The role of B cells in periodontitis

Introduction: Varying degrees of periodontal disease affect the majority of the population. Severe forms of periodontitis have a considerable impact on oral health and quality of life. Periodontitis results from imbalances in the oral microbiome and the host immune response. The mainstay of periodontal treatment – removal of dental plaque – is only partially successful. B cells infiltrate the gingiva of periodontitis patients, but their role in pathology has not been well characterised. The overarching aim of this research was to better characterise the role of B cells in periodontitis. Periodontitis shares similarities in risk factors and aspects of immunopathology with rheumatoid arthritis. Epidemiological evidence suggests patients with rheumatoid arthritis are more likely to have periodontitis, which cannot be completely explained by shared risk factors. This has led to the hypothesis that the two diseases are immunologically linked, and that periodontitis may precede, and cause, rheumatoid arthritis. A further objective of this research was to investigate whether the autoimmunity characteristic of rheumatoid arthritis emerges in periodontitis. Results: B cell infiltrate in the gingiva of periodontitis patients was confirmed. Periodontitis patients were found to have elevated serum titers of anti-citrullinated peptide antibodies which were generally below the diagnostic threshold for rheumatoid arthritis, and were reduced following non-surgical periodontal treatment. In a murine model of periodontitis, subtle changes to B cell phenotype were observed in tissues regional to the oral cavity in mice with periodontitis, at an early stage of disease. Such changes included increased B cell expression of receptor activator of NfκB ligand in the gingiva, and increased proportions of GC B cells in the draining lymph nodes. Some of these trends were enhanced in mice with periodontitis exacerbated by interleukin-33 treatment. B cell-deficient mice were protected from the alveolar bone loss normally induced in the model of periodontitis. Conclusion: B cells form a substantial proportion of the inflammatory infiltrate in the gingiva of periodontitis patients. Treatment of periodontitis can reduce titers of anti-citrullinated peptide antibodies in patients, potentially reducing their risk of developing rheumatoid arthritis. Evidence from B cell-deficient mice suggests that B cells contribute to pathological alveolar bone loss. Therefore, B cells may be worthy of targeting therapeutically in periodontitis

Moving forward with actionable therapeutic targets and opportunities in endometrial cancer:NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials

The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials

COPD discharge bundle and pulmonary rehabilitation referral and uptake following hospitalisation for acute exacerbation of COPD

Pulmonary rehabilitation (PR) following hospitalisations for acute exacerbation of COPD (AECOPD) is associated with improved exercise capacity and quality of life, and reduced readmissions. However, referral for, and uptake of, post-hospitalisation PR are low. In this prospective cohort study of 291 consecutive hospitalisations for AECOPD, COPD discharge bundles delivered by PR practitioners compared with non-PR practitioners were associated with increased PR referral (60% vs 12%, p<0.001; adjusted OR: 14.46, 95% CI: 5.28 to 39.57) and uptake (40% vs 32%, p=0.001; adjusted OR: 8.60, 95% CI: 2.51 to 29.50). Closer integration between hospital and PR services may increase post-hospitalisation PR referral and uptake

Diffusion of Subsidized ACTs in Accredited Drug Shops in Tanzania: Determinants of Stocking and Characteristics of Early and Late Adopters.

Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly influenced by the behavior of competing shops. Efforts to expand access to new pharmaceutical products in developing country markets could benefit from initial targeting of high profile shops in competitive markets and wholesale suppliers to encourage faster product diffusion across all drug retailers

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Do patients adhere to over-the-counter artemisinin combination therapy for malaria? evidence from an intervention study in Uganda

<p>Abstract</p> <p>Background</p> <p>Increasing affordability of artemisinin combination therapy (ACT) in the African retail sector could be critical to expanding access to effective malaria treatment, but must be balanced by efforts to protect the efficacy of these drugs. Previous research estimates ACT adherence rates among public sector patients, but adherence among retail sector purchasers could differ substantially. This study aimed to estimate adherence rates to subsidized, over-the-counter ACT in rural Uganda.</p> <p>Methods</p> <p>An intervention study was conducted with four licensed drug shops in Eastern Uganda in December 2009. Artemether-lumefantrine (AL) was made available for sale at a 95% subsidy over-the counter. Customers completed a brief survey at the time of purchase and then were randomly assigned to one of three study arms: no follow-up, follow-up after two days or follow-up after three days. Surveyors recorded the number of pills remaining through blister pack observation or through self-report if the pack was unavailable. The purpose of the three-day follow-up arm was to capture non-adherence in the sense of an incomplete treatment course ("under-dosing"). The purpose of the two-day follow-up arm was to capture whether participants completed the full course too soon ("over-dosing").</p> <p>Results</p> <p>Of the 106 patients in the two-day follow-up sample, 14 (13.2%) had finished the entire treatment course by the second day. Of the 152 patients in the three-day follow-up sample, 49 (32.2%) were definitely non-adherent, three (2%) were probably non-adherent and 100 (65.8%) were probably adherent. Among the 52 who were non-adherent, 31 (59.6%) had more than a full day of treatment remaining.</p> <p>Conclusions</p> <p>Overall, adherence to subsidized ACT purchased over-the-counter was found to be moderate. Further, a non-trivial fraction of those who complete treatment are taking the full course too quickly. Strategies to increase adherence in the retail sector are needed in the context of increasing availability and affordability of ACT in this sector.</p

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument

The Habitable Exoplanet Observatory (HabEx) Mission Concept Study Final Report

The Habitable Exoplanet Observatory, or HabEx, has been designed to be the Great Observatory of the 2030s. For the first time in human history, technologies have matured sufficiently to enable an affordable space-based telescope mission capable of discovering and characterizing Earthlike planets orbiting nearby bright sunlike stars in order to search for signs of habitability and biosignatures. Such a mission can also be equipped with instrumentation that will enable broad and exciting general astrophysics and planetary science not possible from current or planned facilities. HabEx is a space telescope with unique imaging and multi-object spectroscopic capabilities at wavelengths ranging from ultraviolet (UV) to near-IR. These capabilities allow for a broad suite of compelling science that cuts across the entire NASA astrophysics portfolio. HabEx has three primary science goals: (1) Seek out nearby worlds and explore their habitability; (2) Map out nearby planetary systems and understand the diversity of the worlds they contain; (3) Enable new explorations of astrophysical systems from our own solar system to external galaxies by extending our reach in the UV through near-IR. This Great Observatory science will be selected through a competed GO program, and will account for about 50% of the HabEx primary mission. The preferred HabEx architecture is a 4m, monolithic, off-axis telescope that is diffraction-limited at 0.4 microns and is in an L2 orbit. HabEx employs two starlight suppression systems: a coronagraph and a starshade, each with their own dedicated instrument.Comment: Full report: 498 pages. Executive Summary: 14 pages. More information about HabEx can be found here: https://www.jpl.nasa.gov/habex