First large-scale study of antimicrobial susceptibility data, and genetic resistance determinants, in Fusobacterium necrophorum highlighting the importance of continuing focused susceptibility trend surveillance

Objectives: The objective of the study was to explore antimicrobial resistance gene determinant, and phenotypic antibiotic susceptibility, data for Fusobacterium necrophorum from a collection of UK strains. In addition, antimicrobial resistance genes detected in publicly available assembled whole genome sequences were investigated for comparison.Methods: Three hundred and eighty five F. necrophorum strains (1982-2019) were revived from cryovials (Prolab). Subsequent to sequencing (Illumina) and quality checking, 374 whole genomes were available for analysis. These genomes, in addition to publicly available assembled F. necrophorum genetic data, were interrogated using BioNumerics (bioMérieux; v 8.1), for the presence of known antimicrobial resistance genes (ARGs). Agar dilution susceptibility results for 313 F. necrophorum isolates (2016-2021) were also examined.Results: The phenotypic antibiotic test data for the 313 contemporary strains demonstrated potential resistance to penicillin, without increased dosing, in only three isolates. Otherwise, all strains were susceptible to ceftriaxone, clindamycin, co-amoxiclav, meropenem, metronidazole, penicillin and piperacillin/tazobactam, using EUCAST (v 11.0) interpretive guidance. The tet(O), tet(M), tet(40), aph(3’)-III, ant(6)-la and blaOXA-85 ARGs were present in publicly available assembled genomes. tet(M), tet(32), erm(A) and erm(B) were found within the UK strains, with correspondingly raised clindamycin and tetracycline minimum inhibitory concentrations.Conclusions: Current antibiotics recommended for the treatment of infections caused by F. necrophorum, including Lemierre’s disease, are likely to be effective in most cases. However, with evidence of potential ARG transmission from oral bacteria, and the detection of a transposon-mediated beta-lactamase resistance determinant in F. necrophorum, surveillance of both phenotypic and genotypic antimicrobial susceptibility trends must continue, and increase.<br/

Perceptions of the New Role of the Research Champion in Developing a New ITE Partnership: Challenges and Opportunities for Schools and Universities

After a process of competitive tendering for the provision of initial teacher education in Wales, there is an opportunity to re-examine the relationship between schools and universities. With the growing importance of research for both student and serving teachers, the Cardiff Partnership developed a model where a school-based 'Research Champion' (RC) would be an integral part of the support for capacity building and developing excellence. Although this model has previously been used in different forms at Oxford and Manchester Universities, the role was new to schools in the Cardiff Partnership. Semi-structured one-to-one interviews were conducted with a representative sample of RCs in primary and secondary schools and university staff to reflect on the challenges and opportunities in the early stages in developing this unique role in the context of an evolving education context in Wales. This study uses data from these interviews to establish key ideas around the emerging role of the RC, the shift in working relationships between schools and universities and what is needed to bridge the gap between research and practice. Interviews were transcribed and, after open-ended thematic analysis, opportunities and challenges are reported. These themes include: bridging the gap between educational research and classroom practitioners; types of knowledge drawn upon by teachers; changes in role and identity. Suggestions for further research monitoring the ongoing development of the role are suggested

Experiences and views of people who frequently call emergency ambulance services: a qualitative study of UK service users

Introduction: People who call emergency ambulances frequently are often vulnerable because of health and social circumstances, have unresolved problems or cannot access appropriate care. They have higher mortality rates. Case management by interdisciplinary teams can help reduce demand for emergency services and is available in some UK regions. We report results of interviews with people who use emergency ambulance services frequently to understand their experiences of calling and receiving treatment. Methods: We used a two‐stage recruitment process. A UK ambulance service identified six people who were known to them as frequently calling emergency services. Through third‐sector organisations, we also recruited nine individuals with healthcare experiences reflecting the characteristics of people who call frequently. We gained informed consent to record and transcribe all telephone interviews. We used thematic analysis to explore the results. Results: People said they make frequent calls to emergency ambulance services as a last resort when they perceive their care needs are urgent and other routes to help have failed. Those with the most complex health needs generally felt their immediate requirements were not resolved and underlying mental and physical problems led them to call again. A third of respondents were also attended to by police and were arrested for behaviour associated with their health needs. Those callers receiving case management did not know they were selected for this. Some respondents were concerned that case management could label frequent callers as troublemakers. Conclusion: People who make frequent calls to emergency ambulance services feel their health and care needs are urgent and ongoing. They cannot see alternative ways to receive help and resolve problems. Communication between health professionals and service users appears inadequate. More research is needed to understand service users' motivations and requirements to inform design and delivery of accessible and effective services. Patient or Public Contribution: People with relevant experience were involved in developing, undertaking and disseminating this research. Two public contributors helped design and deliver the study, including developing and analysing service user interviews and drafting this paper. Eight public members of a Lived Experience Advisory Panel contributed at key stages of study design, interpretation and dissemination. Two more public contributors were members of an independent Study Steering Committee

STRategies to manage Emergency ambulance Telephone Callers with sustained High needs: an Evaluation using linked Data (STRETCHED) – a study protocol

Introduction UK ambulance services have identified a concern with high users of the 999 service and have set up ‘frequent callers’ services, ranging from within-service management to cross-sectoral multidisciplinary case management approaches. There is little evidence about how to address the needs of this patient group. Aim To evaluate effectiveness, safety and efficiency of case management approaches to the care of people who frequently call the emergency ambulance service, and gain an understanding of barriers and facilitators to implementation. Objectives (1) Develop an understanding of predicted mechanisms of change to underpin evaluation. (2) Describe epidemiology of sustained high users of 999 services. (3) Evaluate case management approaches to the care of people who call the 999 ambulance service frequently in terms of: (i) Further emergency contacts (999, emergency department, emergency admissions to hospital) (ii) Effects on other services (iii) Adverse events (deaths, injuries, serious medical emergencies and police arrests) (iv) Costs of intervention and care (v) Patient experience of care. (4) Identify challenges and opportunities associated with using case management models, including features associated with success, and develop theories about how case management works in this population. Methods and analysis We will conduct a multisite mixed-methods evaluation of case management for people who use ambulance services frequently by using anonymised linked routine data outcomes in a ‘natural experiment’ cohort design, in four regional ambulance services. We will conduct interviews and focus groups with service users, commissioners and emergency and non-acute care providers. The planned start and end dates of the study are 1 April 2019 and 1 September 2022, respectively Ethics and dissemination The study received approval from the UK Health Research Authority (Confidentiality Advisory Group reference number: 19/CAG/0195; research ethics committee reference number: 19/WA/0216). We will collate feedback from our Lived Experience Advisory Panel, the Frequent Caller National Network and Research Management Group for targeted dissemination activities

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

STRategies to manage Emergency ambulance Telephone Callers with sustained High needs: an Evaluation using linked Data (STRETCHED) – a study protocol

Introduction UK ambulance services have identified a concern with high users of the 999 service and have set up ‘frequent callers’ services, ranging from within-service management to cross-sectoral multidisciplinary case management approaches. There is little evidence about how to address the needs of this patient group.Aim To evaluate effectiveness, safety and efficiency of case management approaches to the care of people who frequently call the emergency ambulance service, and gain an understanding of barriers and facilitators to implementation.Objectives (1) Develop an understanding of predicted mechanisms of change to underpin evaluation. (2) Describe epidemiology of sustained high users of 999 services. (3) Evaluate case management approaches to the care of people who call the 999 ambulance service frequently in terms of: (i) Further emergency contacts (999, emergency department, emergency admissions to hospital) (ii) Effects on other services (iii) Adverse events (deaths, injuries, serious medical emergencies and police arrests) (iv) Costs of intervention and care (v) Patient experience of care. (4) Identify challenges and opportunities associated with using case management models, including features associated with success, and develop theories about how case management works in this population.Methods and analysis We will conduct a multisite mixed-methods evaluation of case management for people who use ambulance services frequently by using anonymised linked routine data outcomes in a ‘natural experiment’ cohort design, in four regional ambulance services. We will conduct interviews and focus groups with service users, commissioners and emergency and non-acute care providers. The planned start and end dates of the study are 1 April 2019 and 1 September 2022, respectivelyEthics and dissemination The study received approval from the UK Health Research Authority (Confidentiality Advisory Group reference number: 19/CAG/0195; research ethics committee reference number: 19/WA/0216)

Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study

Introduction Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system’s biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age.Methods and analysis We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 μL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent.Ethics and dissemination The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites.Trial registration number NCT04904523

Standards for the care of people with cystic fibrosis (CF); Planning for a longer life

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.</p

Can stress promote the pathophysiology of brain metastases? A critical review of biobehavioral mechanisms

Chronic stress can promote tumor growth and progression through immunosuppressive effects and bi-directional interactions between tumor cells and their microenvironment. β-Adrenergic receptor signaling plays a critical role in mediating stress-related effects on tumor progression. Stress-related mechanisms that modulate the dissemination of tumor cells to the brain have received scant attention. Brain metastases are highly resistant to chemotherapy and contribute considerably to morbidity and mortality in various cancers, occurring in up to 20% of patients in some cancer types. Understanding the mechanisms promoting brain metastasis could help to identify interventions that improve disease outcomes. In this review, we discuss biobehavioral, sympathetic, neuroendocrine, and immunological mechanisms by which chronic stress can impact tumor progression and metastatic dissemination to the brain. The critical role of the inflammatory tumor microenvironment in tumor progression and metastatic dissemination to the brain, and its association with stress pathways are delineated. We also discuss translational implications for biobehavioral and pharmacological interventions