Objective
This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti–neutrophil extracellular trap (anti‐NET) antibodies in a multinational cohort ...of antiphospholipid (aPL) antibody–positive patients who did not have lupus.
Methods
Anti‐NET IgG/IgM levels were measured in serum samples from 389 aPL‐positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform.
Results
We found elevated levels of anti‐NET IgG and/or IgM in 45% of the aPL‐positive patients. High anti‐NET antibody levels are associated with more circulating myeloperoxidase (MPO)–DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti‐NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti‐NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti‐NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti‐NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO–DNA complexes, and nucleosomes. Anti‐NET IgM positivity was associated with autoantibodies targeting single‐stranded DNA, double‐stranded DNA, and proliferating cell nuclear antigen.
Conclusion
These data reveal high levels of anti‐NET antibodies in 45% of aPL‐positive patients, where they potentially activate the complement cascade. While anti‐NET IgM may especially recognize DNA in NETs, anti‐NET IgG species appear to be more likely to target NET‐associated protein antigens.
Negative contrast magnetic resonance imaging (MRI) methods using magnetic susceptibility shifting agents have become one of the most important approaches in cellular imaging research. However, ...visualizing and tracking labeled cells on the basis of negative contrast is often met with limited specificity and sensitivity. Here we report on a MRI method for cellular imaging that generates a new contrast with a distinct topology for identifying labeled cells that has the potential to significantly improve both the sensitivity and the specificity. Specifically, we show that low flip-angle steady-state free precession MRI can be used to generate fast three-dimensional images of tissue that can be rapidly processed to generate quantitative metrics enabling color overlays indicative of regions containing labeled cells. The technique substantially improves the ability of MRI for detecting labeled cells by overcoming the fundamental limits that currently plague negative contrast methods.
A new RF structure: bent-vane type RFQ Yang, Lei; Lu, Liang; Zhang, Zhouli ...
Journal of physics. Conference series,
01/2020, Letnik:
1401, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A new RFQ accelerator cavity structure with bent vanes is proposed to meet the miniaturization requirement of low frequency accelerators. The news structure has a downsized cross section by bending ...the vanes while maintaining a certain vane length. It also possesses the advantage of a simple cooling configuration. The new RFQ structure is presented in this paper.
Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international ...cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients.
In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage.
Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio OR 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aβ2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016).
DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.
Objective
This study aimed to use cluster analysis (CA) to identify different clinical phenotypes among antiphospholipid antibodies (aPL)-positive patients.
Methods
The Alliance for Clinical Trials ...and International Networking (APS ACTION) Registry includes persistently positive aPL of any isotype based on the Sydney antiphospholipid syndrome (APS) classification criteria. We performed CA on the baseline characteristics collected retrospectively at the time of the registry entry of the first 500 patients included in the registry. A total of 30 clinical data points were included in the primary CA to cover the broad spectrum of aPL-positive patients.
Results
A total of 497 patients from international centres were analysed, resulting in three main exclusive clusters: (a) female patients with no other autoimmune diseases but with venous thromboembolism (VTE) and triple-aPL positivity; (b) female patients with systemic lupus erythematosus, VTE, aPL nephropathy, thrombocytopaenia, haemolytic anaemia and a positive lupus anticoagulant test; and (c) older men with arterial thrombosis, heart valve disease, livedo, skin ulcers, neurological manifestations and cardiovascular disease (CVD) risk factors.
Conclusions
Based on our hierarchical cluster analysis, we identified different clinical phenotypes of aPL-positive patients discriminated by aPL profile, lupus or CVD risk factors. Our results, while supporting the heterogeneity of aPL-positive patients, also provide a foundation to understand disease mechanisms, create new approaches for APS classification and ultimately develop new management approaches.
Objective
The present study was undertaken to longitudinally evaluate titers of antibodies against β2‐glycoprotein I (anti‐β2GPI) and domain 1 (anti‐D1), to identify predictors of variations in ...anti‐β2GPI and anti‐D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry.
Methods
Patients with available blood samples from at least 4 time points (at baseline year 1 and at years 2–4 of follow‐up) were included. Detection of anti‐β2GPI and anti‐D1 IgG antibodies was performed using chemiluminescence (BIO‐FLASH; INOVA Diagnostics).
Results
Among 230 patients in the study cohort, anti‐D1 and anti‐β2GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti‐D1 and anti‐β2GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3‐fold and 1.4‐fold decreases in anti‐D1 and anti‐β2GPI titers, respectively. Incident vascular events were associated with 1.9‐fold and 2.1‐fold increases in anti‐D1 and anti‐β2GPI titers, respectively. Anti‐D1 and anti‐β2GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6‐fold decrease in anti‐D1 titers and a 2‐fold decrease in anti‐β2GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval 95% CI 0.62–59.3) and 9.4 (95% CI 1.1–80.2), respectively.
Conclusion
Treatment with HCQ and incident vascular events in aPL‐positive patients predicted significant anti‐D1 and anti‐β2GPI titer fluctuations over time. Both anti‐D1 and anti‐β2GPI titers decreased around the time of thrombosis, with potential clinical relevance.
Several antiphospholipid antibody (aPL) profiles ("triple" and lupus anticoagulant LA positivity) are associated with a higher risk for clinical manifestations of antiphospholipid syndrome (APS). ...Further risk is correlated with higher levels of anticardiolipin antibody (aCL) and anti-β
glycoprotein-I antibody (aβ
GPI), and with aPL persistence. Given that the 3 aPL tests detect partially overlapping sets of antibodies, the primary goal of this study was to characterize the associations among aPL tests using AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) core laboratory data. The APS ACTION Registry includes annually followed adult patients with positive aPL based on the Revised Sapporo Classification Criteria. We analyzed baseline and prospective core laboratory data of the registry for associations among aPL tests using the Spearman rank correlation with Bonferroni-adjusted significance level for multiple comparisons. An aPL Load was calculated based on 6 tests (aCL IgG/IgM/IgA and aβ
GPI IgG/IgM/IgA); a receiver operating characteristic curve was used to evaluate the diagnostic performance of the aPL Load in predicting LA positivity. In 351 patients simultaneously tested for LA, aCL, and aβ
GPI, the frequency of moderate-to-high (≥40 U) titers of aCL and aβ
GPI IgG/IgM/IgA was higher in patients who were positive for LA vs those who were negative. An aPL Load was calculated for each patient to assess the overall aPL burden. For every 1-point increase in the aPL Load, the possibility of a positive LA test increased by 32% (odds ratio, 1.32; 95% CI, 1.2-1.5; P < .001). Based on core laboratory data from a large international registry, most aPL enzyme-linked immunosorbent assay ≥40 U and a high calculated aPL Load combining 6 aPL enzyme-linked immunosorbent assays were predictive of a positive LA. These data suggest that the combined quantitative burden of aPL may provide a mechanistic explanation of a positive LA.
Background
Doxorubicin and doxorubicin‐trastuzumab combination chemotherapy have been associated with cardiotoxicity that eventually leads to heart failure and may limit dose‐effective cancer ...treatment. Current diagnostic strategies rely on decreased ejection fraction (EF) to diagnose cardiotoxicity.
Purpose
The aim of this study is to explore the potential of cardiac MR (CMR) imaging to identify imaging biomarkers in a mouse model of chemotherapy‐induced cardiotoxicity.
Methods
A cumulative dose of 25 mg/kg doxorubicin was administered over three weeks using subcutaneous pellets (n = 9, Dox). Another group (n = 9) received same dose of Dox and a total of 10 mg/kg trastuzumab (DT). Mice were imaged at baseline, 5/6 weeks and 10 weeks post‐treatment on a 7T MRI system. The protocol included short‐axis cine MRI covering the left ventricle (LV) and mid‐ventricular short‐axis tissue phase mapping (TPM), pre‐ and post‐contrast T1 mapping, T2 mapping and Displacement Encoding with Stimulated Echoes (DENSE) strain encoded MRI. EF, peak myocardial velocities, native T1, T2, extracellular volume (ECV), and myocardial strain were quantified. N = 7 mice were sacrificed for histopathologic assessment of apoptosis at 5/6 weeks.
Results
Global peak systolic longitudinal velocity was reduced at 5/6 weeks in Dox (0.6 ± 0.3 vs 0.9 ± 0.3, p = 0.02). In the Dox group, native T1 was reduced at 5/6 weeks (1.3 ± 0.2 ms vs 1.6 ± 0.2 ms, p = 0.02), and relatively normalized at week 10 (1.4 ± 0.1 ms vs 1.6 ± 0.2 ms, p > 0.99). There was no change in EF and other MRI parameters and histopathologic results demonstrated minimal apoptosis in all mice (~1–2 apoptotic cell/high power field), suggesting early‐stage cardiotoxicity.
Conclusions
In a mouse model of chemotherapy‐induced cardiotoxicity using doxorubicin and trastuzumab, advanced CMR shows promise in identifying treatment‐related decrease in myocardial velocity and native T1 prior to the onset of cardiomyocyte apoptosis and reduction of EF.
Advanced MRI shows promise in identifying imaging biomarkers of early cardiac dysfunction related to anthracycline induced cardiotoxicity in a mouse model. We saw treatment related reduction in myocardial tissue velocity and native T1 with preserved ejection fraction in a mouse model of chemotherapy‐induced cardiotoxicity using doxorubicin and trastuzumab. In this study, we show for the first time that myocardial tissue velocity may be a promising early imaging biomarker of anthracycline induced cardiotoxicity.
An 81.25MHz continuous wave (CW) radio frequency quadrupole (RFQ) accelerator has been designed for the Low Energy Accelerator Facility (LEAF) at the Institute of Modern Physics (IMP) of the Chinese ...Academy of Science (CAS). In the CW operating mode, the proposed RFQ design adopted the conventional four-vane structure. The main design goals are providing high shunt impendence with low power losses. In the electromagnetic (EM) design, the π-mode stabilizing loops (PISLs) were optimized to produce a good mode separation. The tuners were also designed and optimized to tune the frequency and field flatness of the operating mode. The vane undercuts were optimized to provide a flat field along the RFQ cavity. Additionally, a full length model with modulations was set up for the final EM simulations. Following the EM design, thermal analysis of the structure was carried out. In this paper, detailed EM design and thermal simulations of the LEAF-RFQ will be presented and discussed. Structure error analysis was also studied.
Introduction
Both mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC) have been recommended in the induction therapy of lupus nephritis (LN) for years; nevertheless, their ...effectiveness and safety in a real-world setting are extremely lacking. Therefore, we decided to conduct this real-world study.
Methods
A total of 195 Chinese patients with LN who were initially treated with MMF (
n
= 98), or intravenous CYC (
n
= 97) as induction therapy were enrolled. All of the patients were followed up to 12 months. Complete renal remission (CRR) was defined as 24-h urinary protein (24 h-UTP) < 0.5 g, and partial renal remission (PRR) was defined as ≥ 50% reduction in 24 h-UTP to the subnephrotic level, however > 0.5 g, both with a change of serum creatinine (SCr) within 10% from baseline. The proportions of CRR, PRR, and total renal remission (TRR), as well as adverse events, were compared by Chi-square test and Kaplan–Meier analysis (log-rank test). Inverse probability of treatment weighting (IPTW) was used for propensity score matching and multivariable logistic regression analyses were employed.
Results
The cumulative proportion of TRR in 6 months (79.4 vs. 63.8%,
p
= 0.026) and CRR in 12 months (72.8 vs. 57.6%,
p
= 0.049) in MMF group were significantly higher than CYC group, and the above conclusions were further confirmed by IPTW. The proportions of PRR, CRR, and TRR at other time points were equivalent between two groups. Further subgroup analysis in 111 patients with biopsy-proven III–V LN also showed a significantly higher proportion of TRR at 6 months in the MMF group than in the CYC group (78.3 vs. 56.9%,
p
= 0.026). In the Kaplan–Meier analysis and after IPTW, the MMF group showed better TRR and CRR responses than CYC group in 12 months. Multivariable logistic regression analyses revealed that MMF use was the only predictor of CRR (HR 2.12, 95% CI 1.90–4.09,
p
= 0.026), while low complement level was also a predictor, albeit risk was reduced (HR 0.38, 95% CI 0.17–0.86,
p
= 0.019). Moreover, compared to the CYC group, MMF group patients were more likely to have significantly lower SCr (μmol/l) 72.5 (62.5, 86.5) vs. 79.0 (71.1, 97.5),
p
= 0.001 and daily dose of prednisone (mg/day) (15.7 ± 5.2 vs. 18.6 ± 11.3,
p
= 0.022) at 6 months; lower 24 h-UTP (g) 0.1 (0.1, 0.3) vs. 0.2 (0.1, 0.9),
p
= 0.005 and daily dose of prednisone (mg/day) (9.6 ± 3.3 vs. 11.2 ± 5.5,
p
= 0.023) at 12 months. Infection was the most common adverse event. Pneumonia and gastrointestinal discomfort were more frequently observed in the CYC group.
Conclusions
Real-world data are a key component of the evidence supporting the effectiveness of drugs and are of interest to all stakeholders. Our comparative study demonstrated the effectiveness of MMF in LN induction therapy was at least equivalent to intravenous CYC, with superior tolerance.
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