Giant Cell Arteritis (GCA): An international, multicentre, longitudinal evaluation of clinical, laboratory and ultrasound parameters in the diagnosis, prognosis and monitoring of GCA.

Background: Giant cell arteritis (GCA) is a vasculitis, varies in extent, severity and outcomes, hence requires disease stratification for targeted management. Ultrasound (US) non-compressible halo is currently categorised in a dichotomous pattern. We developed a US scoring system to quantify the extent of vascular inflammation and investigated its diagnostic accuracy and association with clinical factors in GCA. Methods: HAS GCA is a prospective study recruited from 7 European GCA fast-track clinics. Southend probability score (GCAPS) risk-stratified patients into 3 categories. Temporal and axillary US Halo Scores (HS) were calculated from the halo thickness and extent in bilateral temporal arteries, parietal and frontal branches (TAHS) and axillary arteries (AAHS). These scores were summed to generate a Total Halo Score (THS). GCA patients had US at baseline,1,3,6,12 months. Primary outcome was remission at 12 months (prednisolone ≤ 5mg). Results: 229 participants (84 GCA) were included: 73 completed follow-ups, 11 lost to follow-up and 65 achieved remissions (figure). GCA median age was 75 years. GCAPS stratified GCA and controls to Low risk (0% vs 46%; Sn-undefined, Sp-99), Intermediate risk (21% vs 38%; Sn-83, Sp-98) and High risk (79% vs 16%; Sn-99, Sp-91). The optimal GCAPS cut-off point was ≥12 (Sn-89, Sp-78). Median THS was 21.5 in GCA and 8 in controls. Optimal cut-off Halo Score in diagnosis was TAHS ≥6 (Sn-86, Sp-92), AAHS ≥11 (Sn-52, Sp-75), THS ≥17 (Sn-76%, Sp-91%). At 12 months, median TAHS, AAHS and THS reduced from 13 to 3, 12 to 9 and 21.5 to 12, respectively. Conclusion: Along with GCAPS, Halo Score successfully discriminates GCA from non-GCA. Extent of arterial inflammation in GCA can be quantified by ultrasound halo scoring

ROSSi a graphical programming interface for ROS 2

The Robot Operating System (ROS) offers developers a large number of ready-made packages for developing robot programs. The multitude of packages and the different interfaces or adapters is also the reason why ROS projects often tend to become confusing. Concepts of model-driven software development using a domain-specific modeling language could counteract this and at the same time speed up the development process of such projects. This is investigated in this paper by transferring the core concepts from ROS 2 into a graphical programming interface. Elements of established graphical programming tools are compared and approaches from modeling languages such as UML are used to create a novel approach for graphical development of ROS projects. The resulting interface is evaluated through the development of a project built on ROS, and the approach shows promise towards facilitating work with the Robot Operating System

In Situ X-Ray Diffraction Analysis of Microstructure Evolution during Deep Cryogenic Treatment and Tempering of Tool Steels

Deep cryogenic treatment of tool steels, incorporated in conventional hardening and tempering, has been a topic of intensive research in recent years. Yet, the governing microstructural mechanisms involved in the deep cryogenic treatment of high-alloyed tool steels are still controversial. Thus, an in situ X-ray diffraction study is conducted on three tool steels X38CrMoV5-3, X153CrMoV12, and ~X190CrVMo20-4 to shed light on microstructural evolution during cryogenic treatment and subsequent tempering. For these high-alloyed tool steels, the transformation of retained austenite into martensite is detected during the cooling phase of the cryogenic treatment. A change in tetragonality of martensite occurs mainly in the heating phase of the subsequent tempering process, which indicates the diffusion of carbon and carbide precipitation from the martensite. The microstructure evolution of the tool steels after hardening, cryogenic treatment, and tempering is further examined by scanning electron microscopy. © 2021 The Authors. Steel Research International published by Wiley-VCH Gmb

Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry

Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Herein, we pioneered the first application of dynamic combinatorial chemistry (DCC) to a PPI target, to find modulators of 14-3-3 proteins. Evaluation of the amplified hits from the DCC experiments for their binding affinity via surface plasmon resonance (SPR), revealed that the low-micromolar (KD 15-16 μM) acylhydrazones are 14-3-3/synaptopodin PPI stabilizers. Thus, DCC appears to be ideally suited for the discovery of not only modulators but even the more elusive stabilizers of notoriously challenging PPIs

Efficacy and safety of tocilizumab in giant cell arteritis:a single centre NHS experience using imaging (ultrasound and PET-CT) as a diagnostic and monitoring tool

Tocilizumab (TCZ), an IL-6 receptor blocker, is approved for relapsing, refractory giant cell arteritis (GCA). We report real-life clinical experience with TCZ in GCA including assessment of responses on imaging (ultrasound (US) and 18F-Fluorodeoxyglucose Positron Emission Tomography-computed Tomography ((18)FDG-PET-CT)) during the first year of treatment. We included 22 consecutive patients with GCA treated with TCZ where EULAR core data set on disease activity, quality of life (QoL) and treatment-related complications were collected. Pre-TCZ US and (18)FDG-PET/CT findings were available for 21 and 4 patients, respectively, where we determined the effect on US halo thickness, temporal and axillary artery Southend Halo Score and Total Vascular Score on (18)FDG-PET-CT. The 22 patients with GCA (10 cranial, 10 large vessel, 2 both) had a median disease duration of 58.5 (range, 1-370) weeks prior to initiation of TCZ. Half had used prior conventional synthetic disease-modifying antirheumatic drug (csDMARDs). TCZ was initiated for refractory (50%), ischaemic (36%) or relapsing (14%) disease. Median follow-up was 43 (12-52) weeks. TCZ was discontinued due to serious adverse events (SAEs) in two patients. On treatment with TCZ, 4 discontinued prednisolone, 11 required doses = 5 mg daily. QoL improved by 50%. Total US halo thickness decreased in 38 arterial segments, median temporal artery Halo Score decreased from 11 to 0, axillary artery Halo Score remained stable. Median Total Vascular Score on FDG-PET/CT reduced from 11.5 to 6.5. In our experience, TCZ showed an excellent response with acceptable safety in GCA, with improvement on US and FDG-PET/CT imaging

Disease stratification in giant cell arteritis to reduce relapses and prevent long-term vascular damage

For years, clinicians and researchers working on giant cell arteritis have been battling with the conundrum of a disease that displays a short-term steroid responsiveness but is burdened by a remarkable risk of flares and chronic damage in the long term. This issue should be addressed by a change in the direction of research and clinical practice. Evidence suggests that giant cell arteritis is not a monolithic disease; it varies in extent and severity. Hence, treatment should be guided by disease stratification. The current one-size-fits-all strategy leads to overreliance on glucocorticoids and progression of glucocorticoid-related and disease-related complications. A new approach requires disease stratification using clinical, laboratory, histology, and imaging parameters. A giant cell arteritis registry might offer opportunities to scrutinise disease course and prognostic variables early; however, more studies that directly incorporate disease stratification through the above parameters are required. This Series paper also suggests that future clinical trials should be targeted at patients with different disease strata of giant cell arteritis and should incorporate ultrasound, PET-CT scanning, and other imaging modalities as key outcomes

Halo score (temporal artery, its branches and axillary artery) as a diagnostic, prognostic and disease monitoring tool for Giant Cell Arteritis (GCA)

Background Giant cell arteritis (GCA) is a common large vessel vasculitis of the elderly, often associated with sight loss. Glucocorticoids (GC remain the mainstay of treatment, although biologic treatments have been approved. Biomarkers predicting disease severity, relapse rates and damage are lacking in GCA. EULAR recommends ultrasound (US) as the first investigation for suspected GCA. The cardinal US finding, a non-compressible halo, is currently categorised as either negative or positive. However, the extent and severity of this finding may vary. In this study, we hypothesise whether the extent and severity of the halo sign [calculated as a single composite Halo score (HS)] of temporal and axillary arteries may be of diagnostic, prognostic and monitoring importance; whether baseline HS is linked to disease outcomes, relapses and damage; whether HS can stratify GCA patients for individual treatment needs; whether HS can function as an objective monitoring tool during follow up. Methods This is a prospective, observational study. Suspected GCA Participants will be selected from the GCA FTC at the participating centres in the UK. Informed consent will be obtained, and patients managed as part of standard care. Patients with GCA will have HS (temporal and axillary arteries) measured at baseline and months 1,3,6 and 12 long with routine clinical assessments, blood sampling and patient-reported outcomes (EQ5D). Non-GCA patients will be discharged back to the referral team and will have a telephone interview in 6 months. We aim to recruit 272 suspected GCA referrals which should yield 68 patients (25% of referrals) with confirmed GCA. The recruitment will be completed in 1 year with an estimated total study period of 24 months. Discussion The identification of prognostic factors in GCA is both timely and needed. A prognostic marker, such as the HS, could help to stratify GCA patients for an appropriate treatment regimen. Tocilizumab, an IL-6R blocking agent, switches off the acute phase response (C-Reactive Protein), making it difficult to measure the disease activity. Therefore, an independent HS, and changes in that score during treatment and follow-up, maybe a more objective measure of response compare to patient-reported symptoms and clinical assessment alone

Ultrasonographic Halo Score in giant cell arteritis:association with intimal hyperplasia and ischaemic sight loss

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

Role of the halo sign in the assessment of giant cell arteritis: a systematic review and meta-analysis

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

Goal-Directed Fluid Therapy Using Stroke Volume Variation Does Not Result in Pulmonary Fluid Overload in Thoracic Surgery Requiring One-Lung Ventilation

Background. Goal-directed fluid therapy (GDT) guided by functional parameters of preload, such as stroke volume variation (SVV), seems to optimize hemodynamics and possibly improves clinical outcome. However, this strategy is believed to be rather fluid aggressive, and, furthermore, during surgery requiring thoracotomy, the ability of SVV to predict volume responsiveness has raised some controversy. So far it is not known whether GDT is associated with pulmonary fluid overload and a deleterious reduction in pulmonary function in thoracic surgery requiring one-lung-ventilation (OLV). Therefore, we assessed the perioperative course of extravascular lung water index (EVLWI) and p a O 2 /F i O 2 -ratio during and after thoracic surgery requiring lateral thoracotomy and OLV to evaluate the hypothesis that fluid therapy guided by SVV results in pulmonary fluid overload. Methods. A total of 27 patients (group T) were enrolled in this prospective study with 11 patients undergoing lung surgery (group L) and 16 patients undergoing esophagectomy (group E). Goal-directed fluid management was guided by SVV (SVV < 10%). Measurements were performed directly after induction of anesthesia (baseline-BL), 15 minutes after implementation OLV (OLVimpl15), and 15 minutes after termination of OLV (OLVterm15). In addition, postoperative measurements were performed at 6 (6postop), 12 (12postop), and 24 (24postop) hours after surgery. EVLWI was measured at all predefined steps. The p a O 2 /F i O 2 -ratio was determined at each point during mechanical ventilation (group L: BL-OLVterm15; group E: BL-24postop). Results. In all patients (group T), there was no significant change (P > 0.05) in EVLWI during the observation period (BL: 7.8 ± 2.5, 24postop: 8.1 ± 2.4 mL/kg). A subgroup analysis for group L and group E also did not reveal significant changes of EVLWI. The p a O 2 /F i O 2 -ratio decreased significantly during the observation period (group L: BL: 462 ± 140, OLVterm15: 338 ± 112 mmHg; group E: BL: 389 ± 101, 24postop: 303 ± 74 mmHg) but remained >300 mmHg except during OLV. Conclusions. SVV-guided fluid management in thoracic surgery requiring lateral thoracotomy and one-lung ventilation does not result in pulmonary fluid overload. Although oxygenation was reduced, pulmonary function remained within a clinically acceptable range