The immune cell landscape in kidneys of patients with lupus nephritis.

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies

Development of a Prediction Model for COVID-19 Acute Respiratory Distress Syndrome in Patients With Rheumatic Diseases: Results From the Global Rheumatology Alliance Registry

OBJECTIVE: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. METHODS: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. RESULTS: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. CONCLUSION: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people

A search for an unexpected asymmetry in the production of e+μ− and e−μ+ pairs in proton-proton collisions recorded by the ATLAS detector at root s = 13 TeV

This search, a type not previously performed at ATLAS, uses a comparison of the production cross sections for e(+)mu(-) and e(-)mu(+) pairs to constrain physics processes beyond the Standard Model. It uses 139 fb(-1) of proton-proton collision data recorded at root s = 13 TeV at the LHC. Targeting sources of new physics which prefer final states containing e(+)mu(-) and e(-)mu(+), the search contains two broad signal regions which are used to provide model-independent constraints on the ratio of cross sections at the 2% level. The search also has two special selections targeting supersymmetric models and leptoquark signatures. Observations using one of these selections are able to exclude, at 95% confidence level, singly produced smuons with masses up to 640 GeV in a model in which the only other light sparticle is a neutralino when the R-parity-violating coupling lambda(23)(1)' is close to unity. Observations using the other selection exclude scalar leptoquarks with masses below 1880 GeV when g(1R)(eu) = g(1R)(mu c) = 1, at 95% confidence level. The limit on the coupling reduces to g(1R)(eu) = g(1R)(mu c) = 0.46 for a mass of 1420 GeV

Measurement of the nuclear modification factor for muons from charm and bottom hadrons in Pb+Pb collisions at 5.02 TeV with the ATLAS detector

Heavy-flavour hadron production provides information about the transport properties and microscopic structure of the quark-gluon plasma created in ultra-relativistic heavy-ion collisions. A measurement of the muons from semileptonic decays of charm and bottom hadrons produced in Pb+Pb and pp collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV with the ATLAS detector at the Large Hadron Collider is presented. The Pb+Pb data were collected in 2015 and 2018 with sampled integrated luminosities of 208 mu b(-1) and 38 mu b(-1), respectively, and pp data with a sampled integrated luminosity of 1.17 pb(-1) were collected in 2017. Muons from heavy-flavour semileptonic decays are separated from the light-flavour hadronic background using the momentum imbalance between the inner detector and muon spectrometer measurements, and muons originating from charm and bottom decays are further separated via the muon track's transverse impact parameter. Differential yields in Pb+Pb collisions and differential cross sections in pp collisions for such muons are measured as a function of muon transverse momentum from 4 GeV to 30 GeV in the absolute pseudorapidity interval vertical bar eta vertical bar < 2. Nuclear modification factors for charm and bottom muons are presented as a function of muon transverse momentum in intervals of Pb+Pb collision centrality. The bottom muon results are the most precise measurement of b quark nuclear modification at low transverse momentum where reconstruction of B hadrons is challenging. The measured nuclear modification factors quantify a significant suppression of the yields of muons from decays of charm and bottom hadrons, with stronger effects for muons from charm hadron decays

Methods for high-dimensonal analysis of cells dissociated from cyropreserved synovial tissue

Background: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. Methods: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq. Results: Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified. Conclusions: We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers

Biomarkers of stroke recovery: consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable

The most difficult clinical questions in stroke rehabilitation are ‘‘What is this patient’s potential for recovery?’’ and ‘‘What is the best rehabilitation strategy for this person, given her/his clinical profile?’’ Without answers to these questions, clinicians struggle to make decisions regarding the content and focus of therapy, and researchers design studies that inadvertently mix participants who have a high likelihood of responding with those who do not. Developing and implementing biomarkers that distinguish patient subgroups will help address these issues and unravel the factors important to the recovery process. The goal of the present paper is to provide a consensus statement regarding the current state of the evidence for stroke recovery biomarkers. Biomarkers of motor, somatosensory, cognitive and language domains across the recovery timeline post-stroke are considered; with focus on brain structure and function, and exclusion of blood markers and genetics. We provide evidence for biomarkers that are considered ready to be included in clinical trials, as well as others that are promising but not ready and so represent a developmental priority. We conclude with an example that illustrates the utility of biomarkers in recovery and rehabilitation research, demonstrating how the inclusion of a biomarker may enhance future clinical trials. In this way, we propose a way forward for when and where we can include biomarkers to advance the efficacy of the practice of, and research into, rehabilitation and recovery after stroke

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. Al this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of ly. Serious clinical signs pr exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished