Pain hypersensitivity in juvenile idiopathic arthritis: a quantitative sensory testing study

Background: Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children. Synovial inflammation results in pain, swelling and stiffness. Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity. The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission. Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children. Methods: 60 children aged 7–17 years with JIA participated. QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence. Joint site included finger, wrist, knee and ankle. Clinical status was measured using objective and subjective markers of disease severity. Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue. QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92). Statistical analyses were performed using Kruskal-Wallis with Dunn’s post-hoc comparison, Mann-Whitney or Fisher’s exact test, where appropriate. Results: Overall, children with JIA reported low pain scores and low degrees of functional disability. Sensory detection thresholds and pain thresholds were similar in “active” compared to “inactive” joints. Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs. EU p < 0.001), light touch (vs. EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001). Conclusions: JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity. Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes. Electronic supplementary material The online version of this article (doi:10.1186/1546-0096-12-39) contains supplementary material, which is available to authorized users

Large-scale temperature response to external forcing in simulations and reconstructions of the last millennium

Understanding natural climate variability and its driving factors is crucial to assessing future climate change. Therefore, comparing proxy-based climate reconstructions with forcing factors as well as comparing these with paleo-climate model simulations is key to gaining insights into the relative roles of internal versus forced variability. A review of the state of modelling of the climate of the last millennium prior to the CMIP5-PMIP3 (Coupled Model Intercomparison Project Phase 5-Paleoclimate Modelling Intercomparison Project Phase 3) coordinated effort is presented and compared to the available temperature reconstructions. Simulations and reconstructions broadly agree on reproducing the major temperature changes and suggest an overall linear response to external forcing on multidecadal or longer timescales. Internal variability is found to have an important influence at hemispheric and global scales. The spatial distribution of simulated temperature changes during the transition from the Medieval Climate Anomaly to the Little Ice Age disagrees with that found in the reconstructions. Thus, either internal variability is a possible major player in shaping temperature changes through the millennium or the model simulations have problems realistically representing the response pattern to external forcing. A last millennium transient climate response (LMTCR) is defined to provide a quantitative framework for analysing the consistency between simulated and reconstructed climate. Beyond an overall agreement between simulated and reconstructed LMTCR ranges, this analysis is able to single out specific discrepancies between some reconstructions and the ensemble of simulations. The disagreement is found in the cases where the reconstructions show reduced covariability with external forcings or when they present high rates of temperature change

Angioedema severity and impact on quality of life: Chronic histaminergic angioedema versus chronic spontaneous urticaria

Histamine-mediated angioedema is the most frequent form of angioedema. It is classified as idiopathic histaminergic acquired angioedema (IH-AAE)1 when allergies and other causes have been excluded and a positive treatment response to antihistamines, corticosteroids, or omalizumab has been reported. Idiopathic histaminergic acquired angioedema may occur in isolation, when it is termed chronic histaminergic angioedema (CHA), or it may be associated with wheals in chronic spontaneous urticaria angioedema (CSU-AE). The term CHA is equivalent to IH-AAE and mast cell-mediated angioedema. However, this term reflects the chronic and recurrent course of the disease. Therefore, we propose that the term CHA be internationally discussed in the following guidelines. Chronic spontaneous urticaria is classically characterized by the presence of recurrent episodes of wheals (hives) with or without angioedema for at least 6 weeks.2 Chronic histaminergic angioedema is typically considered a subtype of CSU without wheals. However, a recent study3 found several features that differentiate CHA from CSU, which suggests that CHA is a separate entity. Quality of life (QoL) studies specifically for CHA patients have not been performed, and their QoL has been assessed only in the context of CSU-AE

The PMIP4 contribution to CMIP6 – Part 1: overview and over-arching analysis plan

This paper is the first of a series of four GMD papers on the PMIP4-CMIP6 experiments. Part 2 (Otto-Bliesner et al., 2017) gives details about the two PMIP4-CMIP6 interglacial experiments, Part 3 (Jungclaus et al., 2017) about the last millennium experiment, and Part 4 (Kageyama et al., 2017) about the Last Glacial Maximum experiment. The mid-Pliocene Warm Period experiment is part of the Pliocene Model Intercomparison Project (PlioMIP) – Phase 2, detailed in Haywood et al. (2016). The goal of the Paleoclimate Modelling Intercomparison Project (PMIP) is to understand the response of the climate system to different climate forcings for documented climatic states very different from the present and historical climates. Through comparison with observations of the environmental impact of these climate changes, or with climate reconstructions based on physical, chemical, or biological records, PMIP also addresses the issue of how well state-of-the-art numerical models simulate climate change. Climate models are usually developed using the present and historical climates as references, but climate projections show that future climates will lie well outside these conditions. Palaeoclimates very different from these reference states therefore provide stringent tests for state-of-the-art models and a way to assess whether their sensitivity to forcings is compatible with palaeoclimatic evidence. Simulations of five different periods have been designed to address the objectives of the sixth phase of the Coupled Model Intercomparison Project (CMIP6): the millennium prior to the industrial epoch (CMIP6 name: past1000); the mid-Holocene, 6000 years ago (midHolocene); the Last Glacial Maximum, 21 000 years ago (lgm); the Last Interglacial, 127 000 years ago (lig127k); and the mid-Pliocene Warm Period, 3.2 million years ago (midPliocene-eoi400). These climatic periods are well documented by palaeoclimatic and palaeoenvironmental records, with climate and environmental changes relevant for the study and projection of future climate changes. This paper describes the motivation for the choice of these periods and the design of the numerical experiments and database requests, with a focus on their novel features compared to the experiments performed in previous phases of PMIP and CMIP. It also outlines the analysis plan that takes advantage of the comparisons of the results across periods and across CMIP6 in collaboration with other MIPs

An abrupt weakening of the subpolar gyre as trigger of Little Ice Age-type episodes

We investigate the mechanism of a decadal-scale weakening shift in the strength of the subpolar gyre (SPG) that is found in one among three last millennium simulations with a state-of-the-art Earth system model. The SPG shift triggers multicentennial anomalies in the North Atlantic climate driven by long-lasting internal feedbacks relating anomalous oceanic and atmospheric circulation, sea ice extent, and upper-ocean salinity in the Labrador Sea. Yet changes throughout or after the shift are not associated with a persistent weakening of the Atlantic Meridional Overturning Circulation or shifts in the North Atlantic Oscillation. The anomalous climate state of the North Atlantic simulated after the shift agrees well with climate reconstructions from within the area, which describe a transition between a stronger and weaker SPG during the relatively warm medieval climate and the cold Little Ice Age respectively. However, model and data differ in the timing of the onset. The simulated SPG shift is caused by a rapid increase in the freshwater export from the Arctic and associated freshening in the upper Labrador Sea. Such freshwater anomaly relates to prominent thickening of the Arctic sea ice, following the cluster of relatively small-magnitude volcanic eruptions by 1600 CE. Sensitivity experiments without volcanic forcing can nonetheless produce similar abrupt events; a necessary causal link between the volcanic cluster and the SPG shift can therefore be excluded. Instead, preconditioning by internal variability explains discrepancies in the timing between the simulated SPG shift and the reconstructed estimates for the Little Ice Age onset

Separating Forced from Chaotic Climate Variability over the Past Millennium

Reconstructions of past climate show notable temperature variability over the past millennium, with relatively warm conditions during the Medieval Climate Anomaly (MCA) and a relatively cold Little Ice Age (LIA). Multimodel simulations of the past millennium are used together with a wide range of reconstructions of Northern Hemispheric mean annual temperature to separate climate variability from 850 to 1950 CE into components attributable to external forcing and internal climate variability. External forcing is found to contribute significantly to long-term temperature variations irrespective of the proxy reconstruction, particularly from 1400 onward. Over the MCA alone, however, the effect of forcing is only detectable in about half of the reconstructions considered, and the response to forcing in the models cannot explain the warm conditions around 1000 CE seen in some reconstructions. The residual from the detection analysis is used to estimate internal variability independent from climate modeling, and it is found that the recent observed 50- and 100-yr hemispheric temperature trends are substantially larger than any of the internally generated trends even using the large residuals over the MCA. Variations in solar output and explosive volcanism are found to be the main drivers of climate change from 1400 to 1900, but for the first time a significant contribution from greenhouse gas variations to the cold conditions during 1600-1800 is also detected. The proxy reconstructions tend to show a smaller forced response than is simulated by the models. This discrepancy is shown, at least partly, to be likely associated with the difference in the response to large volcanic eruptions between reconstructions and model simulations

Assessing reconstruction techniques of the Atlantic Ocean circulation variability during the last millennium

We assess the use of the meridional thermal-wind transport estimated from zonal density gradients to reconstruct the oceanic circulation variability during the last millennium in a forced simulation with the ECHO-G coupled climate model. Following a perfect-model approach, model-based pseudo-reconstructions of the Atlantic meridional overturning circulation (AMOC) and the Florida Current volume transport (FCT) are evaluated against their true simulated variability. The pseudo-FCT is additionally verified as proxy for AMOC strength and compared with the available proxy-based reconstruction. The thermal-wind component reproduces most of the simulated AMOC variability, which is mostly driven by internal climate dynamics during the preindustrial period and by increasing greenhouse gases afterwards. The pseudo-reconstructed FCT reproduces well the simulated FCT and reasonably well the variability of the AMOC strength, including the response to external forcing. The pseudo-reconstructed FCT, however, underestimates/overestimates the simulated variability at deep/shallow levels. Density changes responsible for the pseudo-reconstructed FCT are mainly driven by zonal temperature differences; salinity differences oppose but play a minor role. These results thus support the use of the thermal-wind relationship to reconstruct the oceanic circulation past variability, in particular at multidecadal timescales. Yet model-data comparison highlights important differences between the simulated and the proxy-based FCT variability. ECHO-G simulates a prominent weakening in the North Atlantic circulation that contrasts with the reconstructed enhancement. Our model results thus do not support the reconstructed FC minimum during the Little Ice Age. This points to a failure in the reconstruction, misrepresented processes in the model, or an important role of internal ocean dynamics

Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study

Introduction: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). Methods: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients &lt;18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's ?. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. Results: Of the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (? ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. Conclusions: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis

Multispectral analysis of Northern Hemisphere temperature records over the last five millennia

Aiming to describe spatio-temporal climate variability on decadal-to-centennial time scales and longer, we analyzed a data set of 26 proxy records extending back 1,000–5,000 years; all records chosen were calibrated to yield temperatures. The seven irregularly sampled series in the data set were interpolated to a regular grid by optimized methods and then two advanced spectral methods—namely singular-spectrum analysis (SSA) and the continuous wavelet transform—were applied to individual series to separate significant oscillations from the high noise background. This univariate analysis identified several common periods across many of the 26 proxy records: a millennial trend, as well as oscillations of about 100 and 200 years, and a broad peak in the 40–70-year band. To study common NH oscillations, we then applied Multichannel SSA. Temperature variations on time scales longer than 600 years appear in our analysis as a dominant trend component, which shows climate features consistent with the Medieval Warm Period and the Little Ice Age. Statistically significant NH-wide peaks appear at 330, 250 and 110&nbsp;years, as well as in a broad 50–80-year band. Strong variability centers in several bands are located around the North Atlantic basin and are in phase opposition between Greenland and Western Europe