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  • Director of Interventional Cardiovascular Research and
  • Co-Director of the Ischemia and Metabolism
  • Thematic Research Davis Heart and Lung Institute, Assistant
  • Professor of Internal Medicine, The Ohio State University

In spite of these efforts medicine emoji disulfiram 250 mg otc, no opioid formulation prevents consumption of a large number of intact capsules or tablets treatment glaucoma 250mg disulfiram, which continues to be the most common method of abuse medicine 7 year program order disulfiram amex. Opioid Agent Conversion Factor fi Multiply the daily dosage for each opioid by the conversion factor to determine the equianalgesic Codeine1 0 medications over the counter order disulfiram 250 mg line. Equianalgesic dose conversions are only estimates and cannot account for individual variability in genetics and pharmacokinetics treatment broken toe purchase generic disulfiram on-line. Hydrocodone 1 fi Use particular caution with fentanyl because it is dosed in mcg/hr instead of mg/d symptoms joint pain and tiredness cheap 500mg disulfiram visa, and absorption is affected by heat and other factors. Oxymorphone 3 Hydromorphone 4 1When converting from weak opioid analgesics to more potent opioids, use the recommended initial doses of the new opioid for opioid-naive patients. Titration should be based on patient response and not solely based on equianalgesic dosing tables. Overview Methadone is indicated for persistent, moderate-to-severe chronic pain in patients requiring continuous, around-the-clock opioid administration over an extended time. Also, as a result of the dissociation between half-life and analgesic duration, tissue accumulation of methadone can occur. It may take ten days for plasma levels to stabilize; thus, as a general rule, dose titration should not be more frequent than every 5-7 days. Dosing Strategies the dosing recommendations listed below (in Table D-5) are provided to offer guidance on using methadone in the treatment of patients with chronic pain, particularly when converting from another opioid to methadone. If such resources are not readily available, other long-acting opioids should be considered. Various methadone dosing strategies have been employed [224,238,239] and methods are still evolving. Older, prospective studies found no evidence to support the superiority of one dosing strategy over another. For opioid tolerant patients, a number of different equianalgesic dose ratio tables can be used to determine the dose of methadone. No equianalgesic dose ratio table is considered superior and all have similar limitations. Once the dose is determined, there are two different methods to make the switch: a rapid conversion method and a stepwise/phased conversion. Then the previous opioid dose is decreased by an additional 1/3 and the methadone dose is increased by 1/3. Finally, the remaining 1/3 of the previous opioid dose is discontinued and the methadone dose is increased to the initial calculated dose. As-needed methadone has also been used in a palliative care setting;[224,238,240] however, it is generally discouraged to avoid drug accumulation. Converting from Methadone to Oral Morphine Switching from methadone to another opioid is not simply the reverse process; the equianalgesic dose ratio tables previously mentioned are not bi-directional and cannot be used in reverse. A proposed safe and conservative approach is a 1:3 methadone to morphine ratio (10 mg methadone/day = 30 mg oral morphine/day). Special Patient Populations Patients 65 years and older may have decreased clearance of methadone. Dosage adjustments may be necessary in patients with end-stage liver or renal disease. Patients should never take extra doses without getting approval from the prescriber. Adding medications or changing dosing of other medications can affect methadone and should be coordinated with the methadone prescriber. It includes the condition(s), populations or subP Population, or populations, disease severity or stage, co-occurring conditions, and other patient Problem characteristics or demographics. Intervention or Refers to the specific treatments or approaches used with the patient or population. It I Exposure includes doses, frequency, methods of administering treatments, etc. Describes the interventions or care that is being compared with the intervention(s) of C Comparison interest described above. It includes alternatives such as placebo, drugs, surgery, lifestyle changes, standard of care, etc. Outcomes can include short, intermediate, and O Outcome long-term outcomes, or specific results such as quality of life, complications, mortality, morbidity, etc. Timing, if Describes the duration of time that is of interest for the particular patient intervention and (T) applicable outcome, benefit, or harm to occur (or not occur). Setting can be a location (such as primary, (S) applicable specialty, or inpatient care). Thus, the Champions and Work Group determined which questions were of highest priority, and those were included in the review. Population(s) Adults 18 years or older with chronic cancer or non-cancer pain treated in any clinical setting were covered in this systematic review. Intervention(s) Table E-2 lists the interventions that were covered in this systematic review. Comparator(s) Table E-3 lists the comparators of interest to this systematic review. Of those, 11,633 were excluded upon title review for clearly not meeting inclusion criteria. Searches to address these sub-questions were highly targeted to include systematic reviews only. Additionally, one systematic review was identified through hand searches of the literature and was also included in the final evidence base. Searches to address this intervention were highly targeted to include systematic reviews assessing use of take-home naloxone. Searches to address this sub-question were broad, but the selection criteria were highly targeted to focus on prospective studies assessing risks associated with acute opioid use to treat acute pain. Four retrospective cohorts and one secondary data analysis were included in the evidence base. Systematic reviews were supplemented with clinical studies published subsequent to the systematic review. Similarly, letters, editorials, and other publications that were not full-length clinical studies were not accepted as evidence. If the percentage is less than 80%, then data must have been reported separately for this patient subgroup. Large retrospective database studies (200 patients minimum) that performed multivariate statistical analyses of the effect of co-occurring conditions on patient outcomes were also acceptable. Literature Search Strategy Information regarding the bibliographic databases, date limits, and platform/provider can be found in Table E-5, below. Additional information on the search strategies, including topic-specific search terms and search strategies can be found in Appendix J. The subject matter experts were divided into two smaller subgroups at this meeting. Each recommendation was graded by assessing the quality of the overall evidence base, the associated benefits and harms, the variation in values and preferences, and other implications of the recommendation. They discussed the available evidence as well as changes in clinical practice since 2010, as necessary, to update the algorithm. Balance of desirable and undesirable outcomes refers to the size of anticipated benefits. This domain is based on the understanding that the majority of clinicians will offer patients therapeutic or preventive measures as long as the advantages of the intervention exceed the risks and adverse effects. The certainty or uncertainty of the clinician about the risk-benefit balance will greatly influence the strength of the recommendation. Confidence in the quality of the evidence reflects the quality of the evidence base and the certainty in that evidence. This second domain reflects the methodological quality of the studies for each outcome variable. In general, the strength of recommendation follows the level of evidence, but not always, as other domains may increase or decrease the strength. More precisely, it refers to the processes that individuals use in considering the potential benefits, harms, costs, limitations, and inconvenience of the therapeutic or preventive measures in relation to one another. In a situation in which the balance of benefits and risks are uncertain, eliciting the values, concerns, and preferences of patients and empowering them or their surrogates to make decisions consistent with patient goals of care becomes even more important. Other implications consider the practicality of the recommendation, including resources use, equity, acceptability, feasibility and subgroup considerations. Resource use is related to the uncertainty around the cost-effectiveness of a therapeutic or preventive measure. For example statin use in the frail elderly and others with multiple co-occurring conditions may not be effective and depending on the societal benchmark for willingness to pay, may not be a good use of resources. Equity, acceptability, feasibility, and subgroup considerations require similar judgments around the practically of the recommendation. The framework below (Table E-6) was used by the Work Group to guide discussions on each domain. Evidence to Recommendation Framework Decision Domain Judgment Balance of desirable and undesirable outcomes fi Given the best estimate of typical values and preferences, are you Benefits outweigh harms/burden confident that the benefits outweigh the harms and burden or vice Benefits slightly outweigh harms/burden versafi Benefits and harms/burden are balanced fi Are the desirable anticipated effects largefi Harms/burden slightly outweigh benefits fi Are the undesirable anticipated effects smallfi Harms/burden outweigh benefits fi Are the desirable effects large relative to undesirable effectsfi Confidence in the quality of the evidence High fi Is there highor moderate quality evidence that answers this Moderate questionfi Very low Values and preferences fi Are you confident about the typical values and preferences and are they similar across the target populationfi Some variation fi Are the assumed or identified relative values similar across the target Large variation populationfi Various considerations fi Is this intervention and its effects worth withdrawing or not allocating resources from other interventionsfi The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four domains. While strong recommendations are usually based on high or moderate confidence in the estimates of effect (quality of the evidence) there may be instances where strong recommendations are warranted even when the quality of evidence is low. If the Work Group is less confident of the balance between desirable and undesirable outcomes, they present a weak recommendation. Similarly, a recommendation for a therapy or preventive measure indicates that the desirable consequences outweigh the undesirable consequences. A recommendation against a therapy or preventive measure indicates that the undesirable consequences outweigh the desirable consequences. Recommendations may be at the discretion of the patient and clinician, or they may be qualified with an explanation about the issues that would lead decisions to vary. Categorizing Recommendations with an Updated Review of the Evidence Recommendations were first categorized by whether or not they were based on an updated review of the evidence. These recommendations could have also included clinically significant changes to the previous version. This occurred if the evidence supporting the recommendations was out of date, to the extent that there was no longer any basis to recommend a particular course of care and/or new evidence suggests a shift in care, rendering recommendations in the previous version of the guideline obsolete. For areas of research that have not changed, and for which recommendations made in the previous version of the guideline were still relevant, recommendations could have been carried forward to the updated guideline without an updated systematic review of the evidence. The categories for the recommendations included in the 2017 version of the guideline are noted in the Recommendations. During this time, the Champions and Work Group also made additional revisions to the algorithm, as necessary. The Work Group also produced a set of guideline toolkit materials, which included a provider summary, pocket card, and a patient summary. However, recruitment focused on eliciting a range of perspectives likely to be relevant and informative in the guideline development process. Patients were not incentivized for their participation or reimbursed for travel expenses. The facilitator from Lewin led the discussion using interview questions prepared by the Work Group as a general guide to elicit the most important information from the patients regarding their experiences and views about their treatment and overall care. Given the limited time and the range of interests and expressiveness of the participants, not all of the listed questions were addressed.

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It is a collaborative effort: though we see far treatment 7 purchase 500mg disulfiram free shipping, it is only because we stand on the shoulders of those who have come before symptoms 5dp5dt buy cheap disulfiram online. Please feel free to contact the University Librarian on your campus with questions or concerns symptoms gestational diabetes buy discount disulfiram 500mg online, or any of us treatment refractory order disulfiram 500 mg visa. Sincerely treatment resistant anxiety disulfiram 500mg with amex, Laine Farley Executive Director California Digital Library University of California symptoms 2 days before period disulfiram 500mg discount, Office of the President laine. Please consult with your University Librarian for more information about online journal subscriptions at each of the ten campuses. More than 30,000 journals are available systemwide including aggregated databases. I find publications of public research both educational and interesting to read and I would hate to see my access limited. Extending enhanced public access policies to other federal agencies is long overdue. Question 1) Are there steps that agencies could take to grow existing and new markets related to the access and analysis of peer-reviewed publications that result from federally funded scientific researchfi Comment 1) There are a number of steps that agencies should take to grow existing and new markets relating to access and analysis of peer-reviewed publications resulting from federally funded scientific research. All peer-reviewed articles resulting from publicly funded research should be freely available immediately so that scientists, researchers, students, teachers, citizen scientists, and members of the public can utilize these resources. It is time to take full advantage of networked, information technologies in order to spur innovation, advance science, and grow new markets. Despite the growing market share of open access journals, a large percentage of federally funded, peer-reviewed research results are still only available via subscriptions, or sometimes through the purchase of individual articles at a very high 2 cost. This marketplace model significantly limits access to those who could both conduct research and design new tools and services and, yet, are handicapped by cost and access barriers. There is ample evidence that openly available data and research resources leads to more research, quickens the pace of that research, and yields greater commercialization and development of new tools and services. For example, two reports described below provide clear evidence that openly available resources with no reuse restrictions promoted economic growth and created new jobs and markets. In 2010 alone, the human genome sequencing projects and associated genomics research and industry activity directly and indirectly generated $67 billion in U. By making federally funded research results publicly accessible, new audiences and new innovators with differing perspectives are able to benefit from such access. For example, recently we have seen the emergence of new services such as Google Scholar, BioCreAtivE, CoPub, PubGene, and more. There are deep linkages between openly accessible federally funded, peer-reviewed 3 research literature and scientific productivity. Research has shown that open access to research literature provides many benefits to science and discovery. For example, it expands the use of research papers, thus increasing citations and the ability to build on the work of others. Reproducibility and building on the work of others are integral to science, and they are also necessities in this new budget environment. Open access to research resources sparks new approaches to scientific discovery, particularly across scientific disciplines, and such access is especially critical as science is increasingly interdisciplinary and global. It is widely understood that these investments are central to advancing science, education, innovation, and our competitive marketplace. And these investments have given rise to new forms of research, allowing scientists to be more productive and explore new research pathways via computational research and analysis. Examples of such insights include the identification of patient subsets who do or do not respond to a specific therapy during a clinical trial, which has the potential to drive 4 personalized medicine; identification of patient subsets with differential safety profiles, efficacy, or side effects related to age or gender; evaluations of standard of care; analyses of disease progression; assessment of current endpoints based on aggregated data; and potential to generate better endpoints and insight into placebo effects. Such an approach would avoid duplication of effort and is the most logical given the current budgetary environment. In order to maximize the investments in cyber and information infrastructure, advance science, and promote innovation, free immediate access with full reuse rights to federally funded research literature would achieve the most benefits. There should be no restrictions placed on use of this literature or on who is able to use these federally funded information resources. This would be consistent with existing federal policy, the Paperwork Reduction Act and Circular A-130, concerning government information. Question 2) What specific steps can be taken to protect the intellectual property interests of publishers, scientists, Federal agencies, and other stakeholders involved with the publication and dissemination of peer-reviewed scholarly publications resulting from federally funded scientific researchfi Use of these licenses permits the user full use rights to mine data and text, and manipulate, reuse, and integrate data and information in publicly accessible digital repositories. As the White House considers a new federal open/public access policy, it is essential that the results of federally funded research be accessible in the most effective manner. So for example, if an embargo is deemed necessary, it should be as short as possible. And once the embargo is lifted, then full reuse rights should be associated with the research literature. Regardless of where the publications reside, full reuse rights are essential elements of an effective policy. Question 3) What are the pros and cons of centralized and decentralized approaches to managing public access to peer-reviewed scholarly publications that result from federally funded research in terms of interoperability, search, development of analytic tools, and other scientific and commercial opportunitiesfi For example, through a provision in the Copyright Act, printed copyrighted and public domain works are placed on deposit at the Library of Congress. Beginning in 2010, the Library extended this deposit requirement to include electronic-only serials. The National Library of Medicine has been providing long-term preservation of and access to biomedical information for 175 years. As more and more institutions and organizations establish digital repositories, there will be many sites providing access to federally funded research literature, nationally and internationally. For example, PubMed Central is one of many sources for the biomedical literature it archives once any embargo period for an article has expired. As we have learned, long-term preservation of and access to digital resources requires use; dark archives are not an option. To ensure that there is not deterioration of these digital resources and that there is a valid record going forward, continuous use is required. And as these partnerships emerge, clearly delineating roles and responsibilities will be key. Question 4) Are there models or new ideas for public-private partnerships that take advantage of existing publisher archives and encourage innovation in accessibility and interoperability, while ensuring long-term stewardship of the results of federally funded researchfi Comment 4) Libraries and many universities have a long history of partnering with others to ensure the long-term preservation of and access to research resources. It is an archive of 726,955 electronic preprints of research papers in the fields of mathematics, physics, computer science, quantitative biology, statistics, and quantitative finance arxiv. More recently, HathiTrust Digital Library was established and is a partnership of major national and international research institutions and libraries working to ensure that the cultural record is preserved and accessible in the future. These partnerships demonstrate the commitment of research libraries and universities to the long-term preservation of and access to cultural and scientific records. Key to their success includes requiring the appropriate terms and conditions for long-term preservation, curation, interoperability, and use rights. Question 5) What steps can be taken by Federal agencies, publishers, and/or scholarly and professional societies to encourage interoperable search, discovery, and analysis capacity across disciplines and archivesfi What are the minimum core metadata for 7 scholarly publications that must be made available to the public to allow such capabilitiesfi How should Federal agencies make certain that such minimum core metadata associated with peer-reviewed publications resulting from federally funded scientific research are publicly available to ensure that these publications can be easily found and linked to Federal science fundingfi Comment 5) Well-documented metadata is an important means to enable use, reuse, and analysis of the research literature and data. Readers, both human and machine, must know the terms and conditions and provenance under which this research may be used. Thus federal agencies should understand the important linkages between metadata and achieving a robust open/public access policy for science and technology-related agencies. Finally, there is value in looking to other existing organization such as the National Information Standards Organization, a non-profit organization devoted to collaborative standards development amongst content publishers, libraries, and software developers. Question 6) How can Federal agencies that fund science maximize the benefit of public access policies to U. Comment 6) Ensuring that all federally funded research results are accessible, and available in an effective and timely manner, will maximize the benefits to the scientific enterprise and to the public. For any open/public access policy to be successful, there must be consistency of requirements and mandates. It will be difficult for research universities to comply with multiple and differing mandates, in part, because a federal open/public access policy may involve multiple research funding agencies. Research universities have faculty members and researchers who hold grants from all or several federal funding agencies, and some of them have grants from multiple agencies concurrently. To the extent practicable, uniform requirements and procedures regarding deposit of peer-reviewed literature should be established across all funding agencies, as uniformity of deposit requirements will reduce the complexity and cost, while at the same time increase the rate of compliance. Ensuring relative consistency across agency policies is one key element to ensure a valuable return on investment and foster a culture where sharing of these resources continues to promote the interests of science. Such measures build on accountability metrics that many research universities are actively integrating into the research enterprise. These metrics assist the research university in detailing their research outputs and the local, state, national and international value of their institution. It is in this context that many institutions have invested in digital repositories so that the research results of their institution are publicly available, and for their community of users to build upon these repository resources as teaching tools and to advance scientific discovery. Question 7) Besides scholarly journal articles, should other types of peer-reviewed publications resulting from federally funded research, such as book chapters and conference proceedings, be covered by these public access policiesfi Comment 7) There are other important types of scholarly communications beyond the peer-reviewed research literature. Monographs and book chapters, conference presentations, theses and dissertations, working papers, and datasets are also increasingly being made available via open access or public access policies. Since there are different terms and conditions associated with each of these educational materials, it will be important to distinguish the various approaches to each type of scholarly output. Nevertheless, data is central to the scholarly and research enterprise and should be treated equally in terms of importance to the scholarly record and tenure and promotion. Question 8) What is the appropriate embargo period after publication before the public is granted free access to the full content of peer-reviewed scholarly publications resulting from federally funded researchfi It is time to accelerate such advances by significantly decreasing or eliminating embargoes to currently available, published research resources. Nationally and internationally, embargo periods of 12 months or less are the standard for journal 9 publishing highwire. Any determination of the need for a different embargo period must be based on data provided by a subscription-based publisher that shows a negative market impact resulting from the open/public access policy. First, the pricing history of the journal and other journals within that discipline must be compared. Third, peer-reviewed journals include information well beyond articles stemming from federally funded research. They include articles based on other funding sources and also include information about conferences, professional development, and more. As a result, it will be important to identify the percentage of articles based on federally funded research in a subscriptionbased journal to truly understand the need for a different embargo period. Fourth, it is incumbent upon a subscription-based publisher to provide data on the revenue that results from long-tail citation articles. Finally, the economy has significantly affected research universities, and as a result has impacted research library budgets. This is particularly true for public institutions as state budgets face weak economic growth, receive fewer federal dollars, and local governments are unable to keep pace with demands for services. This all translates into fewer and fewer dollars from states to their public institutions. Of the 61% that had real dollar budget reductions, the maximum budget cut was a striking 22%. Understanding the relationship between these fiscal challenges, indeed all of the factors noted above, and subscription cancellations is very important.

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Ceramic stereolithography: additive manufacturing for ceramics by photopolymerization medicine 1800s buy disulfiram cheap. Light scattering in absorbing ceramic suspensions: effect on the width and depth of photopolymerized features medications hypertension safe disulfiram 250 mg. Optimization of rheological properties of photopolymerizable alumina suspensions for ceramic microsterelithography treatment 1 degree burn buy disulfiram online. Microstructures and strengths of metals and cermaics made by photopolyer-based rapid prototyping treatment 2 go order disulfiram 500 mg online. Light curing strategies for lithography-based additive manufacturing of customized ceramics medications mobic disulfiram 250mg low cost. Influence of residual monomer on cracking in ceramics fabricated by stereolithography medications pancreatitis cheapest generic disulfiram uk. Manufacture the futurewhy decision makes should care about additive manufacturing. Lithography-based additive manufacturing of ceramic biodevices with design-controlled surface topographies. Fabrication of dense zirconia-toughened alumina ceramics through a stereolithography-based additive manufacturing. Preparation of a defect-free alumina cutting tool via additive manufacturing based on stereolithographyoptimization of the drying and debinding processes. Fabrication of fine-grained alumina ceramics by a novel process integrating stereolithography and liquid precursor infiltration processing. Influence of resin composition on the defect formation in alumina manufactured by stereolithography. Interfacial characteristics of composites fabricated by laminated object manufacturing. Production of alumina parts by powder injection molding with a binder system based on high density polyethylene. Muthukumar Vice-Chancellor Bharathidasan University Tiruchirapplli-620 024 Vice-Chairman Dr. Thiruchelvam Registrar Bharathidasan University Tiruchirapplli-620 024 Course Director Dr. Babu Rajendran Director i/c Centre for Distance Education Bharathidasan University Tiruchirapplli-620 024 Course Material Co-ordinator Dr. To understand the nature and scope of environmental education with regard to Indian policies. To have faith in conservation of bio-diversity and understand population and environment. To know environmental laws and grasp the concept of environmental legislation and its application in international environmental agreement. Environmental Movements and Developments: Environmental movements in India: Silent Valley movement, Chipko movement, Narmada Bachao, Andolan, National Test Range at Balipal, Orissa. Environmental education empowers learners by enabling them to participate in a sustainable future. Environment is a complex of many variables, which surrounds man as well as the living organisms. Environmental education describe the interrelationships among organisms, the environment and all the factors, which influence life on earth, including atmospheric conditions, food chains, the water cycle, etc. It is a basic science about our earth and its daily activities, and therefore, this science is important for everyone. This study is important and necessary not only for children but also for everyone. The study creates awareness among the people to know about various renewable and nonrenewable resources of the region. The endowment or potential, patterns of utilization and the balance of various resources available for future use in the state of a country are analysed in the study. It provides the knowledge about ecological systems and cause and effect relationships. It provides necessary information about biodiversity richness and the potential dangers to the species of plants, animals and microorganisms in the environment. The study enables one to understand the causes and consequences due to natural and induced disasters (flood, earthquake, landslide, cyclones etc. It enables one to evaluate alternative responses to environmental issues before deciding an alternative course of action. The study enables environmentally literate citizens (by knowing the environmental acts, rights, rules, legislations, etc. The study tries to identify and develop appropriate and indigenous eco-friendly skills and technologies to various environmental issues. It teaches the citizens the need for sustainable utilization of resources as these resources are inherited from our ancestors to the younger generation without deteriorating their quality. The study enables theoretical knowledge into practice and the multiple uses of environment. It aims to make the citizens competent to do scientific work and to find out practical solutions to current environmental problems. The citizens acquire the ability to analyze the environmental parameters like the aquatic, terrestrial and atmospheric systems and their interactions with the biosphere and antrosphere. World population is increasing at an alarming rate especially in developing countries. The resources are over-exploited and there is no foresight of leaving the resources to the future generations. The unplanned exploitation of natural resources lead to pollution of all types and at all levels. The pollution and degraded environment seriously affect the health of all living things on earth, including man. The people should take a combined responsibility for the deteriorating environment and begin to take appropriate actions to save the earth. Education and training are needed to save the biodiversity and species extinction. The number and area extinct under protected area should be increased so that the wild life is protected at least in these sites. The study enables the people to understand the complexities of the environment and need for the people to adapt appropriate activities and pursue sustainable development, which are harmonious with the environment. The study motivates students to get involved in community action, and to participate in various environment and management projects. It is a high time to reorient educational systems and curricula towards these needs. Environmental education takes a multidisciplinary approach to the study of human interactions with the natural environment. Environmental study is a key instrument for bringing about the changes in the knowledge, values, behaviors and lifestyles required to achieve sustainability and stability within and among countries. It is essentially a multidisciplinary approach that brings about an appreciation of our natural world and human impacts on its integrity. Environment is the basis of all life and therefore deserves proper care and management. If the environment is threatened on a continuous basis, numerous problems which would constitute a danger to human existence could arise. The environment is part of our cultural heritage which should be handed down to prosperity. Some resources of the environment are not easily replaceable and should be managed on a sustainable basis, to prevent the extinction of certain components of the environment such as plants and animals. There is need to enhance the sanity and aesthetic quality of our environment in order to promote healthy living. A major goal of environmental education in India as entrenched in National Policy on Education is the provision of the expertise that can utilize scientific knowledge towards the preservation and solution of environmental problems. Knowledge about the changes that have altered the environment land, water, weather, and vegetation; social, cultural and political environment are essential components of environmental education. Consequently, the general public should be equipped with all these to be able to solve the problems of the environment. Land, water, forest and other mineral resources utilization is the dominant feature of rural economy with agriculture the driving force. Environmental Education is therefore necessary to create awareness of the causes and effects of these problems vise: food and water scarcity, pollution, outbreak of epidemics and natural disaster such as flood, erosion and desert encroachment. The developed countries rely on the high technology for the exploitation of natural resources while developing countries like India totally depend on agriculture, forestry and the mineral resources thereby leading to intensive and over-exploitation of the natural resources and these have serious implications on the resources. Awareness of such global environmental issues is an essential component of environmental education which ordinary citizen should be aware of. Environmental education for the over-all social and economic emancipation of women and children. These form a substantial percentage in the utilization of natural resources especially at the rural setting. The natural resources and cultural heritage need to be protected not only for this generation but for future generation. Consider the environment in its totality, natural and built technological and social structures (economic, political, technological, cultural, historical, moral and aesthetic). Environmental education to be a continuous life saving process (beginning at the pre-school level continuing through all formal and non-formal stages). Examine major environmental issues from local, national and international point of view. Environmental education to focus on current and potential environmental situations. Promote the values and necessity of local, national and international cooperation in the prevention and solution to environmental problems. Enhance the position of learners in making decision concerning their environment and accept responsibility. Enable learners to discover symptoms and real and potential causes of environmental problems. Utilize different learning environment and approaches to learning/teaching about and form of the environment with emphasis on first hand information. Objectives of Environmental Education at Primary Level (a) To know and understand true aspects of the environment in general. Human, animals and plants are continuously adapting themselves to the environment. Human alters and modifies the environment with great caution and came in order to fulfill numerous living needs. Identification between human and nature and between environmental elements giving rise to various phenomena which affect them. Society would take active steps to conserve the environment and the balance of nature through careful plans and processing. Objectives of Environmental Education at Secondary Level Environmental education to be taught as integrated science in which environmental education concepts are included. To create an environmental conducive to greater reliance on the use of principles and practices of science. To develop an outlook which emphasizes the method employed in different disciplines of science. Lack of proper resources in terms of equipment, supplementary materials and reference materials. Ecology can be approached from the viewpoints of (1) the environment and the demands it places on the organisms in it or (2) organisms and how they adapt to their environmental conditions. An ecosystem consists of an assembly of mutually interacting organisms and their environment in which materials are interchanged in a largely cyclical manner. An ecosystem has physical, chemical, and biological components along with energy sources and pathways of energy and materials interchange. For the study of ecology it is often convenient to divide the environment into four broad categories. Terrestrial environment the terrestrial environment is based on land and consists of biomes, such as grasslands, one of several kinds of forests, savannas, or deserts. Freshwater environment the freshwater environment can be further subdivided between standing-water habitats (lakes, reservoirs) and running-water habitats (streams, rivers). Oceanic marine environment the oceanic marine environment is characterized by saltwater and may be divided broadly into the shallow waters of the continental shelf composing the neritic zone 4. Oceanic region the deeper waters of the ocean that constitute the oceanic region. Descriptive ecology describes the types and nature of organisms and their environment, emphasizing structures of ecosystems and communities and dispersions and structures of populations. Functional ecology explains how things work in an ecosystem, including how populations respond to environmental alteration and how matter and energy move through ecosystems.

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While osteoporosis occurs in both men and women medicine organizer box best disulfiram 250mg, it is most common among women following menopause treatment ringworm cheap disulfiram online mastercard. In healthy humans kapous treatment purchase generic disulfiram, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone medicine nobel prize 2016 buy disulfiram 500 mg on-line. In postmenopausal osteoporosis medicine keeper disulfiram 500 mg for sale, bone resorption exceeds bone formation treatment quotes and sayings buy disulfiram with visa, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture during their remaining lifetimes. Changes in markers of bone formation (osteocalcin) were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation. The main outcome measure was the occurrence of new radiographically diagnosed, vertebral fractures after 3 years of treatment. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of two events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height. The two treatment groups were also similar with regard to the number of fractures reported at the individual non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip (Daily Oral Tablet Treatment Study). The histological analysis of bone biopsies showed bone of normal quality and no indication of osteomalacia or a mineralization defect. The histological analysis of bone biopsies after 22 months of treatment with 3 mg intravenous ibandronate every 3 months (n=30) or 23 months of treatment with 2 mg intravenous ibandronate every 2 months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of a mineralization defect. Animal Pharmacology Animal studies have shown that ibandronate is an inhibitor of osteoclast-mediated bone resorption. In the Schenk assay in growing rats, ibandronate inhibited bone resorption and increased bone volume, based on histologic examination of the tibial metaphyses. There was no evidence of impaired mineralization at the highest dose of 5 mg/kg/day (subcutaneously), which is 1000 times the lowest antiresorptive dose of 0. Long-term daily or intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. Ibandronate maintained the positive correlation between bone mass and strength at the ulna and femoral neck. New bone formed in the presence of ibandronate had normal histologic structure and did not show mineralization defects. Renal Impairment Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function (ie, increased serum creatinine) and in rare cases, acute renal failure. The risk of serious renal toxicity with other intravenous bisphosphonates appears to be inversely related to the rate of drug administration. Patients with concomitant diseases that have the potential for adverse effects on the kidney or patients who are taking concomitant medications that have the potential for adverse effects on the kidney should be assessed, as clinically appropriate. Jaw Osteonecrosis Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (eg, anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally. The time to onset of symptoms varied from one day to several months after starting the drug. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. If the dose is missed, the injection should be administered as soon as it can be rescheduled. Mutagenesis There was no evidence for a mutagenic or clastogenic potential of ibandronate in the following assays: in vitro bacterial mutagenesis assay in Salmonella typhimurium and Escherichia coli (Ames test), mammalian cell mutagenesis assay in Chinese hamster V79 cells, and chromosomal aberration test in human peripheral lymphocytes, each with and without metabolic activation. Ibandronate was not genotoxic in the in vivo mouse micronucleus tests for chromosomal damage. In male rats treated for 28 days prior to mating, a decrease in sperm production and altered sperm morphology were observed at intravenous doses fi0. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at 0. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses fi0. Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Therefore, there is a theoretical risk of fetal harm (eg, skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. Pediatric Use Safety and effectiveness in pediatric patients have not been established. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity in some older individuals cannot be ruled out. The percentage of patients who withdrew from treatment due to adverse events was approximately 6. Table 4 lists the adverse events reported in >2% of patients without attribution of causality. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hours. Ocular Adverse Events Bisphosphonates may be associated with ocular inflammation such as uveitis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. Laboratory Test Findings There were no clinically significant changes from baseline values or shifts in any laboratory variable with oral ibandronate. As expected with bisphosphonate treatment, a decrease in total alkaline phosphatase levels was seen with 2. There was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, hypocalcemia, or hypophosphatemia. Intravenous overdosage may result in hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. Dialysis would not be beneficial unless it is administered within 2 hours following the overdose. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Patients with Renal Impairment No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 mL/min. Each syringe is a 5 mL (5 cc) volume syringe supplied with a 25-gauge, 3/4 inch needle with wings, needle-stick protection device, and a 9 cm plastic tubing for attachment. The low profile neck increases the range of motion of the stem within the cup before the neck impinges on the cup. Although suffering from severe osteoporosis, she was then a very active woman a keen alpine skier and mountaineer. Although this patient has been reoperated for acetabular wear, she is doing well after 30 years and participates in winter sports with family and friends. Recent results of fractured neck of femur trials show that primary arthroplasty provides a better solution than hemi-arthroplasty or internal fixation. Both hydroxyapatite coated and cemented options share exactly the same broach envelope and instrumentation. Templating should be done with a medium neck so that the possibility to change to a short or a long neck still remains in order to adjust leg length. In these cases consideration should be given to distal reaming to enlarge the canal to accommodate a broach of the appropriate size. The neck resection guide should be used to determine the level of the femoral neck resection in conjunction with pre-operative templating. Proximal Cancellous Bone Compaction It is important to select a point of entry posterolaterally to the Piriformis Fossa to avoid varus positioning. To prevent under-sizing or varus positioning, the greater trochanter may be prepared with an osteotome to allow better insertion of the broaches. The broach should run parallel to the posterior cortex following the natural anatomy of the femur. Begin with the smallest broach attached to the broach handle and increase the size of broach sequentially until longitudinal and rotational stability is achieved, broaching should then be stopped. Calcar Reaming If concern around sizing still exists, intraoperative x-rays could be considered, where available. Femoral Component Insertion Important Note: the protective covers should be left on until the components are ready to be implanted. Reduce the hip and assess what adjustments, if any, are required to ensure stability through a full range of motion. All 12/14 heads available in the DePuy Synthes Portfolio are compatible with this stem. Pre-operative Planning X-ray templates are used during the pre-operative planning to define the femoral neck cutting plane, the degree of lateralisation and the positioning of the cup inside the native acetabular cavity. Pre-op templating Femoral Neck Resection Following exposure of the proximal femur, the first neck cut is made higher than the one planned, in order to remove the femoral head. The second neck cut will depend on the implant chosen during the pre-operative planning. If the implant chosen is the K6A, then the neck cut will be biplaner as identified. Implant K6S Implant K6A Trial Reduction the femoral cavity is prepared using the single monobloc broach specific to each type of implant. The chosen broach is inserted firmly down to the level of the cervical cutting plane. Implant K6S Implant K6A Femoral Head Impaction the stem is introduced by hand first and then impacted down to the level of either the hydroxyapatite coating in case of the K6S or at the level of the trochanteric bearing in case of the K6A. A final trial reduction is carried out to confirm joint stability and range of motion. Cement Restrictor Trial Select the size of trial cement restrictor identified during pre-operative templating to fit the distal canal. Attach it to the cement restrictor inserter and insert the trial cement restrictor to the planned depth. Crotch Point Distal Tip Pulse Lavage the use of pulse lavage is recommended to clean the femoral canal of debris and to open the interstices of the bone. By using pulse lavage prior to setting the cement restrictor, the risks of creating fatty embolism will be reduced. Note: the size of the cement restrictor should be one size larger than the last trial restrictor inserted to the planned level. The planned level should be 1cm below the tip of the implant Implant Stem Length Restrictor Size Crotch point to distal tip Depth 8 95 mm 105 mm 9 110 mm 120 mm 10 120 mm 130 mm 11 125 mm 135 mm 12 130 mm 140 mm 13 135 mm 145 mm 14 140 mm 150 mm 15 145 mm 155 mm 16 150 mm 160 mm 18 160 mm 170 mm 20 170 mm 180 mm Table 1 Final Bone Preparation the bone can be dried by passing a swab down the femoral canal which helps to remove any remaining debris. Start at the distal part of the femoral canal and inject the cement in a retrograde fashion, allowing the cement to push the nozzle gently back, until the canal is completely filled and the distal tip of the nozzle is clear of the canal.

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Continuing support of improved and novel approaches to gene therapy is important for rare diseases treatment of shingles purchase 500mg disulfiram overnight delivery, which for the most part have genetic causes that will often be difficult to treat with simpler therapies symptoms internal bleeding buy disulfiram no prescription. Diagnostics Rare disorders are identified in a variety of ways medicine woman cast buy disulfiram 500mg line, including by physical examination for clinical phenotypes medications and grapefruit juice 250 mg disulfiram with amex, by biochemical assays medicine list order on line disulfiram, by testing for chromosomal abnormalities medicine mart order 250mg disulfiram amex, by testing for gene mutations, and by imaging to detect structural and functional abnormalities. There are many rare diseases for which no diagnostic tests are available, which then must be diagnosed on the basis of carefully defined clinical characteristics. Box 4-2 highlights some of the enabling technologies to support advances in diagnostics. Once the primary genes are identified, the development of laboratory tests for rare disorders becomes feasible. Finally, genetic testing for polymorphisms of genes coding for drug metabolizing enzymes (pharmacogenetics) will be increasingly useful for identifying drug responders and nonresponders with rare as well as common diseases. In addition, research in the area of development of new technologies for newborn screening is advancing reasonably quickly; most targeted conditions are rare diseases (see Chapter 2). For example, tandem mass spectrometry for the direct assay of enzymes in dried blood spots has been applied to newborn screening for Krabbe disease (Li et al. As new biomarkers are described, cheaper and more facile diagnostic methods will undoubtedly be developed and used at an early age to identify presymptomatic rare conditions. This extended genetic testing, when coupled with meticulous patient phenotyping, has the potential to explain clinical variation within defined rare disorders and offers opportunities to more accurately predict the clinical course of the disease. Such diagnostic information will be useful in guiding decisions about the timing of therapeutic interventions and their intensity. As is true of most diagnostic testing, genetic testing also may identify variants of uncertain significance that puzzle clinicians and do not yet assist decisions about patient care. In addition to genetic markers, other biomarkers may be useful in predicting disease severity or progression. They may include specific patterns of peptides and metabolites identified by proteomic or metabolomic analysis. In selected disorders, longitudinal assessments of environmental exposures may predict variation in outcomes. Along with them, models for providing the resources necessary for discovery research have also undergone a transformation in recent years. This section describes some elements of the necessary infrastructure, including animal models, patient registries and biospecimen repositories, research funding, and training and also describes innovations in the area of sharing data and other resources, which can lower the considerable costs of basic and translational research. Although collaboration and innovation in the sharing of data and other scarce resources are particularly useful for advancing research on rare diseases, commonly cited barriers include concerns related to the protection of intellectual property. These concerns involve legal, technical, and financial issues related to the patent process itself, but they also derive from the significance of intellectual property, broadly construed, to the success of institutions and individuals. The committee was not asked to examine the protection of intellectual property, but it is importance to recognize that the protection through the issuing of patents and copyrights is a fundamental element of the infrastructure linking biomedical research to product development. The passage of the Orphan Drug Act was in part a response to the lack of incentives for companies to investigate rare diseases applications of off-patent or unpatentable drugs (Asbury, 1985). At the institutional level, developing feasible mechanisms for data and resource sharing in both academic and commercial research is not a straightforward process (see. For example, university technology transfer offices have been criticized for being slow and cumbersome. Moreover, because the patenting process is costly, institutions with limited resources may be forced to choose which discoveries they will seek to protect and which they will not. In these circumstances, the limited commercial prospects for many products for rare diseases may influence institutions to bypass future commercialization opportunities, and the lack of patent protection may discourage the sharing of data and materials with potential collaborators. One study of access to genetic data and materials reported that nearly 50 percent of genetic researchers have encountered negative responses to their requests for data or materials related to published research (Campbell et al. Reasons cited for denying access included not only desires to protect the commercial value of the intellectual property but also to maintain publication opportunities. Although barriers are significant, a range of infrastructure and information sharing innovations can be cited, including several that operate under the auspices of the National Center for Biotechnology. A significant incentive for such submissions is the requirement by scientific journals for deposition to GenBank or a similar database so that an accession number will be included in a published article. More examples of initiatives to increase access to information and other infrastructure resources are described below and in Chapter 5. Recently, in a case involving gene patents held by Myriad Genetics, the ruling of a federal district court would, if upheld on appeal, invalidate or restrict patents on individual genes (Pollack, 2010). Mouse models are common, but simpler, more rapidly reproducing models such as the zebrafish are also valuable where genetic mouse models do not fully recreate human disease. Technological advances have allowed the development of long-sought alternative animal models for Huntington disease (monkey) and cystic fibrosis (pig) (Wolfe, 2009), but satisfactory animal models still await many rare diseases, for example, Smith Lemli Opitz syndrome (Merkens et al. Mouse models, and occasionally other animal models, can be created using both forward and reverse genetic manipulation. Forward genetics involves the altering of specific genes to change their expression patterns and products. Although expensive and time-consuming, this approach is now a fundamental experimental strategy and has been an important contributor to research advances for an array of rare diseases. Reverse genetics is carried out by exposing animals to mutagenic agents and identifying genetic disorders by careful genotyping and phenotyping of the animals. The ability to carry out these studies requires animal (especially mouse) manipulation and maintenance facilities that are now available in most major academic research centers. Adequate funding for these studies is a challenge for fledgling research programs. Expanded development and access to genetically modified mice that are relevant to rare diseases will promote research progress and accelerate work aimed at identifying potential therapeutic agents for rare diseases. Other research approaches have used cultured cells from mouse models of rare disease. Interestingly, it was research on tyrosinemia, a rare disease that led to this model (Azuma et al. Progress at the preclinical stage will undoubtedly be aided by the creative use of human cells, both normal and those derived from patients with genetic defects. An emerging option may be the in vitro generation of normal or disorder-specific differentiated cells from human pluripotent cells. Mice with genetic disorders are collected, studied, and made available to researchers by various organizations, including the National Cancer Institute mouse. One initiative of the Friedreich Ataxia Research Alliance was to arrange with Jackson Laboratories to make mice available so that researchers no longer had to maintain their own research animals (Farmer, 2009). They can also serve as a recruitment tool for the launch of studies focused on disease etiology, pathogenesis, diagnosis, or therapy. When combined with genetic information, patient registries can inform the correlation of patient genotype with the distribution, onset, severity, or progression of clinical manifestations or response to treatment (phenotype-genotype correlations). In essence, for rare disorders it is necessary to collect as much information as possible on as many patients as possible to discriminate predictive patterns from chance correlations, to validate these patterns using statistical methods, and to apply them productively in individual patient diagnosis, prognostication, counseling, and management. Decisions about whether a registry should attempt to capture a comprehensive or representative sample are often influenced by disease prevalence. This approach can serve as a model for certain other rare disorders, although it will be limited to patient advocacy groups or other coordinating entities that have substantial sophistication, organization, and resources to exert as leverage. In addition to patient registries, a number of advocacy groups have promoted the development of repositories of biospecimens. In recognition of the challenges this undertaking presents for many groups, the Genetic Alliance Biobank provides infrastructure coordination for multiple rare diseases, and it includes clinical records and questionnaires as well as biological materials (Genetic Alliance, 2010). This type of federated approach also lowers the barriers for access to patient samples by individual researchers. The National Disease Research Interchange, a federally funded private organization, takes a different approach to biospecimens. It provides academic and industry researchers with a national human tissue and organ retrieval system. The organization recently created an alliance with a number of rare diseases organizations to increase awareness of its resources and develop new resources, including the National Rare Disease Biospecimen Resource. Many complex details will need to be considered to implement these recommendations. Funding of Basic Research and Drug Discovery for Rare Diseases the discussion below focuses on government and nonprofit organizations as funders of basic research on rare diseases, but it also includes some data and some concerns related to the financing of clinical studies. In health care, publicly funded basic research is a foundation for pharmaceutical development. This would allow a more systematic assessment of current resources and resource allocation. Figure 4-1 presents a scatter plot for 32 rare diseases (selected to be generally representative of different kinds of conditions), with disorder prevalence displayed on the horizontal axis and numbers of awards on the vertical axis. Grant numbers include American Recovery and Reinvestment Act grant supplements and training grants. Third, one feature of research on a rare disease, especially an extremely rare disease, is that only one or two investigators may be funded to study the condition, which means that the loss of funding can bring research virtually to a halt. The variation is fivefold and does not appear to be related to knowledge of genetic or molecular causation, which the committee believes is similar for all four. Most of the awards are directed to basic science exploration of biological mechanisms that are related to the gene(s) of interest for that disorder. A much smaller number of awards fund preclinical (animal models) research examining both pathogenesis and therapeutic interventions. Likewise, this reader also evaluated whether the research involved preclinical (largely animal model) research, a clinic trial, or other clinical research. Supplementary grants under the American Recovery and Reinvestment Act are counted as separate awards. Prevalence data were taken from Orphanet, 2009 (see discussion of these data in Chapter 2). Beyond those cited above, other factors contributing to the variation in federal funding of rare diseases research may include the number of scientific issues raised by a particular rare disease, the potential broader relevance of those issues, the availability of pilot grants from disease-specific foundations, the extent to which clinical care and clinical research are focused in disorder-specific clinics or centers, and workforce issues such as numbers of trained basic and clinical investigators. Department of Defense, which has been mandated to conduct research on several rare conditions. Advocacy Groups and Foundations An increasing number of disease-specific foundations and advocacy groups provide funding for research. The aim of many of these foundations is to attract investigators with skills and research track records in other areas to devote their attention and skills to a particular rare disease. Several also support research training and career development in an attempt to engage future investigators in research efforts that advance their medical scientific agendas. Other groups such as the Fanconi Anemia Research Fund have more recently entered the research funding arena and have been successful in attracting substantial but smaller numbers of investigators. In some cases, advocacy groups have been responsible for funding the fundamental scientific breakthroughs that were necessary for progress toward new therapies. As part of their strategic planning, some rare diseases research foundations have undertaken analyses of public and private research spending on specific conditions. Of the funding, 94 percent was directed to basic research, with the largest share of both public and private funds devoted to finding and validating potential drug targets. A number of foundations sponsor annual research meetings at which investigators share their research results and discuss opportunities in therapeutic development. In some cases, the foundations provide the impetus for the first gatherings of researchers working in areas of rare diseases. Foundations have also partnered with federal agencies to promote research or launch clinical trials. Although disease-specific foundations do fund important research, private foundations collectively account for less than 10 percent of all support for biomedical research (Dorsey et al. When this support is divided into research on particular diseases and weighed against the cost of clinical trials, the amount available from private nonprofit sources for development of therapies is typically quite small. Investigator Training and Recruitment A decision to pursue basic or translational rare diseases research is inherently risky, especially for young investigators. It is important that this reality be appreciated, both by funding agencies and by host academic institutions. Although academic investigators are attracted to the intellectual challenge of a rare diseases puzzle, they confront numerous vulnerabilities, including the scarce funding for research on most rare diseases, the limited number of potential collaborators, the limited access to biospecimens that are necessary for basic research, and the substantial uncertainty about industry interest in translating discoveries into products for rare diseases. All of these factors add to the difficulties normally confronted by academic researchers trying to establish research careers. Other issues, which are not confined to research on rare diseases in the university setting, include the complexities of negotiating contracts and materials transfer and other intellectual property agreements and the need to identify and manage or eliminate conflicts of interest that may arise from financial relationships with industry. Existing study sections may be predisposed toward more common diseases, may not appreciate the critical importance of natural history studies for rare diseases, or may lack expertise to evaluate proposals that involve innovative trial designs and analytic methods for small populations. Specialized incentives to attract young investigators to the field include loan repayment, targeted requests for proposals from young investigators, and fellow-tofaculty transition awards. These mechanisms are useful in attracting young investigators into all disease areas and could be targeted specifically to investigators in areas of rare disease. Areas of training particularly relevant to the development of rare diseasesoriented basic science careers include research in clinical genetics, tissue engineering and cell therapies, gene therapy, and bioinformatics. Training of clinicians in medical genetics, pediatric cardiology, or adult hematology-oncology represents a possible entry point to careers focused on a number of rare diseases encountered in these subspecialty areas. In addition to programs associated with the Rare Diseases Clinical Research Network (see Chapter 5), a few training programs focused on rare diseases exist, for example, in juvenile rheumatoid arthritis, cystic fibrosis, muscular dystrophy, and sickle cell disease.

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