Real-world experience of IL-17Ai drug survival in a large cohort of axial spondyloarthritis and psoriatic arthritis.

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.

Does the halo count on temporal and axillary ultrasound predict time to relapse in giant cell arteritis?

OBJECTIVES: To determine whether the halo count (HC) on temporal and axillary artery US (TAUS) predicts time to relapse in giant cell arteritis (GCA). METHODS: We conducted a single-centre retrospective study of GCA patients. HC, the number of vessels with non-compressible halo on the TAUS at diagnosis, was determined by retrospective review of the US report and images. Relapse was defined as increase in GCA disease activity requiring treatment escalation. Cox proportional hazard regression was used to identify predictors of time to relapse. RESULTS: A total of 72 patients with confirmed GCA were followed up for a median of 20.9 months. Thirty-seven of 72 (51.4%) relapsed during follow-up, at a median prednisolone dose of 9 mg (range 0-40 mg). Large-vessel (axillary artery) involvement did not predict relapse. On univariable analysis, a higher HC was associated with shorter time to relapse (per-halo hazard ratio 1.15, 95% CI 1.02, 1.30; P = 0.028). However, statistical significance was lost when the 10 GCA patients with an HC of zero were excluded from analysis. CONCLUSION: In this real-world setting, relapse occurred at a wide range of glucocorticoid doses and was not predicted by axillary artery involvement. GCA patients with a higher HC at diagnosis were significantly more likely to relapse, but significance was lost on excluding those with HC of zero. HC is feasible in routine care and may be worth incorporating into future prognostic scores. Further research is required to determine whether confirmed GCA patients with negative TAUS represent a qualitatively different subphenotype within the GCA disease spectrum.

Temporally and Spatially Resolved Reflected Overpressure Measurements in the Extreme Near Field.

The design of blast-resistant structures and protective systems requires a firm understanding of the loadings imparted to structures by blast waves. While empirical methods can reliably predict these loadings in the far field, there is currently a lack of understanding on the pressures experienced in the very near field, where physics-based numerical modelling and semi-empirical fast-running engineering model predictions can vary by an order of magnitude. In this paper, we present the design of an experimental facility capable of providing definitive spatially and temporally resolved reflected pressure data in the extreme near field (Z<0.5 m/kg1/3). The Mechanisms and Characterisation of Explosions (MaCE) facility is a specific near-field evolution of the existing Characterisation of Blast Loading (CoBL) facility, which uses an array of Hopkinson pressure bars embedded in a stiff target plate. Maraging steel pressure bars and specially designed strain gauges are used to increase the measurement capacity from 600 MPa to 1800 MPa, and 33 pressure bars in a radial grid are used to improve the spatial resolution from 25 mm to 12.5 mm over the 100 mm radius measurement area. In addition, the pressure bar diameter is reduced from 10 mm to 4 mm, which greatly reduces stress wave dispersion, increasing the effective bandwidth. This enables the observation of high-frequency features in the pressure measurements, which is vital for validating the near-field transient effects predicted by numerical modelling and developing effective blast mitigation methods.

High-Speed Infrared Radiation Thermometer for the Investigation of Early Stage Explosive Development and Fireball Expansion.

The understanding of blast loads is critical for the development of infrastructure that protects against explosions. However, the lack of high-quality experimental work on the characterisation of such loads prevents a better understanding of many scenarios. Blast loads are typically characterised by use of some form of pressure gauge, from which the temperature can be inferred from a pressure measurement. However, such an approach to temperature measurement is limited; it assumes ideal gas laws apply throughout, which may not be the case for high temperature and pressure scenarios. In contrast, infrared radiation thermometers (IRTs) perform a measurement of temperature based upon the emitted radiance from the target object. The IRTs can measure fast changes in transient temperature, making them seemingly ideal for the measurement of a fireball's temperature. In this work, we present the use of a high-speed IRT for the measurement of early-stage explosive development and fireball expansion within a confined blast, with the temperature of the explosive fireball measured from its emitted radiance. The temperature measured by the IRT was corroborated against the temperature inferred from a pressure gauge measurement; both instruments measured the same temperature from the quasi-static pressure (QSP) point onwards. Before the QSP point, it is deduced that the IRT measures the average temperature of the fireball over a wide field-of-view (FOV), as opposed to that inferred from the singular shocks detected by the pressure gauge. Therefore, use of an IRT, in tandem with a pressure gauge, provides a potential invaluable measurement technique for the characterisation the early stages of a fireball as it develops and expands.

Co-infection in critically ill patients with COVID-19: an observational cohort study from England.

Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus.Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship.Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England.Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at <48 and >48 h following hospital admission, corresponding to community and hospital-acquired co-infections.Results. Of 254 patients studied (median age 59 years (IQR 49-69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli. The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3-34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03-3.08, P=0.04) compared to those without co-infections/ co-colonisation.Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay.

Single-cell multi-omics analysis of the immune response in COVID-19.

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.

COVID-19 Management in a UK NHS Foundation Trust with a High Consequence Infectious Diseases Centre: A Retrospective Analysis.

Recent large national and international cohorts describe the baseline characteristics and outcome of hospitalised patients with COVID-19, however there is limited granularity to these reports. We aimed to provide a detailed description of a UK COVID-19 cohort, focusing on management and outcome. We performed a retrospective single-centre analysis of clinical management and 28-day outcomes of consecutive adult inpatients with SARS-CoV-2 PCR-confirmed COVID-19 from 31 January to 16 April 2020 inclusive. In total, 316 cases were identified. Most patients were elderly (median age 75) with multiple comorbidities. One quarter were admitted from residential or nursing care. Mortality was 84 out of 316 (26.6%). Most deaths occurred in patients in whom a ceiling of inpatient treatment had been determined and for whom end of life care and specialist palliative care input was provided where appropriate. No deaths occurred in patients aged under 56 years. Decisions to initiate respiratory support were individualised after consideration of patient wishes, premorbid frailty and comorbidities. In total, 59 (18%) patients were admitted to intensive care, of which 31 (10% overall cohort) required intubation. Multiple logistic regression identified associations between death and age, frailty, and disease severity, with age as the most significant factor (odds ratio 1.07 [95% CI 1.03-1.10] per year increase, p < 0.001). These findings provide important clinical context to outcome data. Mortality was associated with increasing age. Most deaths were anticipated and occurred in patients with advance decisions on ceilings of treatment.

Characterisation of buried blast loading.

While it is well known that detonation of shallow-buried high explosive charges generally results in above-surface loading which is greatly amplified compared with the same detonation in air, uncertainty persists as to the mechanisms leading to this effect. The work presented in this paper is a systematic investigation into the mechanisms of load transfer in buried blast events. This paper details the results from a parametric study into the mechanisms and magnitudes of load transfer following a shallow-buried explosion, where spatial and temporal load distributions are directly measured on a rigid surface using an array of Hopkinson pressure bars. In particular, the investigation has looked at the influence of both geometrical confinement and geotechnical conditions on the loading. The parametric study was separated into four main threads: the influence of physical confinement; gravimetric moisture content; stand-off distance and depth of burial; and soil material/particle size distribution. This study allows a direct observation of the contributions of each of these distinct parameters, and in particular the ability to discern how each parameter influences the temporal form and spatial distribution of the loading.

Initiating factors for the onset of OA: A systematic review of animal bone and cartilage pathology in OA.

There is controversy over whether bone or cartilage is primarily involved in osteoarthritis (OA) pathogenesis; this is important for targeting early interventions. We explored evidence from animal models of knee OA by preforming a systematic review of PubMed, Scopus, and Web of Science for original articles reporting subchondral bone and cartilage pathology in animal models with epiphyseal closure. Extracted data included: method of induction; animal model; cartilage and bone assessment and method; meniscal assessment; skeletal maturity; controls; and time points assessed. Quality scoring was performed. The best evidence was synthesized from high-quality skeletally mature models, without direct trauma to tissues of interest and with multiple time points. Altogether, 2849 abstracts were reviewed. Forty-seven papers were included reporting eight different methods of inducing OA, six different species, six different methods of assessing cartilage, five different bone structural parameters, and four assessed meniscus as a potential initiator. Overall, the simultaneous onset of OA in cartilage and bone was reported in 82% of datasets, 16% reported bone onset, and 2% reported cartilage onset. No dataset containing meniscal data reported meniscal onset. However, using the best evidence synthesis (n = 8), five reported simultaneous onset when OA was induced, while three reported bone onset when OA occurred spontaneously; none reported cartilage onset. In summary, there is a paucity of well-designed studies in this area which makes the conclusions drawn conjectures rather than proven certainties. However, within the limitation of data quality, this review suggests that in animal models, the structural onset of knee OA occurs either in bone prior to cartilage pathology or simultaneously.

Utility of Magnetic Resonance Imaging in Diagnosis and Monitoring Enthesitis in Patients with Spondyloarthritis: An OMERACT Systematic Literature Review.

OBJECTIVE: A systematic literature review was performed to document published magnetic resonance imaging (MRI) lesion definitions and scoring systems for enthesitis in spondyloarthritis (SpA). METHODS: PubMed, Embase, and Cochrane Library databases were searched for original publications involving adult patients with SpA undergoing MRI of axial/peripheral joints. Selected articles were assessed for quality using a standardized assessment tool and metric indices. RESULTS: Considering the heterogeneous design, quality, and outcome measures of studies, statistical data pooling was considered inappropriate. A qualitative narrative of results was undertaken based on study designs. CONCLUSION: Lack of a comprehensive, validated score warrants additional research to develop an MRI enthesitis scoring system. PROSPERO registration number: CRD42018090537.

What Imaging-Detected Pathologies Are Associated With Shoulder Symptoms and Their Persistence? A Systematic Literature Review.

OBJECTIVE: Shoulder symptoms are common, and imaging is being increasingly used to help with management. However, the relationship between imaging and symptoms remains unclear. This review aims to understand the relationship between imaging-detected pathologies, symptoms, and their persistence. METHODS: A systematic review using Medline, EMBASE, Cochrane, and grey literature was conducted to April 2017. The cross-sectional and longitudinal relationships between imaging-detected abnormalities and symptoms were analyzed and associations qualitatively characterized by a best-evidence synthesis based on study design, covariate adjustment, and the Grade of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Modalities included ultrasound, magnetic resonance imaging (MRI), radiographs, positron emission tomography (PET), bone scintigraphy, and computed tomography. RESULTS: A total of 6,569 abstracts was screened and 56 articles were included. In total, 50 studies did not adjust for covariates and 36 analyzed individual pathologies only. The majority of studies showed conflicting results. There was no significant association between most imaging features and symptoms among high-quality, cross-sectional studies. There was low-quality evidence that enhancement of the joint capsule on MRI and increased uptake on PET were associated with symptoms in adhesive capsulitis. Based on high-quality longitudinal studies, enlarging rotator cuff tears were associated with an increased incidence of symptoms. CONCLUSION: There were conflicting results on the association of imaging features with shoulder symptoms and their persistence. The existing evidence was very low in quality, based on the GRADE methodology. Further high-quality studies are required to understand the relationship between imaging and shoulder symptoms and to determine the appropriate role of imaging in care pathways.

High-resolution SOFIA/EXES Spectroscopy of SO2 Gas in the Massive Young Stellar Object MonR2 IRS3: Implications for the Sulfur Budget.

Sulfur has been observed to be severely depleted in dense clouds leading to uncertainty in the molecules that contain it and the chemistry behind their evolution. Here, we aim to shed light on the sulfur chemistry in young stellar objects (YSOs) by using high-resolution infrared spectroscopy of absorption by the ν 3 rovibrational band of SO2 obtained with the Echelon-Cross-Echelle Spectrograph on the Stratospheric Observatory for Infrared Astronomy. Using local thermodynamic equilibrium models we derive physical parameters for the SO2 gas in the massive YSO MonR2 IRS3. This yields a SO2/H abundance lower limit of 5.6 ± 0.5 × 10-7, or >4% of the cosmic sulfur budget, and an intrinsic line width (Doppler parameter) of b < 3.20 km s-1. The small line widths and high temperature (T ex = 234 ± 15 K) locate the gas in a relatively quiescent region near the YSO, presumably in the hot core where ices have evaporated. This sublimation unlocks a volatile sulfur reservoir (e.g., sulfur allotropes as detected abundantly in comet 67P/Churyumov-Gerasimenko), which is followed by SO2 formation by warm, dense gas-phase chemistry. The narrowness of the lines makes formation of SO2 from sulfur sputtered off grains in shocks less likely toward MonR2 IRS3.

The Relationship Between Synovial Pathobiology and Magnetic Resonance Imaging Abnormalities in Rheumatoid Arthritis: A Systematic Review.

OBJECTIVE: Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool for the assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis, bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understanding the exact relationship between each MRI feature and local synovial pathobiology is critical to dissect disease pathogenesis as well as develop future predictive models. METHODS: A systematic review was performed of the current published literature examining the relationship between MRI abnormalities and synovial pathobiology in patients with RA. RESULTS: Eighteen studies were identified; most focused on validation of MRI as a tool to detect and quantify synovitis, with a significant relationship demonstrated. Additionally, from the limited data available, a critical role seems likely for synovial pathways, at least in driving joint damage. However, there was a lack of data examining the relationship between synovial pathobiology and bone marrow abnormalities and JSN. CONCLUSION: Although understanding the interrelationship of these disease biomarkers offers the potential to enhance the predictive validity of modern imaging with concomitant synovial pathobiological analysis, further studies integrating MRI with synovial tissue analysis in well-controlled cohorts at distinct disease stages before and after therapeutic intervention are required to achieve this.

Osteoarthritis.

Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.

The relationship between three-dimensional knee MRI bone shape and total knee replacement-a case control study: data from the Osteoarthritis Initiative.

OBJECTIVE: There is growing understanding of the importance of bone in OA. Our aim was to determine the relationship between 3D MRI bone shape and total knee replacement (TKR). METHODS: A nested case-control study within the Osteoarthritis Initiative cohort identified case knees with confirmed TKR for OA and controls that were matched using propensity scores. Active appearance modelling quantification of the bone shape of all knee bones identified vectors between knees having or not having OA. Vectors were scaled such that -1 and +1 represented the mean non-OA and mean OA shapes. RESULTS: Compared to controls (n = 310), TKR cases (n = 310) had a more positive mean baseline 3D bone shape vector, indicating more advanced structural OA, for the femur [mean 0.98 vs -0.11; difference (95% CI) 1.10 (0.88, 1.31)], tibia [mean 0.86 vs -0.07; difference (95% CI) 0.94 (0.72, 1.16)] and patella [mean 0.95 vs 0.03; difference (95% CI) 0.92 (0.65, 1.20)]. Odds ratios (95% CI) for TKR per normalized unit of 3D bone shape vector for the femur, tibia and patella were: 1.85 (1.59, 2.16), 1.64 (1.42, 1.89) and 1.36 (1.22, 1.50), respectively, all P < 0.001. After including Kellgren-Lawrence grade in a multivariable analysis, only the femur 3D shape vector remained significantly associated with TKR [odds ratio 1.24 (1.02, 1.51)]. CONCLUSION: 3D bone shape was associated with the endpoint of this study, TKR, with femoral shape being most associated. This study contributes to the validation of quantitative MRI bone biomarkers for OA structure-modification trials.

A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis.

INTRODUCTION: Bone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA. METHODS: A search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring. RESULTS: In total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively. CONCLUSION: Subchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target. SYSTEMATIC REVIEW: PROSPERO registration number: CRD 42013005009.