Clostridium perfringens epsilon toxin (Etx) is a pore-forming toxin responsible for a severe and rapidly fatal enterotoxemia of ruminants. The toxin is classified as a category B bioterrorism agent by the U.S. Government Centres for Disease Control and Prevention (CDC), making work with recombinant toxin difficult. To reduce the hazard posed by work with recombinant Etx, we have used a variant of Etx that contains a H149A mutation (Etx-H149A), previously reported to have reduced, but not abolished, toxicity. The three-dimensional structure of H149A prototoxin shows that the H149A mutation in domain III does not affect organisation of the putative receptor binding loops in domain I of the toxin. Surface exposed tyrosine residues in domain I of Etx-H149A (Y16, Y20, Y29, Y30, Y36 and Y196) were mutated to alanine and mutants Y30A and Y196A showed significantly reduced binding to MDCK.2 cells relative to Etx-H149A that correlated with their reduced cytotoxic activity. Thus, our study confirms the role of surface exposed tyrosine residues in domain I of Etx in binding to MDCK cells and the suitability of Etx-H149A for further receptor binding studies. In contrast, binding of all of the tyrosine mutants to ACHN cells was similar to that of Etx-H149A, suggesting that Etx can recognise different cell surface receptors. In support of this, the crystal structure of Etx-H149A identified a glycan (β-octyl-glucoside) binding site in domain III of Etx-H149A, which may be a second receptor binding site. These findings have important implications for developing strategies designed to neutralise toxin activity.
RECOVER is a site-specific decision support system that automatically brings together in a single analysis environment the information necessary for post-fire rehabilitation decision-making. After a major wildfire, law requires that the federal land management agencies certify a comprehensive plan for public safety, burned area stabilization, resource protection, and site recovery. These burned area emergency response (BAER) plans are a crucial part of our national response to wildfire disasters and depend heavily on data acquired from a variety of sources. Final plans are due within 21 days of control of a major wildfire and become the guiding document for managing the activities and budgets for all subsequent remediation efforts. There are few instances in the federal government where plans of such wide-ranging scope and importance are assembled on such short notice and translated into action more quickly. RECOVER has been designed in close collaboration with our agency partners and directly addresses their high-priority decision-making requirements. In response to a fire detection event, RECOVER uses the rapid resource allocation capabilities of cloud computing to automatically collect Earth observational data, derived decision products, and historic biophysical data so that when the fire is contained, BAER teams will have a complete and ready-to-use RECOVER dataset and GIS analysis environment customized for the target wildfire. Initial studies suggest that RECOVER can transform this information-intensive process by reducing from days to a matter of minutes the time required to assemble and deliver crucial wildfire-related data.
RECOVER is a site-specific decision support system that automatically brings together in a single analysis environment the information necessary for post-fire rehabilitation decision-making. After a major wildfire, law requires that the federal land management agencies certify a comprehensive plan for public safety, burned area stabilization, resource protection, and site recovery. These burned area emergency response (BAER) plans are a crucial part of our national response to wildfire disasters and depend heavily on data acquired from a variety of sources. Final plans are due within 21 days of control of a major wildfire and become the guiding document for managing the activities and budgets for all subsequent remediation efforts. There are few instances in the federal government where plans of such wide-ranging scope and importance are assembled on such short notice and translated into action more quickly. RECOVER has been designed in close collaboration with our agency partners and directly addresses their high-priority decision-making requirements. In response to a fire detection event, RECOVER uses the rapid resource allocation capabilities of cloud computing to automatically collect Earth observational data, derived decision products, and historic biophysical data so that when the fire is contained, BAER teams will have a complete and ready-to-use RECOVER dataset and GIS analysis environment customized for the target wildfire. Initial studies suggest that RECOVER can transform this information-intensive process by reducing from days to a matter of minutes the time required to assemble and deliver crucial wildfire-related data.
Background: Appropriate choice of research design is essential to rightly understand the research problem and derive optimal solutions. The Comorbidity Action in the North project sought to better meet the needs of local people affected by drug, alcohol and mental health comorbidity. The aim of the study focused on the needs of Aboriginal peoples and on developing a truly representative research process. A methodology evolved that best suited working with members of a marginalised Aboriginal community. This paper discusses the process of co-design of a Western methodology (participatory action research) in conjunction with the Indigenous methodologies Dadirri and Ganma. This co-design enabled an international PhD student to work respectfully with Aboriginal community members and Elders, health professionals and consumers, and non-Indigenous service providers in a drug and alcohol and mental health comorbidity project in Adelaide, South Australia. Methods The PhD student, Aboriginal Elder mentor, Aboriginal Working Party, and supervisors (the research team) sought to co-design a methodology and applied it to address the following challenges: the PhD student was an international student with no existing relationship with local Aboriginal community members; many Aboriginal people deeply distrust Western research due to past poor practices and a lack of implementation of findings into practice; Aboriginal people often remain unheard, unacknowledged and unrecognised in research projects; drug and alcohol and mental health comorbidity experiences are often distressing for Aboriginal community members and their families; attempts to access comorbidity care often result in limited or no access; and Aboriginal community members experience acts of racism and discrimination as health professionals and consumers of health and support services. The research team considered deeply how knowledge is shared, interpreted, owned and controlled, by whom and how, within research, co-morbidity care and community settings. The PhD student was supported to co-design a methodology that was equitable, democratic, liberating and life-enhancing, with real potential to develop feasible solutions.Results The resulting combined Participatory Action Research (PAR)-Dadirri-Ganma methodology sought to create a bridge across Western and Aboriginal knowledges, understanding and experiences. Foundation pillars of this bridge were mentoring of the PhD student by senior Elders, who explained and demonstrated the critical importance of Yarning (consulting) and Indigenous methodologies of Dadirri (deep listening) and Ganma (two-way knowledge sharing), and discussions among all involved about the principles of Western PAR. Conclusions Concepts within this paper are shared from the perspective of the PhD student with the permission and support of local Elders and Working Group members. The intention is to share what was learned for the benefit of other students, research projects and community members who are beginning a similar journey. ; Hepsibah Sharmil, Janet Kelly, Margaret Bowden, Cherrie Galletly, Imelda Cairney, Coral Wilson
Funding for this study was provided by: CancerResearch UK (C6199/A10417 and C399/A2291),the European Union Seventh Framework Programme(FP7/207-2013) grant 258236 collaborative projectSYSCOL, European Research Council project EVO-CAN, the Dutch Cancer Society, Research FundFlanders (F.W.O.) grant no. G.0827.13, the MedicalResearch Council, the Wellcome Trust and Departmentof Health as part of a Health Innovation ChallengeFund grant (R6-388), the National Institute for HealthResearch (NIHR) Oxford Biomedical Research Cen-tre, Ovarian Cancer Action and core funding to theWellcome Trust Centre for Human Genetics from theWellcome Trust (090532/Z/09/Z). The views expressedare those of the authors and not necessarily those ofthe NHS, the NIHR, the Department of Health or theWellcome Trust.DT is funded by an EPSRC doctoral training grantvia CoMPLEX. MG is funded by a Studentshipfrom the Wellcome Trust. TB is funded by theDutch Cancer Society Young Investigator Grant10418. ADB acknowledges funding from the Well-come Trust (102732/Z/13/Z), Cancer Research UK(C31641/A23923) and the Medical Research Coun-cil (MR/M016587/1). FA is a senior researcher forthe F.W.O. TG is a Cancer Research UK CareerDevelopment Fellow (A19771) and a Wellcome TrustInvestigator (202778/Z/16/Z). DNC is funded by aHealth Foundation/Academy of Medical SciencesClinician Scientist Fellowship.The cost of open access publication was provided bycore funding to the Wellcome Trust Centre for HumanGenetics from the Wellcome Trust (090532/Z/09/Z).
We are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award. ; Background This Commission addresses several priority areas for psychiatry over the next decade, and into the 21st century. These represent challenges and opportunities for the profession to sustain and develop itself to secure the best possible future for the millions of people worldwide who will face life with mental illness. Part 1: The patient and treatment Who will psychiatrists help? The patient population of the future will reflect general demographic shifts towards older, more urban, and migrant populations. While technical advances such as the development of biomarkers will potentially alter diagnosis and treatment, and digital technology will facilitate assessment of remote populations, the human elements of practice such as cultural sensitivity and the ability to form a strong therapeutic alliance with the patient will remain central. Part 2: Psychiatry and health-care systems Delivering mental health services to those who need them will require reform of the traditional structure of services. Few existing models have evidence of clinical effectiveness and acceptability to service users. Services of the future should consider stepped care, increased use of multidisciplinary teamwork, more of a public health approach, and the integration of mental and physical health care. These services will need to fit into the cultural and economic framework of a diverse range of settings in high-income, low-income, and middle-income countries. Part 3: Psychiatry and society Increased emphasis on social interventions and engagement with societal expectations might be an important area for psychiatry's development. This could encompass advocacy for the rights of individuals living with mental illnesses, political involvement concerning the social risk factors for mental illness, and, on a smaller scale, work with families and local social networks and communities. Psychiatrists should therefore possess communication skills and knowledge of the social sciences as well as the basic biological sciences. Part 4: The future of mental health law Mental health law worldwide tends to be based on concerns about risk rather than the protection of the rights of individuals experiencing mental illness. The United Nations Convention on the Rights of Persons with Disabilities, which states that compulsion based in whole or in part on mental disability is discriminatory, is a landmark document that should inform the future formulation and reform of mental health laws. An evidence-based approach needs to be taken: mental health legislation should mandate mental health training for all health professionals; ensure access to good-quality care; and cover wider societal issues, particularly access to housing, resources, and employment. All governments should include a mental health impact assessment when drafting relevant legislation. Part 5: Digital psychiatry—enhancing the future of mental health Digital technology might offer psychiatry the potential for radical change in terms of service delivery and the development of new treatments. However, it also carries the risk of commercialised, unproven treatments entering the medical marketplace with detrimental effect. Novel research methods, transparency standards, clinical evidence, and care delivery models must be created in collaboration with a wide range of stakeholders. Psychiatrists need to remain up to date and educated in the evolving digital world. Part 6: Training the psychiatrist of the future Rapid scientific advance and evolving models of health-care delivery have broad implications for future psychiatry training. The psychiatrist of the future must not only be armed with the latest medical knowledge and clinical skills but also be prepared to adapt to a changing landscape. Training programmes in an age in which knowledge of facts is less important than how new knowledge is accessed and deployed must refocus from the simple delivery of information towards acquisition of skills in lifelong learning and quality improvement. Conclusion Psychiatry faces major challenges. The therapeutic relationship remains paramount, and psychiatrists will need to acquire the necessary communication skills and cultural awareness to work optimally as patient demographics change. Psychiatrists must work with key stakeholders, including policy makers and patients, to help to plan and deliver the best services possible. The contract between psychiatry and society needs to be reviewed and renegotiated on a regular basis. Mental health law should be reformed on the basis of evidence and the rights of the individual. Psychiatry should embrace the possibilities offered by digital technology, and take an active role in ensuring research and care delivery in this area is ethically sound and evidence based. Psychiatry training must reflect these multiple pressures and demands by focusing on lifelong learning rather than simply knowledge delivery. Introduction ; We are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award.
The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle–income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide.
