IntroductionThe extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM.MethodsWe investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques.ResultsWe have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance.DiscussionOur results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Recurrence of venous thromboembolism (VTE) is associated with high mortality and morbidity but anticoagulation also confers high risks. Cancer, Antiphosholipid Syndrome, vascular disorders, Heparin induced Thrombocytopenia, and Pregnancy are a few known causes for recurrence. Although the acute treatment phase of VTE is 3 months, it is known that the residual effects of prior VTE remain in a significant number of patients eventually causing post thrombotic syndrome. These residual effects can mimic the appearance of acute thrombosis on Venous Doppler, and thus mimic a recurrent thrombotic event. This has the potential to result in a clinical recommendation for continued and possibly life long anticoagulation, with the inherent, potentially unnecessary bleeding risks associated. Elastography, compression and vein diameter are a few methods adopted by radiologists to distinguish between old and new clots on ultrasound. However this requires previous scans for comparison and has limitations. We propose that a Multidisciplinary Meeting (MDM) is vital to confirm if recurrence is indeed true given the significant impact on patient management. Aims: This study aims to assess the value of MDM review of recurrent VTE, which combines radiology, clinical history and d-dimer to evaluate whether a thrombus is truly recurrent. Prospective follow up of patients was then carried out to determine if the MDM decision was correct. Methods: All patients reviewed in the Thrombosis MDM meeting between 2019 and 2021 who were defined as recurrent VTEs were included in this study. The MDM consists of comparing the prior and new scans by an expert Consultant Radiologist in discussion with the Consultant Haematologist and Physician. The clinical presentation, D-dimers, risk factors, treatment regimes, complications and MDM outcome were noted. These patients served as a cohort that were followed up by prospective analysis to 2023 to determine if these patients had further VTEs or anticoagulation related complications based on clinical and radiology review. Results: 45 patients were identified with a recurrent PE (8, 17.8%) or DVT (37, 82.2%). After MDM review, 22 (48.9%) were determined to have evidence of previous VTEs without features of a new VTE. 8 of these 22 patients (36.4%) had an elevated d-dimer with 9 (40.9%) being negative. 19 (42.2%) were deemed to be new and 4 (8.89%) were indeterminate but treated as new. Active treatment was ceased in 10 (22.2%) and 4 (8.89%) had already completed 3 months of anticoagulation prior to MDM. The 3-month anticoagulation course commenced on diagnosis was completed in those who were significantly symptomatic with persisting risk factors (8, 17.8%). 19 (42.2%) patients who were deemed no new VTE had their anticoagulation stopped by three months while 3 (6.66%) were reverted to their prophylactic life-long anticoagulation. Life-long anticoagulation was started in those with a new event where at least one thrombus was deemed to be unprovoked 20 (44.4%). On follow up 20 (44.4%) patients had repeat scans to evaluate further events with only 1 (2.22%) being positive for a breakthrough event. This patient had underlying cancer and was on anticoagulation at this time. Summary/Conclusion: MDM review of patients presenting with recurrent VTE is vital. Clinical assessment with radiology evidence enabled 48.9% of patients to have their diagnosis of a new VTE changed thus allowing cessation of anticoagulation in 42.2% and reversion to prophylaxis in 6.66%. One of these patients on long-term anticoagulation had a subsequent VTE with progression of their lung malignancy. Keywords: Pulmonary embolism, Anticoagulation, Venous thromboembolism, Deep venous thrombosis

Background: Hospital-acquired infections (HAIs) and infectious agents exhibiting antimicrobial resistance (AMR) are challenges globally. Environmental patient-facing wastewater apparatus including handwashing sinks, showers and toilets are increasingly identified as sources of infectious agents and AMR genes.Aim: To provide large-scale metagenomics analysis of wastewater systems in a large teaching hospital in the Republic of Ireland experiencing multi-drug-resistant HAI outbreaks.Methods: Wastewater pipe sections (N=20) were removed immediately prior to refurbishment of a medical ward where HAIs had been endemic. These comprised toilet U-bends, and sink and shower drains. Following DNA extraction, each pipe section underwent metagenomic analysis.FindingsDiverse taxonomic and resistome profiles were observed, with members of phyla Proteobacteria and Actinobacteria dominating (38.23 +/- 5.68% and 15.78 +/- 3.53%, respectively). Genomes of five clinical isolates were analysed. These AMR bacterial isolates were from patients >48 h post-admission to the ward. Genomic analysis determined that the isolates bore a high number of antimicrobial resistance genes (ARGs). Conclusion: Comparison of resistome profiles of isolates and wastewater metagenomes revealed high degrees of similarity, with many identical ARGs shared, suggesting probable acquisition post-admission. The highest numbers of ARGs observed were those encoding resistance to clinically significant and commonly used antibiotic classes. Average nucleotide identity analysis confirmed the presence of highly similar or identical genomes in clinical isolates and wastewater pipes. These unique large-scale analyses reinforce the need for regular cleaning and decontamination of patient-facing hospital wastewater pipes and effective infection control policies to prevent transmission of nosocomial infection and emergence of AMR within potential wastewater reservoirs.2023 The Author(s). Published by Elsevier Ltd on behalf of The Healthcare Infection Society. This is an open access article under the CC BY license

Background Rheumatoid arthritis (RA) is a chronic, inflammatory disease with interstitial lung disease (ILD) being an important extra-articular manifestation, associated with significant morbidity and mortality. Objectives To determine the prevalence of ILD at time of RA diagnosis and identify baseline independent factors associated with ILD. Methods Two early inception cohorts (1986-2001) were used: the early RA network (ERAN) and the early RA study (ERAS). Socio-demographic, clinical and laboratory measures were recorded at baseline, 6 months and yearly thereafter. Baseline variables collected and included in analyses were: seropositivity, body mass index (BMI), ethnicity, measures of deprivation, smoking status. Comorbidity burden was evaluated using the rheumatic disease comorbidity index (RDCI). Baseline prevalence (proportion of individuals with ILD at baseline) and 95% confidence interval was estimated. Multivariable regression analyses were performed to identify risk factors at baseline associated with RA-ILD development. Multiple imputation was used for missing data. Results Data from a total of 2701 patients were included in the study, from whom 101 patients were diagnosed with ILD. Follow up was up to 25 years (mean 6.8 years); 75% of patients followed for ≥10 years. Of these, 12% had ILD at baseline; 46% were diagnosed with ILD during follow up and 43% were diagnosed with ILD post-mortem. The estimated prevalence of ILD at baseline was 0.44% (95% CI 0.19% to 0.69%). Univariable analyses of baseline factors showed age at onset (p<0.001), ever smoking (p=0.010), seropositivity (p=0.002), RDCI (p<0.001) and lung disease (p<0.001) to be associated with developing RA-ILD. Multivariable logistic regression showed age at onset (OR 1.03, 95% CI 1.01 to 1.05), seropositivity (OR 2.39, 95% CI 1.27 to 4.50) and ever smoking (OR 2.01, 95% CI 1.16 to 3.50) to be associated with ILD development. An increase in RDCI predicted higher ILD (OR 1.46, 95% CI 1.16 to 1.82). More recent recruitment year into the cohort was associated with decreased odds of developing ILD. Conclusion Baseline prevalence of ILD was very low. Seropositivity, smoking, higher comorbidity burden and age at onset increased the odds of subsequent ILD development. Identifying RA-ILD predictors early on is important to ensure appropriate screening, timely diagnosis and treatment. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Rositsa Dacheva: None declared, Amanda Busby: None declared, Patrick Kiely: None declared, Adam Young: None declared, David Walsh Consultant of: Consultancy through the University of Nottingham to GlaxoSmithKline plc, AbbVie Ltd, Pfizer Ltd, Eli Lilly and Company, AKL Research & Development Limited, Galapagos, and Reckitt Benckiser Health Limited (each non-personal, pecuniary). Contributed to educational materials through the University of Nottingham, supported by Medscape Education, New York, International Association for the Study of Pain and Osteoarthritis Research Society International (OARSI), each of which received financial support from commercial and non-commercial entities (each non-personal, pecuniary), Grant/research support from: Responsible for research funded by Pfizer Ltd, Eli Lilly and UCB Pharma (non-personal, pecuniary). Receives salary from the University of Nottingham, who have received funding for that purpose directly or indirectly from Sherwood Forest Hospitals NHS Foundation Trust, and UKRI/Versus Arthritis (personal, pecuniary), Daniel McWilliams Grant/research support from: Grant support from Pfizer. Works on collaborative projects between the University of Nottingham and Eli Lilly, UCB and Orion (separately) funded by the relevant pharmaceutical company, but not named as co-investigator, James Galloway: None declared, Elena Nikiphorou Speakers bureau: Speaker honoraria/advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, Lilly, Fresenius, Grant/research support from: Holds research grants from Pfizer and Lilly.Table 1Univariable and Multivariable Analyses.Baseline VariablesUnivariable analysisMultivariable analysisOdds Ratio (95% CI)p-valueAll comorbidities (n=2,689)Odds Ratio (95% CI)Lung Disease (n=2,689)Odds Ratio (95% CI)Age at onset (years)1.03 (1.02, 1.05)<0.0011.03 (1.01, 1.05)**1.03 (1.02, 1.05)**Female Gender0.56 (0.37, 0.86)0.0090.74 (0.47, 1.16)0.74 (0.47, 1.16)Minority Ethnicity1.94 (0.76, 4.91)0.201--IMD quintile0.91 (0.77, 1.07)0.243--Ever Smoked#1.91 (1.15, 3.15)0.0102.01 (1.16, 3.50)*2.01 (1.20, 3.38)**Recruitment year0.98 (0.95, 1.01)0.1460.95 (0.93, 0.98)**0.97 (0.94, 0.99)*Body Mass Index (kg/m2)0.99 (0.95, 1.04)0.706--HAQ-DI1.21 (0.92, 1.58)0.172--DAS281.09 (0.93, 1.27)0.279--Seropositive#2.40 (1.29, 4.44)0.0022.39 (1.27, 4.50)**2.57 (1.37, 4.85)**Time to DMARD (months)1.01 (1.00, 1.02)0.183--RDCI1.51 (1.24, 1.83)<0.0011.46 (1.16, 1.82)**-Lung disease5.29 (3.12, 8.96)<0.001-4.69 (2.72, 8.08)**IMD: Index of Multiple Deprivation, HAQ-DI: Health Assessment Questionnaire Disability Index, DAS28: Disease Activity Score 28 joint count, RDCI: Rheumatic Diseases Comorbidity Index**p<0.01, *p<0.05# Imputed values

Background: Thyroglossal duct cysts (TGDCs) are the most common congenital anomaly of thyroid gland development, with a <1% risk of malignancy occurring within them. It's rare for a TGDC to be located in floor of the mouth region or the sublingual space since both these areas are not part of the typical embryological migration route of the thyroid gland. Methods: Herein we report a 42-year-old female patient presenting with a neck mass. Results: A 42-year-old female patient presented with a neck mass, shown on imaging to be located in the sublingual area, with magnetic resonance imaging (MRI) reported findings of a ranula, which on subsequent ultrasound guided fine needle aspiration cytology (FNAC) showed malignant cytology of thyroid origin. Surgical excision and histopathological analysis revealed a TGDC papillary carcinoma within the cyst, a rare diagnosis. Multidisciplinary discussion included review of the imaging, intraoperative and histopathological findings and the case was stratified as low-risk disease with no adjuvant treatment indicated at the time. The patient will be observed closely with active clinical surveillance. Conclusions: There were several important points worth gathering from this case including the need to include TGDC carcinoma in a list of differential diagnoses for a midline and/or submental neck mass despite its rarity, and the importance of a full workup for an unusual neck mass such as this one in order to avoid misdiagnosis. It also serves as another example that to provide the best management plan and optimise patient outcomes for head and neck cancers, referral to a regional subspecialty multidisciplinary team (MDT) is required.

Background There has been recent advancement of our understanding of pain in rheumatoid arthritis (RA). With the advent of biologic disease-modifying anti-rheumatic drugs (DMARDs), clinicians managing RA have a wide range of treatments to manage active disease. Many DMARDs are effective at achieving suppression of inflammation, but pain remains a key issue in RA. Despite nociceptive pain being a major feature of RA, other aspects of RA pain are associated with neuropathic and nociplastic components. Nociplastic pain is described as widespread, without evidence of proportionate tissue or nerve damage. Pain processing by the central nervous system can maintain and increase RA pain. Objectives This study aimed to evaluate the causes and underlying mechanisms of pain in RA by conducting a randomised feasibility trial. Our study evaluated the pain characteristics in subjects with RA randomised to different classes of biologic therapy including TNF inhibitors (adalimumab) and T cell modulators (abatacept). In this study, we evaluated distinct aspects of pain including nociception by Visual Analog Scale (VAS), neuropathic (PainDETECT questionnaire) and nociplastic pain components using pain pressure thresholds (PPT) by quantitative sensory testing (QST). Methods A total of 25 participants were recruited between August 2020 and October 2022; 13 subjects were randomised to adalimumab and 12 to abatacept. All participants continued with methotrexate therapy during the study ranging between 10-25 mg weekly. The primary outcome measures included change in VAS for pain, painDETECT and PPT after 12 months' treatment in each arm. PPT were measured using a hand-held algometer (Somedic) in the wrist and finger joints, large joints, sternum and malleolus, with 3 readings taken per region and a mean value recorded (kPa) as we have previously described [1]. Subjects were also stratified by CCP antibody status. Results The mean age was similar in the two groups (abatacept: mean (SD) 56.5 (13.5) years versus adalimumab: 53.9 (12.4) years). There were 12 (92%) female participants in the abatacept group and 10 (83%) in the adalimumab group. All subjects recruited to the study had a Disease Activity Score (DAS28) greater than 5.1 at baseline. There was an improvement from baseline over 12 months of follow-up in VAS pain, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.10) in the adalimumab group. For painDETECT measures, there was an improvement in painDETECT scores from baseline over 12 months of treatment (mean (SEM)) by 5.8 (1.93) in the abatacept group and 4.6 (2.54) in the adalimumab group. The change in PPT measures over 12 months is shown in Figure 1. Higher (positive) values for PPT indicate a higher pain threshold, Figure 1 shows a mean improvement with all subjects being able to tolerate more pain on pressure algometry. Conclusion This study demonstrates that subjects with active RA demonstrate specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Furthermore, biologic therapies with different mechanisms of action may improve RA pain through distinct mechanisms. A greater improvement was observed in central (sternum) and peripheral (hand) pain sensitisation with abatacept compared with adalimumab after 12 months' treatment.It is suggested that abatacept, a T-cell modulator, resulted in a greater improvement in pain sensitisation compared with adalimumab. Since T cells are involved in pain mediation, including by infiltrating nerves and impacting memory T cell function, further work is required to investigate the impact of T cell modulation on pain in RA. Larger future studies are required for validation of our findings. Reference [1]Wajed, J, Ejindu V, Heron C, Hermansson, Kiely P, Sofat N. Quantitative sensory testing in painful hand osteoarthritis demonstrates features of peripheral sensitisation. International Journal of Rheumatology 2012; 2012:703138 Acknowledgements: NIL. Disclosure of Interests Liban Ahmed: None declared, Kathryn Biddle: None declared, Anna Blundell: None declared, Soraya Koushesh: None declared, Patrick Kiely Speakers bureau: Pfizer speaker fees, Grant/research support from: Lilly and Janssen support to attend CPD events, Philip Sedgwick: None declared, Nidhi Sofat Consultant of: Dr Sofat has done Consultancy work for Pfizer and Eli Lilly, Grant/research support from: She has received funding from Bristol Myers Squibb and has been responsible for research funded by Pfizer, Eli Lilly, Centrexion and Merck, Sharp and Dohme.Figure 1Changes in PPT in the study population over time

Introduction: In KRAS-mutant NSCLC, co-occurring alter-ations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors.Methods: Using cell lines derived from mouse autochtho-nous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo.Results: Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is asso-ciated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo.Conclusions: Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS- mutant NSCLC with co-occurring LKB1 mutations.& COPY; 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

Abstract Breast cancer is the most prevalent form of cancer worldwide, with surgery remaining a standard treatment. Although a treatable disease, with the survival rate improving due to enhancements in screening and treatment, cancer recurrence remains a dominant contributor to breast cancer related deaths. It has been suggested that systemic factors during the postoperative period, such as surgical site infection (SSI), may increase the risk of recurrence, although the exact role that these infections play in breast cancer recurrence has yet to be elucidated. To investigate the influence of these SSIs in breast cancer recurrence following primary breast cancer surgery, we conducted a systematic literature review1 to examine both the incidence and risk factors related to SSI after primary breast cancer surgery and the contribution of SSIs to breast cancer recurrence. Data were extracted from 99 studies for the SSI-focused searches, and 53 studies for recurrence-focused searches and we found that there was a 13.07% mean incidence of SSIs. 638 Gram-positive and 442 Gram-negative isolates were identified, with Staphylococcus aureus and Escherichia coli appearing as the most abundant bacteria in SSIs of breast cancer patients. 11.8% cases of cancer recurrence were noted, however confounding factors of retrospective study design, surgery type and SSI definition make results challenging to compare and interpret. Only five studies investigated the association between SSI and breast cancer recurrence, three of which highlighting a positive correlation between SSI and breast cancer recurrence. To further explore this link, we are using in vitro models to investigate the molecular mechanisms by which both Gram-positive and Gram-negative bacteria affect the phenotype of breast cancer. Using LTA (a component of the cell wall of Staphylococcus aureus) to model Gram-positive bacteria and LPS (a component of the Escherichia coli cell wall) to model Gram-negative bacteria, we examined the effects of LTA and LPS on the behavior of MCF-7, MDA-MB-231 and ZR-75-1 cells. Using qRT-PCR, we found that treatment of cells with LPS and LTA dysregulates the expression of pro-tumorigenic inflammatory markers TNF-a and IL-6 in MDA-MB-231 cells. Separately, using metabolomic profiling on LPS and LTA treated MDA-MB-231 cells, we observe significant metabolic reprogramming of the cells when stimulated with the bacterial mimics. We believe that these findings may lead to a better understanding of how SSI promotes breast cancer recurrence and may help design surgical procedures and target therapies. 1O’Connor, R. Í., Kiely, P. A., & Dunne, C. P. (2020). The relationship between post-surgery infection and breast cancer recurrence. A systematic review. Journal of Hospital Infection. 106, (522-535) https://doi.org/10.1016/j.jhin.2020.08.004. Citation Format: Ruth Í. O'Connor, Amira F. Mahdi, Joanne Nolan, Catríona M. Dowling, Colum P. Dunne, Patrick A. Kiely. How surgical site infection influences breast cancer cell recurrence and cancer cell reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6345.

BACKGROUND:The University of Limerick Cancer network (ULCaN) was established in 2019 with funding from the Health Research Institute at the University of Limerick in order to build a network between individuals in academia, primary and secondary care and the general public so that cancer services can be coordinated and more effective. The aim of this paper is to outline our experience of engaging with stakeholders to identify gaps in the cancer journey locally.METHODS:Four focus group discussions were conducted with patients; their carers; members of the public; and healthcare providers with 2 main aims: 1) to investigate gaps in cancer services; 2) to identify knowledge, attitudes and opportunities available to promote cancer research. The focus groups were audio recorded, transcribed and thematically analysed.RESULTS:15 themes within the topics of cancer care, palliation, communication, clinical trials, diet and exercise and public and patient involvement in research and advocacy were identified. These include directing people to reliable information and navigating misinformation and stigma linked with cancer, promoting awareness of clinical trials and palliative care services and improving communication when multiple healthcare providers are involved.CONCLUSION:The need to make more coherent, efficient and integrated cancer research amongst local stakeholders was evident. Embedding patients and members of the public into ULCaN is an important deliverable for collaborative research.

Background: Rheumatoid arthritis (RA) is classically described as a symmetric small joint polyarthritis with additional involvement of large joints. There is a paucity of information concerning the time course of damage in large joints, such as shoulder, elbow, hip, knee and ankle, from early to established RA, or of the influence of Rheumatoid Factor (RF) status. There is a historic perception that patients who do not have RF follow a milder less destructive course, which might promote less aggressive treatment strategies in RF-negative patients. The historic nature of the Ealy Rheumatoid Arthritis Study (ERAS) provides a unique opportunity to study RA in the context of less aggressive treatment strategies. Objectives: To examine the progression of large joint involvement from early to established RA in terms of range of movement (ROM) and time to joint surgery, according to the presence of RF. Methods: ERAS was a multi-centre inception cohort of newly diagnosed RA patients (<2 years disease duration, csDMARD naive), recruited from 1985-2001 with yearly follow-up for up to 25 (median 10) years. First line treatment was csDMARD monotherapy with/without steroids, favouring sulphasalazine for the majority. Outcome data was recorded at baseline, at 12 months and then once yearly. Patients were deemed RF negative if all repeated assessments were negative. ROM of individual shoulder, elbow, wrist, hip, knee, ankle and hindfeet joints was collected at 3, 5, 9 and 12-15 years. The rate of progression from normal to any loss of ROM, from years 3 to 14 was modelled using GEE, adjusting for confounders. Radiographs of wrists taken at years 0, 1, 2, 3, 5, 7, 9 were scored according to the Larsen method. Change in the Larsen wrist damage score was modelled using GEE as a continuous variable, while the erosion score was dichotomised into present/absent. Surgical procedure data were obtained by linking to Hospital Episodes Statistics and the National Joint Registry. Time to joint surgery was analysed using multivariable Cox models. Results: A total of 1458 patients from the ERAS cohort were included (66% female, mean age 55 years) and 74% were RF-positive. The prevalence of any loss of ROM, from year 3 through to 14 was highest in the wrist followed by ankle, knee, elbow and hip. The proportion of patients at year 9 with greater than 25% loss of ROM was: wrist 30%, ankle 12%, elbow 7%, knee 7% and hip 5%. Odds of loss of ROM increased over time in all joint regions, at around 7 to 13% per year from year 3 to 14. There was no significant difference between RF-positive and RF-negative patients (see Figure 1). Larsen erosion and damage scores at the wrists progressed in all patients; annual odds of developing any erosions were higher in RF-positives OR 1.28 (95%CI 1.24-1.32) than RF-negatives OR 1.17 (95%CI 1.09-1.26), p 0.013. Time to surgery was similar according to RF-status for the wrist and ankle, but RF-positive cases had a lower hazard of surgery at the elbow (HR 0.37, 0.15-0.90), hip (HR 0.69, 0.48-0.99) and after 10 years at the knee (HR 0.41, 0.25-0.68). Adjustment of the models for Lawrence assessed osteoarthritis of hand and feet radiographs did not influence these results. Figure 1. Odds of progression to any loss of ROM (from no loss of ROM) per year in the overall population and stratified by RF status. Conclusion: Large joints become progressively involved in RA, most frequently affecting the wrist followed by ankle, which is overlooked in some composite disease activity indices. We confirm a higher burden of erosions and damage at the wrists in RF-positive patients, but have not found RF-negative patients to have a better prognosis over time with respect to involvement of other large joints. In contrast RF-negative patients had more joint surgery at the elbow, hip, and knee after 10 years. There is no justification to adopt a less aggressive treatment strategy for RF-negative RA. High vigilance and treat-to-target approaches should be followed irrespective of RF status. Disclosure of Interests: None declared

Bone represents the most common site for breast cancer metastasis. Bone is a highly dynamic organ that is constantly adapting to its biophysical environment, orchestrated largely by the resident osteocyte network. Osteocytes subjected to physiologically relevant biophysical conditions may therefore represent a source of key factors mediating breast cancer cell metastasis to bone. Therefore, we investigated the potential proliferative and migratory capacity of soluble factors released by mechanically stimulated osteocytes on breast cancer cell behaviour. Interestingly the secretome of mechanically stimulated osteocytes enhanced both the proliferation and migration of cancer cells when compared to the secretome of statically cultured osteocytes, demonstrating that mechanical stimuli is an important physiological stimulus that should be considered when identifying potential targets. Using a cytokine array, we further identified a group of mechanically activated cytokines in the osteocyte secretome, which potentially drive breast cancer metastasis. In particular, CXCL1 and CXCL2 cytokines are highly expressed, mechanically regulated, and are known to interact with one another. Lastly, we demonstrate that these specific factors enhance breast cancer cell migration independently and in a synergistic manner, identifying potential osteocyte derived factors mediating breast cancer metastasis to bone.

Background: Fatigue is associated with poor quality of life in people with Rheumatoid Arthritis (RA). The exact burden of fatigue in RA is uncertain. Evidence shows that fatigue may persist, even in people with well-controlled inflammatory disease. However, this is largely based on cross sectional data, and data from people with long standing or refractory disease. This study aims to examine the nature of fatigue in early RA. Objectives: Describe the prevalence of fatigue and longitudinal course of fatigue Investigate heterogeneity in the course of fatigue and identify risk factors associated with fatigue heterogeneity Methods: Data were from the early Rheumatoid Arthritis Network (ERAN), an inception cohort of people with a disease duration of <24mths, recruited from 2002-11 (n=1236). ERAN collected demographic, clinical, quality of life, comorbidities and laboratory data at baseline, 3-6 mths, and then annually. Fatigue was measured using the Vitality subscale of the Short Form Health Survey questionnaire (SF36VT). Fatigue and severe fatigue were classified as SF36VT values lower than 1 and 2 standard deviations (SD) below the UK healthy population average respectively. Baseline prevalence rates standardized to Eurostat 2013 by age and sex were calculated. The course of fatigue was examined using linear mixed effect models. Group Based Trajectory Modelling (GBTM) was used to examine heterogeneity in the course of fatigue. Baseline characteristics were then used to identify predictors of group membership using univariate and multiple regression analysis. Results: Baseline characteristics include female sex (67%), mean age = 57(SD±14) yrs. Mean SF36VT score = 41(SD±11), median disease duration was 11 mths (IQR:7 – 18). The age and sex standardized prevalence rates of fatigue and severe fatigue were 44%(CI:38-50) and 18% (CI:15 – 22) respectively. 729 (59%) participants were included in the longitudinal analysis. Over the course 4 years follow up, and after accounting for the effect of age, sex, patient’s global assessment of disease activity, BMI, pain and mental health, there was a reduction in the population vitality levels from baseline,(β: -0.14CI: -0.26 to -0.02, p ≤ 0.001). Inflammation measured by erythrocyte sedimentation rate (ESR) was not significantly associated with the course of fatigue. GBTM analysis identified 2 sub-groups. These groups were named ‘Fatigue’ and ‘No-fatigue’ groups and comprised about 52% and 47% of the population respectively (Fig 1). Females, participants with, at baseline, higher BMI, higher disability score (HAQ), disease activity score (DAS28), worse pain, mental health scores and higher comorbidity score (RDCI) were more likely to belong to the Fatigue group (each p ≤ 0.05) in univariate analysis. However, higher BMI (OR 1.05 (CI: 1.0 – 1.1), HAQ (OR 2: CI: 1.5 - 2.7), RDCI(OR 1.3, CI: 1.2 – 1.5), worse SF36 pain and mental health scores (OR 0.93 CI: 0.92 – 0.95) and (OR 0.97, CI: 0.95 – 0.99) were collectively associated with fatigue group membership (AUROC=0.81). Fig 1. Fatigue Trajectories Conclusion: Fatigue is a prevalent symptom in RA, even in early disease. Embedded within the RA population are distinct sub-populations, with or without fatigue. Those with fatigue at baseline were likely to continue to report fatigue over 4 years of follow up. Unlike our previous data on pain trajectories within this cohort, a ‘resolving fatigue’ was not found. Diverse baseline characteristics, including pain, were associated with persistent fatigue. Management of fatigue might require strategies additional to disease modification, and people who require such interventions might be identified at presentation with early RA. Disclosure of Interests: Onosi Ifesemen: None declared, Daniel McWilliams Grant/research support from: Grant support from Pfizer Ltd, Adam Young: None declared, Patrick Kiely: None declared, David Walsh Grant/research support from: Grant support from Pfizer Ltd and Eli Lilly, Consultant of: Consultancy to Eli Lilly, Pfizer, Abbvie and GSK (all payments made to University of Nottingham). Consultancy to Love Productions(all payments made to the University of Nottingham).

Breast cancer is amongst the most common forms of cancer, is predominantly a woman's illness, and is the most frequently reported invasive cancer in women worldwide (Bray et al., 2018). Varying risk factors have been identified, including genetics, family history, lifestyle, age and the use of hormone replacement therapy. Mastitis, also predominantly a woman's illness, is an inflammatory condition of the breast that, despite being an inflammation-related condition, is not currently considered a risk factor for breast cancer. This appears counterintuitive as epidemiological studies have identified chronic inflammation as a contributor to cancer risk, for example in gastric, oesophageal and colon cancers (Lin et al., 2016; Qadri et al., 2014; Principe et al., 2017). Previous reports have focused on women hospitalised for mastitis, and most commonly on puerperal mastitis, perhaps underestimating the relationship between breast cancer and non-lactational mastitis. Our hypothesis, based on systematic review, suggests that a longitudinal study of this disease, affecting women predominantly, is warranted.

OBJECTIVES:We evaluated a simulation-based training curriculum with quantitatively defined performance benchmarks for utility workers location and excavation of utility services.BACKGROUND:Damaging buried utilities is associated with considerable safety risks to workers and substantial cost to employers.METHODS:In a prospective, randomized and blinded study we assessed the impact of Proficiency Based Progression (PBP) simulation training on the location and excavation of utility services work.RESULTS:PBP simulation training reduced performance errors (33%, p = 0.006) in comparison a standard trained group. When implemented across all workers in the same division there was a 35-61% reduction in utility strikes (p = 0.028) and an estimated cost saving of £116,000 -£2,175,000 in the 12 months (47,000 work hours) studied.CONCLUSIONS:The magnitude of the training benefit of PBP simulation training in the utilities sector appears to be the same as it is in surgery, cardiology and procedure-based medicine.APPLICATION:Quality-assured utility worker simulation training significantly reduces utility damage and associated costs.

The transcription factor NF-ĸB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation of DNA-bound NF-ĸB strongly limits the expression of its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase 7) opposes the activities of E3 ligases, stabilizes DNA-bound NF-ĸB, and thereby promotes NF-ĸB–mediated transcription. Using gene expression and synthetic peptide arrays on membrane support and overlay analyses, we found here that inhibiting USP7 increases NF-ĸB ubiquitination and degradation, prevents Toll-like receptor–induced pro-inflammatory cytokine expression, and represents an effective strategy for controlling inflammation. However, the broad regulatory roles of USP7 in cell death pathways, chromatin, and DNA damage responses limit the use of catalytic inhibitors of USP7 as anti-inflammatory agents. To this end, we identified an NF-ĸB–binding site in USP7, ubiquitin-like domain 2, that selectively mediates interactions of USP7 with NF-ĸB subunits but is dispensable for interactions with other proteins. Moreover, we found that the amino acids 757LDEL760 in USP7 critically contribute to the interaction with the p65 subunit of NF-ĸB. Our findings support the notion that USP7 activity could be potentially targeted in a substrate-selective manner through the development of noncatalytic inhibitors of this deubiquitinase to abrogate NF-ĸB activity.

When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.

COVID-19 has generated a global need for technologies that enable communication, collaboration, education and scientific discourse whilst maintaining physical distance. University closures due to COVID-19 and physical distancing measures disrupt academic activities that previously occurred face-to-face. Restrictions placed on universities due to COVID-19 have precluded most conventional forms of education, assessment, research and scientific discourse. Anatomists now require valid, robust and easy-to-use communication tools to facilitate remote teaching, learning and research. Recent advances in communication, video conferencing and digital technologies may facilitate continuity of teaching and research activities. Examples include highly-interactive video conferencing technology, collaborative tools, social media and networking platforms. In this narrative review, we examine the utility of these technologies in supporting effective communication and professional activities of anatomists during COVID-19 and after.

Breast cancer is the second most prevalent form of cancer in women worldwide, with surgery remaining the standard treatment. The adverse impact of the surgery remains controversial. It has been suggested that systemic factors during the postoperative period may increase the risk of recurrence, specifically surgical site infection (SSI). The aim of this review was to critically appraise current published literature regarding the influence of SSIs, after primary breast cancer surgery, on breast cancer recurrence, and to delve into potential links between these. This systematic review adopted two approaches: to identify the incidence rates and risk factors related to SSI after primary breast cancer surgery; and, secondly, to examine breast cancer recurrence following SSI occurrence. Ninety-nine studies with 484,605 patients were eligible in the SSI-focused searches, and 53 studies with 17,569 patients for recurrence-focused. There was a 13.07% mean incidence of SSI. Six-hundred and thirty-eight Gram-positive and 442 Gram-negative isolates were identified, with methicillin-susceptible Staphylococcus aureus and Escherichia coli most commonly identified. There were 2077 cases of recurrence (11.8%), with 563 cases of local recurrence, 1186 cases of distant and 25 cases which recurred both locally and distantly. Five studies investigated the association between SSI and breast cancer recurrence with three concluding that an association did exist. In conclusion, there is association between SSI and adverse cancer outcomes, but the cellular link between them remains elusive. Confounding factors of retrospective study design, surgery type and SSI definition make results challenging to compare and interpret. A standardized prospective study with appropriate statistical power is justified.