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Competing Interests: Conflicts of interest P.S.H. has received speaker fees from Novartis and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and acted in an advisory capacity for Amgen. The remaining authors declare no conflicts of interest.

Despite significant advances in the treatment of psoriatic arthritis (PsA) in the last two decades, remission remains elusive and there is no cure. Evidence from rheumatoid arthritis (RA) confirming enhanced response and outcome from earlier treatment intervention suggests the plausibility of the window of opportunity in the pathogenesis of RA. Yet, data are lacking in PsA. Although treatment response may be enhanced in shorter disease duration, it is unknown how this early intervention may impact long-term outcomes. Furthermore, it remains to be demonstrated whether there is a best treatment strategy and time of intervention. Crucially, the main hurdle when aiming for early treatment intervention is the ability to achieve a timely diagnosis that highlights the need to focus research efforts on characterizing the very early disease stages including the transition to PsA in the at-risk psoriasis population., Competing Interests: OR: none declared. SRH received speaker fees from Janssen and Novartis. GDM received speaker/consultancy fees from Janssen, Novartis. HM-O received research grants from Janssen, Novartis, Pfizer and UCB and honoraria/speaker fees from AbbVie, Amgen, Celgene, Eli-Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB., (© The Author(s), 2024.)

Objectives: Timely diagnosis remains a challenge in axial SpA (axSpA). In addition, data are scarce on the impact of diagnostic delay and disease progression in affected individuals. The British Axial Spondyloarthritis Inception Cohort (BAxSIC) study aims to investigate the impact of newly diagnosed axSpA, the natural history of the disease and the effect of diagnostic delay on disease outcomes., Methods: BAxSIC is a prospective, multicentre, observational study. Eligible participants are adults (≥16 years of age), with a physician-confirmed diagnosis of axSpA in the 6 months prior to study entry, recruited from secondary and tertiary rheumatology centres in the UK. Participants will be followed up for 3 years, with in-person visits at baseline and 24 months. In addition, patient self-reported assessments will be recorded remotely via the online electronic case report form (eCRF) at 6, 12, 18, 30 and 36 months., Results: The first patient was enrolled in BAxSIC in June 2023. Recruitment is currently ongoing and is planned to end in June 2026. Initial results will be available in 2027. Since opening, the trial has undergone two protocol amendments., Conclusion: The BAxSIC study is the first inception cohort designed to investigate the impact of diagnostic delay on clinical presentation and long-term functional outcomes in patients with axSpA in the UK. With an innovative, patient-led virtual longitudinal data collection model, data generated from this study will help inform and improve the care of people newly diagnosed with axSpA., Trial Registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT05676775., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The aim was to assess the use and drug survival of IL-17Ai in a real-world cohort of axial SpA (axSpA) and PsA patients., Methods: Patients ever commenced on an IL-17Ai (secukinumab or ixekizumab) for axSpA or PsA at the Leeds Specialist Spondyloarthritis Service were identified. Demographics, IL-17Ai treatment length and reason for cessation were collected. Drug survival data were plotted as a Kaplan-Meier curve, with log rank test of median survival compared between axSpA and PsA. Cox regression analysis was performed to investigate the relationship between diagnosis and length of drug survival., Results: In total, 228 patients (91 axSpA and 137 PsA) were exposed to IL-17Ai. Drug survival for all patients at 12 months was 69% (95% Confidence Interval (CI) 63, 75%) and at 24 months 60% (95% CI 54, 67%). In axSpA and PsA, drug survival at 12 months was 63% (CI 54, 74%) and 73% (CI 66, 81%), respectively, and at 24 months it was 53% (CI 44, 65%) and 65% (CI 57, 75%), respectively. Median survival did not differ significantly between both diseases (log rank test 0.65). There was no association between diagnosis and survival (hazard ratio 0.92, 95% CI 0.63, 1.33), including when adjusting for age, previous biologic DMARD usage and sex (hazard ratio 0.89, 95% CI 0.61, 1.13)., Conclusion: This is the first study, to our knowledge, to analyse and compare real-world IL-17Ai drug survival in patients with axSpA and PsA from a single centre. We demonstrate that there is no difference in IL-17Ai survival rates and no relationship between diagnosis and drug survival. These results contribute to the body of real-world evidence confirming the role of IL-17Ai in the management of axSpA and PsA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Psoriatic arthritis (PsA) is an inflammatory arthritis characterized by inflammation of peripheral and / or axial joints, with or without other tissue manifestations, including skin psoriasis, dactylitis, enthesitis, uveitis, and inflammatory bowel disease. There has been an exponential increase in PsA treatment options over the last 2 decades, and while guidelines have attempted to keep up with the deluge of emerging data, there are several areas in which guidance remains sparse. This is, in part, due to a lack of robust strategy trials, head‑to‑head studies, and real‑world observational data. In addition, trials seldom address key questions, such as the complex need to balance the treatment of joint disease with the other competing tissue manifestations of PsA, as well as other relevant medical comorbidities and patient lifestyle and personal preferences, all of which may change several times over the course of an individual's lifetime. This article provides a concise summary of the current state of guidelines for the management of PsA, and an in‑depth discussion of some of the areas where guidelines and evidence are still lacking. These areas of unmet clinical need in the treatment of PsA should be a priority for further PsA research in the coming years. Only by working with patients and addressing these gaps in our knowledge can we strive for a future where all PsA patients are able to receive treatment that is the best for them, and tailored to their specific needs at any particular time point in their disease trajectory.

Axial spondyloarthritis (axSpA) was historically considered a disease of men, largely due to the recognition of a more severe, progressive phenotype, ankylosing spondylitis (AS; or radiographic axSpA, r-axSpA) aiding the clinical diagnosis [1,2]. Data demonstrating the near equal prevalence of axSpA in women only started to emerge in the last decades, highlighting intrinsic differences in disease phenotype, and clinical and imaging characteristics between sexes, which partly explain the issue of underdiagnosis in women. Similar to the evolving understanding of spondyloarthritis and the diseases that term describes, the concepts of gender and sex also warrant further clarification to accurately assess their potential role in disease pathophysiology and phenotypic expression. This narrative review delves into the most recent evidence from the literature on the true prevalence of sex differences in axSpA, and the impact of sex and gender on diagnosis, disease characteristics and treatment response in this, still underserved, chronic disease., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose of Review: Disparities in prostate cancer care and outcomes have been well recognized for decades. The purpose of this review is to methodically highlight known racial disparities in the care of prostate cancer patients, and in doing so, recognize potential strategies for overcoming these disparities moving forward., Recent Findings: Over the past few years, there has been a growing recognition and push towards addressing disparities in cancer care. This has led to improvements in care delivery trends and a narrowing of racial outcome disparities, but as we highlight in the following review, there is more to be addressed before we can fully close the gap in prostate cancer care delivery. While disparities in prostate cancer care are well recognized in the literature, they are not insurmountable, and progress has been made in identifying areas for improvement and potential strategies for closing the care gap., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Purpose of Review: An overview of how the treatment landscape of axial spondyloarthritis (axSpA) has shaped our understanding of the disease., Recent Findings: Prior to the millennium, non-steroidal anti-inflammatory drugs (NSAIDs) were the only treatment for axSpA, yet only 30% of patients responded and many developed side effects. In 2003, the first biological disease-modifying drug (bDMARD) was licensed for axSpA which substantially improved outcomes in comparison to NSAIDs. In 2022, there are now several bDMARDs for axSpA; however, they too are not universally efficacious in treating axial inflammation and may have deleterious effects on extramusculoskeletal manifestations. Nevertheless, successful or not, each bDMARD gives invaluable insight into axSpA immunobiology. This review discusses how much we have learned from the use of bDMARDs in axSpA, how this has redefined our understanding of the disease, and how we might use this knowledge to develop new and better treatments for axSpA in the future., (© 2023. The Author(s).)

Objective: To examine the relevance of existing chronic care models to the integration of chronic disease care into primary care services in sub-Saharan Africa and determine whether additional context-specific model elements should be considered., Design: 'Best fit' framework synthesis comprising two systematic reviews. First systematic review of existing chronic care conceptual models with construction of a priori framework. Second systematic review of literature on integrated HIV and diabetes care at a primary care level in sub-Saharan Africa, with thematic analysis carried out against the a priori framework. New conceptual model constructed from a priori themes and new themes. Risk of bias of included studies was assessed using CASP and MMAT., Eligibility Criteria: Conceptual models eligible for inclusion in construction of a priori framework if developed for a primary care context and described a framework for long-term management of chronic disease care. Articles eligible for inclusion in second systematic review described implementation and evaluation of an intervention or programme to integrate HIV and diabetes care into primary care services in SSA., Information Sources: PubMed, Embase, CINAHL Plus, Global Health and Global Index Medicus databases searched in April 2020 and September 2022., Results: Two conceptual models of chronic disease care, comprising six themes, were used to develop the a priori framework. The systematic review of primary research identified 16 articles, within which all 6 of the a priori framework themes, along with 5 new themes: Improving patient access, stigma and confidentiality, patient-provider partnerships, task-shifting, and clinical mentoring. A new conceptual model was constructed from the a priori and new themes., Conclusion: The a priori framework themes confirm a need for co-ordinated, longitudinal chronic disease care integration into primary care services in sub-Saharan Africa. Analysis of the primary research suggests integrated care for HIV and diabetes at a primary care level is feasible and new themes identified a need for a contextualised chronic disease care model for sub-Saharan Africa., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Subjective loss of response immediately prior to routine TNFi therapy can occur in axial spondyloarthritis (axSpA). We investigated clinical outcomes in patients taking the first three licenced TNFis and correlated this with recurrence of MRI bone marrow oedema (MRI-BMO)., Methods: Proof-of-concept study including axSpA patients established on etanercept (ETA), adalimumab (ADA) or infliximab (IFX) reporting symptom deterioration prior to next dose. MRI/clinical data were collected prior to scheduled dose (v1), 4 days post-dose (v2) and at the time of patient-reported symptom return (v3). MRI spine/sacroiliac joints utilizing 3 T were scored using the semi-quantitative Leeds MRI scoring system., Results: A total of 113 clinical assessments and MRIs were performed in 38 participants (ADA = 16, ETA = 12, IFX = 10), mean age 42.1 years ± 24.4(2SD, n = 38), 71.1% male (n = 27/38), 69.7% HLA-B27 positive (n = 23/33). At v1, all patients had high disease activity [ASDAS-CRP = 3 (2.7-3.7)] and 57.9% had MRI-BMO (number of MRI-BMO: ETA = 26, ADA = 59, IFX = 28). Improved clinical responses were seen at v2 [ASDAS-CRP -0.41(-0.81 - 0.30), P =0.018; BASDAI -0.58(-2.2 - 0.52), P =0.024]. Despite just a 4-day interval between v1 and v2, a numerical reduction in MRI-BMO lesions between v1/v2 was observed (ETA = -6, ADA = -10, IFX = -3). By v3, comparatively fewer new BMO lesions were detected in the ETA and ADA groups compared with IFX (ETA = -1, ADA = +3, IFX = +8), although the numbers were too small to enable testing for statistical significance., Conclusions: Short-lived fluctuations in MRI-BMO were commoner with longer-acting agents and corresponded with subjective loss of clinical response before next scheduled TNFi dose. Larger studies are needed to confirm the possible pathogenic implications of this phenomenon., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.

Objectives: The aim was to compare the impact of the first wave of the coronavirus disease 2019 (COVID-19) pandemic and lockdown measures on patients with rheumatic and musculoskeletal diseases (RMDs) in the UK and other European countries (OEC)., Methods: REUMAVID was an online cross-sectional survey of seven European countries. The data collected included the following: demographics, lifestyle, employment, access to health-care services, disease-specific characteristics, the World Health Organization five well-being index (WHO-5), hospital anxiety and depression scale (HADS), visual analogue scale (VAS) disease activity, and the perceived acceptable symptom scale., Results: One thousand eight hundred responses were received between April and July 2020 [UK, n = 558 (31.0%); OEC, n = 1242 (69.0%)]. UK patients were more likely to be older [mean (S.d.): UK 58.5 (13.4) years; OEC 50.0 (12.2) years], university educated [UK n = 302 (54.1%); OEC n = 572 (46.1%), quit smoking [UK n = 92 (59.4%); OEC n = 65 (16.2%)] and continue exercise [UK, n = 216 (49.2%); OEC, n = 228 (33.1%)], although, conversely, alcohol consumption increased [UK n = 99 (36.3%); OEC n = 98 (12.1%)]. UK patients felt informed about COVID-19 (UK 72.7%, OEC 57.4%) and kept their planned rheumatology [UK n = 87 (51.2%); OEC n = 213 (38.6%)] and/or general practice appointments [UK n = 87 (76.3%); OEC n = 310 (53.9%)]. Almost half the patients with RMDs reported a decline in health and well-being, although this was less common in UK patients [UK n = 214 (38.4%), OEC n = 618 (50.2%)], who reported better perceived acceptable symptom scale, VAS pain and HADS scores, but worse WHO-5 scores., Conclusions: UK RMD patients performed better in the physical and mental health domains tested, possibly owing to a less restrictive lockdown and better health-care access. These findings have implications for health-care services globally in planning patient care after the COVID-19 pandemic., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Axial spondyloarthritis (axSpA) is an inflammatory arthritis which affects primarily the entheses of the spine and sacroiliac joints with peripheral joint synovitis and extra-articular manifestations. In 2017, the first IL-17A inhibitor (IL-17Ai) secukinumab was approved for the treatment of radiographic axSpA not responding adequately to conventional therapies, and this was followed in 2019 by a second IL-17Ai, ixekizumab. These agents represent the first alternative class of biological treatments after the TNF inhibitor which dominated the therapeutic landscape of axSpA for over a decade., Areas Covered: This review discusses the role of IL-17Ais in the treatment in axSpA focusing on the newest IL-17Ai ixekizumab. It provides a detailed overview of the drug pharmacodynamic, pharmacokinetics, and clinical trial data, including areas of future research needed in the post-marketing era., Expert Opinion: Early trials of ixekizumab for axSpA have shown encouraging results and an acceptable safety profile. Future phase IV trials should focus on direct head-to-head comparisons between ixekizumab and other biologic drugs, and stratify patients according to important disease characteristics known to affect treatment response including sex, HLA-B27 status, presence of MRI bone marrow edema at baseline, disease duration and any extra-articular manifestations.

Objective: Ankylosing spondylitis (AS) is a chronic inflammatory arthritis primarily affecting the spine and sacroiliac joints. TNF inhibitor (TNFi) drugs are recommended for patients not responding to NSAIDs; however, there is a significant need for biomarkers of response. IFN-regulated genes (IRGs) and other cytokines/chemokines are linked to autoimmune diseases and have been associated with treatment response. Our objective was to explore whether IRGs and cytokines/chemokines can be associated with response to TNFiagents in AS., Methods: Peripheral blood mononuclear cells were obtained from 26 AS patients who were to receive a TNFi (I, n = 15) or placebo (P, n = 11) at week 0 and week 22. Response (R)/non-response (NR) was defined as reduction in ASDAS ≥ 1.2 points or reduction in sacroiliac/vertebral MRI lesions. The expression of 96 genes was quantified using TaqMan assays. Finally, ELISA was used to measure IL-6 in serum samples from another 38 AS patients., Results: Analysis of gene expression in 26 baseline samples segregated patients into four groups defined by a signature of 15 genes (mainly IRGs). ASDAS response was associated with one group independently of treatment received. We then analysed response to the TNFi (n = 15) and identified a 12-gene signature associated with MRI response. A third IRG signature was also associated with a reduction in IRGs expression post-TNFi samples (n = 10 pairs). Finally, decreased circulating IL-6 was associated with BASDAI-R., Conclusion: This pilot study suggests an association between IRG expression and response to TNFi in AS. These findings require validation in a larger cohort in order to construct predictive algorithms for patient stratification., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Radiological and pathological studies in severe COVID-19 pneumonia (SARS-CoV-2) have demonstrated extensive pulmonary immunovascular thrombosis and infarction. This study investigated whether these focal changes may present with chest pain mimicking pulmonary emoblism (PE) in ambulant patients., Methods: CTPAs from outpatients presenting with chest pain to Leeds Teaching Hospital NHS Trust 1st March to 31 May 2020 (n = 146) and 2019 (n = 85) were compared. Regions of focal ground glass opacity (GGO), consolidation and/or atelectasis (parenchymal changes) were determined, and all scans were scored using British Society for Thoracic Imaging (BSTI) criteria for COVID-19, and the 2020 cohort was offered SARS-CoV-2 antibody testing., Results: Baseline demographic and clinical data were similar between groups with absence of fever, normal lymphocytes and marginally elevated CRP and D-Dimer values. Evidence of COVID-19 or parenchymal changes was observed in 32.9% (48/146) of cases in 2020 compared to 16.5% (14/85) in 2019 (P = 0.007). 11/146 (7.5%) patients met BSTI criteria for COVID-19 in 2020 compared with 0/14 in 2019 (P = 0.008). 3/39 patients tested had detectable COVID-19 antibodies (2 with parenchymal changes and 1 with normal parenchyma) however 0/6 patients whose CTPA met BSTI criteria "likely/suspicious for COVID-19" and attended antibody testing were SARS-CoV-2 antibody positive., Conclusions: 32.8% ambulatory patients with suspected PE in 2020 had parenchymal changes with 7.5% diagnosed as COVID-19 infection by imaging criteria, despite the absence of other COVID-19 symptoms. These findings suggest that localized COVID-19 pneumonitis with immunothrombosis occurs distal to the bronchiolar arteriolar circulation, causing pleural irritation and chest pain without viraemia, accounting for the lack of fever and systemic symptoms., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Previous studies have linked rheumatoid arthritis (RA) risk and disease activity with vitamin D-deficiency (low serum 25-hydroxyvitamin D (25OHD)), but a causal role for vitamin D in RA is still unclear, with conflicting results from many previous studies, partly due to heterogeneity in study design and patient populations. In this study we aimed to (1) analyse serum 25OHD in early inflammatory arthritis, (2) compare 25OHD with disease activity and fatigue in early RA and (3) determine whether low 25OHD is associated with progression to RA., Methods: An analysis of 790 patients recruited to the Birmingham Early Inflammatory Arthritis Cohort and followed longitudinally to determine clinical outcomes. The following were recorded at baseline: demographic data, duration of symptoms, duration of early morning stiffness (EMS), tender and swollen joint counts, Visual Analogue Scale (VAS) pain/fatigue/EMS, PHQ-9, HAQ and FACIT-Fatigue scores, DAS28-ESR, DAS28-CRP, CRP, ESR, anti-CCP antibody status, rheumatoid factor status, and serum 25OHD (ng/ml). Diagnosis was recorded at 0 and 12 months onwards as either RA, Undifferentiated Inflammatory Arthritis (UIA; synovitis not meeting other classification/diagnostic criteria), Clinically Suspect Arthralgia (CSA; arthralgia of an inflammatory type without synovitis), or Other., Results: Baseline demographic data were similar between all groups, with median symptom duration of 16.8-34.0 days. Baseline 25OHD was not significantly different between groups [median, interquartile range (IQR): RA 46.7, 30.0-73.3; UIA 51.4, 30.0-72.3; CSA 47.7, 30.3-73.0; Other 39.9, 28.6-62.2]. In RA ( n  = 335), there were no significant differences between 25OHD and measures of disease activity or fatigue. No association between 25OHD and progression from UIA or CSA to RA was observed., Conclusions: There was no clear association between serum 25OHD and baseline diagnosis, RA disease activity, or progression from UIA or CSA to RA. Future studies of other vitamin D metabolites may better define the complex role of vitamin D in RA., Competing Interests: Competing interestsThe authors have no competing interests to declare., (© The Author(s) 2020.)

Breast lymphoscintigraphy with 99m Tc-sulfur colloid is frequently performed before breast-conserving surgery to delineate drainage to a sentinel node. Tracer injection for lymphoscintigraphy can be painful. Our aims were to determine whether administering a solution of buffered lidocaine immediately before lymphoscintigraphy injection could both reduce the patients' pain and increase nuclear medicine technologists' satisfaction with performing the procedure. Methods: A pain scale survey was obtained from patients undergoing breast lymphoscintigraphy with or without buffered lidocaine. Our nuclear medicine technologists were also surveyed for their satisfaction with the procedure, both with and without the addition of buffered lidocaine. Results: The patients' reported pain decreased by 86% with the addition of buffered lidocaine. Technologist satisfaction with performing the procedure increased by 36%. Conclusion: Lidocaine buffered with sodium bicarbonate injected before lymphoscintigraphy significantly reduces pain experienced by the patient and improves nuclear medicine technologist satisfaction in performing the procedure., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH) 2 D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH) 2 D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH) 2 D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.

Coastal erosion outpaces land generation along many of the world's deltas and a significant percentage of shorelines, and human-caused alterations to coastal sediment budgets can be important drivers of this erosion. For sediment-starved and erosion-prone coasts, large-scale enhancement of sediment supply may be an important, but poorly understood, management option. Here we provide new topographic measurements that show patterns and trends of beach accretion following the restoration of sediment supply from a massive dam removal project. River sediment was initially deposited in intertidal-to-subtidal deltaic lobes, and this sediment was reworked by ocean waves into subaerial river mouth bars over time scales of several months. These river mouth bars welded to the shoreline and then initiated waves of sediment accretion along adjacent upcoast and downcoast beaches. Although the downcoast shoreline has a high wave-angle setting, the sedimentation waves straightened the downcoast shoreline rather than forming self-organized quasi-periodic instabilities, which suggests that simple coastal evolution theory did not hold under these conditions. Combined with other mega-nourishment projects, these findings provide new understanding of littoral responses to the restoration of sediment supplies.

Vitamin D-deficiency has been linked to inflammatory diseases including rheumatoid arthritis (RA). Studies to date have focused on the impact of serum 25-hydroxyvitamin D3 (25(OH)D3), an inactive form of vitamin D, on RA disease activity and progression. However, anti-inflammatory actions of vitamin D are likely to be mediated at sites of RA disease, namely the inflamed joint, and may involve other vitamin D metabolites notably the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH) 2 D3). In the current study serum and synovial fluid samples from n = 20 patients with persistent RA and n = 7 patients with reactive arthritis (ReA) were analysed for multiple vitamin D metabolites. Serum data for RA and ReA patients were compared to healthy controls (HC). There was no significant difference between RA or ReA patients relative to HC for 25(OH)D3, 24,25(OH) 2 D3, 1,25(OH) 2 D3 or 25(OH)D2. However, 3-epi-25(OH)D3 was significantly lower in RA and ReA patients compared to HC (p < 0.05). All vitamin D metabolites, apart from 25(OH)D2, were lower in SF compared to serum, and SF 1,25(OH) 2 D3 was unquantifiable in 13/20 RA and 4/7 ReA samples. SF 25(OH)D3, 3-epi-25(OH)D3 and DBP correlated inversely with swollen joint score, and serum 25(OH)D2 and SF DBP correlated directly with C-reactive protein levels. These data indicate that serum 25(OH)D3 provides only limited insight into the role of vitamin D in RA. Alternative serum metabolites such as 3-epi-25(OH) 2 D3, and SF metabolites, notably lack of SF 1,25(OH) 2 D3, may be more closely linked to RA disease severity and progress., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB). In this study, we hypothesized that proinflammatory cytokine signaling in TRAPS downregulates these two miRs, resulting in LPS-induced hyperresponsiveness in TRAPS dermal fibroblasts (DFs), irrespective of the underlying genetic mutation. Primary DF were isolated from skin biopsies of TRAPS patients and healthy controls (HC). TNFR1 cell surface expression was measured using immunofluorescence. DF were stimulated with LPS, interleukin (IL)-1β, thapsigargin, or TNF, with and without inositol-requiring enzyme 1 (IRE1) inhibitor (4u8C), following which miR-146a and miR-155 expression was measured by RT-qPCR. IL-1β, IL-6, and TNF secretion was measured by enzyme-linked immunosorbent assays, and baseline expression of 384 different miRs was assessed using microfluidics assays. TNFR1 was found to be expressed on the surface of HC DF but expression was deficient in all samples with TRAPS-associated mutations. HC DF showed significant dose-dependent increases in both miR-146a and miR-155 expression levels in response to LPS; however, TRAPS DF failed to upregulate either miR-146a or miR-155 under the same conditions. This lack of miR-146a and miR-155 upregulation was associated with increased proinflammatory cytokine production in TRAPS DF in response to LPS challenge, which was abrogated by 4u8C. Incubation of HC DF with IL-1β led to downregulation of miR-146a and miR-155 expression, which was dependent on IRE1 enzyme. We observed global dysregulation of hundreds of other miRs at baseline in the TRAPS DF. In summary, these data suggest a mechanism whereby IL-1β, produced in response to activation of the UPR in TRAPS DF, downregulates miR-146a and miR-155, by inducing IRE1-dependent cleavage of both these miRs, thereby impairing negative regulation of NF-κB and increasing proinflammatory cytokine production.

Background: Some adult patients presenting with unexplained pyrexia, serositis, skin rashes, arthralgia, myalgia, and other symptoms commonly found in autoinflammatory disorders may not fit a specific diagnosis, either because their clinical phenotype is nondiagnostic or genetic tests are negative. We used the term undifferentiated systemic autoinflammatory disorder (uSAID) to describe such cases. Given that well-defined autoinflammatory diseases show responses to IL-1 blockade, we evaluated whether anakinra was useful for both diagnosing and treating uSAID patients., Methods: We performed a retrospective analysis of consecutive patients presenting with uSAID between 2012-2015 who were treated with the recombinant IL-1 receptor antagonist anakinra. uSAID was diagnosed after excluding malignancy, infection, and pathogenic mutations in known hereditary fever syndromes (HFS) genes and where clinical criteria for adult onset Still's disease (AOSD) were not met., Results: A total of 11 patients presented with uSAID (5 males and 6 females), with a mean time to diagnosis of 3.5 years (1-8 years). Patients were unresponsive or only partially controlled on disease-modifying antirheumatic drug (DMARD)/steroid treatment. Anakinra controlled symptoms within 4-6 weeks of starting treatment in 9 of 11 cases. Two patients discontinued therapy - one due to incomplete response and another due to severe injection-site reactions., Conclusion: This retrospective case series demonstrates that the spectrum of poorly defined autoinflammatory disorders that show responsiveness to anakinra is considerable. Anakinra seems a viable treatment option for these patients, who are unresponsive to standard steroid/DMARD treatments. Moreover, given the mechanisms of action, response to anakinra implicates underlying IL-1 dysregulation in the disease pathogenesis of responding uSAIDs patients.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of "self-eating" where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.

Study Objective: We describe current alcohol screening and brief intervention practices in emergency departments (EDs) at Level I and Level II trauma centers and characterize ED directors' attitudes and perceived barriers associated with these practices among injured patients in the ED., Methods: ED directors at Level I and Level II trauma centers were surveyed about current alcohol screening and intervention practices in the ED, as well as knowledge, attitudes, and perceived barriers to these practices., Results: Nearly half (46.0%) of ED directors surveyed responded. The majority (64.5%) reported using a serum alcohol level to routinely screen for unhealthy alcohol use; only 23.6% routinely use standardized instruments. Sixty-five percent of ED directors support screening and 70% support intervention among injured ED patients. Only 15% reported having formal screening and intervention policies in their ED, and 9% reported offering brief alcohol intervention by trained personnel. The most commonly perceived barriers to implementation are provider time (83%) and financial resources (55%). Of injured patients identified as exhibiting alcohol misuse, few (12%) receive brief intervention conducted by trained personnel., Conclusion: Current alcohol screening and brief intervention practices are lagging behind national guidelines. Although the majority of ED directors support the idea of alcohol screening and intervention, these beliefs have not yet been translated to routine clinical care., (Copyright (c) 2009 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Objective: To determine prevalence and correlates of handgun access among adolescents seeking care in an urban Emergency Department (ED) in order to inform future injury prevention strategies., Methods: In this observational cross-sectional study performed in the ED of a large urban hospital, 14- to 18-year-old adolescents completed a computerized survey of risk behaviors. Adolescents seeking ED care (for injury or medical complaint) were approached seven days a week over a 22-month period. Validated measures included measures of demographics, sexual activity, substance use, injury, violent behavior, and handgun access. A logistic regression model predicting handgun access was performed., Results: A total of 3050 adolescents completed the survey (44% male, 58.9% African-American), with 417 (12%) refusing to participate. One-third of the sample (n=1003) reported access to a handgun, and of those 54% were males (n=542). Logistic regression results indicated that older age (AOR: 1.58; 95% CI: 1.30-1.94), African-American race (AOR: 1.34; 95% CI: 1.11-1.61), male gender (AOR: 1.99; 95% CI: 1.66-2.37), and being employed (AOR: 1.35; 95% CI: 1.11-1.65), as well as seeking ED care for a medical complaint as compared to intentional injury (AOR: 1.69; 95% CI 1.62-2.50) predicted handgun access. Binge drinking (AOR: 1.75; 95% CI: 1.37-2.27), marijuana use (AOR: 1.93; 95% CI: 1.58-2.36), sexual activity (AOR: 1.64; 95% CI: 1.32-2.02), prior injury by a gun (AOR: 1.80; 95% CI: 1.32-2.46), serious physical violence (AOR: 1.37; 95% CI: 1.13-1.66) and group fighting (AOR: 2.07; 95% CI: 1.68-2.56) also predicted access., Conclusions: High rates of handgun access were evident among adolescents presenting in an inner city ED, including those seeking care for non-injury related reasons. Adolescents with access to handguns were more likely to report risk behaviors and past injury, providing clinicians with an opportunity for injury prevention initiatives., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objectives: The objective was to describe the prevalence and correlates of past-year weapon involvement among adolescents seeking care in an inner-city emergency department (ED)., Methods: This cross-sectional study administered a computerized survey to all eligible adolescents (age 14-18 years), 7 days a week, who were seeking care over an 18-month period at an inner-city Level 1 ED. Validated measures were administered, including measures of demographics, sexual activity, substance use, injury, violent behavior, weapon carriage, and/or weapon use. Zero-inflated Poisson (ZIP) regression models were used to identify correlates of the occurrence and past-year frequency of these weapons variables., Results: Adolescents (n = 2069, 86% response rate) completed the computerized survey. Fifty-five percent were female; 56.5% were African American. In the past year, 20% of adolescents reported knife or razor carriage, 7% reported gun carriage, and 6% pulled a knife or gun on someone. Although gun carriage was more frequent among males, females were as likely to carry a knife or pull a weapon in the past year., Conclusions: One-fifth of all adolescents seeking care in this inner-city ED have carried a weapon. Understanding weapon carriage among teens seeking ED care is a critical first step to future ED-based injury prevention initiatives., ((c) 2010 by the Society for Academic Emergency Medicine.)

Objective: To determine whether short-acting beta-agonist (SABA) prescriber continuity was associated with emergency department visits among children with asthma., Study Design: An analysis of Michigan Medicaid administrative claims (2004-2005) for children ages 5 to 18 with asthma. Logistic regression models assessed the effect of SABA prescriber continuity (the number and site of prescribers) on emergency department visits, controlling for demographics, historical (2004) asthma use and SABA prescription frequency (2-5 low; > or = 6 high)., Results: Most children had one SABA prescriber (62%); 13% had multiple prescribers in the same practice as the primary care provider and 25% had multiple prescribers in different practices. Children with multiple prescribers in different practices had increased odds of an emergency department visit compared with those with 1 prescriber, among those with high SABA prescription frequency (AOR: 2.7, 95% CI: 1.9, 3.9), as well as those with low prescription frequency (AOR: 1.7, 95% CI: 1.3, 2.2)., Conclusions: Children with discontinuity of SABA prescribers have an increased risk of asthma emergency department visits, irrespective of their SABA prescription frequency. Primary care providers may have difficulty identifying patients at high risk with asthma solely on the basis of SABAs prescribed within their own practices.

Continuation in substance abuse treatment is one of the strongest predictors of successful post-treatment outcomes across all major treatment modalities. However, since rates of attrition are highest within the first month of treatment, many clients drop out before these positive outcomes are realized. The impact of organizational and therapeutic factors on treatment continuation in therapeutic communities has received little attention in the literature. This study was conducted to determine whether a brief induction to treatment was associated with improved treatment continuation in a therapeutic community. Multivariable logistic regression analysis indicated that induction was associated with 30-day continuation. Prior treatment and court-mandated treatment were also associated with continuation.

Aims: The aim of this study was to evaluate an innovative approach to the provision of primary care-based diabetes services in Bradford, UK. The service model differs from others in comprising 19 clinics which offer a specialist service, intermediate between primary and secondary care, to all patients within the Bradford area., Methods: The study included: analysis of referral, attendance and register data; questionnaires to general practitioners (GPs) and specialist clinic providers; qualitative interviews with clinic and other professional staff and patients; and an economic analysis., Results: The 19 clinics adopt a range of organizational models. In the first 3 1/2 years, 2415 patients were referred. There was a significant reduction in out-patient attendances at hospital, but also a significant increase in overall patient attendances. Specialist clinic patients differed from hospital patients in being older and having had diabetes for longer since diagnosis. Ten of the 14 clinics run by practising GPs attracted more referrals from within their practices than from outside. GPs and patients across the city believed the clinics were valuable, the main benefits being geographical accessibility, availability of specialists in a community setting, short waiting times for first appointments at most clinics, and continuity of staff. Their reservations included a lack of strategic planning in the location of clinics, long waiting times at some clinics, and poor communication at some clinics with referring GPs. The cost of the primary care clinics is similar to hospital clinics., Conclusions: This model of specialist primary care services offers an opportunity to develop diabetes services that are convenient to patients, popular with practitioners, and increase capacity. However, the shortcomings as well as the advantages of the model need to be addressed if it is to be implemented elsewhere or for other patient groups.

While riparin vegetation can play a major role in protecting land, water and natural habitat in catchments, there are high costs associated with tree planting and establishment and in diverting land from cropping. The distribution of costs and benefits of riparian revegetation creates conflicts in the objectives of various stakeholder groups. Multicriteria analysis provides an appropriate tool to evaluate alternative riparian revegetation options, and to accommodate the conflicting views of various stakeholder groups. This paper discusses an application of multicriteria analysis in an evaluation of riparian revegetation policy options for Scheu Creek, a small sub-catchment in the Johnstone River catchment in north Queensland, Australia. Clear differences are found in the rankings of revegetation options for different stakeholder groups with respect to environmental, social and economic impacts. Implementation of a revegetation option will involve considerable cost for landholders for the benefits of society. Queensland legislation does not provide a means to require farmers to implement riparian revegetation, hence the need for subsidies, tax incentives and moral suasion.

Background: This qualitative study aimed to explore the views of key stakeholders regarding the role that public health professionals have or should have in the provision of effective health care within the National Health Service., Methods: A national (England) questionnaire survey generated a sample for qualitative telephone interviews and two site case studies. The interviews were conducted in three stages: first, 27 interviews were based on assessed reported levels of organizational activity, including non-respondents; next, views in six areas were consolidated by extra interviews; finally, two extra areas were visited for individual and group interviews. The interviews were analysed for salient themes., Results: There was a widespread view that public health had not delivered its potential. Many Trusts currently wanted public health to have influence over commissioning, provide health needs assessments and epidemiological skills, and provide a strategic focus and unbiased advice. Evaluation of actual activity varied widely; local history and congruent personalities seemed to be associated with perceived success. In some cases there was mutual suspicion between Health Authorities and Trusts. Public health was often perceived by Trusts to have been marginalized. This perception was not shared by Public Health Consultants, who highlighted lack of resources as a reason for lack of involvement. The contribution of public health professionals working in Trusts was highly regarded. Barriers included overcoming initial prejudice and combating isolation within Trusts. There were four categories of response in respect of the potential future role for public health in implementing effective health care: no role; collaborative working between Health Authority Public Health Departments and Trusts; deployment of public health workers within Trusts, and an undecided group. Overall, the skills of public health, especially strategic vision and population perspectives, were seen as valuable but as yet unrealized., Conclusions: Public health skills (but not necessarily professionals) may be valuable in implementing effective health care in Trusts. However, public health professionals must refocus and market their skills to Trusts if the discipline is to play a key role in this task.

The authors discuss the evaluation of the economic impacts of endemic livestock diseases, and economic issues in control of these diseases. Particular attention is focused on helminths and on endemic vector-transmitted infections (particularly ticks and tick-borne diseases). Decisions relating to disease control have to be made by government and by the producer. Government requires information on the level of control to adopt, the extent of involvement needed, and how to fund animal health programmes (particularly how to share costs between taxpayers and livestock producers). Individual producers require information as to how much effort to invest in disease control, including information collection effort, and how to design control strategies. Economics can shed light on these issues. However, experience suggests that animal health policies are particularly difficult to evaluate from an economic viewpoint, with complex relationships between animal health, production impacts, market access, and non-production benefits of livestock. While little information is available concerning the cost of helminth diseases, many estimates have been made of the costs of ticks and tick-borne diseases at a regional and national level, sometimes demonstrating that eradication is warranted.