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Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.

Introduction BO is the strongest precursor of oesophageal adenocarcinoma. Participation patterns and effectiveness of BO community screening using unsedated transnasal endoscopy (uTNE) is unknown. Feasibility of mobile van screening closer to home is also unknown. We aimed to assess the effectiveness of this technique compared to sedated endoscopy (SE). Methods A population cohort ≥50 years of age, with no history of endoscopic evaluation, was identified from a group of subjects who previously completed a validated symptom questionnaire. Patients were randomised (stratified by age, sex and reflux symptoms) and invited to undergo either uTNE in a mobile research van (muTNE), uTNE in outpatient endoscopy suite (huTNE) or SE. uTNE was performed using a portable oesophagoscope with a disposable sheath. Procedure performance characteristics and validated tolerability scales (0 = none and 10 = severe) were recorded. Results 459 subjects were contacted and 209 (46%) agreed to undergo study procedures (muTNE n = 76, huTNE n = 72, SE n = 61). Baseline characteristics were comparable among the three groups. Participation rates were numerically higher in the unsedated arms (muTNE 47.5%, huTNE 45.7%) than in the SE arm (40.7%) (p = 0.27). Patients with acid reflux symptoms ≥1/week were more likely to participate (odds ratio 2.94, 95% confidence interval 1.47, 5.88). Complete evaluation of the oesophagus was comparable using muTNE (99%), huTNE (96%) and SE (100%) techniques. Successful biopsy acquisition was lower in the muTNE (79%) and huTNE (83%) groups compared to SE (100%) (p = 0.001). Mean duration (minutes) of examination was shorter in the SE arm (4.7) than in muTNE (8.0) and huTNE (8.5) groups (p < 0.001). However, recovery time was much longer for SE (67.3) compared to muTNE (15.5) and huTNE (18.5) techniques (p < 0.001). While overall tolerability for SE was better than muTNE and huTNE (mean score 0.4 vs. 1.9 and 2.2 respectively, p < 0.001), the majority of patients who underwent muTNE and huTNE were willing to undergo the same procedure again in future (79% and 83%, respectively). No serious adverse events were reported. 16 subjects (7.6%) were diagnosed with BO. Conclusion In this first large randomised trial evaluating novel approaches for community screening for BO, unsedated mobile van and clinic screening with TNE was feasible and effective. The patients’ visit was significantly shorter with adequate tolerability, acceptability and safety profiles. Mobile and outpatient techniques may provide a cost-effective alternative to SE for BO screening. Disclosure of Interest S. Sami: None Declared, K. Dunagan: None Declared, M. Johnson: None Declared, C. Schlek: None Declared, A. Zinsmeister: None Declared, L. M. Wong Kee Song: None Declared, K. Wang: None Declared, D. Katzka: None Declared, K. Ragunath Grant/research support from: Olympus (keymed, UK) and Intromed Ltd. (Seoul, South Korea), P. Iyer: None Declared.

Human adipose‐derived mesenchymal stromal cells (AMSCs) grown in platelet lysate are promising agents for therapeutic tissue regeneration. Here, we investigated whether manipulation of epigenetic events by the clinically relevant histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alters differentiation of AMSCs. The multipotency of AMSCs was validated by their ability to differentiate into osteogenic, chondrogenic, and adipogenic lineages. High‐throughput RNA sequencing and RT‐qPCR established that human histone deacetylases (HDAC1 to HDAC11, and SIRT1 to SIRT7) are differentially expressed in AMSCs. SAHA induces hyper‐acetylation of histone H3 and H4, stimulates protein expression of the HDAC‐responsive gene SLC9A3R1/NHERF1 and modulates the AKT/FOXO1 pathway. Biologically, SAHA interferes with osteogenic, chondrogenic and adipogenic lineage commitment of multipotent AMSCs. Mechanistically, SAHA‐induced loss of differentiation potential of uncommitted AMSCs correlates with multiple changes in the expression of principal transcription factors that control mesenchymal or pluripotent states. We propose that SAHA destabilizes the multi‐potent epigenetic state of uncommitted human AMSCs by hyper‐acetylation and perturbation of key transcription factor pathways. Furthermore, AMSCs grown in platelet lysate may provide a useful biological model for screening of new HDAC inhibitors that control the biological fate of human mesenchymal stromal cells. J. Cell. Physiol. 230: 52–62, 2015. © 2014 Wiley Periodicals, Inc.

Objectives Debriefing is a common feature of technology‐enhanced simulation ( TES ) education. However, evidence for its effectiveness remains unclear. We sought to characterise how debriefing is reported in the TES literature, identify debriefing features that are associated with improved outcomes, and evaluate the effectiveness of debriefing when combined with TES . Methods We systematically searched databases, including MEDLINE , EMBASE and Scopus, and reviewed previous bibliographies for original comparative studies investigating the use of TES with debriefing in training health care providers. Reviewers, in duplicate, evaluated study quality and abstracted information on instructional design, debriefing and outcomes. Effect sizes ( ES ) were pooled using random‐effects meta‐analysis. Results From 10 903 potentially eligible studies, we identified 177 studies (11 511 learners) that employed debriefing as part of TES . Key characteristics of debriefing (e.g. duration, educator presence and characteristics, content, structure/method, timing, use of video) were usually incompletely reported. A meta‐analysis of four studies demonstrated that video‐assisted debriefing has negligible and non‐significant effects for time skills ( ES = 0.10) compared with non‐video‐assisted debriefing. Meta‐analysis demonstrated non‐significant effects in favour of expert modelling with short debriefing in comparison with long debriefing (ES range = 0.21–0.74). Among studies comparing terminal with concurrent debriefing, results were variable depending on outcome measures and the context of training (e.g. medical resuscitation versus technical skills). Eight additional studies revealed insight into the roles of other debriefing‐related factors (e.g. multimedia debriefing, learner‐led debriefing, debriefing duration, content of debriefing). Among studies that compared simulation plus debriefing with no intervention, pooled ES s were favourable for all outcomes (ES range = 0.28–2.16). Conclusions Limited evidence suggests that video‐assisted debriefing yields outcomes similar to those of non‐video‐assisted debriefing. Other debriefing design features show mixed or non‐significant results. As debriefing characteristics are usually incompletely reported, future debriefing research should describe all the key debriefing characteristics along with their associated descriptors.

ABSTRACTIntracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age‐related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25–7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age‐related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse‐ or age‐related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age‐ and disuse‐related osteoporoses in humans. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc.

AbstractNeurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10‐point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7‐10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9‐9.8] vs. 9.8 [4.6‐13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1‐10.2] vs. 13.7 [8.5‐14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01‐1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88‐38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01‐9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid‐requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA. © 2014 International Parkinson and Movement Disorder Society

Rationale : Macrophages regulate blood vessel structure and function in health and disease. The origins of tissue macrophages are diverse, with evidence for local production and circulatory renewal. Objective : We identified a vascular adventitial population containing macrophage progenitor cells and investigated their origins and fate. Methods and Results : Single-cell disaggregates from adult C57BL/6 mice were prepared from different tissues and tested for their capacity to form hematopoietic colony-forming units. Aorta showed a unique predilection for generating macrophage colony-forming units. Aortic macrophage colony-forming unit progenitors coexpressed stem cell antigen-1 and CD45 and were adventitially located, where they were the predominant source of proliferating cells in the aortic wall. Aortic Sca-1 + CD45 + cells were transcriptionally and phenotypically distinct from neighboring cells lacking stem cell antigen-1 or CD45 and contained a proliferative (Ki67 + ) Lin − c-Kit + CD135 − CD115 + CX 3 CR1 + Ly6C + CD11b − subpopulation, consistent with the immunophenotypic profile of macrophage progenitors. Adoptive transfer studies revealed that Sca-1 + CD45 + adventitial macrophage progenitor cells were not replenished via the circulation from bone marrow or spleen, nor was their prevalence diminished by depletion of monocytes or macrophages by liposomal clodronate treatment or genetic deficiency of macrophage colony-stimulating factor. Rather adventitial macrophage progenitor cells were upregulated in hyperlipidemic ApoE −/− and LDL-R −/− mice, with adventitial transfer experiments demonstrating their durable contribution to macrophage progeny particularly in the adventitia, and to a lesser extent the atheroma, of atherosclerotic carotid arteries. Conclusions : The discovery and characterization of resident vascular adventitial macrophage progenitor cells provides new insight into adventitial biology and its participation in atherosclerosis and provokes consideration of the broader existence of local macrophage progenitors in other tissues.

BackgroundLong‐term follow‐up after stent dilation of native and acquired pulmonary artery stenosis is scarce in the pediatric population. Most cohorts include a myriad of anatomies and associated conditions.MethodIn order to establish objective performance criteria, we performed a retrospective review of all patients who underwent unilateral pulmonary artery stenting in biventricular physiology at three centers from June 2006 to June 2011.ResultsFifty‐eight patients received 60 stents with Palmaz Genesis stent used most commonly (78%). Average age at implantation was 10.4 ± 10.3 years and weight 31.6 ± 21.8 kg. The immediate success rate was 98%, with improvement in minimal diameter from 5.1 ± 2 cm to 10.6 ± 3 cm (P < 0.01). There were 10 complications (7 major and 3 minor) and no acute mortality. One‐year follow‐up studies were available in 48 patients (83%), including echocardiogram (60%), catheterization (28%), MRI (29%), and lung perfusion (31%). Follow‐up echocardiogram showed mild increase in stent gradient, from 5.7 ± 6.7 mm Hg post‐procedure to 17.1 ± 11.7 mm Hg. Follow‐up catheterization showed no significant change in minimal stent diameter (8.8 ± 2.6 to 7.8 ± 2.3 mm), gradient (7.7 ± 8.4 to 12.6 ± 12.2 mm Hg), or right ventricular pressures (43.7 ± 9 to 47.7 ± 10.5 mm Hg). Nine patients (16%) underwent scheduled stent redilation over a period of 12 days to 25 months.ConclusionIn conclusion, stent implantation shows excellent immediate and 1‐year follow‐up results with maintenance of improved caliber of the stented vessel and lowered right ventricular systolic pressures. © 2014 Wiley Periodicals, Inc.