Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes

Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in CFTR (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from β cells in the pancreatic islet, but the mechanisms underlying the loss of β cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in β cells and an increase in α, δ and γ cell abundance. The small amount of available data suggest that substantial loss of pancreatic/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the β cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD

Urban Foraging and the Relational Ecologies of Belonging

Through a discussion of urban foraging in Seattle, Washington, USA, we examine how people\u27s plant and mushroom harvesting practices in cities are linked to relationships with species, spaces, and ecologies. Bringing a relational approach to political ecology, we discuss the ways that these particular nature–society relationships are formed, legitimated, and mobilized in discursive and material ways in urban ecosystems. Engaging closely with and as foragers, we develop an ethnographically grounded ‘relational ecologies of belonging’ framework to conceptualize and examine three constituent themes: cultural belonging and identity, belonging and place, and belonging and more-than-human agency. Through this case study, we show the complex ways that urban foraging is underpinned by interconnected and multiple notions of identity, place, mobility, and agency for both humans and more-than-human interlocutors. The focus on relational ecologies of belonging illuminates important challenges for environmental management and public space planning in socioecologically diverse areas. Ultimately, these challenges reflect negotiated visions about how we organize ourselves and live together in cosmopolitan spaces such as cities

Predicted risks of radiogenic cardiac toxicity in two pediatric patients undergoing photon or proton radiotherapy

BACKGROUND: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB. METHODS: In the treatment plans, each patient’s heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed. RESULTS: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors. CONCLUSIONS: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study

Objectively measured patterns of sedentary time and physical activity in young adults of the Raine study cohort

Background: To provide a detailed description of young adults' sedentary time and physical activity. Methods: 384 young women and 389 young men aged 22.1±0.6 years, all participants in the 22 year old follow-up of the Raine Study pregnancy cohort, wore Actigraph GT3X+ monitors on the hip for 24 h/day over a one-week period for at least one 'valid' day (=10 h of waking wear time). Each minute epoch was classified as sedentary, light, moderate or vigorous intensity using 100 count and Freedson cut-points. Mixed models assessed hourly and daily variation; t-tests assessed gender differences. Results: The average (mean±SD) waking wear time was 15.0±1.6 h/day, of which 61.4±10.1 % was spent sedentary, 34.6±9.1 % in light-, 3.7±5.3 % in moderate- and, 0.3±0.6 % in vigorous-intensity activity. Average time spent in moderate to vigorous activity (MVPA) was 36.2±27.5 min/day. Relative to men, women had higher sedentary time, but also higher vigorous activity time. The 'usual' bout duration of sedentary time was 11.8±4.5 min in women and 11.7±5.2 min in men. By contrast, other activities were accumulated in shorter bout durations. There was large variation by hour of the day and by day of the week in both sedentary time and MVPA. Evenings and Sundays through Wednesdays tended to be particularly sedentary and/or inactive. Conclusion: For these young adults, much of the waking day was spent sedentary and many participants were physically inactive (low levels of MVPA). We provide novel evidence on the time for which activities were performed and on the time periods when young adults were more sedentary and/or less active. With high sedentary time and low MVPA, young adults may be at risk for the life-course sequelae of these behaviours

Integration of robotic surgery into routine practice and impacts on communication, collaboration, and decision making: A realist process evaluation protocol

Background: Robotic surgery offers many potential benefits for patients. While an increasing number of healthcare providers are purchasing surgical robots, there are reports that the technology is failing to be introduced into routine practice. Additionally, in robotic surgery, the surgeon is physically separated from the patient and the rest of the team, with the potential to negatively impact teamwork in the operating theatre. The aim of this study is to ascertain: how and under what circumstances robotic surgery is effectively introduced into routine practice; and how and under what circumstances robotic surgery impacts teamwork, communication and decision making, and subsequent patient outcomes. Methods and design: We will undertake a process evaluation alongside a randomised controlled trial comparing laparoscopic and robotic surgery for the curative treatment of rectal cancer. Realist evaluation provides an overall framework for the study. The study will be in three phases. In Phase I, grey literature will be reviewed to identify stakeholders' theories concerning how robotic surgery becomes embedded into surgical practice and its impacts. These theories will be refined and added to through interviews conducted across English hospitals that are using robotic surgery for rectal cancer resection with staff at different levels of the organisation, along with a review of documentation associated with the introduction of robotic surgery. In Phase II, a multi-site case study will be conducted across four English hospitals to test and refine the candidate theories. Data will be collected using multiple methods: the structured observation tool OTAS (Observational Teamwork Assessment for Surgery); video recordings of operations; ethnographic observation; and interviews. In Phase III, interviews will be conducted at the four case sites with staff representing a range of surgical disciplines, to assess the extent to which the results of Phase II are generalisable and to refine the resulting theories to reflect the experience of a broader range of surgical disciplines. The study will provide (i) guidance to healthcare organisations on factors likely to facilitate successful implementation and integration of robotic surgery, and (ii) guidance on how to ensure effective communication and teamwork when undertaking robotic surgery

Abstracts from the NIHR INVOLVE Conference 2017

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Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes