The role of interleukin-21 in type-1 diabetes

Cytokines are an essential component of both normal and aberrant immune responses, such as in autoimmune disease. Interleukin (IL)-21 is a member of the common gamma chain family of cytokines and is adjacent to IL-2 within the strongest non-MHC-linked locus for type-1 diabetes (T1D) susceptibility in non-obese diabetic (NOD) mice. Recent studies demonstrate that IL-21 is necessary for the development of autoimmune disease in several models including T1D in NOD mice. This study explores the critical role of IL-21 in the pathogenesis of T1D. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. Whilst IL-21 is found in high expressing and low expressing allelic forms, IL-2 appears to be kept at a similar level between mouse strains due to differences in mRNA stability. IL-21 is produced in abundance within the autoimmune lesions of the NOD mouse by a novel CD4+ T helper (Th) subset, marked by co-expression of the gut-homing chemokine receptor CCR9. Whilst these CCR9+ IL-21-producing Th cells could be found in healthy mice and humans, they were concentrated in the inflamed pancreas. Critically, the ultimate target of IL-21 is CD8+ T cells whose receptiveness to IL-21 is necessary for the development of diabetes. We also demonstrate successful intervention at a late preclinical stage through neutralisation of IL-21 with IL-21R/Fc. Indeed, when combined with islet allograft transplantation, this therapeutic approach could cure diabetes. We found that the influence of IL-21 on a graft-mounted immune response was robust, as absence of IL-21 signalling was also found to prevent islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with T1D

Real-world questions and concerns about disease-modifying antirheumatic drugs (DMARDs): A retrospective analysis of questions to a medicine call center

Background: Disease-modifying antirheumatic drugs (DMARDs) have transformed the treatment of numerous autoimmune and inflammatory diseases but their perceived risk of harm may be a barrier to use. Methods: In a retrospective mixed-methods study, we analysed conventional (c) and biologic (b) DMARDs-related calls and compared them with rest of calls (ROC) from consumers to an Australian national medicine call center operated by clinical pharmacists from September 2002 to June 2010. This includes the period where bDMARDs became available on the Pharmaceutical Benefits Scheme, the government-subsidized prescription medicines formulary. We compared caller and patient demographics, enquiry types and motivation to information-seek for both cDMARDs and bDMARDs with ROC, using a t-test for continuous data and a chi-square test for categorical data. We explored call narratives to identify common themes. Results: There were 1547 calls involving at least one DMARD. The top three cDMARD enquiry types were side effects (27.2%), interactions (21.9%), and risk versus benefit (11.7%). For bDMARDs, the most common queries involved availability and subsidized access (18%), mechanism and profile (15.8%), and side effects (15.1%). The main consumer motivations to information-seek were largely independent of medicines type and included: inadequate information (44%), wanting a second opinion (23.6%), concern about a worrying symptom (18.8%), conflicting information (6.9%), or information overload (2.3%). Question themes common to conventional and biological DMARDs were caller overemphasis on medication risk and the need for reassurance. Callers seeking information about bDMARDs generally overestimated effectiveness and focused their attention on availability, cost, storage, and medicine handling. Conclusion: Consumers have considerable uncertainty regarding DMARDs and may overemphasise risk. Patients cautiously assess the benefits and risks of their DMARDs but when new treatments emerge, they tend to overestimate their effectivenes

Minimizing Obstetric Hemorrhage

Patients undergoing cesarean deliveries are at risk for hemorrhage. In fact, hemorrhage is the leading cause of preventable maternal mortality and accounts for more than 140,000 deaths each year worldwide (O’Brien & Ulh, 2016). Hemorrhage has been associated with a number of well-established risk factors which could be recognized prior to delivery. Women who do not have these risk factors could still experience postpartum hemorrhage, but using a risk assessment tool has been shown to identify 60-85% of women who will experience hemorrhage (Shields, Goffman, & Caughey, 2017). The postpartum hemorrhage (PPH) risk assessment tool, developed by the Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN), identifies women with PPH risk factors. The tool allows clinicians to prepare for possible interventions and close monitoring of women at increased risk of bleeding, to ultimately prevent mortality. At a metropolitan hospital PPH risk assessments were not being discussed during standard pre-procedure huddles. This quality improvement project added the PPH risk assessment tool to the pre procedure huddle sheet. This facilitated interdisciplinary team discussion of PPH risk factors for patients undergoing cesarean deliveries. There were a total of 575 mothers in the study with 297 in the pre intervention period and 278 in the post. There was a statistically significant increase in estimated blood loss (EBL) between the pre and post intervention groups. While the study tool did not result in a decrease in EBL, it increased awareness among the interdisciplinary care team by facilitating discussion about PPH

Patient-based benefit-risk assessment of medicines: development, refinement, and validation of a content search strategy to retrieve relevant studies

INTRODUCTION: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area. METHODS: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis. RESULTS: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer

Narrowing the "digital divide" - facilitating access to computer technology to enhance the lives of those with aphasia: a feasibility study

Background: Despite advances in technology and the universal accessibility of the Internet, the aptly named “digital divide” still prevents equal access to, and use of, computer technology by people with aphasia. The use of technology has clear potential for improved quality of life in terms of increased methods for communicating as well as the facilitation of self-management; however, substantial barriers still pervade. Aims: The aims of this study were to evaluate a bespoke computer training course appropriate for people with aphasia and examine the personal experiences of a small sample of individuals with aphasia following their participation on the course. Methods & Procedures: This feasibility study with mixed-methods evaluation recruited participants with a range of aphasia severity and different experiences in using computers. Participants (n = 17) discussed their personal experiences of attending the computer course, gathered through topic-guided small focus groups, immediately postcourse and follow-up Refresher class. A Framework Method approach was considered an appropriate methodological design and data were analysed using thematic analysis. Participants also self-rated their skills in using computers before and following this bespoke computer course (n = 16) and at follow-up (n = 10), which was statistically analysed. Outcomes & Results: Statistically significant differences were found in the improved self-rated ability of a range of computer skills following course attendance. However, participants who attended a Refresher class (5, 9, or 12 months following course completion) reported that without support a number of these skills had notably declined. Three main themes emerged from the focus group data: (i) Facilitation of Social Engagement—technology offered new opportunities to communicate and more independently self-manage day-to-day tasks; (ii) Course Framework—participants reflected on their preferred model of delivery of the course; and finally (iii) Overcoming Barriers to Technology—the advantages of bespoke computer training, and requirements for ongoing support were highlighted as essential components of a training course appropriate for people with aphasia. Conclusions: The personal experiences of this group of people with aphasia highlight the advantages of accessing technology as a way of facilitating increased communication and an enhanced ability to manage their day-to-day lives. Yet, despite these benefits and the necessity for many people with aphasia to learn or relearn computer skills, finding courses that can accommodate individual needs is problematic. This research highlights the need for bespoke computer training and follow-on support, and highlights the necessary components of such training as identified by this group of people with aphasia

TCR deep sequencing of transgenic RAG-1-deficient mice reveals endogenous TCR recombination: a cause for caution

The utility of T‐cell receptor (TCR) transgenic mice in medical research has been considerable, with applications ranging from basic biology all the way to translational and clinical investigations. Crossing of TCR transgenic mice with either recombination‐activating gene (RAG)‐1 or RAG‐2 knockouts is frequently used to generate mice with a monoclonal T‐cell repertoire. However, low level productive TCR rearrangement has been reported in RAG‐deficient mice expressing transgenic TCRs. Using deep sequencing, we set out to directly examine and quantify the presence of these endogenous TCRs. Our demonstration that functional nontransgenic TCRs are present in nonmanipulated mice has wide reaching ramifications worthy of critical consideration

Final Report: International Workshop to Reconcile Methane Budgets in the Northern Permafrost Region

Keywords: methane, Arctic, permafrostAn International Workshop to Reconcile Methane Budgets in the Northern Permafrost Region, organized by the Study of Environmental Arctic Change (SEARCH), was held in Seattle on 7-9 March 2017. The workshop was funded by the National Science Foundation, the National Aeronautics and Space Administration, the U.S. Geological Survey, and the U.S. Arctic Research Commission. The primary goal was to produce a plan for reconciling methane budgets in the northern permafrost region. Forty-two scientists, including representatives of the atmospheric, inland (wetland and lakes), marine (coastal and oceanic), and remote sensing communities studying methane dynamics participated in developing the research plan. Eleven of the participants were early career scientists, and nine of the scientists were from institutions outside the United States. The first day of the workshop included keynote presentations that provided atmospheric, inland, and marine perspectives on developing a plan to reconcile methane budgets. There were also keynote presentations on the role of remote sensing in reconciling methane budgets. The second day of the workshop was devoted to breakout groups that developed plans from disciplinary perspectives, followed by breakouts of mixed disciplinary groups that discussed all three plans. The breakout groups identified key uncertainties and near-term and longer-term priorities for addressing questions about methane dynamics in the northern permafrost region. Participants committed to completing a paper describing a roadmap for the synthesis plan by the end of 2017, and each of the groups developed plans to address, by the end of 2018, near-term priorities to reduce uncertainties in methane budgets. The longer-term priorities include addressing possible sensitivities of methane emissions to climate variability and change in the region and evaluating the degree to which changes in methane dynamics are detectable. To address these longer-term priorities, there is a need to organize extant methane data for the northern permafrost region so that studies using these data can evaluate how enhancements to the methane observation network would improve estimates of methane emissions and the detection of trends. The Permafrost Action Team of SEARCH will develop research summaries and briefs based on the follow-on activities from the workshop.The National Science Foundation, the National Aeronautics and Space Administration, the U.S. Geological Survey, and the U.S. Arctic Research Commissio

Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis:Relationship to Gray Matter Volume

Background: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume. Methods: Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume. Results: At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p < .05) but higher glutamine in the anterior cingulate (p < .05). Within the ARMS group, the level of thalamic glutamate was directly correlated with gray matter volume in the medial temporal cortex and insula (p < .01). Conclusions: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness. © 2009 Society of Biological Psychiatry