Summary Loss of functional movement is a common consequence of stroke for which a wide range of interventions has been developed. In this Review, we aimed to provide an overview of the available ...evidence on interventions for motor recovery after stroke through the evaluation of systematic reviews, supplemented by recent randomised controlled trials. Most trials were small and had some design limitations. Improvements in recovery of arm function were seen for constraint-induced movement therapy, electromyographic biofeedback, mental practice with motor imagery, and robotics. Improvements in transfer ability or balance were seen with repetitive task training, biofeedback, and training with a moving platform. Physical fitness training, high-intensity therapy (usually physiotherapy), and repetitive task training improved walking speed. Although the existing evidence is limited by poor trial designs, some treatments do show promise for improving motor recovery, particularly those that have focused on high-intensity and repetitive task-specific practice.
Cyclic di-adenosine monophosphate (c-di-AMP) is a widely distributed second messenger that appears to be essential in multiple bacterial species, including the Gram-positive facultative intracellular ...pathogen Listeria monocytogenes. In this study, the only L. monocytogenes diadenylate cyclase gene, dacA, was deleted using a Cre-lox system activated during infection of cultured macrophages. All ΔdacA strains recovered from infected cells harbored one or more suppressor mutations that allowed growth in the absence of c-di-AMP. Suppressor mutations in the synthase domain of the bi-functional (p)ppGpp synthase/hydrolase led to reduced (p)ppGpp levels. A genetic assay confirmed that dacA was essential in wild-type but not strains lacking all three (p)ppGpp synthases. Further genetic analysis suggested that c-di-AMP was essential because accumulated (p)ppGpp altered GTP concentrations, thereby inactivating the pleiotropic transcriptional regulator CodY. We propose that c-di-AMP is conditionally essential for metabolic changes that occur in growth in rich medium and host cells but not minimal medium.
Display omitted
•c-di-AMP is predicted to be essential in many pathogens and is thus an ideal PAMP•ΔdacA mutants lacking c-di-AMP contain suppressor mutations within a (p)ppGpp synthase•Decreased c-di-AMP increases (p)ppGpp, which inhibits growth via inactivation of CodY•In minimal medium, which favors CodY inactivation, dacA is no longer essential
c-di-AMP is a nucleotide second messenger recognized by the innate immune system and is predicted to be essential in many bacteria. Whiteley et al. show that depletion of c-di-AMP within Listeria monocytogenes leads to accumulation of (p)ppGpp, which inhibits bacterial growth but is also necessary for virulence.
Overviews of systematic reviews are a relatively new approach to synthesising evidence, and research methods and associated guidance are developing. Within this paper we aim to help readers ...understand key issues which are essential to consider when taking the first steps in planning an overview. These issues relate to the development of clear, relevant research questions and objectives prior to the development of an overview protocol.
Initial discussions and key concepts for this paper were formed during a workshop on overview methods at the 2016 UK Cochrane Symposium, at which all members of this author group presented work and contributed to wider discussions. Detailed descriptions of the various key features of overviews and their different objectives were created by the author group based upon current evidence (Higgins J, Green S. Cochrane Handbook Syst Rev Interv. 2011;4:5, Pollock M, et al. Sys Rev. 2016;5:190-205, Pollock A, et al. Cochrane overviews of reviews: exploring the methods and challenges. UK and Ireland: Cochrane Symposium; 2016, Pieper D, et al. Res Syn Meth. 2014;5:187-99, Lunny C, et al. Sys Rev. 2016;5:4-12, Hartling L, et al. Comparing multiple treatments: an introduction to overviews of reviews. In 23rd Cochrane Colloquium; 2015, Hartling L, et al. Plos One. 2012;7:1-8, Ballard M, Montgomery P. Res Syn Meth. 2017;8:92-108) and author experiences conducting overviews.
Within this paper we introduce different types of overviews and suggest common research questions addressed by these overviews. We briefly reflect on the key features and objectives of the example overviews discussed.
Clear decisions relating to the research questions and objectives are a fundamental first step during the initial planning stages for an overview. Key stakeholders should be involved at the earliest opportunity to ensure that the planned overview is relevant and meaningful to the potential end users of the overview. Following best practice in common with other forms of systematic evidence synthesis, an overview protocol should be published, ensuring transparency and reducing opportunities for introduction of bias in the conduct of the overview.
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.
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.
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.
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.
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.
PROSPERO 2017 CRD42017075411.
The challenge of addressing unhealthy lifestyle choice is of global concern. Motivational Interviewing has been widely implemented to help people change their behaviour, but it is unclear for whom it ...is most beneficial. This overview aims to appraise and synthesise the review evidence for the effectiveness of Motivational Interviewing on health behaviour of adults in health and social care settings.
A systematic review of reviews. Methods were pre-specified and documented in a protocol (PROSPERO-CRD42016049278). We systematically searched 7 electronic databases: CDSR; DARE; PROSPERO; MEDLINE; CINAHL; AMED and PsycINFO from 2000 to May 2018. Two reviewers applied pre-defined selection criteria, extracted data using TIDIER guidelines and assessed methodological quality using the ROBIS tool. We used GRADE criteria to rate the strength of the evidence for reviews including meta-analyses.
Searches identified 5222 records. One hundred and four reviews, including 39 meta-analyses met the inclusion criteria. Most meta-analysis evidence was graded as low or very low (128/155). Moderate quality evidence for mainly short term (<6 months) statistically significant small beneficial effects of Motivational Interviewing were found in 11 of 155 (7%) of meta-analysis comparisons. These outcomes include reducing binge drinking, frequency and quantity of alcohol consumption, substance abuse in people with dependency or addiction, and increasing physical activity participation.
We have created a comprehensive map of reviews relating to Motivational Interviewing to signpost stakeholders to the best available evidence. More high quality research is needed to be confident about the effectiveness of Motivational Interviewing. We identified a large volume of low quality evidence and many areas of overlapping research. To avoid research waste, it is vital for researchers to be aware of existing research, and the implications arising from that research. In the case of Motivational Interviewing issues relating to monitoring and reporting fidelity of interventions need to be addressed.
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.
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.
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.
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.
Replication-transcription collisions shape genomes, influence evolution, and promote genetic diseases. Although unclear why, head-on transcription (lagging strand genes) is especially disruptive to ...replication and promotes genomic instability. Here, we find that head-on collisions promote R-loop formation in Bacillus subtilis. We show that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression. Accordingly, the activity of the R-loop processing enzyme RNase HIII at collision regions is crucial for stress survival in B. subtilis, as many stress response genes are head-on to replication. Remarkably, without RNase HIII, the ability of the intracellular pathogen Listeria monocytogenes to infect and replicate in hosts is weakened significantly, most likely because many virulence genes are head-on to replication. We conclude that the detrimental effects of head-on collisions stem primarily from excessive R-loop formation and that the resolution of these structures is critical for bacterial stress survival and pathogenesis.
Display omitted
•Head-on replication-transcription collisions lead to pervasive R-loop formation•R-loops at head-on genes stall replication, increase mutagenesis, and prevent restart•Gene-expression defects occur if R-loops at head-on genes are not resolved•Bacterial stress survival and pathogenesis requires R-loop processing at head-on genes
Head-on replication-transcription collisions lead to pervasive R-loop formation, which must be resolved for bacterial stress survival and pathogenesis.
PDF
