Development of spirulina for the manufacture and oral delivery of protein therapeutics.

The use of the edible photosynthetic cyanobacterium Arthrospira platensis (spirulina) as a biomanufacturing platform has been limited by a lack of genetic tools. Here we report genetic engineering methods for stable, high-level expression of bioactive proteins in spirulina, including large-scale, indoor cultivation and downstream processing methods. Following targeted integration of exogenous genes into the spirulina chromosome (chr), encoded protein biopharmaceuticals can represent as much as 15% of total biomass, require no purification before oral delivery and are stable without refrigeration and protected during gastric transit when encapsulated within dry spirulina. Oral delivery of a spirulina-expressed antibody targeting campylobacter-a major cause of infant mortality in the developing world-prevents disease in mice, and a phase 1 clinical trial demonstrated safety for human administration. Spirulina provides an advantageous system for the manufacture of orally delivered therapeutic proteins by combining the safety of a food-based production host with the accessible genetic manipulation and high productivity of microbial platforms.

A Rationally Designed c-di-AMP Förster Resonance Energy Transfer Biosensor To Monitor Nucleotide Dynamics.

3'3'-Cyclic di-AMP (c-di-AMP) is an important nucleotide second messenger found throughout the bacterial domain of life. c-di-AMP is essential in many bacteria and regulates a diverse array of effector proteins controlling pathogenesis, cell wall homeostasis, osmoregulation, and central metabolism. Despite the ubiquity and importance of c-di-AMP, methods to detect this signaling molecule are limited, particularly at single-cell resolution. In this work, crystallization of the Listeria monocytogenes c-di-AMP effector protein Lmo0553 enabled structure-guided design of a Förster resonance energy transfer (FRET)-based biosensor, which we have named CDA5. CDA5 is a fully genetically encodable, specific, and reversible biosensor which allows the detection of c-di-AMP dynamics both in vitro and within live cells in a nondestructive manner. Our initial studies identified a distribution of c-di-AMP in Bacillus subtilis populations first grown in Luria broth and then resuspended in diluted Luria broth compatible with fluorescence analysis. Furthermore, we found that B. subtilis mutants lacking either a c-di-AMP phosphodiesterase and cyclase have higher and lower FRET responses, respectively. These findings provide novel insight into the c-di-AMP distribution within bacterial populations and establish CDA5 as a powerful platform for characterizing new aspects of c-di-AMP regulation. IMPORTANCE c-di-AMP is an important nucleotide second messenger for which detection methods are severely limited. In this work we engineered and implemented a c-di-AMP-specific FRET biosensor to remedy this dearth. We present this biosensor, CDA5, as a versatile tool to investigate previously intractable facets of c-di-AMP biology.

Non-pharmacological interventions for spatial neglect or inattention following stroke and other non-progressive brain injury.

BACKGROUND: People with spatial neglect after stroke or other brain injury have difficulty attending to one side of space. Various rehabilitation interventions have been used, but evidence of their benefit is unclear. OBJECTIVES: The main objective was to determine the effects of non-pharmacological interventions for people with spatial neglect after stroke and other adult-acquired non-progressive brain injury. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched October 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; last searched October 2020), MEDLINE (1966 to October 2020), Embase (1980 to October 2020), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1983 to October 2020), and PsycINFO (1974 to October 2020). We also searched ongoing trials registers and screened reference lists. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any non-pharmacological intervention specifically aimed at spatial neglect. We excluded studies of general rehabilitation and studies with mixed participant groups, unless separate neglect data were available. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Review authors categorised the interventions into eight broad types deemed to be applicable to clinical practice through iterative discussion: visual interventions, prism adaptation, body awareness interventions, mental function interventions, movement interventions, non-invasive brain stimulation, electrical stimulation, and acupuncture. We assessed the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included 65 RCTs with 1951 participants, all of which included people with spatial neglect following stroke. Most studies measured outcomes using standardised neglect assessments. Fifty-one studies measured effects on ADL immediately after completion of the intervention period; only 16 reported persisting effects on ADL (our primary outcome). One study (30 participants) reported discharge destination, and one (24 participants) reported depression. No studies reported falls, balance, or quality of life. Only two studies were judged to be entirely at low risk of bias, and all were small, with fewer than 50 participants per group. We found no definitive (phase 3) clinical trials. None of the studies reported any patient or public involvement. Visual interventions versus any control: evidence is very uncertain about the effects of visual interventions for spatial neglect based on measures of persisting functional ability in ADL (2 studies, 55 participants) (standardised mean difference (SMD) -0.04, 95% confidence interval (CI) -0.57 to 0.49); measures of immediate functional ability in ADL; persisting standardised neglect assessments; and immediate neglect assessments. Prism adaptation versus any control: evidence is very uncertain about the effects of prism adaptation for spatial neglect based on measures of persisting functional ability in ADL (2 studies, 39 participants) (SMD -0.29, 95% CI -0.93 to 0.35); measures of immediate functional ability in ADL; persisting standardised neglect assessments; and immediate neglect assessments. Body awareness interventions versus any control: evidence is very uncertain about the effects of body awareness interventions for spatial neglect based on measures of persisting functional ability in ADL (5 studies, 125 participants) (SMD 0.61, 95% CI 0.24 to 0.97); measures of immediate functional ability in ADL; persisting standardised neglect assessments; immediate neglect assessments; and adverse events. Mental function interventions versus any control: we found no trials of mental function interventions for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of mental function interventions on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. Movement interventions versus any control: we found no trials of movement interventions for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of body awareness interventions on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. Non-invasive brain stimulation (NIBS) versus any control: evidence is very uncertain about the effects of NIBS on spatial neglect based on measures of persisting functional ability in ADL (3 studies, 92 participants) (SMD 0.35, 95% CI -0.08 to 0.77); measures of immediate functional ability in ADL; persisting standardised neglect assessments; immediate neglect assessments; and adverse events. Electrical stimulation versus any control: we found no trials of electrical stimulation for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of electrical stimulation on spatial neglect based on immediate neglect assessments. Acupuncture versus any control: we found no trials of acupuncture for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of acupuncture on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. AUTHORS' CONCLUSIONS: The effectiveness of non-pharmacological interventions for spatial neglect in improving functional ability in ADL and increasing independence remains unproven. Many strategies have been proposed to aid rehabilitation of spatial neglect, but none has yet been sufficiently researched through high-quality fully powered randomised trials to establish potential or adverse effects. As a consequence, no rehabilitation approach can be supported or refuted based on current evidence from RCTs. As recommended by a number of national clinical guidelines, clinicians should continue to provide rehabilitation for neglect that enables people to meet their rehabilitation goals. Clinicians and stroke survivors should have the opportunity, and are strongly encouraged, to participate in research. Future studies need to have appropriate high-quality methodological design, delivery, and reporting to enable appraisal and interpretation of results. Future studies also must evaluate outcomes of importance to patients, such as persisting functional ability in ADL. One way to improve the quality of research is to involve people with experience with the condition in designing and running trials.

4-Hydroxy-2-nonenal antimicrobial toxicity is neutralized by an intracellular pathogen.

Pathogens encounter numerous antimicrobial responses during infection, including the reactive oxygen species (ROS) burst. ROS-mediated oxidation of host membrane poly-unsaturated fatty acids (PUFAs) generates the toxic alpha-beta carbonyl 4-hydroxy-2-nonenal (4-HNE). Although studied extensively in the context of sterile inflammation, research into 4-HNE's role during infection remains limited. Here, we found that 4-HNE is generated during bacterial infection, that it impacts growth and survival in a range of bacteria, and that the intracellular pathogen Listeria monocytogenes induces many genes in response to 4-HNE exposure. A component of the L. monocytogenes 4-HNE response is the expression of the genes lmo0103 and lmo0613, deemed rha1 and rha2 (reductase of host alkenals), respectively, which code for two NADPH-dependent oxidoreductases that convert 4-HNE to the product 4-hydroxynonanal (4-HNA). Loss of these genes had no impact on L. monocytogenes bacterial burdens during murine or tissue culture infection. However, heterologous expression of rha1/2 in Bacillus subtilis significantly increased bacterial resistance to 4-HNE in vitro and promoted bacterial survival following phagocytosis by murine macrophages in an ROS-dependent manner. Thus, Rha1 and Rha2 are not necessary for 4-HNE resistance in L. monocytogenes but are sufficient to confer resistance to an otherwise sensitive organism in vitro and in host cells. Our work demonstrates that 4-HNE is a previously unappreciated component of ROS-mediated toxicity encountered by bacteria within eukaryotic hosts.

Goal adjustment by people living with long-term conditions: A scoping review of literature published from January 2007 to June 2018.

Long-term health conditions can limit achievement of personal goals. We aimed to map and synthesize definitions of goal adjustment, theoretical underpinnings, associations with recovery and supportive interventions for adults with long-term conditions. We searched multiple databases (January 2007-June 2018) and identified peer-reviewed research relating to goal adjustment. Data were charted, mapped and synthesized using content analysis and descriptive summaries. Two stakeholder consultations informed the review. Ninety-one articles were included. A range of long-term conditions were represented including cancer (22%), stroke (12%) and mixed neurological conditions (8%). Goal adjustment was one available option when faced with unattainable goals; other options were goal disengagement and goal re-engagement. Most studies were quantitative (58%), reporting mainly positive associations between goal adjustment, disengagement, reengagement and recovery. The Dual Process Model, Goal Adjustment Model and Self-Regulation Theory were most cited underpinning models/theory. Five interventions were identified; only one (self-system therapy) was evaluated in a randomized controlled trial. Our review provides original and significant insights into goal adjustment definitions, theoretical underpinnings and association with recovery. Effective interventions to support goal adjustment, disengagement and reengagement are lacking. This research-practice gap warrants attention to ensure people with long-term conditions are optimally supported when facing unattainable goals.

The Structure of Research Questions in Randomized Controlled Trials in the Rehabilitation Field: A Methodological Study.

OBJECTIVE: The aim of this study is to assess whether and how the PICO (Population, Intervention, Comparator, and Outcomes) format is described to frame research questions in randomized controlled trials looking at effectiveness of rehabilitation interventions. DESIGN: A methodological study was conducted. Randomized controlled trials in the rehabilitation field, published between July 1, 2019, and December 31, 2019, were included. The framing of the primary research question from each trial was evaluated. RESULTS: A total of 97 randomized controlled trials were included in the analysis. The most frequent framing of the primary research question was as an "objective" statement (55%), and in 33% of the articles, this was stated as an "objective" together with a "hypothesis" description. All PICO elements were present in 55% of research questions, but only 49% have used the statement suggested by Cochrane. CONCLUSION: The findings of this study suggest that a specific item about the "research question" and the rationale that drove the proposed design following the form suggested by Cochrane should be included in the RCT Rehabilitation Checklist.

International consensus recommendations for outcome measurement in post-stroke arm rehabilitation trials.

BACKGROUND: Existing randomized controlled trials (RCTs) of arm rehabilitation interventions after stroke use a wide range of outcome measures, limiting ability to pool data to determine efficacy. Published recommendations also lack stroke survivor, carer and clinician involvement specifically about perceived relevance and importance of outcomes and measures. AIM: To generate international consensus recommendations for selection of outcome measures for use in future stroke RCTs in arm rehabilitation, considering outcomes important to stroke survivors, carers and clinicians. The recommendations are the Standardizing Measurement in Arm Rehabilitation Trials (SMART) Toolbox. DESIGN: Two-round international e-Delphi Survey and consensus meeting. SETTING: Online and University. POPULATION: Fifty-five researchers and clinicians with expertise in stroke upper limb rehabilitation from 18 countries (e-Delphi); N.=13 researchers and clinicians, N.=2 stroke survivors, N.=1 carer (consensus meeting). METHODS: Using systematically identified outcome measures from published RCTs, we conducted a two-round international e-Delphi Survey with researchers and clinicians to identify the most important measures for inclusion in the toolbox. Measures that achieved ≥60% consensus were categorized using the International Classification of Functioning, Disability and Health Framework (ICF); psychometric properties were ascertained from literature and research resources. At a final consensus meeting, expert stakeholders selected measures for inclusion in the toolbox. RESULTS: e-Delphi participants recommended 28/170 measures for discussion at the final consensus meeting. Expert stakeholders (N.=16) selected the Visual Analogue Scale for pain/0-10 Numeric Pain Rating Scale, dynamometry, Action Research Arm Test, Wolf Motor Function Test, Barthel Index, Motricity Index and Fugl-Meyer Assessment (upper limb section of each), Box and Block Test, Motor Activity Log 14, Nine Hole Peg Test, Functional Independence Measure, EQ-5D, Canadian Occupational Performance Measure and Modified Rankin Scale for inclusion in the toolbox. CONCLUSIONS: The SMART Toolbox provides a refined selection of measures that capture outcomes considered important by stakeholders for each ICF domain. CLINICAL REHABILITATION IMPACT: The toolbox will facilitate data aggregation for efficacy analyses thereby strengthening evidence to inform clinical practice. Clinicians can also use the toolbox to guide selection of measures ensuring a patient-centered focus.

A Luminescence-Based Coupled Enzyme Assay Enables High-Throughput Quantification of the Bacterial Second Messenger 3'3'-Cyclic-Di-AMP.

Cyclic dinucleotide signaling systems, which are found ubiquitously throughout nature, allow organisms to rapidly and dynamically sense and respond to alterations in their environments. In recent years, the second messenger, cyclic di-(3',5')-adenosine monophosphate (c-di-AMP), has been identified as an essential signaling molecule in a diverse array of bacterial genera. We and others have shown that defects in c-di-AMP homeostasis result in severe physiological defects and virulence attenuation in many bacterial species. Despite significant advancements in the field, there is still a major gap in the understanding of the environmental and cellular factors that influence c-di-AMP dynamics due to a lack of tools to sensitively and rapidly monitor changes in c-di-AMP levels. To address this limitation, we describe here the development of a luciferase-based coupled enzyme assay that leverages the cyclic nucleotide phosphodiesterase, CnpB, for the sensitive and high-throughput quantification of 3'3'-c-di-AMP. We also demonstrate the utility of this approach for the quantification of the cyclic oligonucleotide-based anti-phage signaling system (CBASS) effector, 3'3'-cGAMP. These findings establish CDA-Luc as a more affordable and sensitive alternative to conventional c-di-AMP detection tools with broad utility for the study of bacterial cyclic dinucleotide physiology.

Interventions to support the resilience and mental health of frontline health and social care professionals during and after a disease outbreak, epidemic or pandemic: a mixed methods systematic review.

BACKGROUND: Evidence from disease epidemics shows that healthcare workers are at risk of developing short- and long-term mental health problems. The World Health Organization (WHO) has warned about the potential negative impact of the COVID-19 crisis on the mental well-being of health and social care professionals. Symptoms of mental health problems commonly include depression, anxiety, stress, and additional cognitive and social problems; these can impact on function in the workplace. The mental health and resilience (ability to cope with the negative effects of stress) of frontline health and social care professionals ('frontline workers' in this review) could be supported during disease epidemics by workplace interventions, interventions to support basic daily needs, psychological support interventions, pharmacological interventions, or a combination of any or all of these. OBJECTIVES: Objective 1: to assess the effects of interventions aimed at supporting the resilience and mental health of frontline health and social care professionals during and after a disease outbreak, epidemic or pandemic. Objective 2: to identify barriers and facilitators that may impact on the implementation of interventions aimed at supporting the resilience and mental health of frontline health and social care professionals during and after a disease outbreak, epidemic or pandemic. SEARCH METHODS: On 28 May 2020 we searched the Cochrane Database of Systematic Reviews, CENTRAL, MEDLINE, Embase, Web of Science, PsycINFO, CINAHL, Global Index Medicus databases and WHO Institutional Repository for Information Sharing. We also searched ongoing trials registers and Google Scholar. We ran all searches from the year 2002 onwards, with no language restrictions. SELECTION CRITERIA: We included studies in which participants were health and social care professionals working at the front line during infectious disease outbreaks, categorised as epidemics or pandemics by WHO, from 2002 onwards. For objective 1 we included quantitative evidence from randomised trials, non-randomised trials, controlled before-after studies and interrupted time series studies, which investigated the effect of any intervention to support mental health or resilience, compared to no intervention, standard care, placebo or attention control intervention, or other active interventions. For objective 2 we included qualitative evidence from studies that described barriers and facilitators to the implementation of interventions. Outcomes critical to this review were general mental health and resilience. Additional outcomes included psychological symptoms of anxiety, depression or stress; burnout; other mental health disorders; workplace staffing; and adverse events arising from interventions. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently applied selection criteria to abstracts and full papers, with disagreements resolved through discussion. One review author systematically extracted data, cross-checked by a second review author. For objective 1, we assessed risk of bias of studies of effectiveness using the Cochrane 'Risk of bias' tool. For objective 2, we assessed methodological limitations using either the CASP (Critical Appraisal Skills Programme) qualitative study tool, for qualitative studies, or WEIRD (Ways of Evaluating Important and Relevant Data) tool, for descriptive studies. We planned meta-analyses of pairwise comparisons for outcomes if direct evidence were available. Two review authors extracted evidence relating to barriers and facilitators to implementation, organised these around the domains of the Consolidated Framework of Implementation Research, and used the GRADE-CERQual approach to assess confidence in each finding. We planned to produce an overarching synthesis, bringing quantitative and qualitative findings together. MAIN RESULTS: We included 16 studies that reported implementation of an intervention aimed at supporting the resilience or mental health of frontline workers during disease outbreaks (severe acute respiratory syndrome (SARS): 2; Ebola: 9; Middle East respiratory syndrome (MERS): 1; COVID-19: 4). Interventions studied included workplace interventions, such as training, structure and communication (6 studies); psychological support interventions, such as counselling and psychology services (8 studies); and multifaceted interventions (2 studies). Objective 1: a mixed-methods study that incorporated a cluster-randomised trial, investigating the effect of a work-based intervention, provided very low-certainty evidence about the effect of training frontline healthcare workers to deliver psychological first aid on a measure of burnout. Objective 2: we included all 16 studies in our qualitative evidence synthesis; we classified seven as qualitative and nine as descriptive studies. We identified 17 key findings from multiple barriers and facilitators reported in studies. We did not have high confidence in any of the findings; we had moderate confidence in six findings and low to very low confidence in 11 findings. We are moderately confident that the following two factors were barriers to intervention implementation: frontline workers, or the organisations in which they worked, not being fully aware of what they needed to support their mental well-being; and a lack of equipment, staff time or skills needed for an intervention. We are moderately confident that the following three factors were facilitators of intervention implementation: interventions that could be adapted for local needs; having effective communication, both formally and socially; and having positive, safe and supportive learning environments for frontline workers. We are moderately confident that the knowledge or beliefs, or both, that people have about an intervention can act as either barriers or facilitators to implementation of the intervention. AUTHORS' CONCLUSIONS: There is a lack of both quantitative and qualitative evidence from studies carried out during or after disease epidemics and pandemics that can inform the selection of interventions that are beneficial to the resilience and mental health of frontline workers. Alternative sources of evidence (e.g. from other healthcare crises, and general evidence about interventions that support mental well-being) could therefore be used to inform decision making. When selecting interventions aimed at supporting frontline workers' mental health, organisational, social, personal, and psychological factors may all be important. Research to determine the effectiveness of interventions is a high priority. The COVID-19 pandemic provides unique opportunities for robust evaluation of interventions. Future studies must be developed with appropriately rigorous planning, including development, peer review and transparent reporting of research protocols, following guidance and standards for best practice, and with appropriate length of follow-up. Factors that may act as barriers and facilitators to implementation of interventions should be considered during the planning of future research and when selecting interventions to deliver within local settings.

A comparison and synthesis of rehabilitation definitions used by consumers (Google), major Stakeholders (survey) and researchers (Cochrane Systematic Reviews): a terminological analysis.

BACKGROUND: The term "rehabilitation" is heterogeneously used in the health context. Different interpretations can lead to disagreements, misunderstandings and different interpretations of what rehabilitation is between who provides it, who receives it and who studies it. The aim of this study was to conduct a terminological analysis of the different rehabilitation definitions used by different audiences: consumers, rehabilitation stakeholders and researchers. METHODS: We performed a terminological analysis with comparison of three different collections of rehabilitation definitions in English language. We performed: systematic reviews of databases representing consumers and lay persons (Google) and researchers (Cochrane Systematic Reviews [CSRs]), and a survey of rehabilitation stakeholders (Cochrane Rehabilitation Advisory Board). To aggregate words that had the same underlying concepts, their roots were extracted, and their occurrences counted. The 30 most frequent roots of each search were included. The 3 obtained collections were compared and similarities calculated. An overall collection of the most important 30 roots was obtained weighting those obtained in each single collection. All analyses have been performed using Excel. RESULTS: One hundred and eighty-seven rehabilitation definitions were identified: 23 from CSRs, 36 from the survey and 128 from Google. The most frequent roots were "function*" (92%), followed by "proces*" (69‰), "health*" (59‰), "disab*" (53‰), and "person*" (50‰). The most common relevant roots related to rehabilitation concept were "proces*" (73‰) in Google, "function*" (109‰) in the survey and "disab*" (41‰) in CSRs. The noun "function" prevailed in Google and "functioning" in the survey. CONCLUSIONS: According to our findings, any definition of rehabilitation for research purposes should include the identified terms, focusing on the concept of process and considering the main elements of functioning (and function), disability, person, health, optimization and environment.

Systematic review with network meta-analysis of randomized controlled trials of robotic-assisted arm training for improving activities of daily living and upper limb function after stroke.

BACKGROUND: The aim of the present study was to to assess the relative effectiveness of the various types of electromechanical-assisted arm devices and approaches after stroke. METHOD: This is a systematic review of randomized controlled trials with network meta-analysis. Our primary endpoints were activities of daily living (measured e.g. with Barthel-Index) and hand-arm function (measured e.g. with the Fugl-Meyer Scale for the upper limb), our secondary endpoints were hand-arm strength (measured e.g. with the Motricity Index) and safety. We used conventional arm training as our reference category and compared it with different intervention categories of electromechanical-assisted arm training depending on the therapy approach. We did indirect comparisons between the type of robotic device. We considered the heterogeneity of the studies by means of confidence and prediction intervals. RESULTS: Fifty five randomized controlled trials, including 2654 patients with stroke, met our inclusion criteria. For the primary endpoints activities of daily living and hand-arm function and the secondary endpoint hand-arm strength, none of the interventions achieved statistically significant improvements, taking into account the heterogeneity of the studies. Safety did not differ with regard to the individual interventions of arm rehabilitation after stroke. CONCLUSION: The outcomes of robotic-assisted arm training were comparable with conventional therapy. Indirect comparisons suggest that no one type of robotic device is any better or worse than any other device, providing no clear evidence to support the selection of specific types of robotic device to promote hand-arm recovery. TRIAL REGISTRATION: PROSPERO 2017 CRD42017075411.

A STING-based biosensor affords broad cyclic dinucleotide detection within single living eukaryotic cells.

Cyclic dinucleotides (CDNs) are second messengers conserved across all three domains of life. Within eukaryotes they mediate protective roles in innate immunity against malignant, viral, and bacterial disease, and exert pathological effects in autoimmune disorders. Despite their ubiquitous role in diverse biological contexts, CDN detection methods are limited. Here, using structure guided design of the murine STING CDN binding domain, we engineer a Förster resonance energy transfer (FRET) based biosensor deemed BioSTING. Recombinant BioSTING affords real-time detection of CDN synthase activity and inhibition. Expression of BioSTING in live human cells allows quantification of localized bacterial and eukaryotic CDN levels in single cells with low nanomolar sensitivity. These findings establish BioSTING as a powerful kinetic in vitro platform amenable to high throughput screens and as a broadly applicable cellular tool to interrogate the temporal and spatial dynamics of CDN signaling in a variety of infectious, malignant, and autoimmune contexts.

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation.

BACKGROUND: Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health.

Commercial gaming devices for stroke upper limb rehabilitation: The stroke survivor experience.

INTRODUCTION: Approximately 30% of stroke survivors experience an upper limb impairment, which impacts on participation and quality of life. Gaming devices (Nintendo Wii) are being incorporated into rehabilitation to improve function. We explored the stroke survivor experience of gaming as an upper limb intervention. METHODS: Semi-structured, individual interviews with stroke survivors living within the UK were completed. Interviews were audio-recorded, transcribed verbatim and analysed using Framework methods. Transcripts were coded and summarised into thematic charts. Thematic charts were refined during analysis until the final framework emerged. RESULTS: We captured experiences of 12 stroke survivors who used Nintendo Wii. Gaming devices were found to be acceptable for all ages but varying levels of enthusiasm existed. Enthusiastic players described gaming as having a positive impact on their motivation to engage in rehabilitation. For some, this became a leisure activity, encouraging self-practice. Non-enthusiastic players preferred sports to gaming. CONCLUSION: An in-depth account of stroke survivor experiences of gaming within upper limb rehabilitation has been captured. Suitability of gaming should be assessed individually and stroke survivor abilities and preference for interventions should be taken into consideration. There was no indication that older stroke survivors or those with no previous experience of gaming were less likely to enjoy the activity.

A pragmatic, multi-centered, stepped wedge, cluster randomized controlled trial pilot of the clinical and cost effectiveness of a complex Stroke Oral healthCare intervention pLan Evaluation II (SOCLE II) compared with usual oral healthcare in stroke wards.

BACKGROUND: Patients with stroke-associated pneumonia experience poorer outcomes (increased hospital stays, costs, discharge dependency, and risk of death). High-quality, organized oral healthcare may reduce the incidence of stroke-associated pneumonia and improve oral health and quality of life. AIMS: We piloted a pragmatic, stepped-wedge, cluster randomized controlled trial of clinical and cost effectiveness of enhanced versus usual oral healthcare for people in stroke rehabilitation settings. METHODS: Scottish stroke rehabilitation wards were randomly allocated to stepped time-points for conversion from usual to enhanced oral healthcare. All admissions and nursing staff were eligible for inclusion. We piloted the viability of randomization, intervention, data collection, record linkage procedures, our sample size, screening, and recruitment estimates. The stepped-wedge trial design prevented full blinding of outcome assessors and staff. Predetermined criteria for progression included the validity of enhanced oral healthcare intervention (training, oral healthcare protocol, assessment, equipment), data collection, and stroke-associated pneumonia event rate and relationship between stroke-associated pneumonia and plaque. RESULTS: We screened 1548/2613 (59%) admissions to four wards, recruiting n = 325 patients and n = 112 nurses. We observed marked between-site diversity in admissions, recruitment populations, stroke-associated pneumonia events (0% to 21%), training, and resource use. No adverse events were reported. Oral healthcare documentation was poor. We found no evidence of a difference in stroke-associated pneumonia between enhanced versus usual oral healthcare (P = 0.62, odds ratio = 0.61, confidence interval: 0.08 to 4.42). CONCLUSIONS: Our stepped-wedge cluster randomized control trial accommodated between-site diversity. The stroke-associated pneumonia event rate did not meet our predetermined progression criteria. We did not meet our predefined progression criteria including the SAP event rate and consequently were unable to establish whether there is a relationship between SAP and plaque. A wide confidence interval did not exclude the possibility that enhanced oral healthcare may result in a benefit or detrimental effect. TRIAL REGISTRATION: NCT01954212.

Rehabilitation interventions for improving balance following stroke: An overview of systematic reviews.

BACKGROUND: The aim of this study was to synthesize evidence from systematic reviews, to summarise the effects of rehabilitation interventions for improving balance in stroke survivors. METHODS: We conducted an overview of systematic reviews (SRs). We included Cochrane Systematic Reviews and non-Cochrane Systematic Reviews of randomized-controlled clinical trials and not-randomized clinical trials, in all types of stroke, comparing the effects of interventions, control interventions and no interventions on balance-related outcomes. We conducted a comprehensive search of electronic databases, from inception to December 2017. Data extracted included: number and type of participants, type of intervention, control intervention, method of assessing risk of bias of primary studies, balance outcome measures and results of statistical meta-analyses. Methodological quality of included reviews was assessed using AMSTAR 2. A narrative description of the characteristics of the SRs was provided and results of meta-analyses summarised with reference to their methodological quality. RESULTS: 51 SRs (248 primary studies and 10,638 participants) met the inclusion criteria and were included in the overview. All participants were adults with stroke. A wide variety of different balance and postural control outcomes were included. 61% of SRs focussed on the effectiveness of physical therapy, 20% virtual reality, 6% electromechanical devices, 4% Tai-Chi, whole body vibration and circuit training intervention, and 2% cognitive rehabilitation. The methodology of 54% of SRs were judged to be of a "low or critically low" quality, 23% "moderate" quality and 22% "high" quality. CONCLUSIONS: There are 51 SRs of evidence relating to the effectiveness of interventions to improve balance in people with stroke, but the majority of these are of poor methodological quality, limiting our ability to draw clear implications. Only 22% of these SRs were judged to be of high quality, highlighting the need to address important methodological issues within rehabilitation research.

Interventions for visual field defects in people with stroke.

BACKGROUND: Visual field defects are estimated to affect 20% to 57% of people who have had a stroke. Visual field defects can affect functional ability in activities of daily living (commonly affecting mobility, reading and driving), quality of life, ability to participate in rehabilitation, and depression and anxiety following stroke. There are many interventions for visual field defects, which are proposed to work by restoring the visual field (restitution); compensating for the visual field defect by changing behaviour or activity (compensation); substituting for the visual field defect by using a device or extraneous modification (substitution); or ensuring appropriate diagnosis, referral and treatment prescription through standardised assessment or screening, or both. OBJECTIVES: To determine the effects of interventions for people with visual field defects after stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register, the Cochrane Eyes and Vision Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, AMED, PsycINFO, and PDQT Databse, and clinical trials databases, including ClinicalTrials.gov and WHO Clinical Trials Registry, to May 2018. We also searched reference lists and trials registers, handsearched journals and conference proceedings, and contacted experts. SELECTION CRITERIA: Randomised trials in adults after stroke, where the intervention was specifically targeted at improving the visual field defect or improving the ability of the participant to cope with the visual field loss. The primary outcome was functional ability in activities of daily living and secondary outcomes included functional ability in extended activities of daily living, reading ability, visual field measures, balance, falls, depression and anxiety, discharge destination or residence after stroke, quality of life and social isolation, visual scanning, adverse events, and death. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, extracted data and appraised trials. We undertook an assessment of methodological quality for allocation concealment, blinding of outcome assessors, method of dealing with missing data, and other potential sources of bias. We assessed the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: Twenty studies (732 randomised participants, with data for 547 participants with stroke) met the inclusion criteria for this review. However, only 10 of these studies compared the effect of an intervention with a placebo, control, or no treatment group, and eight had data which could be included in meta-analyses. Only two of these eight studies presented data relating to our primary outcome of functional abilities in activities of daily living. One study reported evidence relating to adverse events.Three studies (88 participants) compared a restitutive intervention with a control, but data were only available for one study (19 participants). There was very low-quality evidence that visual restitution therapy had no effect on visual field outcomes, and a statistically significant effect on quality of life, but limitations with these data mean that there is insufficient evidence to draw any conclusions about the effectiveness of restitutive interventions as compared to control.Four studies (193 participants) compared the effect of scanning (compensatory) training with a control or placebo intervention. There was low-quality evidence that scanning training was more beneficial than control or placebo on quality of life, measured using the Visual Function Questionnaire (VFQ-25) (two studies, 96 participants, mean difference (MD) 9.36, 95% confidence interval (CI) 3.10 to 15.62). However, there was low or very-low quality evidence of no effect on measures of visual field, extended activities of daily living, reading, and scanning ability. There was low-quality evidence of no significant increase in adverse events in people doing scanning training, as compared to no treatment.Three studies (166 participants) compared a substitutive intervention (a type of prism) with a control. There was low or very-low quality evidence that prisms did not have an effect on measures of activities of daily living, extended activities of daily living, reading, falls, or quality of life, and very low-quality evidence that they may have an effect on scanning ability (one study, 39 participants, MD 9.80, 95% CI 1.91 to 17.69). There was low-quality evidence of an increased odds of an adverse event (primarily headache) in people wearing prisms, as compared to no treatment.One study (39 participants) compared the effect of assessment by an orthoptist to standard care (no assessment) and found very low-quality evidence that there was no effect on measures of activities of daily living.Due to the quality and quantity of evidence, we remain uncertain about the benefits of assessment interventions. AUTHORS' CONCLUSIONS: There is a lack of evidence relating to the effect of interventions on our primary outcome of functional ability in activities of daily living. There is limited low-quality evidence that compensatory scanning training may be more beneficial than placebo or control at improving quality of life, but not other outcomes. There is insufficient evidence to reach any generalised conclusions about the effect of restitutive interventions or substitutive interventions (prisms) as compared to placebo, control, or no treatment. There is low-quality evidence that prisms may cause minor adverse events.

Cochrane overviews: how can we optimize their impact on evidence-based rehabilitation?

INTRODUCTION: Overviews (i.e. reviews of multiple systematic reviews) comprise a relatively novel methodology to systematically synthesize research findings. Overviews aim for a beneficial impact on clinical practice, but their methods and pathways to impact have so far not been mapped. The aim of this paper was to inform recommendations for optimizing impact on rehabilitation practice and research by mapping methods and pathways to impact in Cochrane overviews relevant to rehabilitation. EVIDENCE ACQUISITION: We systematically searched and identified published Cochrane overviews (to June 2018) relevant to rehabilitation. We extracted data and compared overviews on key characteristics, methods of evidence synthesis, statements about impact, and access metrics. We explored one overview in detail regarding beneficiaries, activities and outputs, mapped potential pathways to impact, and, using an iterative process, refined this into a generic map. Through exploration of all synthesized data, we propose further recommendations for planning, conducting and reporting of future overviews in order to optimize impact on rehabilitation. EVIDENCE SYNTHESIS: We identified seven Cochrane overviews relevant to rehabilitation. Their focus and methods varied, but they were broadly related to rehabilitation interventions for populations of people with diverse long-term conditions. Overviews also varied regarding their intended impact; only 4 overviews identified specific beneficiaries. All overviews included multiple tables and figures, but only one synthesized key findings into a single figure. For five overviews, the Altmetric Attention Score (a weighted count of attention that an output receives based on a range of online sources) was in the top 5% of all research outputs scored by Altmetric. The overview within our worked example had four key impact goals, each with different beneficiaries and required actions; this example led to a generic map of potential pathways to impact for other overviews. CONCLUSIONS: Cochrane overviews have the potential to play a key role in knowledge translation and therefore to be useful in supporting evidence-based rehabilitation practice. However, current overviews relating to rehabilitation differ in methods, approaches and intended impact, and sometimes fall short of promoting easy access to key information for beneficiaries. Future Cochrane overviews should address topics of importance to key beneficiaries and clearly outline potential pathways to impact in order to have a potential beneficial impact on evidence-based rehabilitation and to improve rehabilitation outcomes.