usual stimulation or attention control long term post-stroke) trial evaluated the use of speech and language therapy software for people with aphasia to practise finding words independently at home on their own computer or one loaned by the NHS. People with aphasia who had had a stroke at least 4 months previously were randomly allocated to one of three groups: usual speech and language therapy caredaily use of computerised speech and language therapy for 6 months, tailored by a speech and language therapist and supported by a volunteer or speech and language therapy assistantdaily completion of puzzles and supportive telephone calls from a researcher to mimic the activity/attention the computerised speech and language therapy group received. All groups received usual speech and language therapy. A total of 278 people with aphasia took part in this trial, from 21 UK NHS speech and language therapy departments. They had their strokes between 4 months and 36 years previously. Computerised speech and language therapy enabled more practice (28 hours on average) than usual speech and language therapy (3.8 hours). The computerised speech and language therapy group significantly improved their ability to say words they chose to practise compared with those in the usual speech and language therapy or puzzle book groups. Although computerised speech and language therapy can help people with aphasia to learn new words for years after stroke, no improvements in conversation or quality of life were seen. The cost-effectiveness for the NHS is still uncertain. However, our best estimate is that it is unlikely to be cost-effective for everyone with aphasia, but it may be cost-effective for people with mild and moderate word-finding difficulties. Next steps will focus on how to encourage use of new words in conversation to have an impact on quality of life.

Self-managed, computerised speech and language therapy for patients with chronic aphasia post-stroke compared with usual care or attention control (Big CACTUS): a multicentre, single-blinded, randomised controlled trial.

BACKGROUND: Post-stroke aphasia might improve over many years with speech and language therapy; however speech and language therapy is often less readily available beyond a few months after stroke. We assessed self-managed computerised speech and language therapy (CSLT) as a means of providing more therapy than patients can access through usual care alone. METHODS: In this pragmatic, superiority, three-arm, individually randomised, single-blind, parallel group trial, patients were recruited from 21 speech and language therapy departments in the UK. Participants were aged 18 years or older and had been diagnosed with aphasia post-stroke at least 4 months before randomisation; they were excluded if they had another premorbid speech and language disorder caused by a neurological deficit other than stroke, required treatment in a language other than English, or if they were currently using computer-based word-finding speech therapy. Participants were randomly assigned (1:1:1) to either 6 months of usual care (usual care group), daily self-managed CSLT plus usual care (CSLT group), or attention control plus usual care (attention control group) with the use of computer-generated stratified blocked randomisation (randomly ordered blocks of sizes three and six, stratified by site and severity of word finding at baseline based on CAT Naming Objects test scores). Only the outcome assessors and trial statistician were masked to the treatment allocation. The speech and language therapists who were doing the outcome assessments were different from those informing participants about which group they were assigned to and from those delivering all interventions. The statistician responsible for generating the randomisation schedule was separate from those doing the analysis. Co-primary outcomes were the change in ability to retrieve personally relevant words in a picture naming test (with 10% mean difference in change considered a priori as clinically meaningful) and the change in functional communication ability measured by masked ratings of video-recorded conversations, with the use of Therapy Outcome Measures (TOMs), between baseline and 6 months after randomisation (with a standardised mean difference in change of 0·45 considered a priori as clinically meaningful). Primary analysis was based on the modified intention-to-treat (mITT) population, which included randomly assigned patients who gave informed consent and excluded those without 6-month outcome measures. Safety analysis included all participants. This trial has been completed and was registered with the ISRCTN, number ISRCTN68798818. FINDINGS: From Oct 20, 2014, to Aug 18, 2016, 818 patients were assessed for eligibility, of which 278 (34%) participants were randomly assigned (101 [36%] to the usual care group; 97 [35%] to the CSLT group; 80 [29%] to the attention control group). 86 patients in the usual care group, 83 in the CSLT group, and 71 in the attention control group contributed to the mITT. Mean word finding improvements were 1·1% (SD 11·2) in the usual care group, 16·4% (15·3) in the CSLT group, and 2·4% (8·8) in the attention control group. Word finding improvement was 16·2% (95% CI 12·7 to 19·6; p<0·0001) higher in the CSLT group than in the usual care group and was 14·4% (10·8 to 18·1) higher than in the attention control group. Mean changes in TOMs were 0·05 (SD 0·59) in the usual care group (n=84), 0·04 (0·58) in the CSLT group (n=81), and 0·10 (0·61) in the attention control group (n=68); the mean difference in change between the CSLT and usual care groups was -0·03 (-0·21 to 0·14; p=0·709) and between the CSLT and attention control groups was -0·01 (-0·20 to 0·18). The incidence of serious adverse events per year were rare with 0·23 events in the usual care group, 0·11 in the CSLT group, and 0·16 in the attention control group. 40 (89%) of 45 serious adverse events were unrelated to trial activity and the remaining five (11%) of 45 serious adverse events were classified as unlikely to be related to trial activity. INTERPRETATION: CSLT plus usual care resulted in a clinically significant improvement in personally relevant word finding but did not result in an improvement in conversation. Future studies should explore ways to generalise new vocabulary to conversation for patients with chronic aphasia post-stroke. FUNDING: National Institute for Health Research, Tavistock Trust for Aphasia.

Design and synthesis of synthetic UP elements for modulation of gene expression in Escherichia coli.

Metabolic engineering requires fine-tuned gene expression for most pathway optimization applications. To develop a suitable suite of promoters, traditional bacterial promoter engineering efforts have focused on modifications to the core region, especially the -10 and -35 regions, of native promoters. Here, we demonstrate an alternate, unexplored route of promoter engineering through randomization of the UP element of the promoter-a region that contacts the alpha subunit carboxy-terminal domain instead of the sigma subunit of the RNA polymerase holoenzyme. Through this work, we identify five novel UP element sequences through library-based searches in Escherichia coli. The resulting elements were used to activate the E. coli core promoter, rrnD promoter, to levels on par and higher than the prevalent strong bacterial promoter, OXB15. These relative levels of expression activation were transferrable when applied upstream of alternate core promoter sequences, including rrnA and rrnH. This work thus presents and validates a novel strategy for bacterial promoter engineering with transferability across varying core promoters and potential for transferability across bacterial species.

A Highly Sensitive A-Kinase Activity Reporter for Imaging Neuromodulatory Events in Awake Mice.

Neuromodulation imposes powerful control over brain function, and cAMP-dependent protein kinase (PKA) is a central downstream mediator of multiple neuromodulators. Although genetically encoded PKA sensors have been developed, single-cell imaging of PKA activity in living mice has not been established. Here, we used two-photon fluorescence lifetime imaging microscopy (2pFLIM) to visualize genetically encoded PKA sensors in response to the neuromodulators norepinephrine and dopamine. We screened available PKA sensors for 2pFLIM and further developed a variant (named tAKARα) with increased sensitivity and a broadened dynamic range. This sensor allowed detection of PKA activation by norepinephrine at physiologically relevant concentrations and kinetics, and by optogenetically released dopamine. In vivo longitudinal 2pFLIM imaging of tAKARα tracked bidirectional PKA activities in individual neurons in awake mice and revealed neuromodulatory PKA events that were associated with wakefulness, pharmacological manipulation, and locomotion. This new sensor combined with 2pFLIM will enable interrogation of neuromodulation-induced PKA signaling in awake animals. VIDEO ABSTRACT.

Challenges in building interpersonal care in organized hospital stroke units: The perspectives of stroke survivors, family caregivers and the multidisciplinary team.

AIMS: To explore the organized stroke unit experience from the multiple perspectives of stroke survivor, family carer and the multi-disciplinary team. BACKGROUND: Organized stroke unit care reduces morbidity, mortality and institutionalization and is promoted globally as the most effective form of acute and postacute provision. Little research has focused on how care is experienced in this setting from the perspectives of those who receive and provide care. DESIGN: This study used a qualitative approach, employing Framework Analysis. This methodology allows for a flexible approach to data collection and a comprehensive and systematic method of analysis. METHOD: Semi-structured interviews were undertaken during 2011 and 2012 with former stroke unit stroke survivors, family carers and senior stroke physicians. In addition, eight focus groups were conducted with members of the multi-disciplinary team. RESULTS: One hundred and twenty-five participants were recruited. Three key themes were identified across all data sets. First, two important processes are described: responses to the impact of stroke and seeking information and stroke-specific knowledge. These are underpinned by a third theme: the challenge in building relationships in organized stroke unit care. CONCLUSIONS: Stroke unit care provides satisfaction for stroke survivors, particularly in relation to highly specialized medical and nursing care and therapy. It is proposed that moves towards organized stroke unit care, particularly with the emphasis on reduction of length of stay and a focus on hyper-acute models, have implications for interpersonal care practices and the sharing of stroke-specific knowledge.

Psychological and emotional needs, assessment, and support post-stroke: a multi-perspective qualitative study.

BACKGROUND: International stroke care guidelines recommend the routine assessment and management of psychological and emotional problems post-stroke. Understanding the experiences of those delivering and receiving these services is vital to improving the provision of psychological support post-stroke. OBJECTIVES: To explore patients', carers', and health professionals' experiences of psychological need, assessment, and support post-stroke while in hospital and immediately post-discharge. METHODS: Participants were recruited from seven specialist stroke services in the north of England. Qualitative semi-structured interviews and focus groups were conducted with 31 stroke patients, 28 carers, and 66 health professionals. The interviews were recorded and transcribed verbatim and analyzed using thematic analysis. RESULTS: Two central themes emerged minding the gap: psychological expertise, and protective factors perceived to reduce the need for formal psychological support. The lack of psychological expertise among healthcare professionals working on stroke units was a source of frustration and resulted in other disciplines assuming the role of a psychologist without the required skills and training. Multiple stakeholders discussed the importance of protective factors, including downward social comparison, social support, peer support, communication, and information provision, that were perceived to reduce the need for formal psychological support. DISCUSSION: Stroke patients need better access to psychological support, including information, advice, and peer or social support. More research is required to establish the effectiveness of alternative options to formal psychological support.

Negotiating excess treatment costs in a clinical research trial: the good, the bad and the innovative.

UNLABELLED: Barriers to recovering the excess treatment costs associated with health research from local organisations in the United Kingdom can increase research costs, delay completion of high- quality studies and risk disenfranchising health trusts and patients from participation. The authors demonstrate how the process for recovering excess treatment costs at a local National Health Service (NHS) trust level in a multicentre study was inconsistent and resulted in excess effort and cost to the research budget. An innovative example of how an organisation acting as a broker between commissioners and researchers facilitated a more timely excess treatment cost agreement is highlighted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68798818, registered on 18 February 2014.

Exploring patient and public involvement in stroke research: a qualitative study.

PURPOSE: To explore the experiences of patients and carers involved in patient and public involvement (PPI) activities for stroke research. METHODS: Semi-structured interviews conducted with stroke survivors and carers (n = 11) were analysed using thematic analysis. RESULTS: Four key themes emerged: impact of PPI on the individual and the research process, credibility and expertise, level of involvement and barriers and facilitators to PPI for stroke survivors and carers. The perceived benefits to the research process included: asking questions, keeping researchers grounded and directing the research agenda. All participants drew upon their experiential expertise in their PPI role, but some also drew upon their professional expertise to provide additional credibility. Stroke survivors and carers can be involved in PPI at different levels of involvement simultaneously and the majority of participants wanted to be more involved. Barriers to involvement included: location, transport and stroke survivors capacity to concentrate and comprehend complex information. Facilitators included: reimbursement for travel and time and professionals effort to facilitate involvement. CONCLUSIONS: PPI in stroke research benefits stroke survivors and carers and is perceived to benefit the research process. The barriers and facilitators should be considered by professionals intending to engage stroke survivors and carers collaboratively in research. IMPLICATIONS FOR REHABILITATION: This study has implications for PPI in stroke rehabilitation research, which could also be extrapolated to stroke rehabilitation service development and evaluation. Professionals facilitating PPI need to invest in developing supportive relationships in order to maintain ongoing involvement. Professionals need to be aware of how the varied consequences of stroke might impede participation and strategies to facilitate involvement for all who wish to be involved. For each rehabilitation issue being considered professionals need to decide: (1) how representative of the specific rehabilitation population the PPI members need to be, (2) whether experience alone is sufficient or whether additional professional skills are required and (3) whether training is likely to assist involvement or potentially reduce the lay representation.

Provision of palliative and end-of-life care in stroke units: a qualitative study.

BACKGROUND: Stroke is a leading cause of death; between 20% and 30% of people die within 30 days of a stroke. High-quality palliative and end-of-life care are advocated for patients not expected to recover from stroke. AIM: To explore the perspectives of health professionals regarding the provision of palliative and end-of-life care in UK stroke units. DESIGN AND SETTING: Qualitative focus groups and individual interviews were held with 66 health professionals working in UK specialist stroke units. Data were analysed thematically. RESULTS: Three themes emerged from the data. Palliative care was recognised as an important component of stroke care; however, there was uncertainty when initiating transitions to palliative care in stroke, and issues were identified with the integration of acute stroke care and palliative care. CONCLUSIONS: The findings provide encouraging evidence that palliative and end-of-life care have been adopted as key components of specialist stroke care in UK stroke units. However, many patients stand to benefit from earlier identification of palliative care need and a consideration of quality-of-life approaches during active care. Encouraging collaboration and partnership when working with specialist palliative care services would optimise palliative care service delivery and may provide patients and their families with greater opportunities for documenting and achieving preferences for care and achieving a better quality of death.