Disruption of Histone Modification and CARM1 Recruitment by Arsenic Represses Transcription at Glucocorticoid Receptor-Regulated Promoters

Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promoter were identified by chromatin immunoprecipitation analysis following exposure to steroid hormone 6 iAs. Histone H3K18 and H3R17 amino acid residues had significantly different patterns of PTMs after treatment with iAs. Promoter interaction of the coactivator CARM1 was disrupted, but the interaction of GRIP1, a p160 coactivator through which CARM1 interacts with a promoter, was intact. Over-expression of CARM1 was able to fully restore and GRIP1 partially restored iAs-repressed transcription indicating that these coactivators are functionally associated with iAs-mediated transcriptional repression. Both are essential for robust transcription at steroid hormone regulated genes and both are associated with disease when inappropriately expressed. We postulate that iAs effects on CARM1 and GRIP1 may underlie some of its therapeutic effects and as well be associated with its toxic effects

Integrated palliative care in oncology: a protocol for a realist synthesis

Introduction Emerging evidence suggests improved quality of life, reduced symptom burden and lower health services costs when integrated palliative care and cancer care are implemented. Integrated palliative care aims to achieve care continuity by integrating organisational, administrative and clinical services involved in patient care networks. However, integrated palliative care for cancer is not common practice. This project, therefore, aims to understand how integrated palliative care and cancer care works in different healthcare settings (inpatient/outpatient), and for which groups of people (at what stage of the cancer journey), so we can develop guidance for optimal delivery. Methods and analysis We will conduct a realist synthesis to develop a programme theory of how integrated palliative care in cancer works, for whom and in what contexts to achieve improved symptom management and quality of life for patients and their families. This realist synthesis will follow the five stages outlined by Pawson: (1) locating existing theories, (2) searching for evidence, (3) article selection, (4) extracting and organising data and (5) synthesising the evidence and drawing conclusions. We will work closely with our expert stakeholder group, which includes health and social care professionals providing palliative care and oncology; management and policy groups and members of the public and patients. We will adhere to RAMESES quality standards for undertaking a realist synthesis. Ethics and dissemination Ethics approval for this project is not required. The realist synthesis will develop a programme theory that provides clarity on the optimal delivery of palliative care for adults with cancer. We will use the programme theory to coproduce guidance and user-friendly outputs, working with stakeholders to inform delivery of best practice. Findings will inform further research in integrated palliative care and cancer. Stakeholder engagement will assist in the dissemination of our findings. PROSPERO registration number CRD42023389791

Identification of families in need of support : correlates of adverse childhood experiences in the right@home sustained nurse home visiting program

Background Little is known about the efficacy of pregnancy screening tools using non-sensitive sociodemographic questions to identify the possible presence of as yet undiagnosed disease in individuals and later adverse childhood events disclosure. Objectives The study aims were to: 1) record the prevalence of risk disclosed by families during receipt of a sustained nurse home visiting program; and 2) explore patterns of relationships between the disclosed risks for their child having adverse experiences and the antenatal screening tool, which used non-sensitive demographic questions. Design Retrospective, observational study. Participants and methods Data about the participants in the intervention arm of the Australian right@home trial, which is scaffolded on the Maternal Early Childhood Sustained Home-visiting model, collected between 2013 and 2017 were used. Screening data from the 10-item antenatal survey of non-sensitive demographic risk factors and disclosed risks recorded by the nurse in audited case files during the subsequent 2 year intervention were examined (n = 348). Prevalence of disclosed risks for their child having adverse experiences were analysed in 2019 using multiple response frequencies. Phi correlations were conducted to test associations between screening factors and disclosed risks. Results Among the 348 intervention participants whose files were audited, 300 were noted by nurses to have disclosed risks during the intervention, with an average of four disclosures. The most prevalent maternal disclosures were depression or anxiety (57.8%). Mental health issues were the most prevalent partner and family disclosures. Screening tool questions on maternal smoking in pregnancy, not living with another adult, poverty and self-reporting anxious mood were significantly associated with a number of disclosed risks for their child having adverse experiences. Conclusions These findings suggest that a non-sensitive sociodemographic screening tool may help to identify families at higher risk for adverse childhood experiences for whom support from a sustained nurse home visiting program may be beneficial

The Nuclear Spectroscopic Telescope Array (NuSTAR)

The Nuclear Spectroscopic Telescope Array (NuSTAR) is a NASA Small Explorer mission that will carry the first focusing hard X-ray (5 -- 80 keV) telescope to orbit. NuSTAR will offer a factor 50 -- 100 sensitivity improvement compared to previous collimated or coded mask imagers that have operated in this energy band. In addition, NuSTAR provides sub-arcminute imaging with good spectral resolution over a 12-arcminute field of view. After launch, NuSTAR will carry out a two-year primary science mission that focuses on four key programs: studying the evolution of massive black holes through surveys carried out in fields with excellent multiwavelength coverage, understanding the population of compact objects and the nature of the massive black hole in the center of the Milky Way, constraining explosion dynamics and nucleosynthesis in supernovae, and probing the nature of particle acceleration in relativistic jets in active galactic nuclei. A number of additional observations will be included in the primary mission, and a guest observer program will be proposed for an extended mission to expand the range of scientific targets. The payload consists of two co-aligned depth-graded multilayer coated grazing incidence optics focused onto solid state CdZnTe pixel detectors. To be launched in early 2012 on a Pegasus rocket into a low-inclination Earth orbit. Data will be publicly available at GSFC's High Energy Astrophysics Science Archive Research Center (HEASARC) following validation at the science operations center located at Caltech.Comment: 9 pages, 5 figures, to appear in Proceedings of the SPIE, Space Telescopes and Instrumentation 2010: Ultraviolet to Gamma Ra

Economic evaluation of an Australian nurse home visiting programme : a randomised trial at 3 years

Objectives To investigate the additional programme cost and cost-effectiveness of ‘right@home’ Nurse Home Visiting (NHV) programme in relation to improving maternal and child outcomes at child age 3 years compared with usual care. Design A cost–utility analysis from a government-as-payer perspective alongside a randomised trial of NHV over 3-year period. Costs and quality-adjusted lifeyears (QALYs) were discounted at 5%. Analysis used an intention-to-treat approach with multiple imputation. Setting The right@home was implemented from 2013 in Victoria and Tasmania states of Australia, as a primary care service for pregnant women, delivered until child age 2 years. Participants 722 pregnant Australian women experiencing adversity received NHV (n=363) or usual care (clinic visits) (n=359). Primary and secondary outcome measures First, a cost–consequences analysis to compare the additional costs of NHV over usual care, accounting for any reduced costs of service use, and impacts on all maternal and child outcomes assessed at 3 years. Second, cost–utility analysis from a government-as-payer perspective compared additional costs to maternal QALYs to express cost-effectiveness in terms of additional cost per additional QALY gained. Results When compared with usual care at child age 3 years, the right@home intervention cost $A7685 extra per woman (95$A7006 to $A8364) and generated 0.01 more QALYs (95$A50 000 per QALY. Conclusions Benefits of NHV to parenting at 2 years and maternal health and well-being at 3 years translate into marginal maternal QALY gains. Like previous cost-effectiveness results for NHV programmes, right@home is not cost-effective at 3 years. Given the relatively high up-front costs of NHV, long-term follow-up is needed to assess the accrual of health and economic benefits over time

Patients’ preferences for fracture risk communication : the Risk Communication in Osteoporosis (RICO) study

Summary The RICO study indicated that most patients would like to receive information regarding their fracture risk but that only a small majority have actually received it. Patients globally preferred a visual presentation of fracture risk and were interested in an online tool showing the risk. Purpose The aim of the Risk Communication in Osteoporosis (RICO) study was to assess patients’ preferences regarding fracture risk communication. Methods To assess patients’ preferences for fracture risk communication, structured interviews with women with osteoporosis or who were at risk for fracture were conducted in 11 sites around the world, namely in Argentina, Belgium, Canada at Hamilton and with participants from the Osteoporosis Canada Canadian Osteoporosis Patient Network (COPN), Japan, Mexico, Spain, the Netherlands, the UK, and the USA in California and Washington state. The interviews used to collect data were designed on the basis of a systematic review and a qualitative pilot study involving 26 participants at risk of fracture. Results A total of 332 women (mean age 67.5 ± 8.0 years, 48% with a history of fracture) were included in the study. Although the participants considered it important to receive information about their fracture risk (mean importance of 6.2 ± 1.4 on a 7-point Likert scale), only 56% (i.e. 185/332) had already received such information. Globally, participants preferred a visual presentation with a traffic-light type of coloured graph of their FRAX® fracture risk probability, compared to a verbal or written presentation. Almost all participants considered it important to discuss their fracture risk and the consequences of fractures with their healthcare professionals in addition to receiving information in a printed format or access to an online website showing their fracture risk. Conclusions There is a significant communication gap between healthcare professionals and patients when discussing osteoporosis fracture risk. The RICO study provides insight into preferred approaches to rectify this communication gap

InnateDB: facilitating systems-level analyses of the mammalian innate immune response

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems-level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity-relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user-supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems-oriented manner

The Human Transcriptome During Nontyphoid Salmonella and HIV Coinfection Reveals Attenuated NFκB-Mediated Inflammation and Persistent Cell Cycle Disruption

Background. Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses

A 2018 Horizon Scan of Emerging Issues for Global Conservation and Biological Diversity.

This is our ninth annual horizon scan to identify emerging issues that we believe could affect global biological diversity, natural capital and ecosystem services, and conservation efforts. Our diverse and international team, with expertise in horizon scanning, science communication, as well as conservation science, practice, and policy, reviewed 117 potential issues. We identified the 15 that may have the greatest positive or negative effects but are not yet well recognised by the global conservation community. Themes among these topics include new mechanisms driving the emergence and geographic expansion of diseases, innovative biotechnologies, reassessments of global change, and the development of strategic infrastructure to facilitate global economic priorities

The "Petechiae in children" (PiC) study: Evaluating potential clinical decision rules for the management of feverish children with non-blanching rashes, including the role of point of care testing for Procalcitonin & Neisseria meningitidis DNA - a stu

© 2018 The Author(s). Background: Children commonly present to Emergency Departments (ED) with a non-blanching rash in the context of a feverish illness. While most have a self-limiting viral illness, this combination of features potentially represents invasive serious bacterial infection, including meningococcal septicaemia. A paucity of definitive diagnostic testing creates diagnostic uncertainty for clinicians; a safe approach mandates children without invasive disease are often admitted and treated with broad-spectrum antibiotics. Conversely, a cohort of children still experience significant mortality and morbidity due to late diagnosis. Current management is based on evidence which predates (i) the introduction of meningococcal B and C vaccines and (ii) availability of point of care testing (POCT) for procalcitonin (PCT) and Neisseria meningitidis DNA. Methods: This PiC study is a prospective diagnostic accuracy study evaluating (i) rapid POCT for PCT and N. meningitidis DNA and (ii) performance of existing clinical practice guidelines (CPG) for feverish children with non-blanching rash. All children presenting to the ED with a history of fever and non-blanching rash are eligible. Children are managed as normal, with detailed prospective collection of data pertinent to CPGs, and a throat swab and blood used for rapid POCT. The study is running over 2years and aims to recruit 300 children. Primary objective: Report on the diagnostic accuracy of POCT for (i) N. meningitidis DNA and (ii) PCT in the diagnosis of early MD Discussion: The PiC study will provide important information for policy makers regarding the value of POCT and on the utility and cost of emerging diagnostic strategies. The study will also identify which elements of existing CPGs may merit inclusion in any future study to derive clinical decision rules for this population