Using serum urate as a validated surrogate end point for flares in patients with gout:protocol for a systematic review and meta-regression analysis

INTRODUCTION: Gout is the most common inflammatory arthritis in men over 40 years of age. Long-term urate-lowering therapy is considered a key strategy for effective gout management. The primary outcome measure for efficacy in clinical trials of urate-lowering therapy is serum urate levels, effectively acting as a surrogate for patient-centred outcomes such as frequency of gout attacks or pain. Yet it is not clearly demonstrated that the strength of the relationship between serum urate and clinically relevant outcomes is sufficiently strong for serum urate to be considered an adequate surrogate. Our objective is to investigate the strength of the relationship between changes in serum urate in randomised controlled trials and changes in clinically relevant outcomes according to the ‘Biomarker-Surrogacy Evaluation Schema version 3’ (BSES3), documenting the validity of selected instruments by applying the ‘OMERACT Filter 2.0’. METHODS AND ANALYSIS: A systematic review described in terms of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines will identify all relevant studies. Standardised data elements will be extracted from each study by 2 independent reviewers and disagreements are resolved by discussion. The data will be analysed by meta-regression of the between-arm differences in the change in serum urate level (independent variable) from baseline to 3 months (or 6 and 12 months if 3-month values are not available) against flare rate, tophus size and number and pain at the final study visit (dependent variables). ETHICS AND DISSEMINATION: This study will not require specific ethics approval since it is based on analysis of published (aggregated) data. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-reviewed publications. TRIAL REGISTRATION NUMBER: CRD42016026991

Hemispheric asymmetry of endogenous neural oscillations in young children: implications for hearing speech in noise

Speech signals contain information in hierarchical time scales, ranging from short-duration (e.g., phonemes) to long-duration cues (e.g., syllables, prosody). A theoretical framework to understand how the brain processes this hierarchy suggests that hemispheric lateralization enables specialized tracking of acoustic cues at different time scales, with the left and right hemispheres sampling at short (25 ms; 40 Hz) and long (200 ms; 5 Hz) periods, respectively. In adults, both speech-evoked and endogenous cortical rhythms are asymmetrical: low-frequency rhythms predominate in right auditory cortex, and high-frequency rhythms in left auditory cortex. It is unknown, however, whether endogenous resting state oscillations are similarly lateralized in children. We investigated cortical oscillations in children (3–5 years; N = 65) at rest and tested our hypotheses that this temporal asymmetry is evident early in life and facilitates recognition of speech in noise. We found a systematic pattern of increasing leftward asymmetry for higher frequency oscillations; this pattern was more pronounced in children who better perceived words in noise. The observed connection between left-biased cortical oscillations in phoneme-relevant frequencies and speech-in-noise perception suggests hemispheric specialization of endogenous oscillatory activity may support speech processing in challenging listening environments, and that this infrastructure is present during early childhood

Future Research and Developments on Reuse and Recycling of Steelmaking By-Products

In the steel sector, sustainable management of by-products is a key challenge to preserve natural resources and achieve the zero waste goal. In this paper, the main trends of future research and development on reuse and recycling of by-products of the steel industry are presented in the form of a roadmap, which is the outcome of a dissemination project funded by the European Union based on the analysis of the most relevant and recent European projects concerning reuse and recycling of by-products from the steel production cycle. In particular, the developed roadmap highlights the most important topics of future research activities and challenges related to reuse and recycling of by-products from the existing or alternative steelmaking routes. A time horizon of 10 years has been considered, taking into account the European Commission targets to achieve carbon neutrality in a circular economy context. In addition, current technological trends derived from past and ongoing research projects are analysed. Research needs are based on the main categories of by-products and residual materials. Due to the different pathways to reduce CO2 emissions, each category is divided into subcategories considering both current and novel process routes targeting decarbonization of steel production. This work identifies the most urgent and demanding research directions for the coming years based on a survey targeting the steel companies, services providers of the steel industry and research organizations active in the field

Temporal Dynamics of Visual Attention Allocation

We often temporally prepare our attention for an upcoming event such as a starter pistol. In such cases, our attention should be properly allocated around the expected moment of the event to process relevant sensory input efficiently. In this study, we examined the dynamic changes of attention levels near the expected moment by measuring contrast sensitivity to a target that was temporally cued by a five-second countdown. We found that the overall attention level decreased rapidly after the expected moment, while it stayed relatively constant before it. Results were not consistent with the predictions of existing explanations of temporal attention such as the hazard rate or the stimulus-driven oscillations. A control experiment ruled out the possibility that the observed pattern was due to biased time perception. In a further experiment with a wider range of cue-stimulus-intervals, we observed that attention level increased until the last 500 ms of the interval range, and thereafter, started to decrease. Based on the performances of a generative computational model, we suggest that our results reflect the nature of temporal attention that takes into account the subjectively estimated hazard rate and the probability of relevant events occurring in the near future

Identification of ‘Candidatus Phytoplasma’ species in “huanglongbing” infected citrus orchards in the Caribbean

“Huanglongbing” (HLB) is one of the most devastating diseases of citrus orchards worldwide. Samples from 183 citrus plants of different cultivars and rootstock/cultivar combinations, showing HLB symptoms in three Caribbean countries (Cuba, Jamaica, and Guadeloupe-France), were collected to verify the possible co-infection of ‘Candidatus Phytoplasma’ and ‘Candidatus Liberibacter’ species. The 64% of the samples resulted positive to the ‘Ca. L. asiaticus’ and the 27% to diverse ‘Ca. Phytoplasma’-related species, moreover about the 14% of the samples infected with ‘Ca. Liberibacter’ were also found positive to phytoplasmas, indicating the presence of mixed infection especially in the orchards located in Cuba. Moreover, in one of the samples from Jamaica mixed phytoplasma infection was detected. Moreover the detection of only phytoplasmas in 11 symptomatic citrus samples collected from Cuba and Guadeloupe without ‘Ca. Liberibacter’ detection, confirmed that the symptomatology cannot be the sole criterium to discriminate between the presence of the two pathogens, and molecular detection is necessary to identify single or mixed infections. Diaphorina citri insects collected from Cuba and Guadeloupe resulted infected with ‘Ca. L. asiaticus’ confirming its active role in the dissemination of the pathogen. Only one insect of the Cicadidae family, collected in Guadeloupe, was found positive for phytoplasma presence. Considering that the phytoplasmas belonging to some ‘Candidatus species’ were detected in the three countries in different citrus varieties, a relevant role as phytoplasma reservoir can be attribute to citrus orchards

Systemic long-term metabolic effects of acute non-severe paediatric burn injury

A growing body of evidence supports the concept of a systemic response to non-severe thermal trauma. This provokes an immunosuppressed state that predisposes paediatric patients to poor recovery and increased risk of secondary morbidity. In this study, to understand the long-term systemic effects of non-severe burns in children, targeted mass spectrometry assays for biogenic amines and tryptophan metabolites were performed on plasma collected from child burn patients at least three years post injury and compared to age and sex matched non-burn (healthy) controls. A panel of 12 metabolites, including urea cycle intermediates, aromatic amino acids and quinolinic acid were present in significantly higher concentrations in children with previous burn injury. Correlation analysis of metabolite levels to previously measured cytokine levels indicated the presence of multiple cytokine-metabolite associations in the burn injury participants that were absent from the healthy controls. These data suggest that there is a sustained immunometabolic imprint of non-severe burn trauma, potentially linked to long-term immune changes that may contribute to the poor long-term health outcomes observed in children after burn injury

Use of integral experiments for the assessment of a new 235

The Working Party on International Nuclear Data Evaluation Co-operation (WPEC) subgroup 29 (SG 29) was established to investigate an issue with the 235U capture cross-section in the energy range from 0.1 to 2.25 keV, due to a possible overestimation of 10% or more. To improve the 235U capture crosssection, a new 235U evaluation has been proposed by the Institut de Radioprotection et de Sûreté Nucléaire (IRSN) and the CEA, mainly based on new time-of-flight 235U capture cross-section measurements and recent fission cross-section measurements performed at the n_TOF facility from CERN. IRSN and CEA Cadarache were in charge of the thermal to 2.25 keV energy range, whereas the CEA DIF was responsible of the high energy region. Integral experiments showing a strong 235U sensitivity are used to assess the new evaluation, using Monte-Carlo methods. The keff calculations were performed with the 5.D.1 beta version of the MORET 5 code, using the JEFF-3.2 library and the new 235U evaluation, as well as the JEFF-3.3T1 library in which the new 235U has been included. The benchmark selection allowed highlighting a significant improvement on keff due to the new 235U evaluation. The results of this data testing are presented here

The reality of pervasive transcription.

International audienc

Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies

Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell–specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell–specific T-cell tolerance at the onset of clinical diabetes