Patients with rheumatoid arthritis (RA) display distinct patterns of synovitis. To define the inflammatory mechanisms driving this heterogeneity, we analyzed the inflamed synovium of wild-type (WT), Il6ra -/-, and Il27ra -/- mice with antigen-induced arthritis (AIA). Remarkably, each strain developed a joint pathology mirroring a major RA synovial pathotype: myeloid-rich (WT), fibroblast-rich/pauci-immune ( Il6ra -/-), and lymphoid-rich ( Il27ra -/-) synovitis. Histology confirmed minimal immune infiltration in Il6ra -/- joints, while WT and Il27ra -/- mice exhibited prominent immune involvement, including organized synovial lymphoid-like aggregates in Il27ra -/- mice. Transcriptomic and epigenomic profiling revealed both shared and distinct regulatory programs among genotypes. Il6ra -/- mice showed increased WNT, DKK, and AMPK signaling associated with fibroblast, chondrocyte, and osteoclast activation (e.g., Adamts19 , Dkk1 , Ecm1 ). Consistent with synovial ectopic lymphoid-like structures, Il27ra -/- mice showed enrichment of lymphocyte activation (e.g., Il17a , Il22 , Bhlhe40 ). WT mice exhibited hallmarks of MAP kinase activation. These molecular signatures parallel those of fibroblast-, lymphoid-, and myeloid-rich synovitis in RA. Defining a STAT1–STAT3 regulatory interplay influencing transcriptional decisions in WT and Il27ra -/- mice, our findings offer insights into cytokine-driven disease heterogeneity. Together, these results establish a framework for mechanism-based classification of synovitis and introduce new mouse models to study the molecular drivers of synovial pathotypes and treatment response. ### Competing Interest Statement The authors have declared no competing interest. UKRI-MRC, MR/X00077X/1 Versus Arthritis, https://ror.org/02jkpm469, 20770, 19796, 20305, 22706

Introduction: Although rheumatoid arthritis (RA) is a disease of articular joints, patients often suffer from co-morbid neuropsychiatric changes, such as anxiety, that may reflect links between heightened systemic inflammation and abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we apply behavioral neuroscience methods to assess the impact of antigen-induced arthritis (AIA) on behavioral performance in wild type (WT) and interleukin-10 deficient ( Il10 -/- ) mice. Our aim was to identify limb-specific motor impairments, as well as neuropsychological responses to inflammatory arthritis. Methods: Behavioral testing was performed longitudinally in WT and Il10 -/- mice before and after the induction of arthritic joint pathology. Footprint analysis, beam walking and open field assessment determined a range of motor, exploratory and anxiety-related parameters. Specific gene changes in HPA axis tissues were analyzed using qPCR. Results: Behavioral assessment revealed transient motor and exploratory impairments in mice receiving AIA, coinciding with joint swelling. Hind limb coordination deficits were independent of joint pathology. Behavioral impairments returned to baseline by 10 days post-AIA in WT mice. Il10 -/- mice demonstrated comparable levels of swelling and joint pathology as WT mice up to 15 days post-AIA, but systemic differences were evident in mRNA expression in HPA axis tissues from Il10 -/- mice post-AIA. Interestingly, the behavioral profile of Il10 -/- mice revealed a significantly longer time post-AIA for activity and anxiety-related behaviors to recover. Conclusions: The novel application of sensitive behavioral tasks has enabled dissociation between behaviors that occur due to transient joint-specific pathology and those generated by more subtle systemic alterations that manifest post-AIA.

Immune-mediated inflammatory diseases (IMIDs) are commonly associated with complex coexisting conditions, and cardiovascular comorbidities are a common cause of mortality in systemic inflammation. Experimental models of disease provide an opportunity to dissect inflammatory mechanisms that promote damage to vascular tissues affected by comorbidity. Here, we describe methods to recover the thoracic aorta from mice during experimental inflammatory arthritis and assess vascular constriction responses by isometric tension myography. To complement the assessment of functional changes in the vasculature during inflammatory arthritis, we also outline a method to characterize vascular inflammation by immunohistochemistry.

S1. Tumor HEV identified by PNAd staining are also positive for MAdCAM-1. S2. Efficacy of monoclonal antibody treatments to deplete immune cell subsets. S3. Splenic Marginal Zone B cells are profoundly decreased after treatment with LTbetaR.Fc. S4. Splenic Follicular Dendritic Cells and MAdCAM-1 staining are lost after treatment with LTbetaR.Fc or TNFRII.Ig. S5. Lymph Node architecture is disrupted following treatment with LTbetaR.Fc or TNFRII.Ig. S6. Tumor HEV identified by PNAd staining following blockade of LTbetaR or TNFR signalling are also positive for MAdCAM-1. S7. Agonism of LTβR induces formation of High Endothelial Venules in Treg replete tumors, but without concomitant increased T cell infiltration and reduced tumor growth. S8. Relative gene expression of TNF and LTalpha by intratumoral CD4+ and CD8+ T cells and dendritic cells (DC). Data are expressed as fold change in gene expression relative to splenic B cells, and represent two independent experiments.

Abstract Objectives Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. Methods Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). Results sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT ‘rapid progressors’ at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. Conclusions IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population.

Musculoskeletal disorders represent the third greatest burden in terms of death and disability in the developed world. Osteoarthritis is the single greatest cause of chronic pain, has no cure, and affects 8.5 and 27 million people in the UK and US, respectively. Osteoarthritis is most prevalent in older people, but as it commonly occurs after joint injury, young people with such injuries are also susceptible. Painful joints are often treated with steroid or hyaluronic acid (HA) injections, but treatments to prevent subsequent joint degeneration remain elusive. In animals, joint injury increases glutamate release into the joint, acting on nerves to cause pain, and joint tissues to cause inflammation and degeneration. This study investigated synovial fluid glutamate concentrations and glutamate receptor (GluR) expression in injured human joints and compared the efficacy of GluR antagonists with current treatments in a mouse model of injury-induced osteoarthritis (ACL rupture). GluRs were expressed in the ligaments and meniscus after knee injury, and synovial fluid glutamate concentrations ranged from 19 to 129 μM. Intra-articular injection of NBQX (GluR antagonist) at the time of injury substantially reduced swelling and degeneration in the mouse ACL rupture model. HA had no effect, and Depo-Medrone reduced swelling for 1 day but increased degeneration by 50%. Intra-articular administration of NBQX modified both symptoms and disease to a greater extent than current treatments. There is an opportunity for repurposing related drugs, developed for CNS disorders and with proven safety in humans, to prevent injury-induced osteoarthritis. This could quickly reduce the substantial burden associated with osteoarthritis.

Objective CD3 + CD8 + CD28 − cells are increased in the periphery and tissues of rheumatoid arthritis (RA) patients. The aim of this study was to characterise CD3 + CD8 + CD28 − cells for the presence of cell surface receptors that regulate immune activation and function and to track their presence in a disease model of RA. Cell surface receptors expressed by CD3 + CD8 + CD28 − cells were then related to serological and clinical disease parameters to establish whether these cells are prognostic of a clinical response to conventional DMARDs. Method Using healthy donor peripheral blood mononuclear (PBMC) cell surface expression of > 50 candidate markers were tested using flow cytometry and compared against CD28 expression. The prevalence of cells expressing the most suitable candidate was investigated in the collagen induced arthritis (CIA) and the antigen-induced arthritis (AIA) models. Fifty RA patients were recruited from University Hospital of Wales (UHW) rheumatology outpatient clinic. Clinical and serological markers of inflammation were noted, and PBMC were analysed using flow cytometry +/− in vitro stimulation. Results CD3 + CD8 + CD28 − T cells express CD244, CD57, CX3CR1 and KLRG1. The strongest inverse correlate of CD28 expression was KLRG1. CD3 + CD8 + CD28 − KLRG1 + cells were elevated in experimental models of RA. Notably, Il-10-deficiency was linked with exacerbated arthritis and an increase in the number of CD3 + CD8 + CD28 − KLRG1 + cells, suggesting a regulatory role for Il-10 in their development or survival. In RA patients, CD3 + CD8 + CD28 − KLRG1 + cells correlate with ACPA, RF and ESR, and produce more IL-10 than controls. Finally, these cells are higher in early arthritis patients that do not respond to treatment with synthetic DMARDs at six months. Conclusion KLRG1 is a marker for regulatory CD3 + CD8 + CD28 − cells. The presence of CD3 + CD8 + CD28-KLRG1 + cells increases with certain measures of disease, and is indicative of poor treatment response to DMARDs in early arthritis. Key Messages KLRG1 is a marker of CD28 negativity on CD8 T cells CD3 + CD8 + CD28 − KLRG1 + cells are increased in CIA mice and correlate with disease severity. CD3 + CD8 + CD28 − KLRG1 + cells positively correlate with ESR / ACPA and RF in patients. CD3 + CD8 + CD28 − KLRG1 + cells are increased in Il-10-deficient mice with inflammatory arthritis. CD3 + CD8 + CD28 − KLRG1 + cells produce more Il-10 than CD3 + CD8 + CD28 + KLRG1 − cells in RA patients. CD3 + CD8 + CD28 − KLRG1 + cells are higher in patients who do not respond to treatment with synthetic DMARDs after six months.

Objective: CD3(+)CD8(+)CD28(-) cells are higher in Rheumatoid Arthritis (RA). The aim of this study was to assess CD3(+)CD8(+)CD28(-) cells in patients with early RA and assess the effects of cytomegalovirus (CMV) seropositivity. Method: In this prospective observation study, 50 RA patients were recruited from Cardiff University Hospital of Wales (UHW) rheumatology outpatient, 25 patients with early disease (disease duration 0-6 months) and 25 patients with established disease (>2 years). These were compared with 25 healthy controls. Clinical and serological markers of inflammation were noted, and peripheral blood mononuclear cells were analyzed using flow cytometry. Results: The percentage of the CD8(+)CD28(-) T cells was increased in RA patients and was associated with disease duration. The percentage of CD8(+)CD28(-) T cells was increased in CMV positive early and established RA grouped and early RA patients in comparison to CMV negative patients (p < 0.05). There is a weak but statistically significant correlation between the percentage of CD3(+)CD8(+)CD28(-) cells and CRP in CMV positive RA patients (r = 0.227, p < 0.05). Conclusion: The percentage of CD8(+)CD28(-) T cells is higher in RA patients and correlates with disease duration, highlighting a potential role early in the disease process. These cells were also higher in CMV positive early RA patients which may suggest a role of CMV in disease development.

Although the historical bases for graduate training in the United Kingdom (UK) and Scandinavia both stem from the original concept developed by von Humboldt, and both award a ‘PhD degree', their paths have diverged. There are thus significant differences in the manner in which graduate training is organised. To analyse these differences, two UK graduate programmes (School of Medicine, Cardiff University; Institute of Integrative Biology, University of Liverpool) and two Scandinavian graduate schools (Faculty of Medicine and Dentistry, University of Bergen; Karolinska Institutet, Stockholm) completed a Self‐evaluation questionnaire developed by Organisation of PhD Education in Biomedicine and Health Sciences in the European System (ORPHEUS)). Analysis of the completed questionnaires shows differences concerning requirements for admission, the training content of PhD programmes, the format of the PhD thesis, how the thesis is assessed and the financial model. All programmes recognise that PhD training should prepare for employment both inside and outside of academia, with emphasis on transferable skills training. However, the analysis reveals some fundamental differences in the direction of graduate programmes in the UK and Scandinavia. In the UK, graduate programmes are directed primarily towards teaching PhD students to do research, with considerable focus on practical techniques. In Scandinavia, the focus is on managing projects and publishing papers. To some extent, the differences lead to a lack of full recognition of each other's theses as a basis for doing a postdoc. This paper describes the basis for these differences and compares the two approaches and points to areas in which there is, or might be, convergence.

BackgroundOestrogen-deficiency induced by menopause is associated with reduced bone density and primary osteoporosis, resulting in an increased risk of fracture. While the exact etiology of menopause-induced primary osteoporotic bone loss is not fully known, members of the tumour necrosis factor super family (TNFSF) are known to play a role. Recent studies have revealed that the TNFSF members death receptor 3 (DR3) and one of its ligands, TNF-like protein 1A (TL1A) have a key role in secondary osteoporosis; enhancing CD14(+) peripheral blood mononuclear cell (PBMC) osteoclast formation and bone resorption. Whether DR3 and TL1A contribute towards bone loss in menopause-induced primary osteoporosis however, remains unknown.MethodsTo investigate this we performed flow cytometry analysis of DR3 expression on CD14(+) PBMCs isolated from pre- and early post-menopausal females and late post-menopausal osteoporotic patients. Serum levels of TL1A, CCL3 and total MMP-9 were measured by ELISA. In vitro osteoclast differentiation assays were performed to determine CD14(+) monocyte osteoclastogenic potential. In addition, splenic CD4(+) T cell DR3 expression was investigated 1week and 8weeks post-surgery, using the murine ovariectomy model.ResultsIn contrast to pre-menopausal females, CD14(+) monocytes isolated from post-menopausal females were unable to induce DR3 expression. Serum TL1A levels were decreased approx. 2-fold in early post-menopausal females compared to pre-menopausal controls and post-menopausal osteoporotic females; no difference was observed between pre-menopausal and late post-menopausal osteoporotic females. Analysis of in vitro CD14(+) monocyte osteoclastogenic potential revealed no significant difference between the post-menopausal and post-menopausal osteoporotic cohorts. Interestingly, in the murine ovariectomy model splenic CD4(+) T cell DR3 expression was significantly increased at 1week but not 8weeks post-surgery when compared to the sham control.ConclusionOur results reveals for the first time that loss of oestrogen has a significant effect on DR3; decreasing expression on CD14(+) monocytes and increasing expression on CD4(+) T cells. These data suggest that while oestrogen-deficiency induced changes in DR3 expression do not affect late post-menopausal bone loss they could potentially have an indirect role in early menopausal bone loss through the modulation of T cell activity.

Objective. Macrophage inflammatory protein 1-alpha (CCL3) is a chemokine that regulates macrophage trafficking to the inflamed joint. The agonistic effect of CCL3 on osteolytic lesions in patients with multiple myeloma is recognized; however, its role in skeletal damage during inflammatory arthritis has not been established. The aim of the study was to explore the role of osteoclast-associated CCL3 upon bone resorption, and to test its pharmacological blockade for protecting against bone pathology during inflammatory arthritis. Methods. CCL3 production was studied during osteoclast differentiation from osteoclast precursor cells: human CD14-positive mononuclear cells. Mice with CIA were treated with an anti-CCL3 antibody. The effect of CCL3 blockade through mAb was studied through osteoclast number, cytokine production and bone resorption on ivory disks, and in vivo through CIA progression (clinical score, paw diameter, synovial inflammation and bone damage). Results. Over time, CCL3 increased in parallel with the number of osteoclasts in culture. Anti-CCL3 treatment achieved a concentration-dependent inhibition of osteoclast fusion and reduced pit formation on ivory disks (P <= 0.05). In CIA, anti-CCL3 treatment reduced joint damage and significantly decreased multinucleated tartrate-resistant acid phosphatase-positive osteoclasts and erosions in the wrists (P < 0.05) and elbows (P < 0.05), while also reducing joint erosions in the hind (P < 0.01) and fore paws (P < 0.01) as confirmed by X-ray. Conclusion. Inhibition of osteoclast-associated CCL3 reduced osteoclast formation and function whilst attenuating arthritis-associated bone loss and controlling development of erosion in murine joints, thus uncoupling bone damage from inflammation. Our findings may help future innovations for the diagnosis and treatment of inflammatory arthritis.

In vivo mouse models of inflammatory arthritis are extensively used to investigate pathogenic mechanisms governing inflammation-driven joint damage. Two commonly utilized models include collagen-induced arthritis (CIA) and methylated bovine serum albumin (mBSA) antigen-induced arthritis (AIA). These offer unique advantages for modeling different aspects of human disease. CIA involves breach of immunological tolerance resulting in systemic autoantibody-driven arthritis, while AIA results in local resolving inflammatory flares and articular T cell-mediated damage. Despite limitations that apply to all animal models of human disease, CIA and AIA have been instrumental in identifying pathogenic mediators, immune cell subsets and stromal cell responses that determine disease onset, progression, and severity. Moreover, these models have enabled investigation of disease phases not easily studied in patients and have served as testing beds for novel biological therapies, including cytokine blockers and small molecule inhibitors of intracellular signaling that have revolutionized rheumatoid arthritis treatment.

Introduction The link between rheumatoid arthritis (RA) and cardiovascular disease (CVD) is well established but not yet fully understood. Anti-TNF treatment, e.g. with Enbrel, is one of most common therapies used in RA patients and has been shown to have beneficial effects on RA-associated cardiovascular pathologies in these patients.1 Initial studies in the collagen-induced arthritis (CIA) model revealed an increase in cardiac fibrosis marker galectin-3, both locally in perivascular adipose tissue (PVAT) and systemically in blood plasma during inflammatory arthritis and correlated with impaired vascular function.2 Objectives This study aims to investigate the impact of anti-TNF treatment on galectin-3 expression and vascular function during CIA. Methods Male DBA/1 mice underwent CIA induction and received either Enbrel or phosphate buffered saline (PBS) by intravenous injection. Vascular function was determined by measuring the constriction response of the thoracic aorta at termination using a myograph. Galectin-3 was measured locally in thoracic PVAT by immunohistochemistry and quantitative polymerise chain reaction (qPCR), and systemically by ELISA. Results Anti-TNF treatment during CIA resulted in a decrease in arthritis severity and progression compared to PBS treated mice, and partially restored vascular function. Galectin-3 expression was significantly reduced in thoracic PVAT, but not in blood plasma, in CIA mice treated with Enbrel. Conclusions In conclusion, decreased galectin-3 expression in Enbrel treated mice is associated with an improvement in arthritis-associated disease activity including arthritis clinical score, joint swelling and vascular function. References . Allanore Y, Avouac J. Cardiovascular risk in rheumatoid arthritis: Effects of anti-TNF drugs. Expert Opin Pharmacother2008May;9(7):1121–8. doi:10.1517/14656566.9.7.1121 . Sime K, Choy EH, Williams AS. Alterations to adipose tissue morphology during inflammatory arthritis is indicative of vasculopathology in DBA/1 mice. Adipocyte2017April 3;6(2):87–101. doi:10.1080/21623945.2017.1295174 (Accessed: 2017 February 21). Disclosure of interest None declared

Introduction Rheumatoid Arthritis (RA) patients have increased cardiovascular risk (CV) due to accelerated atherosclerosis (ATS), which significantly contributes to excess mortality in RA.1 The increased CV risk cannot be fully explained by traditional risk factors and systemic chronic inflammation appears to play a crucial role. Interestingly, IL-7, a proinflammatory cytokine involved in RA pathogenesis, appears to play a role also in ATS2 but its effect on cardiovascular disease (CVD) in RA has not been studied yet. Objectives To examine serum IL-7 levels and expression of IL-7, IL-7R, CD3 and CD20 in aortic adventitia of RA and non-RA patients with coronary artery disease (CAD) and to search for relationships between systemic IL-7 levels and expression of vascular markers, cardiovascular risk factors including metabolic and inflammatory parameters. Methods We examined 19 RA and 20 non-RA patients undergoing coronary artery bypass graft surgery included in the Feiring Heart Biopsy Study. Serum IL-7 levels were measured by chemiluminescence (MSD). Biopsies from the adventitia of thoracic aorta from a subset of patients (12 RA and 14 non-RA) were stained for IL-7, IL-7R, CD3 and CD20 by immunohistochemistry and scored per mm2 of tissue. Results Non-RA patients had lower IL-7 serum levels than RA (3.4±3.3 vs. 6.7±3.5, p<0.05). Independently of RA diagnosis, IL-7 significantly correlated with CRP (rho=0.450, p=0.008), triglycerides (TG, rho=0.566, p=0.005), glucose (rho=0.642, p=0.001) and hypertension (p=0.036). Levels of IL-7 were associated with New York Heart Association class (rho=0.429, p=0.014) and this was stronger in non-RA patients (rho=0.577, p=0.010). No associations were found with smoking or markers of CVD severity (i.e., numbers of arteries with stenosis or previous myocardial infarcts (MI)). The number of IL-7 +and IL-7R+cells/mm2 in adventitia were significantly higher in RA (134.2±45.5 and 144±49.9 respectively) than non-RA patients (46.9±22.8 and 54.4±20.2, p<0.005) and were associated with serum IL-7 levels (rho=0.551 and rho=0.588, p<0.01). Both IL-7 +and IL7R+cells were associated with a positive history of MI (p=0.047 and p=0.005) and IL-7R+cells with the number of previous MIs (rho=0.408, p=0.038). Only in RA patients, IL-7R+cells showed a trend for correlation with TG (rho=0.771, p=0.072). IL-7 +and IL-7R+cells correlated with CD3 (rho=0.688, p=0.013 and rho=0.630, p=0.028), but no correlation was found with CD20. Cholesterol and HDL levels were associated with IL-7 +cells only in non-RA patients (rho=0.729, p=0.04 and rho=0.733, p=0.038). Conclusions Among patients with CAD, those with RA had higher serum IL-7 and a greater expression of both IL-7 and IL-7R is aortic adventitia. Systemic levels of IL-7 were related to its vascular expression. Thus, the IL-7/IL-7R axis may play a role in the accelerated ATS observed in RA; further studies are needed to elucidate the precise role of IL-7 in CV risk in RA. References . Kaplan MJ. Curr. Opin. Rheumatol2006;18(3):289–297. . Damås JK, et al. Circulation2003;107(21):2670–2676. Acknowledgements None. Disclosure of interest None declared

Aim/Purpose: Understanding the educational needs of postgraduate research candidates (PGRs) is essential to facilitate development, support attainment, and maintain graduate quality. Background: The production and effective defence of the research thesis are the summative assessment tools used in postgraduate research education. Examiners’ reports provide a rich source of feedback and indicate the gap between the candidate’s level of performance and that expected for the award. This provides a lens through which to view the unmet training needs of PGR cohorts. Methodology: Following a review of all examiner reports for PGR assessments held over a 12 month period, we explored the quantitative and qualitative dimension data in context in order to identify common training needs for our PGR students. Utilising this theoretical framework and standard thematic analysis, we identified recurring themes and were able to determine key areas for future focus. Contribution: This study utilises independent comment from postgraduate research candidate thesis and oral examination assessment to identify unmet core research training needs. Findings: We recognised seven key areas identified by the examiners for improvement: i) quality of scientific writing, ii) general presentation of thesis, iii) statistics /data analysis, iv) understanding / critical appraisal, v) experimental design, vi) English language and vii) supervision. Academic literacy and numeracy stood out as key areas for future training focus. The results highlight areas for future focus in educational provision and targeted training for PGRs undertaking biomedical and life sciences research within our faculty. Recommendations for Practitioners: Evaluation of postgraduate research programmes should include feedback from a variety of sources and not rely solely on employability and completion rates as measures of success. The examination committees are an important source of feedback on the individual and the programme with regard to attainment of core research skills. Recommendation for Researchers: Regular and wide reaching evaluation of postgraduate research programmes and support available is required to ensure the sector can meet the changing needs of our PGR cohorts. Impact on Society: Doctoral graduates are entering increasingly diverse employment fields. Ensuring the quality of graduates and supporting their journey through candidature ensures the greatest value for society once in the work place. Future Research: This study highlights unmet training needs of PGRs as identified by an inde-pendent expert. The impact of engagement with training and the importance of prior experience are not explored in this study, nor is the student perspective on the process. These will reveal additional dimensions to the evaluation process.

Background: The influence of patient demographics and mode of admission on the 'weekend effect' remains unclear. This study examins the relationship between day of admission, patient demographics, mode of presentation and survival. Methods: Hospital admissions over a three-year period were studied. Patients with an inpatient stay less than 24 h and those who were discharged from the emergency department were excluded. In-hospital mortality was correlated with day of admission, age, gender and mode of presentation in a binary logistical regression analysis. Results: There were 448,827 admissions, of which 350,648 (85.7%) occurred during a weekday. 256,777 (62.7%) were emergency presentations, which was closely related to a weekend admission (92.3% vs 57.8%, p < 0.001). There were 8099 deaths of which 6336 (78.2%) related to a weekday admission and 1736 (21.4%) related a weekend admission. Mortality for elective admissions was 78 (0.05%) compared to 8021 (3.12%), p < 0.001 in emergency admissions. Univariable regression analysis revealed a weekend admission (Odds Ratio (OR) 1.68 (95% confidence interval (CI) 1.60-1.78, p < 0.001) and emergency presentation (OR 63.02 (95%CI 50.42-78.77), p < 0.011) were associated with weekend mortality. On multi variable analysis the OR for weekend admission reduced to 1.07 (95%CI 1.01-1.13), p = 0.013 and the OR for emergency presentation increased to 76.68 (95%CI 61.40-96.00), p < 0.001. Conclusion: This study highlights that higher weekend mortality rates are a consequence of a lower proportion of elective admissions. Extending the working week to seven days might reduce weekend mortality without reducing the total number of deaths. (C) 2018 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Background The physiological function of adipose tissue is altered by the host’s inflammatory response. The implications for maintaining human health or causing inflammation-associated cardiovascular disease are ill defined. The purpose of this study was to determine morphological and molecular alterations to perivascular adipose tissue (PVAT) that functionally impair normal vascular function during inflammatory arthritis. Materials and methods Aorta (PVAT intact), renal and gonadal white adipose tissue (WAT) and brown adipose tissue (BAT) from the inter-scapular region were harvested from mice with established Collagen-induced arthritis (CIA) and age-matched naïve controls. Morphological analyses were undertaken on paraffin-embedded tissue sections. Molecular markers for WAT, BAT and macrophages were measured by qPCR. Results Cell number increased significantly by 1.8 fold in all adipose (CIA versus naïve mice). Adipocytes were compressed by CIA and voluminosity was significantly reduced in PVAT (2-fold) and BAT (4-fold) but not WAT. The classical M1 macrophage marker CD11c was significantly increase by CIA together with M2 markers such as Arg1 and CD206 in thoracic PVAT. iNOS expression (M1 marker) was not altered by CIA. Anti-TNF therapy reduced PVAT-associated inflammation and restored impaired constriction responses caused by CIA in excised aortae. Conclusions These data, reveal potentially important arthritis-associated mechanisms and tissue changes in PVAT and BAT that may be important in the initiation and progression of cardiovascular disease during inflammatory arthritis. We identify CIA as a relevant model to study the abnormal body composition phenotype that are overrepresented in patients with RA and RA-associated cardiovascular comorbidities.

Background Cardiovascular (CV) mortality in patients with rheumatoid arthritis (RA) is up to 50% higher than the general population. Whilst traditional CV risk factors such as smoking, diabetes and hypertension contribute to this increased mortality in RA, they do not fully explain the increase in risk. The British Society for Rheumatology, National Institute for Health and Clinical Excellence and European League Against Rheumatism (EULAR) recommend annual assessment of CV risk in RA patients. Furthermore, EULAR recommends multiplying such traditional CV risk scores by 1.5 for RA patients who meet two of three criteria consisting of (1) disease duration >10 years, (2) positive rheumatoid factor or anti-cyclic citrullinated peptide (anti-CCP) serology, (3) presence of severe extra-articular manifestation, to account for the unexplained increased CV risk in RA. Objectives This study assessed CV risk by QRISK2 score and used carotid ultrasound to determine cardiovascular risk and prevalence of subclinical atherosclerosis at the time of diagnosis of RA. Methods Patients ≥18 years-old with early RA, defined by ACR/EULAR 2010 criteria and diagnosis of RA <6 months were recruited from The University Hospital of Wales, Cardiff. Exclusion criteria included definite other autoimmune or inflammatory rheumatic disease, ACR Classification of Functional Status stage IV, previous history of CV disease and diabetes mellitus. Demographic details were collected, blood pressure, body mass index, ESR, CRP and lipid profile were measured and QRISK2 was calculated. Carotid ultrasound was performed and mean carotid intima media thickness (CIMT) and presence of plaque were measured. The study was approved by Research Ethics Committee for Wales (11/WA/0326). Results 40 patients, 10 males and 30 females with early RA were recruited. Mean age was 55.7±14.8 years. Rheumatoid factor and anti-CCP antibodies were positive in 62% and 80% of patients respectively. Mean BMI was 27.2±5.9. Twenty-nine percent were current smokers. Mean DAS28 was 3.8±1.3. According to the QRISK2, 54% of patients had >10% risk of CV disease over 10 years. Carotid ultrasound was conducted in 35 patients. Mean CIMT was 0.71±0.19 mm. 10 patients (29%) had carotid plaques. Fourteen patients (40%) had either plaque or CIMT >0.9mm, both considered markers of high CV risk. These patients were termed “ultrasound positive” patients. The sensitivity and specificity of the QRISK2 to predict US positive patients was 82% and 56% respectively. The positive predictive value of the QRISK2 was 63% and the negative predictive value of the QRISK2 was 88%. No patients met >1 criteria for EULAR adjustment of risk as all patients had early RA and none had severe extra-articular manifestations. Conclusions Many patients with early RA have significant CV disease at the time of diagnosis. This suggests subclinical CV disease may be developing before patients become symptomatic. More than half of the patients with early RA fulfil current NICE guidelines for starting lipid-lowering therapy, although of these, over one-third had no subclinical disease on carotid ultrasound. There is scope to improve the sensitivity and specificity of the QRISK2 calculation in RA patients, perhaps with a biomarker. Acknowledgements This work was funded by Arthritis Research UK, grant number 20760 Disclosure of Interest None declared

Introduction: Terminal ileum resection in patients with Crohn’s disease results in vitamin B12 deficiency and these patients are routinely given B12 supplementation to prevent anemia and neuropsychiatric disease. The effect of right hemicolectomy on B12 status in cancer patients has not previously been studied. Total serum B12 is an unreliable test. Second-line diagnostic tests measure methylmalonic acid (MMA) and homocysteine (tHcy) are also used. An assay measuring an active form of B12 is available for routine use. This observational study investigated whether B12 deficiency exists in patients after a right hemicolectomy for cancer. Methods: Patients (n=28; age range=52-88 years) who had undergone a right hemicolectomy for cancer and been in remission for two years were identified from a database and recruited to an outpatient clinic along with an age-matched control group (n=27; age range=52-89 years). Vitamin B12 status in both patients and controls was assessed by the measurement of vitamin B12 (total and active), MMA and tHcy. Results: Concentration of tHcy was significantly higher (p<0.05) in the surgical group (14.0 μmol/L) compared with the controls (11.1 μmol/L). There were no significant differences in total and active B12, folate and MMA concentrations between the two groups (p>0.05). Discussion: Right hemicolectomy for malignancy is associated with an increase in tHcy concentrations although a larger study is required to determine the B12 status in post-operative right hemicolectomy patients.