A Survey of Statistical Models for Reverse Engineering Gene Regulatory Networks

PubMed Central

Huang, Yufei; Tienda-Luna, Isabel M.; Wang, Yufeng

2009-01-01

Statistical models for reverse engineering gene regulatory networks are surveyed in this article. To provide readers with a system-level view of the modeling issues in this research, a graphical modeling framework is proposed. This framework serves as the scaffolding on which the review of different models can be systematically assembled. Based on the framework, we review many existing models for many aspects of gene regulation; the pros and cons of each model are discussed. In addition, network inference algorithms are also surveyed under the graphical modeling framework by the categories of point solutions and probabilistic solutions and the connections and differences among the algorithms are provided. This survey has the potential to elucidate the development and future of reverse engineering GRNs and bring statistical signal processing closer to the core of this research. PMID:20046885

Climate change adaptation in regulated water utilities

NASA Astrophysics Data System (ADS)

Vicuna, S.; Melo, O.; Harou, J. J.; Characklis, G. W.; Ricalde, I.

2017-12-01

Concern about climate change impacts on water supply systems has grown in recent years. However, there are still few examples of pro-active interventions (e.g. infrastructure investment or policy changes) meant to address plausible future changes. Deep uncertainty associated with climate impacts, future demands, and regulatory constraints might explain why utility planning in a range of contexts doesn't explicitly consider climate change scenarios and potential adaptive responses. Given the importance of water supplies for economic development and the cost and longevity of many water infrastructure investments, large urban water supply systems could suffer from lack of pro-active climate change adaptation. Water utilities need to balance the potential for high regret stranded assets on the one side, with insufficient supplies leading to potentially severe socio-economic, political and environmental failures on the other, and need to deal with a range of interests and constraints. This work presents initial findings from a project looking at how cities in Chile, the US and the UK are developing regulatory frameworks that incorporate utility planning under uncertainty. Considering for example the city of Santiago, Chile, recent studies have shown that although high scarcity cost scenarios are plausible, pre-emptive investment to guard from possible water supply failures is still remote and not accommodated by current planning practice. A first goal of the project is to compare and contrast regulatory approaches to utility risks considering climate change adaptation measures. Subsequently we plan to develop and propose a custom approach for the city of Santiago based on lessons learned from other contexts. The methodological approach combines institutional assessment of water supply regulatory frameworks with simulation-based decision-making under uncertainty approaches. Here we present initial work comparing the regulatory frameworks in Chile, UK and USA evaluating their ability to incorporate uncertain climate and other changes into long-term infrastructure investment planning. The potential for regulatory and financial adaptive measures is explored in addition to a discussion on evaluating their appropriateness via various modelling-based intervention decision-making approaches.

A Regulatory Framework for Nanotechnology

DTIC Science & Technology

informed by a map of the regulatory landscape of nanotechnology and a review of the regulatory frameworks for the aviation and biotechnology industries...aviation and biotechnology and maps the regulatory landscape in the United States by examining stakeholders, regulatory entities, and applicable legislation...state of nanotechnology if the limitations of technical expertise are addressed. This expertise can be provided by advisory committees of technical

Steam Generator tube integrity -- US Nuclear Regulatory Commission perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murphy, E.L.; Sullivan, E.J.

1997-02-01

In the US, the current regulatory framework was developed in the 1970s when general wall thinning was the dominant degradation mechanism; and, as a result of changes in the forms of degradation being observed and improvements in inspection and tube repair technology, the regulatory framework needs to be updated. Operating experience indicates that the current U.S. requirements should be more stringent in some areas, while in other areas they are overly conservative. To date, this situation has been dealt with on a plant-specific basis in the US. However, the NRC staff is now developing a proposed steam generator rule asmore » a generic framework for ensuring that the steam generator tubes are capable of performing their intended safety functions. This paper discusses the current U.S. regulatory framework for assuring steam generator (SG) tube integrity, the need to update this regulatory framework, the objectives of the new proposed rule, the US Nuclear Regulatory Commission (NRC) regulatory guide (RG) that will accompany the rule, how risk considerations affect the development of the new rule, and some outstanding issues relating to the rule that the NRC is still dealing with.« less

The pluralization of the international: Resistance and alter-standardization in regenerative stem cell medicine

PubMed Central

Rosemann, Achim; Chaisinthop, Nattaka

2016-01-01

The article explores the formation of an international politics of resistance and ‘alter-standardization’ in regenerative stem cell medicine. The absence of internationally harmonized regulatory frameworks in the clinical stem cell field and the presence of lucrative business opportunities have resulted in the formation of transnational networks adopting alternative research standards and practices. These oppose, as a universal global standard, strict evidence-based medicine clinical research protocols as defined by scientists and regulatory agencies in highly developed countries. The emergence of transnational spaces of alter-standardization is closely linked to scientific advances in rapidly developing countries such as China and India, but calls for more flexible regulatory frameworks, and the legitimization of experimental for-profit applications outside of evidence-based medical care, are emerging increasingly also within more stringently regulated countries, such as the United States and countries in the European Union. We can observe, then, a trend toward the pluralization of the standards, practices, and concepts in the stem cell field. PMID:26983174

The European Regulatory Environment of RNA-Based Vaccines.

PubMed

Hinz, Thomas; Kallen, Kajo; Britten, Cedrik M; Flamion, Bruno; Granzer, Ulrich; Hoos, Axel; Huber, Christoph; Khleif, Samir; Kreiter, Sebastian; Rammensee, Hans-Georg; Sahin, Ugur; Singh-Jasuja, Harpreet; Türeci, Özlem; Kalinke, Ulrich

2017-01-01

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.

The regulatory framework for safe decommissioning of nuclear power plants in Korea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sangmyeon Ahn; Jungjoon Lee; Chanwoo Jeong

We are having 23 units of nuclear power plants in operation and 5 units of nuclear power plants under construction in Korea as of September 2012. However, we don't have any experience on shutdown permanently and decommissioning of nuclear power plants. There are only two research reactors being decommissioned since 1997. It is realized that improvement of the regulatory framework for decommissioning of nuclear facilities has been emphasized constantly from the point of view of IAEA's safety standards. It is also known that IAEA will prepare the safety requirement on decommissioning of facilities; its title is the Safe Decommissioning ofmore » Facilities, General Safety Requirement Part 6. According to the result of IAEA's Integrated Regulatory Review Service (IRRS) mission to Korea in 2011, it was recommended that the regulatory framework should require decommissioning plans for nuclear installations to be constructed and operated and these plans should be updated periodically. In addition, after the Fukushima nuclear disaster in Japan in March of 2011, preparedness for early decommissioning caused by an unexpected severe accident became important issues and concerns. In this respect, it is acknowledged that the regulatory framework for decommissioning of nuclear facilities in Korea need to be improved. First of all, we focus on identifying the current status and relevant issues of regulatory framework for decommissioning of nuclear power plants compared to the IAEA's safety standards in order to achieve our goal. And then the plan is established for improvement of regulatory framework for decommissioning of nuclear power plants in Korea. It is expected that if the things will go forward as planned, the revised regulatory framework for decommissioning could enhance the safety regime on the decommissioning of nuclear power plants in Korea in light of international standards. (authors)« less

Call for a dedicated European legal framework for bacteriophage therapy.

PubMed

Verbeken, Gilbert; Pirnay, Jean-Paul; Lavigne, Rob; Jennes, Serge; De Vos, Daniel; Casteels, Minne; Huys, Isabelle

2014-04-01

The worldwide emergence of antibiotic resistances and the drying up of the antibiotic pipeline have spurred a search for alternative or complementary antibacterial therapies. Bacteriophages are bacterial viruses that have been used for almost a century to combat bacterial infections, particularly in Poland and the former Soviet Union. The antibiotic crisis has triggered a renewed clinical and agricultural interest in bacteriophages. This, combined with new scientific insights, has pushed bacteriophages to the forefront of the search for new approaches to fighting bacterial infections. But before bacteriophage therapy can be introduced into clinical practice in the European Union, several challenges must be overcome. One of these is the conceptualization and classification of bacteriophage therapy itself and the extent to which it constitutes a human medicinal product regulated under the European Human Code for Medicines (Directive 2001/83/EC). Can therapeutic products containing natural bacteriophages be categorized under the current European regulatory framework, or should this framework be adapted? Various actors in the field have discussed the need for an adapted (or entirely new) regulatory framework for the reintroduction of bacteriophage therapy in Europe. This led to the identification of several characteristics specific to natural bacteriophages that should be taken into consideration by regulators when evaluating bacteriophage therapy. One important consideration is whether bacteriophage therapy development occurs on an industrial scale or a hospital-based, patient-specific scale. More suitable regulatory standards may create opportunities to improve insights into this promising therapeutic approach. In light of this, we argue for the creation of a new, dedicated European regulatory framework for bacteriophage therapy.

A combined park management framework based on regulatory and behavioral strategies: use of visitors' knowledge to assess effectiveness.

PubMed

Papageorgiou, K

2001-07-01

In light of the increasing mandate for greater efficiency in conservation of natural reserves such as national parks, the present study suggests educational approaches as a tool to achieve conservation purposes. Currently, the management of human-wildlife interactions is dominated by regulatory strategies, but considerable potential exists for environmental education to enhance knowledge in the short run and to prompt attitude change in the long run. A framework for conservation based on both traditional regulatory- and behavior-oriented strategies was proposed whereby the level of knowledge that park visitors have acquired comprises an obvious outcome and establishes a basis upon which the effectiveness of regulatory- and behavior-based regimes could be assessed. The perceptions regarding park-related issues of two distinct visitor groups (locals and nonlocals) are summarized from a survey undertaken in Vikos-Aoos national park. The findings suggest a superficial knowledge for certain concepts but little profound understanding of the content of such concepts, indicating that knowledge-raising efforts should go a long way towards establishing a positive attitude for the resource. Visitors' poor knowledge of the park's operation regulation contest the efficiency of the presently dominant regulatory management regime. While geographical distances did not appear to significantly differentiate knowledge between the two groups, wilderness experience (as certified by visits to other parks) was proved to be an impetus for generating substantial learner interest in critical park issues among nonlocal visitors. School education and media were found to be significant knowledge providers.

Carousel: A Moral Framework for Inquiring into the Culture of Prisons and Academe.

ERIC Educational Resources Information Center

Mullen, Carol A.

The moral framework of a carousel is used to advance possible connections between the institutional and regulatory life within prisons and teacher education programs. The moral paradigm case narrated is based on the researcher's field experience in a prison as a researcher-teacher. Connections are drawn to restrictions within a correctional…

A prior-based integrative framework for functional transcriptional regulatory network inference

PubMed Central

Siahpirani, Alireza F.

2017-01-01

Abstract Transcriptional regulatory networks specify regulatory proteins controlling the context-specific expression levels of genes. Inference of genome-wide regulatory networks is central to understanding gene regulation, but remains an open challenge. Expression-based network inference is among the most popular methods to infer regulatory networks, however, networks inferred from such methods have low overlap with experimentally derived (e.g. ChIP-chip and transcription factor (TF) knockouts) networks. Currently we have a limited understanding of this discrepancy. To address this gap, we first develop a regulatory network inference algorithm, based on probabilistic graphical models, to integrate expression with auxiliary datasets supporting a regulatory edge. Second, we comprehensively analyze our and other state-of-the-art methods on different expression perturbation datasets. Networks inferred by integrating sequence-specific motifs with expression have substantially greater agreement with experimentally derived networks, while remaining more predictive of expression than motif-based networks. Our analysis suggests natural genetic variation as the most informative perturbation for network inference, and, identifies core TFs whose targets are predictable from expression. Multiple reasons make the identification of targets of other TFs difficult, including network architecture and insufficient variation of TF mRNA level. Finally, we demonstrate the utility of our inference algorithm to infer stress-specific regulatory networks and for regulator prioritization. PMID:27794550

Human Genome Editing in the Clinic: New Challenges in Regulatory Benefit-Risk Assessment.

PubMed

Abou-El-Enein, Mohamed; Cathomen, Toni; Ivics, Zoltán; June, Carl H; Renner, Matthias; Schneider, Christian K; Bauer, Gerhard

2017-10-05

As genome editing rapidly progresses toward the realization of its clinical promise, assessing the suitability of current tools and processes used for its benefit-risk assessment is critical. Although current regulations may initially provide an adequate regulatory framework, improvements are recommended to overcome several existing technology-based safety and efficacy issues. Copyright © 2017 Elsevier Inc. All rights reserved.

Deciphering RNA regulatory elements in trypanosomatids: one piece at a time or genome-wide?

PubMed

Gazestani, Vahid H; Lu, Zhiquan; Salavati, Reza

2014-05-01

Morphological and metabolic changes in the life cycle of Trypanosoma brucei are accomplished by precise regulation of hundreds of genes. In the absence of transcriptional control, RNA-binding proteins (RBPs) shape the structure of gene regulatory maps in this organism, but our knowledge about their target RNAs, binding sites, and mechanisms of action is far from complete. Although recent technological advances have revolutionized the RBP-based approaches, the main framework for the RNA regulatory element (RRE)-based approaches has not changed over the last two decades in T. brucei. In this Opinion, after highlighting the current challenges in RRE inference, we explain some genome-wide solutions that can significantly boost our current understanding about gene regulatory networks in T. brucei. Copyright © 2014 Elsevier Ltd. All rights reserved.

78 FR 70354 - Conceptual Example of a Proposed Risk Management Regulatory Framework Policy Statement

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-25

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0254] Conceptual Example of a Proposed Risk Management... issuing a document entitled: ``White Paper on a Conceptual Example of a Proposed Risk Management... ``openness,'' a white paper on a Conceptual Example of a Proposed Risk Management Regulatory Framework (RMRF...

An Observation-Driven Agent-Based Modeling and Analysis Framework for C. elegans Embryogenesis.

PubMed

Wang, Zi; Ramsey, Benjamin J; Wang, Dali; Wong, Kwai; Li, Husheng; Wang, Eric; Bao, Zhirong

2016-01-01

With cutting-edge live microscopy and image analysis, biologists can now systematically track individual cells in complex tissues and quantify cellular behavior over extended time windows. Computational approaches that utilize the systematic and quantitative data are needed to understand how cells interact in vivo to give rise to the different cell types and 3D morphology of tissues. An agent-based, minimum descriptive modeling and analysis framework is presented in this paper to study C. elegans embryogenesis. The framework is designed to incorporate the large amounts of experimental observations on cellular behavior and reserve data structures/interfaces that allow regulatory mechanisms to be added as more insights are gained. Observed cellular behaviors are organized into lineage identity, timing and direction of cell division, and path of cell movement. The framework also includes global parameters such as the eggshell and a clock. Division and movement behaviors are driven by statistical models of the observations. Data structures/interfaces are reserved for gene list, cell-cell interaction, cell fate and landscape, and other global parameters until the descriptive model is replaced by a regulatory mechanism. This approach provides a framework to handle the ongoing experiments of single-cell analysis of complex tissues where mechanistic insights lag data collection and need to be validated on complex observations.

Favorable genomic environments for cis-regulatory evolution: A novel theoretical framework.

PubMed

Maeso, Ignacio; Tena, Juan J

2016-09-01

Cis-regulatory changes are arguably the primary evolutionary source of animal morphological diversity. With the recent explosion of genome-wide comparisons of the cis-regulatory content in different animal species is now possible to infer general principles underlying enhancer evolution. However, these studies have also revealed numerous discrepancies and paradoxes, suggesting that the mechanistic causes and modes of cis-regulatory evolution are still not well understood and are probably much more complex than generally appreciated. Here, we argue that the mutational mechanisms and genomic regions generating new regulatory activities must comply with the constraints imposed by the molecular properties of cis-regulatory elements (CREs) and the organizational features of long-range chromatin interactions. Accordingly, we propose a new integrative evolutionary framework for cis-regulatory evolution based on two major premises for the origin of novel enhancer activity: (i) an accessible chromatin environment and (ii) compatibility with the 3D structure and interactions of pre-existing CREs. Mechanisms and DNA sequences not fulfilling these premises, will be less likely to have a measurable impact on gene expression and as such, will have a minor contribution to the evolution of gene regulation. Finally, we discuss current comparative cis-regulatory data under the light of this new evolutionary model, and propose that the two most prominent mechanisms for the evolution of cis-regulatory changes are the overprinting of ancestral CREs and the exaptation of transposable elements. Copyright © 2015 Elsevier Ltd. All rights reserved.

Glycoconjugate Vaccines: The Regulatory Framework.

PubMed

Jones, Christopher

2015-01-01

Most vaccines, including the currently available glycoconjugate vaccines, are administered to healthy infants, to prevent future disease. The safety of a prospective vaccine is a key prerequisite for approval. Undesired side effects would not only have the potential to damage the individual infant but also lead to a loss of confidence in the respective vaccine-or vaccines in general-on a population level. Thus, regulatory requirements, particularly with regard to safety, are extremely rigorous. This chapter highlights regulatory aspects on carbohydrate-based vaccines with an emphasis on analytical approaches to ensure the consistent quality of successive manufacturing lots.

The Regulatory Challenges of Decommissioning Nuclear Power Plants in Korea - 13101

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jungjoon; Ahn, Sangmyeon; Choi, Kyungwoo

As of 2012, 23 units of nuclear power plants are in operation, but there is no experience of permanent shutdown and decommissioning of nuclear power plant in Korea. It is realized that, since late 1990's, improvement of the regulatory framework for decommissioning has been emphasized constantly from the point of view of International Atomic Energy Agency (IAEA)'s safety standards. And it is known that now IAEA prepare the safety requirement on decommissioning of facilities, its title is the Safe Decommissioning of Facilities, General Safety Requirement Part 6. According to the result of IAEA's Integrated Regulatory Review Service (IRRS) mission tomore » Korea in 2011, it was recommended that the regulatory framework for decommissioning should require decommissioning plans for nuclear installations to be constructed and operated and these plans should be updated periodically. In addition, after the Fukushima nuclear disaster in Japan in March of 2011, preparedness for early decommissioning caused by an unexpected severe accident became also important issues and concerns. In this respect, it is acknowledged that the regulatory framework for decommissioning of nuclear facilities in Korea need to be improved. First of all, we identify the current status and relevant issues of regulatory framework for decommissioning of nuclear power plants compared to the IAEA's safety standards in order to achieve our goal. And then the plan is to be established for improvement of regulatory framework for decommissioning of nuclear power plants in Korea. After dealing with it, it is expected that the revised regulatory framework for decommissioning could enhance the safety regime on the decommissioning of nuclear power plants in Korea in light of international standards. (authors)« less

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies.

PubMed

Barazzetti, Gaia; Hurst, Samia A; Mauron, Alexandre

2016-08-01

: As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine. ©AlphaMed Press.

[Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].

PubMed

Kuhlmann-Gottke, Johanna; Duchow, Karin

2015-11-01

At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.

From molecule to market access: drug regulatory science as an upcoming discipline.

PubMed

Gispen-de Wied, Christine C; Leufkens, Hubertus G M

2013-11-05

Regulatory science as a discipline has evolved over the past years with the object to boost and promote scientific rationale behind benefit/risk and decision making by regulatory authorities. The European Medicines Agency, EMA, the Food and Drug Administration, FDA, and the Japanese Pharmaceutical and Medical Devices Agency, PMDA, highlighted in their distinct ways the importance of regulatory science as a basis of good quality assessment in their strategic plans. The Medicines Evaluation Board, MEB, states: 'regulatory science is the science of developing and validating new standards and tools to evaluate and assess the benefit/risk of medicinal products, facilitating sound and transparent regulatory decision making'. Through analysis of regulatory frameworks itself and their effectiveness, however, regulatory science can also advance knowledge of these systems in general. The comprehensive guidance that is issued to complete an application dossier for regulatory product approval has seldomly been scrutinized for its efficiency. Since it is the task of regulatory authorities to protect and promote public health, it is understood that they take a cautious approach in regulating drugs prior to market access. In general, the authorities are among the first to be blamed if dangerous or useless drugs were allowed to the market. Yet, building a regulatory framework that is not challenged continuously in terms of deliverables for public health and cost-effectiveness, might be counterproductive in the end. Regulatory science and research can help understand how and why regulatory decisions are made, and where renewed discussions may be warranted. The MEB supports regulatory science as an R&D activity to fuel primary regulatory processes on product evaluation and vigilance, but also invests in a 'looking into the mirror' approach. Along the line of the drug life-cycle, publicly available data are reviewed and their regulatory impact highlighted. If made explicit, regulatory research can open the door to evidence based regulatory practice and serve the regulator's contribution to innovative drug licensing today. Copyright © 2013 Elsevier B.V. All rights reserved.

Multi-Hazard Advanced Seismic Probabilistic Risk Assessment Tools and Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coleman, Justin L.; Bolisetti, Chandu; Veeraraghavan, Swetha

Design of nuclear power plant (NPP) facilities to resist natural hazards has been a part of the regulatory process from the beginning of the NPP industry in the United States (US), but has evolved substantially over time. The original set of approaches and methods was entirely deterministic in nature and focused on a traditional engineering margins-based approach. However, over time probabilistic and risk-informed approaches were also developed and implemented in US Nuclear Regulatory Commission (NRC) guidance and regulation. A defense-in-depth framework has also been incorporated into US regulatory guidance over time. As a result, today, the US regulatory framework incorporatesmore » deterministic and probabilistic approaches for a range of different applications and for a range of natural hazard considerations. This framework will continue to evolve as a result of improved knowledge and newly identified regulatory needs and objectives, most notably in response to the NRC activities developed in response to the 2011 Fukushima accident in Japan. Although the US regulatory framework has continued to evolve over time, the tools, methods and data available to the US nuclear industry to meet the changing requirements have not kept pace. Notably, there is significant room for improvement in the tools and methods available for external event probabilistic risk assessment (PRA), which is the principal assessment approach used in risk-informed regulations and risk-informed decision-making applied to natural hazard assessment and design. This is particularly true if PRA is applied to natural hazards other than seismic loading. Development of a new set of tools and methods that incorporate current knowledge, modern best practice, and state-of-the-art computational resources would lead to more reliable assessment of facility risk and risk insights (e.g., the SSCs and accident sequences that are most risk-significant), with less uncertainty and reduced conservatisms.« less

Advancing the adverse outcome pathway framework and its ...

EPA Pesticide Factsheets

Regulatory agencies worldwide are confronted with the challenging task of assessing the risks of thousands of chemicals to protect both human health and the environment. Traditional toxicity testing largely relies on apical endpoints from whole animal studies, which, in addition to ethical concerns, is costly and time prohibitive. As a result, the utility of mechanism-based in silico, in vitro, and in vivo approaches to support chemical safety evaluations have increasingly been explored. An approach that has gained traction for capturing available knowledge describing the linkage between mechanistic data and apical toxicity endpoints, required for regulatory assessments, is the adverse outcome pathway (AOP) framework. A number of international workshops and expert meetings have been held over the past years focusing on the AOP framework and its applications to chemical risk assessment. Although, these interactions have illustrated the necessity of expert guidance in moving the science of AOPs and their applications forward, there is also the recognition that a broader survey of the scientific community could be useful in guiding future initiatives in the AOP arena. To that end, a Horizon Scanning exercise was conducted to solicit questions from the global scientific community concerning the challenges or limitations that must be addressed in order to realize the full potential of the AOP framework in research and regulatory decision making. Over a 4 month ques

Let it grow-the open market solution to marijuana control.

PubMed

Gettman, Jon; Kennedy, Michael

2014-11-18

This commentary evaluates regulatory frameworks for the legalized production, sale, and use of marijuana. Specifically, we argue that the primary goal of legalization should be the elimination of the illicit trade in marijuana and that maximizing market participation through open markets and personal cultivation is the best approach to achieving this goal. This argument is based on the assertion that regulatory models based on a tightly controlled government market will fail because they replicate the fatal flaws of the prohibition model. This commentary argues that an examination of the reasons for prohibition's failure-to wit, the inability of government to control the production of marijuana-completely undercuts the basic premise of a tightly controlled market, which depends on the ability of the government to control production. The public interest would be better served by an effective regulatory framework which recognizes and takes advantage of competitive market forces. This analysis argues that reducing teenage access to marijuana requires the elimination of an overcapitalized illicit market. Further, it asserts that this goal and maximization of tax revenue from a legal marijuana market are mutually exclusive objectives.

Proteomics for Adverse Outcome Pathway Discovery using Human Kidney Cells?

EPA Science Inventory

An Adverse Outcome Pathway (AOP) is a conceptual framework that applies molecular-based data for use in risk assessment and regulatory decision support. AOP development is based on effects data of chemicals on biological processes (i.e., molecular initiating events, key intermedi...

EVALUATIONS OF DNAPL REMEDIAL PERFORMANCE BASED ON FIELD MEASUREMENTS OF CONTAMINANT FLUX

EPA Science Inventory

Under a concentration-based regulatory framework, the benefits of conducting dense nonaqueous phase liquid (DNAPL) source-zone remediation are questionable because of the impracticality of complete DNAPL elimination at most sites. Removing a sufficient mass of DNAPL to achieve c...

RegNetwork: an integrated database of transcriptional and post-transcriptional regulatory networks in human and mouse

PubMed Central

Liu, Zhi-Ping; Wu, Canglin; Miao, Hongyu; Wu, Hulin

2015-01-01

Transcriptional and post-transcriptional regulation of gene expression is of fundamental importance to numerous biological processes. Nowadays, an increasing amount of gene regulatory relationships have been documented in various databases and literature. However, to more efficiently exploit such knowledge for biomedical research and applications, it is necessary to construct a genome-wide regulatory network database to integrate the information on gene regulatory relationships that are widely scattered in many different places. Therefore, in this work, we build a knowledge-based database, named ‘RegNetwork’, of gene regulatory networks for human and mouse by collecting and integrating the documented regulatory interactions among transcription factors (TFs), microRNAs (miRNAs) and target genes from 25 selected databases. Moreover, we also inferred and incorporated potential regulatory relationships based on transcription factor binding site (TFBS) motifs into RegNetwork. As a result, RegNetwork contains a comprehensive set of experimentally observed or predicted transcriptional and post-transcriptional regulatory relationships, and the database framework is flexibly designed for potential extensions to include gene regulatory networks for other organisms in the future. Based on RegNetwork, we characterized the statistical and topological properties of genome-wide regulatory networks for human and mouse, we also extracted and interpreted simple yet important network motifs that involve the interplays between TF-miRNA and their targets. In summary, RegNetwork provides an integrated resource on the prior information for gene regulatory relationships, and it enables us to further investigate context-specific transcriptional and post-transcriptional regulatory interactions based on domain-specific experimental data. Database URL: http://www.regnetworkweb.org PMID:26424082

A three-tiered approach for linking pharmacokinetic ...

EPA Pesticide Factsheets

The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreting high throughput (HT) toxicity screening results. Application of the AOP framework and HT predictions in ecological and human health risk assessment, however, requires the consideration of chemical-specific properties that influence external exposure doses and target tissue doses. To address this requirement, a three-tiered approach was developed to provide a workflow for connecting biology-based AOPs to biochemical-based pharmacokinetic properties (absorption, distribution, metabolism, excretion; ADME), and then to chemical/human activity-based exposure pathways. This approach included: (1) The power of the adverse outcome pathway (AOP) framework arisesfrom its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreti

Total Water Management: A Watershed Based Approach

EPA Science Inventory

In this urbanizing world, municipal water managers need to develop planning and management frameworks to meet challenges such as limiting fresh water supplies, degrading receiving waters, increasing regulatory requirements, flooding, aging infrastructure, rising utility (energy) ...

Total Water Management: A Watershed Based Approach - slides

EPA Science Inventory

ABSTRACT In this urbanizing world, municipal water managers need to develop planning and management frameworks to meet challenges such as limiting fresh water supplies, degrading receiving waters, increasing regulatory requirements, flooding, aging infrastructure, rising utility...

77 FR 18176 - Magnuson-Stevens Fishery Conservation and Management Act Provisions; Fisheries of the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-27

... environmental assessment (EA) was prepared for Framework 47 that describes the proposed action and other.... Copies of Framework 47, the draft EA, its Regulatory Impact Review (RIR), and the Initial Regulatory.... The Framework 47 EA/ RIR/IRFA are also accessible via the Internet at http://www.nefmc.org/nemulti...

78 FR 40243 - Self-Regulatory Organizations; ICE Clear Europe Limited; Notice of Filing of Amendment No. 3 and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-03

... framework. \\17\\ Id. Operational Resources. ICE Clear Europe believes it will have the operational and... governance framework. \\33\\ 15 U.S.C. 78q-1(b)(3)(F). IV. Conclusion On the basis of the foregoing, the... having a U.S. residence, based upon the location of its executive office or principal place of business...

Integrating Data Clustering and Visualization for the Analysis of 3D Gene Expression Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Data Analysis and Visualization; nternational Research Training Group ``Visualization of Large and Unstructured Data Sets,'' University of Kaiserslautern, Germany; Computational Research Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720, USA

2008-05-12

The recent development of methods for extracting precise measurements of spatial gene expression patterns from three-dimensional (3D) image data opens the way for new analyses of the complex gene regulatory networks controlling animal development. We present an integrated visualization and analysis framework that supports user-guided data clustering to aid exploration of these new complex datasets. The interplay of data visualization and clustering-based data classification leads to improved visualization and enables a more detailed analysis than previously possible. We discuss (i) integration of data clustering and visualization into one framework; (ii) application of data clustering to 3D gene expression data; (iii)more » evaluation of the number of clusters k in the context of 3D gene expression clustering; and (iv) improvement of overall analysis quality via dedicated post-processing of clustering results based on visualization. We discuss the use of this framework to objectively define spatial pattern boundaries and temporal profiles of genes and to analyze how mRNA patterns are controlled by their regulatory transcription factors.« less

Harnessing Diversity towards the Reconstructing of Large Scale Gene Regulatory Networks

PubMed Central

Yamanaka, Ryota; Kitano, Hiroaki

2013-01-01

Elucidating gene regulatory network (GRN) from large scale experimental data remains a central challenge in systems biology. Recently, numerous techniques, particularly consensus driven approaches combining different algorithms, have become a potentially promising strategy to infer accurate GRNs. Here, we develop a novel consensus inference algorithm, TopkNet that can integrate multiple algorithms to infer GRNs. Comprehensive performance benchmarking on a cloud computing framework demonstrated that (i) a simple strategy to combine many algorithms does not always lead to performance improvement compared to the cost of consensus and (ii) TopkNet integrating only high-performance algorithms provide significant performance improvement compared to the best individual algorithms and community prediction. These results suggest that a priori determination of high-performance algorithms is a key to reconstruct an unknown regulatory network. Similarity among gene-expression datasets can be useful to determine potential optimal algorithms for reconstruction of unknown regulatory networks, i.e., if expression-data associated with known regulatory network is similar to that with unknown regulatory network, optimal algorithms determined for the known regulatory network can be repurposed to infer the unknown regulatory network. Based on this observation, we developed a quantitative measure of similarity among gene-expression datasets and demonstrated that, if similarity between the two expression datasets is high, TopkNet integrating algorithms that are optimal for known dataset perform well on the unknown dataset. The consensus framework, TopkNet, together with the similarity measure proposed in this study provides a powerful strategy towards harnessing the wisdom of the crowds in reconstruction of unknown regulatory networks. PMID:24278007

Industrial Sectors Integrated Solutions (ISIS) - An Engineering–Economic and Multi-Pollutant Modeling Framework for Comprehensive Regulatory Analyses

EPA Science Inventory

Based on the National Academy of Science’s 2004 report, “Air Quality Management in the United States”, the National Research Council (NRC) recommended to the US Environmental Protection Agency (EPA) that standard setting, planning, and control strategy development should be based...

The impact of biotechnology on agricultural worker safety and health.

PubMed

Shutske, J M; Jenkins, S M

2002-08-01

Biotechnology applications such as the use and production of genetically modified organisms (GMOs) have been widely promoted, adopted, and employed by agricultural producers throughout the world. Yet, little research exists that examines the implications of agricultural biotechnology on the health and safety of workers involved in agricultural production and processing. Regulatory frameworks do exist to examine key issues related to food safety and environmental protection in GMO applications. However, based on the lack of research and regulatory oversight, it would appear that the potential impact on the safety and health of workers is of limited interest. This article examines some of the known worker health and safety implications related to the use and production of GMOs using the host, agent, and environment framework. The characteristics of employers, workers, inputs, production practices, and socio-economic environments in which future agricultural workers perform various tasks is likely to change based on the research summarized here.

75 FR 39391 - Funding and Fiscal Affairs, Loan Policies and Operations, and Funding Operations; Capital...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-08

... framework. System banks do not routinely retire their stock in the ordinary course of business or revolve... adopting a Tier 1/Tier 2 regulatory capital framework for the institutions it regulates. The NCUA has also... capital requirement and, therefore, it will remain part of the System's regulatory capital framework. The...

A quantitative framework for the forward design of synthetic miRNA circuits.

PubMed

Bloom, Ryan J; Winkler, Sally M; Smolke, Christina D

2014-11-01

Synthetic genetic circuits incorporating regulatory components based on RNA interference (RNAi) have been used in a variety of systems. A comprehensive understanding of the parameters that determine the relationship between microRNA (miRNA) and target expression levels is lacking. We describe a quantitative framework supporting the forward engineering of gene circuits that incorporate RNAi-based regulatory components in mammalian cells. We developed a model that captures the quantitative relationship between miRNA and target gene expression levels as a function of parameters, including mRNA half-life and miRNA target-site number. We extended the model to synthetic circuits that incorporate protein-responsive miRNA switches and designed an optimized miRNA-based protein concentration detector circuit that noninvasively measures small changes in the nuclear concentration of β-catenin owing to induction of the Wnt signaling pathway. Our results highlight the importance of methods for guiding the quantitative design of genetic circuits to achieve robust, reliable and predictable behaviors in mammalian cells.

The commercial development of space: is an international regulatory framework needed?

PubMed

Contant, Corinne M; Logsdon, John M

2004-04-01

The commercial space sector to date has failed to develop comprehensive regulations--"rules of the road"--for its international activities. Within the next 5 years, conflicts with respect to international trade in satellite sales and launch services could emerge, highlighting the need for such a regulatory framework. If the commercial space sector is to continue to develop, it is important to begin discussions now, before these conflicts become significant, on the elements of an appropriate international regulatory framework. The existing framework for space activities was developed when government, not commercial, space activities were dominant, or was adapted from regulations in other sectors such as terrestrial telecommunications. c2003 Elsevier Ltd. All rights reserved.

An Ethical Framework for Evaluating Experimental Technology.

PubMed

van de Poel, Ibo

2016-06-01

How are we to appraise new technological developments that may bring revolutionary social changes? Currently this is often done by trying to predict or anticipate social consequences and to use these as a basis for moral and regulatory appraisal. Such an approach can, however, not deal with the uncertainties and unknowns that are inherent in social changes induced by technological development. An alternative approach is proposed that conceives of the introduction of new technologies into society as a social experiment. An ethical framework for the acceptability of such experiments is developed based on the bioethical principles for experiments with human subjects: non-maleficence, beneficence, respect for autonomy, and justice. This provides a handle for the moral and regulatory assessment of new technologies and their impact on society.

Pharmaceutical Regulatory Framework in Ethiopia: A Critical Evaluation of Its Legal Basis and Implementation.

PubMed

Suleman, Sultan; Woliyi, Abdulkadir; Woldemichael, Kifle; Tushune, Kora; Duchateau, Luc; Degroote, Agnes; Vancauwenberghe, Roy; Bracke, Nathalie; De Spiegeleer, Bart

2016-05-01

Effective and enforceable national regulations describing the manufacture and (re)packaging, export and import, distribution and storage, supply and sale, information and pharmaco-vigilance of medicines are required to consistently ensure optimal patient benefit. Expansion of pharmaceutical industries in many countries with advancement in transport technologies facilitated not only trade of genuine pharmaceutical products but also the circulation of poor quality medicines across the globe. In Ethiopia, even though "The Pharmacists and Druggists Proclamation No 43/1942" was used to regulate both the professions and the facilities where they were practiced, comprehensive regulation of the pharmaceutical market was introduced in 1964 by a regulation called "Pharmacy Regulation No. 288/ 1964". This legislation formed the legal basis for official establishment of drug regulation in the history of Ethiopia, enabling the regulation of the practice of pharmacists, druggists and pharmacy technicians; manufacturing, distribution, and sale of medicines. In June 1999, a new regulation called the "Drug Administration and Control Proclamation No. 176/1999" repealed most parts of the regulation 288/1964. The law established an independent Drug Administration and Control Authority (DACA) with further mandate of setting standards of competence for licensing institutions/facilities. DACA was re-structured as Food, Medicine and Health Care Administration and Control Authority (EFMHACA) of Ethiopia by the "Proclamation No. 661/2009" in 2010 bearing additional responsibilities like regulation of food, health care personnel and settings. The mere existence of this legal framework does not guarantee complete absence of illegal, substandard and falsified products as well as illegal establishments in the pharmaceutical chain. Therefore, the objective of the research is to assess the pharmaceutical regulatory system in Ethiopia and to reveal possible reasons for deficiencies in the pharmaceutical chain. An archival review, an in-depth interview of key informants and an institutions-based cross-sectional survey study were conducted during March to April 2013. The comprehensiveness of the pharmaceutical law to protect public health relative to three selected African countries (South Africa, Tanzania and Uganda) and European Union, and implementation was assessed. The study revealed that Ethiopia does have a written national drug policy upon which the Medicines Regulatory Proclamation 661/2009 is based. According to this proclamation, the Ethiopian The Food, Medicines and Healthcare Administration and Control Authority is mandated to execute the regulatory activities as per the council of ministers regulation 189/2010. The legal framework for pharmaceutical regulation of Ethiopia was founded to fulfill all the medicines regulatory functions potentially enabling to combat illegal, substandard and falsified medicines and illegal establishments. Moreover, all the key informants witnessed that the government is commited and proclamation 661/2009 is comprehensive, but they stressed the compelling need of regulatory tools for effective implementation. From the institution-based cross-sectional study, it was revealed that there exist illegal sources formedicine in the pharmaceutical market. The main reasons for their existence were regulatory factors including weak regulatory enforcement (64.5%), lack of informal market control (60.8%), weak port control (50.0%), and poor cooperation between executive bodies (39.6%); and resource constraint (27.8%), which is an institutional factor. From legislative point of view, the medicines regulatory framework in Ethiopia fulfils all regulatory functions required for effective medicines regulation. However, the existence of the legislation by its own is not a guarantee to prevent the existence of unauthorized/illegal medicine sources since this requires effective implementation of the legislation, which is in fact affected by the governments political commitment, resource and intergovernmental cooperation.

Inferring causal genomic alterations in breast cancer using gene expression data

PubMed Central

2011-01-01

Background One of the primary objectives in cancer research is to identify causal genomic alterations, such as somatic copy number variation (CNV) and somatic mutations, during tumor development. Many valuable studies lack genomic data to detect CNV; therefore, methods that are able to infer CNVs from gene expression data would help maximize the value of these studies. Results We developed a framework for identifying recurrent regions of CNV and distinguishing the cancer driver genes from the passenger genes in the regions. By inferring CNV regions across many datasets we were able to identify 109 recurrent amplified/deleted CNV regions. Many of these regions are enriched for genes involved in many important processes associated with tumorigenesis and cancer progression. Genes in these recurrent CNV regions were then examined in the context of gene regulatory networks to prioritize putative cancer driver genes. The cancer driver genes uncovered by the framework include not only well-known oncogenes but also a number of novel cancer susceptibility genes validated via siRNA experiments. Conclusions To our knowledge, this is the first effort to systematically identify and validate drivers for expression based CNV regions in breast cancer. The framework where the wavelet analysis of copy number alteration based on expression coupled with the gene regulatory network analysis, provides a blueprint for leveraging genomic data to identify key regulatory components and gene targets. This integrative approach can be applied to many other large-scale gene expression studies and other novel types of cancer data such as next-generation sequencing based expression (RNA-Seq) as well as CNV data. PMID:21806811

Safety of plant-made pharmaceuticals: product development and regulatory considerations based on case studies of two autologous human cancer vaccines.

PubMed

Tusé, Daniel

2011-03-01

Guidelines issued by regulatory agencies for the development of plant-made pharmaceutical (PMP) products provide criteria for product manufacturing and characterization, safety determination, containment and mitigation of environmental risks. Features of plant-made products do not always enable an easy fit within the criteria subscribed to by regulators. The unconventional nature of plant-based manufacturing processes and peculiarities of plant biology relative to that of traditional biological production systems have led to special considerations in the regulatory scrutiny of PMP. Presented in this review are case studies of two plant-made autologous (patient-specific) cancer vaccines, the nature of which introduced challenges to conventional and standardized development and preclinical evaluation routes. The rationale presented to FDA by the sponsors of each vaccine to build consensus and obtain variances to existing guidelines is discussed. While development of many plant-made biologics can be accomplished within the existing regulatory framework, the development of specialized products can be defended with rational arguments based on strong science.

77 FR 52887 - Regulatory Capital Rules: Standardized Approach for Risk-Weighted Assets; Market Discipline and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-30

... securitization framework designed to address the credit risk of exposures that involve the tranching of the... creditworthiness standards and risk-based capital requirements have been designed to be consistent with safety and...

Protecting the public or setting the bar too high? Understanding the causes and consequences of regulatory actions of front-line regulators and specialized drug shop operators in Kenya.

PubMed

Wafula, Francis; Molyneux, Catherine; Mackintosh, Maureen; Goodman, Catherine

2013-11-01

The problem of poor regulatory compliance has been widely reported across private health providers in developing countries. Less known are the underlying reasons for poor compliance, especially with regards to the roles played by front-line regulatory staff, and the regulatory institution as a whole. We designed a qualitative study to address this gap, with the study questions and tools drawing on a conceptual framework informed by theoretical literature on regulation. Data were collected from specialized drug shops (SDSs) in two rural districts in Western Kenya in 2011 through eight focus group discussions, and from regulatory staff from organizations governing the pharmaceutical sector through a total of 24 in-depth interviews. We found that relationships between front-line regulators and SDS operators were a strong influence on regulatory behaviour, often resulting in non-compliance and perverse outcomes such as corruption. It emerged that separate regulatory streams operated in urban and rural locations, based mainly on differing relationships between the front-line regulators and SDS operators, and on broader factors such as the competition environment and community expectations. Effective incentive structures for regulatory staff were either absent, or poorly linked to performance in regulatory organizations, resulting in divergences between the purposes of the regulatory organization and activities of front-line staff. Given the rural-urban differences in the practice environment, the introduction of lower retail practice requirements for rural SDSs could be considered. This would allow illegally operated shops to be brought within the regulatory framework, facilitating good quality provision of essential commodities to marginalized areas, without lowering the practice requirements for the better complying urban SDSs. In addition, regulatory organizations need to devise incentives that better link the level of effort to rewards such as professional advancement of regulatory staff. Copyright © 2013 Elsevier Ltd. All rights reserved.

Protecting the public or setting the bar too high? Understanding the causes and consequences of regulatory actions of front-line regulators and specialized drug shop operators in Kenya

PubMed Central

Wafula, Francis; Molyneux, Catherine; Mackintosh, Maureen; Goodman, Catherine

2013-01-01

The problem of poor regulatory compliance has been widely reported across private health providers in developing countries. Less known are the underlying reasons for poor compliance, especially with regards to the roles played by front-line regulatory staff, and the regulatory institution as a whole. We designed a qualitative study to address this gap, with the study questions and tools drawing on a conceptual framework informed by theoretical literature on regulation. Data were collected from specialized drug shops (SDSs) in two rural districts in Western Kenya in 2011 through eight focus group discussions, and from regulatory staff from organizations governing the pharmaceutical sector through a total of 24 in-depth interviews. We found that relationships between front-line regulators and SDS operators were a strong influence on regulatory behaviour, often resulting in non-compliance and perverse outcomes such as corruption. It emerged that separate regulatory streams operated in urban and rural locations, based mainly on differing relationships between the front-line regulators and SDS operators, and on broader factors such as the competition environment and community expectations. Effective incentive structures for regulatory staff were either absent, or poorly linked to performance in regulatory organizations, resulting in divergences between the purposes of the regulatory organization and activities of front-line staff. Given the rural-urban differences in the practice environment, the introduction of lower retail practice requirements for rural SDSs could be considered. This would allow illegally operated shops to be brought within the regulatory framework, facilitating good quality provision of essential commodities to marginalized areas, without lowering the practice requirements for the better complying urban SDSs. In addition, regulatory organizations need to devise incentives that better link the level of effort to rewards such as professional advancement of regulatory staff. PMID:24016728

Legislative and Regulatory Actions Needed to Deal with a Changing Domestic Telecommunications Industry.

DTIC Science & Technology

1981-09-24

procedures? GAO recommends that the Congress address these questions by amending the Communications Act of 1934 to establish the basic framework to create...concerns with rate of return/rate base regulation 198 VII Basic procedures used in establishing rates of return 201 VIII Problems regarding AT&T’s rate...prompted a critical reexamination of the basic communications policy and regulatory methods con- tained in the Communications Act of 1934 (47 U.S.C

Physico-chemical properties of manufactured nanomaterials - Characterisation and relevant methods. An outlook based on the OECD Testing Programme.

PubMed

Rasmussen, Kirsten; Rauscher, Hubert; Mech, Agnieszka; Riego Sintes, Juan; Gilliland, Douglas; González, Mar; Kearns, Peter; Moss, Kenneth; Visser, Maaike; Groenewold, Monique; Bleeker, Eric A J

2018-02-01

Identifying and characterising nanomaterials require additional information on physico-chemical properties and test methods, compared to chemicals in general. Furthermore, regulatory decisions for chemicals are usually based upon certain toxicological properties, and these effects may not be equivalent to those for nanomaterials. However, regulatory agencies lack an authoritative decision framework for nanomaterials that links the relevance of certain physico-chemical endpoints to toxicological effects. This paper investigates various physico-chemical endpoints and available test methods that could be used to produce such a decision framework for nanomaterials. It presents an overview of regulatory relevance and methods used for testing fifteen proposed physico-chemical properties of eleven nanomaterials in the OECD Working Party on Manufactured Nanomaterials' Testing Programme, complemented with methods from literature, and assesses the methods' adequacy and applications limits. Most endpoints are of regulatory relevance, though the specific parameters depend on the nanomaterial and type of assessment. Size (distribution) is the common characteristic of all nanomaterials and is decisive information for classifying a material as a nanomaterial. Shape is an important particle descriptor. The octanol-water partitioning coefficient is undefined for particulate nanomaterials. Methods, including sample preparation, need to be further standardised, and some new methods are needed. The current work of OECD's Test Guidelines Programme regarding physico-chemical properties is highlighted. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

An integrative and applicable phylogenetic footprinting framework for cis-regulatory motifs identification in prokaryotic genomes.

PubMed

Liu, Bingqiang; Zhang, Hanyuan; Zhou, Chuan; Li, Guojun; Fennell, Anne; Wang, Guanghui; Kang, Yu; Liu, Qi; Ma, Qin

2016-08-09

Phylogenetic footprinting is an important computational technique for identifying cis-regulatory motifs in orthologous regulatory regions from multiple genomes, as motifs tend to evolve slower than their surrounding non-functional sequences. Its application, however, has several difficulties for optimizing the selection of orthologous data and reducing the false positives in motif prediction. Here we present an integrative phylogenetic footprinting framework for accurate motif predictions in prokaryotic genomes (MP(3)). The framework includes a new orthologous data preparation procedure, an additional promoter scoring and pruning method and an integration of six existing motif finding algorithms as basic motif search engines. Specifically, we collected orthologous genes from available prokaryotic genomes and built the orthologous regulatory regions based on sequence similarity of promoter regions. This procedure made full use of the large-scale genomic data and taxonomy information and filtered out the promoters with limited contribution to produce a high quality orthologous promoter set. The promoter scoring and pruning is implemented through motif voting by a set of complementary predicting tools that mine as many motif candidates as possible and simultaneously eliminate the effect of random noise. We have applied the framework to Escherichia coli k12 genome and evaluated the prediction performance through comparison with seven existing programs. This evaluation was systematically carried out at the nucleotide and binding site level, and the results showed that MP(3) consistently outperformed other popular motif finding tools. We have integrated MP(3) into our motif identification and analysis server DMINDA, allowing users to efficiently identify and analyze motifs in 2,072 completely sequenced prokaryotic genomes. The performance evaluation indicated that MP(3) is effective for predicting regulatory motifs in prokaryotic genomes. Its application may enhance progress in elucidating transcription regulation mechanism, thus provide benefit to the genomic research community and prokaryotic genome researchers in particular.

Regulatory Risk Reduction for Advanced Reactor Technologies – FY2016 Status and Work Plan Summary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moe, Wayne Leland

2016-08-01

Millions of public and private sector dollars have been invested over recent decades to realize greater efficiency, reliability, and the inherent and passive safety offered by advanced nuclear reactor technologies. However, a major challenge in experiencing those benefits resides in the existing U.S. regulatory framework. This framework governs all commercial nuclear plant construction, operations, and safety issues and is highly large light water reactor (LWR) technology centric. The framework must be modernized to effectively deal with non-LWR advanced designs if those designs are to become part of the U.S energy supply. The U.S. Department of Energy’s (DOE) Advanced Reactor Technologiesmore » (ART) Regulatory Risk Reduction (RRR) initiative, managed by the Regulatory Affairs Department at the Idaho National Laboratory (INL), is establishing a capability that can systematically retire extraneous licensing risks associated with regulatory framework incompatibilities. This capability proposes to rely heavily on the perspectives of the affected regulated community (i.e., commercial advanced reactor designers/vendors and prospective owner/operators) yet remain tuned to assuring public safety and acceptability by regulators responsible for license issuance. The extent to which broad industry perspectives are being incorporated into the proposed framework makes this initiative unique and of potential benefit to all future domestic non-LWR applicants« less

State-Based Curriculum-Making, Part 2, the Tool-Kit for the State's Curriculum-Making

ERIC Educational Resources Information Center

Westbury, Ian; Sivesind, Kirsten

2016-01-01

The paper identifies three tools that support the administrative instrument of a state-based curriculum commission: compartmentalization, licensing, and segmentation. These tools channel the state's curriculum-making towards forms of symbolic rather than regulatory action. The state curriculum becomes a framework for the ideological governance of…

Promoting Self-Regulation through School-Based Martial Arts Training

ERIC Educational Resources Information Center

Lakes, Kimberley D.; Hoyt, William T.

2004-01-01

The impact of school-based Tae Kwon Do training on self-regulatory abilities was examined. A self-regulation framework including three domains (cognitive, affective, and physical) was presented. Children (N = 207) from kindergarten through Grade 5 were randomly assigned by homeroom class to either the intervention (martial arts) group or a…

Identification of miRNA-mRNA regulatory modules by exploring collective group relationships.

PubMed

Masud Karim, S M; Liu, Lin; Le, Thuc Duy; Li, Jiuyong

2016-01-11

microRNAs (miRNAs) play an essential role in the post-transcriptional gene regulation in plants and animals. They regulate a wide range of biological processes by targeting messenger RNAs (mRNAs). Evidence suggests that miRNAs and mRNAs interact collectively in gene regulatory networks. The collective relationships between groups of miRNAs and groups of mRNAs may be more readily interpreted than those between individual miRNAs and mRNAs, and thus are useful for gaining insight into gene regulation and cell functions. Several computational approaches have been developed to discover miRNA-mRNA regulatory modules (MMRMs) with a common aim to elucidate miRNA-mRNA regulatory relationships. However, most existing methods do not consider the collective relationships between a group of miRNAs and the group of targeted mRNAs in the process of discovering MMRMs. Our aim is to develop a framework to discover MMRMs and reveal miRNA-mRNA regulatory relationships from the heterogeneous expression data based on the collective relationships. We propose DIscovering COllective group RElationships (DICORE), an effective computational framework for revealing miRNA-mRNA regulatory relationships. We utilize the notation of collective group relationships to build the computational framework. The method computes the collaboration scores of the miRNAs and mRNAs on the basis of their interactions with mRNAs and miRNAs, respectively. Then it determines the groups of miRNAs and groups of mRNAs separately based on their respective collaboration scores. Next, it calculates the strength of the collective relationship between each pair of miRNA group and mRNA group using canonical correlation analysis, and the group pairs with significant canonical correlations are considered as the MMRMs. We applied this method to three gene expression datasets, and validated the computational discoveries. Analysis of the results demonstrates that a large portion of the regulatory relationships discovered by DICORE is consistent with the experimentally confirmed databases. Furthermore, it is observed that the top mRNAs that are regulated by the miRNAs in the identified MMRMs are highly relevant to the biological conditions of the given datasets. It is also shown that the MMRMs identified by DICORE are more biologically significant and functionally enriched.

The Chinese health care regulatory institutions in an era of transition.

PubMed

Fang, Jing

2008-02-01

The purpose of this paper is to contribute to a better understanding of Chinese health care regulation in an era of transition. It describes the major health care regulatory institutions operating currently in China and analyzes the underlying factors. The paper argues that in the transition from a planned to a market economy, the Chinese government has been employing a hybrid approach where both old and new institutions have a role in the management of emerging markets, including the health care market. This approach is consistent with the incremental reform strategy adopted by the Party-state. Although a health care regulatory framework has gradually taken shape, the framework is incomplete, with a particular lack of emphasis on professional self-regulation. In addition, its effectiveness is limited despite the existence of many regulatory institutions. In poor rural areas, the effectiveness of the regulatory framework is further undermined or distorted by the extremely difficult financial position that local governments find themselves in. The interpretations of the principle of 'rule of law' by policy makers and officials at different levels and the widespread informal network of relations between known individuals (Guanxi) play an important role in the operation of the regulatory framework. The findings of this paper reveal the complex nature of regulating health care in transitional China.

Global regulatory framework for production and marketing of crops biofortified with vitamins and minerals.

PubMed

Mejia, Luis A; Dary, Omar; Boukerdenna, Hala

2017-02-01

Biofortification of crops is being introduced in several countries as a strategy to reduce micronutrient deficiencies. Biofortified products, with increased contents of micronutrients, are currently produced by conventional plant breeding, genetic modification, or nutrient-enhanced fertilization. Corn, rice, wheat, beans, pearl millet, sweet potato, and cassava have been biofortified with increased contents of provitamin A carotenoids, iron, or zinc. However, regulatory considerations are rare or nonexistent. The objective of this paper is to review the regulatory framework for production and marketing of biofortified crops in countries that have adopted this strategy. The information was identified using Internet search engines and websites of health and nutrition organizations and nongovernmental organizations and by consulting scientists and government authorities. Thus far, biofortified products introduced in Latin America, Africa, and Asia have been produced only by conventional breeding. Cultivars using other techniques are still under testing. The production and marketing of these products have been conducted without regulatory framework and under limited government control or regulatory guidance. Nevertheless, some countries have integrated biofortified crops into their nutrition agendas. Although improvements by conventional breeding have not been subject to regulations, when biofortification becomes expanded by including other techniques, an appropriate regulatory framework will be necessary. © 2016 New York Academy of Sciences.

Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances

EPA Science Inventory

In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across organizatio...

A structured policy review of the principles of professional self-regulation.

PubMed

Benton, D C; González-Jurado, M A; Beneit-Montesinos, J V

2013-03-01

The International Council of Nurses (ICN) has, for many years, based its work on professional self-regulation on a set of 12 principles. These principles are research based and were identified nearly three decades ago. ICN has conducted a number of reviews of the principles; however, changes have been minimal. In the past 5-10 years, a number of authors and governments, often as part of the review of regulatory systems, have started to propose principles to guide the way regulatory frameworks are designed and implemented. These principles vary in number and content. This study examines the current policy literature on principle-based regulation and compares this with the set of principles advocated by the ICN. A systematic search of the literature on principle-based regulation is used as the basis for a qualitative thematic analysis to compare and contrast the 12 principles of self-regulation with more recently published work. A mapping of terms based on a detailed description of the principles used in the various research and policy documents was generated. This mapping forms the basis of a critique of the current ICN principles. A professional self-regulation advocated by the ICN were identified. A revised and extended set of 13 principles is needed if contemporary developments in the field of regulatory frameworks are to be accommodated. These revised principles should be considered for adoption by the ICN to underpin their advocacy work on professional self-regulation. © 2013 The Authors. International Nursing Review © 2013 International Council of Nurses.

Strengthening the regulatory system through the implementation and use of a quality management system.

PubMed

Eisner, Reinhold; Patel, Rakeshkumar

2017-04-20

Quality management systems (QMS), based on ISO 9001 requirements, are applicable to government service organizations such as Health Canada's Biologics and Genetic Therapies Directorate (BGTD). This communication presents the process that the BGTD followed since the early 2000s to implement a quality management system and describes how the regulatory system was improved as a result of this project. BGTD undertook the implementation of a quality management system based on ISO 9001 and containing aspects of ISO 17025 with the goal of strengthening the regulatory system through improvements in the people, processes, and services of the organization. We discuss the strategy used by BGTD to implement the QMS and the benefits that were realized from the various stages of implementation. The eight quality principals upon which the QMS standards of the ISO 9000 series are based were used by senior management as a framework to guide QMS implementation.

Applying a Developmental Framework to the Self-Regulatory Difficulties of Young Children with Prenatal Alcohol Exposure: A Review.

PubMed

Reid, Natasha; Petrenko, Christie L M

2018-06-01

Prenatal alcohol exposure (PAE) can be associated with significant difficulties in self-regulatory abilities. As such, interventions have been developed that focus on improving varying aspects of self-regulation for this population. The application of a multilevel theoretical framework that describes the development of self-regulation during early childhood could further advance the field. First, this framework could assist in elucidating mechanisms in the trajectories of early adjustment problems in this population and, second, informing the development of more precise assessment and interventions for those affected by PAE. The aims of the current review were to provide an overview of the self-regulatory framework proposed by Calkins and colleagues (e.g., Calkins, 2007; Calkins and Fox, 2002); examine the self-regulatory difficulties that are commonly experienced during infancy (i.e., 0 to 2 years) and early childhood (i.e., 3 to 8 years) in children with PAE in the context of the developmental framework; and describe how the framework can inform the development of future assessment and intervention provision for young children with PAE. The application of a developmental framework, such as proposed by Calkins and colleagues, allows for a systematic and theoretically driven approach to assessment and intervention programs for young children with PAE. Copyright © 2018 by the Research Society on Alcoholism.

Regulatory framework on bioequivalence criteria for locally acting gastrointestinal drugs: the case for oral modified release mesalamine formulations.

PubMed

Sferrazza, Gianluca; Siviero, Paolo D; Nicotera, Giuseppe; Turella, Paola; Serafino, Annalucia; Blandizzi, Corrado; Pierimarchi, Pasquale

2017-09-01

Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs.

Health claims on food products in Southeast Asia: regulatory frameworks, barriers, and opportunities.

PubMed

Tan, Karin Y M; van der Beek, Eline M; Chan, M Y; Zhao, Xuejun; Stevenson, Leo

2015-09-01

The Association of Southeast Asian Nations aims to act as a single market and allow free movement of goods, services, and manpower. The purpose of this article is to present an overview of the current regulatory framework for health claims in Southeast Asia and to highlight the current barriers and opportunities in the regulatory frameworks in the Association of Southeast Asian Nations. To date, 5 countries in Southeast Asia, i.e., Indonesia, Malaysia, the Philippines, Singapore, and Thailand, have regulations and guidelines to permit the use of health claims on food products. There are inconsistencies in the regulations and the types of evidence required for health claim applications in these countries. A clear understanding of the regulatory frameworks in these countries may help to increase trade in this fast-growing region and to provide direction for the food industry and the regulatory community to develop and market food products with better nutritional quality tailored to the needs of Southeast Asian consumers. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

75 FR 36211 - Requirements for Distribution of Byproduct Material

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-24

.... Submitting Comments and Accessing Information II. Background A. Introduction B. Regulatory Framework III.... Introduction The Commission has authority to issue both general and specific licenses for the use of byproduct... Products As noted in the introduction on regulatory framework, class exemptions allow the Commission to...

Applying the Policy Ecology Framework to Philadelphia’s Behavioral Health Transformation Efforts

PubMed Central

Powell, Byron J.; Beidas, Rinad S.; Rubin, Ronnie M.; Stewart, Rebecca E.; Wolk, Courtney Benjamin; Matlin, Samantha L.; Weaver, Shawna; Hurford, Matthew O.; Evans, Arthur C.; Hadley, Trevor R.; Mandell, David S.

2016-01-01

Raghavan et al. (2008) proposed that effective implementation of evidence-based practices requires implementation strategies deployed at multiple levels of the “policy ecology,” including the organizational, regulatory or purchaser agency, political, and social levels. However, much of implementation research and practice targets providers without accounting for contextual factors that may influence provider behavior. This paper examines Philadelphia’s efforts to work toward an evidence-based and recovery-oriented behavioral health system, and uses the policy ecology framework to illustrate how multifaceted, multilevel implementation strategies can facilitate the widespread implementation of evidence-based practices. Ongoing challenges and implications for research and practice are discussed. PMID:27032411

Identifying direct miRNA-mRNA causal regulatory relationships in heterogeneous data.

PubMed

Zhang, Junpeng; Le, Thuc Duy; Liu, Lin; Liu, Bing; He, Jianfeng; Goodall, Gregory J; Li, Jiuyong

2014-12-01

Discovering the regulatory relationships between microRNAs (miRNAs) and mRNAs is an important problem that interests many biologists and medical researchers. A number of computational methods have been proposed to infer miRNA-mRNA regulatory relationships, and are mostly based on the statistical associations between miRNAs and mRNAs discovered in observational data. The miRNA-mRNA regulatory relationships identified by these methods can be both direct and indirect regulations. However, differentiating direct regulatory relationships from indirect ones is important for biologists in experimental designs. In this paper, we present a causal discovery based framework (called DirectTarget) to infer direct miRNA-mRNA causal regulatory relationships in heterogeneous data, including expression profiles of miRNAs and mRNAs, and miRNA target information. DirectTarget is applied to the Epithelial to Mesenchymal Transition (EMT) datasets. The validation by experimentally confirmed target databases suggests that the proposed method can effectively identify direct miRNA-mRNA regulatory relationships. To explore the upstream regulators of miRNA regulation, we further identify the causal feedforward patterns (CFFPs) of TF-miRNA-mRNA to provide insights into the miRNA regulation in EMT. DirectTarget has the potential to be applied to other datasets to elucidate the direct miRNA-mRNA causal regulatory relationships and to explore the regulatory patterns. Copyright © 2014 Elsevier Inc. All rights reserved.

Redesigning the Regulatory Framework for Ambulatory Care Services in New York

PubMed Central

Chokshi, Dave A; Rugge, John; Shah, Nirav R

2014-01-01

Context While hospitals remain important centers of gravity in the health system, services are increasingly being delivered through ambulatory care. This shift to ambulatory care is giving rise to new delivery structures, such as retail clinics and urgent care centers, as well as reinventing existing ambulatory care capacity, as seen with the patient-centered medical home model and the movement toward team-based care. To protect the public's interests, oversight of ambulatory care services must keep pace with these rapid changes. With this purpose, in January 2013 the New York Public Health and Health Planning Council undertook a redesign of the regulatory framework for the state's ambulatory care services. This article describes the principles undergirding the framework as well as the regulatory recommendations themselves. Methods We explored and analyzed the regulation of ambulatory care services in New York in accordance with the available gray and peer-reviewed literature and legislative documents. The deliberations of the Public Health and Health Planning Council informed our review. Findings The vision of high-performing ambulatory care should be rooted in the Triple Aim (better health, higher-quality care, lower costs), with a particular emphasis on continuity of care for patients. There is a pressing need to better define the taxonomy of ambulatory care services. From the state government's perspective, this clarification requires better reporting from new health care entities (eg, retail clinics), connections with regional and state health information technology hubs, and coordination among state agencies. A uniform nomenclature also would improve consumers’ understanding of rights and responsibilities. Finally, the regulatory mechanisms employed—from mandatory reporting to licensure to regional planning to the certificate of need—should remain flexible and match the degree of consensus regarding the appropriate regulatory path. Conclusions Few other states have embarked on a wide-ranging assessment of their regulation of ambulatory care services. By moving toward adopting the regulatory approach described here, New York aims to balance sound oversight with pluralism and innovation in health care delivery. PMID:25492604

Gene network analysis: from heart development to cardiac therapy.

PubMed

Ferrazzi, Fulvia; Bellazzi, Riccardo; Engel, Felix B

2015-03-01

Networks offer a flexible framework to represent and analyse the complex interactions between components of cellular systems. In particular gene networks inferred from expression data can support the identification of novel hypotheses on regulatory processes. In this review we focus on the use of gene network analysis in the study of heart development. Understanding heart development will promote the elucidation of the aetiology of congenital heart disease and thus possibly improve diagnostics. Moreover, it will help to establish cardiac therapies. For example, understanding cardiac differentiation during development will help to guide stem cell differentiation required for cardiac tissue engineering or to enhance endogenous repair mechanisms. We introduce different methodological frameworks to infer networks from expression data such as Boolean and Bayesian networks. Then we present currently available temporal expression data in heart development and discuss the use of network-based approaches in published studies. Collectively, our literature-based analysis indicates that gene network analysis constitutes a promising opportunity to infer therapy-relevant regulatory processes in heart development. However, the use of network-based approaches has so far been limited by the small amount of samples in available datasets. Thus, we propose to acquire high-resolution temporal expression data to improve the mathematical descriptions of regulatory processes obtained with gene network inference methodologies. Especially probabilistic methods that accommodate the intrinsic variability of biological systems have the potential to contribute to a deeper understanding of heart development.

Structure-based control of complex networks with nonlinear dynamics.

PubMed

Zañudo, Jorge Gomez Tejeda; Yang, Gang; Albert, Réka

2017-07-11

What can we learn about controlling a system solely from its underlying network structure? Here we adapt a recently developed framework for control of networks governed by a broad class of nonlinear dynamics that includes the major dynamic models of biological, technological, and social processes. This feedback-based framework provides realizable node overrides that steer a system toward any of its natural long-term dynamic behaviors, regardless of the specific functional forms and system parameters. We use this framework on several real networks, identify the topological characteristics that underlie the predicted node overrides, and compare its predictions to those of structural controllability in control theory. Finally, we demonstrate this framework's applicability in dynamic models of gene regulatory networks and identify nodes whose override is necessary for control in the general case but not in specific model instances.

A Framework for Facilitating Ecosystem Services-based Decision-making and the Development of Decision-making Tools

EPA Science Inventory

There is an increasing understanding that top-down regulatory and technology driven responses are not sufficient to address current and emerging environmental challenges such as climate change, sustainable communities, and environmental justice. The vast majority of environmenta...

Unique Regulatory Approach for Licensing the Port Hope Remediation Project in Canada - 13315

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kostova, M.; Howard, D.; Elder, P.

2013-07-01

The Port Hope remediation project is a part of a larger initiative of the Canadian Federal Government the Port Hope Area Initiative (PHAI) which is based upon a community proposal. The Government of Canada, through Natural Resources Canada (NRCan) is investing $1.28 billion over 10 years to clean up historic low-level radioactive waste in the Port Hope Area and to provide long-term safe management of the low-level radioactive wastes in the Port Hope Area. These wastes arose from the activities of a former Federal Crown Corporation (Eldorado Nuclear) and its private sector predecessors. In Canada, historic waste are defined asmore » low-level radioactive waste that was managed in a manner no longer considered acceptable, but for which the original producer cannot reasonably be held responsible or no longer exists and for which the Federal Government has accepted responsibility. In Canada, under the current regulatory framework, the environmental remediation is not considered as a distinct phase of the nuclear cycle. The regulatory approach for dealing with existing sites contaminated with radioactive residues is defined on the basis of risk and application of existing regulations. A unique regulatory approach was taken by the Canadian Nuclear Safety Commission (CNSC) to address the various licensing issues and to set out the requirements for licensing of the Port Hope Project within the current regulatory framework. (authors)« less

A Framework for Integrating Environmental Justice in Regulatory Analysis

PubMed Central

Nweke, Onyemaechi C.

2011-01-01

With increased interest in integrating environmental justice into the process for developing environmental regulations in the United States, analysts and decision makers are confronted with the question of what methods and data can be used to assess disproportionate environmental health impacts. However, as a first step to identifying data and methods, it is important that analysts understand what information on equity impacts is needed for decision making. Such knowledge originates from clearly stated equity objectives and the reflection of those objectives throughout the analytical activities that characterize Regulatory Impact Analysis (RIA), a process that is traditionally used to inform decision making. The framework proposed in this paper advocates structuring analyses to explicitly provide pre-defined output on equity impacts. Specifically, the proposed framework emphasizes: (a) defining equity objectives for the proposed regulatory action at the onset of the regulatory process, (b) identifying specific and related sub-objectives for key analytical steps in the RIA process, and (c) developing explicit analytical/research questions to assure that stated sub-objectives and objectives are met. In proposing this framework, it is envisioned that information on equity impacts informs decision-making in regulatory development, and that this is achieved through a systematic and consistent approach that assures linkages between stated equity objectives, regulatory analyses, selection of policy options, and the design of compliance and enforcement activities. PMID:21776235

The regulatory sciences for stem cell-based medicinal products.

PubMed

Yuan, Bao-Zhu; Wang, Junzhi

2014-06-01

Over the past few years, several new achievements have been made from stem cell studies, many of which have moved up from preclinical stages to early, or from early to middle or late, stages thanks to relatively safe profile and preliminary evidence of effectiveness. Moreover, some stem cell-based products have been approved for marketing by different national regulatory authorities. However, many critical issues associated mainly with incomplete understanding of stem cell biology and the relevant risk factors, and lack of effective regulations still exist and need to be urgently addressed, especially in countries where establishment of appropriate regulatory system just commenced. More relevantly, the stem cell regulatory sciences need to be established or improved to more effectively evaluate quality, safety and efficacy of stem cell products, and for building up the appropriate regulatory framework. In this review, we summarize some new achievements in stem cell studies, especially the preclinical and clinical studies, the existing regulations, and the associated challenges, and we then propose some considerations for improving stem cell regulatory sciences with a goal of promoting the steadfast growth of the well-regulated stem cell therapies abreast of evolvement of stem cell sciences and technologies.

Creating and testing regulatory focus messages to enhance medication adherence.

PubMed

O'Connor, Ashley; Ladebue, Amy; Peterson, Jamie; Davis, Ryan; Jung Grant, Susan; McCreight, Marina; Lambert-Kerzner, Anne

2018-01-01

Objectives Strategies were explored to improve patient adherence to cardioprotective medications by borrowing from a motivational framework used in psychology, regulatory focus theory. The current study is part of a larger randomized control trial and was aimed at understanding what written educational messages, based on patients' regulatory focus tendency, resonated with each individual as a potential reminder to take medications. This study was also aimed at understanding why messages resonated with the patients. Methods Twenty veterans were tested for regulatory fitand presented with messages dependent on focus tendency. In-person semi-structured interviews were conducted to collect feedback of messages. An iterative analysis drawing primarily on matrix and reflexive team analyses was conducted. Result Six promotion and six prevention messages emerged, such as "team up with your provider to create a combination of medications to prevent illness" and "Live your best life - Take your medications". Five themes related to types of health messages that spoke to patients' regulatory fit were discovered: relatability; empowerment and control; philosophy on life; relationship with provider and medications; and vocabulary effect on the impact of messages. Discussion Motivational messages based on regulatory fit may be useful in improving patient medication adherence, leading to improved cardiovascular outcomes.

An Approach for Implementation of Project Management Information Systems

NASA Astrophysics Data System (ADS)

Běrziša, Solvita; Grabis, Jānis

Project management is governed by project management methodologies, standards, and other regulatory requirements. This chapter proposes an approach for implementing and configuring project management information systems according to requirements defined by these methodologies. The approach uses a project management specification framework to describe project management methodologies in a standardized manner. This specification is used to automatically configure the project management information system by applying appropriate transformation mechanisms. Development of the standardized framework is based on analysis of typical project management concepts and process and existing XML-based representations of project management. A demonstration example of project management information system's configuration is provided.

Ballast water regulations and the move toward concentration-based numeric discharge limits.

PubMed

Albert, Ryan J; Lishman, John M; Saxena, Juhi R

2013-03-01

Ballast water from shipping is a principal source for the introduction of nonindigenous species. As a result, numerous government bodies have adopted various ballast water management practices and discharge standards to slow or eliminate the future introduction and dispersal of these nonindigenous species. For researchers studying ballast water issues, understanding the regulatory framework is helpful to define the scope of research needed by policy makers to develop effective regulations. However, for most scientists, this information is difficult to obtain because it is outside the standard scientific literature and often difficult to interpret. This paper provides a brief review of the regulatory framework directed toward scientists studying ballast water and aquatic invasive species issues. We describe different approaches to ballast water management in international, U.S. federal and state, and domestic ballast water regulation. Specifically, we discuss standards established by the International Maritime Organization (IMO), the U.S. Coast Guard and U.S. Environmental Protection Agency, and individual states in the United States including California, New York, and Minnesota. Additionally, outside the United States, countries such as Australia, Canada, and New Zealand have well-established domestic ballast water regulatory regimes. Different approaches to regulation have recently resulted in variations between numeric concentration-based ballast water discharge limits, particularly in the United States, as well as reliance on use of ballast water exchange pending development and adoption of rigorous science-based discharge standards. To date, numeric concentration-based discharge limits have not generally been based upon a thorough application of risk-assessment methodologies. Regulators, making decisions based on the available information and methodologies before them, have consequently established varying standards, or not established standards at all. The review and refinement of ballast water discharge standards by regulatory agencies will benefit from activity by the scientific community to improve and develop more precise risk-assessment methodologies.

The "déjà vu effect:" evaluation of United States medical device legislation, regulation, and the Food and Drug Administration's contentious 510(k) program.

PubMed

Bauman, Jordan

2012-01-01

With the Medical Device Amendments of 1976, Congress granted FDA authority to regulate medical devices by implementing a risk-based regulatory framework. Several years prior to this legislation, the Cooper Committee reviewed the medical device regulatory landscape and uncovered weaknesses that could be detrimental to public health. However, only after several high-profile incidents involving unsafe medical devices did Congress respond with strong legislation. Since 1976, additional medical device legislative revisions have been enacted to address deficiencies highlighted by various groups representing Congress, FDA, and industry. A repetitive conclusion from these groups has been that the 510(k) program is incapable of serving as a premarket evaluation of safety and effectiveness under the existing statutory framework. However, these legislative revisions did not change the statutory framework despite these repeated findings. In 2009, CDRH convened separate groups to again review the 510(k) program. While more comprehensive than previous initiatives, the observed deficiencies and the proposed recommendations are remarkably similar to those identified by their predecessors. This cyclical review of the medical device regulatory landscape whereby the same observations and recommendations are repeated yet the output of such review does not yield major legislative revision of the existing statutory framework can be described as the "déjà vu effect." This will continue unless Congress enacts legislation that implements a new statutory framework with a different standard other than substantial equivalence. In the past, Congress has implemented major legislation only after a public health crisis. Hopefully this will not be the driving force in the future.

Whither tobacco product regulation?

PubMed

McNeill, Ann; Hammond, David; Gartner, Coral

2012-03-01

Despite decades of industry innovation and regulatory efforts, the harmfulness of conventional cigarettes has not changed. There are several pitfalls in this area, including the long time lag before health impacts of product regulatory changes become apparent, the danger of consumers deriving false reassurance of lesser harm in the interim period, the lack of relevant expertise and the lack of an internationally agreed and evidence-based strategic approach. Articles 9 and 10 of the Framework Convention on Tobacco Control provide the potential for such a global strategy, and knowledge and research has increased significantly over recent years. However, there are huge opportunity costs in implementing product disclosure and regulatory strategies: most national regulators have very limited human and financial resources, which should be focused on other evidence-based tobacco control interventions. We believe therefore that it is now time to abandon the notion of safe or safer cigarettes while moving consumers towards cleaner nicotine products as soon as possible. In parallel to this, we recommend a number of other strategies be implemented including: reducing the appeal of all tobacco products, forbidding new tobacco products or brand variants being marketed without evidence of reduced harm, appeal or addictiveness, and developing a tobacco industry resourced, but industry independent, Framework Convention on Tobacco Control global repository to assist national regulators in understanding and regulating the products on their markets.

Risk Assessment to Underpin Food Regulatory Decisions: An Example of Public Health Nutritional Epidemiology

PubMed Central

Baines, Janis; Cunningham, Judy; Leemhuis, Christel; Hambridge, Tracy; Mackerras, Dorothy

2011-01-01

The approach used by food regulation agencies to examine the literature and forecast the impact of possible food regulations has many similar features to the approach used in nutritional epidemiological research. We outline the Risk Analysis Framework described by FAO/WHO, in which there is formal progression from identification of the nutrient or food chemical of interest, through to describing its effect on health and then assessing whether there is a risk to the population based on dietary exposure estimates. We then discuss some important considerations for the dietary modeling component of the Framework, including several methodological issues that also exist in research nutritional epidemiology. Finally, we give several case studies that illustrate how the different methodological components are used together to inform decisions about how to manage the regulatory problem. PMID:22254081

Decision Analysis for a Sustainable Environment, Economy, and Society: A Participatory Framework for Ecosystem Services-Based Decision-Making

EPA Science Inventory

There is an increasing understanding that top-down regulatory and technology driven responses are not sufficient to address current and emerging environmental challenges such as climate change, sustainable communities, and environmental justice. The vast majority of environmenta...

Biobanking and Privacy Law in Brazil.

PubMed

Dallari, Sueli Gandolfi; Castellaro, Felipe Angel Bocchi; Guerriero, Iara Coelho Zito

2015-01-01

This article analyzes the current regulatory framework for biobanking, genomic research, and protection of privacy in Brazil. It is divided in four parts. The first describes the biobanking context in Brazil and its evolution in recent years. In the second, the entire regulatory framework on biobanking and genomic research is analyzed. The third part focuses on the critical evaluation of this regulatory framework, specifically on some major ethical dilemmas in biobanking. The fourth part describes the characteristics of the Brazilian biobanking and human research governance system, known as the CEP/CONEP system. Finally, the conclusion summarizes the information in the article and its contribution to the study of the biobanking ethical challenges, especially the protection of privacy. It is highlighted that biobanking regulatory harmonization among countries is necessary, since it increases scientific possibilities that can come from broader cooperation among biobanks and several research centers on the national and international levels. © 2015 American Society of Law, Medicine & Ethics, Inc.

Systems identification and the adaptive management of waterfowl in the United States

USGS Publications Warehouse

Williams, B.K.; Nichols, J.D.

2001-01-01

Waterfowl management in the United States is one of the more visible conservation success stories in the United States. It is authorized and supported by appropriate legislative authorities, based on large-scale monitoring programs, and widely accepted by the public. The process is one of only a limited number of large-scale examples of effective collaboration between research and management, integrating scientific information with management in a coherent framework for regulatory decision-making. However, harvest management continues to face some serious technical problems, many of which focus on sequential identification of the resource system in a context of optimal decision-making. The objective of this paper is to provide a theoretical foundation of adaptive harvest management, the approach currently in use in the United States for regulatory decision-making. We lay out the legal and institutional framework for adaptive harvest management and provide a formal description of regulatory decision-making in terms of adaptive optimization. We discuss some technical and institutional challenges in applying adaptive harvest management and focus specifically on methods of estimating resource states for linear resource systems.

Controlling Methane Emissions in the Natural Gas Sector. A Review of Federal and State Regulatory Frameworks Governing Production, Gathering, Processing, Transmission, and Distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paranhos, Elizabeth; Kozak, Tracy G.; Boyd, William

This report provides an overview of the regulatory frameworks governing natural gas supply chain infrastructure siting, construction, operation, and maintenance. Information was drawn from a number of sources, including published analyses, government reports, in addition to relevant statutes, court decisions and regulatory language, as needed. The scope includes all onshore facilities that contribute to methane emissions from the natural gas sector, focusing on three areas of state and federal regulations: (1) natural gas pipeline infrastructure siting and transportation service (including gathering, transmission, and distribution pipelines), (2) natural gas pipeline safety, and (3) air emissions associated with the natural gas supplymore » chain. In addition, the report identifies the incentives under current regulatory frameworks to invest in measures to reduce leakage, as well as the barriers facing investment in infrastructure improvement to reduce leakage. Policy recommendations regarding how federal or state authorities could regulate methane emissions are not provided; rather, existing frameworks are identified and some of the options for modifying existing regulations or adopting new regulations to reduce methane leakage are discussed.« less

Hours of work and rest in the rail industry.

PubMed

Anderson, C; Grunstein, R R; Rajaratnam, S M W

2013-06-01

Currently, the National Transport Commission is considering four options to form the regulatory framework for rail safety within Australia with respect to fatigue. While the National Transport Commission currently recommends no limitations around hours of work or rest, we provide evidence which suggests regulatory frameworks should incorporate a traditional hours of service regulation over more flexible policies. Our review highlights: Shift durations >12 h are associated with a doubling of risk for accident and injury. Fatigue builds cumulatively with each successive shift where rest in between is inadequate (<12 h). A regulatory framework for fatigue management within the rail industry should prescribe limits on hours of work and rest, including maximum shift duration and successive number of shifts. Appropriately, validated biomathematical models and technologies may be used as a part of a fatigue management system, to augment the protection afforded by limits on hours of work and rest. A comprehensive sleep disorder screening and management programme should form an essential component of any regulatory framework. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Examination of the regulatory frameworks applicable to biologic drugs (including stem cells and their progeny) in Europe, the U.S., and Australia: part II--a method of software documentary analysis.

PubMed

Ilic, Nina; Savic, Snezana; Siegel, Evan; Atkinson, Kerry; Tasic, Ljiljana

2012-12-01

A wide range of regulatory standards applicable to production and use of tissues, cells, and other biologics (or biologicals), as advanced therapies, indicates considerable interest in the regulation of these products. The objective of this study was to analyze and compare high-tier documents within the Australian, European, and U.S. biologic drug regulatory environments using qualitative methodology. Eighteen high-tier documents from the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA), and Therapeutic Goods Administration (TGA) regulatory frameworks were subject to automated text analysis. Selected documents were consistent with the legal requirements for manufacturing and use of biologic drugs in humans and fall into six different categories. Concepts, themes, and their co-occurrence were identified and compared. The most frequent concepts in TGA, FDA, and EMA frameworks were "biological," "product," and "medicinal," respectively. This was consistent with the previous manual terminology search. Good Manufacturing Practice documents, across frameworks, identified "quality" and "appropriate" as main concepts, whereas in Good Clinical Practice (GCP) documents it was "clinical," followed by "trial," "subjects," "sponsor," and "data." GCP documents displayed considerably higher concordance between different regulatory frameworks, as demonstrated by a smaller number of concepts, similar size, and similar distance between them. Although high-tier documents often use different terminology, they share concepts and themes. This paper may be a modest contribution to the recognition of similarities and differences between analyzed regulatory documents. It may also fill the literature gap and provide some foundation for future comparative research of biologic drug regulations on a global level.

Mapping regulatory models for medicinal cannabis: a matrix of options.

PubMed

Belackova, Vendula; Shanahan, Marian; Ritter, Alison

2017-05-30

Objective The aim of the present study was to develop a framework for assessing regulatory options for medicinal cannabis in Australia. Methods International regulatory regimes for medicinal cannabis were reviewed with a qualitative policy analysis approach and key policy features were synthesised, leading to a conceptual framework that facilitates decision making across multiple dimensions. Results Two central organising dimensions of medicinal cannabis regulation were identified: cannabis supply and patient authorisation (including patient access). A number of the different supply options can be matched with a number of different patient authorisation options, leading to a matrix of possible regulatory regimes. Conclusions The regulatory options, as used internationally, involve different forms of cannabis (synthetic and plant-based pharmaceutical preparations or herbal cannabis) and the varying extent to which patient authorisation policies and procedures are stringently or more loosely defined. The optimal combination of supply and patient authorisation options in any jurisdiction that chooses to make medicinal cannabis accessible will depend on policy goals. What is known about the topic? Internationally, regulation of medicinal cannabis has developed idiosyncratically, depending on formulations that were made available and local context. There has been no attempt to date in the scientific literature to systematically document the variety of regulatory possibilities for medicinal cannabis. What does this paper add? This paper presents a new conceptual schema for considering options for the regulation of medicinal cannabis, across both supply and patient authorisation aspects. What are the implications for practitioners? The design of regulatory systems in Australia, whether for pharmaceutical or herbal products, is a vital issue for policy makers right now as federal and state and territory governments grapple with the complexities of medicinal cannabis regulation. The conceptual schema presented herein provides a tool for more systematic thinking about the options.

twzPEA: A Topology and Working Zone Based Pathway Enrichment Analysis Framework

USDA-ARS?s Scientific Manuscript database

Sensitive detection of involvement and adaptation of key signaling, regulatory, and metabolic pathways holds the key to deciphering molecular mechanisms such as those in the biomass-to-biofuel conversion process in yeast. Typical gene set enrichment analyses often do not use topology information in...

Effects of chlorpyrifos and TCP on human kidney cells using toxicity testing and proteomics

EPA Science Inventory

An Adverse Outcome Pathway (AOP) is a conceptual framework to apply molecular pathway-based data for use in risk assessment and regulatory decision support. The development of AOPs requires data on the effects of chemicals on biological processes (i.e., molecular initiating event...

Toxicogenomics and the Regulatory Framework

EPA Science Inventory

Toxicogenomics presents regulatory agencies with the opportunity to revolutionize their analyses by enabling the collection of information on a broader range of responses than currently considered in traditional regulatory decision making. Analyses of genomic responses are expec...

[Advanced therapy: from European regulatory framework to national regulatory framework].

PubMed

Lucas-Samuel, S

2013-05-01

The European regulation n(o) 1394/2007/CE published on the 13th of November 2007 defined and harmonized the European regulatory framework for advanced therapy medicinal products. It creates a specialized committee located at the European Medicine Agency, in charge of the assessment of these medicinal products. The consequences of this regulation are introduced in the French regulation by the law n(o) 2011-302 published on the 22nd of March 2011. It detailed notably the possibility for public establishments (except health establishments) and nonprofit organisms to create pharmaceutical establishments. This law defined also a specific category of advanced therapy medicinal products, which fall under the "hospital exemption" framework. The rules regarding the authorizations of the establishments able to prepare these types of medicinal products and the authorization of the products are defined by the n(o) 2012-1236 decree published on the 6th of November 2012. Copyright © 2013. Published by Elsevier SAS.

78 FR 62017 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Capital Adequacy...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-11

...The Office of the Comptroller of the Currency (OCC) and Board of Governors of the Federal Reserve System (Board), are adopting a final rule that revises their risk-based and leverage capital requirements for banking organizations. The final rule consolidates three separate notices of proposed rulemaking that the OCC, Board, and FDIC published in the Federal Register on August 30, 2012, with selected changes. The final rule implements a revised definition of regulatory capital, a new common equity tier 1 minimum capital requirement, a higher minimum tier 1 capital requirement, and, for banking organizations subject to the advanced approaches risk-based capital rules, a supplementary leverage ratio that incorporates a broader set of exposures in the denominator. The final rule incorporates these new requirements into the agencies' prompt corrective action (PCA) framework. In addition, the final rule establishes limits on a banking organization's capital distributions and certain discretionary bonus payments if the banking organization does not hold a specified amount of common equity tier 1 capital in addition to the amount necessary to meet its minimum risk-based capital requirements. Further, the final rule amends the methodologies for determining risk-weighted assets for all banking organizations, and introduces disclosure requirements that would apply to top-tier banking organizations domiciled in the United States with $50 billion or more in total assets. The final rule also adopts changes to the agencies' regulatory capital requirements that meet the requirements of section 171 and section 939A of the Dodd-Frank Wall Street Reform and Consumer Protection Act. The final rule also codifies the agencies' regulatory capital rules, which have previously resided in various appendices to their respective regulations, into a harmonized integrated regulatory framework. In addition, the OCC is amending the market risk capital rule (market risk rule) to apply to Federal savings associations, and the Board is amending the advanced approaches and market risk rules to apply to top-tier savings and loan holding companies domiciled in the United States, except for certain savings and loan holding companies that are substantially engaged in insurance underwriting or commercial activities, as described in this preamble.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan.

PubMed

Chang, Lin-Chau; Kang, Jaw-Jou; Gau, Churn-Shiouh

2016-06-01

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process. Copyright © 2016 Elsevier Inc. All rights reserved.

Harmonization of reimbursement and regulatory approval processes: a systematic review of international experiences.

PubMed

Tsoi, Bernice; Masucci, Lisa; Campbell, Kaitryn; Drummond, Michael; O'Reilly, Daria; Goeree, Ron

2013-08-01

A considerable degree of overlap exists between reimbursement and regulatory approval of health technologies, and harmonization of certain aspects is both possible and feasible. Various models to harmonization have been suggested in which a number of practical attempts have been drawn from. Based on a review of the literature, approaches can be categorized into those focused on reducing uncertainty and developing economies of scale in the evidentiary requirements; and/or aligning timeframes and logistical aspects of the review process. These strategies can further be classified based on the expected level of structural and organizational change required to implement them into the existing processes. Passive processes require less modification, whereas active processes are associated with greater restructuring. Attempts so far at harmonization have raised numerous legal and practical issues and these must be considered when introducing a more harmonized framework into the existing regulatory and reimbursement arrangements.

Evidence-based causation in toxicology: A 10-year retrospective.

PubMed

James, R C; Britt, J K; Halmes, N C; Guzelian, P S

2015-12-01

We introduced Evidence-based Toxicology (EBT) in 2005 to address the disparities that exist between the various Weight-of-Evidence (WOE) methods typically applied in the regulatory hazard decision-making arena and urged toxicologists to adopt the evidence-based guidelines long-utilized in medicine (i.e., Evidence-Based Medicine or EBM). This review of the activities leading to the adoption of evidence-based methods and EBT during the last decade demonstrates how fundamental concepts that form EBT, such as the use of systematic reviews to capture and consider all available information, are improving toxicological evaluations performed by various groups and agencies. We reiterate how the EBT framework, a process that provides a method for performing human chemical causation analyses in an objective, transparent and reproducible manner, differs significantly from past and current regulatory WOE approaches. We also discuss why the uncertainties associated with regulatory WOE schemes lead to a definition of the term "risk" that contains unquantifiable uncertainties not present in this term as it is used in epidemiology and medicine. We believe this distinctly different meaning of "risk" should be clearly conveyed to those not familiar with this difference (e.g., the lay public), when theoretical/nomologic risks associated with chemical-induced toxicities are presented outside of regulatory and related scientific parlance. © The Author(s) 2015.

A good chew or good riddance--how to move forward in the regulation of khat consumption.

PubMed

Klein, Axel; Metaal, Pien

2010-12-01

To review the status of khat, the most recent plant based psychoactive substance to reach a global market, and consider policy making processes in general and the framework of drug control in particular. Desk review of literature on khat and wider drug policy processes. The risk assessment and classification of psychoactive drugs is a contested arena where political, economic and moral agendas collide, leaving countries that have banned khat, with significant social costs. To best manage the risks arising from the increasing availability of khat it is therefore suggested to draft a regulatory framework with clear objectives and guiding principles. Given that medical risks of khat use are modest, the objective of the regulatory framework should be the protection of consumers and community. This is best achieved by establishing processes for the quality control of khat imports, and by regulating access and availability. It should therefore not be considered as a drug to be controlled but as a licit substance that needs to be regulated. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

State Regulatory Authority (SRA) Coordination of Safety, Security, and Safeguards of Nuclear Facilities: A Framework for Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mladineo, Stephen V.; Frazar, Sarah L.; Kurzrok, Andrew J.

This paper will explore the development of a framework for conducting an assessment of safety-security-safeguards integration within a State. The goal is to examine State regulatory structures to identify conflicts and gaps that hinder management of the three disciplines at nuclear facilities. Such an analysis could be performed by a State Regulatory Authority (SRA) to provide a self-assessment or as part of technical cooperation with either a newcomer State, or to a State with a fully developed SRA.

Genetic modification through oligonucleotide-mediated mutagenesis. A GMO regulatory challenge?

PubMed

Breyer, Didier; Herman, Philippe; Brandenburger, Annick; Gheysen, Godelieve; Remaut, Erik; Soumillion, Patrice; Van Doorsselaere, Jan; Custers, René; Pauwels, Katia; Sneyers, Myriam; Reheul, Dirk

2009-01-01

In the European Union, the definition of a GMO is technology-based. This means that a novel organism will be regulated under the GMO regulatory framework only if it has been developed with the use of defined techniques. This approach is now challenged with the emergence of new techniques. In this paper, we describe regulatory and safety issues associated with the use of oligonucleotide-mediated mutagenesis to develop novel organisms. We present scientific arguments for not having organisms developed through this technique fall within the scope of the EU regulation on GMOs. We conclude that any political decision on this issue should be taken on the basis of a broad reflection at EU level, while avoiding discrepancies at international level.

Fisheries regulatory regimes and resilience to climate change.

PubMed

Ojea, Elena; Pearlman, Isaac; Gaines, Steven D; Lester, Sarah E

2017-05-01

Climate change is already producing ecological, social, and economic impacts on fisheries, and these effects are expected to increase in frequency and magnitude in the future. Fisheries governance and regulations can alter socio-ecological resilience to climate change impacts via harvest control rules and incentives driving fisher behavior, yet there are no syntheses or conceptual frameworks for examining how institutions and their regulatory approaches can alter fisheries resilience to climate change. We identify nine key climate resilience criteria for fisheries socio-ecological systems (SES), defining resilience as the ability of the coupled system of interacting social and ecological components (i.e., the SES) to absorb change while avoiding transformation into a different undesirable state. We then evaluate the capacity of four fisheries regulatory systems that vary in their degree of property rights, including open access, limited entry, and two types of rights-based management, to increase or inhibit resilience. Our exploratory assessment of evidence in the literature suggests that these regulatory regimes vary widely in their ability to promote resilient fisheries, with rights-based approaches appearing to offer more resilience benefits in many cases, but detailed characteristics of the regulatory instruments are fundamental.

Framework for the quantitative weight-of-evidence analysis of 'omics data for regulatory purposes.

PubMed

Bridges, Jim; Sauer, Ursula G; Buesen, Roland; Deferme, Lize; Tollefsen, Knut E; Tralau, Tewes; van Ravenzwaay, Ben; Poole, Alan; Pemberton, Mark

2017-12-01

A framework for the quantitative weight-of-evidence (QWoE) analysis of 'omics data for regulatory purposes is presented. The QWoE framework encompasses seven steps to evaluate 'omics data (also together with non-'omics data): (1) Hypothesis formulation, identification and weighting of lines of evidence (LoEs). LoEs conjoin different (types of) studies that are used to critically test the hypothesis. As an essential component of the QWoE framework, step 1 includes the development of templates for scoring sheets that predefine scoring criteria with scores of 0-4 to enable a quantitative determination of study quality and data relevance; (2) literature searches and categorisation of studies into the pre-defined LoEs; (3) and (4) quantitative assessment of study quality and data relevance using the respective pre-defined scoring sheets for each study; (5) evaluation of LoE-specific strength of evidence based upon the study quality and study relevance scores of the studies conjoined in the respective LoE; (6) integration of the strength of evidence from the individual LoEs to determine the overall strength of evidence; (7) characterisation of uncertainties and conclusion on the QWoE. To put the QWoE framework in practice, case studies are recommended to confirm the relevance of its different steps, or to adapt them as necessary. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Steering healthcare service delivery: a regulatory perspective.

PubMed

Prakash, Gyan

2015-01-01

The purpose of this paper is to explore regulation in India's healthcare sector and makes recommendations needed for enhancing the healthcare service. The literature was reviewed to understand healthcare's regulatory context. To understand the current healthcare system, qualitative data were collected from state-level officials, public and private hospital staff. A patient survey was performed to assess service quality (QoS). Regulation plays a central role in driving healthcare QoS. India needs to strengthen market and institutional co-production based approaches for steering its healthcare in which delivery processes are complex and pose different challenges. This study assesses current healthcare regulation in an Indian state and presents a framework for studying and strengthening regulation. Agile regulation should be based on service delivery issues (pull approach) rather than monitoring and sanctions based regulatory environment (push approach). Healthcare pitfalls across the world seem to follow similar follies. India's complexity and experience is useful for emerging and developed economies. The author reviewed around 70 publications and synthesised them in healthcare regulatory contexts. Patient's perception of private providers could be a key input towards steering regulation. Identifying gaps across QoS dimensions would be useful in taking corrective measures.

Implementing Ethics Policies in Developing Countries: Ploughing on Parched Ground?

ERIC Educational Resources Information Center

Mazonde, Isaac N.; Jackson-Malete, Jose; Sugarman, Jeremy

2007-01-01

It is globally expected that universities will ensure that policies guiding researchers' conduct are in place and adhered to. This expectation is not waived in developing countries. Successful implementation of an ethics policy is facilitated by an appropriate national regulatory framework on which to base the argument for compliance. However, it…

Application of adverse outcome pathways (AOPs) in human health and ecotoxicology capturing divergent consequences of conserved molecular initiating events via AOP networks

EPA Science Inventory

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making...

Application of Adverse Outcome Pathways (AOPs) in Human Health and Ecotoxicology Capturing Divergent Consequences of Conserved Molecular Initiating Events via AOP Networks (Presentation)

EPA Science Inventory

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making...

Parental Involvement: Title I, Part A. Non-Regulatory Guidance

ERIC Educational Resources Information Center

US Department of Education, 2004

2004-01-01

This report discusses the No Child Left Behind Act of 2001 (NCLB Act), which reauthorized the Elementary and Secondary Education Act of 1965 (ESEA). It is based on four principles that provide a framework through which families, educators, and communities can work together to improve teaching and learning. These principles are accountability for…

Treatment of Depression From a Self-Regulation Perspective: Basic Concepts and Applied Strategies in Self-System Therapy.

PubMed

Strauman, Timothy J; Eddington, Kari M

2017-02-01

Self-regulation models of psychopathology provide a theory-based, empirically supported framework for developing psychotherapeutic interventions that complement and extend current cognitive-behavioral models. However, many clinicians are only minimally familiar with the psychology of self-regulation. The aim of the present manuscript is twofold. First, we provide an overview of self-regulation as a motivational process essential to well-being and introduce two related theories of self-regulation which have been applied to depression. Second, we describe how self-regulatory concepts and processes from those two theories have been translated into psychosocial interventions, focusing specifically on self-system therapy (SST), a brief structured treatment for depression that targets personal goal pursuit. Two randomized controlled trials have shown that SST is superior to cognitive therapy for depressed clients with specific self-regulatory deficits, and both studies found evidence that SST works in part by restoring adaptive self-regulation. Self-regulation-based psychotherapeutic approaches to depression hold significant promise for enhancing treatment efficacy and ultimately may provide an individualizable framework for treatment planning.

Enhancer scanning to locate regulatory regions in genomic loci

PubMed Central

Buckley, Melissa; Gjyshi, Anxhela; Mendoza-Fandiño, Gustavo; Baskin, Rebekah; Carvalho, Renato S.; Carvalho, Marcelo A.; Woods, Nicholas T.; Monteiro, Alvaro N.A.

2016-01-01

The present protocol provides a rapid, streamlined and scalable strategy to systematically scan genomic regions for the presence of transcriptional regulatory regions active in a specific cell type. It creates genomic tiles spanning a region of interest that are subsequently cloned by recombination into a luciferase reporter vector containing the Simian Virus 40 promoter. Tiling clones are transfected into specific cell types to test for the presence of transcriptional regulatory regions. The protocol includes testing of different SNP (single nucleotide polymorphism) alleles to determine their effect on regulatory activity. This procedure provides a systematic framework to identify candidate functional SNPs within a locus during functional analysis of genome-wide association studies. This protocol adapts and combines previous well-established molecular biology methods to provide a streamlined strategy, based on automated primer design and recombinational cloning to rapidly go from a genomic locus to a set of candidate functional SNPs in eight weeks. PMID:26658467

Application of Adverse Outcome Pathways to U.S. EPA’s Endocrine Disruptor Screening Program

PubMed Central

Noyes, Pamela D.; Casey, Warren M.; Dix, David J.

2017-01-01

Background: The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) screens and tests environmental chemicals for potential effects in estrogen, androgen, and thyroid hormone pathways, and it is one of the only regulatory programs designed around chemical mode of action. Objectives: This review describes the EDSP’s use of adverse outcome pathway (AOP) and toxicity pathway frameworks to organize and integrate diverse biological data for evaluating the endocrine activity of chemicals. Using these frameworks helps to establish biologically plausible links between endocrine mechanisms and apical responses when those end points are not measured in the same assay. Results: Pathway frameworks can facilitate a weight of evidence determination of a chemical’s potential endocrine activity, identify data gaps, aid study design, direct assay development, and guide testing strategies. Pathway frameworks also can be used to evaluate the performance of computational approaches as alternatives for low-throughput and animal-based assays and predict downstream key events. In cases where computational methods can be validated based on performance, they may be considered as alternatives to specific assays or end points. Conclusions: A variety of biological systems affect apical end points used in regulatory risk assessments, and without mechanistic data, an endocrine mode of action cannot be determined. Because the EDSP was designed to consider mode of action, toxicity pathway and AOP concepts are a natural fit. Pathway frameworks have diverse applications to endocrine screening and testing. An estrogen pathway example is presented, and similar approaches are being used to evaluate alternative methods and develop predictive models for androgen and thyroid pathways. https://doi.org/10.1289/EHP1304 PMID:28934726

Risk-based requirements management framework with applications to assurance cases

NASA Astrophysics Data System (ADS)

Feng, D.; Eyster, C.

The current regulatory approach for assuring device safety primarily focuses on compliance with prescriptive safety regulations and relevant safety standards. This approach, however, does not always lead to a safe system design even though safety regulations and standards have been met. In the medical device industry, several high profile recalls involving infusion pumps have prompted the regulatory agency to reconsider how device safety should be managed, reviewed and approved. An assurance case has been cited as a promising tool to address this growing concern. Assurance cases have been used in safety-critical systems for some time. Most assurance cases, if not all, in literature today are developed in an ad hoc fashion, independent from risk management and requirement development. An assurance case is a resource-intensive endeavor that requires additional effort and documentation from equipment manufacturers. Without a well-organized requirements infrastructure in place, such “ additional effort” can be substantial, to the point where the cost of adoption outweighs the benefit of adoption. In this paper, the authors present a Risk-Based Requirements and Assurance Management (RBRAM) methodology. The RBRAM is an elaborate framework that combines Risk-Based Requirements Management (RBRM) with assurance case methods. Such an integrated framework can help manufacturers leverage an existing risk management to present a comprehensive assurance case with minimal additional effort while providing a supplementary means to reexamine the integrity of the system design in terms of the mission objective. Although the example used is from the medical industry, the authors believe that the RBRAM methodology underlines the fundamental principle of risk management, and offers a simple, yet effective framework applicable to aerospace industry, perhaps, to any industry.

Cosmetic Regulations: A Comparative Study.

PubMed

Suhag, Jyoti; Dureja, Harish

2015-01-01

The regulatory framework, compliance requirement, efficacy, safety, and marketing of cosmetic products are considered the most important factors for growth of the cosmetic industry. There are different regulatory bodies across the globe that have their own insights for regulation; moreover, governments such as the United States, European Union, and Japan follow a stringent regulatory framework, whereas cosmetics are not so much strictly regulated in countries such as India, Brazil, and China. The alignment of a regulatory framework will play a significant role in the removal of barriers to trade, growth of market at an international level, innovation in the development and presentation of new products, and most importantly safety and efficacy of the marketed products. The present contribution gives insight into the important cosmetic regulations in areas of premarket approval, ingredient control, and labeling and warnings, with a special focus on the cosmetic regulatory environments in the United States, European Union, Japan, and India. Most importantly, the authors highlight the dark side of cosmetics associated with allergic reactions and even skin cancer. The importance of cosmetic regulations has been highlighted by dint of which the society can be healthier, accomplished by more stringent and harmonized regulations.

Integrating legal liabilities in nanomanufacturing risk management.

PubMed

Mohan, Mayank; Trump, Benjamin D; Bates, Matthew E; Monica, John C; Linkov, Igor

2012-08-07

Among other things, the wide-scale development and use of nanomaterials is expected to produce costly regulatory and civil liabilities for nanomanufacturers due to lingering uncertainties, unanticipated effects, and potential toxicity. The life-cycle environmental, health, and safety (EHS) risks of nanomaterials are currently being studied, but the corresponding legal risks have not been systematically addressed. With the aid of a systematic approach that holistically evaluates and accounts for uncertainties about the inherent properties of nanomaterials, it is possible to provide an order of magnitude estimate of liability risks from regulatory and litigious sources based on current knowledge. In this work, we present a conceptual framework for integrating estimated legal liabilities with EHS risks across nanomaterial life-cycle stages using empirical knowledge in the field, scientific and legal judgment, probabilistic risk assessment, and multicriteria decision analysis. Such estimates will provide investors and operators with a basis to compare different technologies and practices and will also inform regulatory and legislative bodies in determining standards that balance risks with technical advancement. We illustrate the framework through the hypothetical case of a manufacturer of nanoscale titanium dioxide and use the resulting expected legal costs to evaluate alternative risk-management actions.

The Regulatory Framework for Privacy and Security

NASA Astrophysics Data System (ADS)

Hiller, Janine S.

The internet enables the easy collection of massive amounts of personally identifiable information. Unregulated data collection causes distrust and conflicts with widely accepted principles of privacy. The regulatory framework in the United States for ensuring privacy and security in the online environment consists of federal, state, and self-regulatory elements. New laws have been passed to address technological and internet practices that conflict with privacy protecting policies. The United States and the European Union approaches to privacy differ significantly, and the global internet environment will likely cause regulators to face the challenge of balancing privacy interests with data collection for many years to come.

Human Germline CRISPR-Cas Modification: Toward a Regulatory Framework

PubMed Central

Evitt, Niklaus H.; Mascharak, Shamik; Altman, Russ B.

2015-01-01

CRISPR germline editing therapies (CGETs) hold unprecedented potential to eradicate hereditary disorders. However, the prospect of altering the human germline has sparked a debate over the safety, efficacy, and morality of CGETs, triggering a funding moratorium by the NIH. There is an urgent need for practical paths for the evaluation of these capabilities. We propose a model regulatory framework for CGET research, clinical development, and distribution. Our model takes advantage of existing legal and regulatory institutions but adds elevated scrutiny at each stage of CGET development to accommodate the unique technical and ethical challenges posed by germline editing. PMID:26632357

United States Food and Drug Administration Regulation of Gene and Cell Therapies.

PubMed

Bailey, Alexander M; Arcidiacono, Judith; Benton, Kimberly A; Taraporewala, Zenobia; Winitsky, Steve

2015-01-01

The United States (US) Food and Drug Administration (FDA) is a regulatory agency that has oversight for a wide range of products entering the US market, including gene and cell therapies. The regulatory approach for these products is similar to other medical products within the United States and consists of a multitiered framework of statutes, regulations, and guidance documents. Within this framework, there is considerable flexibility which is necessary due to the biological and technical complexity of these products in general. This chapter provides an overview of the US FDA regulatory oversight of gene and cell therapy products.

A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kocher, D.C.; Hoffman, F.O.

1991-12-31

This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

A proposed framework for consistent regulation of public exposures to radionuclides and other carcinogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kocher, D.C.; Hoffman, F.O.

1991-01-01

This paper discusses a proposed framework for consistent regulation of carcinogenic risks to the public based on establishing de manifestis (i.e., unacceptable) and de minimis (i.e., trivial) lifetime risks from exposure to any carcinogens at levels of about 10{sup {minus}1}--10{sup {minus}3} and 10{sup {minus}4}--10{sup {minus}6}, respectively, and reduction of risks above de minimis levels as low as reasonably achievable (ALARA). We then discuss certain differences in the way risks from exposure to radionuclides and other carcinogens currently are regulated or assessed which would need to be considered in implementing the proposed regulatory framework for all carcinogens.

Multicriteria mapping of stakeholder preferences in regulating nanotechnology

NASA Astrophysics Data System (ADS)

Hansen, Steffen Foss

2010-08-01

In order to facilitate stakeholder discussions on how to regulate nanotechnology, the opensource program multicriteria mapping (MCM) was used to structure 26 interviews with stakeholders in the USA. MCM offers a systematic part quantitative, part qualitative approach to clarify why some regulatory options (bans, moratoriums, voluntary measures, etc.) were deemed to be acceptable/unacceptable by various stakeholders and which criteria stakeholders used to evaluate the different regulatory options. Adopting an incremental approach and implementing a new regulatory framework was evaluated as the best options whereas a complete ban and no additional regulation of nanotechnology were found to be the least favorable. Criteria applied differed substantially among stakeholders and included social, ethical, regulatory, environmental, and health issues. Opinions on future regulation seem far less polarized than expected and it seems that stakeholders would welcome a combination of voluntary measures, an incremental approach and forming of a new regulatory framework.

Regulating assisted reproductive technologies in Victoria: the impact of changing policy concerning the accessibility of in vitro fertilisation for preimplantation tissue-typing.

PubMed

Smith, Malcolm K

2012-06-01

On 1 January 2010, the Assisted Reproductive Treatment Act 2008 (Vic) came into force. The legislation was the outcome of a detailed review and consultation process undertaken by the Victorian Law Reform Commission. Arguably, the change to the regulatory framework represents a significant shift in policy compared to previous regulatory approaches on this topic in Victoria. This article considers the impact of the new legislation on eligibility for reproductive treatments, focusing on the accessibility of such services for the purpose of creating a "saviour sibling". It also highlights the impact of the Victorian regulatory body's decision to abolish its regulatory policies on preimplantation genetic diagnosis and preimplantation tissue-typing, concluding that the regulatory approach in relation to these latter issues is similar to other Australian jurisdictions where such practices are not addressed by a statutory framework.

Nursing care systematization as a multidimensional and interactive phenomenon.

PubMed

Backes, Dirce Stein; Koerich, Magda Santos; Nascimento, Keyla Cristiane do; Erdmann, Alacoque Lorenzini

2008-01-01

This study aimed to understand the meaning of Nursing Care Systematization (NCS) for multiprofessional health team professionals based on the relationships, interactions and associations of Complex thought. This qualitative study uses Grounded Theory as a methodological reference framework. Data were obtained through interviews with three sample groups, totaling 15 professionals from different institutions. Simultaneous data codification and analysis identified the central theme: 'Glimpsing nursing care systematization as an interactive and multidimensional phenomenon' and the respective reference model. NCS appoints, in addition to interactivity and professional complementarity, the importance of dialog and connection between the academy, health practices and regulatory offices, based on new reference frameworks for the organization of health practices.

CUMMULATIVE EFFECTS OF ADMINISTRATION MIXTURES OF “ANTIANDROGENS” IN RATS: A NEW FRAMEWORK BASED UPON COMMON SYSTEMS RATHER THAN COMMON MECHANISMS

EPA Science Inventory

Since humans and wildlife are exposed to more than one chemical at a time, concern has arisen about the effects of complex mixtures on reproduction and development. To date, different regulatory groups have not yet developed consistent approaches to conducting assessments of the ...

The Public-Private Divide in Ethiopian Higher Education: Issues and Policy Implications

ERIC Educational Resources Information Center

Nega, Mulu

2017-01-01

This article explores the current issues on the public-private divide in the Ethiopian higher education landscape and their policy implications. It critically examines issues related to legal and regulatory frameworks in order to understand the public-private divide in the Ethiopian higher education context. The article is based on two premises.…

Structure-based control of complex networks with nonlinear dynamics

NASA Astrophysics Data System (ADS)

Zanudo, Jorge G. T.; Yang, Gang; Albert, Reka

What can we learn about controlling a system solely from its underlying network structure? Here we use a framework for control of networks governed by a broad class of nonlinear dynamics that includes the major dynamic models of biological, technological, and social processes. This feedback-based framework provides realizable node overrides that steer a system towards any of its natural long term dynamic behaviors, regardless of the dynamic details and system parameters. We use this framework on several real networks, identify the topological characteristics that underlie the predicted node overrides, and compare its predictions to those of classical structural control theory. Finally, we demonstrate this framework's applicability in dynamic models of gene regulatory networks and identify nodes whose override is necessary for control in the general case, but not in specific model instances. This work was supported by NSF Grants PHY 1205840 and IIS 1160995. JGTZ is a recipient of a Stand Up To Cancer - The V Foundation Convergence Scholar Award.

Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks

PubMed Central

Marbach, Daniel; Roy, Sushmita; Ay, Ferhat; Meyer, Patrick E.; Candeias, Rogerio; Kahveci, Tamer; Bristow, Christopher A.; Kellis, Manolis

2012-01-01

Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein–protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level. PMID:22456606

Is there a need for a universal benefit-risk assessment framework for medicines? Regulatory and industry perspectives.

PubMed

Leong, James; McAuslane, Neil; Walker, Stuart; Salek, Sam

2013-09-01

To explore the current status and need for a universal benefit-risk framework for medicines in regulatory agencies and pharmaceutical companies. A questionnaire was developed and sent to 14 mature regulatory agencies and 24 major companies. The data were analysed using descriptive statistics, for a minority of questions preceded by manual grouping of the responses. Overall response rate was 82%, and study participants included key decision makers from agencies and companies. None used a fully quantitative system, most companies preferring a qualitative method. The major reasons for this group not using semi-quantitative or quantitative systems were lack of a universal and scientifically validated framework. The main advantages of a benefit-risk framework were that it provided a systematic standardised approach to decision-making and that it acted as a tool to enhance quality of communication. It was also reported that a framework should be of value to both agencies and companies throughout the life cycle of a product. They believed that it is possible to develop an overarching benefit-risk framework that should involve relevant stakeholders in the development, validation and application of a universal framework. The entire cohort indicated common barriers to implementing a framework were resource limitations, a lack of knowledge and a scientifically validated and acceptable framework. Stakeholders prefer a semi-quantitative, overarching framework that incorporates a toolbox of different methodologies. A coordinating committee of relevant stakeholders should be formed to guide its development and implementation. Through engaging the stakeholders, these outcomes confirm sentiments and need for developing a universal benefit-risk assessment framework. Copyright © 2013 John Wiley & Sons, Ltd.

[Is it possible to improve the preventive usefulness of workers' health surveillance in the current regulatory framework?

PubMed

Rodríguez Jareño, Mari Cruz; De Montserrat I Nonó, Jaume

In Spain, the limited preventive usefulness of health surveillance is determined by the indiscriminate use of nonspecific "generic" health examinations aimed at producing a "fitness for work list", presumably allowing companies to comply with health and safety regulations. This study aimed to produce a technical interpretation of the Spanish Prevention of Risks at Work Act and propose a new conceptual framework to favour greater preventive usefulness of health surveillance within the current regulatory framework. Using qualitative techniques of content analysis, the text of the Law was studied, the key concepts that impeded the fulfilment of the preventive objectives of health surveillance were identified, and a technical interpretation adjusted to regulations was made in order to propose a new conceptual framework RESULTS: This conceptual framework would include: clearly differentiating health surveillance from health examinations (one of its instruments) and from fitness for work evaluations (an independent concept in itself); restricting mandatory health surveillance to situations in which it is "imperative" to carry it out because of the existence of a substantial risk to workers or third parties, including potentially vulnerable workers; and communicating the results of health surveillance through preventive recommendations to the company, reserving fitness for duty certificates -always based on clear, pre-established and justified criteria in relation to risk- for mandatory surveillance. The proposed new conceptual framework falls within the scope of the Spanish Prevention of Risks at Work Act, and its implementation could contribute to improving the preventive usefulness of health surveillance without the need to reform the legislation. Copyright belongs to the Societat Catalana de Salut Laboral.

Broadening the cancer and cognition landscape: the role of self-regulatory challenges.

PubMed

Arndt, Jamie; Das, Enny; Schagen, Sanne B; Reid-Arndt, Stephanie A; Cameron, Linda D; Ahles, Tim A

2014-01-01

The potentially detrimental effects of cancer and related treatments on cognitive functioning have emerged as one of the key foci of cancer survivorship research, but little is known about how psychological variables other than depression influence these relationships. To illustrate the potential of social psychological perspectives, we examine how a self-regulatory analysis and specific self-regulatory challenges of contending with cancer-related expectancies and stereotypes provide conceptual frameworks for understanding some of the potential causes and consequences of cancer-related cognitive deficits. Literatures on cancer-related cognitive deficits, self-regulatory ego depletion, expectancy stereotypes, and their points of convergence are briefly reviewed. A review and conceptual integration of relevant literatures suggest that coping with cancer can impair self-regulatory capacity. There is an overlap between cognitive deficits associated with self-regulatory challenge and with cancer and its treatment, and restoring self-regulatory resources can attenuate cancer-related cognitive deficits. Examination of specific regulatory challenges of contending with expectancies and stereotypes related to treatment suggests insights that can inform when and among whom cognitive deficits may most likely emerge. Integrating social psychological ideas with a substantial knowledge base can illustrate novel research trajectories that can deepen our understanding of cancer-related cognitive deficits and their impact on psychosocial well-being. Copyright © 2013 John Wiley & Sons, Ltd.

Broadening the cancer and cognition landscape: The role of self-regulatory challenges

PubMed Central

Arndt, Jamie; Das, Enny; Schagen, Sanne B.; Reid-Arndt, Stephanie A.; Cameron, Linda D.; Ahles, Tim A.

2013-01-01

Objective The potentially detrimental effects of cancer and related treatments on cognitive functioning have emerged as key foci of cancer survivorship research, but little is known about how psychological variables other than depression influence these relationships. To illustrate the potential of social psychological perspectives, we examine how a self-regulatory analysis and specific self-regulatory challenges of contending with cancer-related expectancies and stereotypes provide conceptual frameworks for understanding some of the potential causes and consequences of cancer-related cognitive deficits. Methods Literatures on cancer-related cognitive deficits, self-regulatory ego depletion, expectancy-stereotypes and their points of convergence are briefly reviewed. Results A review and conceptual integration of relevant literatures suggests that coping with cancer can impair self-regulatory capacity, there is overlap between cognitive deficits associated with self-regulatory challenge and with cancer and its treatment, and restoring self-regulatory resources can attenuate cancer-related cognitive deficits. Examination of specific regulatory challenges of contending with expectancies and stereotypes related to treatment suggest insights that can inform when and among whom cognitive deficits may most likely emerge. Conclusions Integrating social psychological ideas with a substantial knowledge base can illustrate novel research trajectories that can deepen our understanding of cancer-related cognitive deficits and their impact on psychosocial well-being. PMID:23839818

Tobacco regulatory science: research to inform regulatory action at the Food and Drug Administration's Center for Tobacco Products.

PubMed

Ashley, David L; Backinger, Cathy L; van Bemmel, Dana M; Neveleff, Deborah J

2014-08-01

The U.S. Food and Drug Administration (FDA) promotes the development of regulatory science to ensure that a strong evidence base informs all of its regulatory activities related to the manufacture, marketing, and distribution of tobacco products as well as public education about tobacco product constituents and effects. Toward that end, the FDA's Center for Tobacco Products (CTP) provides funding for research studies with scientific aims that fall within its defined regulatory authority. However, given their traditional biomedical focus on basic and applied research, some researchers may not understand the principles of regulatory science or the types of studies CTP funds. The purpose of this paper is (1) to clarify the definition of regulatory science as a distinct scientific discipline, (2) to explore the role of tobacco regulatory science in order to help researchers understand the parameters and types of research that can be funded by CTP, and (3) to describe the types of research efforts that will inform the FDA's public health framework for tobacco product regulation. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Comparison of international food allergen labeling regulations.

PubMed

Gendel, Steven M

2012-07-01

Food allergy is a significant public health issue worldwide. Regulatory risk management strategies for allergic consumers have focused on providing information about the presence of food allergens through label declarations. A number of countries and regulatory bodies have recognized the importance of providing this information by enacting laws, regulations or standards for food allergen labeling of "priority allergens". However, different governments and organizations have taken different approaches to identifying these "priority allergens" and to designing labeling declaration regulatory frameworks. The increasing volume of the international food trade suggests that there would be value in supporting sensitive consumers by harmonizing (to the extent possible) these regulatory frameworks. As a first step toward this goal, an inventory of allergen labeling regulations was assembled and analyzed to identify commonalities, differences, and future needs. Published by Elsevier Inc.

Using resilience and resistance concepts to manage persistent threats to sagebrush ecosystems and greater sage-grouse

USGS Publications Warehouse

Chambers, Jeanne C.; Maestas, Jeremy D.; Pyke, David A.; Boyd, Chad S.; Pellant, Mike; Wuenschel, Amarina

2017-01-01

Conservation of imperiled species often demands addressing a complex suite of threats that undermine species viability. Regulatory approaches, such as the US Endangered Species Act (1973), tend to focus on anthropogenic threats through adoption of policies and regulatory mechanisms. However, persistent ecosystem-based threats, such as invasive species and altered disturbance regimes, remain critical issues for most at-risk species considered to be conservation-reliant. We describe an approach for addressing persistent ecosystem threats to at-risk species based on ecological resilience and resistance concepts that is currently being used to conserve greater sage-grouse (Centrocercus urophasianus)and sagebrush ecosystems. The approach links biophysical indicators of ecosystem resilience and resistance with species-specific population and habitat requisites in a risk-based framework to identify priority areas for management and guide allocation of resources to manage persistent ecosystem-based threats. US federal land management and natural resource agencies have adopted this framework as a foundation for prioritizing sage-grouse conservation resources and determining effective restoration and management strategies. Because threats and strategies to address them cross-cut program areas, an integrated approach that includes wildland fire operations, postfire rehabilitation, fuels management, and habitat restoration is being used. We believe this approach is applicable to species conservation in other largely intact ecosystems with persistent, ecosystem-based threats.

What should a radiation regulator do about naturally occurring radioactive material?

PubMed

Loy, J

2015-06-01

The standard regulatory framework of authorisation, review and assessment, inspection and enforcement, and regulation making is directed principally towards ensuring the regulatory control of planned exposure situations. Some mining and industrial activities involving exposures to naturally occurring radioactive material (NORM), such as uranium mining or the treatment and conditioning of NORM residues, may fit readily within this standard framework. In other cases, such as oil and gas exploration and production, the standard regulatory framework needs to be adjusted. For example, it is not sensible to require that an oil company seek a licence from the radiation regulator before drilling a well. The paper discusses other approaches that a regulator might take to assure protection and safety in such activities involving exposures to NORM, including the use of conditional exemptions from regulatory controls. It also suggests some areas where further guidance from the International Commission on Radiological Protection on application of the system of radiological protection to NORM would assist both regulators and operators. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Regulating the unknown: Managing the occupational health risks of nanomedical technologies and nanopharmaceuticals in the research laboratory

NASA Astrophysics Data System (ADS)

Ersin, Ozlem Hacer

Novel technologies and their resultant products demand fresh ways of thinking about pre-market risk analysis and post-market surveillance. A regulatory framework that is responsive to emerging knowledge about the hazards of novel technologies offers repeatable and transparent processes and remains economically and socially feasible. Workers are an especially vulnerable population who are exposed to unknown hazards of novel technologies and serve often as unwitting sentinels of impending risks. This Grounded Theory-based case study identifies gaps in our current ability to regulate novel technologies so as to minimize occupational health risks and offers necessary modifications for an environment that is conducive to proper regulation. Nanopharmaceuticals and the nano-based technologies at their base are used by way of exemplar technologies that are currently taxing the ability of the regulatory system to provide adequate oversight. Ambiguities of definition, absence of a tracking system (of who is doing nanotechnology research), and the paucity of scientific evidence to support risk management efforts are among the findings of the study and need to be addressed as ameliorative steps toward an effective regulatory structure.

Validity of instruments to measure physical activity may be questionable due to a lack of conceptual frameworks: a systematic review

PubMed Central

2011-01-01

Background Guidance documents for the development and validation of patient-reported outcomes (PROs) advise the use of conceptual frameworks, which outline the structure of the concept that a PRO aims to measure. It is unknown whether currently available PROs are based on conceptual frameworks. This study, which was limited to a specific case, had the following aims: (i) to identify conceptual frameworks of physical activity in chronic respiratory patients or similar populations (chronic heart disease patients or the elderly) and (ii) to assess whether the development and validation of PROs to measure physical activity in these populations were based on a conceptual framework of physical activity. Methods Two systematic reviews were conducted through searches of the Medline, Embase, PsycINFO, and Cinahl databases prior to January 2010. Results In the first review, only 2 out of 581 references pertaining to physical activity in the defined populations provided a conceptual framework of physical activity in COPD patients. In the second review, out of 103 studies developing PROs to measure physical activity or related constructs, none were based on a conceptual framework of physical activity. Conclusions These findings raise concerns about how the large body of evidence from studies that use physical activity PRO instruments should be evaluated by health care providers, guideline developers, and regulatory agencies. PMID:21967887

Moving beyond 'rates, roads and rubbish': How do local governments make choices about healthy public policy to prevent obesity?

PubMed Central

Allender, Steven; Gleeson, Erin; Crammond, Brad; Sacks, Gary; Lawrence, Mark; Peeters, Anna; Loff, Bebe; Swinburn, Boyd

2009-01-01

While the causes of obesity are well known traditional education and treatment strategies do not appear to be making an impact. One solution as part of a broader complimentary set of strategies may be regulatory intervention at local government level to create environments for healthy nutrition and increased physical activity. Semi structured interviews were conducted with representatives of local government in Australia. Factors most likely to facilitate policy change were those supported by external funding, developed from an evidence base and sensitive to community and market forces. Barriers to change included a perceived or real lack of power to make change and the complexity of the legislative framework. The development of a systematic evidence base to provide clear feedback on the size and scope of the obesity epidemic at a local level, coupled with cost benefit analysis for any potential regulatory intervention, are crucial to developing a regulatory environment which creates the physical and social environment required to prevent obesity. PMID:19698170

China’s Rapidly Aging Population Creates Policy Challenges In Shaping A Viable Long-Term Care System

PubMed Central

Feng, Zhanlian; Liu, Chang; Guan, Xinping; Mor, Vincent

2013-01-01

In China, formal long-term care services for the large aging population have increased to meet escalating demands as demographic shifts and socioeconomic changes have eroded traditional elder care. We analyze China’s evolving long-term care landscape and trace major government policies and private-sector initiatives shaping it. Although home and community-based services remain spotty, institutional care is booming with little regulatory oversight. Chinese policy makers face mounting challenges overseeing the rapidly growing residential care sector, given the tension arising from policy inducements to further institutional growth, a weak regulatory framework, and the lack of enforcement capacity. We recommend addressing the following pressing policy issues: building a balanced system of services and avoiding an “institutional bias” that promotes rapid growth of elder care institutions over home or community-based care; strengthening regulatory oversight and quality assurance with information systems; and prioritizing education and training initiatives to grow a professionalized long-term care workforce. PMID:23213161

78 FR 32686 - Final Supplemental Environmental Impact Statement on the Issuance of Annual Regulations...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

... process. (2) Frequency of review and adoption of duck regulatory packages. Duck regulatory packages are the set of framework regulations that apply to the general duck hunting seasons. Packages include..., we present two alternatives regarding how frequently duck regulatory packages should be reviewed and...

Deep Borehole Disposal Safety Analysis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freeze, Geoffrey A.; Stein, Emily; Price, Laura L.

This report presents a preliminary safety analysis for the deep borehole disposal (DBD) concept, using a safety case framework. A safety case is an integrated collection of qualitative and quantitative arguments, evidence, and analyses that substantiate the safety, and the level of confidence in the safety, of a geologic repository. This safety case framework for DBD follows the outline of the elements of a safety case, and identifies the types of information that will be required to satisfy these elements. At this very preliminary phase of development, the DBD safety case focuses on the generic feasibility of the DBD concept.more » It is based on potential system designs, waste forms, engineering, and geologic conditions; however, no specific site or regulatory framework exists. It will progress to a site-specific safety case as the DBD concept advances into a site-specific phase, progressing through consent-based site selection and site investigation and characterization.« less

Modeling formalisms in Systems Biology

PubMed Central

2011-01-01

Systems Biology has taken advantage of computational tools and high-throughput experimental data to model several biological processes. These include signaling, gene regulatory, and metabolic networks. However, most of these models are specific to each kind of network. Their interconnection demands a whole-cell modeling framework for a complete understanding of cellular systems. We describe the features required by an integrated framework for modeling, analyzing and simulating biological processes, and review several modeling formalisms that have been used in Systems Biology including Boolean networks, Bayesian networks, Petri nets, process algebras, constraint-based models, differential equations, rule-based models, interacting state machines, cellular automata, and agent-based models. We compare the features provided by different formalisms, and discuss recent approaches in the integration of these formalisms, as well as possible directions for the future. PMID:22141422

Molecular farming on the rise--GMO regulators still walking a tightrope.

PubMed

Spök, Armin

2007-02-01

Recent increases in EU commercial and academic activities in molecular farming, and the proximity to market-stage of the first plant-made pharmaceuticals, represent a call to action for EU regulators. Drawing on the North American debate on molecular farming, it will be argued that both the rationale and the risks of molecular farming will differ significantly from those of first generation GM crops. Based on these differences, the suitability of the existing regulatory frameworks, which were developed in response to the arrival of earlier products, is discussed, and specific options for adapting the already complex EU regulatory system to cater for molecular farming are examined.

Development and delivery of clinical pharmacology in regulatory agencies

PubMed Central

Breckenridge, Alasdair

2012-01-01

Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit–harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit–risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments. PMID:22360651

Toward a Personalized Science of Emotion Regulation

PubMed Central

Doré, Bruce P.; Silvers, Jennifer A.; Ochsner, Kevin N.

2018-01-01

The ability to successfully regulate emotion plays a key role in healthy development and the maintenance of psychological well-being. Although great strides have been made in understanding the nature of regulatory processes and the consequences of deploying them, a comprehensive understanding of emotion regulation that can specify what strategies are most beneficial for a given person in a given situation is still a far-off goal. In this review, we argue that moving toward this goal represents a central challenge for the future of the field. As an initial step, we propose a concrete framework that (i) explicitly considers emotion regulation as an interaction of person, situation, and strategy, (ii) assumes that regulatory effects vary according to these factors, and (iii) sets as a primary scientific goal the identification of person-, situation-, and strategy-based contingencies for successful emotion regulation. Guided by this framework, we review current questions facing the field, discuss examples of contextual variation in emotion regulation success, and offer practical suggestions for continued progress in this area. PMID:29750085

Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine.

PubMed

Verbeken, Gilbert; Pirnay, Jean-Paul; De Vos, Daniel; Jennes, Serge; Zizi, Martin; Lavigne, Rob; Casteels, Minne; Huys, Isabelle

2012-06-01

For practitioners at hospitals seeking to use natural (not genetically modified, as appearing in nature) bacteriophages for treatment of antibiotic-resistant bacterial infections (bacteriophage therapy), Europe's current regulatory framework for medicinal products hinders more than it facilitates. Although many experts consider bacteriophage therapy to be a promising complementary (or alternative) treatment to antibiotic therapy, no bacteriophage-specific framework for documentation exists to date. Decades worth of historical clinical data on bacteriophage therapy (from Eastern Europe, particularly Poland, and the former Soviet republics, particularly Georgia and Russia, as well as from today's 27 EU member states and the US) have not been taken into account by European regulators because these data have not been validated under current Western regulatory standards. Consequently, applicants carrying out standard clinical trials on bacteriophages in Europe are obliged to initiate clinical work from scratch. This paper argues for a reduced documentation threshold for Phase 1 clinical trials of bacteriophages and maintains that bacteriophages should not be categorized as classical medicinal products for at least two reasons: (1) such a categorization is scientifically inappropriate for this specific therapy and (2) such a categorization limits the marketing authorization process to industry, the only stakeholder with sufficient financial resources to prepare a complete dossier for the competent authorities. This paper reflects on the current regulatory framework for medicines in Europe and assesses possible regulatory pathways for the (re-)introduction of bacteriophage therapy in a way that maintains its effectiveness and safety as well as its inherent characteristics of sustainability and in situ self-amplification and limitation.

Bioattractors: dynamical systems theory and the evolution of regulatory processes

PubMed Central

Jaeger, Johannes; Monk, Nick

2014-01-01

In this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype–phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait – such as attractors with associated basins and their bifurcations – define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self-organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection. PMID:24882812

Reconstructing the regulatory network controlling commitment and sporulation in Physarum polycephalum based on hierarchical Petri Net modelling and simulation.

PubMed

Marwan, Wolfgang; Sujatha, Arumugam; Starostzik, Christine

2005-10-21

We reconstruct the regulatory network controlling commitment and sporulation of Physarum polycephalum from experimental results using a hierarchical Petri Net-based modelling and simulation framework. The stochastic Petri Net consistently describes the structure and simulates the dynamics of the molecular network as analysed by genetic, biochemical and physiological experiments within a single coherent model. The Petri Net then is extended to simulate time-resolved somatic complementation experiments performed by mixing the cytoplasms of mutants altered in the sporulation response, to systematically explore the network structure and to probe its dynamics. This reverse engineering approach presumably can be employed to explore other molecular or genetic signalling systems where the activity of genes or their products can be experimentally controlled in a time-resolved manner.

Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

PubMed

Salmikangas, P; Flory, E; Reinhardt, J; Hinz, T; Maciulaitis, R

2010-01-01

The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

Information theory in systems biology. Part I: Gene regulatory and metabolic networks.

PubMed

Mousavian, Zaynab; Kavousi, Kaveh; Masoudi-Nejad, Ali

2016-03-01

"A Mathematical Theory of Communication", was published in 1948 by Claude Shannon to establish a framework that is now known as information theory. In recent decades, information theory has gained much attention in the area of systems biology. The aim of this paper is to provide a systematic review of those contributions that have applied information theory in inferring or understanding of biological systems. Based on the type of system components and the interactions between them, we classify the biological systems into 4 main classes: gene regulatory, metabolic, protein-protein interaction and signaling networks. In the first part of this review, we attempt to introduce most of the existing studies on two types of biological networks, including gene regulatory and metabolic networks, which are founded on the concepts of information theory. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Legal Consequences of Mandating High Stakes Decisions Based on Low Quality Information: Teacher Evaluation in the Race-to-the-Top Era

ERIC Educational Resources Information Center

Baker, Bruce D.; Oluwole, Joseph O.; Green, Preston C., III

2013-01-01

In this article, we explain how overly prescriptive, rigid state statutory and regulatory policy frameworks regarding teacher evaluation, tenure and employment decisions outstrip the statistical reliability and validity of proposed measures of teaching effectiveness. We begin with a discussion of the emergence of highly prescriptive state…

75 FR 39577 - Draft Supplemental Environmental Impact Statement on the Issuance of Annual Regulations...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-09

... timing of the general regulatory process. (2) Frequency of review and adoption of duck regulatory packages. Duck regulatory packages are the set of framework regulations that apply to the general duck... limits), and closed. In the draft SEIS, we present two alternatives regarding how frequently duck...

Guidelines for Bacteriophage Product Certification.

PubMed

Fauconnier, Alan

2018-01-01

Following decades in the wilderness, bacteriophage therapy is now appearing as a credible antimicrobial strategy. However, this reemerging therapy does not rekindle without raising sensitive regulatory concerns. Indeed, whereas the European regulatory framework has been basically implemented to tackle ready-to-use pharmaceuticals produced on a large scale, bacteriophage therapy relies on a dynamic approach requiring a regulation on personalized medicine, nonexistent at present. Because of this, no guideline are currently available for addressing the scientific and regulatory issues specifically related to phage therapy medicinal products (PTMP).Pending to the implementation of an appropriate regulatory framework and to the development of ensuing guidelines, several avenues which might lead to PTMP regulatory compliance are explored here. Insights might come from the multi-strain dossier approach set up for particular animal vaccines, from the homologous group concept developed for the allergen products or from the licensing process for veterinary autogenous vaccines. Depending on national legislations, customized preparations prescribed as magistral formulas or to be used on a named-patient basis are possible regulatory approaches to be considered. However, these schemes are not optimal and should thus be regarded as transitional.

Better by design: business preferences for environmental regulatory reform.

PubMed

Taylor, Christopher M; Pollard, Simon J T; Rocks, Sophie A; Angus, Andrew J

2015-04-15

We present the preferences for environmental regulatory reform expressed by 30 UK businesses and industry bodies from 5 sectors. While five strongly preferred voluntary regulation, seven expressed doubts about its effectiveness, and 18 expressed no general preference between instrument types. Voluntary approaches were valued for flexibility and lower burdens, but direct regulation offered stability and a level playing field. Respondents sought regulatory frameworks that: are coherent; balance clarity, prescription and flexibility; are enabled by positive regulatory relationships; administratively efficient; targeted according to risk magnitude and character; evidence-based and that deliver long-term market stability for regulatees. Anticipated differences in performance between types of instrument can be undermined by poor implementation. Results underline the need for policy makers and regulators to tailor an effective mix of instruments for a given sector, and to overcome analytical, institutional and political barriers to greater coherence, to better coordinate existing instruments and tackle new environmental challenges as they emerge. Copyright © 2015 Elsevier B.V. All rights reserved.

A Framework for Incorporating Patient Preferences Regarding Benefits and Risks into Regulatory Assessment of Medical Technologies.

PubMed

Ho, Martin; Saha, Anindita; McCleary, K Kimberly; Levitan, Bennett; Christopher, Stephanie; Zandlo, Kristen; Braithwaite, R Scott; Hauber, A Brett

In response to 2012 guidance in which the US Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) stated the importance of patient-centric measures in regulatory benefit-risk assessments, the Medical Device Innovation Consortium (MDIC) initiated a project. The project was used to develop a framework to help the Food and Drug Administration (FDA) and industry sponsors understand how patient preferences regarding benefit and risk might be integrated into the review of innovative medical devices. A public-private partnership of experts from medical device industry, government, academia and non-profits collaborated on development of the MDIC patient centered benefit-risk framework. The MDIC Framework examines what patient preference information is and the potential use and value of patient preference information in the regulatory process and across the product development life cycle. The MDIC Framework also includes a catalog of patient preference assessment methods and an agenda for future research to advance the field. This article discusses key concepts in patient preference assessment of particular importance for regulators and researchers that are addressed in the MDIC Framework for patient centered benefit-risk assessment as well as the unique public-private collaboration that led its development. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Impact of the new european paediatric regulatory framework on ethics committees: overview and perspectives.

PubMed

Altavilla, A; Manfredi, C; Baiardi, P; Dehlinger-Kremer, M; Galletti, P; Pozuelo, A Alemany; Chaplin, J; Ceci, A

2012-01-01

To evaluate the impact of the new European paediatric regulatory framework on the activities of Ethics Committees operating in Europe and to assess their involvement and interest in paediatric research. Task-force in Europe for Drug Development for the Young Network of Excellence and Relating Expectations and Needs to the Participation and Empowerment of Children in Clinical Trials project set up an inventory of Ethics Committees existing in Europe and conducted a survey on their approach to paediatric trials. Ethics Committees operating in 22 European Countries participated in this survey. Results showed a high lack of knowledge, understanding and awareness of the current European paediatric regulatory framework and a lack of involvement of Ethics Committees in paediatric research, especially in terms of training and education, demonstrated also by the decreasing number of Ethics Committees answering exhaustively to the whole questionnaire. The majority of participating Ethics Committees expressed interest in future initiatives related to paediatric research. Despite a limited knowledge and understanding of the current paediatric regulatory framework, a significant number of Ethics Committees operating in Europe show interest in initiatives related to paediatric research. Networking may be an essential tool to be used to enhance Ethics Committees role in supporting paediatric research. Any initiative should be undertaken at European level in collaboration with European Union Institutions. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Regulatory experience in applying a radiological environmental protection framework for existing and planned nuclear facilities.

PubMed

Mihok, S; Thompson, P

2012-01-01

Frameworks and methods for the radiological protection of non-human biota have been evolving rapidly at the International Commission on Radiological Protection and through various European initiatives. The International Atomic Energy Agency has incorporated a requirement for environmental protection in the latest revision of its Basic Safety Standards. In Canada, the Canadian Nuclear Safety Commission has been legally obligated to prevent unreasonable risk to the environment since 2000. Licensees have therefore been meeting generic legal requirements to demonstrate adequate control of releases of radioactive substances for the protection of both people and biota for many years. In the USA, in addition to the generic requirements of the Environmental Protection Agency and the Nuclear Regulatory Commission, Department of Energy facilities have also had to comply with specific dose limits after a standard assessment methodology was finalised in 2002. Canadian regulators developed a similar framework for biota dose assessment through a regulatory assessment under the Canadian Environmental Protection Act in the late 1990s. Since then, this framework has been applied extensively to satisfy legal requirements under the Canadian Environmental Assessment Act and the Nuclear Safety and Control Act. After approximately a decade of experience in applying these methods, it is clear that simple methods are fit for purpose, and can be used for making regulatory decisions for existing and planned nuclear facilities. Copyright © 2012. Published by Elsevier Ltd.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products (ATMPs) in Europe: The EMA/CAT Perspective.

PubMed

Salmikangas, Paula; Schuessler-Lenz, Martina; Ruiz, Sol; Celis, Patrick; Reischl, Ilona; Menezes-Ferreira, Margarida; Flory, Egbert; Renner, Matthias; Ferry, Nicolas

2015-01-01

With the release of Regulation 1394/2007, a new framework for gene and cell therapy medicinal products and tissue-engineered products was established in the European Union. For all three product classes, called advanced therapy medicinal products, a centralised marketing authorisation became mandatory. The European Medicines Agency (EMA) together with its Committee for Advanced Therapies, Committee for Human Medicinal Products and the network of national agencies is responsible for scientific evaluation of the marketing authorisation applications. For a new application, data and information relating to manufacturing processes and quality control of the active substance and the final product have to be submitted for evaluation together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMPs are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines. Due to the diversity of ATMPs, a tailored approach for regulating these products is considered necessary. Thus, a risk-based approach has been introduced for ATMPs allowing flexibility for the regulatory requirements. Since the regulatory framework for ATMPs was established, five products have been licenced in the European Union. However, the pipeline of new ATMPs is much bigger, as seen from the significant numbers of different products discussed by the CAT in scientific advice and classification procedures. In 2013, a public consultation on the ATMP Regulation was conducted by the European Commission, and the results were published in 2014. The report proposes several improvements for the current framework and established procedures for the regulation of ATMPs.

Regulatory guidelines for biosimilars in Malaysia.

PubMed

Abas, Arpah

2011-09-01

The biosimilars sector continues to attract huge interest and controversy. Biosimilars are new biopharmaceuticals that are "similar" but not identical to the innovator product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which implies that the products cannot be exactly duplicated. Minuscule differences in the product's structure and manufacturing process can result in different clinical outcome. This raises concerns over the safety, efficacy and even pharmacovigilance of biosimilars. Thus, biosimilars are unique - they are not a true chemical generic and are regulated via a distinct regulatory framework. This report discusses the features of Malaysian regulatory oversight of biosimilars and experience acquired in the evaluation of some products from various countries. Ensuring regulatory position adequately reflects scientific advancement, expertise/resources is key. The regulatory situation is an evolving process. Various guidance documents are being prepared with the aim of developing a uniform global framework towards assuring the dual goal of lower costs and patient safety while expediting the availability of important biosimilar products. Copyright © 2011. Published by Elsevier Ltd.

Multicriteria mapping of stakeholder preferences in regulating nanotechnology.

PubMed

Hansen, Steffen Foss

2010-08-01

In order to facilitate stakeholder discussions on how to regulate nanotechnology, the opensource program multicriteria mapping (MCM) was used to structure 26 interviews with stakeholders in the USA. MCM offers a systematic part quantitative, part qualitative approach to clarify why some regulatory options (bans, moratoriums, voluntary measures, etc.) were deemed to be acceptable/unacceptable by various stakeholders and which criteria stakeholders used to evaluate the different regulatory options. Adopting an incremental approach and implementing a new regulatory framework was evaluated as the best options whereas a complete ban and no additional regulation of nanotechnology were found to be the least favorable. Criteria applied differed substantially among stakeholders and included social, ethical, regulatory, environmental, and health issues. Opinions on future regulation seem far less polarized than expected and it seems that stakeholders would welcome a combination of voluntary measures, an incremental approach and forming of a new regulatory framework. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11051-010-0006-3) contains supplementary material, which is available to authorized users.

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma.

PubMed

Raju, G K; Gurumurthi, Karthik; Domike, Reuben; Kazandjian, Dickran; Landgren, Ola; Blumenthal, Gideon M; Farrell, Ann; Pazdur, Richard; Woodcock, Janet

2018-01-01

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Modeling gene regulatory network motifs using statecharts

PubMed Central

2012-01-01

Background Gene regulatory networks are widely used by biologists to describe the interactions among genes, proteins and other components at the intra-cellular level. Recently, a great effort has been devoted to give gene regulatory networks a formal semantics based on existing computational frameworks. For this purpose, we consider Statecharts, which are a modular, hierarchical and executable formal model widely used to represent software systems. We use Statecharts for modeling small and recurring patterns of interactions in gene regulatory networks, called motifs. Results We present an improved method for modeling gene regulatory network motifs using Statecharts and we describe the successful modeling of several motifs, including those which could not be modeled or whose models could not be distinguished using the method of a previous proposal. We model motifs in an easy and intuitive way by taking advantage of the visual features of Statecharts. Our modeling approach is able to simulate some interesting temporal properties of gene regulatory network motifs: the delay in the activation and the deactivation of the "output" gene in the coherent type-1 feedforward loop, the pulse in the incoherent type-1 feedforward loop, the bistability nature of double positive and double negative feedback loops, the oscillatory behavior of the negative feedback loop, and the "lock-in" effect of positive autoregulation. Conclusions We present a Statecharts-based approach for the modeling of gene regulatory network motifs in biological systems. The basic motifs used to build more complex networks (that is, simple regulation, reciprocal regulation, feedback loop, feedforward loop, and autoregulation) can be faithfully described and their temporal dynamics can be analyzed. PMID:22536967

The Misguided Regulation of Cardiac Emergencies

PubMed Central

Traverse, Jay H

2016-01-01

The increasing regulatory burden and cost of doing clinical trials in cardiac emergencies has greatly impacted the development of novel therapies resulting in increased morbidity and mortality of patients. A new regulatory framework is required. PMID:27789585

Nudging towards nutrition? Soft paternalism and obesity-related reform.

PubMed

Hector, Colin

2012-01-01

Obesity is one of the most contentious issues facing the United States today. Some researchers warn of an obesity "epidemic" that poses a grave threat to our nation's health, while others attack these claims as alarmist and misguided. This divide reinforces the political schism between advocates of government intervention and anti-regulatory groups. As a result, obesity science finds itself entangled in partisan battles that leave little room for compromise. This paper explores the potential for the political philosophy of soft paternalism to provide a regulatory framework that may appeal to both sides of the obesity reform debate. Soft paternalism draws upon social science research in order to develop policies that encourage better decision-making, while preserving individual choice. Applying this framework to the issue of obesity, I look at two areas of potential reform: 1) information-based policies such as nutritional label design, and 2) policies that affect default choices, such as portion size norms. I find that while soft paternalism is an appealing framework that offers many promising reforms, it is not a panacea. Instead, I argue that these proposals should be considered on their own merit, not as a complete solution precluding other measures. In addition, in light of potential criticism concerning the stigmatizing effect of some obesity-related measures, I suggest that reforms based on soft paternalism can and should be tailored to promote more mindful eating habits. With these concerns in mind, I conclude that soft paternalism is a promising approach that warrants serious consideration by policymakers.

Procedure versus process: ethical paradigms and the conduct of qualitative research.

PubMed

Pollock, Kristian

2012-09-27

Research is fundamental to improving the quality of health care. The need for regulation of research is clear. However, the bureaucratic complexity of research governance has raised concerns that the regulatory mechanisms intended to protect participants now threaten to undermine or stifle the research enterprise, especially as this relates to sensitive topics and hard to reach groups. Much criticism of research governance has focused on long delays in obtaining ethical approvals, restrictions imposed on study conduct, and the inappropriateness of evaluating qualitative studies within the methodological and risk assessment frameworks applied to biomedical and clinical research. Less attention has been given to the different epistemologies underlying biomedical and qualitative investigation. The bioethical framework underpinning current regulatory structures is fundamentally at odds with the practice of emergent, negotiated micro-ethics required in qualitative research. The complex and shifting nature of real world settings delivers unanticipated ethical issues and (occasionally) genuine dilemmas which go beyond easy or formulaic 'procedural' resolution. This is not to say that qualitative studies are 'unethical' but that their ethical nature can only be safeguarded through the practice of 'micro-ethics' based on the judgement and integrity of researchers in the field. This paper considers the implications of contrasting ethical paradigms for the conduct of qualitative research and the value of 'empirical ethics' as a means of liberating qualitative (and other) research from an outmoded and unduly restrictive research governance framework based on abstract prinicipalism, divorced from real world contexts and values.

Health risk assessment procedures for endocrine disrupting compounds within different regulatory frameworks in the European Union.

PubMed

Beronius, Anna; Rudén, Christina; Hanberg, Annika; Håkansson, Helen

2009-11-01

In this study we have investigated how different regulatory frameworks in Europe cope with identification and risk assessment of endocrine disrupting compounds (EDCs). Four regulatory groups were selected for the investigation: existing industrial chemicals, environmental pollutants in food, pharmaceuticals and plant protection products. The legislation and guidelines for each of these groups were scrutinized and compared in detail. In addition, one recent European risk assessment document each for three identified EDCs, i.e. bisphenol A, dioxins and vinclozolin, were reviewed and compared. We found that the requirements for toxicity testing and availability and scope of risk assessment guidelines varied between the four regulatory frameworks. Also, the general principles regarding the human relevance of the mode of action identified in animal tests differed in the different risk assessments. In conclusion, there is little conformity in the risk assessment processes between these groups of chemicals. Because of the complicated nature of endocrine disruption, test methods, principles and criteria for data interpretation traditionally used might not be directly applicable to EDCs and further development of a transparent and reliable risk assessment process for this type of substances is needed.

78 FR 16341 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-14

... regulatory regime applicable to the over-the-counter derivatives markets. Title VII provides the SEC and the CFTC with tools to oversee these markets.\\4\\ Under the comprehensive framework established in Title VII... Rule),\\11\\ arising from the daily mark to market of the CDS (``variation margin''). FINRA notes that...

A Framework for Organizing Current and Future Electric Utility Regulatory and Business Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Satchwell, Andrew; Cappers, Peter; Schwartz, Lisa

In this report, we will present a descriptive and organizational framework for incremental and fundamental changes to regulatory and utility business models in the context of clean energy public policy goals. We will also discuss the regulated utility's role in providing value-added services that relate to distributed energy resources, identify the "openness" of customer information and utility networks necessary to facilitate change, and discuss the relative risks, and the shifting of risks, for utilities and customers.

DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli.

PubMed

Lemmens, Karen; De Bie, Tijl; Dhollander, Thomas; De Keersmaecker, Sigrid C; Thijs, Inge M; Schoofs, Geert; De Weerdt, Ami; De Moor, Bart; Vanderleyden, Jos; Collado-Vides, Julio; Engelen, Kristof; Marchal, Kathleen

2009-01-01

We present DISTILLER, a data integration framework for the inference of transcriptional module networks. Experimental validation of predicted targets for the well-studied fumarate nitrate reductase regulator showed the effectiveness of our approach in Escherichia coli. In addition, the condition dependency and modularity of the inferred transcriptional network was studied. Surprisingly, the level of regulatory complexity seemed lower than that which would be expected from RegulonDB, indicating that complex regulatory programs tend to decrease the degree of modularity.

Automated Design Framework for Synthetic Biology Exploiting Pareto Optimality.

PubMed

Otero-Muras, Irene; Banga, Julio R

2017-07-21

In this work we consider Pareto optimality for automated design in synthetic biology. We present a generalized framework based on a mixed-integer dynamic optimization formulation that, given design specifications, allows the computation of Pareto optimal sets of designs, that is, the set of best trade-offs for the metrics of interest. We show how this framework can be used for (i) forward design, that is, finding the Pareto optimal set of synthetic designs for implementation, and (ii) reverse design, that is, analyzing and inferring motifs and/or design principles of gene regulatory networks from the Pareto set of optimal circuits. Finally, we illustrate the capabilities and performance of this framework considering four case studies. In the first problem we consider the forward design of an oscillator. In the remaining problems, we illustrate how to apply the reverse design approach to find motifs for stripe formation, rapid adaption, and fold-change detection, respectively.

Interpreter of maladies: redescription mining applied to biomedical data analysis.

PubMed

Waltman, Peter; Pearlman, Alex; Mishra, Bud

2006-04-01

Comprehensive, systematic and integrated data-centric statistical approaches to disease modeling can provide powerful frameworks for understanding disease etiology. Here, one such computational framework based on redescription mining in both its incarnations, static and dynamic, is discussed. The static framework provides bioinformatic tools applicable to multifaceted datasets, containing genetic, transcriptomic, proteomic, and clinical data for diseased patients and normal subjects. The dynamic redescription framework provides systems biology tools to model complex sets of regulatory, metabolic and signaling pathways in the initiation and progression of a disease. As an example, the case of chronic fatigue syndrome (CFS) is considered, which has so far remained intractable and unpredictable in its etiology and nosology. The redescription mining approaches can be applied to the Centers for Disease Control and Prevention's Wichita (KS, USA) dataset, integrating transcriptomic, epidemiological and clinical data, and can also be used to study how pathways in the hypothalamic-pituitary-adrenal axis affect CFS patients.

Optimizing participation of children with autism spectrum disorder experiencing sensory challenges: a clinical reasoning framework.

PubMed

Ashburner, Jill K; Rodger, Sylvia A; Ziviani, Jenny M; Hinder, Elizabeth A

2014-02-01

Remedial sensory interventions currently lack supportive evidence and can be challenging to implement for families and clinicians. It may be timely to shift the focus to optimizing participation of children with autism spectrum disorders (ASD) through accommodation and self-regulation of their sensory differences. A framework to guide practitioners in selecting strategies is proposed based on clinical reasoning considerations, including (a) research evidence, (b) client- and family-centredness, (c) practice contexts, (d) occupation-centredness, and (e) risks. Information-sharing with families and coaching constitute the basis for intervention. Specific strategies are identified where sensory aversions or seeking behaviours, challenges with modulation of arousal, or sensory-related behaviours interfere with participation. Self-regulatory strategies are advocated. The application of universal design principles to shared environments is also recommended. The implications of this framework for future research, education, and practice are discussed. The clinical utility of the framework now needs to be tested.

Bringing New PET Drugs to Clinical Practice - A Regulatory Perspective

PubMed Central

Hung, Joseph C.

2013-01-01

The regulatory framework for radioactive drugs, in particular those used in positron emission tomography (PET) scans, has been gradually established since the release of the Food and Drug Administration Modernization Act in 1997. Various guidances specially tailored to accommodate special properties of PET drugs have been issued by the Food and Drug Administration (FDA) in order to ensure this valuable technology (i.e., PET molecular imaging) will continue to be available to patients and yet the safety and efficacy of PET drugs are well regulated so that public health will be protected. This article presents several key elements of this regulatory framework for PET drugs. New regulatory avenues proposed by the FDA to facilitate the research and development process to bring more new PET drugs to clinical practice, as well as to foster the opportunity of using “orphan” PET drugs in clinical practice are also discussed in this paper. PMID:24312157

Multi-scale genetic dynamic modelling II: application to synthetic biology: an algorithmic Markov chain based approach.

PubMed

Kirkilionis, Markus; Janus, Ulrich; Sbano, Luca

2011-09-01

We model in detail a simple synthetic genetic clock that was engineered in Atkinson et al. (Cell 113(5):597-607, 2003) using Escherichia coli as a host organism. Based on this engineered clock its theoretical description uses the modelling framework presented in Kirkilionis et al. (Theory Biosci. doi: 10.1007/s12064-011-0125-0 , 2011, this volume). The main goal of this accompanying article was to illustrate that parts of the modelling process can be algorithmically automatised once the model framework we called 'average dynamics' is accepted (Sbano and Kirkilionis, WMI Preprint 7/2007, 2008c; Kirkilionis and Sbano, Adv Complex Syst 13(3):293-326, 2010). The advantage of the 'average dynamics' framework is that system components (especially in genetics) can be easier represented in the model. In particular, if once discovered and characterised, specific molecular players together with their function can be incorporated. This means that, for example, the 'gene' concept becomes more clear, for example, in the way the genetic component would react under different regulatory conditions. Using the framework it has become a realistic aim to link mathematical modelling to novel tools of bioinformatics in the future, at least if the number of regulatory units can be estimated. This should hold in any case in synthetic environments due to the fact that the different synthetic genetic components are simply known (Elowitz and Leibler, Nature 403(6767):335-338, 2000; Gardner et al., Nature 403(6767):339-342, 2000; Hasty et al., Nature 420(6912):224-230, 2002). The paper illustrates therefore as a necessary first step how a detailed modelling of molecular interactions with known molecular components leads to a dynamic mathematical model that can be compared to experimental results on various levels or scales. The different genetic modules or components are represented in different detail by model variants. We explain how the framework can be used for investigating other more complex genetic systems in terms of regulation and feedback.

Small drinking water systems under spatiotemporal water quality variability: a risk-based performance benchmarking framework.

PubMed

Bereskie, Ty; Haider, Husnain; Rodriguez, Manuel J; Sadiq, Rehan

2017-08-23

Traditional approaches for benchmarking drinking water systems are binary, based solely on the compliance and/or non-compliance of one or more water quality performance indicators against defined regulatory guidelines/standards. The consequence of water quality failure is dependent on location within a water supply system as well as time of the year (i.e., season) with varying levels of water consumption. Conventional approaches used for water quality comparison purposes fail to incorporate spatiotemporal variability and degrees of compliance and/or non-compliance. This can lead to misleading or inaccurate performance assessment data used in the performance benchmarking process. In this research, a hierarchical risk-based water quality performance benchmarking framework is proposed to evaluate small drinking water systems (SDWSs) through cross-comparison amongst similar systems. The proposed framework (R WQI framework) is designed to quantify consequence associated with seasonal and location-specific water quality issues in a given drinking water supply system to facilitate more efficient decision-making for SDWSs striving for continuous performance improvement. Fuzzy rule-based modelling is used to address imprecision associated with measuring performance based on singular water quality guidelines/standards and the uncertainties present in SDWS operations and monitoring. This proposed R WQI framework has been demonstrated using data collected from 16 SDWSs in Newfoundland and Labrador and Quebec, Canada, and compared to the Canadian Council of Ministers of the Environment WQI, a traditional, guidelines/standard-based approach. The study found that the R WQI framework provides an in-depth state of water quality and benchmarks SDWSs more rationally based on the frequency of occurrence and consequence of failure events.

Redesigning the regulatory framework for ambulatory care services in New York.

PubMed

Chokshi, Dave A; Rugge, John; Shah, Nirav R

2014-12-01

Policy Points: The landscape of ambulatory care services in the United States is rapidly changing on account of payment reform, primary care transformation, and the rise of convenient care options such as retail clinics. New York State has undertaken a redesign of regulatory policy for ambulatory care rooted in the Triple Aim (better health, higher-quality care, lower costs)-with a particular emphasis on continuity of care for patients. Key tenets of the regulatory approach include defining and tracking the taxonomy of ambulatory care services as well as ensuring that convenient care options do not erode continuity of care for patients. While hospitals remain important centers of gravity in the health system, services are increasingly being delivered through ambulatory care. This shift to ambulatory care is giving rise to new delivery structures, such as retail clinics and urgent care centers, as well as reinventing existing ambulatory care capacity, as seen with the patient-centered medical home model and the movement toward team-based care. To protect the public's interests, oversight of ambulatory care services must keep pace with these rapid changes. With this purpose, in January 2013 the New York Public Health and Health Planning Council undertook a redesign of the regulatory framework for the state's ambulatory care services. This article describes the principles undergirding the framework as well as the regulatory recommendations themselves. We explored and analyzed the regulation of ambulatory care services in New York in accordance with the available gray and peer-reviewed literature and legislative documents. The deliberations of the Public Health and Health Planning Council informed our review. The vision of high-performing ambulatory care should be rooted in the Triple Aim (better health, higher-quality care, lower costs), with a particular emphasis on continuity of care for patients. There is a pressing need to better define the taxonomy of ambulatory care services. From the state government's perspective, this clarification requires better reporting from new health care entities (eg, retail clinics), connections with regional and state health information technology hubs, and coordination among state agencies. A uniform nomenclature also would improve consumers' understanding of rights and responsibilities. Finally, the regulatory mechanisms employed-from mandatory reporting to licensure to regional planning to the certificate of need-should remain flexible and match the degree of consensus regarding the appropriate regulatory path. Few other states have embarked on a wide-ranging assessment of their regulation of ambulatory care services. By moving toward adopting the regulatory approach described here, New York aims to balance sound oversight with pluralism and innovation in health care delivery. © 2014 Milbank Memorial Fund.

Cross-border issues in the development of medical tourism in Malaysia: legal challenges and opportunities.

PubMed

Nemie, Puteri; Kassim, Jahn

2009-08-01

Strategically located at the crossroads of Asia, Malaysia has become one of the key players in the fast-growing and lucrative market for health care services in Asia. Medical travel across international boundaries has been made possible through affordable airfares and the favourable exchange rates of the Malaysian ringgit has contributed to the rise of the "medical tourism phenomenon" where medical travel is combined with visiting popular tourist destinations in Malaysia. Further, competitive medical fees and modern medical facilities have also made Malaysia a popular destination for medical tourists. Nevertheless, the increased number of foreign patients has opened up possibilities of Malaysian health care providers being subjected to malpractice claims and triggering a myriad of cross-border legal issues. Presently, there is no internationally accepted legal framework to regulate medical tourism and issues of legal redress in relation to unsatisfactory provision of treatment across international boundaries. The economic benefits of medical tourism must be based upon a solid legal regulatory framework and strong ethical standards as well as upon high-quality medical and health care services. It is therefore important to assess the existing legal framework affecting the development of medical tourism in Malaysia in order to explore the gaps, deficiencies and possibilities for legal and regulatory reform.

Vaccines for minor use and minor species (MUMS)--industry's views.

PubMed

Bönisch, B

2004-01-01

Over the past 30 years the importance of vaccines for minor use and minor species has changed for multinational animal health companies. The major reasons for this are being reviewed, with a particular focus on technical, financial and business aspects. Key regulatory obstacles to the development of new products for minor uses and minor species are identified, and examples of vaccines falling into the various categories are provided. A number of proposals are offered with the intention of resolving the medicines availability problem between all the stakeholders involved. Finally, based on the presented scientific and regulatory considerations, ideas are shared as to where the legal and economical framework would need to change to reach a viable solution.

Regulating genetically modified food. Policy trajectories, political culture, and risk perceptions in the U.S., Canada, and EU.

PubMed

Wohlers, Anton E

2010-09-01

This paper examines whether national differences in political culture add an explanatory dimension to the formulation of policy in the area of biotechnology, especially with respect to genetically modified food. The analysis links the formulation of protective regulatory policies governing genetically modified food to both country and region-specific differences in uncertainty tolerance levels and risk perceptions in the United States, Canada, and European Union. Based on polling data and document analysis, the findings illustrate that these differences matter. Following a mostly opportunistic risk perception within an environment of high tolerance for uncertainty, policymakers in the United States and Canada modified existing regulatory frameworks that govern genetically modified food in their respective countries. In contrast, the mostly cautious perception of new food technologies and low tolerance for uncertainty among European Union member states has contributed to the creation of elaborate and stringent regulatory policies governing genetically modified food.

Advancing a Framework for Regulatory Use of Real-World Evidence: When Real Is Reliable.

PubMed

Dreyer, Nancy A

2018-05-01

There is growing interest in regulatory use of randomized pragmatic trials and noninterventional real-world (RW) studies of effectiveness and safety, but there is no agreed-on framework for assessing when this type of evidence is sufficiently reliable. Rather than impose a clinical trial-like paradigm on RW evidence, like blinded treatments or complete, source-verified data, the framework for assessing the utility of RW evidence should be grounded in the context of specific study objectives, clinical events that are likely to be detected in routine care, and the extent to which systematic error (bias) is likely to impact effect estimation. Whether treatment is blinded should depend on how well the outcome can be measured objectively. Qualification of a data source should be based on (1) numbers of patients of interest available for study; (2) if "must-have" data are likely to be recorded, and if so, how and where; (3) the accessibility of systematic follow-up data for the time period of interest; and (4) the potential for systematic errors (bias) in data collection and the likely magnitude of any such bias. Accessible data may not be representative of an entire population, but still may provide reliable evidence about the experience of typical patients treated under conditions of conventional care. Similarly, RW data that falls short of optimal length of follow-up or study size may still be useful in terms of its ability to provide evidence for regulators for subgroups of special interest. Developing a framework to qualify RW evidence in the context of a particular study purpose and data asset will enable broader regulatory use of RW data for approval of new molecular entities and label changes. Reliable information about diverse populations and settings should also help us move closer to more affordable, effective health care.

DEVELOPMENT OF A FRAMEWORK FOR METALS RISK ASSESSMENT

EPA Science Inventory

Many EPA programs are faced with deciding whether and how to regulate toxic metals. These decisions range from setting regulatory standards for environmental releases, to establishing safe levels in different environmental media, to setting priorities for regulatory or voluntary...

Response lags and environmental dynamics of restoration efforts for Lake Rotorua, New Zealand

NASA Astrophysics Data System (ADS)

Mueller, Hannah; Hamilton, David P.; Doole, Graeme J.

2015-07-01

Regulatory responses to degradation of freshwater ecosystems have been characterized by long response times and have often failed to prevent declining health or to implement successful restoration programs. We studied environmental and management dynamics of ecosystem restoration in Lake Rotorua, New Zealand, where land use intensification is the main driver of water quality decline. Water quality decline, invasions by exotic submerged plants and occurrences of algal blooms have led to a number of in-lake interventions such as herbicide spraying (to control submerged plants) and dosing of inflows with Alum to flocculate phosphorus (and reduce algal blooms). Management of land use to reduce nutrient run-off has also been initiated. Based on the drivers-pressures-state-impact-response (DPSIR) framework, water quality changes and management responses were examined by studying research publications and data from 1922 to 2013. Multinomial regression analysis based on the generalized maximum entropy model was used to investigate the five categories of DPSIR and examine relationships of environmental dynamics and regulatory responses. We tested whether the visibility of ecosystem degradation in the public sphere, and social lag times to respond to them, were drivers of failures of these regulatory responses. Our study shows that management was reactive, and regulations often took effect only when ecosystem decline was already well advanced. There was a disconnect between land use intensification and its role in driving water quality change. Our results indicate that science can better inform management decision making by providing a holistic framework integrating ecological knowledge, economic interest and societal constraints.

Department of Commerce Semiannual Regulatory Agenda

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

... Clarify Amendment 13 and Subsequent Frameworks of 0648-AW95 the Northeast Multispecies Fishery Management... 0648-AY41 70 Framework 21 to the Atlantic Sea Scallop Fishery Management Plan 0648-AY43 71 Fishery...-Grouper Fishery Management Plan of the South Atlantic 0648-AX75 85 Framework Adjustment 44 and...

Capacity for ethical and regulatory review of herbal trials in developing countries: a case study of Moringa oleifera research in HIV-infected patients.

PubMed

Monera-Penduka, Tsitsi G; Maponga, Charles C; Morse, Gene D; Nhachi, Charles F B

2017-01-01

Lack of regulatory capacity limits the conduct of ethical and rigorous trials of herbal medicines in developing countries. Sharing ethical and regulatory experiences of successful herbal trials may accelerate the field while assuring human subjects protection. The methods and timelines for the ethical and regulatory review processes for the first drug regulatory authority approved herbal trial in Zimbabwe are described in this report. The national drug regulatory authority and ethics committee were engaged for pre-submission discussions. Six applications were submitted. Application procedures and communications with the various regulatory and ethics review boards were reviewed. Key issues raised and timelines for communications were summarized. There was no special framework for the approval of herbal trials. One local institutional review committee granted an exemption. Key issues raised for revision were around pre-clinical efficacy and safety data, standardization and quality assurance of the intervention as well as consenting procedures. Approval timelines ranged between eight and 72 weeks. In the absence of a defined framework for review of herbal trials, approval processes can be delayed. Dialogue between researchers and regulators is important for successful and efficient protocol approval for herbal trials in developing countries. The study was registered prospectively on August 3, 2011 with clinicaltrials.gov (NCT01410058).

Bioattractors: dynamical systems theory and the evolution of regulatory processes.

PubMed

Jaeger, Johannes; Monk, Nick

2014-06-01

In this paper, we illustrate how dynamical systems theory can provide a unifying conceptual framework for evolution of biological regulatory systems. Our argument is that the genotype-phenotype map can be characterized by the phase portrait of the underlying regulatory process. The features of this portrait--such as attractors with associated basins and their bifurcations--define the regulatory and evolutionary potential of a system. We show how the geometric analysis of phase space connects Waddington's epigenetic landscape to recent computational approaches for the study of robustness and evolvability in network evolution. We discuss how the geometry of phase space determines the probability of possible phenotypic transitions. Finally, we demonstrate how the active, self-organizing role of the environment in phenotypic evolution can be understood in terms of dynamical systems concepts. This approach yields mechanistic explanations that go beyond insights based on the simulation of evolving regulatory networks alone. Its predictions can now be tested by studying specific, experimentally tractable regulatory systems using the tools of modern systems biology. A systematic exploration of such systems will enable us to understand better the nature and origin of the phenotypic variability, which provides the substrate for evolution by natural selection. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Modeling the evolution of regulatory elements by simultaneous detection and alignment with phylogenetic pair HMMs.

PubMed

Majoros, William H; Ohler, Uwe

2010-12-16

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation.

Framework for Derivation of Water Quality Criteria Using the Biotic Ligand Model: Copper as a Case Study.

PubMed

Gondek, John C; Gensemer, Robert W; Claytor, Carrie A; Canton, Steven P; Gorsuch, Joseph W

2018-06-01

Acceptance of the Biotic Ligand Model (BLM) to derive aquatic life criteria, for metals in general and copper in particular, is growing amongst regulatory agencies worldwide. Thus, it is important to ensure that water quality data are used appropriately and consistently in deriving such criteria. Here we present a suggested BLM implementation framework (hereafter referred to as "the Framework") to help guide the decision-making process when designing sampling and analysis programs for use of the BLM to derive water quality criteria applied on a site-specific basis. Such a framework will help inform stakeholders on the requirements needed to derive BLM-based criteria, and thus, ensure the appropriate types and amount of data are being collected and interpreted. The Framework was developed for calculating BLM-based criteria when data are available from multiple sampling locations on a stream. The Framework aspires to promote consistency when applying the BLM across datasets of disparate water quality, data quantity, and spatial and temporal representativeness, and is meant to be flexible to maximize applicability over a wide range of scenarios. Therefore, the Framework allows for a certain level of interpretation and adjustment to address the issues unique to each dataset. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Chemical contaminants entering the marine environment from sea-based sources: A review with a focus on European seas.

PubMed

Tornero, Victoria; Hanke, Georg

2016-11-15

Anthropogenic contaminants reach the marine environment mostly directly from land-based sources, but there are cases in which they are emitted or re-mobilized in the marine environment itself. This paper reviews the literature, with a predominant focus on the European environment, to compile a list of contaminants potentially released into the sea from sea-based sources and provide an overview of their consideration under existing EU regulatory frameworks. The resulting list contains 276 substances and for some of them (22 antifouling biocides, 32 aquaculture medicinal products and 34 warfare agents) concentrations and toxicity data are additionally provided. The EU Marine Strategy Framework Directive Descriptor 8, together with the Water Framework Directive and the Regional Sea Conventions, provides the provisions against pollution of marine waters by chemical substances. This literature review should inform about the current state of knowledge regarding marine contaminant sources and provide support for setting-up of monitoring approaches, including hotspots screening. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Considerations that will determine if competency-based assessment is a sustainable innovation.

PubMed

Dauphinee, W Dale; Boulet, John R; Norcini, John J

2018-05-18

Educational assessment for the health professions has seen a major attempt to introduce competency based frameworks. As high level policy developments, the changes were intended to improve outcomes by supporting learning and skills development. However, we argue that previous experiences with major innovations in assessment offer an important road map for developing and refining assessment innovations, including careful piloting and analyses of their measurement qualities and impacts. Based on the literature, numerous assessment workshops, personal interactions with potential users, and our 40 years of experience in implementing assessment change, we lament the lack of a coordinated approach to clarify and improve measurement qualities and functionality of competency based assessment (CBA). To address this worrisome situation, we offer two roadmaps to guide CBA's further development. Initially, reframe and address CBA as a measurement development opportunity. Secondly, using a roadmap adapted from the management literature on sustainable innovation, the medical assessment community needs to initiate an integrated plan to implement CBA as a sustainable innovation within existing educational programs and self-regulatory enterprises. Further examples of down-stream opportunities to refocus CBA at the implementation level within faculties and within the regulatory framework of the profession are offered. In closing, we challenge the broader assessment community in medicine to step forward and own the challenge and opportunities to reframe CBA as an innovation to improve the quality of the clinical educational experience. The goal is to optimize assessment in health education and ultimately improve the public's health.

Legal aspects of satellite teleconferencing

NASA Technical Reports Server (NTRS)

Smith, D. D.

1971-01-01

The application of satellite communications for teleconferencing purposes is discussed. The legal framework within which such a system or series of systems could be developed is considered. The analysis is based on: (1) satellite teleconferencing regulation, (2) the options available for such a system, (3) regulatory alternatives, and (4) ownership and management aspects. The system is designed to provide a capability for professional education, remote medical diagnosis, business conferences, and computer techniques.

The current status of NORM/TENORM industries and establishment of regulatory framework in Korea.

PubMed

Chang, Byung-Uck; Kim, Yongjae; Oh, Jang-Jin

2011-07-01

During the last several years, a nationwide survey on naturally occurring radioactive material (NORM)/technologically enhanced naturally occurring radioactive materials (TENORM) industries has been conducted. Because of the rapid economic growth in Korea, the huge amount of raw materials, including NORM have been consumed in various industrial areas, and some representative TENORM industries exist in Korea. Recently, the Korean government decided to establish a regulatory framework for natural radiation, including NORM/TENORM and is making efforts to introduce relevant publically consent regulations on the basis of international safety standards.

DISTILLER: a data integration framework to reveal condition dependency of complex regulons in Escherichia coli

PubMed Central

Lemmens, Karen; De Bie, Tijl; Dhollander, Thomas; De Keersmaecker, Sigrid C; Thijs, Inge M; Schoofs, Geert; De Weerdt, Ami; De Moor, Bart; Vanderleyden, Jos; Collado-Vides, Julio; Engelen, Kristof; Marchal, Kathleen

2009-01-01

We present DISTILLER, a data integration framework for the inference of transcriptional module networks. Experimental validation of predicted targets for the well-studied fumarate nitrate reductase regulator showed the effectiveness of our approach in Escherichia coli. In addition, the condition dependency and modularity of the inferred transcriptional network was studied. Surprisingly, the level of regulatory complexity seemed lower than that which would be expected from RegulonDB, indicating that complex regulatory programs tend to decrease the degree of modularity. PMID:19265557

Development and delivery of clinical pharmacology in regulatory agencies.

PubMed

Breckenridge, Alasdair

2012-06-01

Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit-harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit-risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments. © 2012 The Author. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Experience from use of GMOs in Argentinian agriculture, economy and environment.

PubMed

Burachik, Moisés

2010-11-30

Argentina is the second largest grower of genetically modified (GM) crops. This high level of adoption of this new agricultural technology is the result of a complex combination of circumstances. We can identify four main causes that led to this: political support (from agriculture officials), ability to solve prevalent farmers' needs, economic and environmental factors and an early implementation of effective regulations. The political willingness to study this new technology and crops as well as the recruitment of sound professionals and scientists to perform the task was crucial. These professionals, with very diverse backgrounds, created the necessary regulatory framework to work with these new crops. Farmers played a decisive role, as adopting this new technology solved some of their agronomic problems, helped them perform more sustainable agronomic practices and provided economic benefits. Nonetheless, all these advancements had not been possible without a rational, science-based and flexible regulatory framework that would make sure that the GM crops were safe for food, feed and processing. Copyright © 2010 Elsevier B.V. All rights reserved.

Building a Conceptual Framework to Study the Effect of HIV Stigma-Reduction Intervention Strategies on HIV Test Uptake: A Scoping Review.

PubMed

Thapa, Subash; Hannes, Karin; Cargo, Margaret; Buve, Anne; Aro, Arja R; Mathei, Catharina

A scoping review of grey and peer-reviewed literature was conducted to develop a conceptual framework to illustrate mechanisms involved in reducing HIV stigma and increasing HIV test uptake. We followed a three-step approach to exploring the literature: developing concepts, organizing and categorizing concepts, and synthesizing concepts into a framework. The framework contains four types of intervention strategies: awareness creation, influencing normative behavior, providing support, and developing regulatory laws. The awareness creation strategy generally improves knowledge and the influencing normative behavior strategy changes stigmatizing attitudes and behaviors, and subsequently, increases HIV test uptake. Providing support and development of regulatory law strategies changes actual stigmatizing behaviors of the people, and subsequently, increases HIV test uptake. The framework further outlines that the mechanisms described are influenced by the interaction of various social-contextual and individual factors. The framework sheds new light on the effects of HIV stigma-reduction intervention strategies and HIV test uptake. Copyright © 2017 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved.

A strategy for regulatory action when new adverse effects of a licensed product emerge.

PubMed

Aronson, Jeffrey K; Price, Deirdre; Ferner, Robin E

2009-01-01

Regulatory agencies grant product licences (marketing authorizations) for medicinal products in the light of evidence that the balance between benefit and harm in the population is favourable. Here we consider a framework for allowing regulatory agencies to make rational decisions when reviewing product licences in the light of new information about harms that change that balance. The regulator can revoke the product licence, restrict the product's availability or change the 'label' in different ways. We examine the features of the adverse effect that may be relevant in making the decision: namely, individual differences in susceptibility; the possibility of monitoring; and the availability of protective strategies. The balance of benefit and harm, and the time-course and dose relation of the adverse effect play important roles in the decision-making process. We set out how these factors can help determine the logical response to new information on the balance between benefit and harm, and provide a series of relevant examples. We believe that when regulatory agencies have to decide how to amend the product licence of a drug when new serious adverse effects cause concern, they would find it useful to adopt a framework of this kind, using different strategies for different cases. Our proposed framework could also be useful in risk management planning during drug development.

GMO Reignited in Science but Not in Law: A Flawed Framework Fuels France's Stalemate.

PubMed

Robbins, Patricia B

2014-01-01

Following a statement released by a multitude of prominent scientists contesting the idea that there is a consensus on the safety of genetically modified organisms ("GMO"), this article addresses the European Union's ("EU") GMO regulatory framework, which has reluctantly permitted France to maintain an illegal ban on. MON8 10 for over a decade now. It notes that while the statement did nothing more than reignite the debate on GMO, much could and should be done to improve the framework to accommodate for the lack of true scientific understanding about the effects of GMO. This article identifies the specific areas of weakness in the EU GMO regulatory framework and recommends specific alterations. It concludes that although France's MON810 ban is illegal under existing law, the country's fears are neither unfounded nor unsupported and that the EU should work to alter its existing legal structure to parallel today's scientific uncertainty regarding GMO safety.

Procedure versus process: ethical paradigms and the conduct of qualitative research

PubMed Central

2012-01-01

Background Research is fundamental to improving the quality of health care. The need for regulation of research is clear. However, the bureaucratic complexity of research governance has raised concerns that the regulatory mechanisms intended to protect participants now threaten to undermine or stifle the research enterprise, especially as this relates to sensitive topics and hard to reach groups. Discussion Much criticism of research governance has focused on long delays in obtaining ethical approvals, restrictions imposed on study conduct, and the inappropriateness of evaluating qualitative studies within the methodological and risk assessment frameworks applied to biomedical and clinical research. Less attention has been given to the different epistemologies underlying biomedical and qualitative investigation. The bioethical framework underpinning current regulatory structures is fundamentally at odds with the practice of emergent, negotiated micro-ethics required in qualitative research. The complex and shifting nature of real world settings delivers unanticipated ethical issues and (occasionally) genuine dilemmas which go beyond easy or formulaic ‘procedural’ resolution. This is not to say that qualitative studies are ‘unethical’ but that their ethical nature can only be safeguarded through the practice of ‘micro-ethics’ based on the judgement and integrity of researchers in the field. Summary This paper considers the implications of contrasting ethical paradigms for the conduct of qualitative research and the value of ‘empirical ethics’ as a means of liberating qualitative (and other) research from an outmoded and unduly restrictive research governance framework based on abstract prinicipalism, divorced from real world contexts and values. PMID:23016663

Public-Private Partnerships in the health sector: the Danish experience.

PubMed

Vrangbaek, Karsten

2008-04-01

This article investigates the current use of Public-Private Partnerships (PPP) in the Danish health sector based on an initial discussion of theoretical approaches that analyze PPP. The empirical analysis concludes that PPP has been used very sparsely in the Danish health sector. There are few examples of large-scale partnership projects with joint investment and risk taking, but a number of smaller partnerships such as jointly owned companies at the regional level. When defining PPP more broadly, we can identify a long tradition for various types of collaboration between public and private actors in health care in Denmark. An analysis of the regulatory environment is offered as an explanation for the limited use of PPPs in Denmark. Major political and institutional actors at the central level differ in their enthusiasm for the PPP concept, and the regulatory framework is somewhat uncertain. A number of general issues and concerns related to PPPs are also discussed. It is suggested that a risk-based framework can be useful for mapping the potential and challenges for both private and public partners. Such a framework can be used to feed into game theoretical models of pros and cons for PPP projects. In general terms, it is concluded that more empirical research is needed for the assessment of the various risk factors involved in using PPPs in health care. Most PPPs are still very young, and the evidence on performance and broader governance issues is only just emerging. Ideally, such assessments should include comparisons with a purely public alternative.

Integrated Regulatory and Metabolic Networks of the Marine Diatom Phaeodactylum tricornutum Predict the Response to Rising CO 2 Levels

DOE PAGES

Levering, Jennifer; Dupont, Christopher L.; Allen, Andrew E.; ...

2017-02-14

Diatoms are eukaryotic microalgae that are responsible for up to 40% of the ocean’s primary productivity. How diatoms respond to environmental perturbations such as elevated carbon concentrations in the atmosphere is currently poorly understood. We developed a transcriptional regulatory network based on various transcriptome sequencing expression libraries for different environmental responses to gain insight into the marine diatom’s metabolic and regulatory interactions and provide a comprehensive framework of responses to increasing atmospheric carbon levels. This transcriptional regulatory network was integrated with a recently published genome-scale metabolic model of Phaeodactylum tricornutum to explore the connectivity of the regulatory network and sharedmore » metabolites. The integrated regulatory and metabolic model revealed highly connected modules within carbon and nitrogen metabolism. P. tricornutum’s response to rising carbon levels was analyzed by using the recent genome-scale metabolic model with cross comparison to experimental manipulations of carbon dioxide. Using a systems biology approach, we studied the response of the marine diatom Phaeodactylum tricornutum to changing atmospheric carbon concentrations on an ocean-wide scale. By integrating an available genome-scale metabolic model and a newly developed transcriptional regulatory network inferred from transcriptome sequencing expression data, we demonstrate that carbon metabolism and nitrogen metabolism are strongly connected and the genes involved are coregulated in this model diatom. These tight regulatory constraints could play a major role during the adaptation of P. tricornutum to increasing carbon levels. The transcriptional regulatory network developed can be further used to study the effects of different environmental perturbations on P. tricornutum’s metabolism.« less

Integrated Regulatory and Metabolic Networks of the Marine Diatom Phaeodactylum tricornutum Predict the Response to Rising CO 2 Levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levering, Jennifer; Dupont, Christopher L.; Allen, Andrew E.

Diatoms are eukaryotic microalgae that are responsible for up to 40% of the ocean’s primary productivity. How diatoms respond to environmental perturbations such as elevated carbon concentrations in the atmosphere is currently poorly understood. We developed a transcriptional regulatory network based on various transcriptome sequencing expression libraries for different environmental responses to gain insight into the marine diatom’s metabolic and regulatory interactions and provide a comprehensive framework of responses to increasing atmospheric carbon levels. This transcriptional regulatory network was integrated with a recently published genome-scale metabolic model of Phaeodactylum tricornutum to explore the connectivity of the regulatory network and sharedmore » metabolites. The integrated regulatory and metabolic model revealed highly connected modules within carbon and nitrogen metabolism. P. tricornutum’s response to rising carbon levels was analyzed by using the recent genome-scale metabolic model with cross comparison to experimental manipulations of carbon dioxide. Using a systems biology approach, we studied the response of the marine diatom Phaeodactylum tricornutum to changing atmospheric carbon concentrations on an ocean-wide scale. By integrating an available genome-scale metabolic model and a newly developed transcriptional regulatory network inferred from transcriptome sequencing expression data, we demonstrate that carbon metabolism and nitrogen metabolism are strongly connected and the genes involved are coregulated in this model diatom. These tight regulatory constraints could play a major role during the adaptation of P. tricornutum to increasing carbon levels. The transcriptional regulatory network developed can be further used to study the effects of different environmental perturbations on P. tricornutum’s metabolism.« less

Rhodobase, a meta-analytical tool for reconstructing gene regulatory networks in a model photosynthetic bacterium.

PubMed

Moskvin, Oleg V; Bolotin, Dmitry; Wang, Andrew; Ivanov, Pavel S; Gomelsky, Mark

2011-02-01

We present Rhodobase, a web-based meta-analytical tool for analysis of transcriptional regulation in a model anoxygenic photosynthetic bacterium, Rhodobacter sphaeroides. The gene association meta-analysis is based on the pooled data from 100 of R. sphaeroides whole-genome DNA microarrays. Gene-centric regulatory networks were visualized using the StarNet approach (Jupiter, D.C., VanBuren, V., 2008. A visual data mining tool that facilitates reconstruction of transcription regulatory networks. PLoS ONE 3, e1717) with several modifications. We developed a means to identify and visualize operons and superoperons. We designed a framework for the cross-genome search for transcription factor binding sites that takes into account high GC-content and oligonucleotide usage profile characteristic of the R. sphaeroides genome. To facilitate reconstruction of directional relationships between co-regulated genes, we screened upstream sequences (-400 to +20bp from start codons) of all genes for putative binding sites of bacterial transcription factors using a self-optimizing search method developed here. To test performance of the meta-analysis tools and transcription factor site predictions, we reconstructed selected nodes of the R. sphaeroides transcription factor-centric regulatory matrix. The test revealed regulatory relationships that correlate well with the experimentally derived data. The database of transcriptional profile correlations, the network visualization engine and the optimized search engine for transcription factor binding sites analysis are available at http://rhodobase.org. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Nanopharmaceuticals: Tiny challenges for the environmental risk assessment of pharmaceuticals.

PubMed

Berkner, Silvia; Schwirn, Kathrin; Voelker, Doris

2016-04-01

Many new developments and innovations in health care are based on nanotechnology. The field of nanopharmaceuticals is diverse and not as new as one might think; indeed, nanopharmaceuticals have been marketed for many years, and the future is likely to bring more nanosized compounds to the market. Therefore, it is time to examine whether the environmental risk assessment for human pharmaceuticals is prepared to assess the exposure, fate, and effects of nanopharmaceuticals in an adequate way. Challenges include the different definitions for nanomaterials and nanopharmaceuticals, different regulatory frameworks, the diversity of nanopharmaceuticals, the scope of current regulatory guidelines, and the applicability of test protocols. Based on the current environmental risk assessment for human medicinal products in the European Union, necessary adaptations for the assessment procedures and underlying study protocols are discussed and emerging solutions identified. © 2015 The Authors. Environmental Toxicology & Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Understanding the Effects of Users' Behaviors on Effectiveness of Different Exogenous Regulatory Common Pool Resource Management Institutions

NASA Astrophysics Data System (ADS)

Madani, K.; Dinar, A.

2013-12-01

Tragedy of the commons is generally recognized as one of the possible destinies for common pool resources (CPRs). To avoid the tragedy of the commons and prolonging the life of CPRs, users may show different behavioral characteristics and use different rationales for CPR planning and management. Furthermore, regulators may adopt different strategies for sustainable management of CPRs. The effectiveness of different regulatory exogenous management institutions cannot be evaluated through conventional CPR models since they assume that either users base their behavior on individual rationality and adopt a selfish behavior (Nash behavior), or that the users seek the system's optimal solution without giving priority to their own interests. Therefore, conventional models fail to reliably predict the outcome of CPR problems in which parties may have a range of behavioral characteristics, putting them somewhere in between the two types of behaviors traditionally considered. This work examines the effectiveness of different regulatory exogenous CPR management institutions through a user-based model (as opposed to a system-based model). The new modeling framework allows for consideration of sensitivity of the results to different behavioral characteristics of interacting CPR users. The suggested modeling approach is applied to a benchmark groundwater management problem. Results indicate that some well-known exogenous management institutions (e.g. taxing) are ineffective in sustainable management of CPRs in most cases. Bankruptcy-based management can be helpful, but determination of the fair level of cutbacks remains challenging under this type of institution. Furthermore, some bankruptcy rules such as the Constrained Equal Award (CEA) method are more beneficial to wealthier users, failing to establish social justice. Quota-based and CPR status-based management perform as the most promising and robust regulatory exogenous institutions in prolonging the CPR's life and increasing the long-term benefits to its users.

Making message recipients "feel right": how nonverbal cues can increase persuasion.

PubMed

Cesario, Joseph; Higgins, E Tory

2008-05-01

Nonverbal cues are an inherent component of most persuasive appeals. We use regulatory-fit theory as a framework for understanding the effect of nonverbal cues on a message's effectiveness, and as a foundation for developing a new persuasion technique. We propose that when the nonverbal cues of a message source sustain the motivational orientation of the recipient, the recipient experiences regulatory fit and feels right, and that this experience influences the message's effectiveness. Experimental results support these predictions. Participants experiencing regulatory fit (promotion-focus participants viewing messages delivered in an eager nonverbal style, prevention-focus participants viewing messages delivered in a vigilant nonverbal style) had more positive attitudes toward a message's topic and greater intentions to behave in accordance with its recommendation than did participants experiencing nonfit. Feeling right was also greater for participants experiencing fit than for those experiencing nonfit and was associated with greater message effectiveness. Regulatory-fit theory provides a framework for making precise predictions about when and for whom a nonverbal cue will affect persuasion.

Sociotechnical systems as a framework for regulatory system design and evaluation: Using Work Domain Analysis to examine a new regulatory system.

PubMed

Carden, Tony; Goode, Natassia; Read, Gemma J M; Salmon, Paul M

2017-03-15

Like most work systems, the domain of adventure activities has seen a series of serious incidents and subsequent calls to improve regulation. Safety regulation systems aim to promote safety and reduce accidents. However, there is scant evidence they have led to improved safety outcomes. In fact there is some evidence that the poor integration of regulatory system components has led to adverse safety outcomes in some contexts. Despite this, there is an absence of methods for evaluating regulatory and compliance systems. This article argues that sociotechnical systems theory and methods provide a suitable framework for evaluating regulatory systems. This is demonstrated through an analysis of a recently introduced set of adventure activity regulations. Work Domain Analysis (WDA) was used to describe the regulatory system in terms of its functional purposes, values and priority measures, purpose-related functions, object-related processes and cognitive objects. This allowed judgement to be made on the nature of the new regulatory system and on the constraints that may impact its efficacy following implementation. Importantly, the analysis suggests that the new system's functional purpose of ensuring safe activities is not fully supported in terms of the functions and objects available to fulfil them. Potential improvements to the design of the system are discussed along with the implications for regulatory system design and evaluation across the safety critical domains generally. Copyright © 2017 Elsevier Ltd. All rights reserved.

Testing use of payers to facilitate evidence-based practice adoption: protocol for a cluster-randomized trial

PubMed Central

2013-01-01

Background More effective methods are needed to implement evidence-based findings into practice. The Advancing Recovery Framework offers a multi-level approach to evidence-based practice implementation by aligning purchasing and regulatory policies at the payer level with organizational change strategies at the organizational level. Methods The Advancing Recovery Buprenorphine Implementation Study is a cluster-randomized controlled trial designed to increase use of the evidence-based practice buprenorphine medication to treat opiate addiction. Ohio Alcohol, Drug Addiction, and Mental Health Services Boards (ADAMHS), who are payers, and their addiction treatment organizations were recruited for a trial to assess the effects of payer and treatment organization changes (using the Advancing Recovery Framework) versus treatment organization changes alone on the use of buprenorphine. A matched-pair randomization, based on county characteristics, was applied, resulting in seven county ADAMHS boards and twenty-five treatment organizations in each arm. Opioid dependent patients are nested within cluster (treatment organization), and treatment organization clusters are nested within ADAMHS county board. The primary outcome is the percentage of individuals with an opioid dependence diagnosis who use buprenorphine during the 24-month intervention period and the 12-month sustainability period. The trial is currently in the baseline data collection stage. Discussion Although addiction treatment providers are under increasing pressure to implement evidence-based practices that have been proven to improve patient outcomes, adoption of these practices lags, compared to other areas of healthcare. Reasons frequently cited for the slow adoption of EBPs in addiction treatment include, regulatory issues, staff, or client resistance and lack of resources. Yet the way addiction treatment is funded, the payer’s role—has not received a lot of attention in research on EBP adoption. This research is unique because it investigates the role of payers in evidence-based practice implementation using a randomized controlled design instead of case examples. The testing of the Advancing Recovery Framework is designed to broaden the understanding of the impact payers have on evidence-based practice (EBP) adoption. Trial registration http://NCT01702142 (ClinicalTrials.gov registry, USA) PMID:23663749

The Devil Is in the Details! On Regulating Cannabis Use in Canada Based on Public Health Criteria

PubMed Central

Rehm, Jürgen; Crépault, Jean-François; Fischer, Benedikt

2017-01-01

This commentary to the editorial of Hajizadeh argues that the economic, social and health consequences of legalizing cannabis in Canada will depend in large part on the exact stipulations (mainly from the federal government) and on the implementation, regulation and practice of the legalization act (on provincial and municipal levels). A strict regulatory framework is necessary to minimize the health burden attributable to cannabis use. This includes prominently control of production and sale of the legal cannabis including control of price and content with ban of marketing and advertisement. Regulation of medical marijuana should be part of such a framework as well. PMID:28812798

Intrinsic limits to gene regulation by global crosstalk

NASA Astrophysics Data System (ADS)

Friedlander, Tamar; Prizak, Roshan; Guet, Calin; Barton, Nicholas H.; Tkacik, Gasper

Gene activity is mediated by the specificity of binding interactions between special proteins, called transcription factors, and short regulatory sequences on the DNA, where different protein species preferentially bind different DNA targets. Limited interaction specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to spurious interactions or remains erroneously inactive. Since each protein can potentially interact with numerous DNA targets, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyze the effects of global crosstalk on gene regulation, using statistical mechanics. We find that crosstalk in regulatory interactions puts fundamental limits on the reliability of gene regulation that are not easily mitigated by tuning proteins concentrations or by complex regulatory schemes proposed in the literature. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA Grant agreement Nr. 291734 (T.F.) and ERC Grant Nr. 250152 (N.B.).

Toward a Regulatory Framework for the Waterpipe.

PubMed

Salloum, Ramzi G; Asfar, Taghrid; Maziak, Wasim

2016-10-01

Waterpipe smoking has been dramatically increasing among youth worldwide and in the United States. Despite its general association with misperceptions of reduced harm, evidence suggests this is a harmful and dependence-inducing tobacco use method that represents a threat to public health. Waterpipe products continue to be generally unregulated, which likely has contributed to their spread. The Family Smoking Prevention and Tobacco Control Act of 2009 granted the US Food and Drug Administration (FDA) the authority to regulate waterpipe products, and the FDA finalized a rule extending its authority over waterpipe products in May 2016. This critical step in addressing the alarming increase in waterpipe smoking in the United States has created urgency for research to provide the evidence needed for effective regulatory initiatives for waterpipe products. We aim to stimulate such research by providing a framework that addresses the scope of waterpipe products and their unique context and use patterns. The proposed framework identifies regulatory targets for waterpipe product components (i.e., tobacco, charcoal, and device), the waterpipe café setting, and its marketing environment dominated by Internet promotion.

Toward a Regulatory Framework for the Waterpipe

PubMed Central

Salloum, Ramzi G.; Asfar, Taghrid

2016-01-01

Waterpipe smoking has been dramatically increasing among youth worldwide and in the United States. Despite its general association with misperceptions of reduced harm, evidence suggests this is a harmful and dependence-inducing tobacco use method that represents a threat to public health. Waterpipe products continue to be generally unregulated, which likely has contributed to their spread. The Family Smoking Prevention and Tobacco Control Act of 2009 granted the US Food and Drug Administration (FDA) the authority to regulate waterpipe products, and the FDA finalized a rule extending its authority over waterpipe products in May 2016. This critical step in addressing the alarming increase in waterpipe smoking in the United States has created urgency for research to provide the evidence needed for effective regulatory initiatives for waterpipe products. We aim to stimulate such research by providing a framework that addresses the scope of waterpipe products and their unique context and use patterns. The proposed framework identifies regulatory targets for waterpipe product components (i.e., tobacco, charcoal, and device), the waterpipe café setting, and its marketing environment dominated by Internet promotion. PMID:27552262

Constraints based analysis of extended cybernetic models.

PubMed

Mandli, Aravinda R; Venkatesh, Kareenhalli V; Modak, Jayant M

2015-11-01

The cybernetic modeling framework provides an interesting approach to model the regulatory phenomena occurring in microorganisms. In the present work, we adopt a constraints based approach to analyze the nonlinear behavior of the extended equations of the cybernetic model. We first show that the cybernetic model exhibits linear growth behavior under the constraint of no resource allocation for the induction of the key enzyme. We then quantify the maximum achievable specific growth rate of microorganisms on mixtures of substitutable substrates under various kinds of regulation and show its use in gaining an understanding of the regulatory strategies of microorganisms. Finally, we show that Saccharomyces cerevisiae exhibits suboptimal dynamic growth with a long diauxic lag phase when growing on a mixture of glucose and galactose and discuss on its potential to achieve optimal growth with a significantly reduced diauxic lag period. The analysis carried out in the present study illustrates the utility of adopting a constraints based approach to understand the dynamic growth strategies of microorganisms. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Perspective for the development of companion diagnostics and regulatory landscape to encourage personalized medicine in Japan.

PubMed

Tazawa, Yoshiaki

2016-01-01

On July 1st, 2013, the Ministry of Health, Labor and Welfare (MHLW) issued an official notification regarding the co-development of companion diagnostics (CDx) with a drug which requires any exclusive diagnostic test or medical device to predict efficacy or adverse reactions to the drug. The main frame and contents in the MHLW's notification are quite similar to the summaries in the final guidance issued by the US Food and Drug Administration (FDA) on August 6th, 2014 Guidance for Industry and Food and Drug Administration Staff (In Vitro Companion Diagnostic Devices, [2014] ), and these recommend industries to develop, study and submit CDx and the corresponding drug contemporaneously as much as possible. Following the MHLW's notification, the Pharmaceutical and Medical Device Agency (PMDA) notified on December 26th, 2013, "the technical guidance for co-development of CDx and the drug" that mentioned the regulatory requirements for clinical trial of the drug and CDx as well as analytical validity of CDx required for the trials. These official notifications from the Ministry and the Agency may be useful for pharmaceutical and diagnostics makers to understand how they should co-develop and validate CDx for clinical trials and regulatory submission. However, since the most anticipated technologies such as the next generation sequencer (NGS) are more complex and its medical risks could be high level, the existing regulatory system focusing on only diagnostics reagents and devices that are developed and manufactured by in vitro diagnostics (IVD) makers may be no longer suitable for the characteristics of CDx for the future.As an increase of clinical needs for multiple biomarkers assay by DNA sequencer, on November 19th, 2013, the FDA cleared 510 K for NGS and its universal kit. On October 3rd, 2014, moreover, the agency notified two drafts of guidance (Anticipated Details of the Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratory in Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), [2014]; Anticipated Details of the Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratory in FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDT), [2014]) for oversight of laboratory developed tests (LDTs) with medium or high medical risks. These FDA's strategic decisions and new regulatory frameworks may allow the clinical laboratories to develop and perform more easily NGS-based CDx under the certification of Clinical Laboratory Improvement Amendments (CLIA). However, neither law nor regulated quality management system similar to the CLIA exists in Japan. To effectively validate LDTs and NGS for medical practice, Japan should learn more the current regulatory changes and initiatives in the US, as well as to reform the regulatory frameworks and create any regulated quality management system for clinical laboratory testing to be reimbursed.

78 FR 909 - Further Proposed Guidance Regarding Compliance With Certain Swap Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-07

... establish a new regulatory framework for swaps. The legislation was enacted to reduce systemic risk... increase understanding of each other's regulatory approaches and to harmonize the cross-border approaches... may lead to divergent approaches to cross-border activities. The Commission also recognizes the...

Clinical trial regulation in Argentina: overview and analysis of regulatory framework, use of existing tools, and researchers' perspectives to identify potential barriers.

PubMed

White, Lauren; Ortiz, Zulma; Cuervo, Luis G; Reveiz, Ludovic

2011-11-01

To review and analyze the regulatory framework of clinical trial registration, use of existing tools (publicly accessible national/international registration databases), and users' perspectives to identify possible barriers to registration compliance by sponsors and researchers in Argentina. Internationally registered trials recruiting patients in Argentina were found through clincialtrials.gov and the International Clinical Trial Registration Platform (ICTRP) and compared with publically available clinical trials registered through the National Administration of Drugs, Foods, and Medical Devices (ANMAT). A questionnaire addressing hypothesized attitudinal, knowledge-related, idiomatic, technical, economic, and regulatory barriers that could discourage or impede registration of clinical trials was developed, and semi-structured, in-depth interviews were conducted with a purposively selected sample of researchers (investigators, sponsors, and monitors) in Argentina. A response rate of 74.3% (n = 29) was achieved, and 27 interviews were ultimately used for analysis. Results suggested that the high proportion of foreign-sponsored or multinational trials (64.8% of all protocols approved by ANMAT from 1994-2006) may contribute to a communication gap between locally based investigators and foreign-based administrative officials. A lack of knowledge about available international registration tools and limited awareness of the importance of registration were also identified as limiting factors for local investigators and sponsors. To increase compliance and promote clinical trial registration in Argentina, national health authorities, sponsors, and local investigators could take the following steps: implement a grassroots educational campaign to improve clinical trial regulation, support local investigator-sponsor-initiated clinical trials, and/or encourage local and regional scientific journal compliance with standards from the International Committee of Medical Journal Editors (ICMJE) and/or the World Association of Medical Editors (WAME).

Heuristic Identification of Biological Architectures for Simulating Complex Hierarchical Genetic Interactions

PubMed Central

Moore, Jason H; Amos, Ryan; Kiralis, Jeff; Andrews, Peter C

2015-01-01

Simulation plays an essential role in the development of new computational and statistical methods for the genetic analysis of complex traits. Most simulations start with a statistical model using methods such as linear or logistic regression that specify the relationship between genotype and phenotype. This is appealing due to its simplicity and because these statistical methods are commonly used in genetic analysis. It is our working hypothesis that simulations need to move beyond simple statistical models to more realistically represent the biological complexity of genetic architecture. The goal of the present study was to develop a prototype genotype–phenotype simulation method and software that are capable of simulating complex genetic effects within the context of a hierarchical biology-based framework. Specifically, our goal is to simulate multilocus epistasis or gene–gene interaction where the genetic variants are organized within the framework of one or more genes, their regulatory regions and other regulatory loci. We introduce here the Heuristic Identification of Biological Architectures for simulating Complex Hierarchical Interactions (HIBACHI) method and prototype software for simulating data in this manner. This approach combines a biological hierarchy, a flexible mathematical framework, a liability threshold model for defining disease endpoints, and a heuristic search strategy for identifying high-order epistatic models of disease susceptibility. We provide several simulation examples using genetic models exhibiting independent main effects and three-way epistatic effects. PMID:25395175

Interventional radiology virtual simulator for liver biopsy.

PubMed

Villard, P F; Vidal, F P; ap Cenydd, L; Holbrey, R; Pisharody, S; Johnson, S; Bulpitt, A; John, N W; Bello, F; Gould, D

2014-03-01

Training in Interventional Radiology currently uses the apprenticeship model, where clinical and technical skills of invasive procedures are learnt during practice in patients. This apprenticeship training method is increasingly limited by regulatory restrictions on working hours, concerns over patient risk through trainees' inexperience and the variable exposure to case mix and emergencies during training. To address this, we have developed a computer-based simulation of visceral needle puncture procedures. A real-time framework has been built that includes: segmentation, physically based modelling, haptics rendering, pseudo-ultrasound generation and the concept of a physical mannequin. It is the result of a close collaboration between different universities, involving computer scientists, clinicians, clinical engineers and occupational psychologists. The technical implementation of the framework is a robust and real-time simulation environment combining a physical platform and an immersive computerized virtual environment. The face, content and construct validation have been previously assessed, showing the reliability and effectiveness of this framework, as well as its potential for teaching visceral needle puncture. A simulator for ultrasound-guided liver biopsy has been developed. It includes functionalities and metrics extracted from cognitive task analysis. This framework can be useful during training, particularly given the known difficulties in gaining significant practice of core skills in patients.

The impact of council directive 2011/70/EURATOM and IAEA joint convention review meetings on the ongoing establishment of the Portuguese regulatory framework and on the future of national radioactive waste

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paiva, Isabel; Trindade, Romao B.

Council Directive 2011/70/EURATOM of 19 July 2011, establishing a Community framework for the responsible and safe management of spent fuel and radioactive waste will enter in force August 2013 in all EU Member States. Portugal has already started preparing its legislative framework to accommodate the new legislative piece. However, the first report of Portugal to the Joint Convention on the Safety of Spent Fuel Management and on the Safety of Radioactive Waste Management of the IAEA, in Vienna, 2012, has shown that Portugal still has many steps to overcome to establish a successful and effective basic regulatory framework. The existencemore » of many competent authorities related to the radiological protection area and a newly independent commission that is still looking on how to fulfill its regulator role in other areas such as the radioactive waste management makes quite challenging the full application of the new directive as well as compliance that Portugal will have to show in the next Joint Convention review meeting in order to meet the obligations of the Convention. In this paper, the reality of the regulatory Portuguese framework on radiological protection, nuclear safety and radioactive waste management is presented. Discussion of the future impact of the new legislation and its consequences such as the need to setup the national program on radioactive waste management is critical discussed. (authors)« less

Setting the stage to advance the adverse outcome pathway (AOP) framework through horizon scanning

EPA Science Inventory

Recognizing the international interest surrounding the adverse outcome pathway framework, which captures existing information describing causal linkages between a molecular initiating event through levels of biological organization to an adverse outcome of regulatory significance...

A Framework for the Evaluation of Biosecurity, Commercial, Regulatory, and Scientific Impacts of Plant Viruses and Viroids Identified by NGS Technologies

PubMed Central

Massart, Sebastien; Candresse, Thierry; Gil, José; Lacomme, Christophe; Predajna, Lukas; Ravnikar, Maja; Reynard, Jean-Sébastien; Rumbou, Artemis; Saldarelli, Pasquale; Škorić, Dijana; Vainio, Eeva J.; Valkonen, Jari P. T.; Vanderschuren, Hervé; Varveri, Christina; Wetzel, Thierry

2017-01-01

Recent advances in high-throughput sequencing technologies and bioinformatics have generated huge new opportunities for discovering and diagnosing plant viruses and viroids. Plant virology has undoubtedly benefited from these new methodologies, but at the same time, faces now substantial bottlenecks, namely the biological characterization of the newly discovered viruses and the analysis of their impact at the biosecurity, commercial, regulatory, and scientific levels. This paper proposes a scaled and progressive scientific framework for efficient biological characterization and risk assessment when a previously known or a new plant virus is detected by next generation sequencing (NGS) technologies. Four case studies are also presented to illustrate the need for such a framework, and to discuss the scenarios. PMID:28174561

Simultaneous learning of instantaneous and time-delayed genetic interactions using novel information theoretic scoring technique

PubMed Central

2012-01-01

Background Understanding gene interactions is a fundamental question in systems biology. Currently, modeling of gene regulations using the Bayesian Network (BN) formalism assumes that genes interact either instantaneously or with a certain amount of time delay. However in reality, biological regulations, both instantaneous and time-delayed, occur simultaneously. A framework that can detect and model both these two types of interactions simultaneously would represent gene regulatory networks more accurately. Results In this paper, we introduce a framework based on the Bayesian Network (BN) formalism that can represent both instantaneous and time-delayed interactions between genes simultaneously. A novel scoring metric having firm mathematical underpinnings is also proposed that, unlike other recent methods, can score both interactions concurrently and takes into account the reality that multiple regulators can regulate a gene jointly, rather than in an isolated pair-wise manner. Further, a gene regulatory network (GRN) inference method employing an evolutionary search that makes use of the framework and the scoring metric is also presented. Conclusion By taking into consideration the biological fact that both instantaneous and time-delayed regulations can occur among genes, our approach models gene interactions with greater accuracy. The proposed framework is efficient and can be used to infer gene networks having multiple orders of instantaneous and time-delayed regulations simultaneously. Experiments are carried out using three different synthetic networks (with three different mechanisms for generating synthetic data) as well as real life networks of Saccharomyces cerevisiae, E. coli and cyanobacteria gene expression data. The results show the effectiveness of our approach. PMID:22691450

77 FR 52791 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Minimum Regulatory...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-30

...The Office of the Comptroller of the Currency (OCC), Board of Governors of the Federal Reserve System (Board), and the Federal Deposit Insurance Corporation (FDIC) (collectively, the agencies) are seeking comment on three Notices of Proposed Rulemaking (NPR) that would revise and replace the agencies' current capital rules. In this NPR, the agencies are proposing to revise their risk-based and leverage capital requirements consistent with agreements reached by the Basel Committee on Banking Supervision (BCBS) in ``Basel III: A Global Regulatory Framework for More Resilient Banks and Banking Systems'' (Basel III). The proposed revisions would include implementation of a new common equity tier 1 minimum capital requirement, a higher minimum tier 1 capital requirement, and, for banking organizations subject to the advanced approaches capital rules, a supplementary leverage ratio that incorporates a broader set of exposures in the denominator measure. Additionally, consistent with Basel III, the agencies are proposing to apply limits on a banking organization's capital distributions and certain discretionary bonus payments if the banking organization does not hold a specified amount of common equity tier 1 capital in addition to the amount necessary to meet its minimum risk- based capital requirements. This NPR also would establish more conservative standards for including an instrument in regulatory capital. As discussed in the proposal, the revisions set forth in this NPR are consistent with section 171 of the Dodd-Frank Wall Street Reform and Consumer Protection Act (Dodd-Frank Act), which requires the agencies to establish minimum risk-based and leverage capital requirements. In connection with the proposed changes to the agencies' capital rules in this NPR, the agencies are also seeking comment on the two related NPRs published elsewhere in today's Federal Register. The two related NPRs are discussed further in the SUPPLEMENTARY INFORMATION.

Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data

PubMed Central

Liu, Zhi-Ping

2015-01-01

Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high-throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented. PMID:25937810

Taiwan Regulation of Biobanks.

PubMed

Fan, Chien-Te; Hung, Tzu-Hsun; Yeh, Chan-Kun

2015-01-01

This paper introduces legal framework and governance structure in relation to the management and development of biobanks in Taiwan. At first, we briefly describe Taiwan's population, political system and health care system. Secondly, this research introduces biobanking framework of Taiwan including 25 biobanks established with the approval of the Ministry of Health and Welfare. In those biobanks, "Taiwan Biobank" is the first and the largest government-supported biobank which comprises population-based cohort study and disease- oriented study. Since the collection of information, data, and biological specimen of biobanks often involve highly sensitive personal information, in the legal framework of Taiwan, there is a specific regulation, "Human Biobank Management Act" (HBMA), which plays an important role in regulating biobanks in Taiwan. HBMA, the Personal Information Act and other regulations constitute a comprehensive legal and regulatory privacy framework of biobanks. Through the introduction and analysis of the current legal framework applicable to biobanks, we found that there are several challenges that need to be solved appropriately that involve duplicate review systems, the obstacles in the international collaboration, and data sharing between biobanks in Taiwan. © 2015 American Society of Law, Medicine & Ethics, Inc.

Review on the worldwide regulatory framework for biosimilars focusing on the Mexican case as an emerging market in Latin America.

PubMed

Ibarra-Cabrera, Ricardo; Mena-Pérez, Sandra Carolina; Bondani-Guasti, Augusto; García-Arrazola, Roeb

2013-12-01

The global biopharmaceutical market is worth over $100 billion USD. Nearly 90% of these products will lose their patent in the next ten years, leading to the commercialization of their subsequent versions, known as 'biosimilars'. Biosimilars are much more complex molecules than chemically synthesized generics in terms of size, structure, stability, microheterogeneity, manufacture, etc. Therefore, a specific regulatory framework is needed in order to demonstrate their comparability with innovative products, as well as their quality, safety and efficacy. The EU published the first regulatory pathway in 2005 and has approved 14 biosimilars. Mexico has recently developed a clear regulatory pathway for these products. Their legal basis was established in Article 222 Bis of General Law of Health in 2009, clear specifications in the Regulation for Health Goods in 2011, and further requirements in the Mexican Official Norm NOM-EM-001-SSA1-2012. The aim of this review is to summarize the regulatory pathways for biosimilars in the world with a special focus on Mexican experience, so as contribute to the development of regulations in other countries. Copyright © 2013 Elsevier Inc. All rights reserved.

The Tasman Spirit oil spill: implications for regulatory change in Pakistan.

PubMed

Mian, Saima; Bennett, Suzan

2009-07-01

An oil spill in July 2003 from the tanker Tasman Spirit attracted considerable public and media attention in Pakistan. This paper focuses on the experience of a developing country such as Pakistan in dealing with a major oil spill and its impact on bringing about change in the national regulatory framework. A major outcome has been the ratification of the International Convention on Civil Liability for Oil Pollution Damage 1992, which came into force in March 2006 in Pakistan. The convention provides a compensation mechanism for victims incurring oil pollution damages from maritime casualties involving oil laden ships. Several additional changes are still required to improve the country's ability to cope with marine oil spills. These include the development of a comprehensive domestic regulatory framework, implementation of an effective contingency plan, and capacity building of all relevant agencies.

Weight of evidence evaluation of adverse outcome pathways converging at impaired vitellogenin synthesis leading to reproductive impairment

EPA Science Inventory

Adverse outcome pathways (AOPs) provide a framework that supports greater use of mechanistic data measured at lower levels of biological organization as a basis for regulatory decision-making. However, it is recognized that different types of regulatory applications and decisions...

Patient safety and efficacy as measured by clinical trials and regulatory policy.

PubMed

Harvey, B E; Alpert, S

1997-01-01

Virtual Reality and other technological innovations in medicine provide new challenges to the regulatory framework of the premarket review process for medical devices. By reinventing the government-academia-industry partnership, clinical trial data necessary for a medical device to enter the market can be more efficiently obtained.

A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies.

PubMed

White, Michael; Whittaker, Roger; Gándara, Carolina; Stoll, Elizabeth A

2017-08-01

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.

A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies

PubMed Central

White, Michael; Whittaker, Roger; Gándara, Carolina; Stoll, Elizabeth A.

2017-01-01

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy. PMID:28817344

Emergent self-regulatory activity among young children during scientific inquiry: An analysis of six kindergarten children

NASA Astrophysics Data System (ADS)

Lomangino, Adrienne Gelpi

2000-10-01

This qualitative investigation extends the study of self-regulation to examine young children's developing self-regulated learning competencies. The framework for this research draws upon social cognitive, developmental, and sociocultural perspectives on self-regulation and research on children's scientific thinking. Taking a multiple case study approach, this study examines six kindergarten children's emerging self-regulatory competencies during inquiry-based science instruction. Data were collected during two inquiry-based science programs of study, one pertaining to light and shadow and a second pertaining to motion on inclined planes. Data sources included: videotaped records of the instruction, transcriptions of the videotapes, interviews with the children and teacher, student work, and field notes. Taking an inductive approach to analysis, patterns in the children's activity were identified through a recursive process of defining and refining categories that characterized the children's verbal and behavioral activity. Each case study examines a child's behavior within each phase of the inquiry for evidence of emerging self-regulatory competence. Analysis revealed nascent forms of goal-setting and planning, monitoring, resource management, seeking social assistance, and evaluating. Monitoring activity occurred more frequently than planning or evaluating. For several children, animating materials served to promote motivation. Children's efforts to support peers' activity and monitor the meaning of ongoing discourse contrast with common assumptions about children's attention to others' thinking. Variations in self-regulatory activity were found across phases of instruction. The children exhibited interpersonal self-regulatory efforts, in which monitoring and control of the self was entwined with the activity of others. Joint participation also played a critical role in supporting the metacognitive demands of self-regulation and prompting metacognitive awareness. However, planning and self-evaluation were constrained by the opportunities provided within the instruction for engaging in self-regulatory activity.

Impact of illness and its treatment on workplace costs: regulatory and measurement issues.

PubMed

Greenberg, P E; Birnbaum, H G; Kessler, R C; Morgan, M; Stang, P

2001-01-01

In an attempt to document a broader spectrum of the benefits of their pharmaceutical products, drug companies increasingly seek to include productivity claims in their promotional campaigns. We describe the existing regulatory framework of the Food and Drug Administration (FDA) for considering productivity claims, distinguishing between the traditional "substantial evidence" standard and the "competent and reliable scientific evidence" standard. But the notion of competent and reliable scientific evidence may itself be problematic, even when it is the appropriate regulatory standard, because there exists no consistent measurement approach across diseases, workplaces, jobs, and worker capabilities that is widely accepted in this emerging area of health outcomes research. We examine the various measurement approaches that have been used to quantify the impact of illness and its treatment on workplace productivity, and we describe some of the shortcomings associated with each alternative. This discussion highlights the possible difficulties faced by the FDA in reviewing productivity-based promotional claims. Finally, we suggest possible strategies for furthering this field of investigation.

Effective standards and regulatory tools for respiratory gas monitors and pulse oximeters: the role of the engineer and clinician.

PubMed

Weininger, Sandy

2007-12-01

Developing safe and effective medical devices involves understanding the hazardous situations that can arise in clinical practice and implementing appropriate risk control measures. The hazardous situations may have their roots in the design or in the use of the device. Risk control measures may be engineering or clinically based. A multidisciplinary team of engineers and clinicians is needed to fully identify and assess the risks and implement and evaluate the effectiveness of the control measures. In this paper, I use three issues, calibration/accuracy, response time, and protective measures/alarms, to highlight the contributions of these groups. This important information is captured in standards and regulatory tools to control risk for respiratory gas monitors and pulse oximeters. This paper begins with a discussion of the framework of safety, explaining how voluntary standards and regulatory tools work. The discussion is followed by an examination of how engineering and clinical knowledge are used to support the assurance of safety.

Ethical and Regulatory Challenges with Autologous Adult Stem Cells: A Comparative Review of International Regulations.

PubMed

Lysaght, Tamra; Kerridge, Ian H; Sipp, Douglas; Porter, Gerard; Capps, Benjamin J

2017-06-01

Cell and tissue-based products, such as autologous adult stem cells, are being prescribed by physicians across the world for diseases and illnesses that they have neither been approved for or been demonstrated as safe and effective in formal clinical trials. These doctors often form part of informal transnational networks that exploit differences and similarities in the regulatory systems across geographical contexts. In this paper, we examine the regulatory infrastructure of five geographically diverse but socio-economically comparable countries with the aim of identifying similarities and differences in how these products are regulated and governed within clinical contexts. We find that while there are many subtle technical differences in how these regulations are implemented, they are sufficiently similar that it is difficult to explain why these practices appear more prevalent in some countries and not in others. We conclude with suggestions for how international governance frameworks might be improved to discourage the exploitation of vulnerable patient populations while enabling innovation in the clinical application of cellular therapies.

Integration of systems biology with bioprocess engineering: L: -threonine production by systems metabolic engineering of Escherichia coli.

PubMed

Lee, Sang Yup; Park, Jin Hwan

2010-01-01

Random mutation and selection or targeted metabolic engineering without consideration of its impact on the entire metabolic and regulatory networks can unintentionally cause genetic alterations in the region, which is not directly related to the target metabolite. This is one of the reasons why strategies for developing industrial strains are now shifted towards targeted metabolic engineering based on systems biology, which is termed systems metabolic engineering. Using systems metabolic engineering strategies, all the metabolic engineering works are conducted in systems biology framework, whereby entire metabolic and regulatory networks are thoroughly considered in an integrated manner. The targets for purposeful engineering are selected after all possible effects on the entire metabolic and regulatory networks are thoroughly considered. Finally, the strain, which is capable of producing the target metabolite to a high level close to the theoretical maximum value, can be constructed. Here we review strategies and applications of systems biology successfully implemented on bioprocess engineering, with particular focus on developing L: -threonine production strains of Escherichia coli.

Opportunities for animal alternatives implementation in the evolving OECD fish testing framework

EPA Science Inventory

This presentation reviews opportunities for animal alternative approaches in the FTF. These will be placed in the context of in vivo tests required in many regulatory situations for the registration of industrial chemicals, pharmaceuticals, and agrochemicals. The Framework inte...

Regulatory challenges for GM crops in developing economies: the African experience.

PubMed

Nang'ayo, Francis; Simiyu-Wafukho, Stella; Oikeh, Sylvester O

2014-12-01

Globally, transgenic or genetically modified (GM) crops are considered regulated products that are subject to regulatory oversight during trans-boundary movement, testing and environmental release. In Africa, regulations for transgenic crops are based on the outcomes of the historic Earth Summit Conference held in Rio, Brazil two decades ago, namely, the adoption of the Convention on Biological Diversity (CBD) and the subsequent adoption of the Cartagena Protocol on Biosafety. To exploit the potential benefits of transgenic crops while safeguarding the potential risks on human health and environment, most African countries have signed and ratified the CBD and the Cartagena Protocol on Biosafety. Consequently, these countries are required to take appropriate legal, administrative and other measures to ensure that the handling and utilization of living modified organisms are undertaken in a manner that reduces the risks to humans and the environment. These countries are also expected to provide regulatory oversight on transgenic crops through functional national biosafety frameworks (NBFs). While in principle this approach is ideal, NBFs in most African countries are steeped in a host of policy, legal and operational challenges that appear to be at cross-purposes with the noble efforts of seeking to access, test and deliver promising GM crops for use by resource-limited farmers in Africa. In this paper we discuss the regulatory challenges faced during the development and commercialization of GM crops based on experiences from countries in Sub-Saharan Africa.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spogen, L.R.; Cleland, L.L.

An approach to the development of performance based regulations (PBR's) is described. Initially, a framework is constructed that consists of a function hierarchy and associated measures. The function at the top of the hierarchy is described in terms of societal objectives. Decomposition of this function into subordinate functions and their subsequent decompositions yield the function hierarchy. ''Bottom'' functions describe the roles of system components. When measures are identified for the performance of each function and means of aggregating performances to higher levels are established, the framework may be employed for developing PBR's. Consideration of system flexibility and performance uncertainty guidemore » in determining the hierarchical level at which regulations are formulated. Ease of testing compliance is also a factor. To show the viability of the approach, the framework developed by Lawrence Livermore Laboratory for the Nuclear Regulatory Commission for evaluation of material control systems at fixed facilities is presented.« less

Disrupting incrementalism in health care innovation.

PubMed

Soleimani, Farzad; Zenios, Stefanos

2011-08-01

To build enabling innovation frameworks for health care entrepreneurs to better identify, evaluate, and pursue entrepreneurial opportunities. Powerful frameworks have been developed to enable entrepreneurs and investors identify which opportunity areas are worth pursuing and which start-up ideas have the potential to succeed. These frameworks, however, have not been clearly defined and interpreted for innovations in health care. Having a better understanding of the process of innovation in health care allows physician entrepreneurs to innovate more successfully. A review of academic literature was conducted. Concepts and frameworks related to technology innovation were analyzed. A new set of health care specific frameworks was developed. These frameworks were then applied to innovations in various health care subsectors. Health care entrepreneurs would greatly benefit from distinguishing between incremental and disruptive innovations. The US regulatory and reimbursement systems favor incrementalism with a greater chance of success for established players. Small companies and individual groups, however, are more likely to thrive if they adopt a disruptive strategy. Disruption in health care occurs through various mechanisms as detailed in this article. While the main mechanism of disruption might vary across different health care subsectors, it is shown that disruptive innovations consistently require a component of contrarian interpretation to guarantee considerable payoff. If health care entrepreneurs choose to adopt an incrementalist approach, they need to build the risk of disruption into their models and also ascertain that they have a very strong intellectual property (IP) position to weather competition from established players. On the contrary, if they choose to pursue disruption in the market, albeit the competition will be less severe, they need to recognize that the regulatory and reimbursement hurdles are going to be very high. Thus, they would benefit from seeking market opportunities that are large enough to warrant greater regulatory and reimbursement risks.

78 FR 55339 - Regulatory Capital Rules: Regulatory Capital, Implementation of Basel III, Capital Adequacy...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-10

...The Federal Deposit Insurance Corporation (FDIC) is adopting an interim final rule that revises its risk-based and leverage capital requirements for FDIC-supervised institutions. This interim final rule is substantially identical to a joint final rule issued by the Office of the Comptroller of the Currency (OCC) and the Board of Governors of the Federal Reserve System (Federal Reserve) (together, with the FDIC, the agencies). The interim final rule consolidates three separate notices of proposed rulemaking that the agencies jointly published in the Federal Register on August 30, 2012, with selected changes. The interim final rule implements a revised definition of regulatory capital, a new common equity tier 1 minimum capital requirement, a higher minimum tier 1 capital requirement, and, for FDIC-supervised institutions subject to the advanced approaches risk-based capital rules, a supplementary leverage ratio that incorporates a broader set of exposures in the denominator. The interim final rule incorporates these new requirements into the FDIC's prompt corrective action (PCA) framework. In addition, the interim final rule establishes limits on FDIC-supervised institutions' capital distributions and certain discretionary bonus payments if the FDIC-supervised institution does not hold a specified amount of common equity tier 1 capital in addition to the amount necessary to meet its minimum risk-based capital requirements. The interim final rule amends the methodologies for determining risk-weighted assets for all FDIC-supervised institutions. The interim final rule also adopts changes to the FDIC's regulatory capital requirements that meet the requirements of section 171 and section 939A of the Dodd-Frank Wall Street Reform and Consumer Protection Act. The interim final rule also codifies the FDIC's regulatory capital rules, which have previously resided in various appendices to their respective regulations, into a harmonized integrated regulatory framework. In addition, the FDIC is amending the market risk capital rule (market risk rule) to apply to state savings associations. The FDIC is issuing these revisions to its capital regulations as an interim final rule. The FDIC invites comments on the interaction of this rule with other proposed leverage ratio requirements applicable to large, systemically important banking organizations. This interim final rule otherwise contains regulatory text that is identical to the common rule text adopted as a final rule by the Federal Reserve and the OCC. This interim final rule enables the FDIC to proceed on a unified, expedited basis with the other federal banking agencies pending consideration of other issues. Specifically, the FDIC intends to evaluate this interim final rule in the context of the proposed well- capitalized and buffer levels of the supplementary leverage ratio applicable to large, systemically important banking organizations, as described in a separate Notice of Proposed Rulemaking (NPR) published in the Federal Register August 20, 2013. The FDIC is seeking commenters' views on the interaction of this interim final rule with the proposed rule regarding the supplementary leverage ratio for large, systemically important banking organizations.

Establishing a regulatory value chain model: An innovative approach to strengthening medicines regulatory systems in resource-constrained settings.

PubMed

Chahal, Harinder Singh; Kashfipour, Farrah; Susko, Matt; Feachem, Neelam Sekhri; Boyle, Colin

2016-05-01

Medicines Regulatory Authorities (MRAs) are an essential part of national health systems and are charged with protecting and promoting public health through regulation of medicines. However, MRAs in resource-constrained settings often struggle to provide effective oversight of market entry and use of health commodities. This paper proposes a regulatory value chain model (RVCM) that policymakers and regulators can use as a conceptual framework to guide investments aimed at strengthening regulatory systems. The RVCM incorporates nine core functions of MRAs into five modules: (i) clear guidelines and requirements; (ii) control of clinical trials; (iii) market authorization of medical products; (iv) pre-market quality control; and (v) post-market activities. Application of the RVCM allows national stakeholders to identify and prioritize investments according to where they can add the most value to the regulatory process. Depending on the economy, capacity, and needs of a country, some functions can be elevated to a regional or supranational level, while others can be maintained at the national level. In contrast to a "one size fits all" approach to regulation in which each country manages the full regulatory process at the national level, the RVCM encourages leveraging the expertise and capabilities of other MRAs where shared processes strengthen regulation. This value chain approach provides a framework for policymakers to maximize investment impact while striving to reach the goal of safe, affordable, and rapidly accessible medicines for all.

State Policies to Transform Struggling Schools: How Various State Policies Can Be Used to Enable School & District Turnaround. Meeting the Turnaround Challenge: Strategies, Resources & Tools to Transform a Framework into Practice

ERIC Educational Resources Information Center

Mass Insight Education (NJ1), 2009

2009-01-01

State governments wield significant authority in the management of public schools. As a nexus for federal funding, state funding, and regulatory authority, states have both the legal and financial power to help drive school change. The "No Child Left Behind Act" has required each state to create a system of standards-based assessment and…

Homeland security challenges in nursing practice.

PubMed

Boatright, Connie; McGlown, K Joanne

2005-09-01

Nurses need a comprehensive knowledge of doctrine, laws, regulations,programs, and processes that build the operational framework for health care preparedness. Key components of this knowledge base reside in the areas of: evolution of homeland security: laws and mandates affecting health care and compliance and regulatory issues for health care organizations. This article addresses primary components in both of these areas, after first assessing the status of nursing's involvement (in homeland security), as portrayed in the professional literature.

Ecosystem Services: a Framework for Environmental Management of the Deep Sea

NASA Astrophysics Data System (ADS)

Le, J. T.; Levin, L. A.; Carson, R. T.

2016-02-01

As demand for deep-sea resources rapidly expands in the food, energy, mineral, and pharmaceutical sectors, it has become increasingly clear that a regulatory structure for extracting these resources is not yet in place. There are jurisdictional gaps and a lack of regulatory consistency regarding what aspects of the deep sea need protection and what requirements might help guarantee that protection. Given the mining sector's intent to exploit seafloor massive sulphides, Mn nodules, cobalt crusts, and phosphorites in the coming years, there is an urgent need for deep-ocean environmental management. Here, we propose an ecosystem services-based framework to inform decisions and best practices regarding resource exploitation, and to guide baseline studies, preventative actions, monitoring, and remediation. With policy in early stages of development, an ecosystem services approach has the potential to serve as an overarching framework that takes protection of natural capital provided by the environment into account during the decision-making process. We show how an ecosystem services approach combined with economic tools, such as benefit transfer techniques, should help illuminate issues where there are direct conflicts among different industries, and between industry and conservation. We argue for baseline and monitoring measurements and metrics that inform about deep-sea ecosystem services that would be impaired by mining, and discuss ways to incorporate the value of those losses into decision making, mitigation measures, and ultimately product costs. This proposal is considered relative to current International Seabed Authority recommendations and contractor practices, and new actions are proposed. An ecosystem services-based understanding of how these systems work and their value to society can improve sustainability and stewardship of the deep ocean.

Memory in Microbes: Quantifying History-Dependent Behavior in a Bacterium

PubMed Central

Bischofs, Ilka; Price, Gavin; Keasling, Jay; Arkin, Adam P.

2008-01-01

Memory is usually associated with higher organisms rather than bacteria. However, evidence is mounting that many regulatory networks within bacteria are capable of complex dynamics and multi-stable behaviors that have been linked to memory in other systems. Moreover, it is recognized that bacteria that have experienced different environmental histories may respond differently to current conditions. These “memory” effects may be more than incidental to the regulatory mechanisms controlling acclimation or to the status of the metabolic stores. Rather, they may be regulated by the cell and confer fitness to the organism in the evolutionary game it participates in. Here, we propose that history-dependent behavior is a potentially important manifestation of memory, worth classifying and quantifying. To this end, we develop an information-theory based conceptual framework for measuring both the persistence of memory in microbes and the amount of information about the past encoded in history-dependent dynamics. This method produces a phenomenological measure of cellular memory without regard to the specific cellular mechanisms encoding it. We then apply this framework to a strain of Bacillus subtilis engineered to report on commitment to sporulation and degradative enzyme (AprE) synthesis and estimate the capacity of these systems and growth dynamics to ‘remember’ 10 distinct cell histories prior to application of a common stressor. The analysis suggests that B. subtilis remembers, both in short and long term, aspects of its cell history, and that this memory is distributed differently among the observables. While this study does not examine the mechanistic bases for memory, it presents a framework for quantifying memory in cellular behaviors and is thus a starting point for studying new questions about cellular regulation and evolutionary strategy. PMID:18324309

Optimal bioprocess design through a gene regulatory network - growth kinetic hybrid model: Towards Replacing Monod kinetics.

PubMed

Tsipa, Argyro; Koutinas, Michalis; Usaku, Chonlatep; Mantalaris, Athanasios

2018-05-02

Currently, design and optimisation of biotechnological bioprocesses is performed either through exhaustive experimentation and/or with the use of empirical, unstructured growth kinetics models. Whereas, elaborate systems biology approaches have been recently explored, mixed-substrate utilisation is predominantly ignored despite its significance in enhancing bioprocess performance. Herein, bioprocess optimisation for an industrially-relevant bioremediation process involving a mixture of highly toxic substrates, m-xylene and toluene, was achieved through application of a novel experimental-modelling gene regulatory network - growth kinetic (GRN-GK) hybrid framework. The GRN model described the TOL and ortho-cleavage pathways in Pseudomonas putida mt-2 and captured the transcriptional kinetics expression patterns of the promoters. The GRN model informed the formulation of the growth kinetics model replacing the empirical and unstructured Monod kinetics. The GRN-GK framework's predictive capability and potential as a systematic optimal bioprocess design tool, was demonstrated by effectively predicting bioprocess performance, which was in agreement with experimental values, when compared to four commonly used models that deviated significantly from the experimental values. Significantly, a fed-batch biodegradation process was designed and optimised through the model-based control of TOL Pr promoter expression resulting in 61% and 60% enhanced pollutant removal and biomass formation, respectively, compared to the batch process. This provides strong evidence of model-based bioprocess optimisation at the gene level, rendering the GRN-GK framework as a novel and applicable approach to optimal bioprocess design. Finally, model analysis using global sensitivity analysis (GSA) suggests an alternative, systematic approach for model-driven strain modification for synthetic biology and metabolic engineering applications. Copyright © 2018. Published by Elsevier Inc.

[The system of the quality control and the safety of baby food, the prospects of its development].

PubMed

Georgieva, O V; Konovalova, L S; Kon', I Ya

In the article there is considered the substantiation of raise demands to the chemical composition of children’s food and indices of their safety, with taking into account the immaturity of metabolic and physiological processes and limitations of “depot” of nutrients in babies. Based on research results of leading experts in the field of children’s nutritiology and according to the recommendations of the Codex Alimentarius of the Commission of FAO/WHO, ESPGHAN Committee on Nutrition, the EFSA recommendations and EUDirectives there were specified requirements for the ingredient composition, content of essential components and indices of the nutritional value of substitutes for human milk and functional products for the nutrition of infants of the first year of life. There are shown stages of the development of the Russian system of hygienic requirements for baby food, and the direction of its harmonization with international and European standards, particularly for substitutes for human milk and products of dietary therapeutic and dietary preventive nutrition for babies. There are considered aspects of the introduction ofproducts and weaning food dishes into the food ration of infants. There is presented the classification ofproducts of children’s food and the assortment of each group of weaning foods. There is provided the modern legislative framework in the field of the quality and safety for infant nutrition. There was shown the difference between domestic legislation and regulatory framework of the EurAsEC Customs Union of the European countries in the field offood products safety for children older three years. There are presented proposals on the creation of the single regulatory base within the framework of the EurAsEC Customs Union for control the quality and safety of all the baby foods.

PathCase-SB architecture and database design

PubMed Central

2011-01-01

Background Integration of metabolic pathways resources and regulatory metabolic network models, and deploying new tools on the integrated platform can help perform more effective and more efficient systems biology research on understanding the regulation in metabolic networks. Therefore, the tasks of (a) integrating under a single database environment regulatory metabolic networks and existing models, and (b) building tools to help with modeling and analysis are desirable and intellectually challenging computational tasks. Description PathCase Systems Biology (PathCase-SB) is built and released. The PathCase-SB database provides data and API for multiple user interfaces and software tools. The current PathCase-SB system provides a database-enabled framework and web-based computational tools towards facilitating the development of kinetic models for biological systems. PathCase-SB aims to integrate data of selected biological data sources on the web (currently, BioModels database and KEGG), and to provide more powerful and/or new capabilities via the new web-based integrative framework. This paper describes architecture and database design issues encountered in PathCase-SB's design and implementation, and presents the current design of PathCase-SB's architecture and database. Conclusions PathCase-SB architecture and database provide a highly extensible and scalable environment with easy and fast (real-time) access to the data in the database. PathCase-SB itself is already being used by researchers across the world. PMID:22070889

Toward refined environmental scenarios for ecological risk assessment of down-the-drain chemicals in freshwater environments.

PubMed

Franco, Antonio; Price, Oliver R; Marshall, Stuart; Jolliet, Olivier; Van den Brink, Paul J; Rico, Andreu; Focks, Andreas; De Laender, Frederik; Ashauer, Roman

2017-03-01

Current regulatory practice for chemical risk assessment suffers from the lack of realism in conventional frameworks. Despite significant advances in exposure and ecological effect modeling, the implementation of novel approaches as high-tier options for prospective regulatory risk assessment remains limited, particularly among general chemicals such as down-the-drain ingredients. While reviewing the current state of the art in environmental exposure and ecological effect modeling, we propose a scenario-based framework that enables a better integration of exposure and effect assessments in a tiered approach. Global- to catchment-scale spatially explicit exposure models can be used to identify areas of higher exposure and to generate ecologically relevant exposure information for input into effect models. Numerous examples of mechanistic ecological effect models demonstrate that it is technically feasible to extrapolate from individual-level effects to effects at higher levels of biological organization and from laboratory to environmental conditions. However, the data required to parameterize effect models that can embrace the complexity of ecosystems are large and require a targeted approach. Experimental efforts should, therefore, focus on vulnerable species and/or traits and ecological conditions of relevance. We outline key research needs to address the challenges that currently hinder the practical application of advanced model-based approaches to risk assessment of down-the-drain chemicals. Integr Environ Assess Manag 2017;13:233-248. © 2016 SETAC. © 2016 SETAC.

Reporting of meta-analyses of randomized controlled trials with a focus on drug safety: an empirical assessment.

PubMed

Hammad, Tarek A; Neyarapally, George A; Pinheiro, Simone P; Iyasu, Solomon; Rochester, George; Dal Pan, Gerald

2013-01-01

Due to the sparse nature of serious drug-related adverse events (AEs), meta-analyses combining data from several randomized controlled trials (RCTs) to evaluate drug safety issues are increasingly being conducted and published, influencing clinical and regulatory decision making. Evaluation of meta-analyses involves the assessment of both the individual constituent trials and the approaches used to combine them. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting framework is designed to enhance the reporting of systematic reviews and meta-analyses. However, PRISMA may not cover all critical elements useful in the evaluation of meta-analyses with a focus on drug safety particularly in the regulatory-public health setting. This work was conducted to (1) evaluate the adherence of a sample of published drug safety-focused meta-analyses to the PRISMA reporting framework, (2) identify gaps in this framework based on key aspects pertinent to drug safety, and (3) stimulate the development and validation of a more comprehensive reporting tool that incorporates elements unique to drug safety evaluation. We selected a sample of meta-analyses of RCTs based on review of abstracts from high-impact journals as well as top medical specialty journals between 2009 and 2011. We developed a preliminary reporting framework based on PRISMA with specific additional reporting elements critical for the evaluation of drug safety meta-analyses of RCTs. The reporting of pertinent elements in each meta-analysis was reviewed independently by two authors; discrepancies in the independent evaluations were resolved through discussions between the two authors. A total of 27 meta-analyses, 12 from highest impact journals, 13 from specialty medical journals, and 2 from Cochrane reviews, were identified and evaluated. The great majority (>85%) of PRISMA elements were addressed in more than half of the meta-analyses reviewed. However, the majority of meta-analyses (>60%) did not address most (>80%) of the additional reporting elements critical for the evaluation of drug safety. Some of these elements were not addressed in any of the reviewed meta-analyses. This review included a sample of meta-analyses, with a focus on drug safety, recently published in high-impact journals; therefore, we may have underestimated the extent of the reporting problem across all meta-analyses of drug safety. Furthermore, temporal trends in reporting could not be evaluated in this review because of the short time interval selected. While the majority of PRISMA elements were addressed by most studies reviewed, the majority of studies did not address most of the additional safety-related elements. These findings highlight the need for the development and validation of a drug safety reporting framework and the importance of the current initiative by the Council for International Organizations of Medical Sciences (CIOMS) to create a guidance document for drug safety information synthesis/meta-analysis, which may improve reporting, conduct, and evaluation of meta-analyses of drug safety and inform clinical and regulatory decision making.

Universal Design as a Booster for Housing Quality and Architectural Practice.

PubMed

Denizou, Karine

2016-01-01

Norwegian central government has for the last decade increasingly focused on universal design. Fundamental changes in the Norwegian building code and corresponding regulations in 2010 give an apparently clear framework for the implementation of accessibility and universal design. However, it seems that neither increased awareness of accessibility requirements and universal design, nor compliance with the building code guarantees improvement of housing quality and usability. The Norwegian regulations have gone further in the direction of performance requirements than most other countries. This applies to all types of requirements, including requirements for usability, functionality and accessibility. Hardly any specifications are to be found in the regulations. Ideally, this lack of specifications should give designers the opportunity to develop innovative answers and hence to respond to different contexts and needs. Still, many architects and builders ask for clear specifications, in order to simplify and speed up design processes and make control of solutions easier. Many architects understand guidelines as minimum requirements, and are thus reproducing the identical solutions without considering the context and the needs of the users. They see accessibility as another regulatory pressure and requirements as restrictions rather than positive incentives. However, there are examples of designers who have internalised the regulatory framework and thus are able to create and integrate inclusive design in their daily work. Based on recent research conducted by SINTEF Building and Infrastructure and financed by the Norwegian State Housing Bank, this paper presents examples of practice where dwellings have been developed within a framework of universal design. Focus of the research has been on the approach of the design team and their understanding and use of the regulatory framework in order to create better homes in dialogue with the building authorities. Main objectives are to: - Contribute to better understanding of universal design as a tool and a method to improve housing quality and usability - Investigate the conditions for developing dwellings with innovative and functional solutions in compliance with the building code - Discuss challenges in interpreting the requirements and in taking the needs of various resident groups into account.

Using Digital Health Technology to Better Generate Evidence and Deliver Evidence-Based Care.

PubMed

Sharma, Abhinav; Harrington, Robert A; McClellan, Mark B; Turakhia, Mintu P; Eapen, Zubin J; Steinhubl, Steven; Mault, James R; Majmudar, Maulik D; Roessig, Lothar; Chandross, Karen J; Green, Eric M; Patel, Bakul; Hamer, Andrew; Olgin, Jeffrey; Rumsfeld, John S; Roe, Matthew T; Peterson, Eric D

2018-06-12

As we enter the information age of health care, digital health technologies offer significant opportunities to optimize both clinical care delivery and clinical research. Despite their potential, the use of such information technologies in clinical care and research faces major data quality, privacy, and regulatory concerns. In hopes of addressing both the promise and challenges facing digital health technologies in the transformation of health care, we convened a think tank meeting with academic, industry, and regulatory representatives in December 2016 in Washington, DC. In this paper, we summarize the proceedings of the think tank meeting and aim to delineate a framework for appropriately using digital health technologies in healthcare delivery and research. Copyright © 2018 American College of Cardiology Foundation. All rights reserved.

Autologous cell therapies: challenges in US FDA regulation.

PubMed

McAllister, Todd N; Audley, David; L'Heureux, Nicolas

2012-11-01

Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare, yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry, examples of clinical and commercial success are still relatively rare. With 30 years of laboratory and clinical efforts fueled by countless billions in public and private funding, one must contemplate why CBTs have not made a greater impact. The current regulatory environment, with its zero-risk stance, stymies clinical innovation while fueling a potentially risky medical tourism industry. Here, we highlight the challenges the US FDA faces and present talking points for an improved regulatory framework for autologous CBTs.

A Framework for Human Performance Criteria for Advanced Reactor Operational Concepts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacques V Hugo; David I Gertman; Jeffrey C Joe

2014-08-01

This report supports the determination of new Operational Concept models needed in support of the operational design of new reactors. The objective of this research is to establish the technical bases for human performance and human performance criteria frameworks, models, and guidance for operational concepts for advanced reactor designs. The report includes a discussion of operating principles for advanced reactors, the human performance issues and requirements for human performance based upon work domain analysis and current regulatory requirements, and a description of general human performance criteria. The major findings and key observations to date are that there is some operatingmore » experience that informs operational concepts for baseline designs for SFR and HGTRs, with the Experimental Breeder Reactor-II (EBR-II) as a best-case predecessor design. This report summarizes the theoretical and operational foundations for the development of a framework and model for human performance criteria that will influence the development of future Operational Concepts. The report also highlights issues associated with advanced reactor design and clarifies and codifies the identified aspects of technology and operating scenarios.« less

Regulatory constraints as seen from the pharmaceutical industry.

PubMed

Galligani, G; David-Andersen, I; Fossum, B

2005-01-01

In Chile, Canada, Europe, Japan, and the USA, which are the main geographical areas for fish farming of high value fish such as salmonids, sea bass, sea bream, yellowtail and catfish, vaccination has been established as an important method for the prevention of infectious diseases. To make new vaccines available to the fish farming industry, pharmaceutical companies must comply with the regulatory framework for licensing of fish vaccines, which in recent years has become more regulated. Considerable scientific and regulatory skills are thus required to develop, document and license vaccines in accordance with the requirements in the different geographical areas. International co-operation to harmonise requirements for the licensing documentation is ongoing. Even though there are obvious benefits to the pharmaceutical industry from the harmonisation process, it may sometimes impose unreasonable requirements. The regulatory framework for fish vaccines clearly has an impact on the time for bringing a new fish vaccine to the market. Several hurdles need to be passed to complete the regulatory process, i.e. obtain a licence. Fulfilment of the rather detailed and extensive requirements for documentation of the production and controls, as well as safety and efficacy of the vaccine, represent a challenge to the pharmaceutical industry, as do the different national and regional licensing procedures. This paper describes regulatory constraints related to the documentation, the licensing process, the site of production and the continuing international harmonisation work, with emphasis on inactivated conventional fish vaccines.

Protecting workers and the environment: An environmental NGO's perspective on nanotechnology

NASA Astrophysics Data System (ADS)

Balbus, John M.; Florini, Karen; Denison, Richard A.; Walsh, Scott A.

2007-01-01

Nanotechnology, the design and manipulation of materials at the atomic scale, may well revolutionize many of the ways our society manufactures products, produces energy, and treats diseases. New materials based on nanotechnology are already reaching the market in a wide variety of consumer products. Some of the observed properties of nanomaterials call into question the adequacy of current methods for determining hazard and exposure and for controlling resulting risks. Given the limitations of existing regulatory tools and policies, we believe two distinct kinds of initiatives are needed: first, a major increase in the federal investment in nanomaterial risk research; second, rapid development and implementation of voluntary standards of care pending development of adequate regulatory safeguards in the longer term. Several voluntary programs are currently at various stages of evolution, though the eventual outputs of each of these are still far from clear. Ultimately, effective regulatory safeguards are necessary to provide a level playing field for industry while adequately protecting human health and the environment. This paper reviews the existing toxicological literature on nanomaterials, outlines and analyzes the current regulatory framework, and provides our recommendations, as an environmental non-profit organization, for safe nanotechnology development.

Federal/State Regulatory Enhancement, Cost Allocation, and CATV/TELCO Distance Learning Initiatives in Connecticut.

ERIC Educational Resources Information Center

Pietras, Jesse John

Connecticut has adopted a moderate approach to communications infrastructure modernization, covering a 4-year implementation period from 1993 to 1996. The state's remote educational framework, with regulatory enhancements, will allow the state to be technologically competitive with neighboring states as it allows subscribers to use evolving…

77 FR 45700 - Advisory Committee On Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee On Fukushima...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-01

... NUCLEAR REGULATORY COMMISSION Advisory Committee On Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee On Fukushima; Notice of Meeting The ACRS Subcommittee on Fukushima will hold a meeting on August... Fukushima Near Term Task Force (NTTF) Recommendation 1: Enhanced Regulatory Framework. The Subcommittee will...

CONSIDERATIONS FOR A REGULATORY FRAMEWORK FOR LARGE-SCALE GEOLOGIC SEQUESTRATION OF CARBON DIOXIDE: A NORTH AMERICAN PERSPECTIVE

EPA Science Inventory

Large scale geologic sequestration (GS) of carbon dioxide poses a novel set of challenges for regulators. This paper focuses on the unique needs of large scale GS projects in light of the existing regulatory regimes in the United States and Canada and identifies several differen...

Self-Regulatory Climate: A Positive Attribute of Public Schools

ERIC Educational Resources Information Center

Adams, Curt M.; Ware, Jordan K.; Miskell, Ryan C.; Forsyth, Patrick B.

2016-01-01

This study contributes to the development of a positive framework for effective public schools in 2 ways. First, it advances the construct self-regulatory climate as consisting of 3 generative school norms--collective faculty trust in students, collective student trust in teachers, and student-perceived academic emphasis. The authors argue these…

An audit of implant practice websites: content and regulatory compliance.

PubMed

Raimundo, H; Robinson, P K

2014-12-01

To audit the content of dental practice websites offering dental implant services against a framework based on the GDC 2012 Guidelines for Ethical Advertising and other relevant advertising standards. An audit framework was constructed and applied to the top fifty websites resulting from a Google UK search using the search term 'dental implant specialist'. Compliance with many elements of the GDC Guidance remains poor. Sixty-eight percent of websites claimed that the practitioner providing the service was a GDC registered specialist, though examples were found where this claim was unfounded. Fourteen percent of practice websites claimed that the service was being carried out by an 'implant specialist' and 16% claimed the practitioner was an 'implantologist'; the majority of sites using these terms (10%) involved practitioners that had no specialist status. The display of potentially misleading memberships and fellowships of a range of dental associations, academies, societies and foundations remains common (52%), as does the adoption of the title 'Dr' (60%). Comparison with earlier studies indicates that compliance with recent GDC standards is generally improving, though whether the pace of improvement is seen as acceptable or not is something that policymakers and regulatory authorities may need to consider further.

Multi-scale genetic dynamic modelling I : an algorithm to compute generators.

PubMed

Kirkilionis, Markus; Janus, Ulrich; Sbano, Luca

2011-09-01

We present a new approach or framework to model dynamic regulatory genetic activity. The framework is using a multi-scale analysis based upon generic assumptions on the relative time scales attached to the different transitions of molecular states defining the genetic system. At micro-level such systems are regulated by the interaction of two kinds of molecular players: macro-molecules like DNA or polymerases, and smaller molecules acting as transcription factors. The proposed genetic model then represents the larger less abundant molecules with a finite discrete state space, for example describing different conformations of these molecules. This is in contrast to the representations of the transcription factors which are-like in classical reaction kinetics-represented by their particle number only. We illustrate the method by considering the genetic activity associated to certain configurations of interacting genes that are fundamental to modelling (synthetic) genetic clocks. A largely unknown question is how different molecular details incorporated via this more realistic modelling approach lead to different macroscopic regulatory genetic models which dynamical behaviour might-in general-be different for different model choices. The theory will be applied to a real synthetic clock in a second accompanying article (Kirkilioniset al., Theory Biosci, 2011).

Accessing the medical devices market in Egypt and Saudi Arabia: a systematic review of policies and regulations.

PubMed

Gad, Mohamed; Kriza, Christine; Fidler, Armin; Kolominsky-Rabas, Peter

2016-07-01

Despite the significant medical devices market size in Egypt and Saudi Arabia, information regarding policies and regulations for medical devices market access is highly deficient. The aim of this paper is to provide a systematic review on market access policies and regulations in both countries, to allow safe and timely access to medical technology. The following databases were searched: PubMed, Science Direct, Scopus, and Al Manhal Arabic database. Additionally, the web portals of regulatory authorities of both countries were searched. There are 34 records included in the qualitative synthesis of this review. Expert commentary: Main findings include; adopted regulatory framework from reference countries, and interim main regulatory documents, In conclusion, the market access schemes are relatively structured. However, some recommendations are put forward to navigate towards a more comprehensive policy framework in both countries.

RCRA, superfund and EPCRA hotline training module. Introduction to: RCRA corrective action updated July 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1996-07-01

The module discusses the regulatory and statutory requirements and authorities governing the Resource Conservation and Recovery Act (RCRA) corrective action process. There are minimal regulatory requirements at present, but the Agency has issued a proposed rule (55 FR 30798; July 27, 1990) that would establish a comprehensive regulatory framework for implementing the corrective action program. This proposed rule and other guidance developed pursuant to statutory authorities are used to structure corrective action requirements in facility permits and orders. This module describes the current statutory and regulatory structure and discusses the future of the proposed rule.

Abalone farm discharges the withering syndrome pathogen into the wild

PubMed Central

Lafferty, Kevin D.; Ben-Horin, Tal

2013-01-01

An intracellular bacterium Candidatus Xenohaliotis californiensis, also called Withering-Syndrome Rickettsia-Like Organism (WS-RLO), is the cause of mass mortalities that are the chief reason for endangerment of black abalone (Haliotis cracherodii). Using a real-time PCR assay, we found that a shore-based abalone farm (AF) in Santa Barbara, CA, USA discharged WS-RLO DNA into the ocean. Several other shore-based AFs discharge effluent into critical habitat for black abalone in California and this might affect the recovery of wild black abalone. Existing regulatory frameworks exist that could help protect wild species from pathogens released from shore-based aquaculture. PMID:24367359

Abalone farm discharges the withering syndrome pathogen into the wild.

PubMed

Lafferty, Kevin D; Ben-Horin, Tal

2013-01-01

An intracellular bacterium Candidatus Xenohaliotis californiensis, also called Withering-Syndrome Rickettsia-Like Organism (WS-RLO), is the cause of mass mortalities that are the chief reason for endangerment of black abalone (Haliotis cracherodii). Using a real-time PCR assay, we found that a shore-based abalone farm (AF) in Santa Barbara, CA, USA discharged WS-RLO DNA into the ocean. Several other shore-based AFs discharge effluent into critical habitat for black abalone in California and this might affect the recovery of wild black abalone. Existing regulatory frameworks exist that could help protect wild species from pathogens released from shore-based aquaculture.

Abalone farm discharges the withering syndrome pathogen into the wild

USGS Publications Warehouse

Lafferty, Kevin D.; Ben-Horin, Tal

2014-01-01

An intracellular bacterium Candidatus Xenohaliotis californiensis, also called Withering-Syndrome Rickettsia-Like Organism (WS-RLO), is the cause of mass mortalities that are the chief reason for endangerment of black abalone (Haliotis cracherodii). Using a real-time PCR assay, we found that a shore-based abalone farm (AF) in Santa Barbara, CA, USA discharged WS-RLO DNA into the ocean. Several other shore-based AFs discharge effluent into critical habitat for black abalone in California and this might affect the recovery of wild black abalone. Existing regulatory frameworks exist that could help protect wild species from pathogens released from shore-based aquaculture.

Generation of Diverse Biological Forms through Combinatorial Interactions between Tissue Polarity and Growth

PubMed Central

Kennaway, Richard; Coen, Enrico; Green, Amelia; Bangham, Andrew

2011-01-01

A major problem in biology is to understand how complex tissue shapes may arise through growth. In many cases this process involves preferential growth along particular orientations raising the question of how these orientations are specified. One view is that orientations are specified through stresses in the tissue (axiality-based system). Another possibility is that orientations can be specified independently of stresses through molecular signalling (polarity-based system). The axiality-based system has recently been explored through computational modelling. Here we develop and apply a polarity-based system which we call the Growing Polarised Tissue (GPT) framework. Tissue is treated as a continuous material within which regionally expressed factors under genetic control may interact and propagate. Polarity is established by signals that propagate through the tissue and is anchored in regions termed tissue polarity organisers that are also under genetic control. Rates of growth parallel or perpendicular to the local polarity may then be specified through a regulatory network. The resulting growth depends on how specified growth patterns interact within the constraints of mechanically connected tissue. This constraint leads to the emergence of features such as curvature that were not directly specified by the regulatory networks. Resultant growth feeds back to influence spatial arrangements and local orientations of tissue, allowing complex shapes to emerge from simple rules. Moreover, asymmetries may emerge through interactions between polarity fields. We illustrate the value of the GPT-framework for understanding morphogenesis by applying it to a growing Snapdragon flower and indicate how the underlying hypotheses may be tested by computational simulation. We propose that combinatorial intractions between orientations and rates of growth, which are a key feature of polarity-based systems, have been exploited during evolution to generate a range of observed biological shapes. PMID:21698124

Professionalism in Vocational Education: International Perspectives

ERIC Educational Resources Information Center

Atkins, Liz; Tummons, Jonathan

2017-01-01

This paper explores notions of professionalism amongst vocational teachers in the United Kingdom and Australia, through an analysis of voluntarism/regulatory frameworks and professional body frameworks. In terms of empirical evidence, the paper reports on data drawn from a documentary analysis of government policy documents, standards for the…

The OECD Fish Testing Framework Project

EPA Science Inventory

OECD Project 2.30 on a Fish Testing Framework was initiated in mid-2009, with the United States as the lead country. The objectives of the project are to review the regulatory needs and data requirements for fish testing and review the currency of existing OECD Test Guidelines. ...

NEWS RELEASE - Agencies Agree to Joint Regulatory Framework for Processing Applications for Surface Coal Mining Operations

EPA Pesticide Factsheets

News release from February 10, 2005 announcing a memorandum of understanding (MOU) that offers a joint framework to improve permit application procedures for surface coal mining operations that place dredged or fill material in waters of the United States.

A Framework for Measuring the Economic Benefits of Ground Water (1995)

EPA Pesticide Factsheets

The primary goal of this 1995 report is to develop a framework for assessing the economic value of ground water that is applicable to all offices within U.S. EPA that consider the value of ground water resources when conducting Regulatory Impact Analyses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kobos, Peter Holmes; Malczynski, Leonard A.; Walker, La Tonya Nicole

People save for retirement throughout their career because it is virtually impossible to save all you’ll need in retirement the year before you retire. Similarly, without installing incremental amounts of clean fossil, renewable or transformative energy technologies throughout the coming decades, a radical and immediate change will be near impossible the year before a policy goal is set to be in place. This notion of steady installation growth over acute installations of technology to meet policy goals is the core topic of discussion for this research. This research operationalizes this notion by developing the theoretical underpinnings of regulatory and marketmore » acceptance delays by building upon the common Technology Readiness Level (TRL) framework and offers two new additions to the research community. The new and novel Regulatory Readiness Level (RRL) and Market Readiness Level (MRL) frameworks were developed. These components, collectively called the Technology, Regulatory and Market (TRM) readiness level framework allow one to build new constraints into existing Integrated Assessment Models (IAMs) to address research questions such as, ‘To meet our desired technical and policy goals, what are the factors that affect the rate we must install technology to achieve these goals in the coming decades?’« less

Tiered Approach to Resilience Assessment.

PubMed

Linkov, Igor; Fox-Lent, Cate; Read, Laura; Allen, Craig R; Arnott, James C; Bellini, Emanuele; Coaffee, Jon; Florin, Marie-Valentine; Hatfield, Kirk; Hyde, Iain; Hynes, William; Jovanovic, Aleksandar; Kasperson, Roger; Katzenberger, John; Keys, Patrick W; Lambert, James H; Moss, Richard; Murdoch, Peter S; Palma-Oliveira, Jose; Pulwarty, Roger S; Sands, Dale; Thomas, Edward A; Tye, Mari R; Woods, David

2018-04-25

Regulatory agencies have long adopted a three-tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies. Published 2018. This article is a U.S. government work and is in the public domain in the USA.

Toward the framework and implementation for clearance of materials from regulated facilities.

PubMed

Chen, S Y; Moeller, D W; Dornsife, W P; Meyer, H R; Lamastra, A; Lubenau, J O; Strom, D J; Yusko, J G

2005-08-01

The disposition of solid materials from nuclear facilities has been a subject of public debate for several decades. The primary concern has been the potential health effects resulting from exposure to residual radioactive materials to be released for unrestricted use. These debates have intensified in the last decade as many regulated facilities are seeking viable management decisions on the disposition of the large amounts of materials potentially containing very low levels of residual radioactivity. Such facilities include the nuclear weapons complex sites managed by the U.S. Department of Energy, commercial power plants licensed by the U.S. Nuclear Regulatory Commission (NRC), and other materials licensees regulated by the NRC or the Agreement States. Other facilities that generate radioactive material containing naturally occurring radioactive materials (NORM) or technologically enhanced NORM (TENORM) are also seeking to dispose of similar materials that may be radioactively contaminated. In contrast to the facilities operated by the DOE and the nuclear power plants licensed by the U.S. Nuclear Regulatory Commission, NORM and TENORM facilities are regulated by the individual states. Current federal laws and regulations do not specify criteria for releasing these materials that may contain residual radioactivity of either man-made or natural origin from regulatory controls. In fact, the current regulatory scheme offers no explicit provision to permit materials being released as "non-radioactive," including those that are essentially free of contamination. The only method used to date with limited success has been case-by-case evaluation and approval. In addition, there is a poorly defined and inconsistent regulatory framework for regulating NORM and TENORM. Some years ago, the International Atomic Energy Agency introduced the concept of clearance, that is, controlling releases of any such materials within the regulatory domain. This paper aims to clarify clearance as an important disposition option for solid materials, establish the framework and basis of release, and discuss resolutions regarding the implementation of such a disposition option.

Risk-Based Contaminated Land Investigation and Assessment

NASA Astrophysics Data System (ADS)

Davis, Donald R.

With increasing frequency, problems of environmental contamination are being analyzed from a risk perspective. Risk-Based Contaminated Land Investigation and Assessment is written for those who wish to present the results of their examination of contaminated land in terms of risk.The opening chapters introduce the concepts of risk analysis for contaminated land. Risk management and the risk assessment process are based on a source-pathway-target framework. Readers are warned against an “over-reliance on the identification of contaminants rather than the potential pathways by which targets may be exposed to these hazards.” In the risk management framework presented in this book, risk evaluation and resultant decision making are seen as part of both the risk assessment and risk reduction process. The sharp separation of risk assessment from risk management as seen in the National Academy of Sciences' (NAS) risk assessment paradigm is not advocatedsemi; perhaps this is because the NAS' concern was regulatory decision while the book's concern is the assessment of a specific site.

Regulatory assessment of chemical mixtures: Requirements, current approaches and future perspectives.

PubMed

Kienzler, Aude; Bopp, Stephanie K; van der Linden, Sander; Berggren, Elisabet; Worth, Andrew

2016-10-01

This paper reviews regulatory requirements and recent case studies to illustrate how the risk assessment (RA) of chemical mixtures is conducted, considering both the effects on human health and on the environment. A broad range of chemicals, regulations and RA methodologies are covered, in order to identify mixtures of concern, gaps in the regulatory framework, data needs, and further work to be carried out. Also the current and potential future use of novel tools (Adverse Outcome Pathways, in silico tools, toxicokinetic modelling, etc.) in the RA of combined effects were reviewed. The assumptions made in the RA, predictive model specifications and the choice of toxic reference values can greatly influence the assessment outcome, and should therefore be specifically justified. Novel tools could support mixture RA mainly by providing a better understanding of the underlying mechanisms of combined effects. Nevertheless, their use is currently limited because of a lack of guidance, data, and expertise. More guidance is needed to facilitate their application. As far as the authors are aware, no prospective RA concerning chemicals related to various regulatory sectors has been performed to date, even though numerous chemicals are registered under several regulatory frameworks. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation

PubMed Central

Portales-Casamar, Elodie; Kirov, Stefan; Lim, Jonathan; Lithwick, Stuart; Swanson, Magdalena I; Ticoll, Amy; Snoddy, Jay; Wasserman, Wyeth W

2007-01-01

PAZAR is an open-access and open-source database of transcription factor and regulatory sequence annotation with associated web interface and programming tools for data submission and extraction. Curated boutique data collections can be maintained and disseminated through the unified schema of the mall-like PAZAR repository. The Pleiades Promoter Project collection of brain-linked regulatory sequences is introduced to demonstrate the depth of annotation possible within PAZAR. PAZAR, located at , is open for business. PMID:17916232

PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation.

PubMed

Portales-Casamar, Elodie; Kirov, Stefan; Lim, Jonathan; Lithwick, Stuart; Swanson, Magdalena I; Ticoll, Amy; Snoddy, Jay; Wasserman, Wyeth W

2007-01-01

PAZAR is an open-access and open-source database of transcription factor and regulatory sequence annotation with associated web interface and programming tools for data submission and extraction. Curated boutique data collections can be maintained and disseminated through the unified schema of the mall-like PAZAR repository. The Pleiades Promoter Project collection of brain-linked regulatory sequences is introduced to demonstrate the depth of annotation possible within PAZAR. PAZAR, located at http://www.pazar.info, is open for business.

Regulatory frameworks for mobile medical applications.

PubMed

Censi, Federica; Mattei, Eugenio; Triventi, Michele; Calcagnini, Giovanni

2015-05-01

A mobile application (app) is a software program that runs on mobile communication devices such as a smartphone. The concept of a mobile medical app has gained popularity and diffusion but its reference regulatory context has raised discussion and concerns. Theoretically, a mobile app can be developed and uploaded easily by any person or entity. Thus, if an app can have some effects on the health of the users, it is mandatory to identify its reference regulatory context and the applicable prescriptions.

Enhancing Tissue Engineering and Regenerative Medicine Product Commercialization: The Role of Science in Regulatory Decision-Making for the TE/RM Product Development.

PubMed

Bertram, Timothy A; Johnson, Peter C; Tawil, Bill J; Van Dyke, Mark; Hellman, Kiki B

2015-10-01

TERMIS-AM Industry Committee (TERMIS-AM/IC), in collaboration with the TERMIS-Europe (EU)/IC, conducted a symposium involving the European Medicines Agency and the U.S. Food and Drug Administration (FDA) toward building an understanding of the rational basis for regulatory decision-making and providing a framework for decisions made during the evaluation of safety and efficacy of TE/RM technologies. This symposium was held in August 2012 during the TERMIS-WC in Vienna, Austria. Emerging from this international initiative by the European Union and the United States, representatives from the respective agencies demonstrated that there are ongoing interagency efforts for developing common national practices toward harmonization of regulatory requirements for the TE/RM products. To extend a broad-based understanding of the role of science in regulatory decision-making, TERMIS-AM/IC, in cooperation with the FDA, organized a symposium at the 2014 TERMIS-AM Annual Meeting, which was held in Washington, DC. This event provided insights from leaders in the FDA and TERMIS on the current status of regulatory approaches for the approved TE/RM products, the use of science in making regulatory decisions, and TE/RM technologies that are in the development pipeline to address unmet medical needs. A far-ranging discussion with FDA representatives, industrialists, physicians, regenerative medicine biologists, and tissue engineers considered the gaps in today's scientific and regulatory understanding of TE/RM technologies. The identified gaps represent significant opportunities to advance TE/RM technologies toward commercialization.

Reconstructing Mammalian Sleep Dynamics with Data Assimilation

PubMed Central

Sedigh-Sarvestani, Madineh; Schiff, Steven J.; Gluckman, Bruce J.

2012-01-01

Data assimilation is a valuable tool in the study of any complex system, where measurements are incomplete, uncertain, or both. It enables the user to take advantage of all available information including experimental measurements and short-term model forecasts of a system. Although data assimilation has been used to study other biological systems, the study of the sleep-wake regulatory network has yet to benefit from this toolset. We present a data assimilation framework based on the unscented Kalman filter (UKF) for combining sparse measurements together with a relatively high-dimensional nonlinear computational model to estimate the state of a model of the sleep-wake regulatory system. We demonstrate with simulation studies that a few noisy variables can be used to accurately reconstruct the remaining hidden variables. We introduce a metric for ranking relative partial observability of computational models, within the UKF framework, that allows us to choose the optimal variables for measurement and also provides a methodology for optimizing framework parameters such as UKF covariance inflation. In addition, we demonstrate a parameter estimation method that allows us to track non-stationary model parameters and accommodate slow dynamics not included in the UKF filter model. Finally, we show that we can even use observed discretized sleep-state, which is not one of the model variables, to reconstruct model state and estimate unknown parameters. Sleep is implicated in many neurological disorders from epilepsy to schizophrenia, but simultaneous observation of the many brain components that regulate this behavior is difficult. We anticipate that this data assimilation framework will enable better understanding of the detailed interactions governing sleep and wake behavior and provide for better, more targeted, therapies. PMID:23209396

Consultation: Professional Learning Framework for the Teaching Profession.

ERIC Educational Resources Information Center

Ontario College of Teachers, Toronto.

This publication describes the professional learning framework for teaching that was developed by the Ontario College of Teachers, a self-regulatory body for the teaching profession in Ontario. The Ontario College of Teachers has a mandate, in legislation, to identify and accredit professional learning programs that support standards of practice…

The OECD Fish Testing Framework Project: Summary of Workshop Recommendations

EPA Science Inventory

An integrated Fish Testing Framework was initiated in mid-2009 as OECD Project 2.30 with the United States as the lead country. The objectives of the project were to review the regulatory needs and data requirements for fish testing and review the currency of existing OECD Test ...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tweedie, A.; Doris, E.

Establishing interconnection to the grid is a recognized barrier to the deployment of distributed energy generation. This report compares interconnection processes for photovoltaic projects in California and Germany. This report summarizes the steps of the interconnection process for developers and utilities, the average length of time utilities take to process applications, and paperwork required of project developers. Based on a review of the available literature, this report finds that while the interconnection procedures and timelines are similar in California and Germany, differences in the legal and regulatory frameworks are substantial.

Cancer drug development and the evolving regulatory framework for companion diagnostics in the European union.

PubMed

Pignatti, Francesco; Ehmann, Falk; Hemmings, Robert; Jonsson, Bertil; Nuebling, Micha; Papaluca-Amati, Marisa; Posch, Martin; Rasi, Guido

2014-03-15

The European Union (EU) legal framework for medical device regulation is currently under revision. The European Commission has proposed a new framework to ensure that medical devices serve the needs and ensure the safety of European citizens, aiming for a framework that is fit for purpose, more transparent, and better adapted to scientific and technological progress. The proposed new framework is described as an evolution of the current regime keeping the same legal approach. An important proposed change is that companion diagnostics will no longer be considered as low risk and subject to self-certification by the manufacturer. According to the new proposal, companion diagnostics will be classified as high individual risk or moderate public health risk (category C) and require conformity assessment by a notified body. It has also been proposed that evidence of the clinical utility of the device for the intended purpose should be required for companion diagnostics. In this article, we review the EU legal framework relevant for companion diagnostics, describe the proposed changes, and summarize the available scientific guidance from the European Medicines Agency and its regulatory experience with cancer drug development including companion diagnostics. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development." ©2014 AACR.

The Pollution Game: A Classroom Game Demonstrating the Relative Effectiveness of Emissions Taxes and Tradable Permits

ERIC Educational Resources Information Center

Corrigan, Jay R.

2011-01-01

This classroom game illustrates the strengths and weaknesses of various regulatory frameworks aimed at internalizing negative externalities from pollution. Specifically, the game divides students into three groups--a government regulatory agency and two polluting firms--and allows them to work through a system of uniform command-and-control…

"Body Work--Regulation of a Swimmer Body": An Autoethnography from an Australian Elite Swimmer

ERIC Educational Resources Information Center

McMahon, Jenny; DinanThompson, Maree

2011-01-01

This paper contributes to studies on sociology and the body by exploring my bodily experiences as an Australian elite swimmer in an autoethnographic framework. More specifically, it focuses on the relationship between the regulatory practices of others on my body and my development of self-regulatory practices. The stories in this paper reveal…

[European Marketing Authorisation: a long process. Experiences of small biotech companies with the ATMP regulation].

PubMed

Buljovčić, Z

2011-07-01

On 30 December 2008, the Regulation (EC) 1394/2007 on advanced therapy medicinal products (ATMPs) entered into force. Herewith the first EU-wide regulatory framework for ATMPs was established. It requires a central marketing authorisation application to the EMA (European Medicinal Agency). This new framework especially changes the code of regulatory practice for tissue engineered products (TEPs), as no registration procedure had been previously required for autologous TEPs. This also meant that no clinical proof of efficacy achieved by a pivotal clinical trial was necessary. Difficulties and their background as well as the vast requirements for product development that have to be addressed by small companies within a very short time frame are presented. Hereby, it is obvious that regulatory experience which is required to identify and implement the resulting implications was not in place yet and still had to be established. The lack of regulatory experience also resulted in difficulties with scientific advice preparation, expectations toward regulatory agencies, consultants, and transformation of regulatory requirements. Addressing the regulatory requirements within the transition period is even more difficult for entrepreneurs with products which are assigned for indications resulting in complex challenges to the trial design. Due to the enormous time pressure to generate data and due to the implied financial pressure, different adaptation strategies are evolving. In Germany the "hospital exemption" according to §4b AMG (German Medicinal Products Law) is of major importance. A reorientation toward acellular products and a slow down in development of new ATMP products is expected.

Societal challenges of precision medicine: Bringing order to chaos.

PubMed

Salgado, Roberto; Moore, Helen; Martens, John W M; Lively, Tracy; Malik, Shakun; McDermott, Ultan; Michiels, Stefan; Moscow, Jeffrey A; Tejpar, Sabine; McKee, Tawnya; Lacombe, Denis

2017-10-01

The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th-9th September 2016, Brussels, Belgium). Copyright © 2017 Elsevier Ltd. All rights reserved.

Unmanned Aircraft Hazards and their Implications for Regulation

NASA Technical Reports Server (NTRS)

Hayhurst, Kelly J.; Maddalon, Jeffrey M.; Miner, Paul S.; DeWalt, Michael P.; McCormick, G. Frank

2006-01-01

Use of unmanned aircraft systems (UASs) has been characterized as the next great step forward in the evolution of civil aviation. Indeed, UASs are in limited civil use in the United States today, and many believe that the time is rapidly approaching when they will move into the commercial marketplace, too. To make this a reality, a number of challenges must be overcome to develop the necessary regulatory framework for assuring safe operation of this special class of aircraft. This paper discusses some of what must be done to establish that framework. In particular, we examine hazards specific to the design, operation, and flight crew of UASs, and discuss implications of these hazards for existing policy and guidance. Understanding unique characteristics of UASs that pose new hazards is essential to developing a cogent argument, and the corresponding regulatory framework, for safely integrating these aircraft into civil airspace.

Reverse engineering of logic-based differential equation models using a mixed-integer dynamic optimization approach

PubMed Central

Henriques, David; Rocha, Miguel; Saez-Rodriguez, Julio; Banga, Julio R.

2015-01-01

Motivation: Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. Results: In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cells. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: julio@iim.csic.es or saezrodriguez@ebi.ac.uk PMID:26002881

Reverse engineering of logic-based differential equation models using a mixed-integer dynamic optimization approach.

PubMed

Henriques, David; Rocha, Miguel; Saez-Rodriguez, Julio; Banga, Julio R

2015-09-15

Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cells. Supplementary data are available at Bioinformatics online. julio@iim.csic.es or saezrodriguez@ebi.ac.uk. © The Author 2015. Published by Oxford University Press.

Genetically modified organisms: an analysis of the regulatory framework currently employed within the European Union.

PubMed

Gent, R N

1999-09-01

Genetic engineering technology is starting to bring many commercial products to the market. These genetically modified organisms (GMOs) and their derived products are subject to topical debate as to their benefits and risks. The strengths and weaknesses of the regulatory framework that controls their development and application is central to the question of whether this technology poses significant risk to the public health during this critical phase of its evolution. A critical review was carried out of the legal framework regulating the contained use, deliberate release and some aspects of consumer protection relevant to the control of GMOs in Europe and the United Kingdom. The current legal framework is failing to provide a speed of adaptation commensurate with the development of the science of genetic engineering; failing to properly respond to democratic control; failing to resolve significant conflict between the protection of free markets and protection of public health and the environment; and failing to implement obligations on biodiversity. The present legal framework must be replaced. Current European Union proposals for new standards of regulation are welcome, but provide only for further incremental change, and do not address some significant fundamental flaws in our current laws.

Comparative Human Health Impact Assessment of Engineered Nanomaterials in the Framework of Life Cycle Assessment.

PubMed

Fransman, Wouter; Buist, Harrie; Kuijpers, Eelco; Walser, Tobias; Meyer, David; Zondervan-van den Beuken, Esther; Westerhout, Joost; Klein Entink, Rinke H; Brouwer, Derk H

2017-07-01

For safe innovation, knowledge on potential human health impacts is essential. Ideally, these impacts are considered within a larger life-cycle-based context to support sustainable development of new applications and products. A methodological framework that accounts for human health impacts caused by inhalation of engineered nanomaterials (ENMs) in an indoor air environment has been previously developed. The objectives of this study are as follows: (i) evaluate the feasibility of applying the CF framework for NP exposure in the workplace based on currently available data; and (ii) supplement any resulting knowledge gaps with methods and data from the life cycle approach and human risk assessment (LICARA) project to develop a modified case-specific version of the framework that will enable near-term inclusion of NP human health impacts in life cycle assessment (LCA) using a case study involving nanoscale titanium dioxide (nanoTiO 2 ). The intent is to enhance typical LCA with elements of regulatory risk assessment, including its more detailed measure of uncertainty. The proof-of-principle demonstration of the framework highlighted the lack of available data for both the workplace emissions and human health effects of ENMs that is needed to calculate generalizable characterization factors using common human health impact assessment practices in LCA. The alternative approach of using intake fractions derived from workplace air concentration measurements and effect factors based on best-available toxicity data supported the current case-by-case approach for assessing the human health life cycle impacts of ENMs. Ultimately, the proposed framework and calculations demonstrate the potential utility of integrating elements of risk assessment with LCA for ENMs once the data are available. © 2016 Society for Risk Analysis.

Timing is everything :

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kobos, Peter Holmes; Walker, La Tonya Nicole; Malczynski, Leonard A.

People save for retirement throughout their career because it is virtually impossible to save all youll need in retirement the year before you retire. Similarly, without installing incremental amounts of clean fossil, renewable or transformative energy technologies throughout the coming decades, a radical and immediate change will be near impossible the year before a policy goal is set to be in place. Therefore, our research question is, To meet our desired technical and policy goals, what are the factors that affect the rate we must install technology to achieve these goals in the coming decades? Existing models do not includemore » full regulatory constraints due to their often complex, and inflexible approaches to solve for optimal engineering instead of robust and multidisciplinary solutions. This project outlines the theory and then develops an applied software tool to model the laboratory-to-market transition using the traditional technology readiness level (TRL) framework, but develops subsequent and a novel regulatory readiness level (RRL) and market readiness level (MRL). This tool uses the ideally-suited system dynamics framework to incorporate feedbacks and time delays. Future energy-economic-environment models, regardless of their programming platform, may adapt this software model component framework or module to further vet the likelihood of new or innovative technology moving through the laboratory, regulatory and market space. The prototype analytical framework and tool, called the Technology, Regulatory and Market Readiness Level simulation model (TRMsim) illustrates the interaction between technology research, application, policy and market dynamics as they relate to a new or innovative technology moving from the theoretical stage to full market deployment. The initial results that illustrate the models capabilities indicate for a hypothetical technology, that increasing the key driver behind each of the TRL, RRL and MRL components individually decreases the time required for the technology to progress through each component by 63, 68 and 64%, respectively. Therefore, under the current working assumptions, to decrease the time it may take for a technology to move from the conceptual stage to full scale market adoption one might consider expending additional effort to secure regulatory approval and reducing the uncertainty of the technologys demand in the marketplace.« less

The interaction between intellectual property and drug regulatory systems: global perspectives.

PubMed

Madden, Edward A

2007-02-01

Regulatory compliance in the development, production and sale of new drugs accounts for the largest single expense in bringing a drug product to market. To justify developmental and regulatory compliance costs, drug innovators turn to the intellectual property (IP) system to provide a means for securing returns on investment. Because the drug regulatory system in most countries operates in isolation of the IP system, one of the greatest challenges facing the pharmaceutical industry is the extent to which IP rights can be managed against an independent drug regulatory system. Many regulatory bodies in developed countries have sought to ensure a compromise between the rights of generic companies and IP owners by including safeguards in the regulatory framework, such as patent linking and data protection; however, these efforts are yet to be applied in some of the biggest potential drug markets in emerging economies.

Revolution or evolution: the challenges of conceptualizing patient and public involvement in a consumerist world

PubMed Central

Tritter, Jonathan Q.

2009-01-01

Abstract Background  Changing the relationship between citizens and the state is at the heart of current policy reforms. Across England and the developed world, from Oslo to Ontario, Newcastle to Newquay, giving the public a more direct say in shaping the organization and delivery of healthcare services is central to the current health reform agenda. Realigning public services around those they serve, based on evidence from service user’s experiences, and designed with and by the people rather than simply on their behalf, is challenging the dominance of managerialism, marketization and bureaucratic expertise. Despite this attention there is limited conceptual and theoretical work to underpin policy and practice. Objective  This article proposes a conceptual framework for patient and public involvement (PPI) and goes on to explore the different justifications for involvement and the implications of a rights‐based rather than a regulatory approach. These issues are highlighted through exploring the particular evolution of English health policy in relation to PPI on the one hand and patient choice on the other before turning to similar patterns apparent in the United States and more broadly. Conclusions  A framework for conceptualizing PPI is presented that differentiates between the different types and aims of involvement and their potential impact. Approaches to involvement are different in those countries that adopt a rights‐based rather than a regulatory approach. I conclude with a discussion of the tension and interaction apparent in the globalization of both involvement and patient choice in both policy and practice. PMID:19754691

Automated visualization of rule-based models

PubMed Central

Tapia, Jose-Juan; Faeder, James R.

2017-01-01

Frameworks such as BioNetGen, Kappa and Simmune use “reaction rules” to specify biochemical interactions compactly, where each rule specifies a mechanism such as binding or phosphorylation and its structural requirements. Current rule-based models of signaling pathways have tens to hundreds of rules, and these numbers are expected to increase as more molecule types and pathways are added. Visual representations are critical for conveying rule-based models, but current approaches to show rules and interactions between rules scale poorly with model size. Also, inferring design motifs that emerge from biochemical interactions is an open problem, so current approaches to visualize model architecture rely on manual interpretation of the model. Here, we present three new visualization tools that constitute an automated visualization framework for rule-based models: (i) a compact rule visualization that efficiently displays each rule, (ii) the atom-rule graph that conveys regulatory interactions in the model as a bipartite network, and (iii) a tunable compression pipeline that incorporates expert knowledge and produces compact diagrams of model architecture when applied to the atom-rule graph. The compressed graphs convey network motifs and architectural features useful for understanding both small and large rule-based models, as we show by application to specific examples. Our tools also produce more readable diagrams than current approaches, as we show by comparing visualizations of 27 published models using standard graph metrics. We provide an implementation in the open source and freely available BioNetGen framework, but the underlying methods are general and can be applied to rule-based models from the Kappa and Simmune frameworks also. We expect that these tools will promote communication and analysis of rule-based models and their eventual integration into comprehensive whole-cell models. PMID:29131816

Toward Advancing Nano-Object Count Metrology: A Best Practice Framework

PubMed Central

Boyko, Volodymyr; Meyers, Greg; Voetz, Matthias; Wohlleben, Wendel

2013-01-01

Background: A movement among international agencies and policy makers to classify industrial materials by their number content of sub–100-nm particles could have broad implications for the development of sustainable nanotechnologies. Objectives: Here we highlight current particle size metrology challenges faced by the chemical industry due to these emerging number percent content thresholds, provide a suggested best-practice framework for nano-object identification, and identify research needs as a path forward. Discussion: Harmonized methods for identifying nanomaterials by size and count for many real-world samples do not currently exist. Although particle size remains the sole discriminating factor for classifying a material as “nano,” inconsistencies in size metrology will continue to confound policy and decision making. Moreover, there are concerns that the casting of a wide net with still-unproven metrology methods may stifle the development and judicious implementation of sustainable nanotechnologies. Based on the current state of the art, we propose a tiered approach for evaluating materials. To enable future risk-based refinements of these emerging definitions, we recommend that this framework also be considered in environmental and human health research involving the implications of nanomaterials. Conclusion: Substantial scientific scrutiny is needed in the area of nanomaterial metrology to establish best practices and to develop suitable methods before implementing definitions based solely on number percent nano-object content for regulatory purposes. Strong cooperation between industry, academia, and research institutions will be required to fully develop and implement detailed frameworks for nanomaterial identification with respect to emerging count-based metrics. Citation: Brown SC, Boyko V, Meyers G, Voetz M, Wohlleben W. 2013. Toward advancing nano-object count metrology: a best practice framework. Environ Health Perspect 121:1282–1291; http://dx.doi.org/10.1289/ehp.1306957 PMID:24076973

Registration of Medical Devices

PubMed Central

George, Bobby

2010-01-01

Globally the medical device (MD) market has been growing quite rapidly over the past decade. The regulatory framework for pharmaceuticals and devices differ substantially. The regulatory authorities in different regions of the world recognize different classes of medical devices (MDs), based on their design complexity, their use characteristics, and their potential for harm, if misused. With the vast majority of MDs in developing countries being imported, the respective governments need to put in place policies & regulations to address all elements related to MDs, ranging from its development, manufacturing, registration to post-marketing obligations & disposal so that public can have access to high quality, safe & affordable products for appropriate use. This article highlights current regulations pertaining to registration of MDs in India, in light of those existing in Global Harmonization Task Force (GHTF) member countries & Association of Southeast Asian Nations (ASEAN) countries. PMID:21814626

Applying gene regulatory network logic to the evolution of social behavior.

PubMed

Baran, Nicole M; McGrath, Patrick T; Streelman, J Todd

2017-06-06

Animal behavior is ultimately the product of gene regulatory networks (GRNs) for brain development and neural networks for brain function. The GRN approach has advanced the fields of genomics and development, and we identify organizational similarities between networks of genes that build the brain and networks of neurons that encode brain function. In this perspective, we engage the analogy between developmental networks and neural networks, exploring the advantages of using GRN logic to study behavior. Applying the GRN approach to the brain and behavior provides a quantitative and manipulative framework for discovery. We illustrate features of this framework using the example of social behavior and the neural circuitry of aggression.

Regulation and Device Development: Tips for Optimizing Your Experience With the Food and Drug Administration.

PubMed

Brooks, Steven S

2017-06-01

Physician-inventors are in a unique position to identify unserved patient needs, and innovate solutions to clinical problems. These solutions may also have associated commercial opportunities. The logistics of developing these medical products, however, can seem a daunting task. One of the primary barriers in the United States is the regulatory process of the Food and Drug Administration (FDA). In this article, we will explore the risk-based approach used by the FDA which forms a framework to consider the regulatory pathway and the process to gain regulatory clearance or approval for medical devices. Inherent device properties and the procedural risk of the devices will determine the rigor with which they are scrutinized by FDA, and the evidentiary requirements to legally market them. Data and evidentiary development will vary depending on risk and regulatory precedent and may or may not require clinical data This regulatory paradigm will determine into which risk-based device class they fit, and whether they are regulated under the 510(k) or premarket approval application pathways. The FDA, although gatekeeper of the US market and tasked with determining which products are safe and effective, can be a powerful ally for product development. They have significant scientific and medical expertise, and mechanisms to both provide guidance, and also to consider novel approaches to product development and evidence development. Early interaction for routine and novel products alike can result in expedited and efficient development. This collaborative approach can be best practice to most expeditiously develop the next generation of products, getting them into the hands of US doctors and into the treatment of US patients. Copyright © 2017. Published by Elsevier Inc.

Estonian Preschool Teachers' Aspirations for Curricular Autonomy--The Gap between an Ideal and Professional Practice

ERIC Educational Resources Information Center

Tuul, Maire; Mikser, Rain; Neudorf, Evelyn; Ugaste, Aino

2015-01-01

Establishing national framework curricula is a growing tendency in early childhood education internationally, and is considered to be part of the regulatory requirements framework for enhancing preschool teachers' professionalism. A topical issue in this context is whether and how teachers themselves see these practices as contributing to their…

On the regulator-insurer interaction in a structural model

NASA Astrophysics Data System (ADS)

Bernard, Carole; Chen, An

2009-11-01

In this paper, we provide a new insight to the previous work of Briys and de Varenne [E. Briys, F. de Varenne, Life insurance in a contingent claim framework: Pricing and regulatory implications, Geneva Papers on Risk and Insurance Theory 19 (1) (1994) 53-72], Grosen and Jørgensen [A. Grosen, P.L. Jørgensen, Life insurance liabilities at market value: An analysis of insolvency risk, bonus policy, and regulatory intervention rules in a barrier option framework, Journal of Risk and Insurance 69 (1) (2002) 63-91] and Chen and Suchanecki [A. Chen, M. Suchanecki, Default risk, bankruptcy procedures and the market value of life insurance liabilities, Insurance: Mathematics and Economics 40 (2007) 231-255]. We show that the particular risk management strategy followed by the insurance company can significantly change the risk exposure of the company, and that it should thus be taken into account by regulators. We first study how the regulator establishes regulation intervention levels in order to control for instance the default probability of the insurance company. This part of the analysis is based on a constant volatility. Given that the insurance company is informed of regulatory rules, we study how results can be significantly different when the insurance company follows a risk management strategy with non-constant volatilities. We thus highlight some limits of the prior literature and believe that the risk management strategy of the company should be taken into account in the estimation of the risk exposure as well as in that of the market value of liabilities.

How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology

PubMed Central

Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J.; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M. E. (Bette); Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M.; Whelan, Maurice

2017-01-01

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24–25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. PMID:27994170

Environmental risk assessment of pesticides: state of the art and prospective improvement from science.

PubMed

Boivin, Arnaud; Poulsen, Véronique

2017-03-01

Pesticide risk assessment in the European regulatory framework is mandatory performed for active substances (pesticides) and the plant protection products they are constituents of. The aim is to guarantee that safe use can be achieved for the intended use of the product. This paper provides a feedback on the regulatory environmental risk assessment performed for pesticide registration at the EU and member state levels. The different steps of pesticide registration are addressed considering both exposure and hazard. In this paper, we focus on the environmental fate and behaviour in surface water together with the aquatic ecotoxicity of the substances to illustrate pesticide regulatory risk assessment performed for aquatic organisms. Current methodologies are presented along with highlights on potential improvements. For instance, as regards exposure aspects, moving from field based to landscape risk assessments is promising. Regarding ecotoxicology, ecological models may be valuable tools when applied to chemical risk assessment. In addition, interest and further developments to better take into account mitigation measures in risk assessment and management are also presented.

Mesenchymal Stem Cells as Therapeutics Agents: Quality and Environmental Regulatory Aspects

PubMed Central

Sabata, Roger; Verges, Josep; Zugaza, José L.; Ruiz, Adolfina; Clares, Beatriz

2016-01-01

Mesenchymal stem cells (MSCs) are one of the main stem cells that have been used for advanced therapies and regenerative medicine. To carry out the translational clinical application of MSCs, their manufacturing and administration in human must be controlled; therefore they should be considered as medicine: stem cell-based medicinal products (SCMPs). The development of MSCs as SCMPs represents complicated therapeutics due to their extreme complex nature and rigorous regulatory oversights. The manufacturing process of MSCs needs to be addressed in clean environments in compliance with requirements of Good Manufacturing Practice (GMP). Facilities should maintain these GMP conditions according to international and national medicinal regulatory frameworks that introduce a number of specifications in order to produce MSCs as safe SCMPs. One of these important and complex requirements is the environmental monitoring. Although a number of environmental requirements are clearly defined, some others are provided as recommendations. In this review we aim to outline the current issues with regard to international guidelines which impact environmental monitoring in cleanrooms and clean areas for the manufacturing of MSCs. PMID:27999600

Legislative and Regulatory Actions Needed to Deal with a Changing Domestic Telecommunications Industry. Report to the Congress.

ERIC Educational Resources Information Center

Comptroller General of the U.S., Washington, DC.

The Federal Communications Commission's (FCC's) program for regulating domestic telecommunications common carriers is assessed in this report, and several recommendations are made to the Congress and the FCC for improving the regulatory framework provided by the Communications Act of 1934. A digest of the report and a review of the nation's…

International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*

PubMed Central

Bolon, Brad; Barale-Thomas, Erio; Bradley, Alys; Ettlin, Robert A.; Franchi, Carla A.S.; George, Catherine; Giusti, Anna Maria; Hall, Robert; Jacobsen, Matthew; Konishi, Yoichi; Ledieu, David; Morton, Daniel; Park, Jae-Hak; Scudamore, Cheryl L.; Tsuda, Hiroyuki; Vijayasarathi, S.K.; Wijnands, Marcel V.W.

2010-01-01

The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job “apprenticeship,” at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one’s understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID:22272030

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment: A Systematic Review of the Literature.

PubMed

Bujar, Magdalena; McAuslane, Neil; Walker, Stuart R; Salek, Sam

2017-01-01

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

PubMed

Vandenberg, Laura N; Ågerstrand, Marlene; Beronius, Anna; Beausoleil, Claire; Bergman, Åke; Bero, Lisa A; Bornehag, Carl-Gustaf; Boyer, C Scott; Cooper, Glinda S; Cotgreave, Ian; Gee, David; Grandjean, Philippe; Guyton, Kathryn Z; Hass, Ulla; Heindel, Jerrold J; Jobling, Susan; Kidd, Karen A; Kortenkamp, Andreas; Macleod, Malcolm R; Martin, Olwenn V; Norinder, Ulf; Scheringer, Martin; Thayer, Kristina A; Toppari, Jorma; Whaley, Paul; Woodruff, Tracey J; Rudén, Christina

2016-07-14

The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.

Interpretation of ALARA in the Canadian regulatory framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Utting, R.

1995-03-01

The Atomic Energy Control Board (AECB) is responsible for the regulation of all aspects of atomic energy in Canada. This includes the complete nuclear fuel cycle from uranium mining to long-term disposal of nuclear fuel, as well as the medical and industrial utilization of radioisotopes. Clearly, the regulatory approach will differ from practice to practice but, as far as possible, the AECB has attempted to minimize the degree of prescription of regulatory requirements. The traditional modus operandi of the AECB has been to have broad general principles enshrined in regulations with the requirement that licensees submit specific operating policies andmore » procedures to the AECB for approval. In the large nuclear facilities with their sophisticated technical infrastructures, this policy has been largely successful although in a changing legal and political milieu the AECB is finding that a greater degree of proactive regulation is becoming necessary. With the smaller users, the AECB has for a long time found it necessary to have a greater degree of prescription in its regulatory function. Forthcoming General Amendments to the Atomic Energy Control Regulations will, amongst other things, formally incorporate the concept of ALARA into the Canadian regulatory framework. Within the broad range of practices licensed by the AECB it is not practical to provide detailed guidance on optimization that will be relevant and appropriate to all licensees, however the following general principles are proposed.« less

Markov State Models of gene regulatory networks.

PubMed

Chu, Brian K; Tse, Margaret J; Sato, Royce R; Read, Elizabeth L

2017-02-06

Gene regulatory networks with dynamics characterized by multiple stable states underlie cell fate-decisions. Quantitative models that can link molecular-level knowledge of gene regulation to a global understanding of network dynamics have the potential to guide cell-reprogramming strategies. Networks are often modeled by the stochastic Chemical Master Equation, but methods for systematic identification of key properties of the global dynamics are currently lacking. The method identifies the number, phenotypes, and lifetimes of long-lived states for a set of common gene regulatory network models. Application of transition path theory to the constructed Markov State Model decomposes global dynamics into a set of dominant transition paths and associated relative probabilities for stochastic state-switching. In this proof-of-concept study, we found that the Markov State Model provides a general framework for analyzing and visualizing stochastic multistability and state-transitions in gene networks. Our results suggest that this framework-adopted from the field of atomistic Molecular Dynamics-can be a useful tool for quantitative Systems Biology at the network scale.

An Optimal Free Energy Dissipation Strategy of the MinCDE Oscillator in Regulating Symmetric Bacterial Cell Division

PubMed Central

Xiong, Liping; Lan, Ganhui

2015-01-01

Sustained molecular oscillations are ubiquitous in biology. The obtained oscillatory patterns provide vital functions as timekeepers, pacemakers and spacemarkers. Models based on control theory have been introduced to explain how specific oscillatory behaviors stem from protein interaction feedbacks, whereas the energy dissipation through the oscillating processes and its role in the regulatory function remain unexplored. Here we developed a general framework to assess an oscillator’s regulation performance at different dissipation levels. Using the Escherichia coli MinCDE oscillator as a model system, we showed that a sufficient amount of energy dissipation is needed to switch on the oscillation, which is tightly coupled to the system’s regulatory performance. Once the dissipation level is beyond this threshold, unlike stationary regulators’ monotonic performance-to-cost relation, excess dissipation at certain steps in the oscillating process damages the oscillator’s regulatory performance. We further discovered that the chemical free energy from ATP hydrolysis has to be strategically assigned to the MinE-aided MinD release and the MinD immobilization steps for optimal performance, and a higher energy budget improves the robustness of the oscillator. These results unfold a novel mode by which living systems trade energy for regulatory function. PMID:26317492

Canadian regulatory requirements for recombinant fish vaccines.

PubMed

Sethi, M S; Gifford, G A; Samagh, B S

1997-01-01

In Canada, veterinary biological products derived by using conventional and new techniques of biotechnology are licensed and regulated under the Health of Animals Act and Regulations. Biological products include vaccines, bacterins, bacterin-toxoids and diagnostic kits which are used for the prevention, treatment or diagnosis of infectious diseases in all species of animals, including fish. Veterinary biologicals are licensed on the basis of fulfillment of four criteria: purity, potency, safety and efficacy. A risk-based approach is used to evaluate the safety of the product in target species, as well as non-target species, humans and the environment. On the basis of biological characteristics, biotechnology derived veterinary biologicals have been divided into two broad categories, high and low risk products. The paper describes the regulatory framework for the licensing of veterinary biologicals in Canada, with emphasis on the regulatory considerations for recombinant fish vaccines. Stages of movement of the product from research in a contained laboratory facility to a fully licensed product for free sale are discussed. The requirements for field testing and environmental assessment involved in these stages are highlighted. Manufacturers and researchers who intend to commercialize experimental vaccines are encouraged to consult with the Veterinary Biologics and Biotechnology Section early in the product development process so that the research data and quality assurance documentation are consistent with regulatory requirements.

Integration of heterogeneous molecular networks to unravel gene-regulation in Mycobacterium tuberculosis.

PubMed

van Dam, Jesse C J; Schaap, Peter J; Martins dos Santos, Vitor A P; Suárez-Diez, María

2014-09-26

Different methods have been developed to infer regulatory networks from heterogeneous omics datasets and to construct co-expression networks. Each algorithm produces different networks and efforts have been devoted to automatically integrate them into consensus sets. However each separate set has an intrinsic value that is diluted and partly lost when building a consensus network. Here we present a methodology to generate co-expression networks and, instead of a consensus network, we propose an integration framework where the different networks are kept and analysed with additional tools to efficiently combine the information extracted from each network. We developed a workflow to efficiently analyse information generated by different inference and prediction methods. Our methodology relies on providing the user the means to simultaneously visualise and analyse the coexisting networks generated by different algorithms, heterogeneous datasets, and a suite of analysis tools. As a show case, we have analysed the gene co-expression networks of Mycobacterium tuberculosis generated using over 600 expression experiments. Regarding DNA damage repair, we identified SigC as a key control element, 12 new targets for LexA, an updated LexA binding motif, and a potential mismatch repair system. We expanded the DevR regulon with 27 genes while identifying 9 targets wrongly assigned to this regulon. We discovered 10 new genes linked to zinc uptake and a new regulatory mechanism for ZuR. The use of co-expression networks to perform system level analysis allows the development of custom made methodologies. As show cases we implemented a pipeline to integrate ChIP-seq data and another method to uncover multiple regulatory layers. Our workflow is based on representing the multiple types of information as network representations and presenting these networks in a synchronous framework that allows their simultaneous visualization while keeping specific associations from the different networks. By simultaneously exploring these networks and metadata, we gained insights into regulatory mechanisms in M. tuberculosis that could not be obtained through the separate analysis of each data type.

Nonvolatile, semivolatile, or volatile: redefining volatile for volatile organic compounds.

PubMed

Võ, Uyên-Uyén T; Morris, Michael P

2014-06-01

Although widely used in air quality regulatory frameworks, the term "volatile organic compound" (VOC) is poorly defined. Numerous standardized tests are currently used in regulations to determine VOC content (and thus volatility), but in many cases the tests do not agree with each other, nor do they always accurately represent actual evaporation rates under ambient conditions. The parameters (time, temperature, reference material, column polarity, etc.) used in the definitions and the associated test methods were created without a significant evaluation of volatilization characteristics in real world settings. Not only do these differences lead to varying VOC content results, but occasionally they conflict with one another. An ambient evaporation study of selected compounds and a few formulated products was conducted and the results were compared to several current VOC test methodologies: SCAQMD Method 313 (M313), ASTM Standard Test Method E 1868-10 (E1868), and US. EPA Reference Method 24 (M24). The ambient evaporation study showed a definite distinction between nonvolatile, semivolatile, and volatile compounds. Some low vapor pressure (LVP) solvents, currently considered exempt as VOCs by some methods, volatilize at ambient conditions nearly as rapidly as the traditional high-volatility solvents they are meant to replace. Conversely, bio-based and heavy hydrocarbons did not readily volatilize, though they often are calculated as VOCs in some traditional test methods. The study suggests that regulatory standards should be reevaluated to more accurately reflect real-world emission from the use of VOC containing products. The definition of VOC in current test methods may lead to regulations that exclude otherwise viable alternatives or allow substitutions of chemicals that may limit the environmental benefits sought in the regulation. A study was conducted to examine volatility of several compounds and a few formulated products under several current VOC test methodologies and ambient evaporation. This paper provides ample evidence to warrant a reevaluation of regulatory standards and provides a framework for progressive developments based on reasonable and scientifically justifiable definitions of VOCs.

Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence

PubMed Central

Meek, M E (Bette); Palermo, Christine M; Bachman, Ammie N; North, Colin M; Jeffrey Lewis, R

2014-01-01

The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of “how much information is enough” to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose–response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd. The potential value of the mode of action (MOA)/human relevance (species concordance) framework in considering relative weight of evidence (WOE) amongst different cases and hypothesized MOA(s) is explored based on the content of several published assessments. The comparison is based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations for MOA based on experience internationally. PMID:24777878

Regulatory ozone modeling: status, directions, and research needs.

PubMed Central

Georgopoulos, P G

1995-01-01

The Clean Air Act Amendments (CAAA) of 1990 have established selected comprehensive, three-dimensional, Photochemical Air Quality Simulation Models (PAQSMs) as the required regulatory tools for analyzing the urban and regional problem of high ambient ozone levels across the United States. These models are currently applied to study and establish strategies for meeting the National Ambient Air Quality Standard (NAAQS) for ozone in nonattainment areas; State Implementation Plans (SIPs) resulting from these efforts must be submitted to the U.S. Environmental Protection Agency (U.S. EPA) in November 1994. The following presentation provides an overview and discussion of the regulatory ozone modeling process and its implications. First, the PAQSM-based ozone attainment demonstration process is summarized in the framework of the 1994 SIPs. Then, following a brief overview of the representation of physical and chemical processes in PAQSMs, the essential attributes of standard modeling systems currently in regulatory use are presented in a nonmathematical, self-contained format, intended to provide a basic understanding of both model capabilities and limitations. The types of air quality, emission, and meteorological data needed for applying and evaluating PAQSMs are discussed, as well as the sources, availability, and limitations of existing databases. The issue of evaluating a model's performance in order to accept it as a tool for policy making is discussed, and various methodologies for implementing this objective are summarized. Selected interim results from diagnostic analyses, which are performed as a component of the regulatory ozone modeling process for the Philadelphia-New Jersey region, are also presented to provide some specific examples related to the general issues discussed in this work. Finally, research needs related to a) the evaluation and refinement of regulatory ozone modeling, b) the characterization of uncertainty in photochemical modeling, and c) the improvement of the model-based ozone-attainment demonstration process are presented to identify future directions in this area. Images Figure 7. Figure 7. Figure 7. Figure 8. Figure 9. PMID:7614934

Organizing Environmental Flow Frameworks to Meet Hydropower Mitigation Needs

NASA Astrophysics Data System (ADS)

McManamay, Ryan A.; Brewer, Shannon K.; Jager, Henriette I.; Troia, Matthew J.

2016-09-01

The global recognition of the importance of natural flow regimes to sustain the ecological integrity of river systems has led to increased societal pressure on the hydropower industry to change plant operations to improve downstream aquatic ecosystems. However, a complete reinstatement of natural flow regimes is often unrealistic when balancing water needs for ecosystems, energy production, and other human uses. Thus, stakeholders must identify a prioritized subset of flow prescriptions that meet ecological objectives in light of realistic constraints. Yet, isolating aspects of flow regimes to restore downstream of hydropower facilities is among the greatest challenges of environmental flow science due, in part, to the sheer volume of available environmental flow tools in conjunction with complex negotiation-based regulatory procedures. Herein, we propose an organizational framework that structures information and existing flow paradigms into a staged process that assists stakeholders in implementing environmental flows for hydropower facilities. The framework identifies areas where regulations fall short of the needed scientific process, and provide suggestions for stakeholders to ameliorate those situations through advanced preparation. We highlight the strengths of existing flow paradigms in their application to hydropower settings and suggest when and where tools are most applicable. Our suggested framework increases the effectiveness and efficiency of the e-flow implementation process by rapidly establishing a knowledge base and decreasing uncertainty so more time can be devoted to filling knowledge gaps. Lastly, the framework provides the structure for a coordinated research agenda to further the science of environmental flows related to hydropower environments.

Organizing environmental flow frameworks to meet hydropower mitigation needs

USGS Publications Warehouse

McManamay, Ryan A.; Brewer, Shannon K.; Jager, Henriette; Troia, Matthew J.

2016-01-01

The global recognition of the importance of natural flow regimes to sustain the ecological integrity of river systems has led to increased societal pressure on the hydropower industry to change plant operations to improve downstream aquatic ecosystems. However, a complete reinstatement of natural flow regimes is often unrealistic when balancing water needs for ecosystems, energy production, and other human uses. Thus, stakeholders must identify a prioritized subset of flow prescriptions that meet ecological objectives in light of realistic constraints. Yet, isolating aspects of flow regimes to restore downstream of hydropower facilities is among the greatest challenges of environmental flow science due, in part, to the sheer volume of available environmental flow tools in conjunction with complex negotiation-based regulatory procedures. Herein, we propose an organizational framework that structures information and existing flow paradigms into a staged process that assists stakeholders in implementing environmental flows for hydropower facilities. The framework identifies areas where regulations fall short of the needed scientific process, and provide suggestions for stakeholders to ameliorate those situations through advanced preparation. We highlight the strengths of existing flow paradigms in their application to hydropower settings and suggest when and where tools are most applicable. Our suggested framework increases the effectiveness and efficiency of the e-flow implementation process by rapidly establishing a knowledge base and decreasing uncertainty so more time can be devoted to filling knowledge gaps. Lastly, the framework provides the structure for a coordinated research agenda to further the science of environmental flows related to hydropower environments.

Organizing Environmental Flow Frameworks to Meet Hydropower Mitigation Needs.

PubMed

McManamay, Ryan A; Brewer, Shannon K; Jager, Henriette I; Troia, Matthew J

2016-09-01

The global recognition of the importance of natural flow regimes to sustain the ecological integrity of river systems has led to increased societal pressure on the hydropower industry to change plant operations to improve downstream aquatic ecosystems. However, a complete reinstatement of natural flow regimes is often unrealistic when balancing water needs for ecosystems, energy production, and other human uses. Thus, stakeholders must identify a prioritized subset of flow prescriptions that meet ecological objectives in light of realistic constraints. Yet, isolating aspects of flow regimes to restore downstream of hydropower facilities is among the greatest challenges of environmental flow science due, in part, to the sheer volume of available environmental flow tools in conjunction with complex negotiation-based regulatory procedures. Herein, we propose an organizational framework that structures information and existing flow paradigms into a staged process that assists stakeholders in implementing environmental flows for hydropower facilities. The framework identifies areas where regulations fall short of the needed scientific process, and provide suggestions for stakeholders to ameliorate those situations through advanced preparation. We highlight the strengths of existing flow paradigms in their application to hydropower settings and suggest when and where tools are most applicable. Our suggested framework increases the effectiveness and efficiency of the e-flow implementation process by rapidly establishing a knowledge base and decreasing uncertainty so more time can be devoted to filling knowledge gaps. Lastly, the framework provides the structure for a coordinated research agenda to further the science of environmental flows related to hydropower environments.

An Agent-Based Optimization Framework for Engineered Complex Adaptive Systems with Application to Demand Response in Electricity Markets

NASA Astrophysics Data System (ADS)

Haghnevis, Moeed

The main objective of this research is to develop an integrated method to study emergent behavior and consequences of evolution and adaptation in engineered complex adaptive systems (ECASs). A multi-layer conceptual framework and modeling approach including behavioral and structural aspects is provided to describe the structure of a class of engineered complex systems and predict their future adaptive patterns. The approach allows the examination of complexity in the structure and the behavior of components as a result of their connections and in relation to their environment. This research describes and uses the major differences of natural complex adaptive systems (CASs) with artificial/engineered CASs to build a framework and platform for ECAS. While this framework focuses on the critical factors of an engineered system, it also enables one to synthetically employ engineering and mathematical models to analyze and measure complexity in such systems. In this way concepts of complex systems science are adapted to management science and system of systems engineering. In particular an integrated consumer-based optimization and agent-based modeling (ABM) platform is presented that enables managers to predict and partially control patterns of behaviors in ECASs. Demonstrated on the U.S. electricity markets, ABM is integrated with normative and subjective decision behavior recommended by the U.S. Department of Energy (DOE) and Federal Energy Regulatory Commission (FERC). The approach integrates social networks, social science, complexity theory, and diffusion theory. Furthermore, it has unique and significant contribution in exploring and representing concrete managerial insights for ECASs and offering new optimized actions and modeling paradigms in agent-based simulation.

[Human resources for health in Ecuador's new model of care].

PubMed

Espinosa, Verónica; de la Torre, Daniel; Acuña, Cecilia; Cadena, Cristina

2017-06-08

Describe strategies implemented by Ecuador's Ministry of Public Health (MPH) to strengthen human resources for health leadership and respond to the new model of care, as a part of the reform process in the period 2012-2015. A documentary review was carried out of primary and secondary sources on development of human resources for health before and after the reform. In the study period, Ecuador developed a new institutional and regulatory framework for developing human resources for health to respond to the requirements of a model of care based on primary health care. The MPH consolidated its steering role by forging strategic partnerships, implementing human resources planning methods, and making an unprecedented investment in health worker training, hiring, and wage increases. These elements constitute the initial core for development of human resources for health policy and a health-services study program consistent with the reform's objectives. Within the framework of the reform carried out from 2012 to 2015, intersectoral work by the MPH has led to considerable achievements in development of human resources for health. Notable achievements include strengthening of the steering role, development and implementation of standards and regulatory instruments, creation of new professional profiles, and hiring of professionals to implement the comprehensive health care model, which helped to solve problems carried over from the years prior to the reform.

Radiation Safety Culture in the UK Medical Sector: A Top to Bottom Strategy.

PubMed

Chapple, Claire-Louise; Bradley, Andy; Murray, Maria; Orr, Phil; Reay, Jill; Riley, Peter; Rogers, Andy; Sandhu, Navneet; Thurston, Jim

2017-04-01

UK professional bodies have established a number of sectorial working parties to provide guidance on the improvement of radiation safety (RS) culture in the workplace. The medical sector provides unique challenges in this regard, and the remit of the medical group was to review the current state of RS culture and to develop a framework for improvement. The review of current RS culture was based on measurable indicators, including data from regulatory inspections, personal monitoring data and incident data. An online survey to capture the RS-related views and experience of hospital staff at all levels was carried out, and the responses provided a wealth of information on RS awareness and implementation across the country. The framework for improving RS culture includes both 'top-down' initiatives to engage management and regulators, and 'bottom-up' initiatives relating to engagement and training of different staff groups. A 'Ten-point Assessment' on what constitutes a good approach to medical RS culture has been proposed, which provides a tool for management to assess RS culture in the workplace and has potential use in regulatory inspections in the UK. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Regulation of Ocean Iron Fertilization (OIF): a Model for Balancing Research, Environmental and Policy Concerns

NASA Astrophysics Data System (ADS)

Leinen, M.; Lamotte, R.

2008-12-01

The potential of enhancing carbon sequestration by the biosphere for climate mitigation often raises questions of offsetting effects. These questions become more important as the scale of the enhancement increases. Ocean iron fertilization is accompanied by additional questions related to use of the ocean commons. The London Convention (LC) and London Protocol (LP), international treaties adopted in 1972 and 1996 respectively, were designed to prevent use of the ocean for disposal of toxic, harmful and radioactive pollutants. Recently the LC/LP has been called upon to decide whether climate mitigation activities, such as subseafloor injection of CO2 and OIF, are legal under the framework and, if so, how they should be regulated. The broad consultation with the science community by the LC/LP in developing their perspective, and the involvement of the NGO community in these deliberations, provides a model for the process that the international policy community can use to develop science-based regulatory guidelines for carbon mitigation projects involving the commons. And the substance of that emerging regulatory framework -- built on a national-level permitting process informed by internationally agreed guidelines and standards -- may also serve as a model for the oversight of other emerging technologies that take place in the global commons.

Current limitations and recommendations to improve testing ...

EPA Pesticide Factsheets

In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across organizations, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or the environment. Current test systems include in silico, in vitro and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormonal pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1)adequately sensitive species and life-stages, 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern, and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive in regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to, and guidance for existing test methods, and to reduce uncertainty. For example, in vitro high throughput

Bridging the gap between regulatory acceptance and industry use of non-animal methods.

PubMed

Clippinger, Amy J; Hill, Erin; Curren, Rodger; Bishop, Patricia

2016-01-01

Collaboration between industry and regulators resulted in the development of a decision tree approach using in vitro or ex vivo assays to replace animal tests when determining the eye irritation potential of antimicrobial cleaning products (AMCPs) under the United States Environmental Protection Agency (EPA) Office of Pesticide Programs' hazard classification and labeling system. A policy document issued by the EPA in 2013 and updated in 2015 describes the alternate testing framework that industry could apply to new registrations of AMCPs and, on a case-by-case basis, to conventional pesticide products. Despite the collaborative effort, the availability of relevant non-animal methods, and the EPA's change in policy, only a limited number of AMCPs have been registered using the framework. Companies continue to conduct animal tests when registering AMCPs due to various challenges surrounding adoption of the new testing framework; however, recent discussions between industry, regulators, and other interested parties have identified ways these challenges may be overcome. In this article we explore how use of the alternate framework could be expanded through efforts such as increasing international harmonization, more proactively publicizing the framework, and enhancing the training of regulatory reviewers. Not only can these strategies help to increase use of the EPA alternate eye irritation framework, they can also be applied to facilitate the uptake of other alternative approaches to animal testing in the future.

A framework to analyze emissions implications of manufacturing shifts in the industrial sector through integrating bottom-up energy models and economic input-output environmental life cycle assessment models

EPA Science Inventory

Future year emissions depend highly on the evolution of the economy, technology and current and future regulatory drivers. A scenario framework was adopted to analyze various technology development pathways and societal change while considering existing regulations and future unc...

A framework to analyze emissions implications of manufacturing shifts in the industrial sector through integrating bottom-up energy models and economic input/output environmental life cycle assessment models

EPA Science Inventory

Future year emissions depend highly on economic, technological, societal and regulatory drivers. A scenario framework was adopted to analyze technology development pathways and changes in consumer preferences, and evaluate resulting emissions growth patterns while considering fut...

76 FR 25274 - Reopening and Extension of Comment Periods for Rulemakings Implementing the Dodd-Frank Wall...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-04

... establish a comprehensive new framework for the regulation of swaps. In order to provide interested parties... proposed new regulatory framework, the Commission is reopening or extending the comment period for many of its proposed rulemakings. The Commission is also requesting comment on the order in which it should...

Application of Framework for Integrating Safety, Security and Safeguards (3Ss) into the Design Of Used Nuclear Fuel Storage Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Badwan, Faris M.; Demuth, Scott F

Department of Energy’s Office of Nuclear Energy, Fuel Cycle Research and Development develops options to the current commercial fuel cycle management strategy to enable the safe, secure, economic, and sustainable expansion of nuclear energy while minimizing proliferation risks by conducting research and development focused on used nuclear fuel recycling and waste management to meet U.S. needs. Used nuclear fuel is currently stored onsite in either wet pools or in dry storage systems, with disposal envisioned in interim storage facility and, ultimately, in a deep-mined geologic repository. The safe management and disposition of used nuclear fuel and/or nuclear waste is amore » fundamental aspect of any nuclear fuel cycle. Integrating safety, security, and safeguards (3Ss) fully in the early stages of the design process for a new nuclear facility has the potential to effectively minimize safety, proliferation, and security risks. The 3Ss integration framework could become the new national and international norm and the standard process for designing future nuclear facilities. The purpose of this report is to develop a framework for integrating the safety, security and safeguards concept into the design of Used Nuclear Fuel Storage Facility (UNFSF). The primary focus is on integration of safeguards and security into the UNFSF based on the existing Nuclear Regulatory Commission (NRC) approach to addressing the safety/security interface (10 CFR 73.58 and Regulatory Guide 5.73) for nuclear power plants. The methodology used for adaptation of the NRC safety/security interface will be used as the basis for development of the safeguards /security interface and later will be used as the basis for development of safety and safeguards interface. Then this will complete the integration cycle of safety, security, and safeguards. The overall methodology for integration of 3Ss will be proposed, but only the integration of safeguards and security will be applied to the design of the UNFSF. The framework for integration of safeguards and security into the UNFSF will include 1) identification of applicable regulatory requirements, 2) selection of a common system that share dual safeguard and security functions, 3) development of functional design criteria and design requirements for the selected system, 4) identification and integration of the dual safeguards and security design requirements, and 5) assessment of the integration and potential benefit.« less

Which lessons can we learn from the European Union legal framework of medicines for the regulation of direct-to-consumer genetic tests?

PubMed

van Hellemondt, Rachèl; Hendriks, Aart; Breuning, Martijn

2012-01-01

The legal framework of the European Union (EU) for regulating access to and supply of direct-to-consumer (DTC) genetic tests is very liberal compared to the legal and regulatory framework for (internet) medicines. Nevertheless, both health related products can cause equally serious damage to the well being of individuals. In this contribution we examine whether the legal framework of the EU for the safety and responsible use of (internet) medicines could be an example for regulating access to and supply of DTC genetic tests. The EU laws governing medicines can, notwithstanding their shortcomings, serve as an example for (central) authorising the marketing of DTC genetic tests on the internal market in accordance with strict criteria regarding predictive value and clinical usefulness. Furthermore, a legal framework controlling DTC genetic tests also should introduce system supervision as well as quality criteria with respect to the information to be provided to consumers in order to enhance health protection. However, DTC genetic tests purchased through online ordering are difficult to supervise by any agency. Adequately protecting individuals against questionable testing kits calls for international vigilance and comprehensive measures by the international community. For Europe, it is important to rank the regulation of DTC genetic tests on the European regulatory agenda.

Evaluating the effectiveness of risk minimisation measures: the application of a conceptual framework to Danish real-world dabigatran data.

PubMed

Nyeland, Martin Erik; Laursen, Mona Vestergaard; Callréus, Torbjörn

2017-06-01

For both marketing authorization holders and regulatory authorities, evaluating the effectiveness of risk minimization measures is now an integral part of pharmacovigilance in the European Union. The overall aim of activities in this area is to assess the performance of risk minimization measures implemented in order to ensure a positive benefit-risk balance in patients treated with a medicinal product. Following a review of the relevant literature, we developed a conceptual framework consisting of four domains (data, knowledge, behaviour and outcomes) intended for the evaluation of risk minimization measures put into practice in the Danish health-care system. For the implementation of the framework, four classes of monitoring variables can be named and defined: patient descriptors, performance-related indicators of knowledge, behaviour and outcomes. We reviewed the features of the framework when applied to historical, real-world data following the introduction of dabigatran in Denmark for the prophylactic treatment of patients with non-valvular atrial fibrillation. The application of the framework provided useful graphical displays and an opportunity for a statistical evaluation (interrupted time series analysis) of a regulatory intervention. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd. © 2017 Commonwealth of Australia. Pharmacoepidemiology & Drug Safety © 2017 John Wiley & Sons, Ltd.

Frameworks and tools for risk assessment of manufactured nanomaterials.

PubMed

Hristozov, Danail; Gottardo, Stefania; Semenzin, Elena; Oomen, Agnes; Bos, Peter; Peijnenburg, Willie; van Tongeren, Martie; Nowack, Bernd; Hunt, Neil; Brunelli, Andrea; Scott-Fordsmand, Janeck J; Tran, Lang; Marcomini, Antonio

2016-10-01

Commercialization of nanotechnologies entails a regulatory requirement for understanding their environmental, health and safety (EHS) risks. Today we face challenges to assess these risks, which emerge from uncertainties around the interactions of manufactured nanomaterials (MNs) with humans and the environment. In order to reduce these uncertainties, it is necessary to generate sound scientific data on hazard and exposure by means of relevant frameworks and tools. The development of such approaches to facilitate the risk assessment (RA) of MNs has become a dynamic area of research. The aim of this paper was to review and critically analyse these approaches against a set of relevant criteria. The analysis concluded that none of the reviewed frameworks were able to fulfill all evaluation criteria. Many of the existing modelling tools are designed to provide screening-level assessments rather than to support regulatory RA and risk management. Nevertheless, there is a tendency towards developing more quantitative, higher-tier models, capable of incorporating uncertainty into their analyses. There is also a trend towards developing validated experimental protocols for material identification and hazard testing, reproducible across laboratories. These tools could enable a shift from a costly case-by-case RA of MNs towards a targeted, flexible and efficient process, based on grouping and read-across strategies and compliant with the 3R (Replacement, Reduction, Refinement) principles. In order to facilitate this process, it is important to transform the current efforts on developing databases and computational models into creating an integrated data and tools infrastructure to support the risk assessment and management of MNs. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Enforceability of the right to health protection in obstetric services in Mexico].

PubMed

Meza, Alejandro; Mancinas, Sandra; Meneses, Sergio; Meléndez, David

2015-05-01

The inclusion of the framework of human rights in maternal health is mentioned more and more frequently as a feasible proposal to improve the care that women receive in obstetric health care services. Despite the fact Mexico has a solid regulatory framework for obstetric care, mechanisms of enforceability are essential to ensure that health-related human rights are upheld. In addition to being in place, enforceability mechanisms should be effective and accessible to people, particularly in obstetric care, where repeated human rights violations occur that endanger women's health and lives. The objective of this article is to specify the regulatory, legal, and extralegal elements that need to be considered in order to include maternal health in a set of enforceable human rights.

Research Participation as Work: Comparing the Perspectives of Researchers and Economically Marginalized Populations

PubMed Central

Page, Kimberly

2012-01-01

We examined the historical and regulatory framework of research with human participants in the United States, and described some possible unintended consequences of this framework in the context of paying young injection drug users for their time participating in behavioral and medical research. We drew upon our own experiences while conducting a long-running epidemiological study of hepatitis C virus infection. We found that existing ethical and regulatory framings of research participation may lead to injustices from the perspectives of research participants. We propose considering research participation as a specialized form of work and the use of community advisory boards to facilitate discussion about appropriate compensation for research participation among economically marginalized populations. PMID:22594754

Towards a better pesticide policy for the European Union.

PubMed

Storck, Veronika; Karpouzas, Dimitrios G; Martin-Laurent, Fabrice

2017-01-01

This opinion article aims to foster the debate about pesticide legislation in the European Union (EU). Numerous formerly authorized and widely used pesticides are now banned in the EU because unexpected and unacceptable risks emerged after their initial introduction to the market. Throughout this time lapse, environmental quality and human health have been threatened by the use of these compounds. These hazards could have been prevented by a more responsive pesticide regulatory framework. This article provides detailed insights into the pros and cons of pesticides, and points out weaknesses of the current pesticide environmental risk assessment procedures. Possibilities for improving the robustness and reliability of the pesticide regulatory framework are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

Attachment and Chronic Pain in Children and Adolescents

PubMed Central

Donnelly, Theresa J.; Jaaniste, Tiina

2016-01-01

Although attachment theory is not new, its theoretical implications for the pediatric chronic pain context have not been thoroughly considered, and the empirical implications and potential clinical applications are worth exploring. The attachment framework broadly focuses on interactions between a child’s developing self-regulatory systems and their caregiver’s responses. These interactions are believed to create a template for how individuals will relate to others in the future, and may help account for normative and pathological patterns of emotions and behavior throughout life. This review outlines relevant aspects of the attachment framework to the pediatric chronic pain context. The theoretical and empirical literature is reviewed regarding the potential role of attachment-based constructs such as vulnerability and maintaining factors of pediatric chronic pain. The nature and targets of attachment-based pediatric interventions are considered, with particular focus on relevance for the pediatric chronic pain context. The potential role of attachment style in the transition from acute to chronic pain is considered, with further research directions outlined. PMID:27792141

Technical Letter Report: Evaluation and Analysis of a Few International Periodic Safety Review Summary Reports

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chopra, Omesh K.; Diercks, Dwight R.; Ma, David Chia-Chiun

At the request of the United States (U.S.) government, the International Atomic Energy Agency (IAEA) assembled a team of 20 senior safety experts to review the regulatory framework for the safety of operating nuclear power plants in the United States. This review focused on the effectiveness of the regulatory functions implemented by the NRC and on its commitment to nuclear safety and continuous improvement. One suggestion resulting from that review was that the U.S. Nuclear Regulatory Commission (NRC) incorporate lessons learned from periodic safety reviews (PSRs) performed in other countries as an input to the NRC’s assessment processes. In themore » U.S., commercial nuclear power plants (NPPs) are granted an initial 40-year operating license, which may be renewed for additional 20-year periods, subject to complying with regulatory requirements. The NRC has established a framework through its inspection, and operational experience processes to ensure the safe operation of licensed nuclear facilities on an ongoing basis. In contrast, most other countries do not impose a specific time limit on the operating licenses for NPPs, they instead require that the utility operating the plant perform PSRs, typically at approximately 10-year intervals, to assure continued safe operation until the next assessment. The staff contracted with Argonne National Laboratory (Argonne) to perform a pilot review of selected translated PSR assessment reports and related documentation from foreign nuclear regulatory authorities to identify any potential new regulatory insights regarding license renewal-related topics and NPP operating experience (OpE). A total of 14 PSR assessment documents from 9 countries were reviewed. For all of the countries except France, individual reports were provided for each of the plants reviewed. In the case of France, three reports were provided that reviewed the performance assessment of thirty-four 900-MWe reactors of similar design commissioned between 1978 and 1988. All of the reports reviewed were the regulator’s assessment of the PSR findings rather than the original PSR report, and all but one were English translations from the original language. In these reviews, it was found that most of the countries base their regulatory guidance to some extent (and often to a large extent) on U.S. design codes and standards, NRC regulatory guidance, and U.S. industry guidance. In addition, many of the observed operational technical issues and OpE events reported for U.S. reactors are also cited in the PSR reports. The PSR reports also identified a number of potential technical material/component performance issues and OpE events that are not commonly reported for U.S. plants.« less

[Environmental health: the evolution of Colombia's current regulatory framework].

PubMed

García-Ubaque, Cesar A; García-Ubaque, Juan C; Vaca-Bohórquez, Martha L

2013-01-01

This essay presents an analysis of the evolution of environmental health management in Colombia, covering the period from the introduction of the Colombian Healthcare Code (1979) to laws 99 and 100 in 1993 and the introduction of Environmental Health Policy in Bogotá DC (2011). It proposes a conceptual model for environmental health management at three levels: proximal (physical, chemical and biological setting), intermediate (natural and cultural environment) and distal (economic, political and social structures). Relevant aspects of environmental health policy in Bogotá are analysed based on the proposed model.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

PubMed

Barber, Chris; Antonucci, Vincent; Baumann, Jens-Christoph; Brown, Roland; Covey-Crump, Elizabeth; Elder, David; Elliott, Eric; Fennell, Jared W; Gallou, Fabrice; Ide, Nathan D; Jordine, Guido; Kallemeyn, Jeffrey M; Lauwers, Dirk; Looker, Adam R; Lovelle, Lucie E; McLaughlin, Mark; Molzahn, Robert; Ott, Martin; Schils, Didier; Oestrich, Rolf Schulte; Stevenson, Neil; Talavera, Pere; Teasdale, Andrew; Urquhart, Michael W; Varie, David L; Welch, Dennie

2017-11-01

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions. Copyright © 2017 Elsevier Inc. All rights reserved.

Cell-based therapeutics: the next pillar of medicine.

PubMed

Fischbach, Michael A; Bluestone, Jeffrey A; Lim, Wendell A

2013-04-03

Two decades ago, the pharmaceutical industry-long dominated by small-molecule drugs-was revolutionized by the the advent of biologics. Today, biomedicine sits on the cusp of a new revolution: the use of microbial and human cells as versatile therapeutic engines. Here, we discuss the promise of this "third pillar" of therapeutics in the context of current scientific, regulatory, economic, and perceptual challenges. History suggests that the advent of cellular medicines will require the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably altering and regulating cellular behaviors.

Enhancements Needed in GE Crop and Food Regulation in the U.S.

PubMed Central

Benbrook, Charles

2016-01-01

Genetically engineered (GE) crops, multi-ingredient foods derived from one or more GE ingredients, and GE agricultural inputs are regulated in the United States under a “Coordinated Framework” that was literally cobbled together in the early 1990s. Via this Framework, responsibility is spread across three federal agencies for the assessment and management of potential risks arising from the planting of GE crops, the raising of GE animals, or uses of GE inputs. The Framework was incomplete and conceptually flawed from the beginning. Despite multiple, piecemeal efforts to update aspects of GE risk assessment and regulatory policy, the Coordinated Framework survives to this day largely unchanged. Its shortcomings are recognized in both the scientific and legal communities, but meaningful reforms thus far remain out of reach, blocked by the intense controversy now surrounding all things biotech. Five generic reforms and another five specific initiatives are described to create a more robust, science-driven GE regulatory infrastructure in the U.S. PMID:27066473

Interpersonal emotion regulation.

PubMed

Zaki, Jamil; Williams, W Craig

2013-10-01

Contemporary emotion regulation research emphasizes intrapersonal processes such as cognitive reappraisal and expressive suppression, but people experiencing affect commonly choose not to go it alone. Instead, individuals often turn to others for help in shaping their affective lives. How and under what circumstances does such interpersonal regulation modulate emotional experience? Although scientists have examined allied phenomena such as social sharing, empathy, social support, and prosocial behavior for decades, there have been surprisingly few attempts to integrate these data into a single conceptual framework of interpersonal regulation. Here we propose such a framework. We first map a "space" differentiating classes of interpersonal regulation according to whether an individual uses an interpersonal regulatory episode to alter their own or another person's emotion. We then identify 2 types of processes--response-dependent and response-independent--that could support interpersonal regulation. This framework classifies an array of processes through which interpersonal contact fulfills regulatory goals. More broadly, it organizes diffuse, heretofore independent data on "pieces" of interpersonal regulation, and identifies growth points for this young and exciting research domain.

VirtualLeaf: an open-source framework for cell-based modeling of plant tissue growth and development.

PubMed

Merks, Roeland M H; Guravage, Michael; Inzé, Dirk; Beemster, Gerrit T S

2011-02-01

Plant organs, including leaves and roots, develop by means of a multilevel cross talk between gene regulation, patterned cell division and cell expansion, and tissue mechanics. The multilevel regulatory mechanisms complicate classic molecular genetics or functional genomics approaches to biological development, because these methodologies implicitly assume a direct relation between genes and traits at the level of the whole plant or organ. Instead, understanding gene function requires insight into the roles of gene products in regulatory networks, the conditions of gene expression, etc. This interplay is impossible to understand intuitively. Mathematical and computer modeling allows researchers to design new hypotheses and produce experimentally testable insights. However, the required mathematics and programming experience makes modeling poorly accessible to experimental biologists. Problem-solving environments provide biologically intuitive in silico objects ("cells", "regulation networks") required for setting up a simulation and present those to the user in terms of familiar, biological terminology. Here, we introduce the cell-based computer modeling framework VirtualLeaf for plant tissue morphogenesis. The current version defines a set of biologically intuitive C++ objects, including cells, cell walls, and diffusing and reacting chemicals, that provide useful abstractions for building biological simulations of developmental processes. We present a step-by-step introduction to building models with VirtualLeaf, providing basic example models of leaf venation and meristem development. VirtualLeaf-based models provide a means for plant researchers to analyze the function of developmental genes in the context of the biophysics of growth and patterning. VirtualLeaf is an ongoing open-source software project (http://virtualleaf.googlecode.com) that runs on Windows, Mac, and Linux.

Advancing environmental toxicology through chemical dosimetry: External exposures versus tissue residues

USGS Publications Warehouse

McCarty, L.S.; Landrum, P.F.; Luoma, S.N.; Meador, J.P.; Merten, A.A.; Shephard, B.K.; van Wezelzz, A.P.

2011-01-01

The tissue residue dose concept has been used, although in a limited manner, in environmental toxicology for more than 100 y. This review outlines the history of this approach and the technical background for organic chemicals and metals. Although the toxicity of both can be explained in tissue residue terms, the relationship between external exposure concentration, body and/or tissues dose surrogates, and the effective internal dose at the sites of toxic action tends to be more complex for metals. Various issues and current limitations related to research and regulatory applications are also examined. It is clear that the tissue residue approach (TRA) should be an integral component in future efforts to enhance the generation, understanding, and utility of toxicity testing data, both in the laboratory and in the field. To accomplish these goals, several key areas need to be addressed: 1) development of a risk-based interpretive framework linking toxicology and ecology at multiple levels of biological organization and incorporating organism-based dose metrics; 2) a broadly applicable, generally accepted classification scheme for modes/mechanisms of toxic action with explicit consideration of residue information to improve both single chemical and mixture toxicity data interpretation and regulatory risk assessment; 3) toxicity testing protocols updated to ensure collection of adequate residue information, along with toxicokinetics and toxicodynamics information, based on explicitly defined toxicological models accompanied by toxicological model validation; 4) continued development of residueeffect databases is needed ensure their ongoing utility; and 5) regulatory guidance incorporating residue-based testing and interpretation approaches, essential in various jurisdictions. ??:2010 SETAC.

Analysis of Pan-European attitudes to the eradication and control of bovine viral diarrhoea.

PubMed

Heffernan, C; Misturelli, F; Nielsen, L; Gunn, G J; Yu, J

2009-02-07

At present, national-level policies concerning the eradication and control of bovine viral diarrhoea (BVD) differ widely across Europe. Some Scandinavian countries have enacted strong regulatory frameworks to eradicate the disease, whereas other countries have few formal policies. To examine these differences, the attitudes of stakeholders and policy makers in 17 European countries were investigated. A web-based questionnaire was sent to policy makers, government and private sector veterinarians, and representatives of farmers' organisations. In total, 131 individuals responded to the questionnaire and their responses were analysed by applying a method used in sociolinguistics: frame analysis. The results showed that the different attitudes of countries that applied compulsory or voluntary frameworks were associated with different views about the attribution or blame for BVD and the roles ascribed to farmers and other stakeholders in its eradication and control.

A framework for scalable parameter estimation of gene circuit models using structural information.

PubMed

Kuwahara, Hiroyuki; Fan, Ming; Wang, Suojin; Gao, Xin

2013-07-01

Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation. Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems. http://sfb.kaust.edu.sa/Pages/Software.aspx. Supplementary data are available at Bioinformatics online.

A framework for modelling gene regulation which accommodates non-equilibrium mechanisms.

PubMed

Ahsendorf, Tobias; Wong, Felix; Eils, Roland; Gunawardena, Jeremy

2014-12-05

Gene regulation has, for the most part, been quantitatively analysed by assuming that regulatory mechanisms operate at thermodynamic equilibrium. This formalism was originally developed to analyse the binding and unbinding of transcription factors from naked DNA in eubacteria. Although widely used, it has made it difficult to understand the role of energy-dissipating, epigenetic mechanisms, such as DNA methylation, nucleosome remodelling and post-translational modification of histones and co-regulators, which act together with transcription factors to regulate gene expression in eukaryotes. Here, we introduce a graph-based framework that can accommodate non-equilibrium mechanisms. A gene-regulatory system is described as a graph, which specifies the DNA microstates (vertices), the transitions between microstates (edges) and the transition rates (edge labels). The graph yields a stochastic master equation for how microstate probabilities change over time. We show that this framework has broad scope by providing new insights into three very different ad hoc models, of steroid-hormone responsive genes, of inherently bounded chromatin domains and of the yeast PHO5 gene. We find, moreover, surprising complexity in the regulation of PHO5, which has not yet been experimentally explored, and we show that this complexity is an inherent feature of being away from equilibrium. At equilibrium, microstate probabilities do not depend on how a microstate is reached but, away from equilibrium, each path to a microstate can contribute to its steady-state probability. Systems that are far from equilibrium thereby become dependent on history and the resulting complexity is a fundamental challenge. To begin addressing this, we introduce a graph-based concept of independence, which can be applied to sub-systems that are far from equilibrium, and prove that history-dependent complexity can be circumvented when sub-systems operate independently. As epigenomic data become increasingly available, we anticipate that gene function will come to be represented by graphs, as gene structure has been represented by sequences, and that the methods introduced here will provide a broader foundation for understanding how genes work.

Regulating small things: genes, gametes and nanotechnology.

PubMed

Bennett, Belinda

2007-08-01

Biotechnology and nanotechnology both intersect with other technologies in ways that open new possibilities for further technological progress. The potential for increased convergence between technological fields highlights the need for regulatory frameworks to be integrated, flexible and responsive. Within a federal legal system such as Australia's, there is a need to ensure that we adopt a coordinated national approach to the crafting of regulatory solutions. In addition, there is a need for global cooperation in the development of international standards and regulatory harmonisation. Finally, this article considers the role that law plays in negotiating risk in relation to new technologies.

A 3D bioprinting exemplar of the consequences of the regulatory requirements on customized processes.

PubMed

Hourd, Paul; Medcalf, Nicholas; Segal, Joel; Williams, David J

2015-01-01

Computer-aided 3D printing approaches to the industrial production of customized 3D functional living constructs for restoration of tissue and organ function face significant regulatory challenges. Using the manufacture of a customized, 3D-bioprinted nasal implant as a well-informed but hypothetical exemplar, we examine how these products might be regulated. Existing EU and USA regulatory frameworks do not account for the differences between 3D printing and conventional manufacturing methods or the ability to create individual customized products using mechanized rather than craft approaches. Already subject to extensive regulatory control, issues related to control of the computer-aided design to manufacture process and the associated software system chain present additional scientific and regulatory challenges for manufacturers of these complex 3D-bioprinted advanced combination products.

The Normative Structure of Knowledge Production and Utilization in Education: A Report on Work in Progress.

ERIC Educational Resources Information Center

Markley, O. W.

The primary objective of this study is to develop a systems-oriented analytical framework with which to better understand how formal policies serve as regulatory influences on knowledge production and utilization (KPU) in education. When completed, the framework being developed should be able to organize information about the KPU system and its…

Utilising Enterprise Risk Management Strategies to Develop a Governance and Operations Framework for a New Research Complex: A Case Study

ERIC Educational Resources Information Center

Clyde-Smith, Jodi

2014-01-01

Enterprise risk management strategies were used to develop a regulatory and operational framework for a new multi-partner Research Institute that will house up to 900 staff from four different institutions in Queensland, Australia. The Institute will operate in a business environment while functioning as a research resource for the higher…

Transatlantic Regulatory Cooperation: Background and Analysis

DTIC Science & Technology

2008-10-22

Damien Geradin, “Regulatory Co - opetition ,” Journal of International Economic Law (2000), 235-255, p. 236. 15 Transatlantic Policy Network (TPN), Completing... co -chairs (ministerial-level appointees with cabinet rank) from each side, as well as a number of EU Commissioners and U.S. Cabinet Members for the...broad ranging policy areas covered in the Framework. Currently, the co -chairs are Daniel Price, Assistant to the President for International Economic

[Regulatory Framework for Approval of PET Drug in Korea: A Survey Report].

PubMed

Kurihara, Chieko; Inoue, Tomio

2015-11-01

To identify regulatory framework for approval of PET drugs in Korea. Interview and literature survey. In Korea Good Manufacturing Practice (GMP) regulation specific to radiopharmaceuticals, including PET (Positron Emission Tomography) drugs, under the Pharmaceutical Affairs Act was issued in August 2014, to be enforced on July 1, 2015, and its guidance was issued in December 2014. The new facilities to be established after July 1 of 2015 have to be compatible with this new regulation and already established facilities have two years grace period until June 30 of 2017. During this period, the regulatory authority will inspect all of the production sites which hold or submit approvals of radiopharmaceuticals. As of September 2015 in Korea, there are 7 commercial companies and 15 hospitals and institutes, which have approvals of PET drugs mainly FDG, and these companies and/or hospitals can supply PET drugs outside institutions. In this article we introduce the Korean regulations of development and approval of radiopharmaceuticals. The Korean regulatory authorization policy for radiopharmaceuticals are to some extent similar to the policy which the U.S. regulators set as the new regulations of PET drug. It is expected that the situations of production sites in Korea are to be improved through actual discussions among regulators and PET community through the process of actual inspection.

Work-related stress risk assessment in Italy: a methodological proposal adapted to regulatory guidelines.

PubMed

Persechino, Benedetta; Valenti, Antonio; Ronchetti, Matteo; Rondinone, Bruna Maria; Di Tecco, Cristina; Vitali, Sara; Iavicoli, Sergio

2013-06-01

Work-related stress is one of the major causes of occupational ill health. In line with the regulatory framework on occupational health and safety (OSH), adequate models for assessing and managing risk need to be identified so as to minimize the impact of this stress not only on workers' health, but also on productivity. After close analysis of the Italian and European reference regulatory framework and work-related stress assessment and management models used in some European countries, we adopted the UK Health and Safety Executive's (HSE) Management Standards (MS) approach, adapting it to the Italian context in order to provide a suitable methodological proposal for Italy. We have developed a work-related stress risk assessment strategy, meeting regulatory requirements, now available on a specific web platform that includes software, tutorials, and other tools to assist companies in their assessments. This methodological proposal is new on the Italian work-related stress risk assessment scene. Besides providing an evaluation approach using scientifically validated instruments, it ensures the active participation of occupational health professionals in each company. The assessment tools provided enable companies not only to comply with the law, but also to contribute to a database for monitoring and assessment and give access to a reserved area for data analysis and comparisons.

Work-Related Stress Risk Assessment in Italy: A Methodological Proposal Adapted to Regulatory Guidelines

PubMed Central

Persechino, Benedetta; Valenti, Antonio; Ronchetti, Matteo; Rondinone, Bruna Maria; Di Tecco, Cristina; Vitali, Sara; Iavicoli, Sergio

2013-01-01

Background Work-related stress is one of the major causes of occupational ill health. In line with the regulatory framework on occupational health and safety (OSH), adequate models for assessing and managing risk need to be identified so as to minimize the impact of this stress not only on workers' health, but also on productivity. Methods After close analysis of the Italian and European reference regulatory framework and work-related stress assessment and management models used in some European countries, we adopted the UK Health and Safety Executive's (HSE) Management Standards (MS) approach, adapting it to the Italian context in order to provide a suitable methodological proposal for Italy. Results We have developed a work-related stress risk assessment strategy, meeting regulatory requirements, now available on a specific web platform that includes software, tutorials, and other tools to assist companies in their assessments. Conclusion This methodological proposal is new on the Italian work-related stress risk assessment scene. Besides providing an evaluation approach using scientifically validated instruments, it ensures the active participation of occupational health professionals in each company. The assessment tools provided enable companies not only to comply with the law, but also to contribute to a database for monitoring and assessment and give access to a reserved area for data analysis and comparisons. PMID:23961332

Dynamical analysis of cellular ageing by modeling of gene regulatory network based attractor landscape.

PubMed

Chong, Ket Hing; Zhang, Xiaomeng; Zheng, Jie

2018-01-01

Ageing is a natural phenomenon that is inherently complex and remains a mystery. Conceptual model of cellular ageing landscape was proposed for computational studies of ageing. However, there is a lack of quantitative model of cellular ageing landscape. This study aims to investigate the mechanism of cellular ageing in a theoretical model using the framework of Waddington's epigenetic landscape. We construct an ageing gene regulatory network (GRN) consisting of the core cell cycle regulatory genes (including p53). A model parameter (activation rate) is used as a measure of the accumulation of DNA damage. Using the bifurcation diagrams to estimate the parameter values that lead to multi-stability, we obtained a conceptual model for capturing three distinct stable steady states (or attractors) corresponding to homeostasis, cell cycle arrest, and senescence or apoptosis. In addition, we applied a Monte Carlo computational method to quantify the potential landscape, which displays: I) one homeostasis attractor for low accumulation of DNA damage; II) two attractors for cell cycle arrest and senescence (or apoptosis) in response to high accumulation of DNA damage. Using the Waddington's epigenetic landscape framework, the process of ageing can be characterized by state transitions from landscape I to II. By in silico perturbations, we identified the potential landscape of a perturbed network (inactivation of p53), and thereby demonstrated the emergence of a cancer attractor. The simulated dynamics of the perturbed network displays a landscape with four basins of attraction: homeostasis, cell cycle arrest, senescence (or apoptosis) and cancer. Our analysis also showed that for the same perturbed network with low DNA damage, the landscape displays only the homeostasis attractor. The mechanistic model offers theoretical insights that can facilitate discovery of potential strategies for network medicine of ageing-related diseases such as cancer.

How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

PubMed

Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; Maxwell, Gavin; Meek, M E Bette; Paini, Alicia; Perkins, Edward; Sobanski, Tomasz; Villeneuve, Dan; Waters, Katrina M; Whelan, Maurice

2017-02-01

Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.

AhR-mediated gene expression in the developing mouse telencephalon.

PubMed

Gohlke, Julia M; Stockton, Pat S; Sieber, Stella; Foley, Julie; Portier, Christopher J

2009-11-01

We hypothesize that TCDD-induced developmental neurotoxicity is modulated through an AhR-dependent interaction with key regulatory neuronal differentiation pathways during telencephalon development. To test this hypothesis we examined global gene expression in both dorsal and ventral telencephalon tissues in E13.5 AhR-/- and wildtype mice exposed to TCDD or vehicle. Consistent with previous biochemical, pathological and behavioral studies, our results suggest TCDD initiated changes in gene expression in the developing telencephalon are primarily AhR-dependent, as no statistically significant gene expression changes are evident after TCDD exposure in AhR-/- mice. Based on a gene regulatory network for neuronal specification in the developing telencephalon, the present analysis suggests differentiation of GABAergic neurons in the ventral telencephalon is compromised in TCDD exposed and AhR-/- mice. In addition, our analysis suggests Sox11 may be directly regulated by AhR based on gene expression and comparative genomics analyses. In conclusion, this analysis supports the hypothesis that AhR has a specific role in the normal development of the telencephalon and provides a mechanistic framework for neurodevelopmental toxicity of chemicals that perturb AhR signaling.

Reasserting the primacy of human needs to reclaim the 'lost half' of sustainable development.

PubMed

Everard, Mark; Longhurst, James W S

2018-04-15

The concept of sustainable development evolved from growing awareness of the interdependence of social and economic progress with the limits of the supporting natural environment, becoming progressively integrated into global agreements and transposition into local regulatory and implementation frameworks. We argue that transposition of the concept into regulation and supporting tools reduced the focus to minimal environmental and social standards, perceived as imposing constraints rather than opportunities for innovation to meet human needs. The aspirational 'half' of the concept of sustainable development specifically addressing human needs was thus lost in transposing high ideals into regulatory instruments. The Sustainable Development Goals (SDGs) restore focus on interlinked human needs, stimulating innovation of products and processes to satisfy them. Through three case studies - PVC water pipes, river quality management in England, and UK local air quality management - we explore the current operationalisation of the concept in diverse settings, using the SDG framework to highlight the broader societal purposes central to sustainable development. Partnerships involving civil society support evolution of regulatory instruments and their implementation, optimising social and ecological benefits thereby serving more human needs. Restoring the visionary 'lost half' of sustainable development - meeting human needs in sustainable ways - creates incentives for innovation and partnership; an innovation framework rather than a perceived constraint. Copyright © 2017 Elsevier B.V. All rights reserved.

Opportunities and obstacles to the development of nanopharmaceuticals for human use.

PubMed

Nassiri Koopaei, Nasser; Abdollahi, Mohammad

2016-10-06

Pharmaceutical nanotechnology has generated breakthrough developments in improving health care and human life from its emergence. The biomaterials employed mainly aim at improving drug delivery systems, imaging and diagnostic technologies while the nanoscale materials are in widespread use in other industries such as electronics and optics. Such advancement may revolutionize the drug development and therapy with new and more efficient treatments. Although, nanotechnology assists humankind in improving its well being, it has certain limitations that entail thorough investigation by the regulatory and scientific authorities. To address concerns regarding the safety and toxicity profile of the nanopharmaceuticals, we have reviewed the challenges and solutions of nanopharmaceuticals use in human health and the related health risks. In this regard, regulatory and scientific bodies such as countries' Food and Drug Administration (FDA), Organization for Economic Co-operation and Development (OECD), European Medicine Agency (EMA), Environmental Protection Agency (EPA), National Institute for Occupational Safety and Health (NIOSH), and World Health Organization (WHO) can participate in developing and reinforcing safety measures and regulatory frameworks to insure the public health. The regulatory authorities may enforce the nanopharmaceutical industries to conduct comprehensive toxicity tests and monitor the adverse drug reaction reports in close collaboration with the scientific community to act accordingly and inform the public as the implementation of the strategy. Nanopharmaceuticals have tremendous potential for human use as therapeutic or diagnostic agents. But their toxicity profile should be well addressed and the respective regulatory framework developed and reinforced by the authorities.

CMIP: a software package capable of reconstructing genome-wide regulatory networks using gene expression data.

PubMed

Zheng, Guangyong; Xu, Yaochen; Zhang, Xiujun; Liu, Zhi-Ping; Wang, Zhuo; Chen, Luonan; Zhu, Xin-Guang

2016-12-23

A gene regulatory network (GRN) represents interactions of genes inside a cell or tissue, in which vertexes and edges stand for genes and their regulatory interactions respectively. Reconstruction of gene regulatory networks, in particular, genome-scale networks, is essential for comparative exploration of different species and mechanistic investigation of biological processes. Currently, most of network inference methods are computationally intensive, which are usually effective for small-scale tasks (e.g., networks with a few hundred genes), but are difficult to construct GRNs at genome-scale. Here, we present a software package for gene regulatory network reconstruction at a genomic level, in which gene interaction is measured by the conditional mutual information measurement using a parallel computing framework (so the package is named CMIP). The package is a greatly improved implementation of our previous PCA-CMI algorithm. In CMIP, we provide not only an automatic threshold determination method but also an effective parallel computing framework for network inference. Performance tests on benchmark datasets show that the accuracy of CMIP is comparable to most current network inference methods. Moreover, running tests on synthetic datasets demonstrate that CMIP can handle large datasets especially genome-wide datasets within an acceptable time period. In addition, successful application on a real genomic dataset confirms its practical applicability of the package. This new software package provides a powerful tool for genomic network reconstruction to biological community. The software can be accessed at http://www.picb.ac.cn/CMIP/ .

Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.

PubMed

Wang, Edwin; Zaman, Naif; Mcgee, Shauna; Milanese, Jean-Sébastien; Masoudi-Nejad, Ali; O'Connor-McCourt, Maureen

2015-02-01

Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment. To meet these challenges, we discuss a cancer hallmark network framework for modeling genome sequencing data to predict cancer clonal evolution and associated clinical phenotypes. The framework includes: (1) cancer hallmarks that can be represented by a few molecular/signaling networks. 'Network operational signatures' which represent gene regulatory logics/strengths enable to quantify state transitions and measures of hallmark traits. Thus, sets of genomic alterations which are associated with network operational signatures could be linked to the state/measure of hallmark traits. The network operational signature transforms genotypic data (i.e., genomic alterations) to regulatory phenotypic profiles (i.e., regulatory logics/strengths), to cellular phenotypic profiles (i.e., hallmark traits) which lead to clinical phenotypic profiles (i.e., a collection of hallmark traits). Furthermore, the framework considers regulatory logics of the hallmark networks under tumor evolutionary dynamics and therefore also includes: (2) a self-promoting positive feedback loop that is dominated by a genomic instability network and a cell survival/proliferation network is the main driver of tumor clonal evolution. Surrounding tumor stroma and its host immune systems shape the evolutionary paths; (3) cell motility initiating metastasis is a byproduct of the above self-promoting loop activity during tumorigenesis; (4) an emerging hallmark network which triggers genome duplication dominates a feed-forward loop which in turn could act as a rate-limiting step for tumor formation; (5) mutations and other genomic alterations have specific patterns and tissue-specificity, which are driven by aging and other cancer-inducing agents. This framework represents the logics of complex cancer biology as a myriad of phenotypic complexities governed by a limited set of underlying organizing principles. It therefore adds to our understanding of tumor evolution and tumorigenesis, and moreover, potential usefulness of predicting tumors' evolutionary paths and clinical phenotypes. Strategies of using this framework in conjunction with genome sequencing data in an attempt to predict personalized drug targets, drug resistance, and metastasis for cancer patients, as well as cancer risks for healthy individuals are discussed. Accurate prediction of cancer clonal evolution and clinical phenotypes will have substantial impact on timely diagnosis, personalized treatment and personalized prevention of cancer. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

The pearl oyster Pinctada fucata martensii genome and multi-omic analyses provide insights into biomineralization

PubMed Central

Fan, Guangyi; Jiao, Yu; Zhang, He; Huang, Ronglian; Zheng, Zhe; Bian, Chao; Deng, Yuewen; Wang, Qingheng; Wang, Zhongduo; Liang, Xinming; Liang, Haiying; Shi, Chengcheng; Zhao, Xiaoxia; Sun, Fengming; Hao, Ruijuan; Bai, Jie; Liu, Jialiang; Chen, Wenbin; Liang, Jinlian; Liu, Weiqing; Xu, Zhe; Shi, Qiong; Xu, Xun

2017-01-01

Abstract Nacre, the iridescent material found in pearls and shells of molluscs, is formed through an extraordinary process of matrix-assisted biomineralization. Despite recent advances, many aspects of the biomineralization process and its evolutionary origin remain unknown. The pearl oyster Pinctada fucata martensii is a well-known master of biomineralization, but the molecular mechanisms that underlie its production of shells and pearls are not fully understood. We sequenced the highly polymorphic genome of the pearl oyster and conducted multi-omic and biochemical studies to probe nacre formation. We identified a large set of novel proteins participating in matrix-framework formation, many in expanded families, including components similar to that found in vertebrate bones such as collagen-related VWA-containing proteins, chondroitin sulfotransferases, and regulatory elements. Considering that there are only collagen-based matrices in vertebrate bones and chitin-based matrices in most invertebrate skeletons, the presence of both chitin and elements of collagen-based matrices in nacre suggests that elements of chitin- and collagen-based matrices have deep roots and might be part of an ancient biomineralizing matrix. Our results expand the current shell matrix-framework model and provide new insights into the evolution of diverse biomineralization systems. PMID:28873964

Using probabilistic terrorism risk modeling for regulatory benefit-cost analysis: application to the Western hemisphere travel initiative in the land environment.

PubMed

Willis, Henry H; LaTourrette, Tom

2008-04-01

This article presents a framework for using probabilistic terrorism risk modeling in regulatory analysis. We demonstrate the framework with an example application involving a regulation under consideration, the Western Hemisphere Travel Initiative for the Land Environment, (WHTI-L). First, we estimate annualized loss from terrorist attacks with the Risk Management Solutions (RMS) Probabilistic Terrorism Model. We then estimate the critical risk reduction, which is the risk-reducing effectiveness of WHTI-L needed for its benefit, in terms of reduced terrorism loss in the United States, to exceed its cost. Our analysis indicates that the critical risk reduction depends strongly not only on uncertainties in the terrorism risk level, but also on uncertainty in the cost of regulation and how casualties are monetized. For a terrorism risk level based on the RMS standard risk estimate, the baseline regulatory cost estimate for WHTI-L, and a range of casualty cost estimates based on the willingness-to-pay approach, our estimate for the expected annualized loss from terrorism ranges from $2.7 billion to $5.2 billion. For this range in annualized loss, the critical risk reduction for WHTI-L ranges from 7% to 13%. Basing results on a lower risk level that results in halving the annualized terrorism loss would double the critical risk reduction (14-26%), and basing the results on a higher risk level that results in a doubling of the annualized terrorism loss would cut the critical risk reduction in half (3.5-6.6%). Ideally, decisions about terrorism security regulations and policies would be informed by true benefit-cost analyses in which the estimated benefits are compared to costs. Such analyses for terrorism security efforts face substantial impediments stemming from the great uncertainty in the terrorist threat and the very low recurrence interval for large attacks. Several approaches can be used to estimate how a terrorism security program or regulation reduces the distribution of risks it is intended to manage. But, continued research to develop additional tools and data is necessary to support application of these approaches. These include refinement of models and simulations, engagement of subject matter experts, implementation of program evaluation, and estimating the costs of casualties from terrorism events.

An algebra-based method for inferring gene regulatory networks.

PubMed

Vera-Licona, Paola; Jarrah, Abdul; Garcia-Puente, Luis David; McGee, John; Laubenbacher, Reinhard

2014-03-26

The inference of gene regulatory networks (GRNs) from experimental observations is at the heart of systems biology. This includes the inference of both the network topology and its dynamics. While there are many algorithms available to infer the network topology from experimental data, less emphasis has been placed on methods that infer network dynamics. Furthermore, since the network inference problem is typically underdetermined, it is essential to have the option of incorporating into the inference process, prior knowledge about the network, along with an effective description of the search space of dynamic models. Finally, it is also important to have an understanding of how a given inference method is affected by experimental and other noise in the data used. This paper contains a novel inference algorithm using the algebraic framework of Boolean polynomial dynamical systems (BPDS), meeting all these requirements. The algorithm takes as input time series data, including those from network perturbations, such as knock-out mutant strains and RNAi experiments. It allows for the incorporation of prior biological knowledge while being robust to significant levels of noise in the data used for inference. It uses an evolutionary algorithm for local optimization with an encoding of the mathematical models as BPDS. The BPDS framework allows an effective representation of the search space for algebraic dynamic models that improves computational performance. The algorithm is validated with both simulated and experimental microarray expression profile data. Robustness to noise is tested using a published mathematical model of the segment polarity gene network in Drosophila melanogaster. Benchmarking of the algorithm is done by comparison with a spectrum of state-of-the-art network inference methods on data from the synthetic IRMA network to demonstrate that our method has good precision and recall for the network reconstruction task, while also predicting several of the dynamic patterns present in the network. Boolean polynomial dynamical systems provide a powerful modeling framework for the reverse engineering of gene regulatory networks, that enables a rich mathematical structure on the model search space. A C++ implementation of the method, distributed under LPGL license, is available, together with the source code, at http://www.paola-vera-licona.net/Software/EARevEng/REACT.html.

Project Cerberus: tobacco industry strategy to create an alternative to the Framework Convention on Tobacco Control.

PubMed

Mamudu, Hadii M; Hammond, Ross; Glantz, Stanton A

2008-09-01

Between 1999 and 2001, British American Tobacco, Philip Morris, and Japan Tobacco International executed Project Cerberus to develop a global voluntary regulatory regime as an alternative to the Framework Convention on Tobacco Control (FCTC). They aimed to develop a global voluntary regulatory code to be overseen by an independent audit body and to focus attention on youth smoking prevention. The International Tobacco Products Marketing Standards announced in September 2001, however, did not have the independent audit body. Although the companies did not stop the FCTC, they continue to promote the International Tobacco Products Marketing Standards youth smoking prevention as an alternative to the FCTC. Public health civil society groups should help policymakers and governments understand the importance of not working with the tobacco industry.

Project Cerberus: Tobacco Industry Strategy to Create an Alternative to the Framework Convention on Tobacco Control

PubMed Central

Mamudu, Hadii M.; Hammond, Ross; Glantz, Stanton A.

2008-01-01

Between 1999 and 2001, British American Tobacco, Philip Morris, and Japan Tobacco International executed Project Cerberus to develop a global voluntary regulatory regime as an alternative to the Framework Convention on Tobacco Control (FCTC). They aimed to develop a global voluntary regulatory code to be overseen by an independent audit body and to focus attention on youth smoking prevention. The International Tobacco Products Marketing Standards announced in September 2001, however, did not have the independent audit body. Although the companies did not stop the FCTC, they continue to promote the International Tobacco Products Marketing Standards youth smoking prevention as an alternative to the FCTC. Public health civil society groups should help policymakers and governments understand the importance of not working with the tobacco industry. PMID:18633079

Measuring and Modeling the U.S. Regulatory Ecosystem

NASA Astrophysics Data System (ADS)

Bommarito, Michael J., II; Katz, Daniel Martin

2017-09-01

Over the last 23 years, the U.S. Securities and Exchange Commission has required over 34,000 companies to file over 165,000 annual reports. These reports, the so-called "Form 10-Ks," contain a characterization of a company's financial performance and its risks, including the regulatory environment in which a company operates. In this paper, we analyze over 4.5 million references to U.S. Federal Acts and Agencies contained within these reports to measure the regulatory ecosystem, in which companies are organisms inhabiting a regulatory environment. While individuals across the political, economic, and academic world frequently refer to trends in this regulatory ecosystem, far less attention has been paid to supporting such claims with large-scale, longitudinal data. In this paper, in addition to positing a model of regulatory ecosystems, we document an increase in the regulatory energy per filing, i.e., a warming "temperature." We also find that the diversity of the regulatory ecosystem has been increasing over the past two decades. These findings support the claim that regulatory activity and complexity are increasing, and this framework contributes an important step towards improving academic and policy discussions around legal complexity and regulation.

OrganoRelease - A framework for modeling the release of organic chemicals from the use and post-use of consumer products.

PubMed

Tao, Mengya; Li, Dingsheng; Song, Runsheng; Suh, Sangwon; Keller, Arturo A

2018-03-01

Chemicals in consumer products have become the focus of recent regulatory developments including California's Safer Consumer Products Act. However, quantifying the amount of chemicals released during the use and post-use phases of consumer products is challenging, limiting the ability to understand their impacts. Here we present a comprehensive framework, OrganoRelease, for estimating the release of organic chemicals from the use and post-use of consumer products given limited information. First, a novel Chemical Functional Use Classifier estimates functional uses based on chemical structure. Second, the quantity of chemicals entering different product streams is estimated based on market share data of the chemical functional uses. Third, chemical releases are estimated based on either chemical product categories or functional uses by using the Specific Environmental Release Categories and EU Technological Guidance Documents. OrganoRelease connects 19 unique functional uses and 14 product categories across 4 data sources and provides multiple pathways for chemical release estimation. Available user information can be incorporated in the framework at various stages. The Chemical Functional Use Classifier achieved an average accuracy above 84% for nine functional uses, which enables the OrganoRelease to provide release estimates for the chemical, mostly using only the molecular structure. The results can be can be used as input for methods estimating environmental fate and exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

Advancing Drug Safety Through Prospective Pharmacovigilance.

PubMed

Pitts, Peter J; Le Louet, Hervé

2018-01-01

Much has changed in a relatively short period of time. There is a raging debate over the level of evidence expected to first introduce a treatment to patients based on smaller, more adaptive data sets. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in both the review and postmarketing regulatory framework is happening in front of our eyes in real time. To improve the ability of patients to receive high-quality, safe, effective, and timely care, better information via pharmacovigilance must be a priority as the world's many regulatory systems build the capacity to harness electronic health information to improve health, care quality, and safety. Globally, the widely variable ability of nations to build reliable regulatory systems (from precise review to robust pharmacovigilance) is a dangerous source of health care inequality. Developing validated tools and techniques for "predictive pharmacovigilance" will assist all health systems in better understanding the risks and benefits of the medicines they regulate by understanding what should be happening once a new medicine moves from risk-benefit regulatory efficacy to real-world risk-effectiveness. This will be of particular utility for smaller regulatory agencies with fewer resources. By comparing preapproval predictive pharmacovigilance data, developing regulatory authorities will be able to better understand the potential gap between what was predicted and what was actually measured (via more traditional pharmacovigilance methodologies). Predictive pharmacovigilance recognizes the value of understanding the imperfect reporting of real-world clinical use and that the absence of reporting is, in itself, an important postmarketing signal.

Adverse Outcome Pathways for Regulatory Applications: Examination of Four Case Studies With Different Degrees of Completeness and Scientific Confidence.

PubMed

Perkins, Edward J; Antczak, Philipp; Burgoon, Lyle; Falciani, Francesco; Garcia-Reyero, Natàlia; Gutsell, Steve; Hodges, Geoff; Kienzler, Aude; Knapen, Dries; McBride, Mary; Willett, Catherine

2015-11-01

Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as 'Hepatocellular proliferation leading to cancer', were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

The unforeseen challenge: from genotype-to-phenotype in cell populations

NASA Astrophysics Data System (ADS)

Braun, Erez

2015-02-01

Biological cells present a paradox, in that they show simultaneous stability and flexibility, allowing them to adapt to new environments and to evolve over time. The emergence of stable cell states depends on genotype-to-phenotype associations, which essentially reflect the organization of gene regulatory modes. The view taken here is that cell-state organization is a dynamical process in which the molecular disorder manifests itself in a macroscopic order. The genome does not determine the ordered cell state; rather, it participates in this process by providing a set of constraints on the spectrum of regulatory modes, analogous to boundary conditions in physical dynamical systems. We have developed an experimental framework, in which cell populations are exposed to unforeseen challenges; novel perturbations they had not encountered before along their evolutionary history. This approach allows an unbiased view of cell dynamics, uncovering the potential of cells to evolve and develop adapted stable states. In the last decade, our experiments have revealed a coherent set of observations within this framework, painting a picture of the living cell that in many ways is not aligned with the conventional one. Of particular importance here, is our finding that adaptation of cell-state organization is essentially an efficient exploratory dynamical process rather than one founded on random mutations. Based on our framework, a set of concepts underlying cell-state organization—exploration evolving by global, non-specific, dynamics of gene activity—is presented here. These concepts have significant consequences for our understanding of the emergence and stabilization of a cell phenotype in diverse biological contexts. Their implications are discussed for three major areas of biological inquiry: evolution, cell differentiation and cancer. There is currently no unified theoretical framework encompassing the emergence of order, a stable state, in the living cell. Hopefully, the integrated picture described here will provide a modest contribution towards a physics theory of the cell.

Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states

PubMed Central

Jang, Sumin; Choubey, Sandeep; Furchtgott, Leon; Zou, Ling-Nan; Doyle, Adele; Menon, Vilas; Loew, Ethan B; Krostag, Anne-Rachel; Martinez, Refugio A; Madisen, Linda; Levi, Boaz P; Ramanathan, Sharad

2017-01-01

The complexity of gene regulatory networks that lead multipotent cells to acquire different cell fates makes a quantitative understanding of differentiation challenging. Using a statistical framework to analyze single-cell transcriptomics data, we infer the gene expression dynamics of early mouse embryonic stem (mES) cell differentiation, uncovering discrete transitions across nine cell states. We validate the predicted transitions across discrete states using flow cytometry. Moreover, using live-cell microscopy, we show that individual cells undergo abrupt transitions from a naïve to primed pluripotent state. Using the inferred discrete cell states to build a probabilistic model for the underlying gene regulatory network, we further predict and experimentally verify that these states have unique response to perturbations, thus defining them functionally. Our study provides a framework to infer the dynamics of differentiation from single cell transcriptomics data and to build predictive models of the gene regulatory networks that drive the sequence of cell fate decisions during development. DOI: http://dx.doi.org/10.7554/eLife.20487.001 PMID:28296635

Pan-cancer analysis of somatic copy number alterations implicates IRS4 and IGF2 in enhancer hijacking

PubMed Central

Weischenfeldt, Joachim; Dubash, Taronish; Drainas, Alexandros P.; Mardin, Balca R.; Chen, Yuanyuan; Stütz, Adrian M.; Waszak, Sebastian M.; Bosco, Graziella; Halvorsen, Ann Rita; Raeder, Benjamin; Efthymiopoulos, Theocharis; Erkek, Serap; Siegl, Christine; Brenner, Hermann; Brustugun, Odd Terje; Dieter, Sebastian M.; Northcott, Paul A.; Petersen, Iver; Pfister, Stefan M.; Schneider, Martin; Solberg, Steinar K.; Thunissen, Erik; Weichert, Wilko; Zichner, Thomas; Thomas, Roman; Peifer, Martin; Helland, Aslaug; Ball, Claudia R.; Jechlinger, Martin; Sotillo, Rocio; Glimm, Hanno; Korbel, Jan O.

2018-01-01

Extensive prior research has focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearranging cis-regulatory elements remains unclear. Here, we present a framework for inferring cancer-related gene overexpression resulting from cis-regulatory element reorganization (e.g., enhancer hijacking), by integrating SCNAs, gene expression data, and information on chromatin interaction domains. Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer associates with recurrent deletions in cis, and present evidence supporting a tumor-promoting role. We additionally pursued cancer type-specific analyses, uncovering IGF2 as a target for enhancer hijacking in colorectal cancer. IGF2-containing tandem duplications result in the de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, which mediates high-level gene activation. Our framework enables systematic inference of cis-regulatory element rearrangements mediating dysregulation in cancer. PMID:27869826

A mathematical framework for the selection of an optimal set of peptides for epitope-based vaccines.

PubMed

Toussaint, Nora C; Dönnes, Pierre; Kohlbacher, Oliver

2008-12-01

Epitope-based vaccines (EVs) have a wide range of applications: from therapeutic to prophylactic approaches, from infectious diseases to cancer. The development of an EV is based on the knowledge of target-specific antigens from which immunogenic peptides, so-called epitopes, are derived. Such epitopes form the key components of the EV. Due to regulatory, economic, and practical concerns the number of epitopes that can be included in an EV is limited. Furthermore, as the major histocompatibility complex (MHC) binding these epitopes is highly polymorphic, every patient possesses a set of MHC class I and class II molecules of differing specificities. A peptide combination effective for one person can thus be completely ineffective for another. This renders the optimal selection of these epitopes an important and interesting optimization problem. In this work we present a mathematical framework based on integer linear programming (ILP) that allows the formulation of various flavors of the vaccine design problem and the efficient identification of optimal sets of epitopes. Out of a user-defined set of predicted or experimentally determined epitopes, the framework selects the set with the maximum likelihood of eliciting a broad and potent immune response. Our ILP approach allows an elegant and flexible formulation of numerous variants of the EV design problem. In order to demonstrate this, we show how common immunological requirements for a good EV (e.g., coverage of epitopes from each antigen, coverage of all MHC alleles in a set, or avoidance of epitopes with high mutation rates) can be translated into constraints or modifications of the objective function within the ILP framework. An implementation of the algorithm outperforms a simple greedy strategy as well as a previously suggested evolutionary algorithm and has runtimes on the order of seconds for typical problem sizes.

Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence.

PubMed

Meek, M E Bette; Palermo, Christine M; Bachman, Ammie N; North, Colin M; Jeffrey Lewis, R

2014-06-01

The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of "how much information is enough" to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose-response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Organizing environmental flow frameworks to meet hydropower mitigation needs

DOE Office of Scientific and Technical Information (OSTI.GOV)

McManamay, Ryan A.; Brewer, Shannon K.; Jager, Henriette I.

The global recognition of the importance of natural flow regimes to sustain the ecological integrity of river systems has led to increased societal pressure on the hydropower industry to change plant operations to improve downstream aquatic ecosystems. However, a complete reinstatement of natural flow regimes is often unrealistic when balancing water needs for ecosystems, energy production, and other human uses. Thus, stakeholders must identify a prioritized subset of flow prescriptions that meet ecological objectives in light of realistic constraints. Yet, isolating aspects of flow regimes to restore downstream of hydropower facilities is among the greatest challenges of environmental flow sciencemore » due, in part, to the sheer volume of available environmental flow tools in conjunction with complex negotiation-based regulatory procedures. Here, we propose an organizational framework that structures information and existing flow paradigms into a staged process that assists stakeholders in implementing environmental flows for hydropower facilities. The framework identifies areas where regulations fall short of the needed scientific process, and provide suggestions for stakeholders to ameliorate those situations through advanced preparation. We highlight the strengths of existing flow paradigms in their application to hydropower settings and suggest when and where tools are most applicable. In conclusion, our suggested framework increases the effectiveness and efficiency of the e-flow implementation process by rapidly establishing a knowledge base and decreasing uncertainty so more time can be devoted to filling knowledge gaps. As a result, the framework provides the structure for a coordinated research agenda to further the science of environmental flows related to hydropower environments.« less

Organizing environmental flow frameworks to meet hydropower mitigation needs

DOE PAGES

McManamay, Ryan A.; Brewer, Shannon K.; Jager, Henriette I.; ...

2016-06-25

The global recognition of the importance of natural flow regimes to sustain the ecological integrity of river systems has led to increased societal pressure on the hydropower industry to change plant operations to improve downstream aquatic ecosystems. However, a complete reinstatement of natural flow regimes is often unrealistic when balancing water needs for ecosystems, energy production, and other human uses. Thus, stakeholders must identify a prioritized subset of flow prescriptions that meet ecological objectives in light of realistic constraints. Yet, isolating aspects of flow regimes to restore downstream of hydropower facilities is among the greatest challenges of environmental flow sciencemore » due, in part, to the sheer volume of available environmental flow tools in conjunction with complex negotiation-based regulatory procedures. Here, we propose an organizational framework that structures information and existing flow paradigms into a staged process that assists stakeholders in implementing environmental flows for hydropower facilities. The framework identifies areas where regulations fall short of the needed scientific process, and provide suggestions for stakeholders to ameliorate those situations through advanced preparation. We highlight the strengths of existing flow paradigms in their application to hydropower settings and suggest when and where tools are most applicable. In conclusion, our suggested framework increases the effectiveness and efficiency of the e-flow implementation process by rapidly establishing a knowledge base and decreasing uncertainty so more time can be devoted to filling knowledge gaps. As a result, the framework provides the structure for a coordinated research agenda to further the science of environmental flows related to hydropower environments.« less

A Framework for the Next Generation of Risk Science

PubMed Central

Krewski, Daniel; Andersen, Melvin E.; Paoli, Gregory M.; Chiu, Weihsueh A.; Al-Zoughool, Mustafa; Croteau, Maxine C.; Burgoon, Lyle D.; Cote, Ila

2014-01-01

Objectives: In 2011, the U.S. Environmental Protection Agency initiated the NexGen project to develop a new paradigm for the next generation of risk science. Methods: The NexGen framework was built on three cornerstones: the availability of new data on toxicity pathways made possible by fundamental advances in basic biology and toxicological science, the incorporation of a population health perspective that recognizes that most adverse health outcomes involve multiple determinants, and a renewed focus on new risk assessment methodologies designed to better inform risk management decision making. Results: The NexGen framework has three phases. Phase I (objectives) focuses on problem formulation and scoping, taking into account the risk context and the range of available risk management decision-making options. Phase II (risk assessment) seeks to identify critical toxicity pathway perturbations using new toxicity testing tools and technologies, and to better characterize risks and uncertainties using advanced risk assessment methodologies. Phase III (risk management) involves the development of evidence-based population health risk management strategies of a regulatory, economic, advisory, community-based, or technological nature, using sound principles of risk management decision making. Conclusions: Analysis of a series of case study prototypes indicated that many aspects of the NexGen framework are already beginning to be adopted in practice. Citation: Krewski D, Westphal M, Andersen ME, Paoli GM, Chiu WA, Al-Zoughool M, Croteau MC, Burgoon LD, Cote I. 2014. A framework for the next generation of risk science. Environ Health Perspect 122:796–805; http://dx.doi.org/10.1289/ehp.1307260 PMID:24727499

Structural responses to the obesity and non-communicable diseases epidemic: the Chilean Law of Food Labeling and Advertising.

PubMed

Corvalán, C; Reyes, M; Garmendia, M L; Uauy, R

2013-11-01

In 12 July 2012, the Chilean Senate approved the Law of Food Labeling and Advertising, resulting from the joint efforts of a group of health professionals, researchers and legislators who proposed a regulatory framework in support of healthy diets and active living. Its goal was to curb the ongoing epidemic increase of obesity and non-communicable diseases. Two actions included: (i) improving point of food purchase consumer information by incorporating easy-to-understand front-of-packages labeling and specific messages addressing critical nutrients, and (ii) decreasing children's exposure to unhealthy foods by restricting marketing, advertising and sales. We summarize the work related to the law's release and discuss the conclusions reached by the various expert committees that were convened by the Ministry of Health to guide the development of the regulatory norms. Throughout the process, the food industry has overtly expressed its disagreement with the regulatory effort. The final content of the regulatory norms is still pending; however there are suggestions that its implementation will be delayed and might be modified based on the industry lobbying actions. These lessons should contribute to show the need of anticipating and addressing potential barriers to obesity-prevention policy implementation, particularly with respect to the role of the private sector. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.

Extensive cross-talk and global regulators identified from an analysis of the integrated transcriptional and signaling network in Escherichia coli.

PubMed

Antiqueira, Lucas; Janga, Sarath Chandra; Costa, Luciano da Fontoura

2012-11-01

To understand the regulatory dynamics of transcription factors (TFs) and their interplay with other cellular components we have integrated transcriptional, protein-protein and the allosteric or equivalent interactions which mediate the physiological activity of TFs in Escherichia coli. To study this integrated network we computed a set of network measurements followed by principal component analysis (PCA), investigated the correlations between network structure and dynamics, and carried out a procedure for motif detection. In particular, we show that outliers identified in the integrated network based on their network properties correspond to previously characterized global transcriptional regulators. Furthermore, outliers are highly and widely expressed across conditions, thus supporting their global nature in controlling many genes in the cell. Motifs revealed that TFs not only interact physically with each other but also obtain feedback from signals delivered by signaling proteins supporting the extensive cross-talk between different types of networks. Our analysis can lead to the development of a general framework for detecting and understanding global regulatory factors in regulatory networks and reinforces the importance of integrating multiple types of interactions in underpinning the interrelationships between them.

Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling

PubMed Central

Lebensohn, Andres M; Dubey, Ramin; Neitzel, Leif R; Tacchelly-Benites, Ofelia; Yang, Eungi; Marceau, Caleb D; Davis, Eric M; Patel, Bhaven B; Bahrami-Nejad, Zahra; Travaglini, Kyle J; Ahmed, Yashi; Lee, Ethan; Carette, Jan E; Rohatgi, Rajat

2016-01-01

The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1α uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling β-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the β-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems. DOI: http://dx.doi.org/10.7554/eLife.21459.001 PMID:27996937

Functional annotation of regulatory pathways.

PubMed

Pandey, Jayesh; Koyutürk, Mehmet; Kim, Yohan; Szpankowski, Wojciech; Subramaniam, Shankar; Grama, Ananth

2007-07-01

Standardized annotations of biomolecules in interaction networks (e.g. Gene Ontology) provide comprehensive understanding of the function of individual molecules. Extending such annotations to pathways is a critical component of functional characterization of cellular signaling at the systems level. We propose a framework for projecting gene regulatory networks onto the space of functional attributes using multigraph models, with the objective of deriving statistically significant pathway annotations. We first demonstrate that annotations of pairwise interactions do not generalize to indirect relationships between processes. Motivated by this result, we formalize the problem of identifying statistically overrepresented pathways of functional attributes. We establish the hardness of this problem by demonstrating the non-monotonicity of common statistical significance measures. We propose a statistical model that emphasizes the modularity of a pathway, evaluating its significance based on the coupling of its building blocks. We complement the statistical model by an efficient algorithm and software, Narada, for computing significant pathways in large regulatory networks. Comprehensive results from our methods applied to the Escherichia coli transcription network demonstrate that our approach is effective in identifying known, as well as novel biological pathway annotations. Narada is implemented in Java and is available at http://www.cs.purdue.edu/homes/jpandey/narada/.

Current challenges in bioequivalence, quality, and novel assessment technologies for topical products.

PubMed

Yacobi, Avraham; Shah, Vinod P; Bashaw, Edward D; Benfeldt, Eva; Davit, Barbara; Ganes, Derek; Ghosh, Tapash; Kanfer, Isadore; Kasting, Gerald B; Katz, Lindsey; Lionberger, Robert; Lu, Guang Wei; Maibach, Howard I; Pershing, Lynn K; Rackley, Russell J; Raw, Andre; Shukla, Chinmay G; Thakker, Kailas; Wagner, Nathalie; Zovko, Elizabeta; Lane, Majella E

2014-04-01

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

Genomic deletion of a long-range bone enhancer misregulatessclerostin in Van Buchem disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loots, Gabriela G.; Kneissel, Michaela; Keller, Hansjoerg

2005-04-15

Mutations in distant regulatory elements can negatively impact human development and health, yet due to the difficulty of detecting these critical sequences we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem disease (VB), a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis we characterized the expression of human sclerostin (sost) from normal (hSOSTwt) or Van Buchem(hSOSTvb D) alleles. Only the hSOSTwt allele faithfully expressed high levels of human sost in the adult bone and impacted bone metabolism, consistent withmore » the model that the VB noncoding deletion removes a sost specific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays we were able to identify a candidate enhancer element that drives human sost expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the E14.5 mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.« less

BioASF: a framework for automatically generating executable pathway models specified in BioPAX.

PubMed

Haydarlou, Reza; Jacobsen, Annika; Bonzanni, Nicola; Feenstra, K Anton; Abeln, Sanne; Heringa, Jaap

2016-06-15

Biological pathways play a key role in most cellular functions. To better understand these functions, diverse computational and cell biology researchers use biological pathway data for various analysis and modeling purposes. For specifying these biological pathways, a community of researchers has defined BioPAX and provided various tools for creating, validating and visualizing BioPAX models. However, a generic software framework for simulating BioPAX models is missing. Here, we attempt to fill this gap by introducing a generic simulation framework for BioPAX. The framework explicitly separates the execution model from the model structure as provided by BioPAX, with the advantage that the modelling process becomes more reproducible and intrinsically more modular; this ensures natural biological constraints are satisfied upon execution. The framework is based on the principles of discrete event systems and multi-agent systems, and is capable of automatically generating a hierarchical multi-agent system for a given BioPAX model. To demonstrate the applicability of the framework, we simulated two types of biological network models: a gene regulatory network modeling the haematopoietic stem cell regulators and a signal transduction network modeling the Wnt/β-catenin signaling pathway. We observed that the results of the simulations performed using our framework were entirely consistent with the simulation results reported by the researchers who developed the original models in a proprietary language. The framework, implemented in Java, is open source and its source code, documentation and tutorial are available at http://www.ibi.vu.nl/programs/BioASF CONTACT: j.heringa@vu.nl. © The Author 2016. Published by Oxford University Press.

NPDES Permit Writers' Course

EPA Pesticide Factsheets

The objective of the NPDES permit writers' course is to provide the basic regulatory framework and technical considerations that support the development of wastewater discharge permits as required under the NPDES Permit Program.

Software Certification for Temporal Properties With Affordable Tool Qualification

NASA Technical Reports Server (NTRS)

Xia, Songtao; DiVito, Benedetto L.

2005-01-01

It has been recognized that a framework based on proof-carrying code (also called semantic-based software certification in its community) could be used as a candidate software certification process for the avionics industry. To meet this goal, tools in the "trust base" of a proof-carrying code system must be qualified by regulatory authorities. A family of semantic-based software certification approaches is described, each different in expressive power, level of automation and trust base. Of particular interest is the so-called abstraction-carrying code, which can certify temporal properties. When a pure abstraction-carrying code method is used in the context of industrial software certification, the fact that the trust base includes a model checker would incur a high qualification cost. This position paper proposes a hybrid of abstraction-based and proof-based certification methods so that the model checker used by a client can be significantly simplified, thereby leading to lower cost in tool qualification.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.

Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment thatmore » integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches.« less

Drug Development for Pediatric Populations: Regulatory Aspects

PubMed Central

Zisowsky, Jochen; Krause, Andreas; Dingemanse, Jasper

2010-01-01

Pediatric aspects are nowadays integrated early in the development process of a new drug. The stronger enforcement to obtain pediatric information by the regulatory agencies in recent years resulted in an increased number of trials in children. Specific guidelines and requirements from, in particular, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) form the regulatory framework. This review summarizes the regulatory requirements and strategies for pediatric drug development from an industry perspective. It covers pediatric study planning and conduct, considerations for first dose in children, appropriate sampling strategies, and different methods for data generation and analysis to generate knowledge about the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug in children. The role of Modeling and Simulation (M&S) in pediatrics is highlighted—including the regulatory basis—and examples of the use of M&S are illustrated to support pediatric drug development. PMID:27721363

Intrinsic limits to gene regulation by global crosstalk

PubMed Central

Friedlander, Tamar; Prizak, Roshan; Guet, Călin C.; Barton, Nicholas H.; Tkačik, Gašper

2016-01-01

Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. PMID:27489144

The Essential Elements of a Risk Governance Framework for Current and Future Nanotechnologies.

PubMed

Stone, Vicki; Führ, Martin; Feindt, Peter H; Bouwmeester, Hans; Linkov, Igor; Sabella, Stefania; Murphy, Finbarr; Bizer, Kilian; Tran, Lang; Ågerstrand, Marlene; Fito, Carlos; Andersen, Torben; Anderson, Diana; Bergamaschi, Enrico; Cherrie, John W; Cowan, Sue; Dalemcourt, Jean-Francois; Faure, Michael; Gabbert, Silke; Gajewicz, Agnieszka; Fernandes, Teresa F; Hristozov, Danail; Johnston, Helinor J; Lansdown, Terry C; Linder, Stefan; Marvin, Hans J P; Mullins, Martin; Purnhagen, Kai; Puzyn, Tomasz; Sanchez Jimenez, Araceli; Scott-Fordsmand, Janeck J; Streftaris, George; van Tongeren, Martie; Voelcker, Nicolas H; Voyiatzis, George; Yannopoulos, Spyros N; Poortvliet, P Marijn

2017-12-14

Societies worldwide are investing considerable resources into the safe development and use of nanomaterials. Although each of these protective efforts is crucial for governing the risks of nanomaterials, they are insufficient in isolation. What is missing is a more integrative governance approach that goes beyond legislation. Development of this approach must be evidence based and involve key stakeholders to ensure acceptance by end users. The challenge is to develop a framework that coordinates the variety of actors involved in nanotechnology and civil society to facilitate consideration of the complex issues that occur in this rapidly evolving research and development area. Here, we propose three sets of essential elements required to generate an effective risk governance framework for nanomaterials. (1) Advanced tools to facilitate risk-based decision making, including an assessment of the needs of users regarding risk assessment, mitigation, and transfer. (2) An integrated model of predicted human behavior and decision making concerning nanomaterial risks. (3) Legal and other (nano-specific and general) regulatory requirements to ensure compliance and to stimulate proactive approaches to safety. The implementation of such an approach should facilitate and motivate good practice for the various stakeholders to allow the safe and sustainable future development of nanotechnology. © 2017 Society for Risk Analysis.

Watershed Planning within a Quantitative Scenario Analysis Framework.

PubMed

Merriam, Eric R; Petty, J Todd; Strager, Michael P

2016-07-24

There is a critical need for tools and methodologies capable of managing aquatic systems within heavily impacted watersheds. Current efforts often fall short as a result of an inability to quantify and predict complex cumulative effects of current and future land use scenarios at relevant spatial scales. The goal of this manuscript is to provide methods for conducting a targeted watershed assessment that enables resource managers to produce landscape-based cumulative effects models for use within a scenario analysis management framework. Sites are first selected for inclusion within the watershed assessment by identifying sites that fall along independent gradients and combinations of known stressors. Field and laboratory techniques are then used to obtain data on the physical, chemical, and biological effects of multiple land use activities. Multiple linear regression analysis is then used to produce landscape-based cumulative effects models for predicting aquatic conditions. Lastly, methods for incorporating cumulative effects models within a scenario analysis framework for guiding management and regulatory decisions (e.g., permitting and mitigation) within actively developing watersheds are discussed and demonstrated for 2 sub-watersheds within the mountaintop mining region of central Appalachia. The watershed assessment and management approach provided herein enables resource managers to facilitate economic and development activity while protecting aquatic resources and producing opportunity for net ecological benefits through targeted remediation.

Adverse Outcome Pathways – Organizing Toxicological ...

EPA Pesticide Factsheets

The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High throughput screening (HTS) commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a natural framework for connecting high throughput toxicity testing (HTT) results to potential impacts on humans and wildlife populations. An AOP consists of two main components that describe the biological mechanisms driving toxicity. Key events represent biological processes essential for causing the adverse outcome that are also measurable experimentally. Key event relationships capture the biological processes connecting the key events. Evidence documented for each KER based on measurements of the KEs can provide the confidence needed for extrapolating HTT from early key events to overt toxicity represented by later key events based on the AOP. The IPCS mode of action (MOA) framework incorporates information required for making a chemical-specific toxicity determination. Given the close relationship between the AOP and MOA frameworks, it is possible to assemble an MOA by incorporating HTT results, chemical properties including absorption, distribution, metabolism, and excretion (ADME), and an AOP describing the biological basis of toxicity thereby streamlining the process. While current applications focus on the assessment of risk for environmental chemicals,

78 FR 77736 - Sunshine Act Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-24

... a.m. Briefing on Spent Fuel Pool Safety and Consideration of Expedited Transfer of Spent Fuel to Dry... Disposition Fukushima Near-Term Task Force (NTTF) Recommendation 1 on Improving NRC's Regulatory Framework...

Health Effects of Environmental Exposures, Occupational Hazards and Climate Change in Ethiopia: Synthesis of Situational Analysis, Needs Assessment and the Way Forward.

PubMed

Berhane, Kiros; Kumie, Abera; Samet, Jonathan

2016-01-01

The burden of diseases caused by environmental and occupational health hazards and the effects of global climate change are of growing concerns in Ethiopia. However, no adequate information seems to be available on the current situation. This means there is a critical gap in research, policy framework and implementation in the country. The purpose of this paper was to synthesize evidence from a systematic situational analysis and needs assessment to help establish a hub for research and training on three major themes and their related policy frameworks: air pollution and health, occupational health and safety and climate change and health. The methods used in this work include a systematic review of secondary data from peer-reviewed literature, thesis reports from academia, government and national statistical reports. Limited primary data based on key informant interviews held with major stakeholders were also used as sources of data. Exposures to high levels of indoor and outdoor air pollutants were found to be major sources of public health challenges. Lack of occupational safety and health due to agricultural activities and exposure to industries was found to be substantial. Worse is the growing fear that climate change will pose increasingly significant multidimensional challenges to the environment and public health. Across all three areas of focus, there was a paucity of information on local scientific evidence. There is also very limited trained skilled manpower and physical infrastructure to monitor the environment and enforce regulatory guidelines. Research, policy frameworks and regulatory mechanisms were among the cross-cutting issues that needed urgent attention. Critical gaps were observed in research and training across the three themes. Also, there is a limitation in implementing the link between policy and related regulations in the environment and health.

Harnessing private sector expertise to improve complementary feeding within a regulatory framework: Where is the evidence?

PubMed

van Liere, Marti J; Tarlton, Dessie; Menon, Ravi; Yellamanda, M; Reerink, Ietje

2017-10-01

Global recognition that the complex and multicausal problems of malnutrition require all players to collaborate and to invest towards the same objective has led to increased private sector engagement as exemplified through the Scaling Up Nutrition Business Network and mechanisms for blended financing and matched funding, such as the Global Nutrition for Growth Compact. The careful steps made over the past 5 to 10 years have however not taken away or reduced the hesitation and scepticism of the public sector actors towards commercial or even social businesses. Evidence of impact or even a positive contribution of a private sector approach to intermediate nutrition outcomes is still lacking. This commentary aims to discuss the multiple ways in which private sector can leverage its expertise to improve nutrition in general, and complementary feeding in particular. It draws on specific lessons learned in Bangladesh, Côte d'Ivoire, India, Indonesia, and Madagascar on how private sector expertise has contributed, within the boundaries of a regulatory framework, to improve availability, accessibility, affordability, and adequate use of nutritious foods. It concludes that a solid evidence base regarding the contribution of private sector to complementary feeding is still lacking and that the development of a systematic learning agenda is essential to make progress in the area of private sector engagement in nutrition. © 2017 John Wiley & Sons Ltd.

The transition to competency-based pediatric training in the United Arab Emirates.

PubMed

Ibrahim, Halah; Al Tatari, Hossam; Holmboe, Eric S

2015-04-01

Although competency-based medical education has become the standard for physician training in the West, many developing countries have not yet adopted competency-based training. In 2009 in the United Arab Emirates, the government regulatory and operational authorities for healthcare in Abu Dhabi mandated a wide-scale reform of the emirate's postgraduate residency programs to the competency-based framework of the newly formed Accreditation Council for Graduate Medical Education-International (ACGME-I). This article briefly describes the rationale for competency-based medical education and provides an overview of the transition from traditional, time-based residency training to competency-based postgraduate medical education for the Pediatrics residency programs in Abu Dhabi. We will provide data on the initial impact of this transition on resident performance and patient outcomes in a Pediatrics residency program in an academic medical center in the United Arab Emirates.

Use of QSARs in international decision-making frameworks to predict ecologic effects and environmental fate of chemical substances.

PubMed Central

Cronin, Mark T D; Walker, John D; Jaworska, Joanna S; Comber, Michael H I; Watts, Christopher D; Worth, Andrew P

2003-01-01

This article is a review of the use, by regulatory agencies and authorities, of quantitative structure-activity relationships (QSARs) to predict ecologic effects and environmental fate of chemicals. For many years, the U.S. Environmental Protection Agency has been the most prominent regulatory agency using QSARs to predict the ecologic effects and environmental fate of chemicals. However, as increasing numbers of standard QSAR methods are developed and validated to predict ecologic effects and environmental fate of chemicals, it is anticipated that more regulatory agencies and authorities will find them to be acceptable alternatives to chemical testing. PMID:12896861

Overview of cancer vaccines

PubMed Central

Kudrin, Alex

2012-01-01

Cancer immunotherapy has seen a tremendous number of failures and only few recent regulatory successes. This is a review dedicated to determine major regulatory and developmental issues around cancer immunotherapeutics. A three pillar approach should be used in setting a development path: discovery platforms and sufficient pool of validated tumor antigens, product development strategy enabling to bring the product closer to the patient and clinical development strategy accounting for competitive landscape, treatment paradigm, technical and commercial risks. Regulatory framework existing around cancer vaccines in the EU, US, Japan and some developing countries is outlined. In addition, the review covers some specific issues on the design and conduct of clinical trials with cancer vaccines. PMID:22894970

Standalone medical device software: The evolving regulatory framework.

PubMed

McCarthy, Avril D; Lawford, Patricia V

2014-01-01

The paper provides an introduction to the regulatory landscape affecting a particular category of medical technology, namely standalone software-sometimes referred to as 'software as a medical device'. To aid the reader's comprehension of an often complex area, six case studies are outlined and discussed before the paper continues to provide detail of how software with a medical purpose in its own right can potentially be classified as a medical device. The reader is provided an appreciation of how to go about classifying such software and references to support the developer new to the field in locating detailed regulatory support documents and contact points for advice.

Evaluating Quality of Decision-Making Processes in Medicines' Development, Regulatory Review, and Health Technology Assessment: A Systematic Review of the Literature

PubMed Central

Bujar, Magdalena; McAuslane, Neil; Walker, Stuart R.; Salek, Sam

2017-01-01

Introduction: Although pharmaceutical companies, regulatory authorities, and health technology assessment (HTA) agencies have been increasingly using decision-making frameworks, it is not certain whether these enable better quality decision making. This could be addressed by formally evaluating the quality of decision-making process within those organizations. The aim of this literature review was to identify current techniques (tools, questionnaires, surveys, and studies) for measuring the quality of the decision-making process across the three stakeholders. Methods: Using MEDLINE, Web of Knowledge, and other Internet-based search engines, a literature review was performed to systematically identify techniques for assessing quality of decision making in medicines development, regulatory review, and HTA. A structured search was applied using key words and a secondary review was carried out. In addition, the measurement properties of each technique were assessed and compared. Ten Quality Decision-Making Practices (QDMPs) developed previously were then used as a framework for the evaluation of techniques identified in the review. Due to the variation in studies identified, meta-analysis was inappropriate. Results: This review identified 13 techniques, where 7 were developed specifically to assess decision making in medicines' development, regulatory review, or HTA; 2 examined corporate decision making, and 4 general decision making. Regarding how closely each technique conformed to the 10 QDMPs, the 13 techniques assessed a median of 6 QDMPs, with a mode of 3 QDMPs. Only 2 techniques evaluated all 10 QDMPs, namely the Organizational IQ and the Quality of Decision Making Orientation Scheme (QoDoS), of which only one technique, QoDoS could be applied to assess decision making of both individuals and organizations, and it possessed generalizability to capture issues relevant to companies as well as regulatory authorities. Conclusion: This review confirmed a general paucity of research in this area, particularly regarding the development and systematic application of techniques for evaluating quality decision making, with no consensus around a gold standard. This review has identified QoDoS as the most promising available technique for assessing decision making in the lifecycle of medicines and the next steps would be to further test its validity, sensitivity, and reliability. PMID:28443022

Comparative effectiveness research for the clinician researcher: a framework for making a methodological design choice.

PubMed

Williams, Cylie M; Skinner, Elizabeth H; James, Alicia M; Cook, Jill L; McPhail, Steven M; Haines, Terry P

2016-08-17

Comparative effectiveness research compares two active forms of treatment or usual care in comparison with usual care with an additional intervention element. These types of study are commonly conducted following a placebo or no active treatment trial. Research designs with a placebo or non-active treatment arm can be challenging for the clinician researcher when conducted within the healthcare environment with patients attending for treatment.A framework for conducting comparative effectiveness research is needed, particularly for interventions for which there are no strong regulatory requirements that must be met prior to their introduction into usual care. We argue for a broader use of comparative effectiveness research to achieve translatable real-world clinical research. These types of research design also affect the rapid uptake of evidence-based clinical practice within the healthcare setting.This framework includes questions to guide the clinician researcher into the most appropriate trial design to measure treatment effect. These questions include consideration given to current treatment provision during usual care, known treatment effectiveness, side effects of treatments, economic impact, and the setting in which the research is being undertaken.

Writing a Cochrane systematic review on preventive interventions to improve safety: the case of the construction industry.

PubMed

van der Molen, H F; Hoonakker, P L T; Lehtola, Marika M; Hsiao, H; Haslam, R A; Hale, A R; Verbeek, J H

2009-01-01

The objective of this paper is to describe the main steps and to conduct a systematic literature review on preventive interventions concerning work-related injuries and to illustrate the process. Based on the Cochrane handbook, a structured framework of six steps was outlined for the development of a systematic review. This framework was used to describe a Cochrane systematic review (CSR) on the effectiveness of interventions to prevent work related injuries in the construction industry. The 6 main steps to write a CSR were: formulating the problem and objectives; locating and selecting studies; assessing study quality; collecting data; analysing data and presenting results; and interpreting results. The CSR on preventing injuries in the construction industry yielded five eligible intervention studies. Re-analysis of original injury data of the studies on regulatory interventions, through correcting for pre-intervention injury trends led to different conclusions about the effectiveness of interventions than those reported in the original studies. The Cochrane handbook for systematic reviews of interventions provides a practical and feasible six-step framework for developing and reporting a systematic review for preventive interventions.

Diffany: an ontology-driven framework to infer, visualise and analyse differential molecular networks.

PubMed

Van Landeghem, Sofie; Van Parys, Thomas; Dubois, Marieke; Inzé, Dirk; Van de Peer, Yves

2016-01-05

Differential networks have recently been introduced as a powerful way to study the dynamic rewiring capabilities of an interactome in response to changing environmental conditions or stimuli. Currently, such differential networks are generated and visualised using ad hoc methods, and are often limited to the analysis of only one condition-specific response or one interaction type at a time. In this work, we present a generic, ontology-driven framework to infer, visualise and analyse an arbitrary set of condition-specific responses against one reference network. To this end, we have implemented novel ontology-based algorithms that can process highly heterogeneous networks, accounting for both physical interactions and regulatory associations, symmetric and directed edges, edge weights and negation. We propose this integrative framework as a standardised methodology that allows a unified view on differential networks and promotes comparability between differential network studies. As an illustrative application, we demonstrate its usefulness on a plant abiotic stress study and we experimentally confirmed a predicted regulator. Diffany is freely available as open-source java library and Cytoscape plugin from http://bioinformatics.psb.ugent.be/supplementary_data/solan/diffany/.

Comprehensive Care Plan Development Using Resident Assessment Instrument Framework: Past, Present, and Future Practices

PubMed Central

Dellefield, Mary Ellen; Corazzini, Kirsten

2015-01-01

Development of the comprehensive care plan (CCP) is a requirement for nursing homes participating in the federal Medicare and Medicaid programs, referred to as skilled nursing facilities. The plan must be developed within the context of the comprehensive interdisciplinary assessment framework—the Resident Assessment Instrument (RAI). Consistent compliance with this requirement has been difficult to achieve. To improve the quality of CCP development within this framework, an increased understanding of complex factors contributing to inconsistent compliance is required. In this commentary, we examine the history of the comprehensive care plan; its development within the RAI framework; linkages between the RAI and registered nurse staffing; empirical evidence of the CCP’s efficacy; and the limitations of extant standards of practices in CCP development. Because of the registered nurse’s educational preparation, professional practice standards, and licensure obligations, the essential contributions of professional nurses in CCP development are emphasized. Recommendations for evidence-based micro and macro level practice changes with the potential to improve the quality of CCP development and regulatory compliance are presented. Suggestions for future research are given. PMID:27417811

Analysis of functional importance of binding sites in the Drosophila gap gene network model.

PubMed

Kozlov, Konstantin; Gursky, Vitaly V; Kulakovskiy, Ivan V; Dymova, Arina; Samsonova, Maria

2015-01-01

The statistical thermodynamics based approach provides a promising framework for construction of the genotype-phenotype map in many biological systems. Among important aspects of a good model connecting the DNA sequence information with that of a molecular phenotype (gene expression) is the selection of regulatory interactions and relevant transcription factor bindings sites. As the model may predict different levels of the functional importance of specific binding sites in different genomic and regulatory contexts, it is essential to formulate and study such models under different modeling assumptions. We elaborate a two-layer model for the Drosophila gap gene network and include in the model a combined set of transcription factor binding sites and concentration dependent regulatory interaction between gap genes hunchback and Kruppel. We show that the new variants of the model are more consistent in terms of gene expression predictions for various genetic constructs in comparison to previous work. We quantify the functional importance of binding sites by calculating their impact on gene expression in the model and calculate how these impacts correlate across all sites under different modeling assumptions. The assumption about the dual interaction between hb and Kr leads to the most consistent modeling results, but, on the other hand, may obscure existence of indirect interactions between binding sites in regulatory regions of distinct genes. The analysis confirms the previously formulated regulation concept of many weak binding sites working in concert. The model predicts a more or less uniform distribution of functionally important binding sites over the sets of experimentally characterized regulatory modules and other open chromatin domains.

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster.

PubMed

Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F; Arthur, Robert K; Kheradpour, Pouya; Kundaje, Anshul; Nègre, Nicolas; Crofts, Alex; Ptashkin, Ryan; Zieba, Jennifer; Ostapenko, Alexander; Suchy, Sarah; Victorsen, Alec; Jameel, Nader; Grundstad, A Jason; Gao, Wenxuan; Moran, Jennifer R; Rehm, E Jay; Grossman, Robert L; Kellis, Manolis; White, Kevin P

2014-07-01

Annotation of regulatory elements and identification of the transcription-related factors (TRFs) targeting these elements are key steps in understanding how cells interpret their genetic blueprint and their environment during development, and how that process goes awry in the case of disease. One goal of the modENCODE (model organism ENCyclopedia of DNA Elements) Project is to survey a diverse sampling of TRFs, both DNA-binding and non-DNA-binding factors, to provide a framework for the subsequent study of the mechanisms by which transcriptional regulators target the genome. Here we provide an updated map of the Drosophila melanogaster regulatory genome based on the location of 84 TRFs at various stages of development. This regulatory map reveals a variety of genomic targeting patterns, including factors with strong preferences toward proximal promoter binding, factors that target intergenic and intronic DNA, and factors with distinct chromatin state preferences. The data also highlight the stringency of the Polycomb regulatory network, and show association of the Trithorax-like (Trl) protein with hotspots of DNA binding throughout development. Furthermore, the data identify more than 5800 instances in which TRFs target DNA regions with demonstrated enhancer activity. Regions of high TRF co-occupancy are more likely to be associated with open enhancers used across cell types, while lower TRF occupancy regions are associated with complex enhancers that are also regulated at the epigenetic level. Together these data serve as a resource for the research community in the continued effort to dissect transcriptional regulatory mechanisms directing Drosophila development. © 2014 Slattery et al.; Published by Cold Spring Harbor Laboratory Press.

The legal and ethical aspects of the right to health of migrants in Switzerland.

PubMed

Marks-Sultan, Géraldine; Kurt, Stefanie; Leyvraz, Didier; Sprumont, Dominique

The right to health of migrant populations, whether they are foreign nationals, foreign workers, tourists, asylum seekers or refugees, is enshrined in international human rights treaties. The effectiveness of the implementation of this fundamental right thus lies in national legal frameworks. In spite of its long humanitarian tradition, Switzerland has a strict migration policy, and while it has established a non-discriminatory legal framework for the protection and promotion of the right to health, its laws and regulations sometimes codify differences in treatment between foreign nationals and Swiss residents based on distinct situations. On the basis of shared responsibilities between the Federal State and the 26 cantons, this article describes the Swiss legal and regulatory approach to the right to health, the ways it is currently implemented and the possible vectors for an improved integration of migrants into the health system.

Generating political priority for regulatory interventions targeting obesity prevention: an Australian case study.

PubMed

Baker, Phillip; Gill, Timothy; Friel, Sharon; Carey, Gemma; Kay, Adrian

2017-03-01

Effective obesity prevention requires a synergistic mix of population-level interventions including a strong role for government and the regulation of the marketing, labelling, content and pricing of energy-dense foods and beverages. In this paper we adopt the agenda of the Australian Federal Government (AFG) as a case study to understand the factors generating or hindering political priority for such 'regulatory interventions' between 1990 and 2011. Using a theoretically-guided process tracing method we undertook documentary analysis and conducted 27 interviews with a diversity of actors involved in obesity politics. The analysis was structured by a theoretical framework comprising four dimensions: the power of actors involved; the ideas the actors deploy to interpret and portray the issue; the institutional and political context; and issue characteristics. Despite two periods of sustained political attention, political priority for regulatory interventions did not emerge and was hindered by factors from all four dimensions. Within the public health community, limited cohesion among experts and advocacy groups hampered technical responses and collective action efforts. An initial focus on children (child obesity), framing the determinants of obesity as 'obesogenic environments', and the deployment of 'protecting kids', 'industry demonization' and 'economic costs' frames generated political attention. Institutional norms within government effectively selected out regulatory interventions from consideration. The 'productive power' and activities of the food and advertising industries presented formidable barriers, buttressed by a libertarian/neolibertarian rhetoric emphasizing individual responsibility, a negative view of freedom (as free from 'nanny-state' intervention) and the idea that regulation imposes an unacceptable cost on business. Issue complexity, the absence of a supportive evidence base and a strict 'evidence-based' policy-making approach were used as rationales to defer political priority. Overcoming these challenges may be important to future collective action efforts attempting to generate and sustain political priority for regulatory interventions targeting obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.

MIR@NT@N: a framework integrating transcription factors, microRNAs and their targets to identify sub-network motifs in a meta-regulation network model

PubMed Central

2011-01-01

Background To understand biological processes and diseases, it is crucial to unravel the concerted interplay of transcription factors (TFs), microRNAs (miRNAs) and their targets within regulatory networks and fundamental sub-networks. An integrative computational resource generating a comprehensive view of these regulatory molecular interactions at a genome-wide scale would be of great interest to biologists, but is not available to date. Results To identify and analyze molecular interaction networks, we developed MIR@NT@N, an integrative approach based on a meta-regulation network model and a large-scale database. MIR@NT@N uses a graph-based approach to predict novel molecular actors across multiple regulatory processes (i.e. TFs acting on protein-coding or miRNA genes, or miRNAs acting on messenger RNAs). Exploiting these predictions, the user can generate networks and further analyze them to identify sub-networks, including motifs such as feedback and feedforward loops (FBL and FFL). In addition, networks can be built from lists of molecular actors with an a priori role in a given biological process to predict novel and unanticipated interactions. Analyses can be contextualized and filtered by integrating additional information such as microarray expression data. All results, including generated graphs, can be visualized, saved and exported into various formats. MIR@NT@N performances have been evaluated using published data and then applied to the regulatory program underlying epithelium to mesenchyme transition (EMT), an evolutionary-conserved process which is implicated in embryonic development and disease. Conclusions MIR@NT@N is an effective computational approach to identify novel molecular regulations and to predict gene regulatory networks and sub-networks including conserved motifs within a given biological context. Taking advantage of the M@IA environment, MIR@NT@N is a user-friendly web resource freely available at http://mironton.uni.lu which will be updated on a regular basis. PMID:21375730

Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma

PubMed Central

Sun, Jingchun; Gong, Xue; Purow, Benjamin; Zhao, Zhongming

2012-01-01

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers. PMID:22829753

[Quality improvement potential in the pharmaceutical industry].

PubMed

Nusser, Michael

2007-01-01

The performance of the German pharmaceutical industry, future challenges and obstacles to quality improvement are assessed from a systems-of-innovation perspective, using appropriate innovation indicators. The current close-to-market performance indicators paint an unfavourable picture. Early R&D indicators (e.g., publications, patents), however, reveal a positive trend. A lot of obstacles to quality improvements are identified with respect to knowledge base, knowledge/technology transfer, industrial R&D processes, capital markets, market attractiveness and both regulatory and political framework conditions. On this basis, recommendations will finally be derived to improve quality in the pharmaceutical industry.

Cell-Based Therapeutics: The Next Pillar of Medicine

PubMed Central

Fischbach, Michael A.; Bluestone, Jeffrey A.; Lim, Wendell A.

2013-01-01

Two decades ago, the pharmaceutical industry—long dominated by small-molecule drugs—was revolutionized by the the advent of biologics. Today, biomedicine sits on the cusp of a new revolution: the use of microbial and human cells as versatile therapeutic engines. Here, we discuss the promise of this “third pillar” of therapeutics in the context of current scientific, regulatory, economic, and perceptual challenges. History suggests that the advent of cellular medicines will require the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably altering and regulating cellular behaviors. PMID:23552369

Current regulatory issues in cell and tissue therapy.

PubMed

Burger, S R

2003-01-01

Cell-based therapies have grown dramatically in power and scope in recent years. Once limited to blood and BM transplantation, these therapies now encompass tissue repair and regeneration, metabolic support, gene replacement, and immune effector functions, with established and investigational clinical applications in disorders affecting nearly every tissue and organ system. The complexity and novel applications of human cells, tissues, and cellular and tissue-based products (HCT/Ps), however, present potential risks for adverse events. The US Food and Drug Administration, responding to these concerns, has established a tiered, risk-based regulatory structure, in which more rigorous controls and safeguards are required for products thought to pose increased risk. The proposed good tissue practices (GTP) rule and existing good manufacturing practices (GMP) requirements form the principal elements of this regulatory framework. The proposed GTPs are intended to prevent HCT/P contamination with infectious disease agents, and to ensure that these cells and tissues maintain their integrity and function. GMPs focus on production of safe, pure, and potent products, and entail a higher level of process control and product characterization. All HCT/Ps will be required to comply with GTPs. HCT/Ps considered to present greater risks of adverse events, however, will be subject to both GTPs and GMPs, and must obtain premarket approval using the Investigational New Drug (IND) mechanism established for biologics. Although these requirements will present significant challenges for clinician- investigators and laboratories producing HCT/Ps, the regulations fundamentally support good clinical care by increasing safety and control, and enable good science by improving the quality and reliability of data.

Built environment change: a framework to support health-enhancing behaviour through environmental policy and health research.

PubMed

Berke, Ethan M; Vernez-Moudon, Anne

2014-06-01

As research examining the effect of the built environment on health accelerates, it is critical for health and planning researchers to conduct studies and make recommendations in the context of a robust theoretical framework. We propose a framework for built environment change (BEC) related to improving health. BEC consists of elements of the built environment, how people are exposed to and interact with them perceptually and functionally, and how this exposure may affect health-related behaviours. Integrated into this framework are the legal and regulatory mechanisms and instruments that are commonly used to effect change in the built environment. This framework would be applicable to medical research as well as to issues of policy and community planning.

Industrial Adoption of Model-Based Systems Engineering: Challenges and Strategies

NASA Astrophysics Data System (ADS)

Maheshwari, Apoorv

As design teams are becoming more globally integrated, one of the biggest challenges is to efficiently communicate across the team. The increasing complexity and multi-disciplinary nature of the products are also making it difficult to keep track of all the information generated during the design process by these global team members. System engineers have identified Model-based Systems Engineering (MBSE) as a possible solution where the emphasis is placed on the application of visual modeling methods and best practices to systems engineering (SE) activities right from the beginning of the conceptual design phases through to the end of the product lifecycle. Despite several advantages, there are multiple challenges restricting the adoption of MBSE by industry. We mainly consider the following two challenges: a) Industry perceives MBSE just as a diagramming tool and does not see too much value in MBSE; b) Industrial adopters are skeptical if the products developed using MBSE approach will be accepted by the regulatory bodies. To provide counter evidence to the former challenge, we developed a generic framework for translation from an MBSE tool (Systems Modeling Language, SysML) to an analysis tool (Agent-Based Modeling, ABM). The translation is demonstrated using a simplified air traffic management problem and provides an example of a potential quite significant value: the ability to use MBSE representations directly in an analysis setting. For the latter challenge, we are developing a reference model that uses SysML to represent a generic infusion pump and SE process for planning, developing, and obtaining regulatory approval of a medical device. This reference model demonstrates how regulatory requirements can be captured effectively through model-based representations. We will present another case study at the end where we will apply the knowledge gained from both case studies to a UAV design problem.

[The development of the system of medical rehabilitation based at the Russian health resort facilities: investment prospects].

PubMed

Povazhnaya, E L; Gusakova, E V; Moiseenko, S V

2018-05-21

The present work is devoted to the prospects for attracting investments for the maintenance and development of the medical rehabilitation practices based at the Russian health resort facilities. The article describes the prerequisites for the enhancement of the investment attractiveness of the development of the system of medical rehabilitation in the said institutions including the formulation and strengthening of the legal and regulatory framework, the capacity for the organization of the second and third stages of medical rehabilitation in the existing spa and health resort facilities, the attraction of the funds of compulsory medical insurance as an additional source of the financial support. The main legal documents regulating the organization and provision of medical rehabilitation based at the spa and health resort facilities are presented. The results of the implementation of the investment concept of the development of medical rehabilitation in the framework of the system of health resort treatment as exemplified by the experience of JSC «The group of companies «Medsi» are discussed. It is shown that the development of medical rehabilitation based at the spa and health resort facilities greatly contributes to the significant expansion of the potential customer base and promotes the further growth of business scale.

The emerging international regulatory framework for biotechnology.

PubMed

Komen, John

2012-01-01

Debate about the potential risks of genetically modified organisms (GMOs) to the environment or human health spurred attention to biosafety. Biosafety is associated with the safe use of GMOs and, more generally, with the introduction of non-indigenous species into natural or managed ecosystems. Biosafety regulation--the policies and procedures adopted to ensure the environmentally safe application of modern biotechnology--has been extensively discussed at various national and international forums. Much of the discussion has focused on developing guidelines, appropriate legal frameworks and, at the international level, a legally binding international biosafety protocol--the Cartagena Protocol on Biosafety. The Protocol is one among various international instruments and treaties that regulate specific aspects relevant to agricultural biotechnology. The present article presents the main international instruments relevant to biosafety regulation, and their key provisions. While international agreements and standards provide important guidance, they leave significant room for interpretation, and flexibility for countries implementing them. Implementation of biosafety at the national level has proven to be a major challenge, particularly in developing countries, and consequently the actual functioning of the international regulatory framework for biotechnology is still in a state of flux.

Biodiversity Conservation in the REDD

PubMed Central

2010-01-01

Deforestation and forest degradation in the tropics is a major source of global greenhouse gas (GHG) emissions. The tropics also harbour more than half the world's threatened species, raising the possibility that reducing GHG emissions by curtailing tropical deforestation could provide substantial co-benefits for biodiversity conservation. Here we explore the potential for such co-benefits in Indonesia, a leading source of GHG emissions from land cover and land use change, and among the most species-rich countries in the world. We show that focal ecosystems for interventions to reduce emissions from deforestation and forest degradation in Indonesia do not coincide with areas supporting the most species-rich communities or highest concentration of threatened species. We argue that inherent trade-offs among ecosystems in emission reduction potential, opportunity cost of foregone development and biodiversity values will require a regulatory framework to balance emission reduction interventions with biodiversity co-benefit targets. We discuss how such a regulatory framework might function, and caution that pursuing emission reduction strategies without such a framework may undermine, not enhance, long-term prospects for biodiversity conservation in the tropics. PMID:21092321

How We Assess Risks to Pollinators

EPA Pesticide Factsheets

EPA's pollinator risk assessment framework is part of its regulatory decision-making process for all pesticides, relying on a tiered process and focusing on major routes of exposure while distinguishing different types of pesticide treatment.

Premise to Implement a Grading System to Evaluate the Sanitary Level in Food Service Establishments in Milan, Italy

PubMed Central

Razzini, Katia

2015-01-01

The regulatory framework of the official controls on food safety, the criteria and methods from the planning of interventions in the field of official control to the management of information flows, and the standards described in the operation manual of the local competent authorities drafted by the Lombardy Region (2011) were evaluated. A questionnaire consisting of n. 10 questions with multiple answers draft in partnership with EPAM (the Association of Provincial Public Retail and catering businesses in Milan) to n. 107 Food service establishments of Milan shows that 92% of managers approve the introduction of a grading system. The regulatory framework is planned to support the implementation of risk assignment, unfortunately the attribution of risk category of retail and catering businesses is still different among regions. PMID:27800403

From Banking to International Governance: Fostering Innovation in Stem Cell Research

PubMed Central

Isasi, Rosario; Knoppers, Bartha M.

2011-01-01

Stem cell banks are increasingly recognized as an essential resource of biological materials for both basic and translational stem cell research. By providing transnational access to quality controlled and ethically sourced stem cell lines, stem cell banks seek to foster international collaboration and innovation. However, given that national stem cell banks operate under different policy, regulatory and commercial frameworks, the transnational sharing of stem cell materials and data can be complicating. This paper will provide an overview of the most pressing challenges regarding the governance of stem cell banks, and the difficulties in designing regulatory and commercial frameworks that foster stem cell research. Moreover, the paper will shed light on the numerous international initiatives that have arisen to help harmonize and standardize stem cell banking and research processes to overcome such challenges. PMID:21904557

DEEP: a general computational framework for predicting enhancers

PubMed Central

Kleftogiannis, Dimitrios; Kalnis, Panos; Bajic, Vladimir B.

2015-01-01

Transcription regulation in multicellular eukaryotes is orchestrated by a number of DNA functional elements located at gene regulatory regions. Some regulatory regions (e.g. enhancers) are located far away from the gene they affect. Identification of distal regulatory elements is a challenge for the bioinformatics research. Although existing methodologies increased the number of computationally predicted enhancers, performance inconsistency of computational models across different cell-lines, class imbalance within the learning sets and ad hoc rules for selecting enhancer candidates for supervised learning, are some key questions that require further examination. In this study we developed DEEP, a novel ensemble prediction framework. DEEP integrates three components with diverse characteristics that streamline the analysis of enhancer's properties in a great variety of cellular conditions. In our method we train many individual classification models that we combine to classify DNA regions as enhancers or non-enhancers. DEEP uses features derived from histone modification marks or attributes coming from sequence characteristics. Experimental results indicate that DEEP performs better than four state-of-the-art methods on the ENCODE data. We report the first computational enhancer prediction results on FANTOM5 data where DEEP achieves 90.2% accuracy and 90% geometric mean (GM) of specificity and sensitivity across 36 different tissues. We further present results derived using in vivo-derived enhancer data from VISTA database. DEEP-VISTA, when tested on an independent test set, achieved GM of 80.1% and accuracy of 89.64%. DEEP framework is publicly available at http://cbrc.kaust.edu.sa/deep/. PMID:25378307

Fecal Microbiota-based Therapeutics for Recurrent Clostridium difficile Infection, Ulcerative Colitis and Obesity.

PubMed

Carlucci, Christian; Petrof, Elaine O; Allen-Vercoe, Emma

2016-11-01

The human gut microbiome is a complex ecosystem of fundamental importance to human health. Our increased understanding of gut microbial composition and functional interactions in health and disease states has spurred research efforts examining the gut microbiome as a valuable target for therapeutic intervention. This review provides updated insight into the state of the gut microbiome in recurrent Clostridium difficile infection (CDI), ulcerative colitis (UC), and obesity while addressing the rationale for the modulation of the gut microbiome using fecal microbiota transplant (FMT)-based therapies. Current microbiome-based therapeutics in pre-clinical or clinical development are discussed. We end by putting this within the context of the current regulatory framework surrounding FMT and related therapies. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A tutorial for developing a topical cream formulation based on the Quality by Design approach.

PubMed

Simões, Ana; Veiga, Francisco; Vitorino, Carla; Figueiras, Ana

2018-06-20

The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test (QbT) system have been widely acknowledged. The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development. The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner. Copyright © 2018. Published by Elsevier Inc.

A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes.

PubMed

Perron, Gabrielle; Jandaghi, Pouria; Solanki, Shraddha; Safisamghabadi, Maryam; Storoz, Cristina; Karimzadeh, Mehran; Papadakis, Andreas I; Arseneault, Madeleine; Scelo, Ghislaine; Banks, Rosamonde E; Tost, Jorg; Lathrop, Mark; Tanguay, Simon; Brazma, Alvis; Huang, Sidong; Brimo, Fadi; Najafabadi, Hamed S; Riazalhosseini, Yasser

2018-05-08

Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Long-range RNA pairings contribute to mutually exclusive splicing

PubMed Central

Yue, Yuan; Yang, Yun; Dai, Lanzhi; Cao, Guozheng; Chen, Ran; Hong, Weiling; Liu, Baoping; Shi, Yang; Meng, Yijun; Shi, Feng; Xiao, Mu; Jin, Yongfeng

2016-01-01

Mutually exclusive splicing is an important means of increasing the protein repertoire, by which the Down's syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 different isoforms in Drosophila melanogaster. However, the regulatory mechanisms remain obscure due to the complexity of the Dscam exon cluster. Here, we reveal a molecular model for the regulation of the mutually exclusive splicing of the serpent pre-mRNA based on competition between upstream and downstream RNA pairings. Such dual RNA pairings confer fine tuning of the inclusion of alternative exons. Moreover, we demonstrate that the splicing outcome of alternative exons is mediated in relative pairing strength-correlated mode. Combined comparative genomics analysis and experimental evidence revealed similar bidirectional structural architectures in exon clusters 4 and 9 of the Dscam gene. Our findings provide a novel mechanistic framework for the regulation of mutually exclusive splicing and may offer potentially applicable insights into long-range RNA–RNA interactions in gene regulatory networks. PMID:26554032

Long-range RNA pairings contribute to mutually exclusive splicing.

PubMed

Yue, Yuan; Yang, Yun; Dai, Lanzhi; Cao, Guozheng; Chen, Ran; Hong, Weiling; Liu, Baoping; Shi, Yang; Meng, Yijun; Shi, Feng; Xiao, Mu; Jin, Yongfeng

2016-01-01

Mutually exclusive splicing is an important means of increasing the protein repertoire, by which the Down's syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 different isoforms in Drosophila melanogaster. However, the regulatory mechanisms remain obscure due to the complexity of the Dscam exon cluster. Here, we reveal a molecular model for the regulation of the mutually exclusive splicing of the serpent pre-mRNA based on competition between upstream and downstream RNA pairings. Such dual RNA pairings confer fine tuning of the inclusion of alternative exons. Moreover, we demonstrate that the splicing outcome of alternative exons is mediated in relative pairing strength-correlated mode. Combined comparative genomics analysis and experimental evidence revealed similar bidirectional structural architectures in exon clusters 4 and 9 of the Dscam gene. Our findings provide a novel mechanistic framework for the regulation of mutually exclusive splicing and may offer potentially applicable insights into long-range RNA-RNA interactions in gene regulatory networks. © 2015 Yue et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Building regulatory and operational flexibility into accountable care organizations and 'shared savings'.

PubMed

Lieberman, Steven M; Bertko, John M

2011-01-01

The Affordable Care Act created accountable care organizations (ACOs), which will be a new part of Medicare as of January 2012, together with a "shared savings program" that will modify how these organizations will be paid to care for patients. Accountable care organizations have the potential to lower costs, improve the quality of care, facilitate delivery system reform, and promote innovation in health care. The federal government is set to create rules to regulate these organizations and has broad discretion to allow them to pursue a variety of approaches. Drawing on experience from some ACO pilot programs and the Medicare Part D prescription drug coverage program, we argue that regulations governing accountable care organizations should be flexible, encouraging of diversity and innovation and allowing for changes over time based on lessons learned. We recommend using regulations as a general framework, while relying on notices and other guidance below the regulatory level to spell out specific requirements.

Law's Dilemma: Validating Complementary and Alternative Medicine and the Clash of Evidential Paradigms

PubMed Central

Iyioha, Ireh

2011-01-01

This paper examines the (in)compatibility between the diagnostic and therapeutic theories of complementary and alternative medicine (CAM) and a science-based regulatory framework. Specifically, the paper investigates the nexus between statutory legitimacy and scientific validation of health systems, with an examination of its impact on the development of complementary and alternative therapies. The paper evaluates competing theories for validating CAM ranging from the RCT methodology to anthropological perspectives and contends that while the RCT method might be beneficial in the regulation of many CAM therapies, yet dogmatic adherence to this paradigm as the exclusive method for legitimizing CAM will be adverse to the independent development of many CAM therapies whose philosophies and mechanisms of action are not scientifically interpretable. Drawing on history and research evidence to support this argument, the paper sues for a regulatory model that is accommodative of different evidential paradigms in support of a pluralistic healthcare system that balances the imperative of quality assurance with the need to ensure access. PMID:20953428

Are Lead Exposures a Risk in European Fresh Waters? A Regulatory Assessment Accounting for Bioavailability.

PubMed

Peters, Adam; Wilson, Iain; Merrington, Graham; Chowdhury, M Jasim

2018-01-01

An indicative compliance assessment of the Europe-wide bioavailable lead Environmental Quality Standard of 1.2 µg L -1 (EQS) was undertaken against regulatory freshwater monitoring data from six European member states and FOREGS database. Bio-met, a user-friendly tool based upon Biotic Ligand Models (BLMs) was used to account for bioavailability, along with the current European Water Framework Directive lead dissolved organic carbon correction approach. The outputs from both approaches were compared to the BLM. Of the 9054 freshwater samples assessed only 0.6% exceeded the EQS of 1.2 µg L -1 after accounting for bioavailability. The data showed that ambient background concentrations of lead across Europe are unlikely to influence general compliance with the EQS, although there may be isolated local issues. The waters showing the greatest sensitivity to potential lead exposures are characterized by relatively low DOC (< 0.5 mg L -1 ), regardless of the pH and calcium concentrations.

Bringing electricity reform to the Philippines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fe Villamejor-Mendoza, Maria

2008-12-15

Electricity reforms will not translate to competition overnight. But reforms are inching their way forward in institutions and stakeholders of the Philippine electricity industry, through regulatory and competition frameworks, processes, and systems promulgated and implemented. (author)

Framework for developing a regional system architecture for intelligent transportation systems

DOT National Transportation Integrated Search

1997-01-01

Defining an architecture for intelligent transportation systems (ITS) at the regional level, where most ITS deployment occurs, is constrained by jurisdictional, institutional, financial, political, and regulatory factors. These constraints provide op...

Financial Responsibility for Reentry Vehicle Operations

DOT National Transportation Integrated Search

1995-05-01

The Department of Transportation's Office of Commercial Space Transportation is : in the process of assessing the safety of a reentry vehicle and its operation : and is developing an associated regulatory framework for ensuring public safety : while ...

Sediment Toxicity Testing

EPA Science Inventory

Sediment toxicity testing has become a fundamental component of regulatory frameworks for assessing the risks posed by contaminated sediments and for development of chemical sediment quality guidelines. Over the past two decades, sediment toxicity testing methods have advanced co...

Quality Assurance Framework Implementation Guide for Isolated Community Power Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Esterly, Sean R.; Baring-Gould, Edward I.; Burman, Kari A.

This implementation guide is a companion document to the 'Quality Assurance Framework for Mini-Grids' technical report. This document is intended to be used by one of the many stakeholder groups that take part in the implementation of isolated power systems. Although the QAF could be applied to a single system, it was designed primarily to be used within the context of a larger national or regional rural electrification program in which many individual systems are being installed. This guide includes a detailed overview of the Quality Assurance Framework and provides guidance focused on the implementation of the Framework from themore » perspective of the different stakeholders that are commonly involved in expanding energy development within specific communities or regions. For the successful long-term implementation of a specific rural electrification program using mini-grid systems, six key stakeholders have been identified that are typically engaged, each with a different set of priorities 1. Regulatory agency 2. Governmental ministry 3. System developers 4. Mini-utility 5. Investors 6. Customers/consumers. This document is broken into two distinct sections. The first focuses on the administrative processes in the development and operation of community-based mini-grid programs, while the second focuses on the process around the installation of the mini-grid project itself.« less

Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

PubMed

de Matas, Marcel; De Beer, Thomas; Folestad, Staffan; Ketolainen, Jarkko; Lindén, Hans; Lopes, João Almeida; Oostra, Wim; Weimer, Marco; Öhrngren, Per; Rantanen, Jukka

2016-07-30

The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development. Copyright © 2016 Elsevier B.V. All rights reserved.

Integrating machine learning techniques into robust data enrichment approach and its application to gene expression data.

PubMed

Erdoğdu, Utku; Tan, Mehmet; Alhajj, Reda; Polat, Faruk; Rokne, Jon; Demetrick, Douglas

2013-01-01

The availability of enough samples for effective analysis and knowledge discovery has been a challenge in the research community, especially in the area of gene expression data analysis. Thus, the approaches being developed for data analysis have mostly suffered from the lack of enough data to train and test the constructed models. We argue that the process of sample generation could be successfully automated by employing some sophisticated machine learning techniques. An automated sample generation framework could successfully complement the actual sample generation from real cases. This argument is validated in this paper by describing a framework that integrates multiple models (perspectives) for sample generation. We illustrate its applicability for producing new gene expression data samples, a highly demanding area that has not received attention. The three perspectives employed in the process are based on models that are not closely related. The independence eliminates the bias of having the produced approach covering only certain characteristics of the domain and leading to samples skewed towards one direction. The first model is based on the Probabilistic Boolean Network (PBN) representation of the gene regulatory network underlying the given gene expression data. The second model integrates Hierarchical Markov Model (HIMM) and the third model employs a genetic algorithm in the process. Each model learns as much as possible characteristics of the domain being analysed and tries to incorporate the learned characteristics in generating new samples. In other words, the models base their analysis on domain knowledge implicitly present in the data itself. The developed framework has been extensively tested by checking how the new samples complement the original samples. The produced results are very promising in showing the effectiveness, usefulness and applicability of the proposed multi-model framework.

Use of QSARs in international decision-making frameworks to predict health effects of chemical substances.

PubMed Central

Cronin, Mark T D; Jaworska, Joanna S; Walker, John D; Comber, Michael H I; Watts, Christopher D; Worth, Andrew P

2003-01-01

This article is a review of the use of quantitative (and qualitative) structure-activity relationships (QSARs and SARs) by regulatory agencies and authorities to predict acute toxicity, mutagenicity, carcinogenicity, and other health effects. A number of SAR and QSAR applications, by regulatory agencies and authorities, are reviewed. These include the use of simple QSAR analyses, as well as the use of multivariate QSARs, and a number of different expert system approaches. PMID:12896862

Features of Pharmaceutical Compounding in the Republic of Tajikistan.

PubMed

Alfred-Ugbenbo, D S; Valiev, A H; Zdoryk, O A; Georgiyants, V A

2017-01-01

Despite the deep assortment of finished pharmaceutical products and the reduction in the number of compounding and hospital pharmacies in the Republic of Tajikistan, the need for extemporal medicinal products is still preserved and remains relevant. This article discusses the practice of compounding in the Republic of Tajikistan. History, laws, limits, regulatory institutions, protocols for compounding pharmacy set up, challenges, equipment, extemporaneous formulations, quality control, and storage within regulatory framework are discussed. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

A resource-dependence model of hospital contract management.

PubMed Central

Alexander, J A; Morrisey, M A

1989-01-01

This study empirically examines the determinants of hospital entry into management contracts with multihospital systems. Using a resource-dependence framework, the study tests whether market conditions, regulatory climate, management effectiveness, and certain enabling factors affect the probability of hospital entry into a contract management arrangement. The study used a pooled sample of 312 contract-managed and 936 traditionally managed hospitals. Results suggest the importance of management effectiveness, regulatory climate, and hospital ownership (investor owned or nonprofit) as predisposing conditions of contract management. PMID:2732059

Regulatory aspects of total product life cycle.

PubMed

Hausman, Ethan D; Altaie, Sousan S

2004-12-01

Total Product Life Cycle (TPLC) is a conceptual framework for assessing any product or service (medical or otherwise). This article will address how the Center for Devices and Radiological Health of the U.S. Food and Drug Administration utilizes TPLC in a regulatory paradigm. TPLC will help guide the regulation of market-driven evolution of medical devices and radiation-emitting products from conception, through pre-market development, to widespread market use, and finally to obsolescence and replacement by subsequent generations of products.

Current and new developments in transport and regulatory issues concerning radioisotopes: managing change for minimum business impact

NASA Astrophysics Data System (ADS)

Bennett, Neil; Coppell, David; Rogers, David; Schrader, John

2004-09-01

Changes in the regulatory framework governing the Radiation Processing Industry have the potential to make a real business impact on day-to-day profitability. Many areas of the Radiation Processing Industry are affected by changes in the regulatory framework within which these areas are managed. When planning for such changes the transportation element in the shipment of sealed cobalt radiation sources is an area that is often neglected by some parts of the distribution chain. A balance must be struck between the cobalt supplier and the facility operator/customer that rests upon how much the customer needs to know about the intricacies of cobalt shipment. The objective of this paper is to highlight areas of possible business impact and reassure the users of sealed radiation sources that the global suppliers of these products are used to negotiating local variations in regulations governing the physical transportation of radiation sources, changes in regulations governing the design, manufacture and use of transportation containers and changes in the availability of commercial shippers and shipping routes. The major suppliers of industrial quantities of cobalt-60 are well placed to lead their customers through this complex process as a matter of routine.

BREAD: a European coordination action for broadband for all

NASA Astrophysics Data System (ADS)

Van Daele, P.

2006-10-01

The BREAD - co-ordination action, funded by the European Commission through the Framework 6 Programme (FP6) aims at developing a multi-disciplinary approach for the realization of the 'Broadband for All' concept within Europe, bringing together societal, economic, regulatory and technological disciplines and presenting information from regional "success stories" of actual deployment. The EU objective of achieving "Broadband for All" will not be reached by solely a 'technology push' strategy but will need this multi-disciplinary approach and sharing of views and knowledge to develop new strategies and good practice recommendations in the area of 'Broadband for All'. As a co-ordination action the project wants to unite all players active in the field of the end-to-end broadband provisioning for all. It performs a multi-technological analysis of the current and evolving situation, starting from the roadmap information generated by different projects and IST instruments which focus on specific technological domains. The BREAD consortium simultaneously studies the techno-economic, societal and regulatory aspects of this "Broadband for All" concept. It tries to identify the impact of the EU regulatory framework on the successful implementation of new broadband communication services.

A generic Transcriptomics Reporting Framework (TRF) for 'omics data processing and analysis.

PubMed

Gant, Timothy W; Sauer, Ursula G; Zhang, Shu-Dong; Chorley, Brian N; Hackermüller, Jörg; Perdichizzi, Stefania; Tollefsen, Knut E; van Ravenzwaay, Ben; Yauk, Carole; Tong, Weida; Poole, Alan

2017-12-01

A generic Transcriptomics Reporting Framework (TRF) is presented that lists parameters that should be reported in 'omics studies used in a regulatory context. The TRF encompasses the processes from transcriptome profiling from data generation to a processed list of differentially expressed genes (DEGs) ready for interpretation. Included within the TRF is a reference baseline analysis (RBA) that encompasses raw data selection; data normalisation; recognition of outliers; and statistical analysis. The TRF itself does not dictate the methodology for data processing, but deals with what should be reported. Its principles are also applicable to sequencing data and other 'omics. In contrast, the RBA specifies a simple data processing and analysis methodology that is designed to provide a comparison point for other approaches and is exemplified here by a case study. By providing transparency on the steps applied during 'omics data processing and analysis, the TRF will increase confidence processing of 'omics data, and regulatory use. Applicability of the TRF is ensured by its simplicity and generality. The TRF can be applied to all types of regulatory 'omics studies, and it can be executed using different commonly available software tools. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

mRNA translation and protein synthesis: an analysis of different modelling methodologies and a new PBN based approach

PubMed Central

2014-01-01

Background mRNA translation involves simultaneous movement of multiple ribosomes on the mRNA and is also subject to regulatory mechanisms at different stages. Translation can be described by various codon-based models, including ODE, TASEP, and Petri net models. Although such models have been extensively used, the overlap and differences between these models and the implications of the assumptions of each model has not been systematically elucidated. The selection of the most appropriate modelling framework, and the most appropriate way to develop coarse-grained/fine-grained models in different contexts is not clear. Results We systematically analyze and compare how different modelling methodologies can be used to describe translation. We define various statistically equivalent codon-based simulation algorithms and analyze the importance of the update rule in determining the steady state, an aspect often neglected. Then a novel probabilistic Boolean network (PBN) model is proposed for modelling translation, which enjoys an exact numerical solution. This solution matches those of numerical simulation from other methods and acts as a complementary tool to analytical approximations and simulations. The advantages and limitations of various codon-based models are compared, and illustrated by examples with real biological complexities such as slow codons, premature termination and feedback regulation. Our studies reveal that while different models gives broadly similiar trends in many cases, important differences also arise and can be clearly seen, in the dependence of the translation rate on different parameters. Furthermore, the update rule affects the steady state solution. Conclusions The codon-based models are based on different levels of abstraction. Our analysis suggests that a multiple model approach to understanding translation allows one to ascertain which aspects of the conclusions are robust with respect to the choice of modelling methodology, and when (and why) important differences may arise. This approach also allows for an optimal use of analysis tools, which is especially important when additional complexities or regulatory mechanisms are included. This approach can provide a robust platform for dissecting translation, and results in an improved predictive framework for applications in systems and synthetic biology. PMID:24576337

Regulatory requirements and tools for environmental assessment of hazardous wastes: Understanding tribal and stakeholder concerns using Department of Energy sites

PubMed Central

Burger, Joanna; Powers, Charles; Gochfeld, Michael

2014-01-01

Many US governmental and Tribal Nation agencies, as well as state and local entities, deal with hazardous wastes within regulatory frameworks that require specific environmental assessments. In this paper we use Department of Energy (DOE) sites as examples to examine the relationship between regulatory requirements and environmental assessments for hazardous waste sites and give special attention to how assessment tools differ. We consider federal laws associated with environmental protection include the National Environmental Policy Act (NEPA), the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response Compensation and Liability Act (CERCLA), as well as regulations promulgated by the Nuclear Regulatory Commission, Tribal Nations and state agencies. These regulatory regimes require different types of environmental assessments and remedial investigations, dose assessments and contaminant pathways. The DOE case studies illustrate the following points: 1) there is often understandable confusion about what regulatory requirements apply to the site resources, and what environmental assessments are required by each, 2) the messages sent on site safety issued by different regulatory agencies are sometimes contradictory or confusing (e.g. Oak Ridge Reservation), 3) the regulatory frameworks being used to examine the same question can be different, leading to different conclusions (e.g. Brookhaven National Laboratory), 4) computer models used in support of groundwater models or risk assessments are not necessarily successful in convincing Native Americans and others that there is no possibility of risk from contaminants (e.g. Amchitka Island), 5) when given the opportunity to choose between relying on a screening risk assessments or waiting for a full site-specific analysis of contaminants in biota, the screening risk assessment option is rarely selected (e.g. Amchitka, Hanford Site), and finally, 6) there needs to be agreement on whether there has been adequate characterization to support the risk assessment (e.g. Hanford). The assessments need to be transparent and to accommodate different opinions about the relationship between characterizations and risk assessments. This paper illustrates how many of the problems at DOE sites, and potentially at other sites in the U.S. and elsewhere, derive from a lack of either understanding of, or consensus about, the regulatory process, including the timing and types of required characterizations and data in support of site characterizations and risk assessments. PMID:20719428

A simple versatile solution for collecting multidimensional clinical data based on the CakePHP web application framework.

PubMed

Biermann, Martin

2014-04-01

Clinical trials aiming for regulatory approval of a therapeutic agent must be conducted according to Good Clinical Practice (GCP). Clinical Data Management Systems (CDMS) are specialized software solutions geared toward GCP-trials. They are however less suited for data management in small non-GCP research projects. For use in researcher-initiated non-GCP studies, we developed a client-server database application based on the public domain CakePHP framework. The underlying MySQL database uses a simple data model based on only five data tables. The graphical user interface can be run in any web browser inside the hospital network. Data are validated upon entry. Data contained in external database systems can be imported interactively. Data are automatically anonymized on import, and the key lists identifying the subjects being logged to a restricted part of the database. Data analysis is performed by separate statistics and analysis software connecting to the database via a generic Open Database Connectivity (ODBC) interface. Since its first pilot implementation in 2011, the solution has been applied to seven different clinical research projects covering different clinical problems in different organ systems such as cancer of the thyroid and the prostate glands. This paper shows how the adoption of a generic web application framework is a feasible, flexible, low-cost, and user-friendly way of managing multidimensional research data in researcher-initiated non-GCP clinical projects. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The roles of patents and research and development incentives in biopharmaceutical innovation.

PubMed

Grabowski, Henry G; DiMasi, Joseph A; Long, Genia

2015-02-01

Patents and other forms of intellectual property protection play essential roles in encouraging innovation in biopharmaceuticals. As part of the "21st Century Cures" initiative, Congress is reviewing the policy mechanisms designed to accelerate the discovery, development, and delivery of new treatments. Debate continues about how best to balance patent and intellectual property incentives to encourage innovation, on the one hand, and generic utilization and price competition, on the other hand. We review the current framework for accomplishing these dual objectives and the important role of patents and regulatory exclusivity (together, the patent-based system), given the lengthy, costly, and risky biopharmaceutical research and development process. We summarize existing targeted incentives, such as for orphan drugs and neglected diseases, and we consider the pros and cons of proposed voluntary or mandatory alternatives to the patent-based system, such as prizes and government research and development contracting. We conclude that patents and regulatory exclusivity provisions are likely to remain the core approach to providing incentives for biopharmaceutical research and development. However, prizes and other voluntary supplements could play a useful role in addressing unmet needs and gaps in specific circumstances. Project HOPE—The People-to-People Health Foundation, Inc.

Gene regulatory network inference using fused LASSO on multiple data sets

PubMed Central

Omranian, Nooshin; Eloundou-Mbebi, Jeanne M. O.; Mueller-Roeber, Bernd; Nikoloski, Zoran

2016-01-01

Devising computational methods to accurately reconstruct gene regulatory networks given gene expression data is key to systems biology applications. Here we propose a method for reconstructing gene regulatory networks by simultaneous consideration of data sets from different perturbation experiments and corresponding controls. The method imposes three biologically meaningful constraints: (1) expression levels of each gene should be explained by the expression levels of a small number of transcription factor coding genes, (2) networks inferred from different data sets should be similar with respect to the type and number of regulatory interactions, and (3) relationships between genes which exhibit similar differential behavior over the considered perturbations should be favored. We demonstrate that these constraints can be transformed in a fused LASSO formulation for the proposed method. The comparative analysis on transcriptomics time-series data from prokaryotic species, Escherichia coli and Mycobacterium tuberculosis, as well as a eukaryotic species, mouse, demonstrated that the proposed method has the advantages of the most recent approaches for regulatory network inference, while obtaining better performance and assigning higher scores to the true regulatory links. The study indicates that the combination of sparse regression techniques with other biologically meaningful constraints is a promising framework for gene regulatory network reconstructions. PMID:26864687

Suborbital Safety Technical Committee- Summary of Proposed Standards & Guidelines

NASA Astrophysics Data System (ADS)

Quinn, Andy; Atencia Yepez, Amaya; Klicker, Michael; Howard, Diane; Verstraeten, Joram; Other Suborbital Safety TC Members

2013-09-01

There are currently no international safety standards and guidelines to assist designers, operators and authorities in the suborbital domain. There is a launch licensing regime in the United States (US) to assist the forerunners of the suborbital domain however this does not provide a safety approval for the vehicle against set standards or does not have an acceptable level of safety to achieve in terms of design or operation. In Europe a certification framework may be implemented however this (or any regulatory framework) is not in place as yet. This paper summarises the 5 tasks thus far completed by the International Association for the Advancement of Space Safety (IAASS) Suborbital Safety Technical Committee (SS TC) in terms of deriving standards and guidelines for the suborbital domain. The SS TC comprises members from the suborbital industry (US and European vehicle designers), safety experts, legal experts, medical/training experts, prospective spaceport operators and members from the US and European authorities (though these members cannot directly steer the standards and guidelines - they can merely review them for interest and comment on non-policy aspects). The SS TC has been divided into three working groups (WG): Regulatory WG, Technical WG and Operations WG. The 5 tasks that are summarised in this paper include: Regulatory WG - (Task 1) Clarify and promote regulatory framework for suborbital flights (including discussions on Space Law 'v' Air Law for suborbital domain); Technical WG - (Task 1) Defining & Alignment (globally) of Safety Criteria for Suborbital domain using industry best practices, (Task 2) Software/complex hardware certification for suborbital flights; Operations WG - (Task 1) Flight Crew and Spaceflight Participant Medical and Training Standards & Guidelines for suborbital flight, (Task 2) Spaceport Safety Management System. This paper also details the next set of standards and guidelines that will be derived by the SS TC. The paper concludes that these and future IAASS suborbital safety standards and guidelines are needed now and should beconsidered by the industry players before the first commercial flights expected late 2013/early 2014.

Self-Regulation in the Midst of Complexity: A Case Study of High School Physics Students Engaged in Ill-Structured Problem Solving

NASA Astrophysics Data System (ADS)

Milbourne, Jeffrey David

The purpose of this dissertation study was to explore the experiences of high school physics students who were solving complex, ill-structured problems, in an effort to better understand how self-regulatory behavior mediated the project experience. Consistent with Voss, Green, Post, and Penner's (1983) conception of an ill-structured problem in the natural sciences, the 'problems' consisted of scientific research projects that students completed under the supervision of a faculty mentor. Zimmerman and Campillo's (2003) self-regulatory framework of problem solving provided a holistic guide to data collection and analysis of this multi-case study, with five individual student cases. The study's results are explored in two manuscripts, each targeting a different audience. The first manuscript, intended for the Science Education Research community, presents a thick, rich description of the students' project experiences, consistent with a qualitative, case study analysis. Findings suggest that intrinsic interest was an important self-regulatory factor that helped motivate students throughout their project work, and that the self-regulatory cycle of forethought, performance monitoring, and self-reflection was an important component of the problem-solving process. Findings also support the application of Zimmerman and Campillo's framework to complex, ill-structured problems, particularly the cyclical nature of the framework. Finally, this study suggests that scientific research projects, with the appropriate support, can be a mechanism for improving students' selfregulatory behavior. The second manuscript, intended for Physics practitioners, combines the findings of the first manuscript with the perspectives of the primary, on-site research mentor, who has over a decade's worth of experience mentoring students doing physics research. His experience suggests that a successful research experience requires certain characteristics, including: a slow, 'on-ramp' to the research experience, space to experience productive failure, and an opportunity to enjoy the work they are doing.

Cloning and Characterization of 5′ Flanking Regulatory Sequences of AhLEC1B Gene from Arachis Hypogaea L.

PubMed Central

Tang, Guiying; Xu, Pingli; Liu, Wei; Liu, Zhanji; Shan, Lei

2015-01-01

LEAFY COTYLEDON1 (LEC1) is a B subunit of Nuclear Factor Y (NF-YB) transcription factor that mainly accumulates during embryo development. We cloned the 5′ flanking regulatory sequence of AhLEC1B gene, a homolog of Arabidopsis LEC1, and analyzed its regulatory elements using online software. To identify the crucial regulatory region, we generated a series of GUS expression frameworks driven by different length promoters with 5′ terminal and/or 3′ terminal deletion. We further characterized the GUS expression patterns in the transgenic Arabidopsis lines. Our results show that both the 65bp proximal promoter region and the 52bp 5′ UTR of AhLEC1B contain the key motifs required for the essential promoting activity. Moreover, AhLEC1B is preferentially expressed in the embryo and is co-regulated by binding of its upstream genes with both positive and negative corresponding cis-regulatory elements. PMID:26426444

Pharma Opportunities and Risks Multiply as Regulatory Reform Remakes APAC: Expanded Accelerated Pathways Challenge Developer Value Story, Evidence Collection, and Market Access Strategies.

PubMed

Grignolo, Alberto; Mingping, Zhang

2018-01-01

Sweeping reforms in the largest markets of the Asia-Pacific region are transforming the regulatory and commercial landscape for foreign pharmaceutical companies. Japan, South Korea, and China are leading the charge, establishing mechanisms and infrastructure that both reflect and help drive international regulatory convergence and accelerate delivery of needed, innovative products to patients. In this rapidly evolving regulatory and commercial environment, drug developers can benefit from reforms and proliferating accelerated pathway (AP) frameworks, but only with regulatory and evidence-generation strategies tailored to the region. Otherwise, they will confront significant pricing and reimbursement headwinds. Although APAC economies are at different stages of development, they share a common imperative: to balance pharmaceutical innovation with affordability. Despite the complexity of meeting these sometimes conflicting demands, companies that focus on demonstrating and delivering value for money, and that price new treatments reasonably and sustainably, can succeed both for their shareholders and the region's patient population.

NUTRIENT RESPONSE IN GREAT LAKES WETLANDS

EPA Science Inventory

The U.S. EPA National Health and Environmental Effects Laboratory's Aquatic Stressor Framework and associated Nutrient Implementation Plan define scientific and regulatory needs, and lay-out research goals too for a cross divisional program to investigate stressor-response relati...

Florida spaceports : an analysis of the regulatory framework : summary.

DOT National Transportation Integrated Search

2010-12-01

Until recently, government control : has restricted space flight to a few : highly trained persons executing : missions in the public interest : using a very limited number : of facilities and vehicles. This : environment is changing. Imaging : and c...

Corruption and air pollution in Europe.

PubMed

Ivanova, Kate

2011-01-01

This paper examines how the effectiveness of regulatory framework influences levels of sulphur emissions in a scenario where, to reduce its (emission-) tax payments, a polluting firm may under-report emissions level at the risk of being audited and fined. First, a model to explain how changes in regulatory framework (e.g., audit effectiveness) and transboundary spillovers affect both actual and reported emissions is developed. Then the theoretical predictions using data for 39 European countries from 1999 to 2003 are tested and inferences about true emission levels are made. The empirical analysis supports the theoretical predictions with significant implications for the interpretation of pollution data reported to international monitoring agencies. Countries with effective regulation are likely to have relatively high reported emissions of sulphur. But this should not automatically be interpreted as weak environmental performance, because their actual pollution levels are likely to be lower than in nations with less effective regulation.

Optimizing information flow in small genetic networks. IV. Spatial coupling

NASA Astrophysics Data System (ADS)

Sokolowski, Thomas R.; Tkačik, Gašper

2015-06-01

We typically think of cells as responding to external signals independently by regulating their gene expression levels, yet they often locally exchange information and coordinate. Can such spatial coupling be of benefit for conveying signals subject to gene regulatory noise? Here we extend our information-theoretic framework for gene regulation to spatially extended systems. As an example, we consider a lattice of nuclei responding to a concentration field of a transcriptional regulator (the input) by expressing a single diffusible target gene. When input concentrations are low, diffusive coupling markedly improves information transmission; optimal gene activation functions also systematically change. A qualitatively different regulatory strategy emerges where individual cells respond to the input in a nearly steplike fashion that is subsequently averaged out by strong diffusion. While motivated by early patterning events in the Drosophila embryo, our framework is generically applicable to spatially coupled stochastic gene expression models.

Biosimilars: The US Regulatory Framework.

PubMed

Christl, Leah A; Woodcock, Janet; Kozlowski, Steven

2017-01-14

With the passage of the Biologics Price Competition and Innovation Act of 2009, the US Food and Drug Administration established an abbreviated pathway for developing and licensing biosimilar and interchangeable biological products. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a "totality of the evidence" that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. Although questions and concerns about the biosimilars pathway remain and may slow uptake, a robust scientific program has been put in place. With three biosimilars already licensed and numerous development programs under way, clinicians can expect to see many new biosimilars come onto the US market in the coming decade. [Note added in proof: Since the writing of this article, a fourth biosimilar has been approved.].

A Framework for Conducting Deceased Donor Research in the United States.

PubMed

Glazier, Alexandra K; Heffernan, Kate Gallin; Rodrigue, James R

2015-11-01

There are a number of regulatory barriers both perceived and real that have hampered widespread clinical research in the field of donation and transplantation. This article sets forth a framework clarifying the existing legal requirements and their application to the conduct of research on deceased donors and donor organs within the United States. Recommendations are focused on resolving some of the ambiguity surrounding deceased donor authorization for research, Health Insurance Portability and Accountability Act requirements and the role of institutional review board oversight. The successful conduct of clinical research in the field of donation and transplantation requires an understanding of these regulatory nuances as well as identification of important ethical principles to consider. Facilitation of these concepts will ultimately provide support for innovative research designed to increase the availability of organs for transplantation. Further work identifying the optimal infrastructure for overview of clinical research in the field should be given priority.

NICE technology appraisals: working with multiple levels of uncertainty and the potential for bias.

PubMed

Brown, Patrick; Calnan, Michael

2013-05-01

One of the key roles of the English National Institute for Health and Clinical Excellence (NICE) is technology appraisal. This essentially involves evaluating the cost effectiveness of pharmaceutical products and other technologies for use within the National Health Service. Based on a content analysis of key documents which shed light on the nature of appraisals, this paper draws attention to the multiple layers of uncertainty and complexity which are latent within the appraisal process, and the often socially constructed mechanisms for tackling these. Epistemic assumptions, bounded rationality and more explicitly relational forms of managing knowledge are applied to this end. These findings are discussed in the context of the literature highlighting the inherently social process of regulation. A framework is developed which posits the various forms of uncertainty, and responses to these, as potential conduits of regulatory bias-in need of further research. That NICE's authority is itself regulated by other actors within the regulatory regime, particularly the pharmaceutical industry, exposes it to the threat of regulatory capture. Following Lehoux, it is concluded that a more transparent and reflexive format for technological appraisals is necessary. This would enable a more robust, defensible form of decision-making and moreover enable NICE to preserve its legitimacy in the midst of pressures which threaten this.

Regulatory aspects of nanotechnology in the agri/feed/food sector in EU and non-EU countries.

PubMed

Amenta, Valeria; Aschberger, Karin; Arena, Maria; Bouwmeester, Hans; Botelho Moniz, Filipa; Brandhoff, Puck; Gottardo, Stefania; Marvin, Hans J P; Mech, Agnieszka; Quiros Pesudo, Laia; Rauscher, Hubert; Schoonjans, Reinhilde; Vettori, Maria Vittoria; Weigel, Stefan; Peters, Ruud J

2015-10-01

Nanotechnology has the potential to innovate the agricultural, feed and food sectors (hereinafter referred to as agri/feed/food). Applications that are marketed already include nano-encapsulated agrochemicals or nutrients, antimicrobial nanoparticles and active and intelligent food packaging. Many nano-enabled products are currently under research and development, and may enter the market in the near future. As for any other regulated product, applicants applying for market approval have to demonstrate the safe use of such new products without posing undue safety risks to the consumer and the environment. Several countries all over the world have been active in examining the appropriateness of their regulatory frameworks for dealing with nanotechnologies. As a consequence of this, different approaches have been taken in regulating nano-based products in agri/feed/food. The EU, along with Switzerland, were identified to be the only world region where nano-specific provisions have been incorporated in existing legislation, while in other regions nanomaterials are regulated more implicitly by mainly building on guidance for industry. This paper presents an overview and discusses the state of the art of different regulatory measures for nanomaterials in agri/feed/food, including legislation and guidance for safety assessment in EU and non-EU countries. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Synchronous versus asynchronous modeling of gene regulatory networks.

PubMed

Garg, Abhishek; Di Cara, Alessandro; Xenarios, Ioannis; Mendoza, Luis; De Micheli, Giovanni

2008-09-01

In silico modeling of gene regulatory networks has gained some momentum recently due to increased interest in analyzing the dynamics of biological systems. This has been further facilitated by the increasing availability of experimental data on gene-gene, protein-protein and gene-protein interactions. The two dynamical properties that are often experimentally testable are perturbations and stable steady states. Although a lot of work has been done on the identification of steady states, not much work has been reported on in silico modeling of cellular differentiation processes. In this manuscript, we provide algorithms based on reduced ordered binary decision diagrams (ROBDDs) for Boolean modeling of gene regulatory networks. Algorithms for synchronous and asynchronous transition models have been proposed and their corresponding computational properties have been analyzed. These algorithms allow users to compute cyclic attractors of large networks that are currently not feasible using existing software. Hereby we provide a framework to analyze the effect of multiple gene perturbation protocols, and their effect on cell differentiation processes. These algorithms were validated on the T-helper model showing the correct steady state identification and Th1-Th2 cellular differentiation process. The software binaries for Windows and Linux platforms can be downloaded from http://si2.epfl.ch/~garg/genysis.html.

Neural processing of emotional-intensity predicts emotion regulation choice.

PubMed

Shafir, Roni; Thiruchselvam, Ravi; Suri, Gaurav; Gross, James J; Sheppes, Gal

2016-12-01

Emotional-intensity is a core characteristic of affective events that strongly determines how individuals choose to regulate their emotions. Our conceptual framework suggests that in high emotional-intensity situations, individuals prefer to disengage attention using distraction, which can more effectively block highly potent emotional information, as compared with engagement reappraisal, which is preferred in low emotional-intensity. However, existing supporting evidence remains indirect because prior intensity categorization of emotional stimuli was based on subjective measures that are potentially biased and only represent the endpoint of emotional-intensity processing. Accordingly, this study provides the first direct evidence for the role of online emotional-intensity processing in predicting behavioral regulatory-choices. Utilizing the high temporal resolution of event-related potentials, we evaluated online neural processing of stimuli's emotional-intensity (late positive potential, LPP) prior to regulatory-choices between distraction and reappraisal. Results showed that enhanced neural processing of intensity (enhanced LPP amplitudes) uniquely predicted (above subjective measures of intensity) increased tendency to subsequently choose distraction over reappraisal. Additionally, regulatory-choices led to adaptive consequences, demonstrated in finding that actual implementation of distraction relative to reappraisal-choice resulted in stronger attenuation of LPPs and self-reported arousal. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan.

PubMed

Chang, Lin-Chau; Kang, Jaw-Jou; Gau, Churn-Shiouh

2015-12-01

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Four essays on offshore wind power potential, development, regulatory framework, and integration

NASA Astrophysics Data System (ADS)

Dhanju, Amardeep

Offshore wind power is an energy resource whose potential in the US has been recognized only recently. There is now growing interest among the coastal states to harness the resource, particularly in states adjacent to the Mid-Atlantic Bight where the shallow continental shelf allows installation of wind turbines using the existing foundation technology. But the promise of bountiful clean energy from offshore wind could be delayed or forestalled due to policy and regulatory challenges. This dissertation is an effort to identify and address some of the important challenges. Focusing on Delaware as a case study it calculates the extent of the wind resource; considers one means to facilitate resource development---the establishment of statewide and regional public power authorities; analyzes possible regulatory frameworks to manage the resource in state-controlled waters; and assesses the use of distributed storage to manage intermittent output from wind turbines. In order to cover a diversity of topics, this research uses a multi-paper format with four essays forming the body of work. The first essay lays out an accessible methodology to calculate offshore wind resource potential using publicly available data, and uses this methodology to access wind resources off Delaware. The assessment suggests a wind resource approximately four times the average electrical load in Delaware. The second essay examines the potential role of a power authority, a quasi-public institution, in lowering the cost of capital, reducing financial risk of developing and operating a wind farm, and enhancing regional collaboration on resource development and management issues. The analysis suggests that a power authority can lower the cost of offshore wind power by as much as 1/3, thereby preserving the ability to pursue cost-competitive development even if the current federal incentives are removed. The third essay addresses the existing regulatory void in state-controlled waters of Delaware. It outlines a regulatory framework touching on key elements such as the leasing system, length of tenure, and financial terms for allocating property rights. In addition, the framework also provides recommendations on environmental assessment that would be required prior to lease issuance. The fourth essay analyzes offshore wind power integration using electric thermal storage in housing units. It presents a model of wind generation, heating load and wind driven thermal storage to assess the potential of storage to buffer wind intermittency. The analysis suggests that thermal load matches the seasonal excess of offshore wind during winter months, and that electric thermal storage could provide significant temporal, spatial, and cost advantages for balancing output from offshore wind generation, while also converting a major residential load (space heating) now met by fossil fuels to low carbon energy resources. Together, the four essays provide new analyses of policy, regulatory, and system integration issues that could impede resource development, and also analyze and recommend strategies to manage these issues.

Commissioning through competition and cooperation in the English NHS under the Health and Social Care Act 2012: evidence from a qualitative study of four clinical commissioning groups

PubMed Central

Allen, Pauline; Osipovič, Dorota; Shepherd, Elizabeth; Coleman, Anna; Perkins, Neil; Garnett, Emma; Williams, Lorraine

2017-01-01

Objective The Health and Social Care Act 2012 (‘HSCA 2012’) introduced a new, statutory, form of regulation of competition into the National Health Service (NHS), while at the same time recognising that cooperation was necessary. NHS England's policy document, The Five Year Forward View (‘5YFV’) of 2014 placed less emphasis on competition without altering the legislation. We explored how commissioners and providers understand the complex regulatory framework, and how they behave in relation to competition and cooperation. Design We carried out detailed case studies in four clinical commissioning groups, using interviews and documentary analysis to explore the commissioners’ and providers’ understanding and experience of competition and cooperation. Setting/participants We conducted 42 interviews with senior managers in commissioning organisations and senior managers in NHS and independent provider organisations (acute and community services). Results Neither commissioners nor providers fully understand the regulatory regime in respect of competition in the NHS, and have not found that the regulatory authorities have provided adequate guidance. Despite the HSCA 2012 promoting competition, commissioners chose mainly to use collaborative strategies to effect major service reconfigurations, which is endorsed as a suitable approach by providers. Nevertheless, commissioners are using competitive tendering in respect of more peripheral services in order to improve quality of care and value for money. Conclusions Commissioners regard the use of competition and cooperation as appropriate in the NHS currently, although collaborative strategies appear more helpful in respect of large-scale changes. However, the current regulatory framework contained in the HSCA 2012, particularly since the publication of the 5YFV, is not clear. Better guidance should be issued by the regulatory authorities. PMID:28183806

The regulatory contract and restructuring: A modest proposal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartman, R.S.; Tabors, R.

1996-12-01

History does not support the notion that the regulatory contract has treated utilities unfairly. But to the extent it is decided, for other reasons, that utilities should receive transition payments as the industry is pushed to a more competitive framework, there are four important principles to keep firmly in mind. To paraphrase the contemporary bumper sticker, `in the economic, social and/or romantic affairs of man and/or woman, unexpected events happen.` A more thoughtful interpretation of this notion would be that in economic and social interrelationships, individuals formulate behavioral plans based upon expectations about the state of the world and/or themore » behavior of other individuals. Should those expectations turn out to be incorrect, the individuals relying upon those expectations and their plans will be frustrated. The frustrated individuals may rail against their fate; they may accept their disappointment stoically. They may `take arms against a sea of troubles, and by opposing end them.` Alternatively and more likely in late twentieth century America, they may litigate (or threaten litigation) for breach of contract, claiming that some implicit or explicit, oral or written contract has been breached and that reliance upon that contract has consequently damaged them. The discussion of assets potentially stranded by the ongoing restructuring of the U.S. electric power industry has been characterized by the latter response. As some utilities have faced the possible economic obsolescence of particular generation assets in light of technological changes and altered regulatory rules, they have invoked the notion of a `regulatory contract` having governed their expectations, behavior and past capital investment. By implication, these utilities argue that they should be fully compensated for all cost incurred under good faith adherence to past regulatory processes and procedures.« less

Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A Multinational Study.

PubMed

Joseph, Pathma D; Craig, Jonathan C; Tong, Allison; Caldwell, Patrina H Y

2016-10-01

The last decade has seen dramatic changes in the regulatory landscape to support more trials involving children, but child-specific challenges and inequitable conduct across income regions persist. The goal of this study was to describe the attitudes and opinions of stakeholders toward trials in children, to inform additional strategies to promote more high-quality, relevant pediatric trials across the globe. Key informant semi-structured interviews were conducted with stakeholders (researchers, regulators, and sponsors) who were purposively sampled from low- to middle-income countries and high-income countries. The transcripts were thematically analyzed. Thirty-five stakeholders from 10 countries were interviewed. Five major themes were identified: addressing pervasive inequities (paucity of safety and efficacy data, knowledge disparities, volatile environment, double standards, contextual relevance, market-driven forces, industry sponsorship bias and prohibitive costs); contending with infrastructural barriers (resource constraints, dearth of pediatric trial expertise, and logistical complexities); navigating complex ethical and regulatory frameworks ("draconian" oversight, ambiguous requirements, exploitation, excessive paternalism and precariousness of coercion versus volunteerism); respecting uniqueness of children (pediatric research paradigms, child-appropriate approaches, and family-centered empowerment); and driving evidence-based child health (advocacy, opportunities, treatment access, best practices, and research prioritization). Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children, but they contend that inequities and political, regulatory, and resource barriers continue to exist. Embedding trials as part of routine clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders recommended increasing international collaboration, establishing centralized trials infrastructure, and aligning research to child health priorities to encourage trials that address global child health care needs. Copyright © 2016 by the American Academy of Pediatrics.

The policy-practice gap: describing discordances between regulation on paper and real-life practices among specialized drug shops in Kenya.

PubMed

Wafula, Francis; Abuya, Timothy; Amin, Abdinasir; Goodman, Catherine

2014-09-16

Specialized drug shops (SDSs) are popular in Sub-Saharan Africa because they provide convenient access to medicines. There is increasing interest in how policymakers can work with them, but little knowledge on how their operation relates to regulatory frameworks. This study sought to describe characteristics and predictors of regulatory practices among SDSs in Kenya. The regulatory framework governing the Kenya pharmaceutical sector was mapped, and a list of regulations selected for inclusion in a survey questionnaire. An SDS census was conducted, and survey data collected from 213 SDSs from two districts in Western Kenya. The majority of SDSs did not comply with regulations, with only 12% having a refrigerator and 22% having a separate dispensing area for instance. Additionally, less than half had at least one staff with pharmacy qualification (46%), with less than a third of all interviewed operators knowing the name of the law governing pharmacy.Regulatory infringement was more common among SDSs in rural locations; those that did not have staff with pharmacy qualifications; and those whose operator did not know the name of the pharmacy law. Compliance was not significantly associated with the frequency of inspections, with over 80% of both rural and urban SDSs reporting an inspection in the past year. While compliance was low overall, it was particularly poor among SDSs operating in rural locations, and those that did not have staff with pharmacy qualification. This suggested the need for policy to introduce levels of practice in recognition of the variations in resource availability. Under such a system, rural SDSs operating in low-resource setting, and selling a limited range of medicines, may be exempted from certain regulatory requirements, as long as their scope of practice is limited to certain essential services only. Future research should also explore why regulatory compliance is poor despite regular inspections.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

PubMed

Hussaarts, Leonie; Mühlebach, Stefan; Shah, Vinod P; McNeil, Scott; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J A; de Vlieger, Jon S B

2017-11-01

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

'Do no harm'? Professional regulation of disabled nursing students and nurses in Great Britain.

PubMed

Sin, Chih Hoong; Fong, Janice

2008-06-01

This paper is a report of the findings of a General Formal Investigation launched by the Disability Rights Commission, Great Britain into the impact of regulatory fitness standards on disabled people, and on nursing students and nurses in particular. The potential for systemic discrimination against disabled nursing professionals lies in the existence and nature of regulatory fitness standards, as well as in how these are interpreted and implemented in practice. A review of relevant legislation, regulation and guidance was conducted to explore the interaction of the regulatory framework with the Disability Discrimination Act. A formal call to key national stakeholder organizations solicited information on perceptions of the regulatory framework and the adequacy of guidance issued. Independent research was commissioned on disabled people's disclosure of disability, informal and formal decision-making around fitness within the educational, and employment contexts. An Inquiry Panel examined all evidence sources, solicited further oral evidence from key organizations, and developed recommendations. No mention was found of the Disability Discrimination Act in any regulation and guidance governing nursing prior to 2006. There are particular requirements for 'good health and good character'. Respondents from key national stakeholder organizations, higher educational institutions and employers struggle to interpret the fitness requirements consistently. Implementation is variable, with reliance on ad hoc self-initiated strategies. The variability of interpretation and implementation can lead to discrimination against disabled people. The imprecision of fitness requirements and variability of implementation raise serious doubts about their utility in managing risk.

Enhancing faecal sludge management in peri-urban areas of Lusaka through faecal sludge valorisation: challenges and opportunities

NASA Astrophysics Data System (ADS)

Tembo, J. M.; Nyirenda, E.; Nyambe, I.

2017-03-01

Lusaka, the capital city of Zambia, has two million inhabitants with 70% residing in peri-urban areas. Ninety (90) % of this population employ pit latrines for excretion generating approximately 22,680 tons of faecal sludge per annum. This sludge is inadequately managed hence of the generated amount, over 60% remains within the residential environment thereby compromising both the environment and public health. To foster a solution to this problem, a study was commissioned to assess faecal sludge valorisation potential and how it would impact on Faecal Sludge Management. The study evaluated policy, institutional and regulatory frameworks, sanitation practices including latrine construction and usage aspects and also characterised the faecal sludge for selected parameters relevant to valorisation. Four peri-urban areas were adopted as study sites. Policy issues together with existing institutional and regulatory frameworks were assessed through literature review. Sanitation practices were evaluated through physical observations, focus group discussions, interviews and questionnaire administration. Faecal sludge characterisation was through sampling and analysis. It was observed that there are policy gaps in fostering faecal sludge valorisation. Sanitation practices and latrines construction also do not favour valorisation. The quality of the raw sludge has potential for valorisation though again, some parameters like solid waste content require drastic changes in sanitation practices in order not to compromise the reuse potential of the sludge. It was concluded that if faecal sludge management is to be enhanced through valorisation, there is need to have policies promoting pit latrine faecal sludge reuse and strengthened regulatory and institutional frameworks in this respect.

Gamete and Embryo Donation and Surrogacy in Australia: The Social Context and Regulatory Framework

PubMed Central

Hammarberg, Karin; Johnson, Louise; Petrillo, Tracey

2011-01-01

The social and legal acceptability of third-party reproduction varies around the world. In Australia, gamete and embryo donation and surrogacy are permitted within the regulatory framework set out by federal and state governments. The aim of this paper is to describe the social context and regulatory framework for third-party reproduction in Australia. This is a review of current laws and regulations related to third-party reproduction in Australia. Although subtle between-state differences exist, third-party reproduction is by and large a socially acceptable and legally permissible way to form a family throughout Australia. The overarching principles that govern the practice of third-party reproduction are altruism; the right of donorconceived people to be informed of their biological origins; and the provision of comprehensive counselling about the social, psychological, physical, ethical, financial and legal implications of third-party reproduction to those considering donating or receiving gametes or embryos and entering surrogacy arrangements. These principles ensure that donors are not motivated by financial gain, donor offspring can identify and meet with the person or persons who donated gametes or embryos, and prospective donors and recipients are aware of and have carefully considered the potential consequences of third-party reproduction. Australian state laws and federal guidelines prohibit commercial and anonymous third-party reproduction; mandate counselling of all parties involved in gamete and embryo donation and surrogacy arrangements; and require clinics to keep records with identifying and non- identifying information about the donor/s to allow donor-conceived offspring to trace their biological origins. PMID:24851179

Social Values, Regulatory Tensions and Professional Practices with Underprivileged Populations: The Case of Quebec's Oral Healthcare System

PubMed Central

Bedos, Christophe

2011-01-01

Objective: Dentists may experience frustration in their practice with people living on welfare, often perceiving them in a negative light. The difficulties encountered are detrimental to the patient—professional relationship and contribute to compromising access to care for this underprivileged population. In order to fully understand patient—professional interactions, we must consider the macroscopic contexts in which they occur. This paper examines the systemic influences of these interpersonal relationships to deepen our understanding of an important access-to-care determinant for people living on welfare. Methods: Two frameworks are applied to the analysis of Quebec's oral healthcare system: the social values framework and the regulatory logics framework. Results: Our assessment leads us to posit two phenomena: (1) certain negative stereotypes regarding patients living on welfare allow dentists to manage the inevitable regulatory conflicts (i.e., economic vs. professional) involved in their practice and (2) the behaviours of people living on welfare are frequently judged according to the social values embodied in the organization of Quebec's oral healthcare system, delivery and financing. Conclusion: Quebec's oral healthcare system fails to provide effective access to care for individuals living in poverty, and the government must significantly augment its involvement in this healthcare sector. Dentists should also understand the impact that systemic influences have on their rapport with people living on welfare. We argue that new orientations for the field of dental professional education should be considered. This paper was originally published in French, in the journal Pratiques et Organisation des Soins 2011 42(3). PMID:22851989

Gamete and embryo donation and surrogacy in australia: the social context and regulatory framework.

PubMed

Hammarberg, Karin; Johnson, Louise; Petrillo, Tracey

2011-01-01

The social and legal acceptability of third-party reproduction varies around the world. In Australia, gamete and embryo donation and surrogacy are permitted within the regulatory framework set out by federal and state governments. The aim of this paper is to describe the social context and regulatory framework for third-party reproduction in Australia. This is a review of current laws and regulations related to third-party reproduction in Australia. Although subtle between-state differences exist, third-party reproduction is by and large a socially acceptable and legally permissible way to form a family throughout Australia. The overarching principles that govern the practice of third-party reproduction are altruism; the right of donorconceived people to be informed of their biological origins; and the provision of comprehensive counselling about the social, psychological, physical, ethical, financial and legal implications of third-party reproduction to those considering donating or receiving gametes or embryos and entering surrogacy arrangements. These principles ensure that donors are not motivated by financial gain, donor offspring can identify and meet with the person or persons who donated gametes or embryos, and prospective donors and recipients are aware of and have carefully considered the potential consequences of third-party reproduction. Australian state laws and federal guidelines prohibit commercial and anonymous third-party reproduction; mandate counselling of all parties involved in gamete and embryo donation and surrogacy arrangements; and require clinics to keep records with identifying and non- identifying information about the donor/s to allow donor-conceived offspring to trace their biological origins.

An inventory of ambulance service regulatory programs in California.

PubMed

Narad, R A

1998-01-01

Ambulance regulation in California is the responsibility of numerous agencies on the state and local levels. By identifying and analyzing the variety of programs used in one state, this study establishes a framework for evaluation of state and local regulatory programs elsewhere. This study surveyed all California local EMS agencies (LEMSAs: California's equivalent of regional EMS organizations) to identify the types of regulatory programs used, the foci of these programs (e.g., equipment and personnel), and their application (e.g., public and private providers). All data acquired were analyzed using population parameters rather than inferential statistics. A response rate of 100% was obtained. Among the regulatory tools used are ordinances, contracts, and franchises. Regulatory standards vary widely as do their applications. Large counties and those that operate their own LEMSA have more extensive regulatory programs than do smaller counties and those who participate in multicounty agencies. Many of the enforcement mechanisms available are weak. This study suggests several policy implications for California and other states. The wide variation in the types of regulatory programs and the standards that are used suggest that the purpose and impact of regulatory programs should be studied further. The decentralization of the ambulance regulatory program and the lack of integration of ambulance regulations into EMS system planning also raise policy questions. In addition, the role of multicounty EMS agencies, as it relates to regulation of ambulance services, should be reviewed.

Policy Considerations for Commercializing Natural Gas and Biomass CCUS

NASA Astrophysics Data System (ADS)

Abrahams, L.; Clavin, C.

2017-12-01

Captured CO2 from power generation has been discussed as an opportunity to improve the environmental sustainability of fossil fuel-based electricity generation and likely necessary technological solution necessary for meeting long-term climate change mitigation goals. In our presentation, we review the findings of a study of natural gas CCUS technology research and development and discuss their applications to biomass CCUS technology potential. Based on interviews conducted with key stakeholders in CCUS technology development and operations, this presentation will discuss these technical and economic challenges and potential policy opportunities to support commercial scale CCUS deployment. In current domestic and electricity and oil markets, CCUS faces economic challenges for commercial deployment. In particular, the economic viability of CCUS has been impacted by the sustained low oil prices that have limited the potential for enhanced oil recovery (EOR) to serve as a near-term utilization opportunity for the captured CO2. In addition, large scale commercial adoption of CCUS is constrained by regulatory inconsistencies and uncertainties across the United States, high initial capital costs, achieving familiarity with new technology applications to existing markets, developing a successful performance track record to acquire financing agreements, and competing against well-established incumbent technologies. CCUS also has additional technical hurdles for measurement, verification, and reporting within states that have existing policy and regulatory frameworks for climate change mitigation. In addition to fossil-fuel based CCUS, we will discuss emerging opportunities to utilize CCUS fueled by gasified biomass resulting in carbon negative power generation with expanded economic opportunities associated with the enhanced carbon sequestration. Successful technology development of CCUS technology requires a portfolio of research leading to technical advances, advances in financial instruments to leverage the benefits of multiple commodity markets (e.g. natural gas, oil, biomass), and policy instruments that address regulatory hurdles posed CCUS technology deployment.

Use of transcriptome sequencing to understand the pistillate flowering in hickory (Carya cathayensis Sarg.).

PubMed

Huang, You-Jun; Liu, Li-Li; Huang, Jian-Qin; Wang, Zheng-Jia; Chen, Fang-Fang; Zhang, Qi-Xiang; Zheng, Bing-Song; Chen, Ming

2013-10-10

Different from herbaceous plants, the woody plants undergo a long-period vegetative stage to achieve floral transition. They then turn into seasonal plants, flowering annually. In this study, a preliminary model of gene regulations for seasonal pistillate flowering in hickory (Carya cathayensis) was proposed. The genome-wide dynamic transcriptome was characterized via the joint-approach of RNA sequencing and microarray analysis. Differential transcript abundance analysis uncovered the dynamic transcript abundance patterns of flowering correlated genes and their major functions based on Gene Ontology (GO) analysis. To explore pistillate flowering mechanism in hickory, a comprehensive flowering gene regulatory network based on Arabidopsis thaliana was constructed by additional literature mining. A total of 114 putative flowering or floral genes including 31 with differential transcript abundance were identified in hickory. The locations, functions and dynamic transcript abundances were analyzed in the gene regulatory networks. A genome-wide co-expression network for the putative flowering or floral genes shows three flowering regulatory modules corresponding to response to light abiotic stimulus, cold stress, and reproductive development process, respectively. Totally 27 potential flowering or floral genes were recruited which are meaningful to understand the hickory specific seasonal flowering mechanism better. Flowering event of pistillate flower bud in hickory is triggered by several pathways synchronously including the photoperiod, autonomous, vernalization, gibberellin, and sucrose pathway. Totally 27 potential flowering or floral genes were recruited from the genome-wide co-expression network function module analysis. Moreover, the analysis provides a potential FLC-like gene based vernalization pathway and an 'AC' model for pistillate flower development in hickory. This work provides an available framework for pistillate flower development in hickory, which is significant for insight into regulation of flowering and floral development of woody plants.

Use of transcriptome sequencing to understand the pistillate flowering in hickory (Carya cathayensis Sarg.)

PubMed Central

2013-01-01

Background Different from herbaceous plants, the woody plants undergo a long-period vegetative stage to achieve floral transition. They then turn into seasonal plants, flowering annually. In this study, a preliminary model of gene regulations for seasonal pistillate flowering in hickory (Carya cathayensis) was proposed. The genome-wide dynamic transcriptome was characterized via the joint-approach of RNA sequencing and microarray analysis. Results Differential transcript abundance analysis uncovered the dynamic transcript abundance patterns of flowering correlated genes and their major functions based on Gene Ontology (GO) analysis. To explore pistillate flowering mechanism in hickory, a comprehensive flowering gene regulatory network based on Arabidopsis thaliana was constructed by additional literature mining. A total of 114 putative flowering or floral genes including 31 with differential transcript abundance were identified in hickory. The locations, functions and dynamic transcript abundances were analyzed in the gene regulatory networks. A genome-wide co-expression network for the putative flowering or floral genes shows three flowering regulatory modules corresponding to response to light abiotic stimulus, cold stress, and reproductive development process, respectively. Totally 27 potential flowering or floral genes were recruited which are meaningful to understand the hickory specific seasonal flowering mechanism better. Conclusions Flowering event of pistillate flower bud in hickory is triggered by several pathways synchronously including the photoperiod, autonomous, vernalization, gibberellin, and sucrose pathway. Totally 27 potential flowering or floral genes were recruited from the genome-wide co-expression network function module analysis. Moreover, the analysis provides a potential FLC-like gene based vernalization pathway and an 'AC’ model for pistillate flower development in hickory. This work provides an available framework for pistillate flower development in hickory, which is significant for insight into regulation of flowering and floral development of woody plants. PMID:24106755

Potential self-regulatory mechanisms of yoga for psychological health

PubMed Central

Gard, Tim; Noggle, Jessica J.; Park, Crystal L.; Vago, David R.; Wilson, Angela

2014-01-01

Research suggesting the beneficial effects of yoga on myriad aspects of psychological health has proliferated in recent years, yet there is currently no overarching framework by which to understand yoga’s potential beneficial effects. Here we provide a theoretical framework and systems-based network model of yoga that focuses on integration of top-down and bottom-up forms of self-regulation. We begin by contextualizing yoga in historical and contemporary settings, and then detail how specific components of yoga practice may affect cognitive, emotional, behavioral, and autonomic output under stress through an emphasis on interoception and bottom-up input, resulting in physical and psychological health. The model describes yoga practice as a comprehensive skillset of synergistic process tools that facilitate bidirectional feedback and integration between high- and low-level brain networks, and afferent and re-afferent input from interoceptive processes (somatosensory, viscerosensory, chemosensory). From a predictive coding perspective we propose a shift to perceptual inference for stress modulation and optimal self-regulation. We describe how the processes that sub-serve self-regulation become more automatized and efficient over time and practice, requiring less effort to initiate when necessary and terminate more rapidly when no longer needed. To support our proposed model, we present the available evidence for yoga affecting self-regulatory pathways, integrating existing constructs from behavior theory and cognitive neuroscience with emerging yoga and meditation research. This paper is intended to guide future basic and clinical research, specifically targeting areas of development in the treatment of stress-mediated psychological disorders. PMID:25368562

Evolutionary interrogation of human biology in well-annotated genomic framework of rhesus macaque.

PubMed

Zhang, Shi-Jian; Liu, Chu-Jun; Yu, Peng; Zhong, Xiaoming; Chen, Jia-Yu; Yang, Xinzhuang; Peng, Jiguang; Yan, Shouyu; Wang, Chenqu; Zhu, Xiaotong; Xiong, Jingwei; Zhang, Yong E; Tan, Bertrand Chin-Ming; Li, Chuan-Yun

2014-05-01

With genome sequence and composition highly analogous to human, rhesus macaque represents a unique reference for evolutionary studies of human biology. Here, we developed a comprehensive genomic framework of rhesus macaque, the RhesusBase2, for evolutionary interrogation of human genes and the associated regulations. A total of 1,667 next-generation sequencing (NGS) data sets were processed, integrated, and evaluated, generating 51.2 million new functional annotation records. With extensive NGS annotations, RhesusBase2 refined the fine-scale structures in 30% of the macaque Ensembl transcripts, reporting an accurate, up-to-date set of macaque gene models. On the basis of these annotations and accurate macaque gene models, we further developed an NGS-oriented Molecular Evolution Gateway to access and visualize macaque annotations in reference to human orthologous genes and associated regulations (www.rhesusbase.org/molEvo). We highlighted the application of this well-annotated genomic framework in generating hypothetical link of human-biased regulations to human-specific traits, by using mechanistic characterization of the DIEXF gene as an example that provides novel clues to the understanding of digestive system reduction in human evolution. On a global scale, we also identified a catalog of 9,295 human-biased regulatory events, which may represent novel elements that have a substantial impact on shaping human transcriptome and possibly underpin recent human phenotypic evolution. Taken together, we provide an NGS data-driven, information-rich framework that will broadly benefit genomics research in general and serves as an important resource for in-depth evolutionary studies of human biology.