Rheumatoid Arthritis Patients With Circulating Extracellular Vesicles Positive for IgM Rheumatoid Factor Have Higher Disease Activity

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mainly affects synovial joints. Validated laboratory parameters for RA diagnosis are higher blood levels of rheumatoid factor IgM (IgM-RF), anti-citrullinated protein autoantibodies (ACPA), C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR). Clinical parameters used are the number of tender (TJC) and swollen joints (SJC) and the global patient visual analog score (VAS). To determine disease remission in patients a disease activity score (DAS28) can be calculated based on SJC, TJC, VAS, and ESR (or alternatively CRP). However, subtle and better predictive changes to follow treatment responses in individual patients cannot be measured by the above mentioned parameters nor by measuring cytokine levels in blood. As extracellular vesicles (EVs) play a role in intercellular communication and carry a multitude of signals we set out to determine their value as a biomarker for disease activity. EVs were isolated from platelet-free plasma of 41 RA patients and 24 healthy controls (HC) by size exclusion chromatography (SEC). We quantified the particle and protein concentration, using NanoSight particle tracking analysis and micro-BCA, respectively, and observed no differences between RA patients and HC. In plasma of 28 out of 41 RA patients IgM-RF was detectable by ELISA, and in 13 out of these 28 seropositive RA patients (RF+RA) IgM-RF was also detected on their isolated pEVs (IgM-RF+). In seronegative RA patients (RF−RA) we did not find any RF present on pEVs. When comparing disease parameters we found no differences between RF+RA and RF−RA patients, except for increased ESR levels in RF+RA patients. However, RF+RA patients with IgM-RF+ pEVs showed significantly higher levels of CRP and ESR and also VAS and DAS28 were significantly increased compared to RA+ patients without IgM-RF+ pEVs. This study shows for the first time the presence of IgM-RF on pEVs in a proportion of RF+RA patients with a higher disease activity

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients

Psoriasis (Pso) is a chronic inflammatory skin disease, and up to 30% of Pso patients develop psoriatic arthritis (PsA), which can lead to irreversible joint damage. Early detection of PsA in Pso patients is crucial for timely treatment but difficult for dermatologists to implement. We, therefore, aimed to find disease-specific immune profiles, discriminating Pso from PsA patients, possibly facilitating the correct identification of Pso patients in need of referral to a rheumatology clinic. The phenotypes of peripheral blood immune cells of consecutive Pso and PsA patients were analyzed, and disease-specific immune profiles were identified via a machine learning approach. This approach resulted in a random forest classification model capable of distinguishing PsA from Pso (mean AUC = 0.95). Key PsA-classifying cell subsets selected included increased proportions of differentiated CD4+CD196+CD183-CD194+ and CD4+CD196-CD183-CD194+ T-cells and reduced proportions of CD196+ and CD197+ monocytes, memory CD4+ and CD8+ T-cell subsets and CD4+ regulatory T-cells. Within PsA, joint scores showed an association with memory CD8+CD45RA-CD197- effector T-cells and CD197+ monocytes. To conclude, through the integration of in-depth flow cytometry and machine learning, we identified an immune cell profile discriminating PsA from Pso. This immune profile may aid in timely diagnosing PsA in Pso

Phase Space Analysis of Quintessence Cosmologies with a Double Exponential Potential

We use phase space methods to investigate closed, flat, and open Friedmann-Robertson-Walker cosmologies with a scalar potential given by the sum of two exponential terms. The form of the potential is motivated by the dimensional reduction of M-theory with non-trivial four-form flux on a maximally symmetric internal space. To describe the asymptotic features of run-away solutions we introduce the concept of a `quasi fixed point.' We give the complete classification of solutions according to their late-time behavior (accelerating, decelerating, crunch) and the number of periods of accelerated expansion.Comment: 46 pages, 5 figures; v2: minor changes, references added; v3: title changed, refined classification of solutions, 3 references added, version which appeared in JCA

Total ankle prostheses in rheumatoid arthropathy: Outcome in 52 patients followed for 1–9 years

Background and purpose The first generations of total ankle replacements (TARs) showed a high rate of early failure. In the last decades, much progress has been made in the development of TARs, with the newer generation showing better results. We evaluated TARs implanted with rheumatoid arthritis (RA) or juvenile inflammatory arthritis (JIA) as indication

Carotid Artery Intima-Media Thickness, Carotid Plaque and Coronary Heart Disease and Stroke in Chinese

Background: Our aim was to prospectively investigate the association between carotid artery intima-media thickness (IMT) as well as carotid plaque and incidence of coronary heart disease (CHD) and stroke in Chinese, among whom data are limited. Methods and Findings: We conducted a community-based cohort study composed of 2190 participants free of cardiovascular disease at baseline in one community. During a median 10.5-year follow up, we documented 68 new cases of coronary heart disease and 94 cases of stroke. The multivariate relative risks (RRs) associated with a change of 1 standard deviation of maximal common carotid IMT were 1.38 (95% confidence interval [CI], 1.12–1.70) for CHD and 1.47 (95% CI, 1.28–1.69) for stroke. The corresponding RRs with internal carotid IMT were 1.47 (95% CI, 1.21–1.79) for CHD and 1.52 (95% CI, 1.31–1.76) for stroke. Carotid plaque measured by the degree of diameter stenosis was also significantly associated with increased risk of CHD (p for trend<0.0001) and stroke (p for trend<0.0001). However, these associations were largely attenuated when adjusting for IMT measurements. Conclusions: This prospective study indicates a significant association between carotid IMT and incidence of CHD and stroke in Chinese adults. These measurements may be useful for cardiovascular risk assessment and stratification in Chinese

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

Importance: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. Objective: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. Design, Setting, and Participants: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation–registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. Interventions: HSCT vs intravenous pulse cyclophosphamide. Main Outcomes and Measures: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. Results: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. Conclusions and Relevance: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. Trial Registration: isrctn.org Identifier: ISRCTN5437125

Global maps of soil temperature

Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km² resolution for 0–5 and 5–15 cm soil depth. These maps were created by calculating the difference (i.e., offset) between in-situ soil temperature measurements, based on time series from over 1200 1-km² pixels (summarized from 8500 unique temperature sensors) across all the world’s major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in-situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications