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Background\ud \ud Studies have identified young adults as more likely to use emergency departments for ‘clinically unnecessary’ problems, with limited similar evidence for emergency ambulance use. Media portrayals depict young adults as motivated by ‘convenience’, but little research has explored the reasons for their help-seeking behaviour.\ud \ud \ud \ud Methods\ud \ud Qualitative interviews with 16 young adults (18-30) considered by clinicians to have made unnecessary use of emergency ambulance, emergency department or an urgent GP appointment. Data analysis was informed by interpretive phenomenological analysis.\ud \ud \ud \ud Findings\ud \ud A number of interrelated factors contributed to participants’ decisions. They were anxious about the seriousness of their symptoms, sometimes exacerbated by reduced coping capacity due to poor mental health or life stresses. They looked to others to facilitate their decision making, who sometimes encouraged urgent contact. They wanted to avoid impact on existing day-to-day commitments including work or study. They had strong views about different health services, sometimes based on frustration with lack of resolution of on-going health problems. Convenience was not identified as a significant factor, although some actions could be interpreted in this light if the context was not considered.\ud \ud \ud \ud Conclusions\ud \ud Young adults make ‘clinically unnecessary’ use of urgent and emergency care for more than convenience. Their decisions need to be understood in relation to the complexity of their experience, including lack of confidence in making health-related decisions, lowered coping capacity and concern to maintain normal daily life.

Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in nonseptic compensated and decompensated cirrhotic patients using the TruCulture whole blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. Thirty cirrhotics (21 decompensated and 9 compensated) and seven healthy controls (HCs) were recruited. Whole blood was drawn directly into three TruCulture tubes [unstimulated to preloaded with heat-killed Escherichia coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 h. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust proinflammatory response to HKEB compared with HCs, with increased production of interferon-γ-induced protein 10 (IP-10) and IFN-λ1, and to LPS, with increased production of IFN-λ1. Decompensated patients demonstrated an augmented immune response compared with compensated patients, orchestrated by an increase in type I, II, and III interferons, and higher levels of IL-1β, IL-6, and IL-8 post-LPS stimulation. IL-1β, TNF-α, and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6, and IL-8. Poststimulation levels of a number of proinflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease. NEW & NOTEWORTHY Decompensated cirrhotic patients, compared with compensated patients, exhibit a greater exaggerated inflammatory response to bacterial products orchestrated by interferons, IL-6, and IL-8. Postbacterial product stimulation levels of a number of pro-inflammatory cytokines negatively correlate with liver disease severity biomarkers and liver disease severity scores raising the possibility that the switch to an immunodeficient phenotype in cirrhosis-associated immune dysfunction may commence earlier in the course of advanced liver disease.

Summary Background The UK Government's implementation in 2008 of the Improving Access to Psychological Therapies (IAPT) initiative in England has hugely increased the availability of cognitive behavioural therapy (CBT) for the treatment of depression and anxiety in primary care. Counselling for depression—a form of person-centred experiential therapy (PCET)—has since been included as an IAPT-approved therapy, but there is no evidence of its efficacy from randomised controlled trials (RCTs), as required for recommendations by the National Institute for Health and Care Excellence. Therefore, we aimed to examine whether PCET is cost effective and non-inferior to CBT in the treatment of moderate and severe depression within the IAPT service. Methods This pragmatic, randomised, non-inferiority trial was done in the Sheffield IAPT service in England and recruited participants aged 18 years or older with moderate or severe depression on the Clinical Interview Schedule-Revised. We excluded participants presenting with an organic condition, a previous diagnosis of personality disorder, bipolar disorder, or schizophrenia, drug or alcohol dependency, an elevated clinical risk of suicide, or a long-term physical condition. Eligible participants were randomly assigned (1:1), independently of the research team, and stratified by site with permuted block sizes of two, four, or six, to receive either PCET or CBT by use of a remote, web-based system that revealed therapy after patient details were entered. Those assessing outcomes were masked to treatment allocation. Participants were seen by appropriately trained PCET counsellors and CBT therapists in accordance with the IAPT service delivery model. Depression severity and symptomatology measured by the Patient Health Questionnaire-9 (PHQ-9) at 6 months post-randomisation was the primary outcome, with the PHQ-9 score at 12 months post-randomisation being a key secondary outcome. These outcomes were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients with complete data, and the per-protocol population, which comprised all participants who did not switch from their randomised treatment and received between four and 20 sessions. Safety was analysed in all randomly assigned patients. The non-inferiority margin was set a priori at 2 PHQ-9 points. Patient safety was monitored throughout the course of therapy, adhering to service risk procedures for monitoring serious adverse events. This trial is registered at the ISRCTN Registry, ISRCTN06461651, and is complete. Findings From Nov 11, 2014, to Aug 3, 2018, 9898 patients were referred to step three treatments in the Sheffield IAPT service for common mental health problems, of whom 761 (7·7%) were referred to the trial. Of these, we recruited and randomly assigned 510 participants to receive either PCET (n=254) or CBT (n=256). In the PCET group, 138 (54%) participants were female and 116 (46%) were male, and 225 (89%) were White, 16 (6%) were non-White, and 13 (5%) had missing ethnicity data. In the CBT group, 155 (61%) participants were female and 101 (39%) were male, and 226 (88%) were White, 17 (7%) were non-White, and 13 (5%) had missing ethnicity data. The 6-month modified intention-to-treat analysis comprised 401 (79%) of the enrolled participants (201 in the PCET group; 200 in the CBT group) and the 12-month modified intention-to-treat analysis comprised 319 participants (167 in the PCET group; 152 in the CBT group). The 6-month per-protocol analysis comprised 298 participants (154 in the PCET group; 144 in the CBT group). At 6 months post-randomisation, PCET was non-inferior to CBT in the intention-to-treat population (mean PHQ-9 score 12·74 [SD 6·54] in the PCET group and 13·25 [6·35] in the CBT group; adjusted mean difference −0·35 [95% CI −1·53 to 0·84]) and in the per-protocol population (12·73 [SD 6·57] in the PCET group and 12·71 [6·33] in the CBT group; 0·27 [95% CI −1·08 to 1·62]). At 12 months post-randomisation, there was a significant adjusted between-group difference in mean PHQ-9 score in favour of CBT (1·73 [95% CI 0·26–3·19]), with a 95% CI exceeding the 2-point non-inferiority margin. There were two deaths, one death by suicide in the PCET group and one due to chronic obstructive pulmonary disease in the CBT group. Both were assessed by the responsible clinician to be unrelated to the trial. In terms of using emergency departments for depression-related events, four people (three in the PCET group; one in the CBT group) made more than a single use and six people (three in the PCET group; three in the CBT group) made a single use. One patient in the PCET group had inpatient treatment for a depression-related event. Interpretation This trial is the first to examine the two most frequently administered psychological therapies in the IAPT service. The finding of non-inferiority of PCET to CBT at 6 months supports the results from large, routine, non-randomised datasets from the IAPT programme. Given the high demand for psychological therapies and the need for patient choice, our findings suggest the need for continued investment in the training and delivery of PCET for improving short-term outcomes, but suggest that PCET might be inferior to CBT at 12 months. Funding British Association for Counselling and Psychotherapy Research Foundation.

1 Abstract Background & Aims Gut dysbiosis and inflammation perpetuates loss of gut-barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FC) and GBI markers. Methods Faeces and plasma were obtained from patients with stable cirrhosis (SC; n=16), AD (n=47), and healthy controls (HC; n=31). A panel of 15 cytokines and GBI markers including intestinal fatty acid-binding protein-2 (FABP2), D-lactate and faecal calprotectin (FCAL) were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed. Results Faecal (F) IL-1β, IFNγ, TNFα, IL-21, IL-17A/F and IL-22 were significantly elevated in AD vs SC (q, Graphical abstract The intestinal cytokine microenvironment in cirrhosis primes mucosal immune responses determining inflammatory outcomes. Exacerbated gut mucosal immune responses in acutely decompensated (AD) cirrhosis perpetuate intestinal barrier damage and prevent mucosal healing. Intestinal cytokine profiles are different in pattern and absolute quantity from the classical features of systemic inflammation in AD vs stable cirrhosis. There is an upregulation of T-cell meditated type-1 and type-17 effector faecal cytokines in AD but no increase in either faecal IL-8 or faecal IL-10 which are both innate-like cytokines that are increased in the circulation. Faecal cytokines and markers of gut barrier inflammation (FABP2) and integrity (D-lactate) accurately differentiate between stable cirrhosis and AD., 1 Highlights • The gut microenvironment in cirrhosis primes mucosal and systemic immune responses. • Gut inflammation is challenging to study in cirrhosis with a paucity of targeted assays. • Exacerbated gut immune responses and barrier damage occur in acutely decompensated (AD) cirrhosis. • Gut cytokine profiles in AD have very different patterns to innate-like systemic inflammation. • Upregulation of faecal T-cell meditated type-1 and type-17 effector cytokines occurs in AD. • Faecal cytokines and gut barrier markers accurately differentiate between stable cirrhosis and AD., The gut barrier is crucial in liver cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Inflammation affecting the lining of the gut is thought to play an important role in this process and leads to complications seen in cirrhosis due to disturbances of this ‘gut-liver axis’. Gut inflammation is difficult to study in cirrhosis patients without the use of invasive procedures. Most of the current knowledge is therefore based on changes measured in the bloodstream although these are not representative of the local problems happening in the gut itself. This work characterised these processes by measuring different markers in stool samples from patients at different stages of cirrhosis and compared this to healthy people. These markers, when compared to equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.

Background There is widespread concern about the pressure on emergency and urgent services in the UK, particularly emergency ambulances, emergency departments and same-day general practitioner appointments. A mismatch between supply and demand has led to interest in what can be termed ‘clinically unnecessary’ use of services. This is defined by the research team in this study as ‘patients attending services with problems that are classified as suitable for treatment by a lower urgency service or self-care’. This is a challenging issue to consider because patients may face difficulties when deciding the best action to take, and different staff may make different judgements about what constitutes a legitimate reason for service use. Objectives To identify the drivers of ‘clinically unnecessary’ use of emergency ambulances, emergency departments and same-day general practitioner appointments from patient and population perspectives. Design This was a sequential mixed-methods study with three components: a realist review; qualitative interviews (n = 48) and focus groups (n = 3) with patients considered ‘clinically unnecessary’ users of these services, focusing on parents of young children, young adults and people in areas of social deprivation; and a population survey (n = 2906) to explore attitudes towards seeking care for unexpected, non-life-threatening health problems and to identify the characteristics of someone with a tendency for ‘clinically unnecessary’ help-seeking. Results From the results of the three study components, we found that multiple, interacting drivers influenced individuals’ decision-making. Drivers could be grouped into symptom related, patient related and health service related. Symptom-related drivers were anxiety or need for reassurance, which were caused by uncertainty about the meaning or seriousness of symptoms; concern about the impact of symptoms on daily activities/functioning; and a need for immediate relief of intolerable symptoms, particularly pain. Patient-related drivers were reduced coping capacity as a result of illness, stress or limited resources; fear of consequences when responsible for another person’s health, particularly a child; and the influence of social networks. Health service-related drivers were perceptions or previous experiences of services, particularly the attractions of emergency departments; a lack of timely access to an appropriate general practitioner appointment; and compliance with health service staff’s advice. Limitations Difficulty recruiting patients who had used the ambulance service to the interviews and focus groups meant that we were not able to add as much as we had anticipated to the limited evidence base regarding this service. Conclusions Patients use emergency ambulances, emergency departments and same-day general practitioner appointments when they may not need the level of clinical care provided by these services for a multitude of inter-related reasons that sometimes differ by population subgroup. Some of these reasons relate to health services, in terms of difficulty accessing general practice leading to use of emergency departments, and to population-learnt behaviour concerning the positive attributes of emergency departments, rather than to patient characteristics. Social circumstances, such as complex and stressful lives, influence help-seeking for all three services. Demand may be ‘clinically unnecessary’ but completely understandable when service accessibility and patients’ social circumstances are considered. Future work There is a need to evaluate interventions, including changing service configuration, strengthening general practice and addressing the stressors that have an impact on people’s coping capacity. Different subgroups may require different interventions. Study registration This study is registered as PROSPERO CRD42017056273. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 15. See the NIHR Journals Library website for further project information.

ObjectivesThere is considerable variation in non-conveyance rates between ambulance services in England. The aim was to explore variation in how each ambulance service addressed non-conveyance for calls ending in telephone advice and discharge at scene.DesignA qualitative interview study.SettingTen large regional ambulance services covering 99% of the population in England.ParticipantsBetween four and seven interviewees from each ambulance service including managers, paramedics and healthcare commissioners, totalling 49 interviews.MethodsTelephone semistructured interviews.ResultsThe way interviewees in each ambulance service discussed non-conveyance within their organisation varied for three broad themes. First, ambulance service senior management appeared to set the culture around non-conveyance within an organisation, viewing it either as an opportunity or as a risky endeavour. Although motivation levels to undertake non-conveyance did not appear to be directly affected by the stability of an ambulance service in terms of continuity of leadership and externally assessed quality, this stability could affect the ability of the organisation to innovate to increase non-conveyance rates. Second, descriptions of workforce configuration differed between ambulance services, as well as how this workforce was used, trained and valued. Third, interviewees in each ambulance service described health and social care in the wider emergency and urgent care system differently in terms of availability of services that could facilitate non-conveyance, the amount of collaborative working between health and social care services and the ambulance service and complexity related to the numbers of services and healthcare commissioners with whom they had to work.ConclusionsThis study suggests that factors within and outside the control of ambulance services may contribute to variation in non-conveyance rates. These findings can be tested in a quantitative analysis of factors affecting variation in non-conveyance rates between ambulance services in England.

BackgroundIn recent years, a number of emergency departments (EDs) have closed or have been replaced by another facility such as an urgent care centre. With further reorganisation of EDs expected, this study aimed to provide research evidence to inform the public, the NHS and policy-makers when considering local closures.ObjectiveTo understand the impact of ED closures/downgrades on populations and emergency care providers.DesignA controlled interrupted time series of monthly data to assess changes in the patterns of mortality in local populations and changes in local emergency care service activity and performance, following the closure of type 1 EDs.SettingThe populations of interest were in the resident catchment areas of five EDs that closed between 2009 and 2011 (in Newark, Hemel Hempstead, Bishop Auckland, Hartlepool and Rochdale) and of five control areas.Main outcome measuresThe primary outcome measures were ambulance service incident volumes and times, the number of emergency and urgent care attendances at EDs, the number of emergency hospital admissions, mortality, and case fatality ratios.Data sourcesData were sourced from the Office for National Statistics, Hospital Episode Statistics (HES) accident and emergency, HES admitted patient care and ambulance service computer-aided dispatch records.ResultsThere was significant heterogeneity among sites in the results for most of the outcome measures, but the overall findings were as follows: there is evidence of an increase, on average, in the total number of incidents attended by an ambulance following 999 calls, and those categorised as potentially serious emergency incidents; there is no statistically reliable evidence of changes in the number of attendances at emergency or urgent care services or emergency hospital admissions; there is no statistically reliable evidence of any change in the number of deaths from a set of emergency conditions following the ED closure in any site, although, on average, there was a small increase in an indicator of the ‘risk of death’ in the closure areas compared with the control areas.LimitationsUnavailable or unreliable data hindered some of the analysis regarding ED and ambulance service performance.ConclusionsOverall, across the five areas studied, there was no statistically reliable evidence that the reorganisation of emergency care was associated with an increase in population mortality. This suggests that any negative effects caused by increased journey time to the ED can be offset by other factors; for example, if other new services are introduced and care becomes more effective than it used to be, or if the care received at the now-nearest hospital is more effective than that provided at the hospital where the ED closed. However, there may be implications of reorganisation for NHS emergency care providers, with ambulance services appearing to experience a greater burden.Future workUnderstanding why effects vary between sites is necessary. It is also necessary to understand the impact on patient experience. Economic evaluation to understand the cost implications of such reorganisation is also desirable.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

BACKGROUND: It is estimated that between 3% and 15% of patients have a negative experience of psychotherapy, but little is understood about this. AIMS: The aim of this study was to investigate the factors associated with patients' negative therapy experiences. METHOD: The data comprised 185 patient and 304 therapist questionnaires, 20 patient and 20 therapist interviews. Patients reported on an unhelpful or harmful experience of therapy, and therapists on a therapy where they thought the patient they were working with had a poor or harmful experience. These were transcribed and analysed using thematic analysis. RESULTS: There was a Lack of fit between Patient needs, Therapist skills, and Service structures. This could result in Fault Lines, a tension between Safety and containment and Power and control. This tension led to Strain and Poor Engagement, which led to Consequences following the negative therapy experience. CONCLUSIONS: Patients require clear information, choice, involvement in decision-making, explicit contracting and clarity about sessions and progress. Opportunities for patient feedback should be the norm, where the therapist and service are vigilant for signs of deterioration and solutions considered. Clinical and methodological significance of this article: Estimates of "unwanted effects," including long-lasting effects, of psychotherapy have ranged from 3% to 15%. Few empirical studies have been conducted in this area. This study aimed to address this gap and provide clinicians with a model of risk factors for negative therapy effects. The findings of this study indicate the importance of providing patients with a supportive service structure that offers clear information, choice and involvement in decision-making. Explicit contracting at the beginning of therapy and clarity about sessions and progress are also important in managing patient expectations throughout. Opportunities for patient feedback should be provided.

Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para -amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae , alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae .

BackgroundEnteropathogenic (EPEC) and Enteroaggregative (EAEC) E. coli have similar, but distinct clinical symptoms and modes of pathogenesis. Nevertheless when they infect the gastrointestinal tract, it is thought that their flagellin causes IL-8 release leading to neutrophil recruitment and gastroenteritis. However, this may not be the whole story as the effect of bacterial adherence to IEC innate response(s) remains unclear. Therefore, we have characterized which bacterial motifs contribute to the innate epithelial response to EPEC and EAEC, using a range of EPEC and EAEC isogenic mutant strains.MethodologyCaco-2 and HEp-2 cell lines were exposed to prototypical EPEC strain E2348/69 or EAEC strain O42, in addition to a range of isogenic mutant strains. E69 [LPS, non-motile, non-adherent, type three secretion system (TTSS) negative, signalling negative] or O42 [non-motile, non-adherent]. IL-8 and CCL20 protein secretion was measured. Bacterial surface structures were assessed by negative staining Transmission Electron Microscopy. The Fluorescent-actin staining test was carried out to determine bacterial adherence.ResultsPrevious studies have reported a balance between the host pro-inflammatory response and microbial suppression of this response. In our system an overall balance towards the host pro-inflammatory response is seen with the E69 WT and to a greater extent O42 WT, which is in fit with clinical symptoms. On removal of the external EPEC structures flagella, LPS, BFP, EspA and EspC; and EAEC flagella and AAF, the host inflammatory response is reduced. However, removal of E69 lymphostatin increases the host inflammatory response suggesting involvement in the bacterial mediated anti-inflammatory response.ConclusionEpithelial responses were due to combinations of bacterial agonists, with host-bacterial contact a key determinant of these innate responses. Host epithelial recognition was offset by the microbe's ability to down-regulate the inflammatory response. Understanding the complexity of this host-microbial balance will contribute to improved vaccine design for infectious gastroenteritis.

BackgroundCampylobacter jejuni is the most prevalent cause of bacterial gastroenteritis worldwide. Despite the significant health burden this infection presents, molecular understanding of C. jejuni-mediated disease pathogenesis remains poorly defined. Here, we report the characterisation of the early, innate immune response to C. jejuni using an ex-vivo human gut model of infection. Secondly, impact of bacterial-driven dendritic cell activation on T-cell mediated immunity was also sought.MethodologyHealthy, control paediatric terminal ileum or colonic biopsy tissue was infected with C. jejuni for 8-12 hours. Bacterial colonisation was followed by confocal microscopy and mucosal innate immune responses measured by ELISA. Marked induction of IFNγ with modest increase in IL-22 and IL-17A was noted. Increased mucosal IL-12, IL-23, IL-1β and IL-6 were indicative of a cytokine milieu that may modulate subsequent T-cell mediated immunity. C. jejuni-driven human monocyte-derived dendritic cell activation was followed by analyses of T cell immune responses utilising flow cytometry and ELISA. Significant increase in Th-17, Th-1 and Th-17/Th-1 double-positive cells and corresponding cytokines was observed. The ability of IFNγ, IL-22 and IL-17 cytokines to exert host defence via modulation of C. jejuni adhesion and invasion to intestinal epithelia was measured by standard gentamicin protection assay.ConclusionsBoth innate and adaptive T cell-immunity to C. jejuni infection led to the release of IFNγ, IL-22 and IL-17A; suggesting a critical role for this cytokine triad in establishing host anti-microbial immunity during the acute and effectors phase of infection. In addition, to their known anti-microbial functions; IL-17A and IL-17F reduced the number of intracellular C. jejuni in intestinal epithelia, highlighting a novel aspect of how IL-17 family members may contribute to protective immunity against C. jejuni.