Mechanisms of environmental carcinogenesis and metal -induced cellular signaling

Low dose chronic exposure to environmental carcinogens is a major cause of human cancers. More than 375 known or suspected environmental carcinogens have been identified, many of which are transition metals or metal containing compounds (IARC, updated to 2004, http://www-cie.iarc.fr/monoeval/crthall.html). Although much research has focused on the ability of these metals to induce reactive oxygen species formation (ROS), DNA damage, and apoptosis, less effort has been put forth to examine the cellular signaling mechanisms responsible for these effects. Our experimental research has focused on the signaling pathways induced in response to arsenic exposure. Arsenic is a highly interesting transition metal due to its widespread exposure and paradoxic ability to induce carcinogenesis as well as apoptosis. Here, we highlight the importance of the human genome project in advancing the knowledge of the molecular mechanisms of metal-induced toxicology/carcinogenesis. In addition, we review the latest research in the field of metal-induced carcinogenesis. Finally, we describe a mechanism for the induction of the growth-arrest and DNA damage inducible protein 45 alpha (GADD45alpha) involving arsenic-induced ROS formation in the non-tumorigenic human lung airway epithelial cell line, BEAS-2B

Evaluating a tool to improve engagement and recruitment of under-served groups in trials

Acknowledgements Many thanks to all those who participated in the study and particularly the public and community involvement and engagement contributors from Greater Manchester and East Midlands. Thanks to the National Institute for Health Research Applied Research Collaboration Greater Manchester’s Public and Community Involvement and Engagement (PCIE) Forum and Panel and to The Centre for Ethnic Health Research for their support of this work. Thanks also to Francisco Beduschi Neto for creating the participant flow diagram. The Health Services Research Unit, University of Aberdeen, receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. Funding This research was supported by the National Institute for Health Research Applied Research Collaboration Greater Manchester.Peer reviewedPublisher PD

Doing trials within trials: a qualitative study of stakeholder views on barriers and facilitators to the routine adoption of methodology research in clinical trials

Abstract Background Randomised controlled trials are the cornerstone of evidence-based health care, yet many trials struggle with recruitment and retention. All too often the methodologies employed to address these problems are not evidence-based, as rigorous methodological research on these issues is rare. The current research sought to identify barriers to the routine implementation of methodology research around recruitment and retention. Methods All registered UK clinical trials unit directors were sent a short questionnaire and invited to interview. Representatives of funding bodies and other stakeholders were also approached. Interviews were recorded and the content analysed. Results Data were grouped into four themes: acceptance of the need for methodological research; trial funding and development; trial processes; and organisational factors. The need to improve the evidence base for trials methodology is well established, but numerous barriers to implementation were perceived. Conclusions The knowledge and expertise required to routinely implement methodology research exists within the current research structures, and there are clear opportunities to develop the evidence base. However, for this to be achieved there is also a need for clear strategic coordination within the sector and promotion of the necessary resources

Psychometric properties of the Patient Assessment Of Chronic Illness Care measure: acceptability, reliability and validity in United Kingdom patients with long-term conditions.

BACKGROUND: The Patient Assessment of Chronic Illness Care (PACIC) is a US measure of chronic illness quality of care, based on the influential Chronic Care Model (CCM). It measures a number of aspects of care, including patient activation; delivery system design and decision support; goal setting and tailoring; problem-solving and contextual counselling; follow-up and coordination. Although there is developing evidence of the utility of the scale, there is little evidence about its performance in the United Kingdom (UK). We present preliminary data on the psychometric performance of the PACIC in a large sample of UK patients with long-term conditions. METHOD: We collected PACIC, demographic, clinical and quality of care data from patients with long-term conditions across 38 general practices, as part of a wider longitudinal study. We assess rates of missing data, present descriptive and distributional data, assess internal consistency, and test validity through confirmatory factor analysis, and through associations between PACIC scores, patient characteristics and related measures. RESULTS: There was evidence that rates of missing data were high on PACIC (9.6% - 15.9%), and higher than on other scales used in the same survey. Most PACIC sub-scales showed reasonable levels of internal consistency (alpha = 0.68 - 0.94), responses did not demonstrate high skewness levels, and floor effects were more frequent (up to 30.4% on the follow up and co-ordination subscale) than ceiling effects (generally <5%). PACIC demonstrated preliminary evidence of validity in terms of measures of long-term condition care. Confirmatory factor analysis suggested that the five factor PACIC structure proposed by the scale developers did not fit the data: reporting separate factor scores may not always be appropriate. CONCLUSION: The importance of improving care for long-term conditions means that the development and validation of measures is a priority. The PACIC scale has demonstrated potential utility in this regard, but further assessment is required to assess low levels of completion of the scale, and to explore the performance of the scale in predicting outcomes and assessing the effects of interventions.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Patient use of pulse oximetry to support management of COVID-19 in Greater Manchester: A non-randomised evaluation using a target trial approach

Introduction: The pandemic saw widespread use of home pulse oximeters to patients diagnosed with COVID-19 to support early detection of low oxygen saturation levels and appropriate care. Rapid implementation made conventional evaluation challenging, highlighting the need for rigorous non-randomised methods to support decision-making about future use of these technologies. We used routine data to explore the benefits of pulse oximetry in Greater Manchester, under the ‘COVID-19 oximetry at home’ (CO@h) programme. Methods: We used data from the Greater Manchester Secure Data Environment and defined study parameters using a ‘target trial’ model to compare patients receiving pulse oximetry under the CO@h programme, with matched controls using various comparator groups. Primary outcomes were unplanned hospitalisation and all-cause mortality. This study is based on data from the Greater Manchester Care Record (GMCR), using anonymised, routinely collected data provided in a de-identified format for research. Informed written consent is needed for primary care patient data to be collected for service improvement and research, before data extraction to the GMCR. The study was approved under protocol GMCR RQ-048, on 12/05/2022. As indicated by the University of Manchester ethics decision tool, formal ethical approval was not required for this study. Results: The adjusted odds ratios for an unplanned hospitalisation were higher among patients receiving pulse oximetry: OR 1.86 (95% CI 1.54–2.25) at 28 days, 1.5 (95% CI 1.3–1.74) at 90 days and 1.63 (95% CI 1.44–1.83) at 1 year. Overall odds of mortality were lower among patients receiving pulse oximetry: adjusted ORs of 0.5 (95% CI 0.25–0.98) at 28 days, 0.5 (95% CI 0.32–0.78) at 90 days and 0.58 (95% CI 0.44–0.76) at 1 year. The results were robust to different comparison groups. Conclusion: Use of pulse oximetry at home under the CO@h programme, through the resulting prioritisation for appropriate care, was associated with a higher frequency of unplanned admissions and a reduction in the risk of mortality up to 1 year later. Therefore, it is likely effective for early detection of clinical deterioration and timely intervention among patients with COVID-19. Further research is needed to understand whether this is a cost-effective use of healthcare resources

Is bureaucracy being busted in research ethics and governance for health services research in the UK?:Experiences and perspectives reported by stakeholders through an online survey

Acknowledgements: We would like to thank the Board of Trustees of HSRUK for support and advice throughout study. Thank you to all respondents to the survey for contributing their data and views. The HRA and NIHR are also warmly acknowledged for their continued support throughout the study.Peer reviewedPublisher PD

Is bureaucracy being busted in research ethics and governance for health services research in the UK? Experiences and perspectives reported by stakeholders through an online survey

Background: It has long been noted that the chain from identification of need (research gap) to impact in the real world is both long and tortuous. This study aimed to contribute evidence about research ethics and governance arrangements and processes in the UK with a focus on: what works well; problems; impacts on delivery; and potential improvements. Methods: Online questionnaire widely distributed 20th May 2021, with request to forward to other interested parties. The survey closed on 18th June 2021. Questionnaire included closed and open questions related to demographics, role, study objectives. Results: Responses were received from 252 respondents, 68% based in universities 25% in the NHS. Research methods used by respondents included interviews/focus groups (64%); surveys/questionnaires (63%); and experimental/quasi experimental (57%). Respondents reported that participants in the research they conducted most commonly included: patients (91%); NHS staff (64%) and public (50%). Aspects of research ethics and governance reported to work well were: online centralised systems; confidence in rigorous, respected systems; and helpful staff. Problems with workload, frustration and delays were reported, related to overly bureaucratic, unclear, repetitive, inflexible and inconsistent processes. Disproportionality of requirements for low-risk studies was raised across all areas, with systems reported to be risk averse, defensive and taking little account of the risks associated with delaying or deterring research. Some requirements were reported to have unintended effects on inclusion and diversity, particularly impacting Patient and Public Involvement (PPI) and engagement processes. Existing processes and requirements were reported to cause stress and demoralisation, particularly as many researchers are employed on fixed term contracts. High negative impacts on research delivery were reported, in terms of timescales for completing studies, discouraging research particularly for clinicians and students, quality of outputs and costs. Suggested improvements related to system level changes / overall approach and specific refinements to existing processes. Conclusions: Consultation with those involved in Health Services Research in the UK revealed a picture of overwhelming and increasing bureaucracy, delays, costs and demoralisation related to gaining the approvals necessary to conduct research in the NHS. Suggestions for improvement across all three areas focused on reducing duplication and unnecessary paperwork/form filling and reaching a better balance between risks of harm through research and harms which occur because research to inform practice is delayed or deterred

Systematic techniques for assisting recruitment to trials (START): study protocol for embedded, randomized controlled trials

BACKGROUND: Randomized controlled trials play a central role in evidence-based practice, but recruitment of participants, and retention of them once in the trial, is challenging. Moreover, there is a dearth of evidence that research teams can use to inform the development of their recruitment and retention strategies. As with other healthcare initiatives, the fairest test of the effectiveness of a recruitment strategy is a trial comparing alternatives, which for recruitment would mean embedding a recruitment trial within an ongoing host trial. Systematic reviews indicate that such studies are rare. Embedded trials are largely delivered in an ad hoc way, with interventions almost always developed in isolation and tested in the context of a single host trial, limiting their ability to contribute to a body of evidence with regard to a single recruitment intervention and to researchers working in different contexts. METHODS/DESIGN: The Systematic Techniques for Assisting Recruitment to Trials (START) program is funded by the United Kingdom Medical Research Council (MRC) Methodology Research Programme to support the routine adoption of embedded trials to test standardized recruitment interventions across ongoing host trials. To achieve this aim, the program involves three interrelated work packages: (1) methodology - to develop guidelines for the design, analysis and reporting of embedded recruitment studies; (2) interventions - to develop effective and useful recruitment interventions; and (3) implementation - to recruit host trials and test interventions through embedded studies. DISCUSSION: Successful completion of the START program will provide a model for a platform for the wider trials community to use to evaluate recruitment interventions or, potentially, other types of intervention linked to trial conduct. It will also increase the evidence base for two types of recruitment intervention. TRIAL REGISTRATION: The START protocol covers the methodology for embedded trials. Each embedded trial is registered separately or as a substudy of the host trial

Which objective sleep elements predict children’s perceptions of good sleep quality? A preliminary investigation based on polysomnography and actigraphy

Objectives: Objective sleep elements that underlie child ratings of sleep quality are largely unknown. Child-based sleep recommendations, therefore, typically focus on duration. An expert panel recently provided specific recommendations regarding objective sleep parameters that correspond with higher quality sleep, but child-based studies from which to draw conclusions were notably limited. The present study used actigraphy and polysomnography to explore sleep continuity and architectural variables that correspond with higher ratings of sleep quality in a sample of school-aged children.  Methods: Fifty-two healthy, prepubertal children (aged 7–11 years) completed one night of unattended ambulatory polysomnography at home with concurrent actigraphy and provided sleep quality ratings the following morning. Associations between sleep variables and subjective ratings were examined using polynomial regression models to examine potential linear and nonlinear relationships.  Results: In contrast to findings among adults, total sleep time, sleep onset latency, and sleep efficiency values were unrelated to child ratings of sleep quality. Wake after sleep onset (WASO) showed a curvilinear (reversed j-shaped) relationship such that perceptions of sleep quality were high when WASO values were less than approximately 30 minutes. For sleep architecture, N1% showed a significant quadratic association with sleep quality such that N1% between 2% and 6% corresponded with high sleep quality ratings.  Conclusions: Our findings support expert recommendations regarding WASO values that predict high quality sleep in children, but also await replication. There is need for additional research aimed at understanding objective sleep elements and other influences of children's perceptions of sleep quality using linear and nonlinear models

Sleep restriction alters children’s positive emotional responses but effects are moderated by anxiety

Background: An abundance of cross-sectional research links inadequate sleep with poor emotional health, but experimental studies in children are rare. Further, the impact of sleep loss is not uniform across individuals and pre-existing anxiety might potentiate the effects of poor sleep on children’s emotional functioning. Methods: A sample of 53 children (7–11 years, M = 9.0; 56% female) completed multimodal, assessments in the laboratory when rested and after two nights of sleep restriction (7 and 6 hr in bed, respectively). Sleep was monitored with polysomnography and actigraphy. Subjective reports of affect and arousal, psychophysiological reactivity and regulation, and objective emotional expression were examined during two emotional processing tasks, including one where children were asked to suppress their emotional responses. Results: After sleep restriction, deleterious alterations were observed in children’s affect, emotional arousal, facial expressions, and emotion regulation. These effects were primarily detected in response to positive emotional stimuli. The presence of anxiety symptoms moderated most alterations in emotional processing observed after sleep restriction. Conclusions: Results suggest inadequate sleep preferentially impacts positive compared to negative emotion in prepubertal children and that pre-existing anxiety symptoms amplify these effects. Implications for children’s everyday socioemotional lives and long-term affective risk are highlighted