2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice.

OBJECTIVE: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). METHODS: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. RESULTS: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). CONCLUSIONS: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.

Where are the Excess Electrons in Subvalent Compounds? The Case of Ag7Pt2O7.

Subvalent compounds raise the question of where those valence electrons not belonging to chemical bonds are. In the limiting case of Ag7Pt2O7, there is just one-electron excess in the chemical formula requiring the presence of Ag atoms with oxidation states below +1, assuming conventional Pt4+ and O2- ions. Such a situation challenges the understanding of the semiconducting and diamagnetic behavior observed in this oxide. Previous explanations that localize pairwise the electron excess in tetrahedral Ag4 interstices do not suffice in this case, since there are six silver tetrahedral voids and only an excess of nine electrons in the unit cell. Here, we provide an alternative explanation for the subvalent nature of this compound by combining interatomic distances, electron density-based descriptors, and orbital energetic analysis criteria. As a result, Ag atoms that do not participate in their valence electron are revealed. We identify excess electrons located in isolated subvalent silver clusters with electron-deficient multicenter bonds resembling pieces of metallic bonding in fcc-Ag and Ag7Pt2 alloy. Our analysis of the electronic band structure also supports the multicenter bonding picture. This combined approach from the real and reciprocal spaces reconciles existing discrepancies and is key to understanding the new chemistry of silver subvalent compounds.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Neuroinflammation and gliosis in the injured and contralateral retinas after unilateral optic nerve crush.

The main purpose of this study is to analyze the effects of unilateral optic nerve crush in the gene expression of pro- and anti-inflammatory mediators, and gliosis markers in injured and contralateral retinas. Retinas from intact, unilaterally optic nerve injured or sham-operated C57BL/6J mice were analyzed 1, 3, 9 and 30 days after the surgery (n = 5/group and time point) and the relative expression of TGF-ß1, IL-1ß, TNF-α, Iba1, AQP4, GFAP, MHCII, and TSPO was analyzed in injured and contralateral using qPCR. The results indicated that compared with intact retinas, sham-operated animals showed an early (day 1) upregulation of IL-1ß, TNF-α and TSPO and a late (day 30) upregulation of TNF-α. In sham-contralateral retinas, TNF-α and TSPO mRNA expression were upregulated and day 30 while GFAP, Iba1, AQP4 and MHCII downregulated at day 9. Compared with sham-operated animals, in retinas affected by optic nerve crush GFAP and TSPO upregulated at day 1 and TNF-α, Iba1, AQP4 and MHCII at day 3. In the crushed-contralateral retinas, TGF-ß1, TNF-α, Iba1 and MHCII were upregulated at day 1. TSPO was upregulated up to day 30 whereas TGF-ß1 and Iba1 downregulated after day 9. In conclusion, both sham surgery and optic nerve crush changed the profile of inflammatory and gliosis markers in the injured and contralateral retinas, changes that were more pronounced for optic nerve crush when compared to sham.

Comparative Analysis of Retinal Organotypic Cultures and In Vivo Axotomized Retinas.

Retinal organotypic cultures (ROCs) are used as an in vivo surrogate to study retinal ganglion cell (RGC) loss and neuroprotection. In vivo, the gold standard to study RGC degeneration and neuroprotection is optic nerve lesion. We propose here to compare the course of RGC death and glial activation between both models. The left optic nerve of C57BL/6 male mice was crushed, and retinas analyzed from 1 to 9 days after the injury. ROCs were analyzed at the same time points. As a control, intact retinas were used. Retinas were studied anatomically to assess RGC survival, microglial, and macroglial activation. Macroglial and microglial cells showed different morphological activation between models and were activated earlier in ROCs. Furthermore, microglial cell density in the ganglion cell layer was always lower in ROCs than in vivo. RGC loss after axotomy and in vitro followed the same trend up to 5 days. Thereafter, there was an abrupt decrease in viable RGCs in ROCs. However, RGC somas were still immuno-identified by several molecular markers. ROCs are useful for proof-of-concept studies on neuroprotection, but long-term experiments should be carried out in vivo. Importantly, the differential glial activation observed between models and the concomitant death of photoreceptors that occurs in vitro may alter the efficacy of RGC neuroprotective therapies when tested in in vivo models of optic nerve injury.

High-Pressure and High-Temperature Chemistry of Phosphorus and Nitrogen: Synthesis and Characterization of α- and γ-P3N5.

The direct chemical reactivity between phosphorus and nitrogen was induced under high-pressure and high-temperature conditions (9.1 GPa and 2000-2500 K), generated by a laser-heated diamond anvil cell and studied by synchrotron X-ray diffraction, Raman spectroscopy, and DFT calculations. α-P3N5 and γ-P3N5 were identified as reaction products. The structural parameters and vibrational frequencies of γ-P3N5 were characterized as a function of pressure during room-temperature compression and decompression to ambient conditions, determining the equation of state of the material up to 32.6 GPa and providing insight about the lattice dynamics of the unit cell during compression, which essentially proceeds through the rotation of the PN5 square pyramids and the distortion of the PN4 tetrahedra. Although the identification of α-P3N5 demonstrates for the first time the direct synthesis of this compound from the elements, its detection in the outer regions of the laser-heated area suggests α-P3N5 as an intermediate step in the progressive nitridation of phosphorus toward the formation of γ-P3N5 with increasing coordination number of P by N from 4 to 5. No evidence of a higher-pressure phase transition was observed, excluding the existence of predicted structures containing octahedrally hexacoordinated P atoms in the investigated pressure range.

Intermolecular forces at ice and water interfaces: Premelting, surface freezing, and regelation.

Using Lifshitz theory, we assess the role of van der Waals forces at interfaces of ice and water. The results are combined with measured structural forces from computer simulations to develop a quantitative model of the surface free energy of premelting films. This input is employed within the framework of wetting theory and allows us to predict qualitatively the behavior of quasi-liquid layer thickness as a function of ambient conditions. Our results emphasize the significance of vapor pressure. The ice-vapor interface is shown to exhibit only incomplete premelting, but the situation can shift to a state of complete surface melting above water saturation. The results obtained serve also to assess the role of subsurface freezing at the water-vapor interface, and we show that intermolecular forces favor subsurface ice nucleation only in conditions of water undersaturation. We show that ice regelation at ambient pressure may be explained as a process of capillary freezing, without the need to invoke the action of bulk pressure melting. Our results for van der Waals forces are exploited in order to gauge dispersion interactions in empirical point charge models of water.

Prevalence of symptomatic axial osteoarthritis phenotypes in Spain and associated socio-demographic, anthropometric, and lifestyle variables.

OBJECTIVE: Axial osteoarthritis (OA) is a common cause of back and neck pain, however, few studies have examined its prevalence. The aim was to estimate the prevalence and the characteristics of symptomatic axial OA in Spain. METHODS: EPISER2016 is a cross-sectional multicenter population-based study of people aged 40 years or older. Subjects were randomly selected using multistage stratified cluster sampling. Participants were contacted by telephone to complete rheumatic disease screening questionnaires. Two phenotypes were analyzed, patients with Non-exclusive axial OA (NEA-OA) and Exclusive axial OA (EA-OA). To calculate the prevalence and its 95% confidence interval (CI), the sample design was considered and weighting was calculated according to age, sex and geographic origin. RESULTS: Prevalence of NEA-OA by clinical or clinical-radiographic criteria was 19.17% (95% CI: 17.82-20.59). The frequency of NEA-OA increased with age (being 3.6 times more likely in patients aged 80 s or more than in those between 40 and 49 years) and body mass index. It was significantly more frequent in women, as well as in the center of Spain. It was less frequent in those with a higher level of education. Lumbar OA was more frequent than cervical OA. This difference grew with increasing age and was not associated with gender. It was also greater in overweight and obese subjects. CONCLUSIONS: This is the first study on the prevalence of axial OA phenotypes in Europe describing the associated socio-demographic, anthropometric, and lifestyle variables.

Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation.

The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1ß and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia-reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. METHODS: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. FINDINGS: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. INTERPRETATION: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. FUNDING: Menarini, Ipsen, and Teijin Pharma Ltd.

A Highly Conductive All-Carbon Linked 3D Covalent Organic Framework Film.

Here an all-carbon linked 3D covalent organic framework (COF) is introduced by employing a templated surface reaction in a continuous flow (TSRCF). The presented method of synthesis provides spatial control over the reaction chemistry and allows for the creation of ultrasmooth COF films of desired thickness and significant crystallinity. The films show high electrical conductivity (≈3.4 S m-1 ) after being doped with tetracyanoquinodimethane (TCNQ), setting a new record for 3D COF materials. The concurrence of 3D nanosized channels and high conductivity opens up for a number of hitherto unexplored applications for this class of materials, such as high surface area electrodes, electrochemical transistors, and for electronic sensing.

Which factors predict discordance between a patient and physician on a gout flare?

OBJECTIVE: To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. METHODS: Patients' self-reports of current gout flares were assessed with the question, 'Are you having a gout flare today?' which was then compared with a concurrent, blinded, physician's assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups-patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed-were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. RESULTS: Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0-10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. CONCLUSION: Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.

7,8-Dihydroxiflavone Protects Adult Rat Axotomized Retinal Ganglion Cells through MAPK/ERK and PI3K/AKT Activation.

We analyze the 7,8-dihydroxyflavone (DHF)/TrkB signaling activation of two main intracellular pathways, mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3 kinase (PI3K)/AKT, in the neuroprotection of axotomized retinal ganglion cells (RGCs). METHODS: Adult albino Sprague-Dawley rats received left intraorbital optic nerve transection (IONT) and were divided in two groups. One group received daily intraperitoneal DHF (5 mg/kg) and another vehicle (1%DMSO in 0.9%NaCl) from one day before IONT until processing. Additional intact rats were employed as control (n = 4). At 1, 3 or 7 days (d) after IONT, phosphorylated (p)AKT, p-MAPK, and non-phosphorylated AKT and MAPK expression levels were analyzed in the retina by Western blotting (n = 4/group). Radial sections were also immunodetected for the above-mentioned proteins, and for Brn3a and vimentin to identify RGCs and Müller cells (MCs), respectively (n = 3/group). RESULTS: IONT induced increased levels of p-MAPK and MAPK at 3d in DHF- or vehicle-treated retinas and at 7d in DHF-treated retinas. IONT induced a fast decrease in AKT in retinas treated with DHF or vehicle, with higher levels of phosphorylation in DHF-treated retinas at 7d. In intact retinas and vehicle-treated groups, no p-MAPK or MAPK expression in RGCs was observed. In DHF- treated retinas p-MAPK and MAPK were expressed in the ganglion cell layer and in the RGC nuclei 3 and 7d after IONT. AKT was observed in intact and axotomized RGCs, but the signal intensity of p-AKT was stronger in DHF-treated retinas. Finally, MCs expressed higher quantities of both MAPK and AKT at 3d in both DHF- and vehicle-treated retinas, and at 7d the phosphorylation of p-MAPK was higher in DHF-treated groups. CONCLUSIONS: Phosphorylation and increased levels of AKT and MAPK through MCs and RGCs in retinas after DHF-treatment may be responsible for the increased and long-lasting RGC protection afforded by DHF after IONT.

Ly6c as a New Marker of Mouse Blood Vessels: Qualitative and Quantitative Analyses on Intact and Ischemic Retinas.

Ly6c is an antigen commonly used to differentiate between classical and non-classical monocytes/macrophages. Here we show its potential as a marker of the mouse vasculature, particularly of the retinal vascular plexuses. Ly6c was immunodetected in several tissues of C57BL/6 mice using isolectin IB4 as the control of vasculature staining. In the retina, Ly6c expression was analyzed qualitatively and quantitatively in intact, ischemic, and contralateral retinas from 0 to 30 days after the insult. Ly6c expression was observed in all organs and tissues tested, with a brighter signal and more homogeneous staining than the IB4. In the retinas, Ly6c was well expressed, allowing a detailed study of their anatomy. The three retinal plexuses were morphologically different, and from the superficial to the deep one occupied 15 ± 2, 24 ± 7, and 38 ± 1.4 percent of the retinal surface, respectively. In the injured retinas, there was extravasation of the classically activated monocyte/macrophages (Ly6chigh) and the formation of new vessels in the superficial plexus, increasing the area occupied by it to 25 ± 1%. In the contralateral retinas, the superficial plexus area decreased gradually, reaching significance at 30 days, and Ly6c expression progressively disappeared in the intermediate and deep plexuses. Although the role of Ly6c in vascular endothelial cell function is still not completely understood, we demonstrate here that Ly6c can be used as a new specific marker of the mouse vasculature and to assess, qualitatively and quantitatively, vascular changes in health and disease.

Axonal Injuries Cast Long Shadows: Long Term Glial Activation in Injured and Contralateral Retinas after Unilateral Axotomy.

BACKGROUND: To analyze the course of microglial and macroglial activation in injured and contralateral retinas after unilateral optic nerve crush (ONC). METHODS: The left optic nerve of adult pigmented C57Bl/6 female mice was intraorbitally crushed and injured, and contralateral retinas were analyzed from 1 to 45 days post-lesion (dpl) in cross-sections and flat mounts. As controls, intact retinas were studied. Iba1+ microglial cells (MCs), activated phagocytic CD68+MCs and M2 CD206+MCs were quantified. Macroglial cell changes were analyzed by GFAP and vimentin signal intensity. RESULTS: After ONC, MC density increased significantly from 5 to 21 dpl in the inner layers of injured retinas, remaining within intact values in the contralateral ones. However, in both retinas there was a significant and long-lasting increase of CD68+MCs. Constitutive CD206+MCs were rare and mostly found in the ciliary body and around the optic-nerve head. While in the injured retinas their number increased in the retina and ciliary body, in the contralateral retinas decreased. Astrocytes and Müller cells transiently hypertrophied in the injured retinas and to a lesser extent in the contralateral ones. CONCLUSIONS: Unilateral ONC triggers a bilateral and persistent activation of MCs and an opposed response of M2 MCs between both retinas. Macroglial hypertrophy is transient.

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Full Counting Statistics of Topological Defects after Crossing a Phase Transition.

We consider the number distribution of topological defects resulting from the finite-time crossing of a continuous phase transition and identify signatures of universality beyond the mean value, predicted by the Kibble-Zurek mechanism. Statistics of defects follows a binomial distribution with N Bernouilli trials associated with the probability of forming a topological defect at the locations where multiple domains merge. All cumulants of the distribution are predicted to exhibit a common universal power-law scaling with the quench time in which the transition is crossed. Knowledge of the distribution is used to discuss the onset of adiabatic dynamics and bound rare events associated with large deviations.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

Neuronal Death in the Contralateral Un-Injured Retina after Unilateral Axotomy: Role of Microglial Cells.

For years it has been known that unilateral optic nerve lesions induce a bilateral response that causes an inflammatory and microglial response in the contralateral un-injured retinas. Whether this contralateral response involves retinal ganglion cell (RGC) loss is still unknown. We have analyzed the population of RGCs and the expression of several genes in both retinas of pigmented mice after a unilateral axotomy performed close to the optic nerve head (0.5 mm), or the furthest away that the optic nerve can be accessed intraorbitally in mice (2 mm). In both retinas, RGC-specific genes were down-regulated, whereas caspase 3 was up-regulated. In the contralateral retinas, there was a significant loss of 15% of RGCs that did not progress further and that occurred earlier when the axotomy was performed at 2 mm, that is, closer to the contralateral retina. Finally, the systemic treatment with minocycline, a tetracycline antibiotic that selectively inhibits microglial cells, or with meloxicam, a non-steroidal anti-inflammatory drug, rescued RGCs in the contralateral but not in the injured retina. In conclusion, a unilateral optic nerve axotomy triggers a bilateral response that kills RGCs in the un-injured retina, a death that is controlled by anti-inflammatory and anti-microglial treatments. Thus, contralateral retinas should not be used as controls.