Paediatric out-of-hospital clinical deterioration: a mixed-methods scoping review protocol.

INTRODUCTION: In pre-hospital settings, identifying a deteriorating child can be challenging, especially considering that the proportion of paediatric patients with acute illnesses is lower compared with adults. This challenge is exacerbated in pre-hospital settings, where information might be scarce. Physiological alterations indicating changes in a patient's condition can be detected hours preceding a cardiac arrest. Therefore, maintaining continuous monitoring of the patient's clinical condition is crucial to detecting any physiological changes promptly, facilitating early identification of critical illness. This scoping review aims to assess the extent, range and nature of published research related to recognising paediatric out-of-hospital clinical deterioration by pre-hospital staff. METHODS AND ANALYSIS: This scoping review is registered with the Open Science Framework. The review will follow the Joanna Briggs Institute's (JBI) methodology for scoping reviews. A systematic search of relevant databases (MEDLINE, EMBASE, Web of Science, CINAHL and Scopus) will be conducted. In this scoping review, all types of study designs including quantitative and qualitative studies will be considered. The inclusion is limited to English-language studies published between January 1990 and March 2024. Two independent reviewers (AG and SS) will conduct a thorough screening of titles and abstracts against the pre-defined inclusion criteria for the review. For the selected citations, the full texts will undergo detailed assessment by the two reviewers, ensuring alignment with the inclusion criteria. A quality assessment of the included studies will be done using the Mixed Methods Appraisal Tool. The findings will be presented using diagrams or tables, supplemented by narrative summaries following the JBI guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required. The findings will be disseminated through publication in a peer-reviewed journal and presentation at conferences and/or seminars.

MAVMET trial: maraviroc and/or metformin for metabolic dysfunction associated fatty liver disease in adults with suppressed HIV.

OBJECTIVE: Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism. DESIGN: Open-label, 48-week randomized trial with a 2 x 2 factorial design. SETTING: Multicenter HIV clinics. PARTICIPANTS: Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features). INTERVENTION: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone. PRIMARY OUTCOME: Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF). RESULTS: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P  = 0.45]), MET (-0.62 [-1.81 to 0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%. CONCLUSION: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.

Sex differences in the pre-hospital ambulance delay, assessment and treatment of patients with acute coronary syndrome: a rapid evidence review.

Background: Chest pain is a frequent symptom suffered by adult patients attended by ambulance. Evidence suggests female patients may suffer different symptoms to their male counterparts, potentiating differences in pre-hospital time delays, assessment and treatment. Objective: To explore the sex differences in the pre-hospital ambulance delay, assessment and treatment of patients with acute coronary syndrome (ACS). Methods: A rapid evidence review was conducted following the Cochrane rapid review guidelines. MEDLINE and CINAHL Complete were searched via EBSCOhost on 2 February 2023, and reference lists of included studies and reviews were screened. The Joanna Briggs Institute checklist for analytical cross-sectional studies was used to perform critical appraisal, and a narrative synthesis was conducted. Results: From 216 articles screened, nine were included, representing over 3.1 million patients from five different countries. Female patients were more likely to suffer delays in time to first electrocardiogram (ECG) and delays in transport time to the emergency department by ambulance. Female patients were also less likely to receive an ECG, aspirin, glyceryl trinitrate and other analgesics. Conclusion: There are sex disparities in the pre-hospital ambulance delay, assessment and treatment of patients with ACS. Future research is urgently needed to fully understand the reasons for these observations.

Development of indicators for avoidable emergency medical service calls by mapping paramedic clinical impression codes to ambulatory care sensitive conditions and mental health conditions in the UK and Canada.

OBJECTIVE: Paramedic assessment data have not been used for research on avoidable calls. Paramedic impression codes are designated by paramedics on responding to a 911/999 medical emergency after an assessment of the presenting condition. Ambulatory care sensitive conditions (ACSCs) are non-acute health conditions not needing hospital admission when properly managed. This study aimed to map the paramedic impression codes to ACSCs and mental health conditions for use in future research on avoidable 911/999 calls. DESIGN: Mapping paramedic impression codes to existing definitions of ACSCs and mental health conditions. SETTING: East Midlands Region, UK and Southern Ontario, Canada. PARTICIPANTS: Expert panel from the UK-Canada Emergency Calls Data analysis and GEospatial mapping (EDGE) Consortium. RESULTS: Mapping was iterative first identifying the common ACSCs shared between the two countries then identifying the respective clinical impression codes for each country that mapped to those shared ACSCs as well as to mental health conditions. Experts from the UK-Canada EDGE Consortium contributed to both phases and were able to independently match the codes and then compare results. Clinical impression codes for paramedics in the UK were more extensive than those in Ontario. The mapping revealed some interesting inconsistencies between paramedic impression codes but also demonstrated that it was possible. CONCLUSION: This is an important first step in determining the number of ASCSs and mental health conditions that paramedics attend to, and in examining the clinical pathways of these individuals across the health system. This work lays the foundation for international comparative health services research on integrated pathways in primary care and emergency medical services.

What are ambulance personnel experiences of sexual harassment and sexual assault in the workplace? A rapid evidence review.

INTRODUCTION: Sexual assault and harassment of ambulance personnel in the workplace is widespread. Prevention via body worn cameras and legal efforts have been positive, however improvement is still needed to ensure the protection of staff from the negative impact of sexual violence at work. METHODS: A rapid evidence review was conducted following the Cochrane Rapid Review guidance. MEDLINE and CINAHL Complete were searched from inception to February 2023. Screening and data extraction was conducted by one author and verified by the other. Included studies were appraised using a variety of critical appraisal checklists and a narrative synthesis was conducted. RESULTS: From 46 articles screened, 7 were included in the review representing 3994 ambulance personnel from Australia, Canada, the United States, the United Kingdom and South Korea. Seven themes were identified, including a need for more training, education and resources regarding sexual assault and harassment, differences in perpetrators, poor experiences with organisations, effects on victims outside the workplace, effects on victims within the workplace, barriers to reporting, and increased prevalence of sexual assault and harassment against women. CONCLUSION: The effect of sexual assault and harassment has far-reaching negative impact on victims' lives. More training and resources are recommended.

A pre-hospital mixed methods systematic review protocol.

Introduction: Mixed methods research, a methodology entailing the integration of qualitative and quantitative data within a single study, offers researchers the ability to investigate complex processes and systems in health and healthcare. The collective strength gained through the data combination can provide an enhanced understanding of research problems, providing an ideal solution to understanding complex clinical issues in a range of settings. In pre-hospital practice, where often uncontrollable variables and environmental considerations increase healthcare complexity, mixed methods has emerged as a valuable approach to research. Aims: Given the exponential growth of pre-hospital mixed methods research since the publication of our first systematic review in 2014, we aim to provide an update. Our review will explore how mixed methods is utilised in pre-hospital research and identify what standards of reporting are achieved. Methods: This systematic review update will search MEDLINE, CINAHL Complete, Embase and Scopus bibliographic databases from 1 January 2012 to 15 March 2023, using an updated pre-hospital search strategy. Study screening will be performed in duplicate. Articles reported in English, explicitly stating the use of 'mixed methods' in the pre-hospital ambulance setting, including helicopter emergency medical services and community first-responder services, will be included. Data related to underpinning philosophy or theoretical framework, rationale for utilising mixed methods, background of the corresponding author, mode of data integration, model of publication and adherence to reporting standards, utilising the good reporting of a mixed methods study (GRAMMS) guidelines, will be extracted and analysed. All extracted data from study articles will be summarised in a table, allowing analysis of included studies against specified criteria.

Patient, family member, and ambulance staff experiences of prehospital acute pain management in adults: A systematic review and meta-synthesis.

Background: We aimed to synthesize the qualitative experiences of patients, their family members, and ambulance staff involved in the prehospital management of acute pain in adults and generate recommendations to improve the quality of care. Methods: A systematic review was conducted following the enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) guidelines. We searched from inception to June 2021: MEDLINE, CINAHL Complete, PsycINFO and Web of Science (search alerts were screened up to December 2021). Articles were eligible for inclusion if they reported qualitative data and were published in the English language. The Critical Appraisal Skills Program for qualitative studies checklist was used to assess risk of bias, thematic synthesis was performed on included studies and recommendations for clinical practice improvement were generated. Results: Twenty-five articles were included in the review, representing over 464 patients, family members, and ambulance staff from 8 countries. Six analytical themes and several recommendations to improve clinical practice were generated. Strengthening the patient-clinician relationship by building trust, promoting patient empowerment, addressing patient needs and expectations, and providing a holistic approach to pain treatment is key to improving prehospital pain management in adults. Shared pain management guidelines and training across the prehospital and emergency department intersection should improve the patient journey. Conclusion: Interventions and guidelines that strengthen the patient-clinician relationship and span the prehospital and emergency department phase of care are likely to improve the quality of care for adults suffering acute pain in the prehospital setting.

Improving ambulance care for children suffering acute pain: a qualitative interview study.

BACKGROUND: Pain is a highly complex sensory and emotional experience. When a child suffers acute pain through illness or injury, they are often transported to hospital by ambulance. Pre-hospital pain management in children is poor, with 61% of children receiving suboptimal pain management. Consequences of poor pain management include the risk of developing post-traumatic stress disorder and altered pain perception. We aimed to identify clinicians' perceptions of barriers, facilitators and potential improvements for the management of pre-hospital acute pain in children. METHODS: Qualitative face to face semi-structured recorded interviews were performed in one large UK ambulance service. Audio files were transcribed verbatim with thematic analysis used to generate themes. NVivo 12 was used to support data analysis. Findings were combined with existing evidence to generate a driver diagram. RESULTS: Twelve ambulance clinicians participated, including 9 registered paramedics and 3 emergency medical technicians. Median (IQR) age was 43.50 (41.50, 45.75) years, 58% were male, median (IQR) experience was 12 (4.25, 15.50) years and 58% were parents. Several themes relating to barriers and facilitators were identified, including physical, emotional, social, organisational, environmental, management, knowledge and experience. Improvement themes were identified relating to management, organisation and education. These data were combined to create a driver diagram; the three primary drivers were 1) explore methods to increase rates of analgesic administration, including utilising intranasal or inhaled routes; 2) reduce fear and anxiety in children, by using child friendly uniform, additional non-pharmacological techniques and more public interaction and 3) reduce fear and anxiety in clinicians, by enhancing training and optimising crew mix. CONCLUSIONS: The quality of care that children receive for acute pain in the ambulance service may be improved by increasing rates of analgesic administration and reducing the fear and anxiety experienced by children and clinicians. Future research involving children and parents would be useful to determine the most important outcome measures and facilitate intervention development.

Ambulance attendance for substance and/or alcohol use in a pandemic: Interrupted time series analysis of incidents.

INTRODUCTION: The ambulance attendance for substance and/or alcohol use in a pandemic (ASAP) study explores incidents during the COVID-19 lockdown in the East Midlands region of the United Kingdom (23 March-4 July 2020). METHOD: Retrospective cross-sectional count per day of ambulance attendances from the East Midlands Ambulance Service Trust. Ambulance attendances relating to alcohol or other drug use in the year prior, during lockdown and weeks following, were examined using interrupted time series analysis by patient demographics and geographical location. RESULTS: A total of 36 104 records were identified (53.7% male, 84.5% ethnicity classified as White, mean age 38.4 years). A significant drop in the number of attendances per day at the start of lockdown (-25.24, confidence interval - 38.16, -12.32) was observed, followed by a gradual increase during the ongoing lockdown period (0.36, confidence interval 0.23, 0.46). Similar patterns were found across genders, age groups 16-64 and urban/rural locations. DISCUSSION AND CONCLUSION: The pattern of ambulance attendances for alcohol or other drug use changed during the COVID-19 lockdown period. Lockdown significantly affected the use of ambulances for incidents involving alcohol or other drug use, impacting on health-care services. Further research into hazardous use of alcohol or other drugs during the lockdown periods is needed to inform policy, planning and public health initiatives.

Alcohol and other substance use during the COVID-19 pandemic: A systematic review.

BACKGROUND: Although evidence suggests substance and alcohol use may change during the Covid-19 pandemic there has been no full review of the evidence around this. METHODS: A systematic review of all available evidence was carried out to document and interpret the frequency and severity of alcohol and other substance use during the Covid-19 pandemic and their relationship to demographic and mental health variables that may suggest further clinical implications. Peer reviewed articles in MEDLINE, Embase, PsycINFO, CINAHL complete and Sociological Abstracts were searched from December 2019 until November 2020. RESULTS: The search and screening identified 45 articles from 513 deduplicated records. The evidence suggests a mixed picture for alcohol use. Overall, there was a trend towards increased alcohol consumption. The proportion of people consuming alcohol during the pandemic ranged from 21.7% to 72.9% in general population samples. Unlike alcohol use, there was a clear trend towards increased use of other substances use during the COVID-19 pandemic. The proportion of people consuming other substances during the pandemic ranged from 3.6% to 17.5% in the general population. Mental health factors were the most common correlates or triggers for increased use of both alcohol and other substances. CONCLUSION: There is an increased need for treatment for alcohol and other substance use related problems during the pandemic. Increased targeting and evidence-based interventions will also be important in the period which follows this pandemic, to improve the quality of life for individuals and families, but also to prevent additional costs to society and health systems.

Ambulance clinician perspectives of disparity in prehospital child pain management: A mixed methods study.

BACKGROUND: When children suffer acute pain, the ambulance service is often involved to provide initial assessment, treatment, and transport. Several predictors of effective pain management have been identified, including children who are younger (0-5 years), administered analgesics, and living in homes from more affluent areas. OBJECTIVE: To explain previously identified predictors of effective prehospital pain management in children. DESIGN: Mixed methods sequential explanatory study. SETTING AND PARTICIPANTS: East Midlands Ambulance Service National Health Service Trust paramedics and emergency medical technicians (EMTs) participated in face-to-face semi-structured interviews. These were audio recorded, transcribed verbatim, and coded using thematic analysis. Meta-inferences were generated and illustrated within a joint display. RESULTS: Twelve clinicians (9 paramedics and 3 EMTs) were interviewed. Median (interquartile range) age was 43.5 years (41.5, 45.75), 58% were male (n = 7) and 58% were parents (n = 7). Possible explanations were provided for all predictors. Younger children were perceived to express more emotion, were easier to distract, and lived more in the moment than their older counterparts, which explained why younger children were more likely to achieve effective pain management. Analgesics were perceived to have a psychosocial benefit in addition to the pharmacological action. Ambulance clinicians felt that children living in more affluent areas were more likely to achieve effective pain management because the kempt environment facilitated assessment and management and clinicians spent more time on scene; this allowed more time for analgesics to take effect. Participants perceived paramedics to be more confident, and it was found that paramedics were older, more experienced, had a greater scope of practice, and spent more time on scene than EMTs. CONCLUSION: Prehospital pain management in children could be improved by facilitating and prioritizing analgesic administration and by ambulance services ensuring a paramedic, or highly trained clinician, is present on each vehicle, necessitating long-term commitment to staff development.

Unexpected shock in a fallen older adult: a case report.

INTRODUCTION: Falls are common in older adults and frequently require ambulance service assistance. They are the most frequent cause of injury and associated morbidity and mortality in older adults. In recent years, the typical major trauma patient has changed from being young and male to being older in age, with falls of < 2 metres being the most common mechanism of injury. We present a case of an 84-year-old male who had fallen in his home. This case highlights the complex nature of a relatively common incident. CASE PRESENTATION: The patient was laid on the floor in the prone position unable to move for 12 hours. He did not complain of any pain in his neck, back, hips or legs, and wished to be lifted off the floor promptly. On examination, he had bruising to his chest and abdomen and had suffered a suspected cervical spine injury due to a step-like protrusion around C5-C6. Distal sensory and motor function was intact. While in the ambulance his blood pressure dropped from 154/119 mmHg to 49/28 mmHg unexpectedly. We successfully reversed the shock using the modified Trendelenburg position and intravenous fluids. On follow-up he was diagnosed with dislocated C3, C6 and C7 vertebrae. CONCLUSION: The unexpected episode of shock witnessed in this patient may have been caused by a number of phenomena, including but not limited to crush syndrome, spinal cord concussion and orthostatic hypotension. We recommend that clinicians anticipate sudden shock in older adult patients who have fallen and a) have remained static on the floor for an extended period of time or b) are suspected of a spinal injury. We recommend assertive management of these patients to mitigate the impact of shock through postural positioning and consideration of early cannulation.

Mixed methods in pre-hospital research: understanding complex clinical problems.

Healthcare is becoming increasingly complex. The pre-hospital setting is no exception, especially when considering the unpredictable environment. To address complex clinical problems and improve quality of care for patients, researchers need to use innovative methods to create the necessary depth and breadth of knowledge. Quantitative approaches such as randomised controlled trials and observational (e.g. cross-sectional, case control, cohort) methods, along with qualitative approaches including interviews, focus groups and ethnography, have traditionally been used independently to gain understanding of clinical problems and how to address these. Both approaches, however, have drawbacks: quantitative methods focus on objective, numerical data and provide limited understanding of context, whereas qualitative methods explore more subjective aspects and provide perspective, but can be harder to demonstrate rigour. We argue that mixed methods research, where quantitative and qualitative methods are integrated, is an ideal solution to comprehensively understand complex clinical problems in the pre-hospital setting. The aim of this article is to discuss mixed methods in the field of pre-hospital research, highlight its strengths and limitations and provide examples. This article is tailored to clinicians and early career researchers and covers the basic aspects of mixed methods research. We conclude that mixed methods is a useful research design to help develop our understanding of complex clinical problems in the pre-hospital setting.

Predictors of effective management of acute pain in children within a UK ambulance service: A cross-sectional study.

OBJECTIVE: We aimed to identify predictors of effective management of acute pain in children in the pre-hospital setting. METHODS: A retrospective cross-sectional study using electronic clinical records from one large UK ambulance service during 01-Oct-2017 to 30-Sep-2018 was performed using multivariable logistic regression. We included all children <18 years suffering acute pain. Children with a Glasgow Coma Scale score of <15, no documented pain or without a second pain score were excluded. The outcome measure was effective pain management (abolition or reduction of pain by ≥2 out of 10 using the numeric pain rating scale, Wong-Baker FACES® scale or FLACC [face, legs, activity, crying and consolability] scale). RESULTS: 2312 patients were included for analysis. Median (IQR) age was 13 (9-16), 54% were male and the cause of pain was trauma in 66% of cases. Predictors of effective pain management include children who were younger (0-5 years) compared to older (12-17 years) (adjusted odds ratio [AOR] 1.53; 95% confidence interval [CI] 1.18-1.97), administered analgesia (AOR 2.26; CI 1.87-2.73), attended by a paramedic (AOR 1.46; CI 1.19-1.79) or living in an area of low deprivation (index of multiple deprivation [IMD] 8-10) compared to children in an area of high deprivation (IMD 1-3) (AOR 1.37; CI 1.04-1.80). Child sex, type of pain, transport time, non-pharmacological treatments and clinician experience were not significant. CONCLUSION: These predictors highlight disparity in effective pre-hospital management of acute pain in children. Qualitative research is needed to help explain these findings.

Pre-hospital intranasal analgesia for children suffering pain: a rapid evidence review.

INTRODUCTION: Pre-hospital analgesic treatment of injured children is suboptimal, with very few children in pain receiving analgesia. Studies have identified a number of barriers to pre-hospital pain management in children which include the route of analgesia administration. The aim of this review is to critically evaluate the pre-hospital literature, exploring the safety and efficacy of intranasal (IN) analgesics for children suffering pain. METHODS: We performed a rapid evidence review, searching from inception to 17 December 2018, CINAHL, MEDLINE and Google Scholar. We included studies of children < 18 years suffering pain who were administered any IN analgesic in the pre-hospital setting. Our outcomes were effective pain management, defined as a pain score reduction of ≥ 2 out of 10, safety and rates of analgesia administration. Screening and risk of bias assessments were performed in duplicate. We performed a narrative synthesis. RESULTS: From 310 articles screened, 23 received a full-text review resulting in 10 articles included. No interventional studies were found. Most papers reported on the use of intranasal fentanyl (INF) (n = 8) with one reporting IN ketamine and the other IN S-ketamine. Narrative synthesis showed that INF appeared safe and effective at reducing pain; however, its ability to increase analgesia administration rates was unclear. The effectiveness, safety and ability of IN ketamine and S-ketamine to increase analgesia administration rates were unclear. There was no evidence for IN diamorphine for children in this setting. CONCLUSION: Interventional studies are needed to determine with a higher confidence the effectiveness and safety of IN analgesics (fentanyl, ketamine, S-ketamine, diamorphine) for children in the pre-hospital setting.

Predictors of effective management of acute pain in children within a UK ambulance service: a cross-sectional study.

INTRODUCTION: Pre-hospital pain management in children is poor, with very few children in pain receiving analgesia. Without effective pain treatment, children may suffer long-term changes in stress hormone responses and pain perception and are at risk of developing posttraumatic stress disorder. We aimed to identify predictors of effective management of acute pain in children in the pre-hospital setting. METHODS: A retrospective cross-sectional study using electronic clinical records from one large UK ambulance service between 1 October 2017 and 30 September 2018 was performed using multi-variable logistic regression. We included all children < 18 years suffering acute pain. Children with a Glasgow Coma Scale of < 15, no documented pain or without a second pain score were excluded. The outcome measure was effective pain management (abolition or reduction of pain by ≥ 2 out of 10 using the numeric pain rating scale, Wong and Baker FACES® scale or Face, Legs, Activity, Crying and Consolability (FLACC) scale). RESULTS: A total of 2312 patients were included for analysis. Median (IQR) age was 13 (9-16), 54% were male and the cause of pain was trauma in 66% of cases. Predictors of effective pain management include children who were younger (0-5 years) compared to older (12-17 years) (adjusted odds ratio (AOR) 1.57; 95% confidence interval (CI) 1.21-2.03), administered analgesia (AOR 2.35; CI 1.94-2.84), attended by a paramedic (AOR 1.39; CI 1.13-1.70) or living in an area of medium deprivation (index of multiple deprivation (IMD) 4-7) compared to children in an area of high deprivation (IMD 1-3) (AOR 1.41; CI 1.10-1.79). Child gender, type of pain, transport time and clinician experience were not significant. CONCLUSION: These predictors highlight disparity in effective pre-hospital management of acute pain in children. Qualitative research is needed to help explain these findings.

What are the predictors, barriers and facilitators to effective management of acute pain in children by ambulance services? A mixed-methods systematic review protocol.

INTRODUCTION: The management of pain is complex, especially in children, as age, developmental level, cognitive and communication skills and associated beliefs must be considered. Without effective pain treatment, children may suffer long-term changes in stress hormone responses and pain perception and are at risk of developing posttraumatic stress disorder. Pre-hospital analgesic treatment of injured children is suboptimal, with very few children in pain receiving analgesia. The aim of this review is to identify predictors, barriers and facilitators to effective management of acute pain in children by ambulance services. METHODS: A mixed-methods approach has been adopted due to the research question lending itself to qualitative and quantitative inquiry. The segregated methodology will be used where quantitative and qualitative papers are synthesised separately, followed by mixed-methods synthesis (meta-integration). We will search from inception: MEDLINE, CINAHL and PsycINFO via EBSCOHost, EMBASE via Ovid SP, Web of Science and Scopus. The Cochrane Library, the Joanna Briggs Institute, PROSPERO, ISRCTN and ClinicalTrials.gov will be searched. We will include empirical qualitative and quantitative studies. We will exclude animal studies, reviews, audits, service evaluations, simulated studies, letters, Best Evidence Topics, case studies, self-efficacy studies, comments and abstracts. Two authors will perform full screening and selection, data extraction and quality assessment. GRADE and CERQual will determine the confidence in cumulative evidence. DISCUSSION: If confidence in the cumulative evidence is deemed Moderate, Low or Very Low, then this review will inform the development of a novel mixed-methods sequential explanatory study which aims to comprehensively identify predictors, barriers and facilitators to effective pain management of acute pain in children within ambulance services. Future research will be discussed among authors if confidence is deemed High.Systematic Review Registration: PROSPERO: CRD42017058960.

Between a reactant rock and a solvent hard place--molecular corrals guide aromatic substitutions.

A novel reaction mechanism is presented for an ortho-magnesium carboxylate driven aromatic nucleophilic substitution in naphthoic acids, supported by high-level density functional theory. Results show that the rate-determining aspects involve an R-group transfer from a Grignard reagent Mg-atom to the C1-atom on a naphthalene ring. This transfer is moderated by a molecular corral comprised of two solvent THF molecules and the naphthoic acid, which collectively marshal the R-group into position. The CAM-B3LYP method was employed together with the all-electron DZVP basis set. Solvent was treated using an implicit dielectric continuum (PCM method) and IDSCRF atomic-radii. Further evolved solvent models were also investigated, consisting of explicit solvating particles forming a primary solvation layer framing the reaction center. Reaction barriers obtained are in close agreement with experimental trends, with R-group substituent-identity tempering repulsion with the molecular corral, in-turn modulating the free-energy barriers. Partitioning of the dynamic bases of entropy contribution to free-energy was central to the successful experimental-theoretical synergy.

Pd(OAc)2-catalyzed C-H activation/C-O cyclization: mechanism, role of oxidant-probed by density functional theory.

A series of density functional theory determinations have been carried out to characterize Pd(OAc)2-catalyzed C-H activation and subsequent intramolecular C-O bond-coupling of phenyl-tert-butanol in perfluorobenzene (C6F6) solvent. Full, nontruncated models of the real chemical transformations were studied, with structures in agreement with recent X-ray determinations. Conformational analyses have provided thermodynamic validity of the geometric structures used. The B3LYP/DZVP and B3LYP/BS1 methods (BS1 = TZVP(H,C,O) + SDD(Pd,I)) were comparatively employed, with C6F6 solvent contributions accounted for by the IDSCRF method; key transition states were confirmed by intrinsic reaction coordinate determinations. The novel reaction mechanism proposed was divided into the following four steps: C-H activation, oxidation, reductive elimination, catalyst recovery. Two competing reaction routes were quantitatively compared, differing in the oxidation state of Pd (+2 vs +4). Results reveal the pathway involving Pd(IV) intermediates to be more spontaneous and, therefore, more probable than the Pd(II) path, the latter hindered by a kinetically inaccessible reductive elimination step, with total energy and free energy barriers of 41.0 and 38.6 kcal·mol(-1), respectively. The roles played by the oxidant and Pd(IV) species have also been addressed through Bader's atoms-in-molecules wave function analyses, providing a quantitative electronic metric for C-H activation chemistry.