Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation

Brief alcohol intervention for risky drinking in young people aged 14–15 years in secondary schools: the SIPS JR-HIGH RCT

Background: Adverse effects from young people’s alcohol consumption manifest in a range of physical and psychosocial factors, including neurological issues, cognitive impairment and risk-taking behaviours. The SIPS JR-HIGH pilot trial showed alcohol screening and brief intervention (ASBI) to be acceptable to young people and schools in the north-east of England. Objectives: To conduct a two-arm, individually randomised controlled trial to evaluate the effectiveness and cost-effectiveness of ASBI for risky drinking in young people aged 14–15 years in the school setting, to monitor the fidelity of ASBI and to explore the barriers to, and facilitators of, implementation with staff, young people and parents. Design: A baseline survey with a 12-month follow-up. Interviews with 30 school staff, 21 learning mentors and nine teachers, and 33 young people and two parents. Setting: Thirty state schools in four areas of England: north-east, north-west, Kent and London. Participants: Year 10 school pupils who consented to the study (aged 14–15 years, recruited between November 2015 and June 2016), school-based staff and parents of the young people who took part in the study Interventions: Young people who screened positively on a single alcohol screening question andconsented were randomised to the intervention or control arm (blinded). The intervention was a 30-minute one-to-one structured brief intervention with a trained learning mentor and an alcohol leaflet. The control group received a healthy lifestyle leaflet (no alcohol information). Main outcome measures: The primary outcome measure was total alcohol consumed in the last 28 days. Secondary outcomes related to risky drinking, general psychological health, sexual risk-taking, energy drink consumption, age of first smoking, quality of life, quality-adjusted life-years, service utilisation and demographic information. Results: A total of 4523 young people completed the baseline survey, with 1064 screening positively (24%) and 443 being eligible to take part in the trial. Of those 443, 233 (53%) were randomised to the control arm and 210 were randomised to the intervention arm. Of the 443, 374 (84%) were successfully followed up at 12 months (intervention, n = 178; control, n = 196). The results were that the intervention showed no evidence of benefit for any alcohol-related measure when compared with the control arm. At 12 months we found a reduction from 61.9% to 43.3% using the Alcohol Use Disorders Identification Test cut-off point of 8 and cut-off point of 4 (69.0% to 60.7%). These results were not significant. A cost-effectiveness analysis showed that the average net cost saving of the brief intervention was £2865 (95% confidence interval –£11,272 to £2707) per year compared with usual practice, with the intervention showing a 76% probability of being cost saving compared with usual practice. The interview findings showed that school was an acceptable setting to carry out ASBI among staff and young people. Limitations: Recruitment of parents to take part in interviews was poor. Only 18 ASBI sessions were recorded, making it difficult to assess internal validity. Conclusions: Although the intervention was ineffective in reducing risky drinking in young people aged 14–15 years, it was well received by the young people and school staff who participated. Future work: Uniform reporting of the outcomes used for ASBI would generate more robust conclusions on the effectiveness of ASBI in the future. Pilot feasibility studies should include more than one geographical area. Future work on involving parents is needed

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Ten years of Toarcian argilite -carbon steel in situ interaction

International audienc

The nature of bacteriomorphs: biogenicity and its detection N. 3

As the most abundant organisms on Earth since Early Archean, microbes display a wide range of degradation/fossilization possibilities. The discovery of microorganisms living in extreme terrestrial environments makes now plausible the search for life in the ancient deposits of the early Earth with two issues: i) the understanding of the origin of life on Earth, ii) the search for life on Mars and other planetary bodies which experienced environmental settings similar to the ones of early Earth. A crucial aspect in this investigation, however, is the development of criteria for i) a distinction between biogenic and abiogenic structures, and ii) how to distinguish possible contamination products. The planned experiments focus on the recognition of the actual origin of bacteriomorphs and other alleged microbial morphologies. The target is to assess analytical procedures useful for a proper interpretation of alleged biogenic morphologies for which still ambiguous interpretations and the persisting problem of the sample preparation techniques may prevent their use as actual document of biogenic activity

The weathering intensity scale (wis): An alternative approach of the chemical index of alteration (cia)

International audienc