Integrating qualitative research within a clinical trials unit: developing strategies and understanding their implementation in contexts.

BACKGROUND/AIMS: The value of using qualitative methods within clinical trials is widely recognised. How qualitative research is integrated within trials units to achieve this is less clear. This paper describes the process through which qualitative research has been integrated within Cardiff University's Centre for Trials Research (CTR) in Wales, UK. We highlight facilitators of, and challenges to, integration. METHODS: We held group discussions on the work of the Qualitative Research Group (QRG) within CTR. The content of these discussions, materials for a presentation in CTR, and documents relating to the development of the QRG were interpreted at a workshop attended by group members. Normalisation Process Theory (NPT) was used to structure analysis. A writing group prepared a document for input from members of CTR, forming the basis of this paper. RESULTS: Actions to integrate qualitative research comprised: its inclusion in Centre strategies; formation of a QRG with dedicated funding/roles; embedding of qualitative research within operating systems; capacity building/training; monitoring opportunities to include qualitative methods in studies; maximising the quality of qualitative research and developing methodological innovation. Facilitators of these actions included: the influence of the broader methodological landscape within trial/study design and its promotion of the value of qualitative research; and close physical proximity of CTR qualitative staff/students allowing sharing of methodological approaches. Introduction of innovative qualitative methods generated interest among other staff groups. Challenges included: pressure to under-resource qualitative components of research, preference for a statistical stance historically in some research areas and funding structures, and difficulties faced by qualitative researchers carving out individual academic profiles when working across trials/studies. CONCLUSIONS: Given that CTUs are pivotal to the design and conduct of RCTs and related study types across multiple disciplines, integrating qualitative research into trials units is crucial if its contribution is to be fully realised. We have made explicit one trials unit's experience of embedding qualitative research and present this to open dialogue on ways to operationalise and optimise qualitative research in trials. NPT provides a valuable framework with which to theorise these processes, including the importance of sense-making and legitimisation when introducing new practices within organisations.

The proteomic landscape of microglia in health and disease.

Microglia are the resident immune cells of the central nervous system (CNS) and as such play crucial roles in regulating brain homeostasis. Their presence in neurodegenerative diseases is known, with neurodegeneration-associated risk genes heavily expressed in microglia, highlighting their importance in contributing to disease pathogenesis. Transcriptomics studies have uncovered the heterogeneous landscape of microglia in health and disease, identifying important disease-associated signatures such as DAM, and insight into both the regional and temporal diversity of microglia phenotypes. Quantitative mass spectrometry methods are ever increasing in the field of neurodegeneration, utilised as ways to identify disease biomarkers and to gain deeper understanding of disease pathology. Proteins are the main mechanistic indicators of cellular function, yet discordance between transcript and proteomic findings has highlighted the need for in-depth proteomic phenotypic and functional analysis to fully understand disease kinetics at the cellular and molecular level. This review details the current progress of using proteomics to define microglia biology, the relationship between gene and protein expression in microglia, and the future of proteomics and emerging methods aiming to resolve heterogeneous cell landscapes.

Extensive acute and sustained changes to neutrophil proteomes post-SARS-CoV-2 infection.

BACKGROUND: Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery. METHODS: Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale. RESULTS: Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors. CONCLUSIONS: SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines.

Efficacy of Medical Device Alarm Integration into a Simulated H-60 Integrated Communication System.

INTRODUCTION: This study sought to examine the efficacy of integrating medical device alarms into the intercommunication set of a simulated HH-60, allowing medics to hear the alarms over the ambient noise of the aeromedical environment. MATERIALS AND METHODS: U.S. Army critical care flight paramedics were recruited as subjects for this study. Subjects participated in two testing scenarios: One with patient monitor alarms integrated into their communication lines and one without integrated alarms (the control condition). Testing took place in a simulated HH-60 interior with two priority-level patients per testing scenario, one on either side of the interior. Subjects provided care to these two patients for 30 minutes per scenario. After both scenarios were complete, the subjects were given a questionnaire to obtain their feedback on alarm integration. RESULTS: Six subjects took part in this study, so the results do not have sufficient power to represent the population. No statistically significant results were found. Looking at the trends in the data, implementing alarm integration showed the indications of reducing reaction time to alarms, decreasing or matching the amount of time spent with the patient monitor, and equivalent amounts of time dedicated to patient treatment when compared to the nonintegrated scenario.The feedback obtained from the subjects provided a list of perceived benefits, drawbacks, and improvements related to the integration of medical device alarms into the intercommunication set. CONCLUSIONS: Although the study was underpowered, the trends in the data indicate a benefit to the medics when integrating medical device alarms. When coupled with strongly favorable end-user feedback, the results provide justification for pursuing the effort of integrating alarms and performing future studies with improved integration systems to optimize the potential of the system.

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

Paediatric early warning systems: not a simple answer to a complex question.

Paediatric early warning systems (PEWS) to reduce in-hospital mortality have been a laudable endeavour. Evaluation of their impact has rarely examined the internal validity of the components of PEWS in achieving desired outcomes. We highlight the assumptions made regarding the mode of action of PEWS and, as PEWS become more commonplace, this paper asks whether we really understand their function, process and outcome.

Development, implementation and evaluation of an evidence-based paediatric early warning system improvement programme: the PUMA mixed methods study.

BACKGROUND: Paediatric mortality rates in the United Kingdom are amongst the highest in Europe. Clinically missed deterioration is a contributory factor. Evidence to support any single intervention to address this problem is limited, but a cumulative body of research highlights the need for a systems approach. METHODS: An evidence-based, theoretically informed, paediatric early warning system improvement programme (PUMA Programme) was developed and implemented in two general hospitals (no onsite Paediatric Intensive Care Unit) and two tertiary hospitals (with onsite Paediatric Intensive Care Unit) in the United Kingdom. Designed to harness local expertise to implement contextually appropriate improvement initiatives, the PUMA Programme includes a propositional model of a paediatric early warning system, system assessment tools, guidance to support improvement initiatives and structured facilitation and support. Each hospital was evaluated using interrupted time series and qualitative case studies. The primary quantitative outcome was a composite metric (adverse events), representing the number of children monthly that experienced one of the following: mortality, cardiac arrest, respiratory arrest, unplanned admission to Paediatric Intensive Care Unit, or unplanned admission to Higher Dependency Unit. System changes were assessed qualitatively through observations of clinical practice and interviews with staff and parents. A qualitative evaluation of implementation processes was undertaken. RESULTS: All sites assessed their paediatric early warning systems and identified areas for improvement. All made contextually appropriate system changes, despite implementation challenges. There was a decline in the adverse event rate trend in three sites; in one site where system wide changes were organisationally supported, the decline was significant (ß = -0.09 (95% CI: - 0.15, - 0.05); p = < 0.001). Changes in trends coincided with implementation of site-specific changes. CONCLUSIONS: System level change to improve paediatric early warning systems can bring about positive impacts on clinical outcomes, but in paediatric practice, where the patient population is smaller and clinical outcomes event rates are low, alternative outcome measures are required to support research and quality improvement beyond large specialist centres, and methodological work on rare events is indicated. With investment in the development of alternative outcome measures and methodologies, programmes like PUMA could improve mortality and morbidity in paediatrics and other patient populations.

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

BACKGROUND: Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. METHODS: All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). RESULTS: A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. CONCLUSIONS: EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Pro-judge study: Nurses' professional judgement in nurse staffing systems.

AIMS: Aim of this study is to better understand the role of nurses' professional judgment in nurse staffing systems. DESIGN: Qualitative comparative case study design of nurse staffing systems in England and Wales. METHODS: Data will be collected through a variety of sources: individual interviews, observations of relevant meetings and analysis of key documents. Ethical approval for the study was granted in August 2020 from The Healthcare Research Ethics Committee (SREC reference: REC741). Data generation will be informed by science and technology studies and practice theories. DISCUSSION: Ensuring adequate numbers of nurses are available to care for patients in response to shifting demand is an international policy priority. Emerging evidence on the use of formal workforce planning methodologies across the developed world highlights both the centrality of nurses' professional judgement in nurse staffing methodologies and the urgent need for theoretically informed research to better understand and conceptualise its contribution to decision-making. This study is designed to address this gap in understanding. It takes advantage of nurses' experiences of managing the service and staffing impacts of the Covid-19 pandemic and differences in strategic approaches to nurse staffing systems between England and Wales. IMPACT: The research will: make visible the knowledge and skills that underpin professional judgement in nurse staffing decisions and provide a conceptual language with which to articulate this; lay the foundations for evidence-based programmes of nurse education and continuing professional development; furnish the evidence to inform the development of nurse-led decision support tools to augment professional judgement; and generate wider insights into the effectiveness of nurse staffing systems in practice.

-------A type I IFN, prothrombotic hyperinflammatory neutrophil signature is distinct for COVID-19 ARDS--.

Background: Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation. Results: Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population, it does not impact upon prothrombotic hyperinflammatory neutrophil signatures. Conclusions: Given the crucial role of neutrophils in ARDS and the evidence of a disordered myeloid response observed in COVID-19 patients, this work maps the molecular basis for neutrophil reprogramming in the distinct clinical entities of COVID-19 and non-COVID-19 ARDS.

Optimal Physical Space for En Route Care: Medic Posture and Injury Survey.

INTRODUCTION: An anonymous online survey was presented to active duty U.S. Army, Reserve, and National Guard Soldiers with experience as en route care medical providers with the intent of identifying factors which contribute to musculoskeletal disorders in U.S. Army en route care medical providers. The survey looked at transport vehicle design, equipment, and awkward postures that could play a role in causing injuries. MATERIALS AND METHODS: Survey responses were received from 60 en route care providers regarding postures assumed during administration of en route critical care tasks, routine medical transport scenarios, and patient loading. Care providers reported gender, height, weight, experience, tasks, and awkward postures experienced. They also reported occupational injuries that occurred as a result of performing job duties, such as back, neck, and joint pain, injuries, and discomfort. RESULTS: The survey was answered by 56 (93.3%) males and 4 females (6.7%) with an average of 7.34 years of experience as en route care personnel. Lower back injuries were suffered by 87% of respondents. The most common causes were awkward positions and lifting patients. There are statistically significant relationships between shoulder injuries and overextending, lower back injuries and overextending, and lower back injuries and reaching backwards, ankle injuries and care provider height, and knee injuries and the frequency at which care providers utilized the postures of kneeling, squatting, reaching behind themselves, and straining to lift a heavy weight. Loading and unloading patients from evacuation platforms was among the top causes of all awkward postures among respondents. CONCLUSION: Results of this survey emphasize the need for injury mitigation and prevention strategies to reduce impacts on soldier health and readiness.

Generation of pure monocultures of human microglia-like cells from induced pluripotent stem cells.

Microglia are resident tissue macrophages of the central nervous system (CNS) that arise from erythromyeloid progenitors during embryonic development. They play essential roles in CNS development, homeostasis and response to disease. Since microglia are difficult to procure from the human brain, several protocols have been developed to generate microglia-like cells from human induced pluripotent stem cells (hiPSCs). However, some concerns remain over the purity and quality of in vitro generated microglia. Here, we describe a new protocol that does not require co-culture with neural cells and yields cultures of 100% P2Y12+ 95% TMEM119+ ramified human microglia-like cells (hiPSC-MG). In the presence of neural precursor cell-conditioned media, hiPSC-MG expressed high levels of human microglia signature genes, including SALL1, CSF1R, P2RY12, TMEM119, TREM2, HEXB and SIGLEC11, as revealed by whole-transcriptome analysis. Stimulation of hiPSC-MG with lipopolysaccharide resulted in downregulation of P2Y12 expression, induction of IL1B mRNA expression and increase in cell capacitance. HiPSC-MG were phagocytically active and maintained their cell identity after transplantation into murine brain slices and human brain spheroids. Together, our new protocol for the generation of microglia-like cells from human iPSCs will facilitate the study of human microglial function in health and disease.

Optimising paediatric afferent component early warning systems: a hermeneutic systematic literature review and model development.

OBJECTIVE: To identify the core components of successful early warning systems for detecting and initiating action in response to clinical deterioration in paediatric inpatients. METHODS: A hermeneutic systematic literature review informed by translational mobilisation theory and normalisation process theory was used to synthesise 82 studies of paediatric and adult early warning systems and interventions to support the detection of clinical deterioration and escalation of care. This method, which is designed to develop understanding, enabled the development of a propositional model of an optimal afferent component early warning system. RESULTS: Detecting deterioration and initiating action in response to clinical deterioration in paediatric inpatients involves several challenges, and the potential failure points in early warning systems are well documented. Track and trigger tools (TTT) are commonly used and have value in supporting key mechanisms of action but depend on certain preconditions for successful integration into practice. Several supplementary interventions have been proposed to improve the effectiveness of early warning systems but there is limited evidence to recommend their wider use, due to the weight and quality of the evidence; the extent to which systems are conditioned by the local clinical context; and the need to attend to system component relationships, which do not work in isolation. While it was not possible to make empirical recommendations for practice, the review methodology generated theoretical inferences about the core components of an optimal system for early warning systems. These are presented as a propositional model conceptualised as three subsystems: detection, planning and action. CONCLUSIONS: There is a growing consensus of the need to think beyond TTTs in improving action to detect and respond to clinical deterioration. Clinical teams wishing to improve early warning systems can use the model to consider systematically the constellation of factors necessary to support detection, planning and action and consider how these arrangements can be implemented in their local context. PROSPERO REGISTRATION NUMBER: CRD42015015326.

Ability of observer and self-report measures to capture shared decision-making in clinical practice in the UK: a mixed-methods study.

OBJECTIVES: To examine how observer and self-report measures of shared decision-making (SDM) evaluate the decision-making activities that patients and clinicians undertake in routine consultations. DESIGN: Multi-method study using observational and self-reported measures of SDM and qualitative analysis. SETTING: Breast care and predialysis teams who had already implemented SDM. PARTICIPANTS: Breast care consultants, clinical nurse specialists and patients who were making decisions about treatment for early-stage breast cancer. Predialysis clinical nurse specialists and patients who needed to make dialysis treatment decisions. METHODS: Consultations were audio recorded, transcribed and thematically analysed. SDM was measured using Observer OPTION-5 and a dyadic SureScore self-reported measure. RESULTS: Twenty-two breast and 21 renal consultations were analysed. SureScore indicated that clinicians and patients felt SDM was occurring, but scores showed ceiling effects for most participants, making differentiation difficult. There was mismatch between SureScore and OPTION-5 score data, the latter showing that each consultation lacked at least some elements of SDM. Highest scoring items using OPTION-5 were 'incorporating patient preferences into decisions' for the breast team (mean 18.5, range 12.5-20, SD 2.39) and 'eliciting patient preferences to options' for the renal team (mean 16.15, range 10-20, SD 3.48). Thematic analysis identified that the SDM encounter is difficult to measure because decision-making is often distributed across encounters and time, with multiple people, it is contextually adapted and can involve multiple decisions. CONCLUSIONS: Self-reported measures can broadly indicate satisfaction with SDM, but do not tell us about the quality of the interaction and are unlikely to capture the multi-staged nature of the SDM process. Observational measures provide an indication of the extent to which elements of SDM are present in the observed consultation, but cannot explain why some elements might not be present or scored lower. Findings are important when considering measuring SDM in practice.

A descriptive model of shared decision making derived from routine implementation in clinical practice ('Implement-SDM'): Qualitative study.

OBJECTIVE: Research is needed to understand how Shared Decision-Making (SDM) is enacted in routine clinical settings. We aimed to 1) describe the process of SDM between clinicians and patients; 2) examine how well the SDM process compares to a prescriptive model of SDM, and 3) propose a descriptive model based on observed SDM in routine practice. METHODS: Patients with chronic kidney disease and early stage breast cancer were recruited consecutively via Cardiff and Vale University Health Board (UK) teams. Consultations were audio-recorded, transcribed and thematically analysed. RESULTS: Seventy-six consultations were observed: 26 pre-dialysis consultations and two consultations each for 25 breast cancer patients. Key stages of the 'Three Talk Model' were observed. However, we also observed more elements and greater complexity: a distinct preparation phase; tailored and evolving integrative option conversation; patients and clinicians developing 'informed preferences'; distributed and multi-stage decisions; and a more open-ended planning discussion. Use of decision aids was limited. CONCLUSION: A more complex picture was observed compared with previous portrayals in current theoretical models. PRACTICE IIMPLICATIONS: The model can provide a basis for future training and initiatives to promote SDM, and tackle the gap between what is advocated in policy, but rarely achieved in practice.

The pro-remyelination properties of microglia in the central nervous system.

Microglia are resident macrophages of the CNS that are involved in its development, homeostasis and response to infection and damage. Microglial activation is a common feature of neurological disorders, and although in some instances this activation can be damaging, protective and regenerative functions of microglia have been revealed. The most prominent example of the regenerative functions is a role for microglia in supporting regeneration of myelin after injury, a process that is critical for axonal health and relevant to numerous disorders in which loss of myelin integrity is a prevalent feature, such as multiple sclerosis, Alzheimer disease and motor neuron disease. Although drugs that are intended to promote remyelination are entering clinical trials, the mechanisms by which remyelination is controlled and how microglia are involved are not completely understood. In this Review, we discuss work that has identified novel regulators of microglial activation - including molecular drivers, population heterogeneity and turnover - that might influence their pro-remyelination capacity. We also discuss therapeutic targeting of microglia as a potential approach to promoting remyelination.

Central nervous system regeneration is driven by microglia necroptosis and repopulation.

Failed regeneration of CNS myelin contributes to clinical decline in neuroinflammatory and neurodegenerative diseases, for which there is an unmet therapeutic need. Here we reveal that efficient remyelination requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state. We propose that impaired microglia death and/or repopulation may underpin dysregulated microglia activation in neurological diseases, and we reveal therapeutic targets to promote white matter regeneration.

Validity and effectiveness of paediatric early warning systems and track and trigger tools for identifying and reducing clinical deterioration in hospitalised children: a systematic review.

OBJECTIVE: To assess (1) how well validated existing paediatric track and trigger tools (PTTT) are for predicting adverse outcomes in hospitalised children, and (2) how effective broader paediatric early warning systems are at reducing adverse outcomes in hospitalised children. DESIGN: Systematic review. DATA SOURCES: British Nursing Index, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Management Information Centre, Medline, Medline in Process, Scopus and Web of Knowledge searched through May 2018. ELIGIBILITY CRITERIA: We included (1) papers reporting on the development or validation of a PTTT or (2) the implementation of a broader early warning system in paediatric units (age 0-18 years), where adverse outcome metrics were reported. Several study designs were considered. DATA EXTRACTION AND SYNTHESIS: Data extraction was conducted by two independent reviewers using template forms. Studies were quality assessed using a modified Downs and Black rating scale. RESULTS: 36 validation studies and 30 effectiveness studies were included, with 27 unique PTTT identified. Validation studies were largely retrospective case-control studies or chart reviews, while effectiveness studies were predominantly uncontrolled before-after studies. Metrics of adverse outcomes varied considerably. Some PTTT demonstrated good diagnostic accuracy in retrospective case-control studies (primarily for predicting paediatric intensive care unit transfers), but positive predictive value was consistently low, suggesting potential for alarm fatigue. A small number of effectiveness studies reported significant decreases in mortality, arrests or code calls, but were limited by methodological concerns. Overall, there was limited evidence of paediatric early warning system interventions leading to reductions in deterioration. CONCLUSION: There are several fundamental methodological limitations in the PTTT literature, and the predominance of single-site studies carried out in specialist centres greatly limits generalisability. With limited evidence of effectiveness, calls to make PTTT mandatory across all paediatric units are not supported by the evidence base. PROSPERO REGISTRATION NUMBER: CRD42015015326.

A prospective, mixed-methods, before and after study to identify the evidence base for the core components of an effective Paediatric Early Warning System and the development of an implementation package containing those core recommendations for use in the UK: Paediatric early warning system - utilisation and mortality avoidance- the PUMA study protocol.

BACKGROUND: In hospital, staff need to routinely monitor patients to identify those who are seriously ill, so that they receive timely treatment to improve their condition. A Paediatric Early Warning System is a multi-faceted socio-technical system to detect deterioration in children, which may or may not include a track and trigger tool. It functions to monitor, detect and prompt an urgent response to signs of deterioration, with the aim of preventing morbidity and mortality. The purpose of this study is to develop an evidence-based improvement programme to optimise the effectiveness of Paediatric Early Warning Systems in different inpatient contexts, and to evaluate the feasibility and potential effectiveness of the programme in predicting deterioration and triggering timely interventions. METHODS: This study will be conducted in two district and two specialist children's hospitals. It deploys an Interrupted Time Series (ITS) design in conjunction with ethnographic cases studies with embedded process evaluation. Informed by Translational Mobilisation Theory and Normalisation Process Theory, the study is underpinned by a functions based approach to improvement. Workstream (1) will develop an evidence-based improvement programme to optimise Paediatric Early Warning System based on systematic reviews. Workstream (2) consists of observation and recording outcomes in current practice in the four sites, implementation of the improvement programme and concurrent process evaluation, and evaluation of the impact of the programme. Outcomes will be mortality and critical events, unplanned admission to Paediatric Intensive Care (PICU) or Paediatric High Dependency Unit (PHDU), cardiac arrest, respiratory arrest, medical emergencies requiring immediate assistance, reviews by PICU staff, and critical deterioration, with qualitative evidence of the impact of the intervention on Paediatric Early Warning System and learning from the implementation process. DISCUSSION: This paper presents the background, rationale and design for this mixed methods study. This will be the most comprehensive study of Paediatric Early Warning Systems and the first to deploy a functions-based approach to improvement in the UK with the aim to improve paediatric patient safety and reduce mortality. Our findings will inform recommendations about the safety processes for every hospital treating paediatric in-patients across the NHS. TRIAL REGISTRATION: Sponsor: Cardiff University, 30-36 Newport Road, Cardiff, CF24 0DE Sponsor ref.: SPON1362-14. Funder: National Institute for Health Research, Health Services & Delivery Research Programme (NIHR HS&DR) Funder reference: 12/178/17. Research Ethics Committee reference: 15/SW/0084 [13/04/2015]. PROSPERO reference: CRD42015015326 [23/01/2015]. ISRCTN: 94228292 https://doi.org/10.1186/ISRCTN94228292 [date of application 13/05/2015; date of registration: 18/08/2015]. Prospective registration prior to data collection and participant consent commencing in September 2014.

Author Correction: Stem cells from human apical papilla decrease neuro­inflammation and stimulate oligodendrocyte progenitor differentiation via activin­A secretion.

In the original publication, sixth author's surname was incorrectly published as "Llyod" instead of "Lloyd". The correct name should read as "Amy Lloyd".