Active Site-directed Inactivation of Escherichia coli Glucosamine-6-phosphate Synthase DETERMINATION OF THE FRUCTOSE 6-PHOSPHATE BINDING CONSTANT USING A CARBOHYDRATE-BASED INACTIVATOR

Glucosamine-6-phosphate synthase (GlmS) catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate using glutamine as the ammonia source. Because N-acetylglucosamine is an essential building block of both bacterial cell walls and fungal cell wall chitin, the enzyme is a potential target for antibacterial and antifungal agents. N-Iodoacetylglucosamine 6-phosphate is an active site-directed irreversible inactivator of GlmS from Escherichia coli (kinact/KI = 17 (+/-3) m-1 s-1). Both fructose 6-phosphate and glutamine protect the enzyme from inactivation, indicating that this reagent is directed at both the sugar binding site and the glutamine binding site. Protection studies with fructose 6-phosphate demonstrate that the value of the dissociation constant for fructose 6-phosphate is 3.3 (+/-0.5) x 10(-7) m, approximately 3 orders of magnitude less than the Kia value for this substrate determined from initial velocity experiments (Badet, B., Vermoote, P., and Le Goffic, F. (1988) Biochemistry 27, 2282-2287)

The experiences and acceptability of a novel multimodal programme for the management of fibromyalgia: A qualitative service evaluation.

INTRODUCTION: Fibromyalgia guidelines recommend multi-modal, non-pharmacological interventions but there is limited evidence on the optimal programme. The Fibromyalgia Active Management and Exercise programme (FAME) aimed to improve function and quality of life. It consisted of 12 sessions delivered by a multidisciplinary team and incorporated education, exercise, Cognitive Behavioural Therapy and mindfulness approaches. This qualitative service evaluation explored the experience and acceptability of FAME from the perspective of the patients' and healthcare practitioners' (HCP). METHODS: All patients and HCP involved in the first FAME programme were invited to attend either one audio-recorded focus group or an individual semi-structured interview. Topic guides were developed a priori. Data were transcribed verbatim and analysed thematically. RESULTS: Thirteen participants (six HCP (three physiotherapists, two nurses, one psychologist)) and seven patients (mean age 46 (7.5) years, all female,) were enroled. FAME was acceptable to HCP participants but not to all patient participants. Where patient participants understood and anticipated the aims of FAME, the programme was found to be acceptable. Whereas, patient participants who did not fully understand the aims of the programme reported lower acceptability. Three themes were generated: expectations and preparation for FAME, the value of social support, and FAME as a learning opportunity. The themes could be explained by five constructs of the Theoretical Framework of Acceptability. CONCLUSION: FAME was acceptable to HCPs but not to all patient participants. Patient and HCP participants valued social support and regarded this as central to their learning. Further adaptation of FAME is required to optimise acceptability

Exploring how members of the public access and use health research and information: a scoping review

Background Making high-quality health and care information available to members of the general public is crucial to support populations with self-care and improve health outcomes. While attention has been paid to how the public accesses and uses health information generally (including personal records, commercial product information or reviews on healthcare practitioners and organisations) and how practitioners and policy-makers access health research evidence, no overview exists of the way that the public accesses and uses high quality health and care information. Purpose This scoping review aimed to map research evidence on how the public accesses and uses a specific type of health information, namely health research and information that does not include personal, product and organisational information. Methods Electronic database searches [CINAHL Plus, MEDLINE, PsycInfo, Social Sciences Full Text, Web of Science and SCOPUS] for English language studies of any research design published between 2010–2022 on the public’s access and use of health research or information (as defined above). Data extraction and analysis was informed by the Joanna Briggs Institute protocol for scoping reviews, and reported in accordance with the PRISMA extension for scoping reviews. Results The search identified 4410 records. Following screening of 234 full text studies, 130 studies were included. One-hundred-and-twenty-nine studies reported on the public’s sources of health-research or information; 56 reported the reasons for accessing health research or information and 14 reported on the use of this research and information. The scoping exercise identified a substantial literature on the broader concept of ‘health information’ but a lack of reporting of the general public’s access to and use of health research. It found that ‘traditional’ sources of information are still relevant alongside newer sources; knowledge of barriers to accessing information focused on personal barriers and on independent searching, while less attention had been paid to barriers to access through other people and settings, people’s lived experiences, and the cultural knowledge required. Conclusions The review identified areas where future primary and secondary research would enhance current understanding of how the public accesses and utilises health research or information, and contribute to emerging areas of research

The Use of Social Media for Dissemination of Research Evidence to Health and Social Care Practitioners: Protocol for a Systematic Review.

BACKGROUND: Effective dissemination of research to health and social care practitioners enhances clinical practice and evidence-based care. Social media use has potential to facilitate dissemination to busy practitioners. OBJECTIVE: This is a protocol for a systematic review that will quantitatively synthesize evidence of the effectiveness of social media, compared with no social media, for dissemination of research evidence to health and social care practitioners. Social media platforms, formats, and sharing mechanisms used for effective dissemination of research evidence will also be identified and compared. METHODS: Electronic database searches (MEDLINE, PsycINFO, CINAHL, ERIC, LISTA, and OpenGrey) will be conducted from January 1, 2010, to January 10, 2023, for studies published in English. Randomized, nonrandomized, pre-post study designs or case studies evaluating the effect of social media on dissemination of research evidence to postregistration health and social care practitioners will be included. Studies that do not involve social media or dissemination or those that evaluate dissemination of nonresearch information (eg, multisource educational materials) to students or members of the public only, or without quantitative data on outcomes of interest, will be excluded. Screening will be carried out by 2 independent reviewers. Data extraction and quality assessment, using either the Cochrane tool for assessing risk of bias or the Newcastle-Ottawa Scale, will be completed by 2 independent reviewers. Outcomes of interest will be reported in 4 domains (reach, engagement, dissemination, and impact). Data synthesis will include quantitative comparisons using narrative text, tables, and figures. A meta-analysis of standardized pooled effects will be undertaken, and subgroup analyses will be applied, if appropriate. RESULTS: Searches and screening will be completed by the end of May 2023. Data extraction and analyses will be completed by the end of July 2023, after which findings will be synthesized and reported by the end of October 2023. CONCLUSIONS: This systematic review will summarize the evidence for the effectiveness of social media for the dissemination of research evidence to health and social care practitioners. The limitations of the evidence may include multiple outcomes or methodological heterogeneity that limit meta-analyses, potential risk of bias in included studies, and potential publication bias. The limitations of the study design may include potential insensitivity of the electronic database search strategy. The findings from this review will inform the dissemination practice of health and care research. TRIAL REGISTRATION: PROSPERO CRD42022378793; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=378793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45684

Effectiveness of web-based and mobile health interventions designed to enhance adherence to physical activity for people with inflammatory arthritis: a systematic review

Objective: The aim of this systematic review was to assess the evidence from randomized controlled trials (RCTs) and cohort studies for the effectiveness of digital interventions designed to enhance adherence to physical activity (PA) for people with inflammatory arthritis and describe the intervention content using established coding criteria. Methods: Six electronic databases were searched for published and unpublished studies. Independent data extraction and quality assessment (Cochrane risk of bias II or ROBINS-I) were conducted by two reviewers. The primary outcome was self-reported adherence to PA post-intervention. Secondary outcomes included self-reported adherence to PA at other time points, level of PA or engagement with intervention at any follow-up time point. Intervention content was assessed using the Consensus on Exercise Reporting Template and the Behaviour Change Techniques Taxonomy version 1. Results: From 11 136 citations, four moderate risk of bias studies (three RCTs and one cohort study) including 1160 participants with RA or JIA were identified. Owing to heterogeneity of outcomes, a narrative synthesis was conducted. Only one RCT reported a small between-group difference in adherence to PA [mean difference (95% CI) -0.46 (-0.82, -0.09)] in favour of the intervention. There were no between-group differences in any secondary outcomes. Interventions included between 3 and 11 behaviour change techniques but provided minimal information on exercise prescription. Conclusion: There is currently limited moderate-quality evidence available to provide confident evaluation of the effect of web-based and mobile health interventions on adherence to PA or level of PA post-intervention in people with inflammatory arthritis

‘[N]ow I can be a poetic writer’: using action research as a way of reclaiming and implementing professional values in the primary school

This paper explores the impact of an action research intervention to support primary aged children’s confidence as writers. Set in a school where few children (the majority of whom had English as an additional language) were performing at or beyond national expectations in terms of writing, the intervention looked at how to engage children more effectively, by promoting enjoyment of writing and providing quality mentor texts to inspire the children. The school had received a number of critical inspection reports and had consequently adopted a series of measures to improve academic outcomes, which acted as a constraint on my teaching. There was a real sense that as a teacher I was struggling to put my educational values into practice. In addition, my lack of confidence in my abilities as a writer acted as a further constraint. Adopting an action research approach enabled me to develop my personal confidence as a teacher of writing, explore more effective ways to teach writing, resulting in the development of confident and reflective writers in the classroom

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Global, regional, and national burden of low back pain, 1990–2020, its attributable risk factors, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Background: Low back pain is highly prevalent and the main cause of years lived with disability (YLDs). We present the most up-to-date global, regional, and national data on prevalence and YLDs for low back pain from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021. Methods: Population-based studies from 1980 to 2019 identified in a systematic review, international surveys, US medical claims data, and dataset contributions by collaborators were used to estimate the prevalence and YLDs for low back pain from 1990 to 2020, for 204 countries and territories. Low back pain was defined as pain between the 12th ribs and the gluteal folds that lasted a day or more; input data using alternative definitions were adjusted in a network meta-regression analysis. Nested Bayesian meta-regression models were used to estimate prevalence and YLDs by age, sex, year, and location. Prevalence was projected to 2050 by running a regression on prevalence rates using Socio-demographic Index as a predictor, then multiplying them by projected population estimates. Findings: In 2020, low back pain affected 619 million (95% uncertainty interval 554–694) people globally, with a projection of 843 million (759–933) prevalent cases by 2050. In 2020, the global age-standardised rate of YLDs was 832 per 100 000 (578–1070). Between 1990 and 2020, age-standardised rates of prevalence and YLDs decreased by 10·4% (10·9–10·0) and 10·5% (11·1–10·0), respectively. A total of 38·8% (28·7–47·0) of YLDs were attributed to occupational factors, smoking, and high BMI. Interpretation: Low back pain remains the leading cause of YLDs globally, and in 2020, there were more than half a billion prevalent cases of low back pain worldwide. While age-standardised rates have decreased modestly over the past three decades, it is projected that globally in 2050, more than 800 million people will have low back pain. Challenges persist in obtaining primary country-level data on low back pain, and there is an urgent need for more high-quality, primary, country-level data on both prevalence and severity distributions to improve accuracy and monitor change. Funding: Bill and Melinda Gates Foundation

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion ofTrypanosoma cruzi

Proline is crucial for energizing critical events throughout the life cycle of Trypanosoma cruzi, the etiological agent of Chagas disease. The proline breakdown pathway consists of two oxidation steps, both of which producereducing equivalents as follows: the conversion of proline to Δ1-pyrroline-5-carboxylate (P5C), and the subsequent conversion of P5C to glutamate. We have identified and characterized the Δ1-pyrroline-5-carboxylate dehydrogenase from T. cruzi (TcP5CDH) and report here on how this enzyme contributes to a central metabolic pathway in this parasite. Size-exclusionchromatography, two-dimensional gel electrophoresis, and small angle x-ray scattering analysis of TcP5CDH revealed an oligomericstate composed of two subunits of six protomers. TcP5CDH was found to complement a yeast strain deficient in PUT2 activity,confirming the enzyme's functional role; and the biochemical parameters (Km, kcat, and kcat/Km) of the recombinant TcP5CDH were determined, exhibiting values comparable with those from T. cruzi lysates. In addition, TcP5CDH exhibited mitochondrial staining during the main stages of the T. cruzi life cycle. mRNA and enzymatic activity levels indicated the up-regulation (6-fold change) of TcP5CDH during the infectivestages of the parasite. The participation of P5C as an energy source was also demonstrated. Overall, we propose that thisenzymatic step is crucial for the viability of both replicative and infective forms of T. cruzi