Exploring a new ultrasound score as a clinical predictive tool in patients with rheumatoid arthritis starting abatacept: results from the APPRAISE study

Objectives To explore whether changes in a composite (power Doppler/greyscale ultrasound (PDUS)) synovitis score, developed by the OMERACT-EULAR-Ultrasound Task Force, predict disease activity outcomes in rheumatoid arthritis (RA). Methods Patients with RA who were methotrexate inadequate responders starting abatacept were evaluated. Individual joint PDUS scores were combined in the Global OMERACT-EULAR Synovitis Score (GLOESS) for metacarpophalangeal joints (MCPs) 2–5, all joints (22 paired) and a reduced (9 paired) joint set. The predictive value of changes in GLOESS at week 1–16 evaluations for clinical status and response (Disease Activity Score (DAS)28 (C reactive protein, CRP) <2.6; DAS28(CRP) ≤3.2; DAS28(CRP) ≥1.2 improvement) up to week 24, and correlations between DAS28 and GLOESS were assessed. Results Eighty-nine patients completed the 24-week treatment period. Changes in GLOESS (MCPs 2–5) from weeks 1 to 16 were unable to predict DAS28 outcomes up to week 24. However, significant improvements in GLOESS (MCPs 2–5) were observed at week 12 in patients with DAS28 ≥1.2 improvement at week 24 versus those who did not achieve that clinical response. In patients achieving DAS28 ≥1.2 improvement or DAS28 ≤3.2 at week 24, changes in GLOESS (22 and 9 paired joint sets) were greater in patients who already achieved DAS28 ≥1.2 at week 12 than in those who did not. No significant correlations were found between changes in DAS28 and GLOESS definitions at any time point. Conclusions PDUS was not correlated with clinical status or response as measured by DAS28-derived criteria, and PDUS changes were not predictive of clinical outcome. The discrepancies require further exploration. Trial registration number NCT00767325; Results

Very low prevalence of ultrasound detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study

Objectives: This study aimed to determine the prevalence of ultrasound detected tendon abnormalities in healthy subjects (HS) across the age range. / Methods: Adult HS (age 18 to 80 years) were recruited in 23 international Outcome Measures in Rheumatology (OMERACT) ultrasound centres and clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexor (DF) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of Rheumatoid Arthritis (RA) patients was taken from the Birmingham BEACON early arthritis inception cohort. / Results: 939 HS and 144 RA patients were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was statistically significant difference in the proportion of TSH and TPD involvement between HS and RA subjects (HS vs RA p<0.001). In HS there was no difference in the presence of ultrasound abnormalities between age groups. / Conclusions: Ultrasound detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease in newly presenting suspected RA

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ABSTRACT. Objective. To summarize the work performed by the Outcome Measures in Rheumatology (OMERACT) Ultrasound (US) Working Group on the validation of US as a potential outcome measure in gout. Methods. Based on the lack of definitions, highlighted in a recent literature review on US as an outcome tool in gout, a series of iterative exercises were carried out to obtain consensus-based definitions on US elementary components in gout using a Delphi exercise and subsequently testing these definitions in static images and in patients with proven gout. Cohen&apos;s κ was used to test agreement, and values of 0-0.20 were considered poor, 0.20-0.40 fair, 0.40-0.60 moderate, 0.60-0.80 good, and 0.80-1 excellent. Results. With an agreement of &gt; 80%, consensus-based definitions were obtained for the 4 elementary lesions highlighted in the literature review: tophi, aggregates, erosions, and double contour (DC). In static images interobserver reliability ranged from moderate to almost perfect, and similar results were found for the intrareader reliability. In patients the intraobserver agreement was good for all lesions except DC (moderate). The Outcome Measures in Rheumatology (OMERACT) US Working Group (Appendix 1) developed a gout subgroup with the purpose of validating US as an imaging tool for gout. If this objective is achieved, US may be implemented as an outcome measure in gout. Is Ultrasound a Validated Outcome Measure in Gout? In 2013, a systematic literature review was published evaluating US as an outcome tool in gout and asymptomatic hyperuricemia 10 . The report found 18 out of 67 articles published since 1975 to be eligible for review. Described in the literature were 4 main pathologies related solely to gout: tophi, double contour sign (DC), soft tissue abnormalities, and bony lesions. The review highlighted that US was able to detect tophi using magnetic resonance imaging (MRI) as a gold standard, and this measure was found sensitive to change. The DC is an articular cartilage abnormality related to the deposition of crystals on the surface of the hyaline cartilage, which seemed specific to gout, with excellent inter-reader reliability and sensitive to change (the latter only in a very small patient population). Soft tissue pathology such as intrasynovial hyperechogenicity may be indicative of gout. US was less sensitive than MRI for diagnosing erosions (bony lesions) but more sensitive than conventional radiography, as is also known from rheumatoid arthritis studies Criterion and construct validity were assessed only for tophi, and overall there was a lack of consensus on the definitions of the 4 elementary lesions and their validity according to the OMERACT filter 13 . Current Limitations of US in Gout Assessment Despite clear interest in this imaging technique for the management of gout, the literature review clearly pointed to a lack of clear US definitions for the main 4 elementary lesions identified: tophi, DC, soft tissue hyperechogenicity (punctuate crystal aggregates), and bony lesions (erosions). This lack of consensus-based definitions impairs the ability to validate US according to the OMERACT filter and hampers widespread use of US in therapeutic clinical trials, due to the difficulty to measure the same phenomenon. In order to implement US in the management of patients with established or suspected gout the &quot;gout subgroup of the OMERACT US Working Group&quot; initiated a validation process. The first step was to obtain consensus-based definitions for the US elementary lesion as indicated by the literature review. This was accomplished by performing a Delphi exercise 14 . Thirty-five rheumatologists performing US and with an interest in gout were invited to participate, and 32 responded positively. After 3 Delphi rounds, &gt; 80% agreement was obtained for each definition Agreement was obtained to use the existing definitions for both synovitis and tenosynovitis 15 because these may be co-components in gout disease. Agreement could not be obtained to include synovitis (including Doppler activity) as an elementary lesion indicative of gout, because the presence of synovitis alone was not considered specific enough to define gout disease because it is a key component in other inflammatory arthropathies as well 14 . On the other hand, even if erosions may also be seen in other arthropathy conditions, since they may also be found extraarticularly in gout and may possibly have a slightly different appearance, it was decided to test, as part of the Delphi exercise, whether the existing definition worked also in gout. Perfect agreement was obtained to keep the definition close to the definition used for erosions in general. The second step was to test the reliability of the obtained definitions in a Web exercise consisting of static images of the elementary lesions. The Web exercise included 110 US images of the 4 lesions obtained from feet and knees and 20 of these images were shown twice in order to test both interand intrareader reliability. Twenty-seven of the 35 rheumatologists participating in the Delphi exercise participated in the reliability study. Cohen&apos;s κ was used to evaluate interand intrareader reliability. Κ values 0-0.20 were considered poor; 0.20-0.40 fair; 0.40-0.60 moderate; 0.60-0.80 good; and 0.80-1 excellent The third step was to test the agreement and reliability of the elementary lesions in a cohort of patients with gout. Sixteen of the rheumatologists previously involved in the first and second step participated in a workshop with 8 patients with crystal-proven gout. Both intra-and inter-reader reliability was assessed by scanning the patients twice within the same day. The areas of attention were the intercondylar region of the knee, the 1st metatarsophalangeal (MTP) joint, and the patellar tendon. Cohen&apos;s κ was used to evaluate inter-and intrareader reliability. Κ values of 0-0.20 were considered poor; 0.20-0.40 fair; 0.40-0.60 moderate; 0.60-0.80 good; and 0.80-1 excellen

Habitable Zones in the Universe

Habitability varies dramatically with location and time in the universe. This was recognized centuries ago, but it was only in the last few decades that astronomers began to systematize the study of habitability. The introduction of the concept of the habitable zone was key to progress in this area. The habitable zone concept was first applied to the space around a star, now called the Circumstellar Habitable Zone. Recently, other, vastly broader, habitable zones have been proposed. We review the historical development of the concept of habitable zones and the present state of the research. We also suggest ways to make progress on each of the habitable zones and to unify them into a single concept encompassing the entire universe.Comment: 71 pages, 3 figures, 1 table; to be published in Origins of Life and Evolution of Biospheres; table slightly revise

Aerosols in the Pre-industrial Atmosphere

Purpose of Review: We assess the current understanding of the state and behaviour of aerosols under pre-industrial conditions and the importance for climate. Recent Findings: Studies show that the magnitude of anthropogenic aerosol radiative forcing over the industrial period calculated by climate models is strongly affected by the abundance and properties of aerosols in the pre-industrial atmosphere. The low concentration of aerosol particles under relatively pristine conditions means that global mean cloud albedo may have been twice as sensitive to changes in natural aerosol emissions under pre-industrial conditions compared to present-day conditions. Consequently, the discovery of new aerosol formation processes and revisions to aerosol emissions have large effects on simulated historical aerosol radiative forcing. Summary: We review what is known about the microphysical, chemical, and radiative properties of aerosols in the pre-industrial atmosphere and the processes that control them. Aerosol properties were controlled by a combination of natural emissions, modification of the natural emissions by human activities such as land-use change, and anthropogenic emissions from biofuel combustion and early industrial processes. Although aerosol concentrations were lower in the pre-industrial atmosphere than today, model simulations show that relatively high aerosol concentrations could have been maintained over continental regions due to biogenically controlled new particle formation and wildfires. Despite the importance of pre-industrial aerosols for historical climate change, the relevant processes and emissions are given relatively little consideration in climate models, and there have been very few attempts to evaluate them. Consequently, we have very low confidence in the ability of models to simulate the aerosol conditions that form the baseline for historical climate simulations. Nevertheless, it is clear that the 1850s should be regarded as an early industrial reference period, and the aerosol forcing calculated from this period is smaller than the forcing since 1750. Improvements in historical reconstructions of natural and early anthropogenic emissions, exploitation of new Earth system models, and a deeper understanding and evaluation of the controlling processes are key aspects to reducing uncertainties in future

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Permian-Triassic boundary microbialites (PTBMs) in soutwest China: implications for paleoenvironment reconstruction

Permian–Triassic boundary microbialites (PTBMs) are commonly interpreted to be a sedimentary response to upwelling of anoxic alkaline seawater and indicate a harsh marine environment in the Permian–Triassic transition. However, recent studies propose that PTBMs may instead be developed in an oxic environment, therefore necessitating the need to reassess the paleoenvironment of formation of PTBMs. This paper is an integrated study of the PTBM sequence at Yudongzi, northwest Sichuan Basin, which is one of the thickest units of PTBMs in south China. Analysis of conodont biostratigraphy, mega- to microscopic microbialite structures, stratigraphic variations in abundance and size of metazoan fossils, and total organic carbon (TOC) and total sulfur (TS) contents within the PTBM reveals the following results: (1) the microbialites occur mainly in the Hindeodus parvus Zone but may cross the Permian–Triassic boundary, and are comprised of, from bottom to top: lamellar thrombolites, dendritic thrombolites and lamellar-reticular thrombolites; (2) most metazoan fossils of the microbialite succession increase in abundance upsection, so does the sizes of bivalve and brachiopod fossils; (3) TOC and TS values of microbialites account respectively for 0.07 and 0.31 wt% on average, both of which are very low. The combination of increase in abundance and size of metazoan fossils upsection, together with the low TOC and TS contents, is evidence that the Yudongzi PTBMs developed in oxic seawater. We thus dispute the previous view, at least for the Chinese sequences, of low-oxygen seawater for microbialite growth, and question whether it is now appropriate to associate PTBMs with anoxic, harsh environments associated with the end-Permian extinction. Instead, we interpret those conditions as fully oxygenated.13th Five-Year Plan National Scientific and Technology Major Project (2016ZX05004002-001); National Natural Science Foundation of China (41602166)

Functional analysis of liverworts in dual symbiosis with Glomeromycota and Mucoromycotina fungi under a simulated Palaeozoic CO2 decline.

Most land plants form mutualistic associations with arbuscular mycorrhizal fungi of the Glomeromycota, but recent studies have found that ancient plant lineages form mutualisms with Mucoromycotina fungi. Simultaneous associations with both fungal lineages have now been found in some plants, necessitating studies to understand the functional and evolutionary significance of these tripartite associations for the first time. We investigate the physiology and cytology of dual fungal symbioses in the early-diverging liverworts Allisonia and Neohodgsonia at modern and Palaeozoic-like elevated atmospheric CO2 concentrations under which they are thought to have evolved. We found enhanced carbon cost to liverworts with simultaneous Mucoromycotina and Glomeromycota associations, greater nutrient gain compared with those symbiotic with only one fungal group in previous experiments and contrasting responses to atmospheric CO2 among liverwort-fungal symbioses. In liverwort-Mucoromycotina symbioses, there is increased P-for-C and N-for-C exchange efficiency at 440 p.p.m. compared with 1500 p.p.m. CO2. In liverwort-Glomeromycota symbioses, P-for-C exchange is lower at ambient CO2 compared with elevated CO2. No characteristic cytologies of dual symbiosis were identified. We provide evidence of a distinct physiological niche for plant symbioses with Mucoromycotina fungi, giving novel insight into why dual symbioses with Mucoromycotina and Glomeromycota fungi persist to the present day.The ISME Journal advance online publication, 27 November 2015; doi:10.1038/ismej.2015.204

Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study

Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naïve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (∼10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology–European League Against Rheumatism (OMERACT–EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT–EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2–5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2–5): −0.7 (95% CIs −1.2 to −0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change ≥1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325