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This document explores the use of ultrasound (US) in rheumatology practice, specifically focusing on a new model called Point of Care US (POCUS) in Rheumatology (POCRUS). The authors argue that learning US examination skills can improve diagnostic accuracy and clinical confidence in rheumatology. They propose a probability-directed approach to US, using standardized assessments based on international classification criteria for rheumatic and musculoskeletal diseases. The document acknowledges the support of various organizations in organizing and reporting the findings of an online course on POCRUS. [Extracted from the article]

Objectives To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. Methods An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. Results In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. Conclusion This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials. [ABSTRACT FROM AUTHOR]

Ensuring fairness in computational problems has emerged as a key topic during recent years, buoyed by considerations for equitable resource distributions and social justice. It is possible to incorporate fairness in computational problems from several perspectives, such as using optimization, game-theoretic or machine learning frameworks. In this paper we address the problem of incorporation of fairness from a combinatorial optimization perspective. We formulate a combinatorial optimization framework, suitable for analysis by researchers in approximation algorithms and related areas, that incorporates fairness in maximum coverage problems as an interplay between two conflicting objectives. Fairness is imposed in coverage by using coloring constraints that minimizes the discrepancies between number of elements of different colors covered by selected sets; this is in contrast to the usual discrepancy minimization problems studied extensively in the literature where (usually two) colors are not given a priori but need to be selected to minimize the maximum color discrepancy of each individual set. Our main results are a set of randomized and deterministic approximation algorithms that attempts to simultaneously approximate both fairness and coverage in this framework. [ABSTRACT FROM AUTHOR]

The binding of many proteins to their protein partners is tightly regulated via control of their relative intrinsic dynamics during the binding process, a phenomenon which can in turn be modulated. Therefore, investigating the intrinsic dynamics of proteins is necessary to understand function in a comprehensive way. By intrinsic dynamics herein, we principally refer to the vibrational signature of a protein molecule popularly obtained from normal modes or essential modes. For normal modes, one often considers that the molecule under investigation is a collection of springs in a solvent-free or implicit-solvent medium. In the context of a protein-binding partner, the analysis of vibration of the target protein is often complicated due to molecular interaction within the complex. Generally, it is assumed that the isolated bound conformation of the target protein captures the implicit effect of the binding partner on the intrinsic dynamics, therefore suggesting that any influence of the partner molecule is also already integrated. Such an assumption allows large-scale studies of the conservation of protein flexibility. However, in cases where a partner protein directly influences the vibration of the target via critical contacts at the protein-protein interface, the above assumption falls short of providing a detailed view. In this review article, we discuss the implications of considering the dynamics of a protein in a protein-protein complex, as modelled implicitly and explicitly with methods dependent on elastic network models. We further propose how such an explicit consideration can be applied to understand critical protein-protein contacts that can be targeted in future studies. [ABSTRACT FROM AUTHOR]

Background: Although polymyalgia rheumatica (PMR) is a very common rheumatic inflammatory disease, current insight into the pathobiology of PMR is limited and largely based on studies in blood. We investigated T helper 1 (TH1) and T helper 17 (TH17) cell responses in blood, synovial fluid and bursa tissue of patients with PMR. Materials and methods: Blood samples were collected from 18 patients with new-onset PMR and 32 healthy controls. Synovial fluid was aspirated from the inflamed shoulder bursae or biceps tendon sheath of 13 patients. Ultrasound-guided biopsies of the subacromial-subdeltoid (SASD) bursa were obtained from 11 patients. T cells were examined by flow cytometry, immunohistochemistry and immunofluorescence staining. Results: Besides an increase of TH17 (CD4+IL-17+IFN-γ-) cells and T cytotoxic 17 (TC17; CD8+IL-17+IFN-γ-) cells, no other major changes were noted in the circulating T cell compartment of patients with PMR. Absolute numbers of CD4+ and CD8+ T cells were similar in blood and synovial fluid of patients with PMR. Synovial fluid T cells showed an effector-memory (CD45RO+CCR7-) phenotype. Percentages of TH1 (CD4+IFN-γ+IL-17-) cells and TH1/TH17 (CD4+IFN-γ+IL-17+) cells, but not TH17 or TC17 cells, were increased in the synovial fluid. Bursa tissue biopsies contained a small number of T cells, which were mostly CD8 negative. The majority of bursa tissue T cells produced IFN-γ but not IL-17. For comparison, B cells were scarcely detected in the bursa tissue. Conclusion: Although the circulating TH17 cell pool is expanded in patients with PMR, our findings indicate that TH1 cells are involved in the inflammation of bursae and tendon sheaths in this condition. Our study points towards the TH1 cell pathway as a potential target for therapy in PMR. [ABSTRACT FROM AUTHOR]

Objective Tocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with GCA. However, its long-term benefits in new-onset vs relapsing disease are uncertain, and the value of weekly vs every-other-week dosing has not been evaluated. Methods In Giant-Cell Arteritis Actemra (GiACTA) part 1, patients with new-onset or relapsing GCA received blinded tocilizumab weekly (TCZ QW), tocilizumab every-other-week (TCZ Q2W) or placebo for 52 weeks, with a prednisone taper. In part 2 (open-label), patients were treated at investigator discretion for 104 weeks. In this analysis, patients were evaluated according to their original treatment assignments, and outcomes beyond 52 weeks were assessed. Outcomes of interest included time to first flare and cumulative glucocorticoid exposure over 3 years according to baseline disease status. Results Part 1 enrolled 250 patients; 215 entered part 2. At baseline, 48% had new-onset disease and 52% had relapsing disease. In patients with new-onset and relapsing disease, the median time to first flare in the TCZ QW group was 577 and 575 days, respectively, vs 479 and 428 days with TCZ Q2W and 179 and 224 days with placebo; the median cumulative glucocorticoid dose was 3068 mg and 2191 mg with TCZ QW, 4080 mg and 2353 mg with TCZ Q2W, and 4639 mg and 6178 mg with placebo. Conclusion TCZ QW delayed the time to flare and reduced the cumulative glucocorticoid dose in patients with relapsing GCA and new-onset GCA. These data support initiating TCZ QW as part of first-line therapy in all patients with active GCA. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT01791153. [ABSTRACT FROM AUTHOR]

Objectives: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission.Methods: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed.Results: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group.Conclusions: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab.Trial Registration Number: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1). [ABSTRACT FROM AUTHOR]

Objectives We investigated the relationship between the ultrasonographic Halo Score and temporal artery biopsy (TAB) findings in GCA. Methods This is a prospective study including 90 patients suspected of having GCA. Ultrasonography of temporal/axillary arteries and a TAB were obtained in all patients at baseline. An experienced pathologist evaluated whether TAB findings were consistent with GCA, and whether transmural inflammation, giant cells and intimal hyperplasia were present. Ultrasonographic Halo Scores were determined. Receiver operating characteristic analysis was performed. Results Twenty-seven patients had a positive TAB, while 32 patients with a negative TAB received a clinical diagnosis of GCA after 6 months of follow-up. Patients with a positive TAB showed higher Halo Scores than patients with a negative TAB. The presence of intimal hyperplasia in the biopsy, rather than the presence of transmural inflammation or giant cells, was associated with elevated Halo Scores in patients with GCA. The Halo Score discriminated well between TAB-positive patients with and without intimal hyperplasia, as indicated by an area under the curve of 0.82 in the receiver operating characteristic analysis. Patients with a positive TAB and intimal hyperplasia more frequently presented with ocular ischaemia (40%) than the other patients with GCA (13–14%). Conclusion The ultrasonographic Halo Score may help to identify a subset of GCA patients with intimal hyperplasia, a TAB feature associated with ischaemic sight loss. [ABSTRACT FROM AUTHOR]

Objectives This systematic review and meta-analysis aimed to evaluate the diagnostic value of the halo sign in the assessment of GCA. Methods A systematic literature review was performed using MEDLINE, EMBASE and Cochrane central register databases up to August 2020. Studies informing on the sensitivity and specificity of the US halo sign for GCA (index test) were selected. Studies with a minimum of five participants were included. Study articles using clinical criteria, imaging such as PET-CT and/or temporal artery biopsy (TAB) as the reference standards were selected. Meta-analysis was conducted with a bivariate model. Results The initial search yielded 4023 studies. Twenty-three studies (patients n  = 2711) met the inclusion criteria. Prospective (11 studies) and retrospective (12 studies) studies in academic and non-academic centres were included. Using clinical diagnosis as the standard (18 studies) yielded a pooled sensitivity of 67% (95% CI: 51, 80) and a specificity of 95% (95% CI: 89, 98%). This gave a positive and negative likelihood ratio for the diagnosis of GCA of 14.2 (95% CI: 5.7, 35.5) and 0.375 (95% CI: 0.22, 0.54), respectively. Using TAB as the standard (15 studies) yielded a pooled sensitivity of 63% (95% CI: 50, 75) and a specificity of 90% (95% CI: 81, 95). Conclusion The US halo sign is a sensitive and specific approach for GCA assessment and plays a pivotal role in diagnosis of GCA in routine clinical practice. Registration PROSPERO 2020 CRD42020202179. [ABSTRACT FROM AUTHOR]

We analyze networks of functional correlations between brain regions to identify changes in their structure caused by Attention Deficit Hyperactivity Disorder (adhd). We express the task for finding changes as a network anomaly detection problem on temporal networks. We propose the use of a curvature measure based on the Forman–Ricci curvature, which expresses higher-order correlations among two connected nodes. Our theoretical result on comparing this Forman–Ricci curvature with another well-known notion of network curvature, namely the Ollivier–Ricci curvature, lends further justification to the assertions that these two notions of network curvatures are not well correlated and therefore one of these curvature measures cannot be used as an universal substitute for the other measure. Our experimental results indicate nine critical edges whose curvature differs dramatically in brains of adhd patients compared to healthy brains. The importance of these edges is supported by existing neuroscience evidence. We demonstrate that comparative analysis of curvature identifies changes that more traditional approaches, for example analysis of edge weights, would not be able to identify. [ABSTRACT FROM AUTHOR]

Objectives To compare the ultrasound characteristics with clinical features, final diagnosis and outcome; and to evaluate the halo size following glucocorticoid treatment in patients with newly diagnosed GCA. Methods Patients with suspected GCA, recruited from an international cohort, had an ultrasound of temporal (TA) and axillary (AX) arteries performed within 7 days of commencing glucocorticoids. We compared differences in clinical features at disease presentation, after 2 weeks and after 6 months, according to the presence or absence of halo sign. We undertook a cross-sectional analysis of the differences in halo thickness using Pearson's correlation coefficient (r) and Analysis of Variance (ANOVA). Results A total of 345 patients with 6 months follow-up data were included; 226 (65.5%) had a diagnosis of GCA. Jaw claudication and visual symptoms were more frequent in patients with halo sign (P  =0.018 and P  =0.003, respectively). Physical examination abnormalities were significantly associated with the presence of ipsilateral halo (P  <0.05). Stenosis or occlusion on ultrasound failed to contribute to the diagnosis of GCA. During 7 days of glucocorticoid treatment, there was a consistent reduction in halo size in the TA (maximum halo size per patient: r =−0.30, P  =0.001; and all halos r =−0.23, P  <0.001), but not in the AX (P  >0.05). However, the presence of halo at baseline failed to predict future ischaemic events occurring during follow-up. Conclusion In newly diagnosed GCA, TA halo is associated with the presence of ischaemic features and its size decreases following glucocorticoid treatment, supporting its early use as a marker of disease activity, in addition to its diagnostic role. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the efficacy and safety of sirukumab in giant cell arteritis (GCA). Methods: In this multicentre, randomised, double-blind, placebo-controlled, two-part phase 3 trial (NCT02531633; Part A [52-week double-blind treatment]; Part B [104-week follow-up]), patients with GCA were randomised (3:3:2:2:2) to sirukumab 100 mg every 2 weeks plus 6-month or 3-month prednisone taper, sirukumab 50 mg every 4 weeks plus 6-month prednisone taper, or placebo every 2 weeks plus 6-month or 12-month prednisone taper. The primary endpoint was the proportion of patients in sustained remission at week 52. Secondary endpoints included disease flare and safety. The study was terminated early (October 2017; sponsor decision). Results: Of 161 patients randomised (sirukumab: n = 107; placebo: n = 54), 28 (17.4%) completed week 52 (median treatment duration: 24–30 weeks). In a revised intent-to-treat (ITT) subgroup (completed week 52 or discontinued before study termination [n = 55]); six patients (all receiving sirukumab) achieved the primary endpoint. In the ITT population (n = 161), the proportion of patients with flares (week 2–52) was lower with sirukumab (18.4–30.8%) than placebo (37.0–40.0%). The proportion of patients with flares (week 2–12) was highest with sirukumab 100 mg every 2 weeks plus 3-month prednisone taper (23.1%). In Part A, 94.4% of patients reported ≥ 1 treatment-emergent adverse event (TEAE); 19.3% reported serious TEAEs. The proportions of patients with TEAEs were generally similar across treatment arms. No deaths occurred. Conclusions: Although data were limited due to early termination and shortened treatment duration, sirukumab treatment resulted in numerically lower proportions of patients with flare by week 52 versus placebo, with no unexpected safety findings. Trial Registration: Clinicaltrials.gov: NCT02531633. [ABSTRACT FROM AUTHOR]

Objectives To develop a quantitative score based on colour duplex sonography (CDS) to predict the diagnosis and outcome of GCA. Methods We selected patients with positive CDS and confirmed diagnosis of GCA recruited into the TA Biopsy (TAB) vs Ultrasound in Diagnosis of GCA (TABUL) study and in a validation, independent cohort. We fitted four CDS models including combinations of the following: number and distribution of halos at the TA branches, average and maximum intima–media thickness of TA and axillary arteries. We fitted four clinical/laboratory models. The combined CDS and clinical models were used to develop a score to predict risk of positive TAB and clinical outcome at 6 months. Results We included 135 GCA patients from TABUL (female: 68%, age 73 (8) years) and 72 patients from the independent cohort (female: 46%, age 75 (7) years). The best-fitting CDS model for TAB used maximum intima–media thickness size and bilaterality of TA and axillary arteries' halos. The best-fitting clinical model included raised inflammatory markers, PMR, headache and ischaemic symptoms. By combining CDS and clinical models we derived a score to compute the probability of a positive TAB. Model discrimination was fair (area under the receiver operating characteristic curve 0.77, 95% CI: 0.68, 0.84). No significant association was found for prediction of clinical outcome at 6 months. Conclusion A quantitative analysis of CDS and clinical characteristics is useful to identify patients with a positive biopsy, supporting the use of CDS as a surrogate tool to replace TAB. No predictive role was found for worse prognosis. [ABSTRACT FROM AUTHOR]

Partisan gerrymandering is a major cause for voter disenfranchisement in United States. However, convincing US courts to adopt specific measures to quantify gerrymandering has been of limited success to date. Recently, Stephanopoulos and McGhee in several papers introduced a new measure of partisan gerrymandering via the so-called "efficiency gap" that computes the absolute difference of wasted votes between two political parties in a two-party system; from a legal point of view the measure was found legally convincing in a US appeals court in a case that claims that the legislative map of the state of Wisconsin was gerrymandered. The goal of this article is to formalize and provide theoretical and empirical algorithmic analyses of the computational problem of minimizing this measure. To this effect, we show the following: (a) On the theoretical side, we formalize the corresponding minimization problem and provide non-trivial mathematical and computational complexity properties of the problem of minimizing the efficiency gap measure. Specifically, we prove the following results for the formalized minimization problem: (i) We show that the efficiency gap measure attains only a finite discrete set of rational values. (observations of similar nature but using different arguments were also made independently by Cho and Wendy (Univ Pa Law Rev 166(1), Article 2, 2017). (ii) We show that, assuming P ≠ NP , for general maps and arbitrary numeric electoral data the minimization problem does not admit any polynomial time algorithm with finite approximation ratio. Moreover, we show that the problem still remains NP -complete even if the numeric electoral data is linear in the number of districts, provided the map is provided in the form of a planar graph (or, equivalently, a polygonal subdivision of the two-dimensional Euclidean plane). (iii) Notwithstanding the previous hardness results, we show that efficient exact or efficient approximation algorithms can be designed if one assumes some reasonable restrictions on the map and electoral data. Items (ii) and (iii) mentioned above are the first non-trivial computational complexity and algorithmic analyses of this measure of gerrymandering. (b) On the empirical side, we provide a simple and fast algorithm that can "un-gerrymander" the district maps for the states of Texas, Virginia, Wisconsin and Pennsylvania (based on the efficiency gap measure) by bring their efficiency gaps to acceptable levels from the current unacceptable levels. To the best of our knowledge, ours is the first publicly available implementation and its corresponding evaluation on real data for any algorithm for the efficiency gap measure. Our work thus shows that, notwithstanding the general worst-case approximation hardness of the efficiency gap measure as shown by us, finding district maps with acceptable levels of efficiency gaps could be a computationally tractable problem from a practical point of view. Based on these empirical results, we also provide some interesting insights into three practical issues related the efficiency gap measure. [ABSTRACT FROM AUTHOR]

Anomaly detection problems (also called change-point detection problems) have been studied in data mining, statistics and computer science over the last several decades (mostly in non-network context) in applications such as medical condition monitoring, weather change detection and speech recognition. In recent days, however, anomaly detection problems have become increasing more relevant in the context of network science since useful insights for many complex systems in biology, finance and social science are often obtained by representing them via networks. Notions of local and non-local curvatures of higher-dimensional geometric shapes and topological spaces play a fundamental role in physics and mathematics in characterizing anomalous behaviours of these higher dimensional entities. However, using curvature measures to detect anomalies in networks is not yet very common. To this end, a main goal in this paper to formulate and analyze curvature analysis methods to provide the foundations of systematic approaches to find critical components and detect anomalies in networks. For this purpose, we use two measures of network curvatures which depend on non-trivial global properties, such as distributions of geodesics and higher-order correlations among nodes, of the given network. Based on these measures, we precisely formulate several computational problems related to anomaly detection in static or dynamic networks, and provide non-trivial computational complexity results for these problems. This paper must not be viewed as delivering the final word on appropriateness and suitability of specific curvature measures. Instead, it is our hope that this paper will stimulate and motivate further theoretical or empirical research concerning the exciting interplay between notions of curvatures from network and non-network domains, a much desired goal in our opinion. [ABSTRACT FROM AUTHOR]

Objectives: Ultrasound of temporal and axillary arteries may reveal vessel wall inflammation in patients with giant cell arteritis (GCA). We developed a ultrasound scoring system to quantify the extent of vascular inflammation and investigated its diagnostic accuracy and association with clinical factors in GCA.Methods: This is a prospective study including 89 patients suspected of having GCA, of whom 58 had a confirmed clinical diagnosis of GCA after 6 months follow-up. All patients underwent bilateral ultrasound examination of the three temporal artery (TA) segments and axillary arteries, prior to TA biopsy. The extent of vascular inflammation was quantified by (1) counting the number of TA segments and axillary arteries with a halo and (2) calculating a composite Halo Score that also incorporated the thickness of each halo.Results: Halo counts and Halo Scores showed moderate diagnostic accuracy for a clinical diagnosis of GCA. They correlated positively with systemic inflammation. When compared with the halo count, the Halo Score correlated better with C-reactive protein (CRP) levels and allowed to firmly establish the diagnosis of GCA in more patients. Higher halo counts and Halo Scores were associated with a higher risk of ocular ischaemia. They allowed to identify subgroups of patients with low risk (≤5%) and high risk of ocular ischaemia (>30%).Conclusions: Ultrasound halo scoring allows to quantify the extent of vascular inflammation in GCA. Extensive vascular inflammation on ultrasound may provide strong diagnostic confirmation and associates with ocular ischaemia in GCA. [ABSTRACT FROM AUTHOR]

Background: Since the publication of the European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis (LVV) in 2009, several relevant randomised clinical trials and cohort analyses have been published, which have the potential to change clinical care and therefore supporting the need to update the original recommendations.Methods: Using EULAR standardised operating procedures for EULAR-endorsed recommendations, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 13 countries. We modified existing recommendations and created new recommendations.Results: Three overarching principles and 10 recommendations were formulated. We recommend that a suspected diagnosis of LVV should be confirmed by imaging or histology. High dose glucocorticoid therapy (40-60 mg/day prednisone-equivalent) should be initiated immediately for induction of remission in active giant cell arteritis (GCA) or Takayasu arteritis (TAK). We recommend adjunctive therapy in selected patients with GCA (refractory or relapsing disease, presence of an increased risk for glucocorticoid-related adverse events or complications) using tocilizumab. Methotrexate may be used as an alternative. Non-biological glucocorticoid-sparing agents should be given in combination with glucocorticoids in all patients with TAK and biological agents may be used in refractory or relapsing patients. We no longer recommend the routine use of antiplatelet or anticoagulant therapy for treatment of LVV unless it is indicated for other reasons.Conclusions: We have updated the recommendations for the management of LVV to facilitate the translation of current scientific evidence and expert opinion into better management and improved outcome of patients in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Since biological systems are complex and often involve multiple types of genomic relationships, tensor analysis methods can be utilized to elucidate these hidden complex relationships. There is a pressing need for this, as the interpretation of the results of high-throughput experiments has advanced at a much slower pace than the accumulation of data. Results: In this review we provide an overview of some tensor analysis methods for biological systems. Conclusions: Tensors are natural and powerful generalizations of vectors and matrices to higher dimensions and play a fundamental role in physics, mathematics and many other areas. Tensor analysis methods can be used to provide the foundations of systematic approaches to distinguish significant higher order correlations among the elements of a complex systems via finding ensembles of a small number of reduced systems that provide a concise and representative summary of these correlations. [ABSTRACT FROM AUTHOR]

Objectives: To measure serial interleukin (IL)‐6 levels in newly diagnosed patients with giant cell arteritis (GCA), treated in a randomized controlled trial of modified‐release prednisone (MR) vs immediate‐release prednisolone (IR) used in a tapering regimen conforming to British Society for Rheumatology GCA guidelines. Methods: Patients (n = 12) were randomized into 2 treatment arms (7 MR, 5 IR) and followed over 26 weeks. We measured IL‐6 with additional markers. Results: A significantly higher overall mean IL‐6 level (P < .05) was seen in IR (mean = 12.15, standard error [SE] = 1.90) compared with MR (mean = 4.39, SE = 1.84). Mean collagen type 1 cross‐linked C‐telopeptide (CTX) concentration was significantly higher (P <.05) in both groups at week 4 (mean = 0.29, SE = 0.04) compared with week 26 (mean = 0.13, SE = 0.02). MR patients had adrenocorticotropic hormone (ACTH) suppression compared with IR (P < .05) throughout without differences in cortisol levels (P = .34). No significant differences were seen between arms in other markers. Conclusion: Our study suggests that elevated levels of IL‐6 in new GCA are better suppressed by MR prednisone compared with IR prednisolone. CTX was significantly reduced in both treatment arms indicating early metabolic effect of glucocorticoids on bone. ACTH suppression with MR prednisone may reflect a greater impact on the hypothalamic‐pituitary‐adrenal axis although cortisol was not affected. MR prednisone warrants further investigation in GCA. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) represents the most common form of primary systemic vasculitis and is frequently associated with comorbidities related to the disease itself or induced by the treatment. Systematically collected data on disease course, treatment and outcomes of GCA remain scarce. The aim of this EULAR Task Force was to identify a core set of items which can easily be collected by experienced clinicians, in order to facilitate collaborative research into the course and outcomes of GCA. A multidisciplinary EULAR task force group of 20 experts including rheumatologists, internists, epidemiologists and patient representatives was assembled. During a 1-day meeting, breakout groups discussed items from a previously compiled collection of parameters describing GCA status and disease course. Feedback from breakout groups was further discussed. Final consensus was achieved by means of several rounds of email discussions after the meeting. A three-round Delphi survey was conducted to determine a core set of parameters including the level of agreement. 117 parameters were regarded as relevant. Potential items were subdivided into the following categories: General, demographics, GCA-related signs and symptoms, other medical conditions and treatment. Possible instruments and assessment intervals were proposed for documentation of each item. To facilitate implementation of the recommendations in clinical care and clinical research, a minimum core set of 50 parameters was agreed. This proposed core set intends to ensure that relevant items from different GCA registries and databases can be compared for the dual purposes of facilitating clinical research and improving clinical care. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate glucocorticoid dosages and serologic findings in patients with giant cell arteritis (GCA) flares. Methods: Patients with GCA were randomly assigned to receive double‐blind dosing with either subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26‐week prednisone taper (TCZ‐QW + Pred‐26), every‐other‐week TCZ plus 26‐week prednisone taper (TCZ‐Q2W + Pred‐26), placebo plus 26‐week prednisone taper (PBO + Pred‐26), or placebo plus 52‐week prednisone taper (PBO + Pred‐52). Outcome measures were prednisone dosage, C‐reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare. Results: One hundred patients received TCZ‐QW + Pred‐26, 49 received TCZ‐Q2W + Pred‐26, 50 received PBO + Pred‐26, and 51 received PBO + Pred‐52. Of the 149 TCZ‐treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dosage 2.0 mg/day). Among 101 PBO + Pred–treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dosage 5.0 mg/day). Many flares occurred while patients were taking >10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22%) in the placebo groups. Thirty‐three flares (92%) in TCZ‐treated groups and 20 (34%) in PBO + Pred–treated groups occurred with normal CRP levels. More than half of the PBO + Pred–treated patients had elevated CRP levels without flares. Benefits of the TCZ and prednisone combination over prednisone alone for remission induction were apparent by 8 weeks. Conclusion: Most GCA flares occurred while patients were still receiving prednisone. Acute‐phase reactant levels were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control. [ABSTRACT FROM AUTHOR]

The free-energy landscape of interaction between a medium-sized peptide, endothelin 1 (ET1), and its receptor, human endothelin type B receptor (hETB), was computed using multidimensional virtual-system coupled molecular dynamics, which controls the system's motions by introducing multiple reaction coordinates. The hETB embedded in lipid bilayer was immersed in explicit solvent. All molecules were expressed as all-atom models. The resultant free-energy landscape had five ranges with decreasing ET1–hETB distance: completely dissociative, outside-gate, gate, binding pocket, and genuine-bound ranges. In the completely dissociative range, no ET1–hETB interaction appeared. In the outside-gate range, an ET1–hETB attractive interaction was the fly-casting mechanism. In the gate range, the ET1 orientational variety decreased rapidly. In the binding pocket range, ET1 was in a narrow pathway with a steep free-energy slope. In the genuine-bound range, ET1 was in a stable free-energy basin. A G-protein-coupled receptor (GPCR) might capture its ligand from a distant place. [ABSTRACT FROM AUTHOR]

We have reported the existence of a distinct neutrophil phenotype in giant cell arteritis (GCA) patients arising at week 24 of steroid treatment. In the present study, we investigated whether longitudinal analysis of neutrophil phenotype in patients with polymyalgia rheumatica (PMR) could reveal a novel association with disease status and immune cell cross-talk. Thus, we monitored PMR patient neutrophil phenotype and plasma microvesicle (MV) profiles in blood aliquots collected pre-steroid, and then at weeks 1, 4, 12 and 24 post-steroid treatment. Using flow cytometric and flow chamber analyses, we identified 12-week post-steroid as a pivotal time-point for a marked degree of neutrophil activation, correlating with disease activity. Analyses of plasmaMVs indicated elevated AnxA1+ neutrophil-derived vesicles which, in vitro, modulated T-cell reactivity, suggesting distinct neutrophil phenotypic and cross-talk changes at 24 weeks, but not at 12-week post-steroid. Together, these data indicate a clear distinction from GCA patient neutrophil and MV signatures, and provide an opportunity for further investigations on how to 'stratify' PMR patients and monitor their clinical responses through novel use of blood biomarkers. [ABSTRACT FROM AUTHOR]

GCA shares many clinical features with PMR and Takayasu arteritis. The current mainstay of therapy for all three conditions is glucocorticoid therapy. Given the chronic, relapsing nature of these conditions and the morbidity associated with glucocorticoid therapy, there is a need for better treatment options to induce and sustain remission with fewer adverse effects. Conventional immunosuppressive treatments have been studied and have a modest effect. There is a keen interest in biologic therapies with studies showing the efficacy of IL-6 antagonists in PMR and GCA. Recently the first two randomized clinical trials in Takayasu arteritis have been completed. A major challenge for all of these conditions is the lack of standardized measures to assess disease activity. Long-term studies are needed to evaluate the impact of biologic therapies showing potential on important clinical outcomes such as vascular damage, cost-effectiveness and quality of life. The optimal duration of treatment also needs to be assessed. [ABSTRACT FROM AUTHOR]

To develop evidence-based recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV) including giant cell arteritis (GCA) and Takayasu arteritis (TAK). European League Against Rheumatism (EULAR) standardised operating procedures were followed. A systematic literature review was conducted to retrieve data on the role of imaging modalities including ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (PET) in LVV. Based on evidence and expert opinion, the task force consisting of 20 physicians, healthcare professionals and patients from 10 EULAR countries developed recommendations, with consensus obtained through voting. The final level of agreement was voted anonymously. A total of 12 recommendations have been formulated. The task force recommends an early imaging test in patients with suspected LVV, with ultrasound and MRI being the first choices in GCA and TAK, respectively. CT or PET may be used alternatively. In case the diagnosis is still in question after clinical examination and imaging, additional investigations including temporal artery biopsy and/or additional imaging are required. In patients with a suspected flare, imaging might help to better assess disease activity. The frequency and choice of imaging modalities for long-term monitoring of structural damage remains an individual decision; close monitoring for aortic aneurysms should be conducted in patients at risk for this complication. All imaging should be performed by a trained specialist using appropriate operational procedures and settings. These are the first EULAR recommendations providing up-to-date guidance for the role of imaging in the diagnosis and monitoring of patients with (suspected) LVV. [ABSTRACT FROM AUTHOR]

Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit-risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) remains a medical emergency due to the threat of permanent sight loss. High-dose glucocorticoids (GCs) are effective in inducing remission in the majority of patients, however, relapses are common which lengthen GC therapy. GC toxicity remains a major morbidity in this group of patients, and conventional steroid-sparing therapies have not yet shown enough of a clinical benefit to change the standard of care. As the understanding of the underlying immunopathophysiology of GCA has increased, positive clinical observations have been made with the use of IL-6 receptor inhibitor therapies, such as tocilizumab (TCZ). This has led to prospective randomized control trials that have highlighted the safety and efficacy of TCZ in both new-onset and relapsing GCA. [ABSTRACT FROM AUTHOR]

Abstract: Objective: A feasibility study to assess efficacy and safety of modified release (MR) prednisone (Lodotra™) compared to immediate release (IR) prednisolone in patients with newly diagnosed giant cell arteritis (GCA). Methods: Twelve patients with new diagnosis of GCA were initially treated with high‐dose prednisolone (40–60 mg) daily for 4 weeks and then randomized to two open arms to continue tapering steroid treatment with either standard IR prednisolone or MR prednisone. Patients were reviewed every 2 weeks either face to face or by telephone, for a total of 26 weeks. Disease activity, steroid‐related side effects, sleep disturbance, fatigue scores and blood tests were systematically monitored. The primary endpoint (efficacy) was defined as the proportion of patients achieving persistent clinical disease control (without features of active disease and remaining flare free at 26 weeks) in each arm. Results: At 26 weeks, 6/7 patients taking MR prednisone were in persistent control, compared with 4/5 receiving IR prednisone. One patient in each group suffered a disease flare necessitating an increased steroid dose. There were no statistically significant differences between the groups in terms of reduction in inflammatory markers, Health Assessment Questionnaire, visual analogue scale, fatigue and improvement in EuroQol 5D scores. Conclusion: This trial shows that MR prednisone appears to be a safe and effective treatment for GCA with a similar outcome profile to standard IR prednisolone. [ABSTRACT FROM AUTHOR]

Introduction Acute gout occurs in people with chronic kidney disease, who are commonly older people with comorbidities such as hypertension, heart disease and diabetes. Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence. Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease. This paper describes the protocol for a feasibility randomised controlled trial (RCT) comparing anakinra, a novel interleukin-1 antagonist versus steroids in people with chronic kidney disease (ASGARD). Methods and analysis ASGARD is a two-parallel group double-blind, double-dummy multicentre RCT comparing anakinra 100 mg, an interleukin-1 antagonist, subcutaneous for 5 days against intramuscular methylprednisolone 120 mg. The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT. The specific aims are: (1) test recruitment and retention rates and willingness to be randomised; (2) test eligibility criteria; (3) collect and analyse outcome data to inform sample and power calculations for a trial of efficacy; (4) collect economic data to inform a future economic evaluation estimating costs of treatment and (5) assess capacity of the project to scale up to a national multicentre trial. We will also gather qualitative insights from participants. It aims to recruit 32 patients with a 1:1 randomisation. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies. Ethics and dissemination The London-Central Ethics Committee approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences. Trial registration number EudraCT No. 2015-001787-19, NCT/Clinicalstrials.gov No. NCT02578394, pre-results, WHO Universal Trials Reference No. U1111-1175-1977. NIHR Grant PB-PG-0614-34090. [ABSTRACT FROM AUTHOR]

GCA and PMR are conditions of older persons that frequently overlap. The traditional concept of GCA has focused on cranial symptoms such as headache and visual disturbance, but extra-cranial manifestations such as constitutional symptoms, polymyalgia and limb claudication have also long been recognized. These symptoms may coincide with cranial GCA, occur as an independent clinical subset [large-vessel (LV) GCA] or overlap with PMR. Imaging studies have demonstrated that up to one-third of patients with PMR have subclinical LV inflammation at disease outset. The implication of this finding for PMR management is unclear. Pathophysiological studies have emphasized the pivotal role of dendritic cells (DCs) and T cells in the pathogenesis of GCA, and the activation of certain pattern recognition receptors on DCs may determine the clinical subset of GCA. In patients with only PMR clinically, it is conceivable that transmural arterial inflammation has either not yet started or is prevented by unexplored regulatory pathways. This concept is supported by vasculitis of peri-adventitial small-vessels and activated DCs in the adventitia of temporal arteries, in the absence of media-infiltrating T cells. This review examines the clinical and pathophysiological spectrum of GCA and its subsets with PMR, the role of newer imaging techniques for GCA diagnosis and the management of these diseases. [ABSTRACT FROM AUTHOR]

The article discusses updates on giant cell arteritis (GCA) treatment and management. Topics explored include the approval of tocilizumab (TCZ) by the British National Institute for Health and Care Excellence (NICE) and National Health Service (NHS) England for treating patients with GCA, the clinical guidelines for GCA diagnosis, and the challenges associated with disease activity assessment during therapeutic administration of TCZ.

Objective. To create a tool to predict probability of remission and low disease activity (LDA) in patients with RA being considered for anti-TNF treatment in clinical practice. Methods. We analysed data from GO-MORE, an open-label, multinational, prospective study in biologic naïve patients with active RA (DAS28-ESR ≥3.2) despite DMARD therapy. Patients received 50 mg s.c. golimumab (GLM) once monthly for 6 months. In secondary analyses, regression models were used to determine the best set of baseline factors to predict remission (DAS28-ESR<2.6) at month 6 and LDA (DAS28-ESR ≤3.2) at month 1. Results. In 3280 efficacy-evaluable patients, of 12 factors included in initial regression models predicting remission or LDA, six were retained in final multivariable models. Greater likelihood of LDA and remission was associated with being male; younger age; lower HAQ, ESR (or CRP) and tender joint count (or swollen joint count) scores; and absence of comorbidities. In models predicting 1-, 3- and 6-month LDA or remission, area under the receiver operating curve was 0.648-0.809 (R²=0.0397-0.1078). The models also predicted 6-month HAQ and EuroQoL-5-dimension scores. A series of matrices were developed to easily show predicted rates of remission and LDA. Conclusion. A matrix tool was developed to show predicted GLM treatment outcomes in patients with RA, based on a combination of six baseline characteristics. The tool could help provide practical guidance in selection of candidates for anti-TNF therapy. [ABSTRACT FROM AUTHOR]