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Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability
Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-α) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-α mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-α 3′ untranslated region. The p38 pathway is required for the induction of TNF-α RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-α gene expression at a posttranscriptional level.
COMPare: Qualitative analysis of researchers' responses to critical correspondence on a cohort of 58 misreported trials
© 2019 The Author(s). Background: Discrepancies between pre-specified and reported outcomes are an important and prevalent source of bias in clinical trials. COMPare (Centre for Evidence-Based Medicine Outcome Monitoring Project) monitored all trials in five leading journals for correct outcome reporting, submitted correction letters on all misreported trials in real time, and then monitored responses from editors and trialists. From the trialists' responses, we aimed to answer two related questions. First, what can trialists' responses to corrections on their own misreported trials tell us about trialists' knowledge of correct outcome reporting? Second, what can a cohort of responses to a standardised correction letter tell us about how researchers respond to systematic critical post-publication peer review? Methods: All correspondence from trialists, published by journals in response to a correction letter from COMPare, was filed and indexed. We analysed the letters qualitatively and identified key themes in researchers' errors about correct outcome reporting, and approaches taken by researchers when their work was criticised. Results: Trialists frequently expressed views that contradicted the CONSORT (Consolidated Standards of Reporting Trials) guidelines or made inaccurate statements about correct outcome reporting. Common themes were: stating that pre-specification after trial commencement is acceptable; incorrect statements about registries; incorrect statements around the handling of multiple time points; and failure to recognise the need to report changes to pre-specified outcomes in the trial report. We identified additional themes in the approaches taken by researchers when responding to critical correspondence, including the following: ad hominem criticism; arguing that trialists should be trusted, rather than follow guidelines for trial reporting; appealing to the existence of a novel category of outcomes whose results need not necessarily be reported; incorrect statements by researchers about their own paper; and statements undermining transparency infrastructure, such as trial registers. Conclusions: Researchers commonly make incorrect statements about correct trial reporting. There are recurring themes in researchers' responses when their work is criticised, some of which fall short of the scientific ideal. Research on methodological shortcomings is now common, typically in the form of retrospective cohort studies describing the overall prevalence of a problem. We argue that prospective cohort studies which additionally issue correction letters in real time on each individual flawed study - and then follow-up responses from trialists and journals - are more impactful, more informative for those consuming the studies critiqued, more informative on the causes of shortcomings in research, and a better use of research resources.
© 2019 The Author(s). Background: Discrepancies between pre-specified and reported outcomes are an important source of bias in trials. Despite legislation, guidelines and public commitments on correct reporting from journals, outcome misreporting continues to be prevalent. We aimed to document the extent of misreporting, establish whether it was possible to publish correction letters on all misreported trials as they were published, and monitor responses from editors and trialists to understand why outcome misreporting persists despite public commitments to address it. Methods: We identified five high-impact journals endorsing Consolidated Standards of Reporting Trials (CONSORT) (New England Journal of Medicine, The Lancet, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine) and assessed all trials over a six-week period to identify every correctly and incorrectly reported outcome, comparing published reports against published protocols or registry entries, using CONSORT as the gold standard. A correction letter describing all discrepancies was submitted to the journal for all misreported trials, and detailed coding sheets were shared publicly. The proportion of letters published and delay to publication were assessed over 12 months of follow-up. Correspondence received from journals and authors was documented and themes were extracted. Results: Sixty-seven trials were assessed in total. Outcome reporting was poor overall and there was wide variation between journals on pre-specified primary outcomes (mean 76% correctly reported, journal range 25-96%), secondary outcomes (mean 55%, range 31-72%), and number of undeclared additional outcomes per trial (mean 5.4, range 2.9-8.3). Fifty-eight trials had discrepancies requiring a correction letter (87%, journal range 67-100%). Twenty-three letters were published (40%) with extensive variation between journals (range 0-100%). Where letters were published, there were delays (median 99 days, range 0-257 days). Twenty-nine studies had a pre-trial protocol publicly available (43%, range 0-86%). Qualitative analysis demonstrated extensive misunderstandings among journal editors about correct outcome reporting and CONSORT. Some journals did not engage positively when provided correspondence that identified misreporting; we identified possible breaches of ethics and publishing guidelines. Conclusions: All five journals were listed as endorsing CONSORT, but all exhibited extensive breaches of this guidance, and most rejected correction letters documenting shortcomings. Readers are likely to be misled by this discrepancy. We discuss the advantages of prospective methodology research sharing all data openly and pro-actively in real time as feedback on critiqued studies. This is the first empirical study of major academic journals' willingness to publish a cohort of comparable and objective correction letters on misreported high-impact studies. Suggested improvements include changes to correspondence processes at journals, alternatives for indexed post-publication peer review, changes to CONSORT's mechanisms for enforcement, and novel strategies for research on methods and reporting.
Metabolic syndrome and weight management programs in primary care: a comparison of three international healthcare systems.
Lifestyle behaviours are contributing to the increasing incidence of chronic disease across all developed countries. Australia, Canada and the UK have had different approaches to the role of primary care in the prevention and management of lifestyle-related diseases. Both obesity and metabolic syndrome have been targeted by programs to reduce individual risk for chronic disease such as type 2 diabetes. Three interventions are described - for either obesity or metabolic syndrome - that have varying levels of involvement of GPs and other primary care professionals. The structure of a healthcare system for example, financing and physical locations of primary care clinicians, shapes the development of primary care interventions. The type of clinicians involved in interventions, whether they work alone or in teams, is influenced by the primary care setting and resource availability. Australian clinicians and policymakers should take into account the healthcare system where interventions are developed when translating interventions to the Australian context.
'Say no': a feasibility trial of a brief intervention to reduce instances of indulgent energy-intake episodes
© 2018 World Obesity Federation. The aim of this study is to examine the feasibility of a brief intervention to reduce instances of indulgent energy intake. Forty-five participants with a body mass index (BMI) ≥25 kg m-2 were randomized to one of three groups for 8 weeks. The control group was asked to complete a questionnaire every 4 days, the self-monitoring group was given the same instructions but also asked to 'say no' to indulgences. The self-monitoring and feedback group was asked to do the same but in addition to send a photograph or description of that to which they had 'said no' and were then provided with feedback. All participants reported on indulgences for 7 days prospectively at baseline and 8-week follow-up. The follow-up rate was 80%; completion of questionnaires was 63% and 87 text messages were sent. The control group reduced their indulgences by 4.1 (SD 10.0), the self-monitoring group by 13.8 (SD 16.8) and self-monitoring and feedback group by 9.0 (SD 11.7) per week. All bar one, feasibility progression criteria were met and this was the return of the indulgence diaries during the intervention period. The study demonstrates the feasibility of a brief intervention to reduce the number of indulgences people ate. The progression criteria were met and areas of improvement are highlighted.
OBJECTIVES:This study measures the average per person and annual total costs of dementia in England in 2015. METHODS/DESIGN:Up-to-date data for England were drawn from multiple sources to identify prevalence of dementia by severity, patterns of health and social care service utilisation and their unit costs, levels of unpaid care and its economic impacts, and other costs of dementia. These data were used in a refined macrosimulation model to estimate annual per-person and aggregate costs of dementia. RESULTS:There are around 690,000 people with dementia in England, of whom 565,000 receive unpaid care or community care or live in a care home. Total annual cost of dementia in England is estimated to be £24.2 billion in 2015, of which 42% (£10.1 billion) is attributable to unpaid care. Social care costs (£10.2 billion) are three times larger than healthcare costs (£3.8 billion). £6.2 billion of the total social care costs are met by users themselves and their families, with £4.0 billion (39.4%) funded by government. Total annual costs of mild, moderate, and severe dementia are £3.2 billion, £6.9 billion and £14.1 billion, respectively. Average costs of mild, moderate and severe dementia are £24,400, £27,450, and £46,050, respectively, per person per year. CONCLUSIONS:Dementia has huge economic impacts on people living with the illness, their carers and society as a whole. Better support for people with dementia and their carers, as well as fair and efficient financing of social care services, are essential to address the current and future challenges of dementia.
Patient consultation rate and clinical and NHS outcomes: a cross-sectional analysis of English primary care data from 2.7 million patients in 238 practices.
BACKGROUND: Primary care workload is high and increasing in the United Kingdom. We sought to examine the association between rates of primary care consultation and outcomes in England. METHODS: Cross sectional observational study of routine electronic health care records in 283 practices from the Clinical Practice Research Datalink from April 2013 to March 2014. Outcomes included mortality rate, hospital admission rate, Quality and Outcomes Framework (QOF) performance and patient satisfaction. Relationships between consultation rates (with a general practitioner (GP) or nurse) and outcomes were investigated using negative binomial and ordinal logistic regression models. RESULTS: Rates of GP and nurse consultation (per patient person-year) were not associated with mortality or hospital admission rates: mortality incidence rate ratio (IRR) per unit change in GP/ nurse consultation rate = 1.01, 95% CI [0.98 to 1.04]/ 0.97, 95% CI [0.93 to 1.02]; hospital admission IRR per unit change in GP/ nurse consultation rate = 1.02, 95% CI [0.99 to 1.04]/ 0.98, 95% CI [0.94 to 1.032]. Higher rates of nurse but not GP consultation were associated with higher QOF achievement: OR = 1.91, 95% CI [1.39 to 2.62] per unit change in nurse consultation rate vs. OR = 1.04, 95% CI [0.87 to 1.24] per unit change in GP consultation rate. The association between the rates of GP/ nurse consultations and patient satisfaction was mixed. CONCLUSION: There are few associations between primary care consultation rates and outcomes. Previously identified demographic and staffing factors, rather than practice workload, appear to have the strongest relationships with mortality, admissions, performance and satisfaction. Studies with more detailed patient-level data would be required to explore these findings further.
Feasibility and acceptability of a motivational interviewing breastfeeding peer support intervention
© 2018 John Wiley & Sons Ltd An uncontrolled study with process evaluation was conducted in three U.K. community maternity sites to establish the feasibility and acceptability of delivering a novel breastfeeding peer-support intervention informed by motivational interviewing (MI; Mam-Kind). Peer-supporters were trained to deliver the Mam-Kind intervention that provided intensive one-to-one peer-support, including (a) antenatal contact, (b) face-to-face contact within 48 hr of birth, (c) proactive (peer-supporter led) alternate day contact for 2 weeks after birth, and (d) mother-led contact for a further 6 weeks. Peer-supporters completed structured diaries and audio-recorded face-to-face sessions with mothers. Semistructured interviews were conducted with a purposive sample of mothers, health professionals, and all peer-supporters. Interview data were analysed thematically to assess intervention acceptability. Audio-recorded peer-support sessions were assessed for intervention fidelity and the use of MI techniques, using the MITI 4.2 tool. Eight peer-supporters delivered the Mam-Kind intervention to 70 mothers in three National Health Service maternity services. Qualitative interviews with mothers (n = 28), peer-supporters (n = 8), and health professionals (n = 12) indicated that the intervention was acceptable, and health professionals felt it could be integrated with existing services. There was high fidelity to intervention content; 93% of intervention objectives were met during sessions. However, peer-supporters reported difficulties in adapting from an expert-by-experience role to a collaborative role. We have established the feasibility and acceptability of providing breastfeeding peer-support using a MI-informed approach. Refinement of the intervention is needed to further develop peer-supporters' skills in providing mother-centred support. The refined intervention should be tested for effectiveness in a randomised controlled trial.
OBJECTIVE: To explore pregnant women's preferences for birth setting in England. DESIGN: Labelled discrete choice experiment (DCE). SETTING: Online survey. SAMPLE: Pregnant women recruited through social media and an online panel. METHODS: We developed a DCE to assess women's preferences for four hypothetical birth settings based on seven attributes: reputation, continuity of care, distance from home, time to see a doctor, partner able to stay overnight, chance of straightforward birth and safety for baby. We used a mixed logit model, with setting modelled as an alternative-specific constant, and conducted a scenario analysis to evaluate the impact of changes in attribute levels on uptake of birth settings. MAIN OUTCOME MEASURES: Women's preferences for birth setting. RESULTS: 257 pregnant women completed the DCE. All birth setting attributes, except 'time to see doctor', were significant in women's choice (p<0.05). There was significant heterogeneity in preferences for some attributes. Changes to levels for 'safety for the baby' and 'partner able to stay overnight' were associated with larger changes from baseline uptake of birth setting. If the preferences identified were translated into the real-world context up to a third of those who reported planning birth in an obstetric unit might choose a midwifery unit assuming universal access to all settings, and knowledge of the differences between settings. CONCLUSIONS: We found that 'safety for the baby', 'chance of a straightforward birth' and 'can the woman's partner stay overnight following birth' were particularly important in women's preferences for hypothetical birth setting. If all birth settings were available to women and they were aware of the differences between them, it is likely that more low risk women who currently plan birth in OUs might choose a midwifery unit.
INTRODUCTION: Concern about weight gain is a barrier to smoking cessation. E-cigarettes may help quitters to control their weight through continued exposure to the appetite-suppressant effects of nicotine and behavioural aspects of vaping. This study explored the views and practices of smokers, ex-smokers and current e-cigarette users relating to vaping and weight control. METHODS: Cross-sectional survey of past-year smokers (n = 1320), current smokers (n = 1240) and current e-cigarette users (n = 394) in England, conducted April-July 2018. Data were weighted to match the English population on key sociodemographic characteristics. RESULTS: Of e-cigarette users, 4.6% (95%CI 2.6-6.6) reported vaping for weight control, and 1.9% (95%CI 0.6-3.2) reported vaping to replace meals/snacks. It was rare for individuals who had smoked in the past year to have heard (8.8%, 95%CI 7.3-10.3) or believe (6.4%, 95%CI 5.1-7.7) that vaping could help control weight. Women (OR = 0.62, 95%CI 0.42-0.93) and older people (OR = 0.30, 95%CI 0.13-0.72) were less likely to have heard the claim and women were less likely to believe it (OR = 0.44, 95%CI 0.27-0.72). However, 13.4% (95%CI 11.3-15.5) and 13.1% (95%CI 11.0-15.2) of current smokers who did not use e-cigarettes said they would be more likely to try e-cigarettes or quit smoking, respectively, if vaping could help control their weight. CONCLUSION: One in 16 English people who have smoked in the last year believe that vaping would prevent weight gain after stopping. One in 22 people who vape are using e-cigarettes for this purpose. However, should evidence emerge that e-cigarettes prevent weight gain, one in eight people who smoke would be tempted to quit smoking and use e-cigarettes.
Examining Development Processes for Text Messaging Interventions to Prevent Cardiovascular Disease: Systematic Literature Review.
BACKGROUND:Interventions delivered by mobile phones have the potential to prevent cardiovascular disease (CVD) by supporting behavior change toward healthier lifestyles and treatment adherence. To allow replication and adaptation of these interventions across settings, it is important to fully understand how they have been developed. However, the development processes of these interventions have not previously been systematically examined. OBJECTIVE:This study aimed to systematically describe and compare the development process of text messaging interventions identified in the Text2PreventCVD systematic review. METHODS:We extracted data about the development process of the 9 interventions identified in the Text2PreventCVD systematic review. Data extraction, which was guided by frameworks for the development of complex interventions, considered the following development stages: intervention planning, design, development, and pretesting. Following data extraction, we invited the developers of the interventions to contribute to our study by reviewing the accuracy of the extracted data and providing additional data not reported in the available publications. RESULTS:A comprehensive description of the development process was available for 5 interventions. Multiple methodologies were used for the development of each intervention. Intervention planning involved gathering information from stakeholder consultations, literature reviews, examination of relevant theory, and preliminary qualitative research. Intervention design involved the use of behavior change theories and behavior change techniques. Intervention development involved (1) generating message content based on clinical guidelines and expert opinions; (2) conducting literature reviews and primary qualitative research to inform decisions about message frequency, timing, and level of tailoring; and (3) gathering end-user feedback concerning message readability, intervention acceptability, and perceived utility. Intervention pretesting involved pilot studies with samples of 10 to 30 participants receiving messages for a period ranging from 1 to 4 weeks. CONCLUSIONS:The development process of the text messaging interventions examined was complex and comprehensive, involving multiple studies to guide decisions about the scope, content, and structure of the interventions. Additional research is needed to establish whether effective messaging systems can be adapted from work already done or whether this level of development is needed for application in other conditions and settings.