BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

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

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

Painting the Body: Feminist Musings on Visual Autographies

In this paper I look at autographical depictions of the body in the work of Mato Ioannidou, a Greek woman artist, who participated in a wider narrative-based project on visual and textual entanglements between life and art. The paper unfolds in three parts: first, I give an overview of Ioannidou’s artwork, making connections with significant events in her life; then I discuss feminist theorizations of embodiment and visual auto/biography; and finally I draw on insights from Spinozist feminist philosophers to discuss the artist’s portrayal of women’s bodies in three cycles of her work. What I argue is that the body becomes a centerpiece in the attempt to perceive connections between life and art through expressionism rather than representation

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

The integration of complementary and alternative medicine into health care : regulating for consumer choice, autonomy and responsibility

This thesis explicates the role that the law, and particularly regulation, can play in the integration of evidence-based complementary and alternative medicine (CAM) into the Australian health care system. It outlines a regulatory framework to move Australia beyond an ad hoc approach to integration to a national, co-ordinated and systematic one, informed by the guiding principles of choice, autonomy and responsibility. Integration is necessary to ensure that all Australians have the option of safe and effective CAM. A holistic approach - a metaphor, the `regulatory space of health care', and a broad definition of regulation, legal orderings (statutes and common law) and non-legal orderings (guidelines and norms) - is adopted to analyse the current level-of integration of CAM in Australia. This integrative map provides the necessary background to consider key elements of the regulatory framework necessary for integration. A national policy, a national body, a model of integration and regulatory strategies are proposed and discussed. A partnership model of integration is recommended as both biomedicine and CAM have a singular contribution to health care in the future. The model of integration must preserve the integrity of each health care paradigm. It must provide scope for the continued development and exploration of health solutions arising out of the philosophy and methodology of biomedicine and CAM. A holistic relational model, referral, multidisciplinary, and other linking mechanisms, are proposed to unify the two health care paradigms into one health care system. To spearhead, steer and co-ordinate the regulatory change process, a national body - an Australian National Centre for Integrative Healthcare (ANCIH) is recommended. As integration will involve a re-negotiation of the regulatory space of health care, to make room for evidence-based CAM to share in health infrastructure, this national body will require the authority to work with all the stake-holders to effect change

Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin–echo envelope modulation and electron–nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed 15N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His6 site of human calprotectin.National Science Foundation (U.S.) (CHE-1352132)National Institutes of Health (U.S.) (NIH 1DP2OD007045-01)National Institutes of Health (U.S.) (GM069857)National Institutes of Health (U.S.) (F32 GM099257

INTRAVENOUS VITAMIN C SUPPLEMENTATION IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS: SALUTARY IMPACT ON CLINICAL OUTCOMES.

UNLABELLED: Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (SCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic hematopoietic stem cell transplant (HSCT) were evaluated in a phase I/II trial and clinical outcomes compared with a propensity score - matched historical control. METHODS: Patients with advanced hematologic malignancies were enrolled in a phase 2 clinical trial, receiving IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HSCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. RESULTS: 55 patients received IV vitamin C: these include 10/10 HLA-MRD and MUD (n=48) and 9/10 HLA MUD recipients (n=7). All patients enrolled were deficient in vitamin C at day 0, and had restoration to normal levels for the remainder of the course. Vitamin C recipients had lower non-relapse mortality (11% vs. 25%, p-value = 0.07) and improved survival compared to historical controls (82% vs 62% p=0.06), with no attributable grade 3 and 4 toxicities to vitamin C. Vitamin C recipients had similar relapse rate and acute graft versus host disease (GVHD) as historical controls (p=0.35), but lower severe chronic GVHD (11% vs 24%; p-value 0.35) compared to historical controls. Patients with myeloid malignancies had improved survival (83% vs. 54%, p=0.02) and non-relapse mortality (NRM) (10% vs. 37%, p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. CONCLUSIONS: In patients undergoing allogeneic HSCT the administration of IV vitamin C is safe and reduces non-relapse mortality and chronic GVHD improving overall survival. Randomized trials are necessary to confirm these findings

Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X‑ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn­(II)-sequestering protein. Human CP uses Ca­(II) ions to tune its Mn­(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn­(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn­(II)-CP containing one Mn­(II), two Ca­(II), and two Na­(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca­(II)- and Mn­(II)-bound CP prepared with a 10:0.9:1 Ca­(II):Mn­(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (<i>E/D</i> = 0.30) for the <i>S</i> = 5/2 Mn­(II) ion, consistent with the high symmetry of the His₆ binding site observed crystallographically. Results from electron spin–echo envelope modulation and electron–nuclear double resonance experiments reveal that the six Mn­(II)-coordinating histidine residues of Ca­(II)- and Mn­(II)-bound CP are spectroscopically equivalent. The observed ¹⁵N (<i>I</i> = 1/2) hyperfine couplings (<i>A</i>) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (<i>A</i> = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (<i>A</i> = [0.11, 0.18, 0.42] MHz). In the absence of Ca­(II), the binding affinity of CP for Mn­(II) drops by two to three orders of magnitude and coincides with Mn­(II) binding at the His₆ site as well as other sites. This study demonstrates the role of Ca­(II) in enabling high-affinity and specific binding of Mn­(II) to the His₆ site of human calprotectin