Pathways to professionalism? Quality improvement, care pathways, and the interplay of standardisation and clinical autonomy.

Care pathways are a prominent feature of efforts to improve healthcare quality, outcomes and accountability, but sociological studies of pathways often find professional resistance to standardisation. This qualitative study examined the adoption and adaptation of a novel pathway as part of a randomised controlled trial in an unusually complex, non-linear field - emergency general surgery - by teams of surgeons and physicians in six theoretically sampled sites in the UK. We find near-universal receptivity to the concept of a pathway as a means of improving peri-operative processes and outcomes, but concern about the impact on appropriate professional judgement. However, this concern translated not into resistance and implementation failure, but into a nuancing of the pathways-as-realised in each site, and their use as a means of enhancing professional decision-making and inter-professional collaboration. We discuss our findings in the context of recent literature on the interplay between managerialism and professionalism in healthcare, and highlight practical and theoretical implications

Multi-decadal environmental change in the Barents Sea recorded by seal teeth

This work resulted from the ARISE project (NE/P006035/1, NE/P006000/1), part of the Changing Arctic Ocean programme, jointly funded by the UKRI Natural Environment Research Council (NERC). We thank Jim Ball for his help in the isotopic lab in Liverpool University. This work resulted from the ARISE project, part of the Changing Arctic Ocean programme.Multiple environmental forcings, such as warming and changes in ocean circulation and nutrient supply, are affecting the base of Arctic marine ecosystems, with cascading effects on the entire food web through bottom-up control. Stable nitrogen isotopes (δ15N) can be used to detect and unravel the impact of these forcings on this unique ecosystem, if the many processes that affect the δ15N values are constrained. Combining unique 60-year records from compound specific δ15N biomarkers on harp seal teeth alongside state-of-the-art ocean modelling, we observed a significant decline in the δ15N values at the base of the Barents Sea food web from 1951 to 2012. This strong and persistent decadal trend emerges due to the combination of anthropogenic atmospheric nitrogen deposition in the Atlantic, increased northward transport of Atlantic water through Arctic gateways and local feedbacks from increasing Arctic primary production. Our results suggest that the Arctic ecosystem has been responding to anthropogenically induced local and remote drivers, linked to changing ocean biology, chemistry and physics, for at least 60 years. Accounting for these trends in δ15N values at the base of the food web is essential to accurately detect ecosystem restructuring in this rapidly changing environment.Publisher PDFPeer reviewe

Hospital-level evaluation of the effect of a national quality improvement programme: time-series analysis of registry data.

BACKGROUND AND OBJECTIVES: A clinical trial in 93 National Health Service hospitals evaluated a quality improvement programme for emergency abdominal surgery, designed to improve mortality by improving the patient care pathway. Large variation was observed in implementation approaches, and the main trial result showed no mortality reduction. Our objective therefore was to evaluate whether trial participation led to care pathway implementation and to study the relationship between care pathway implementation and use of six recommended implementation strategies. METHODS: We performed a hospital-level time-series analysis using data from the Enhanced Peri-Operative Care for High-risk patients trial. Care pathway implementation was defined as achievement of >80% median reliability in 10 measured care processes. Mean monthly process performance was plotted on run charts. Process improvement was defined as an observed run chart signal, using probability-based 'shift' and 'runs' rules. A new median performance level was calculated after an observed signal. RESULTS: Of 93 participating hospitals, 80 provided sufficient data for analysis, generating 800 process measure charts from 20 305 patient admissions over 27 months. No hospital reliably implemented all 10 processes. Overall, only 279 of the 800 processes were improved (3 (2-5) per hospital) and 14/80 hospitals improved more than six processes. Mortality risk documented (57/80 (71%)), lactate measurement (42/80 (53%)) and cardiac output guided fluid therapy (32/80 (40%)) were most frequently improved. Consultant-led decision making (14/80 (18%)), consultant review before surgery (17/80 (21%)) and time to surgery (14/80 (18%)) were least frequently improved. In hospitals using ≥5 implementation strategies, 9/30 (30%) hospitals improved ≥6 care processes compared with 0/11 hospitals using ≤2 implementation strategies. CONCLUSION: Only a small number of hospitals improved more than half of the measured care processes, more often when at least five of six implementation strategies were used. In a longer term project, this understanding may have allowed us to adapt the intervention to be effective in more hospitals

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Hospital-level evaluation of the effect of a national quality improvement programme: time-series analysis of registry data

Background and objectives: A clinical trial in 93 National Health Service hospitals evaluated a quality improvement programme for emergency abdominal surgery, designed to improve mortality by improving the patient care pathway. Large variation was observed in implementation approaches, and the main trial result showed no mortality reduction. Our objective therefore was to evaluate whether trial participation led to care pathway implementation and to study the relationship between care pathway implementation and use of six recommended implementation strategies. Methods: We performed a hospital-level time-series analysis using data from the Enhanced Peri-Operative Care for High-risk patients trial. Care pathway implementation was defined as achievement of &gt;80% median reliability in 10 measured care processes. Mean monthly process performance was plotted on run charts. Process improvement was defined as an observed run chart signal, using probability-based €shift' and €runs' rules. A new median performance level was calculated after an observed signal. Results: Of 93 participating hospitals, 80 provided sufficient data for analysis, generating 800 process measure charts from 20 305 patient admissions over 27 months. No hospital reliably implemented all 10 processes. Overall, only 279 of the 800 processes were improved (3 (2-5) per hospital) and 14/80 hospitals improved more than six processes. Mortality risk documented (57/80 (71%)), lactate measurement (42/80 (53%)) and cardiac output guided fluid therapy (32/80 (40%)) were most frequently improved. Consultant-led decision making (14/80 (18%)), consultant review before surgery (17/80 (21%)) and time to surgery (14/80 (18%)) were least frequently improved. In hospitals using ≥5 implementation strategies, 9/30 (30%) hospitals improved ≥6 care processes compared with 0/11 hospitals using ≤2 implementation strategies. Conclusion: Only a small number of hospitals improved more than half of the measured care processes, more often when at least five of six implementation strategies were used. In a longer term project, this understanding may have allowed us to adapt the intervention to be effective in more hospitals.</p

Targeting gene expression to endothelium in transgenic animals: A comparison of the human ICAM-2, PECAM-1 and endoglin promoters

It is highly likely that successful pig-to-human xenotransplantation of vascularized organs will require genetic modification of the donor pig, and in particular of donor vascular endothelium. Promoters are generally tested in transgenic mice before generating transgenic pigs. Several promoters have been used to drive endothelial cell-specific expression in mice but none have yet been tested in pigs. We compared the promoters of three human genes that are predominantly expressed in vascular endothelium: intercellular adhesion molecule 2 (ICAM-2), platelet endothelial cell adhesion molecule 1 (PECAM-1) and endoglin. Expression of human complement regulatory proteins (hCRPs), directed by each of the promoters in mice, was largely restricted to vascular endothelium and leukocyte subpopulations. However, expression from the PECAM-1 promoter was weak in liver and non-uniform in the small vessels of heart, kidney, and lung. Conversely, expression from the endoglin promoter was consistently strong in the small vessels of these organs but was absent in larger vessels. The ICAM-2 promoter, which produced strong and uniform endothelial expression in all organs examined, was therefore used to generate hCRP transgenic pigs. Leukocytes from 57 pigs containing at least one intact transgene were tested for transgene expression by flow cytometry. Forty-seven of these transgenic pigs were further analyzed by immunohistochemical staining of liver biopsies, and 18 by staining of heart and kidney sections. Only two of the pigs showed expression, which appeared to be restricted to vascular endothelium in heart and kidney but was markedly weaker than in transgenic mice produced with the same batch of DNA. Thus, in this case, promoter performance in mice and pigs was not equivalent. The weak expression driven by the human ICAM-2 promoter in pigs relative to mice suggests the need for additional regulatory elements to achieve species-specific gene expression in pigs.This work was supported in part by grants from Ministerio de Ciencia y Tecnologia and Comunidad de Madrid to CB.Peer Reviewe

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery: A stepped-wedge cluster randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: Stepped-wedge cluster randomised trial of patients aged ≥40 years undergoing emergency open major abdominal surgery. Hospitals were organised into 15 geographical clusters and commenced the QI programme in random order, based on a computer generated random sequence, over an 85-week period. The trial included an ethnographic study in six hospitals. The primary outcome measure was mortality within 90 days of surgery. Analyses were performed on an intention-to-treat basis. The primary outcome was analysed using a mixed-effects parametric survival model, adjusting for time-related effects. Findings: Of 15,873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. The primary outcome occurred in 1393 patients in the usual care group (16%) compared with 1210 patients in the QI group (16%) (HR QI vs usual care: 1.11 [0.96-1.28]). There were only modest overall improvements in processes of patient care following QI implementation. The ethnographic study revealed good QI engagement but limited time and resources to implement change, affecting which processes teams addressed, the rate of change and eventual success. Interpretation: There was no survival benefit from a QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. The success of the QI intervention may have been limited by the time and resources needed to improve patient care. Funding: National Institute for Health Research, Health Services and Delivery Research.National Institute for Health Research, Health Services and Delivery Research

Immunization strategies producing a humoral IgG immune response against devil facial tumor disease in the majority of Tasmanian devils destined for wild release

Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (N = 19 and N = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol®) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild.Ruth Pye, Amanda Patchett, Elspeth McLennan, Russell Thomson, Scott Carver ... A. Bruce Lyons ... et al

Effects of clusterin over-expression on metastatic progression and therapy in breast cancer

<p>Abstract</p> <p>Background</p> <p>Clusterin is a secreted glycoprotein that is upregulated in a variety of cell lines in response to stress, and enhances cell survival. A second nuclear isoform of clusterin that is associated with cell death has also been identified. The aim of this study was to determine the role(s) of the secretory isoform in breast tumor progression and metastasis.</p> <p>Methods</p> <p>To investigate the role of secretory clusterin in the biology of breast cancer tumor growth and resistance to therapy we have engineered an MCF-7 cell line (MCF-7CLU) that over-expresses clusterin. We have measured the <it>in vitro </it>effects of clusterin over-expression on cell cycle, cell death, and sensitivity to TNFalpha and tamoxifen. Using an orthotopic model of breast cancer, we have also determined the effects of over-expression of clusterin on tumor growth and metastatic progression.</p> <p>Results</p> <p>In vitro, over-expression of secretory clusterin alters the cell cycle kinetics and decreases the rate of cell death, resulting in the enhancement of cell growth. Over-expression of secretory clusterin also blocks the TNFalpha-mediated induction of p21 and abrogates the cleavage of Bax to t-Bax, rendering the MCF-7CLU cells significantly more resistant to the cytokine than the parental cells. Orthotopic primary tumors derived from MCF-7CLU cells grow significantly more rapidly than tumors derived from parental MCF-7 cells and, unlike the parental cells, metastasize frequently to the lungs.</p> <p>Conclusions</p> <p>These data suggest that secretory clusterin, which is frequently up-regulated in breast cancers by common therapies, including anti-estrogens, may play a significant role in tumor growth, metastatic progression and subsequent drug resistance in surviving cells.</p