Following the Footsteps of Chlamydial Gene Regulation

PubMed Central

Domman, D.; Horn, M.

2015-01-01

Regulation of gene expression ensures an organism responds to stimuli and undergoes proper development. Although the regulatory networks in bacteria have been investigated in model microorganisms, nearly nothing is known about the evolution and plasticity of these networks in obligate, intracellular bacteria. The phylum Chlamydiae contains a vast array of host-associated microbes, including several human pathogens. The Chlamydiae are unique among obligate, intracellular bacteria as they undergo a complex biphasic developmental cycle in which large swaths of genes are temporally regulated. Coupled with the low number of transcription factors, these organisms offer a model to study the evolution of regulatory networks in intracellular organisms. We provide the first comprehensive analysis exploring the diversity and evolution of regulatory networks across the phylum. We utilized a comparative genomics approach to construct predicted coregulatory networks, which unveiled genus- and family-specific regulatory motifs and architectures, most notably those of virulence-associated genes. Surprisingly, our analysis suggests that few regulatory components are conserved across the phylum, and those that are conserved are involved in the exploitation of the intracellular niche. Our study thus lends insight into a component of chlamydial evolution that has otherwise remained largely unexplored. PMID:26424812

SIGNALS AND REGULATORS THAT GOVERN STREPTOMYCES DEVELOPMENT

PubMed Central

McCormick, Joseph R.; Flärdh, Klas

2012-01-01

Streptomyces coelicolor is the genetically best characterized species of a populous genus belonging to the Gram-positive Actinobacteria. Streptomycetes are filamentous soil organisms, well known for the production of a plethora of biologically active secondary metabolic compounds. The Streptomyces developmental life cycle is uniquely complex, and involves coordinated multicellular development with both physiological and morphological differentiation of several cell types, culminating in production of secondary metabolites and dispersal of mature spores. This review presents a current appreciation of the signaling mechanisms used to orchestrate the decision to undergo morphological differentiation, and the regulators and regulatory networks that direct the intriguing development of multigenomic hyphae, first to form specialized aerial hyphae, and then to convert them into chains of dormant spores. This current view of S. coelicolor development is destined for rapid evolution as data from “-omics” studies shed light on gene regulatory networks, new genetic screens identify hitherto unknown players, and the resolution of our insights into the underlying cell biological processes steadily improve. PMID:22092088

The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions.

PubMed

Kessler, Larry G; Barnhart, Huiman X; Buckler, Andrew J; Choudhury, Kingshuk Roy; Kondratovich, Marina V; Toledano, Alicia; Guimaraes, Alexander R; Filice, Ross; Zhang, Zheng; Sullivan, Daniel C

2015-02-01

The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Quality in health care and globalization of health services: accreditation and regulatory oversight of medical tourism companies.

PubMed

Turner, Leigh G

2011-02-01

Patients are crossing national borders in search of affordable and timely health care. Many medical tourism companies are now involved in organizing cross-border health services. Despite the rapid expansion of the medical tourism industry, few standards exist to ensure that these businesses organize high-quality, competent international health care. Addressing the regulatory vacuum, 10 standards are proposed as a framework for regulating the medical tourism industry. Medical tourism companies should have to undergo accreditation review. Care should be arranged only at accredited international health-care facilities. Standards should be established to ensure that clients of medical tourism companies make informed choices. Continuity of care needs to become an integral feature of cross-border care. Restrictions should be placed on the use of waiver of liability forms by medical tourism companies. Medical tourism companies must ensure that they conform to relevant legislation governing privacy and confidentiality of patient information. Restrictions must be placed on the types of health services marketed by medical tourism companies. Representatives of medical tourism agencies should have to undergo training and certification. Medical travel insurance and medical complications insurance should be included in the health-care plans of patients traveling for care. To protect clients from financial losses, medical tourism companies should be mandated to contribute to compensation funds. Establishing high standards for the operation of medical tourism companies should reduce risks facing patients when they travel abroad for health care.

New treatments for gout.

PubMed

Mapa, Janet B; Pillinger, Michael H

2010-05-01

Gout is a commonly occurring medical condition that can lead to significant morbidity. Therapies available for the treatment of both acute and chronic gouty arthritis have not changed significantly since the 1960s. Although these treatments are well established, they are often contraindicated in the presence of various different comorbidities, including diabetes, renal insufficiency, hypertension and gastrointestinal disease, all of which can occur frequently in patients with gout. Therefore, new treatments are needed. This review describes recent advances in therapeutics for gout, including drugs designed to reduce levels of urate and to inhibit acute or chronic inflammation. While some of these strategies are currently available, others are undergoing regulatory evaluation or are at earlier stages of development.

78 FR 23507 - Notice of Regulatory Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

.... 2013-N-06] Notice of Regulatory Review AGENCY: Federal Housing Finance Agency. ACTION: Request for comment. SUMMARY: The Federal Housing Finance Agency (FHFA) is issuing a notice of a regulatory review that will be conducted in accordance with the process set forth in the regulatory review plan published...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

21 CFR 60.20 - FDA action on regulatory review period determinations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false FDA action on regulatory review period... SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.20 FDA action on regulatory review period determinations. (a) FDA will consult its records and experts to verify the dates...

76 FR 33181 - Regulatory Review Schedule

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

... DEPARTMENT OF THE INTERIOR National Indian Gaming Commission 25 CFR Chapter III Regulatory Review... conducting a comprehensive review of all its regulations and requesting public comment on the process for conducting the regulatory review. On April 4, 2011, after holding eight consultation meetings and reviewing...

76 FR 26967 - Regulatory Review Schedule

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-10

... DEPARTMENT OF THE INTERIOR National Indian Gaming Commission 25 CFR Chapter III Regulatory Review... review of its regulations and requesting public comment on the process for conducting the regulatory review. On April 4, 2011, after holding eight consultation meetings and reviewing all comments, NIGC...

The genetic network controlling plasma cell differentiation.

PubMed

Nutt, Stephen L; Taubenheim, Nadine; Hasbold, Jhagvaral; Corcoran, Lynn M; Hodgkin, Philip D

2011-10-01

Upon activation by antigen, mature B cells undergo immunoglobulin class switch recombination and differentiate into antibody-secreting plasma cells, the endpoint of the B cell developmental lineage. Careful quantitation of these processes, which are stochastic, independent and strongly linked to the division history of the cell, has revealed that populations of B cells behave in a highly predictable manner. Considerable progress has also been made in the last few years in understanding the gene regulatory network that controls the B cell to plasma cell transition. The mutually exclusive transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors, those that maintain the B cell program, including Pax5, Bach2 and Bcl6, and those that promote and facilitate plasma cell differentiation, notably Irf4, Blimp1 and Xbp1. In this review, we discuss progress in the definition of both the transcriptional and cellular events occurring during late B cell differentiation, as integrating these two approaches is crucial to defining a regulatory network that faithfully reflects the stochastic features and complexity of the humoral immune response. 2011 Elsevier Ltd. All rights reserved.

Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer.

PubMed

Paul, Sourav; Lal, Girdhari

2016-09-01

γδ T cells are an important innate immune component of the tumor microenvironment and are known to affect the immune response in a wide variety of tumors. Unlike αβ T cells, γδ T cells are capable of spontaneous secretion of IL-17A and IFN-γ without undergoing clonal expansion. Although γδ T cells do not require self-MHC-restricted priming, they can distinguish "foreign" or transformed cells from healthy self-cells by using activating and inhibitory killer Ig-like receptors. γδ T cells were used in several clinical trials to treat cancer patient due to their MHC-unrestricted cytotoxicity, ability to distinguish transformed cells from normal cells, the capacity to secrete inflammatory cytokines and also their ability to enhance the generation of antigen-specific CD8(+) and CD4(+) T cell response. In this review, we discuss the effector and regulatory function of γδ T cells in the tumor microenvironment with special emphasis on the potential for their use in adoptive cellular immunotherapy. © 2016 UICC.

Biological and Pathological Implications of an Alternative ATP-Powered Proteasomal Assembly With Cdc48 and the 20S Peptidase.

PubMed

Esaki, Masatoshi; Johjima-Murata, Ai; Islam, Md Tanvir; Ogura, Teru

2018-01-01

The ATP-powered protein degradation machinery plays essential roles in maintaining protein homeostasis in all organisms. Robust proteolytic activities are typically sequestered within protein complexes to avoid the fatal removal of essential proteins. Because the openings of proteolytic chambers are narrow, substrate proteins must undergo unfolding. AAA superfamily proteins (ATPases associated with diverse cellular activities) are mostly located at these openings and regulate protein degradation appropriately. The 26S proteasome, comprising 20S peptidase and 19S regulatory particles, is the major ATP-powered protein degradation machinery in eukaryotes. The 19S particles are composed of six AAA proteins and 13 regulatory proteins, and bind to both ends of a barrel-shaped proteolytic chamber formed by the 20S peptidase. Several recent studies have reported that another AAA protein, Cdc48, can replace the 19S particles to form an alternative ATP-powered proteasomal complex, i.e., the Cdc48-20S proteasome. This review focuses on our current knowledge of this alternative proteasome and its possible linkage to amyotrophic lateral sclerosis.

Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies.

PubMed

Beck, Alain; Reichert, Janice M

2011-01-01

Therapeutic antibodies have captured substantial attention due to the relatively high rate at which these products reach marketing approval, and the subsequent commercial success they frequently achieve. In the 2000s, a total of 20 antibodies (18 full-length IgG and 2 Fab) were approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). In the 2010s to date, an additional 3 antibodies (denosumab, belimumab, ipilimumab) have been approved and one antibody-drug conjugate (brentuximab vedotin) is undergoing regulatory review and may be approved in the US by August 30, 2011. However, a less heralded group of antibody-based therapeutics comprising proteins or peptides fused with an Fc is following the success of classical antibodies.

Metrology Standards for Quantitative Imaging Biomarkers

PubMed Central

Obuchowski, Nancy A.; Kessler, Larry G.; Raunig, David L.; Gatsonis, Constantine; Huang, Erich P.; Kondratovich, Marina; McShane, Lisa M.; Reeves, Anthony P.; Barboriak, Daniel P.; Guimaraes, Alexander R.; Wahl, Richard L.

2015-01-01

Although investigators in the imaging community have been active in developing and evaluating quantitative imaging biomarkers (QIBs), the development and implementation of QIBs have been hampered by the inconsistent or incorrect use of terminology or methods for technical performance and statistical concepts. Technical performance is an assessment of how a test performs in reference objects or subjects under controlled conditions. In this article, some of the relevant statistical concepts are reviewed, methods that can be used for evaluating and comparing QIBs are described, and some of the technical performance issues related to imaging biomarkers are discussed. More consistent and correct use of terminology and study design principles will improve clinical research, advance regulatory science, and foster better care for patients who undergo imaging studies. © RSNA, 2015 PMID:26267831

Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study

PubMed Central

Zeitoun, Jean-David; Lefèvre, Jérémie H; Downing, Nicholas S; Bergeron, Henri; Ross, Joseph S

2015-01-01

Aims Regulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA). Methods We performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30 days before the EMA’s 210 day regulatory deadline. Results Among 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337 days (IQR 276–406) and was not associated with PMSEs (P = 0.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; P = 0.01). Finally, 26 medicines were approved near the 210 day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; P = 0.32). Conclusions Neither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines. PMID:25808713

Regulatory review time and post-market safety events for novel medicines approved by the EMA between 2001 and 2010: a cross-sectional study.

PubMed

Zeitoun, Jean-David; Lefèvre, Jérémie H; Downing, Nicholas S; Bergeron, Henri; Ross, Joseph S

2015-10-01

Regulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA). We performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30 days before the EMA's 210 day regulatory deadline. Among 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337 days (IQR 276-406) and was not associated with PMSEs (P = 0.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; P = 0.01). Finally, 26 medicines were approved near the 210 day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; P = 0.32). Neither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines. © 2015 The British Pharmacological Society.

Air pollution control residues from waste incineration: current UK situation and assessment of alternative technologies.

PubMed

Rani, D Amutha; Boccaccini, A R; Deegan, D; Cheeseman, C R

2008-11-01

Current disposal options for APC residues in the UK and alternative treatment technologies developed world-wide have been reviewed. APC residues are currently landfilled in the UK where they undergo in situ solidification, although the future acceptability of this option is uncertain because the EU waste acceptance criteria (WAC) introduce strict limits on leaching that are difficult to achieve. Other APC residue treatment processes have been developed which are reported to reduce leaching to below relevant regulatory limits. The Ferrox process, the VKI process, the WES-PHix process, stabilisation/solidification using cementitious binders and a range of thermal treatment processes are reviewed. Thermal treatment technologies convert APC residues combined with other wastes into inert glass or glass-ceramics that encapsulate heavy metals. The waste management industry will inevitably use the cheapest available option for treating APC residues and strict interpretation and enforcement of waste legislation is required if new, potentially more sustainable technologies are to become commercially viable.

CoMIC, the hidden dynamics of mitochondrial inner compartments

PubMed Central

Cho, Bongki; Sun, Woong

2017-01-01

Mitochondria have evolutionarily, functionally and structurally distinct outer- (OMM) and inner-membranes (IMM). Thus, mitochondrial morphology is controlled by independent but coordinated activity of fission and fusion of the OMM and IMM. Constriction and division of the OMM are mediated by endocytosis-like machineries, which include dynamin-related protein 1 with additional cytosolic vesicle scissoring machineries such as actin filament and Dynamin 2. However, structural alteration of the IMM during mitochondrial division has been poorly understood. Recently, we found that the IMM and the inner compartments undergo transient and reversible constriction prior to the OMM division, which we termed CoMIC, Constriction of Mitochondrial Inner Compartment. In this short review, we further discuss the evolutionary perspective and the regulatory mechanism of CoMIC during mitochondrial division. PMID:28803609

CoMIC, the hidden dynamics of mitochondrial inner compartments.

PubMed

Cho, Bongki; Sun, Woong

2017-12-01

Mitochondria have evolutionarily, functionally and structurally distinct outer- (OMM) and inner-membranes (IMM). Thus, mitochondrial morphology is controlled by independent but coordinated activity of fission and fusion of the OMM and IMM. Constriction and division of the OMM are mediated by endocytosis-like machineries, which include dynamin-related protein 1 with additional cytosolic vesicle scissoring machineries such as actin filament and Dynamin 2. However, structural alteration of the IMM during mitochondrial division has been poorly understood. Recently, we found that the IMM and the inner compartments undergo transient and reversible constriction prior to the OMM division, which we termed CoMIC, Constriction of Mitochondrial Inner Compartment. In this short review, we further discuss the evolutionary perspective and the regulatory mechanism of CoMIC during mitochondrial division. [BMB Reports 2017; 50(12): 597-598].

Model competencies in regulatory therapeutic product assessment: Health Canada's good review guiding principles as a reviewing community's code of intellectual conduct.

PubMed

Lim, Robyn R

2007-08-01

This article describes some work from the Therapeutic Products Directorate of Health Canada regarding Good Review Practices (GRP). Background information is provided on the Therapeutic Products Directorate (TPD) and its regulatory activities regarding drug and medical device assessment in both the pre- and post-market setting. The TPD Good Review Guiding Principles (GRGP) are described which include a Definition of a Good Therapeutic Product Regulatory Review, Ten Hallmarks of a Good Therapeutic Product Regulatory Review and Ten Precepts. Analysis of the guiding principles discusses possible linkages between the guiding principles and intellectual virtues. Through this analysis an hypothesis is developed that the guiding principles outline a code of intellectual conduct for Health Canada's reviewers of evidence for efficacy, safety, manufacturing quality and benefit-risk regarding therapeutic products. Opportunities to advance therapeutic product regulatory review as a scientific discipline in its own right and to acknowledge that these reviewers constitute a specific community of practice are discussed. Integration of intellectual and ethical approaches across therapeutic product review sectors is also suggested.

Threats to safety during sedation outside of the operating room and the death of Michael Jackson.

PubMed

Webster, Craig S; Mason, Keira P; Shafer, Steven L

2016-03-01

From an understanding of human psychology and the reliability of high-technology systems, this review considers critical threats to the safety of patients undergoing sedation outside of the operating room, and will stratify these threats along what we define as the 'Patient Risk Continuum'. We then consider interventions suitable for addressing identified risks. The technology, organization and delivery of healthcare continue to become more complex, highlighting the importance of maintaining the safety of patients. Sedation outside of the operating room is known to be associated with higher rates of adverse events. However, a number of recent safety initiatives have shown benefit in improving patient safety. The following threats to patients undergoing sedation, in increasing order of risk, are discussed: equipment and environmental factors, known patient risks, poor team performance, combinatorial problems and egregious violations. To address these threats, we discuss a number of approaches consistent with the systems approach to safety, namely: encouraging functions, forcing functions, cognitive safety nets, information sharing, recovery strategies and regulatory change. Demonstrating improvement with any safety initiative relies critically on quality data collected on the problem area in question.

17 CFR 201.421 - Commission consideration of determinations by self-regulatory organizations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... determinations by self-regulatory organizations. 201.421 Section 201.421 Commodity and Securities Exchanges... Commission Review § 201.421 Commission consideration of determinations by self-regulatory organizations. (a..., order review of any determination by a self-regulatory organization that could be subject to an...

17 CFR 201.421 - Commission consideration of determinations by self-regulatory organizations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... determinations by self-regulatory organizations. 201.421 Section 201.421 Commodity and Securities Exchanges... Commission Review § 201.421 Commission consideration of determinations by self-regulatory organizations. (a..., order review of any determination by a self-regulatory organization that could be subject to an...

17 CFR 201.421 - Commission consideration of determinations by self-regulatory organizations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... determinations by self-regulatory organizations. 201.421 Section 201.421 Commodity and Securities Exchanges... Commission Review § 201.421 Commission consideration of determinations by self-regulatory organizations. (a..., order review of any determination by a self-regulatory organization that could be subject to an...

17 CFR 201.420 - Appeal of determinations by self-regulatory organizations.

Code of Federal Regulations, 2014 CFR

2014-04-01

... self-regulatory organizations. 201.420 Section 201.420 Commodity and Securities Exchanges SECURITIES... Review § 201.420 Appeal of determinations by self-regulatory organizations. (a) Application for review... by a self-regulatory organization determination as to which a notice is required to be filed with the...

17 CFR 201.421 - Commission consideration of determinations by self-regulatory organizations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... determinations by self-regulatory organizations. 201.421 Section 201.421 Commodity and Securities Exchanges... Commission Review § 201.421 Commission consideration of determinations by self-regulatory organizations. (a..., order review of any determination by a self-regulatory organization that could be subject to an...

17 CFR 201.420 - Appeal of determinations by self-regulatory organizations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... self-regulatory organizations. 201.420 Section 201.420 Commodity and Securities Exchanges SECURITIES... Review § 201.420 Appeal of determinations by self-regulatory organizations. (a) Application for review... by a self-regulatory organization determination as to which a notice is required to be filed with the...

17 CFR 201.420 - Appeal of determinations by self-regulatory organizations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... self-regulatory organizations. 201.420 Section 201.420 Commodity and Securities Exchanges SECURITIES... Review § 201.420 Appeal of determinations by self-regulatory organizations. (a) Application for review... by a self-regulatory organization determination as to which a notice is required to be filed with the...

17 CFR 201.421 - Commission consideration of determinations by self-regulatory organizations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... determinations by self-regulatory organizations. 201.421 Section 201.421 Commodity and Securities Exchanges... Commission Review § 201.421 Commission consideration of determinations by self-regulatory organizations. (a..., order review of any determination by a self-regulatory organization that could be subject to an...

17 CFR 201.420 - Appeal of determinations by self-regulatory organizations.

Code of Federal Regulations, 2012 CFR

2012-04-01

... self-regulatory organizations. 201.420 Section 201.420 Commodity and Securities Exchanges SECURITIES... Review § 201.420 Appeal of determinations by self-regulatory organizations. (a) Application for review... by a self-regulatory organization determination as to which a notice is required to be filed with the...

17 CFR 201.420 - Appeal of determinations by self-regulatory organizations.

Code of Federal Regulations, 2013 CFR

2013-04-01

... self-regulatory organizations. 201.420 Section 201.420 Commodity and Securities Exchanges SECURITIES... Review § 201.420 Appeal of determinations by self-regulatory organizations. (a) Application for review... by a self-regulatory organization determination as to which a notice is required to be filed with the...

21 CFR 60.28 - Time frame for determining regulatory review periods.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Time frame for determining regulatory review periods. 60.28 Section 60.28 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PATENT TERM RESTORATION Regulatory Review Period Determinations § 60.28 Time frame for...

9 CFR 124.22 - Revision of regulatory review period determination.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Revision of regulatory review period determination. 124.22 Section 124.22 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS PATENT TERM RESTORATION Regulatory Review...

9 CFR 124.22 - Revision of regulatory review period determination.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Revision of regulatory review period determination. 124.22 Section 124.22 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS PATENT TERM RESTORATION Regulatory Review...

9 CFR 124.22 - Revision of regulatory review period determination.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Revision of regulatory review period determination. 124.22 Section 124.22 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS PATENT TERM RESTORATION Regulatory Review...

9 CFR 124.22 - Revision of regulatory review period determination.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Revision of regulatory review period determination. 124.22 Section 124.22 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS PATENT TERM RESTORATION Regulatory Review...

75 FR 32479 - Determination of Regulatory Review Period for Purposes of Patent Extension; ABLAVAR

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-08

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket Nos. FDA-2009-E-0165 and FDA-2009-E-0169] Determination of Regulatory Review Period for Purposes of Patent Extension... Administration (FDA) has determined the regulatory review period for ABLAVAR (previously the trade name of the...

RNA splicing during terminal erythropoiesis.

PubMed

Conboy, John G

2017-05-01

Erythroid progenitors must accurately and efficiently splice thousands of pre-mRNAs as the cells undergo extensive changes in gene expression and cellular remodeling during terminal erythropoiesis. Alternative splicing choices are governed by interactions between RNA binding proteins and cis-regulatory binding motifs in the RNA. This review will focus on recent studies that define the genome-wide scope of splicing in erythroblasts and discuss what is known about its regulation. RNA-seq analysis of highly purified erythroblast populations has revealed an extensive program of alternative splicing of both exons and introns. During normal erythropoiesis, stage-specific splicing transitions alter the structure and abundance of protein isoforms required for optimized red cell production. Mutation or deficiency of splicing regulators underlies hematopoietic disease in myelopdysplasia syndrome patients via disrupting the splicing program. Erythroid progenitors execute an elaborate alternative splicing program that modulates gene expression posttranscriptionally, ultimately regulating the structure and function of the proteome in a differentiation stage-specific manner during terminal erythropoiesis. This program helps drive differentiation and ensure synthesis of the proper protein isoforms required to produce mechanically stable red cells. Mutation or deficiency of key splicing regulatory proteins disrupts the splicing program to cause disease.

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).

Nuclear Forensics at Los Alamos National Laboratory

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

Kinman, William Scott; Steiner, Robert Ernest; Lamont, Stephen Philip

Nuclear forensics assists in responding to any event where nuclear material is found outside of regulatory control; a response plan is presented and a nuclear forensics program is undergoing further development so that smugglers are sufficiently deterred.

Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery.

PubMed

Agabiti-Rosei, Claudia; Trapletti, Valentina; Piantoni, Silvia; Airò, Paolo; Tincani, Angela; De Ciuceis, Carolina; Rossini, Claudia; Mittempergher, Francesco; Titi, Amin; Portolani, Nazario; Caletti, Stefano; Coschignano, Maria Antonietta; Porteri, Enzo; Tiberio, Guido A M; Pileri, Paola; Solaini, Leonardo; Kumar, Rajesh; Ministrini, Silvia; Agabiti Rosei, Enrico; Rizzoni, Damiano

2018-01-01

It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.

Selenium and its supplementation in cardiovascular disease--what do we know?

PubMed

Benstoem, Carina; Goetzenich, Andreas; Kraemer, Sandra; Borosch, Sebastian; Manzanares, William; Hardy, Gil; Stoppe, Christian

2015-04-27

The trace element selenium is of high importance for many of the body's regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery.

Selenium and Its Supplementation in Cardiovascular Disease—What do We Know?

PubMed Central

Benstoem, Carina; Goetzenich, Andreas; Kraemer, Sandra; Borosch, Sebastian; Manzanares, William; Hardy, Gil; Stoppe, Christian

2015-01-01

The trace element selenium is of high importance for many of the body’s regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery. PMID:25923656

Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome

PubMed Central

Dong, Xinran; Wang, Xiao; Zhang, Feng; Tian, Weidong

2016-01-01

Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes. PMID:27401230

Chemical signaling between plants and plant-pathogenic bacteria.

PubMed

Venturi, Vittorio; Fuqua, Clay

2013-01-01

Studies of chemical signaling between plants and bacteria in the past have been largely confined to two models: the rhizobial-legume symbiotic association and pathogenesis between agrobacteria and their host plants. Recent studies are beginning to provide evidence that many plant-associated bacteria undergo chemical signaling with the plant host via low-molecular-weight compounds. Plant-produced compounds interact with bacterial regulatory proteins that then affect gene expression. Similarly, bacterial quorum-sensing signals result in a range of functional responses in plants. This review attempts to highlight current knowledge in chemical signaling that takes place between pathogenic bacteria and plants. This chemical communication between plant and bacteria, also referred to as interkingdom signaling, will likely become a major research field in the future, as it allows the design of specific strategies to create plants that are resistant to plant pathogens.

78 FR 59982 - Revisions to Radiation Protection

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2013-09-30

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0268] Revisions to Radiation Protection AGENCY: Nuclear Regulatory Commission. ACTION: Standard review plan section; issuance. SUMMARY: The U.S. Nuclear Regulatory... for the Review of Safety Analysis Reports for Nuclear Power Plants: LWR Edition'': Section 12.1...

The Regulatory Review Process in South Africa: Challenges and Opportunities for a New Improved System.

PubMed

Keyter, Andrea; Gouws, Joey; Salek, Sam; Walker, Stuart

2018-01-01

The aims of this study were to assess the regulatory review process in South Africa from 2015 to 2017, identify the key milestones and timelines; evaluate the effectiveness of measures to ensure consistency, transparency, timeliness, and predictability in the review process; and to provide recommendations for enhanced regulatory practices. A questionnaire was completed by the Medicines Control Council (MCC) to describe the organization of the authority, record key milestones and timelines in the review process and to identify good review practices (GRevPs). Currently, the MCC conducts a full assessment of quality, efficacy, and safety data in the review of all applications. The overall regulatory median approval time decreased by 14% in 2017 (1411 calendar days) compared with that of 2016, despite the 27% increase in the number of applications. However, the MCC has no target for overall approval time of new active substance applications and no targets for key review milestones. Guidelines, standard operating procedures, and review templates are in place, while the formal implementation of GRevPs and the application of an electronic document management system are planned for the near future. As the MCC transitions to the newly established South Africa Health Products Regulatory Authority, it would be crucial for the authority to recognize the opportunities for an enhanced regulatory review and should consider models such as abridged assessment, which encompass elements of risk stratification and reliance. It is hoped that resource constraints may then be alleviated and capacity developed to meet target timelines.

76 FR 66332 - Appointments to Performance Review Boards for Senior Executive Service

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2011-10-26

... NUCLEAR REGULATORY COMMISSION [NRC-2011-0249] Appointments to Performance Review Boards for Senior Executive Service AGENCY: U.S. Nuclear Regulatory Commission. ACTION: Appointment to Performance Review... the following appointments to the NRC Performance Review Boards. The following individuals are...

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization

PubMed Central

Ahonkhai, Vincent; Portet, Alexandre; Hartman, Dan

2016-01-01

Background The United Nations Millennium Development Goals galvanized global efforts to alleviate suffering of the world’s poorest people through unprecedented public-private partnerships. Donor aid agencies have demonstrably saved millions of lives that might otherwise have been lost to disease through increased access to quality-assured vaccines and medicines. Yet, the introduction of these health interventions in low- and middle-income countries (LMICs) continues to face a time lag due to factors which remain poorly understood. Methods and Findings A recurring theme from our partnership engagements was that an optimized regulatory process would contribute to improved access to quality health products. Therefore, we investigated the current system for medicine and vaccine registration in LMICs as part of our comprehensive regulatory strategy. Here, we report a fact base of the registration timelines for vaccines and drugs used to treat certain communicable diseases in LMICs. We worked with a broad set of stakeholders, including the World Health Organization’s prequalification team, national regulatory authorities, manufacturers, procurers, and other experts, and collected data on the timelines between first submission and last approval of applications for product registration sub-Saharan Africa. We focused on countries with the highest burden of communicable disease and the greatest need for the products studied. The data showed a typical lag of 4 to 7 years between the first regulatory submission which was usually to a regulatory agency in a high-income country, and the final approval in Sub-Saharan Africa. Two of the three typical registration steps which products undergo before delivery in the countries involve lengthy timelines. Failure to leverage or rely on the findings from reviews already performed by competent regulatory authorities, disparate requirements for product approval by the countries, and lengthy timelines by manufacturers to respond to regulatory queries were key underlying factors for the delays. Conclusions We propose a series of measures which we developed in close collaboration with key stakeholders that could be taken to reduce registration time and to make safe, effective medicines more quickly available in countries where they are most needed. Many of these recommendations are being implemented by the responsible stakeholders, including the WHO prequalification team and the national regulatory authorities in Sub-Saharan Africa. Those efforts will be the focus of subsequent publications by the pertinent groups. PMID:27851831

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization.

PubMed

Ahonkhai, Vincent; Martins, Samuel F; Portet, Alexandre; Lumpkin, Murray; Hartman, Dan

2016-01-01

The United Nations Millennium Development Goals galvanized global efforts to alleviate suffering of the world's poorest people through unprecedented public-private partnerships. Donor aid agencies have demonstrably saved millions of lives that might otherwise have been lost to disease through increased access to quality-assured vaccines and medicines. Yet, the introduction of these health interventions in low- and middle-income countries (LMICs) continues to face a time lag due to factors which remain poorly understood. A recurring theme from our partnership engagements was that an optimized regulatory process would contribute to improved access to quality health products. Therefore, we investigated the current system for medicine and vaccine registration in LMICs as part of our comprehensive regulatory strategy. Here, we report a fact base of the registration timelines for vaccines and drugs used to treat certain communicable diseases in LMICs. We worked with a broad set of stakeholders, including the World Health Organization's prequalification team, national regulatory authorities, manufacturers, procurers, and other experts, and collected data on the timelines between first submission and last approval of applications for product registration sub-Saharan Africa. We focused on countries with the highest burden of communicable disease and the greatest need for the products studied. The data showed a typical lag of 4 to 7 years between the first regulatory submission which was usually to a regulatory agency in a high-income country, and the final approval in Sub-Saharan Africa. Two of the three typical registration steps which products undergo before delivery in the countries involve lengthy timelines. Failure to leverage or rely on the findings from reviews already performed by competent regulatory authorities, disparate requirements for product approval by the countries, and lengthy timelines by manufacturers to respond to regulatory queries were key underlying factors for the delays. We propose a series of measures which we developed in close collaboration with key stakeholders that could be taken to reduce registration time and to make safe, effective medicines more quickly available in countries where they are most needed. Many of these recommendations are being implemented by the responsible stakeholders, including the WHO prequalification team and the national regulatory authorities in Sub-Saharan Africa. Those efforts will be the focus of subsequent publications by the pertinent groups.

78 FR 58575 - Review of Experiments for Research Reactors

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2013-09-24

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76 FR 54408 - Regulatory Review Schedule

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2010-01-01

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78 FR 11686 - Agency Information Collection Activities: Submission for the Office of Management and Budget (OMB...

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17 CFR 201.900 - Informal Procedures and Supplementary Information Concerning Adjudicatory Proceedings.

Code of Federal Regulations, 2010 CFR

2010-04-01

... from the initial decision of a hearing officer, a review of a determination by a self-regulatory... review of a determination by a self-regulatory organization, or a remand of a prior Commission decision..., securities industry participants, self-regulatory organizations and other members of the public. The...

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2012-11-20

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

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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...

The test chemical selection procedure of the European Centre for the Validation of Alternative Methods for the EU Project ReProTect.

PubMed

Pazos, Patricia; Pellizzer, Cristian; Stummann, Tina C; Hareng, Lars; Bremer, Susanne

2010-08-01

The selection of reference compounds is crucial for a successful in vitro test development in order to proof the relevance of the test system. This publication describes the criteria and the selection strategy leading to a list of more than 130 chemicals suitable for test development within the ReProTect project. The presented chemical inventory aimed to support the development and optimization of in vitro tests that seek to fulfill ECVAM's criteria for entering into the prevalidation. In order to select appropriate substances, a primary database was established compiling information from existing databases. In a second step, predefined selection criteria have been applied to obtain a comprehensive list ready to undergo a peer review process from independent experts with industrial, academic and regulatory background. Finally, a peer reviewed chemical list containing 13 substances challenging endocrine disrupter tests, additional 50 substances serving as reference chemicals for various tests evaluating effects on male and female fertility, and finally 61 substances were identified as known to provoke effects on the early development of mammalian offspring. The final list aims to cover relevant and specific mode/site of actions as they are known to be relevant for various substance classes. However, the recommended list should not be interpreted as a list of reproductive toxicants, because such a description requires proven associations with adverse effects of mammalian reproduction, which are subject of regulatory decisions done by involved competent authorities. Copyright 2010 Elsevier Inc. All rights reserved.

Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3).

PubMed

Syed, Aleena; Garcia, Marco A; Lyu, Shu-Chen; Bucayu, Robert; Kohli, Arunima; Ishida, Satoru; Berglund, Jelena P; Tsai, Mindy; Maecker, Holden; O'Riordan, Gerri; Galli, Stephen J; Nadeau, Kari C

2014-02-01

The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance. Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy. In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13). Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells. In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Obesity paradox in patients undergoing coronary intervention: A review

PubMed Central

Patel, Nirav; Elsaid, Ossama; Shenoy, Abhishek; Sharma, Abhishek; McFarlane, Samy I

2017-01-01

There is strong relationship exist between obesity and cardiovascular disease including coronary artery disease (CAD). However, better outcomes noted in obese patients undergoing percutaneous cardiovascular interventions for CAD, a phenomenon known as the obesity paradox. In this review, we performed extensive search for obesity paradox in obese patients undergoing percutaneous coronary intervention and discussed possible mechanism and disparities in different race and sex. PMID:29081905

78 FR 60283 - Agency Forms Undergoing Paperwork Reduction Act Review

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2013-10-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-13-0870] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention (CDC) publishes a list of information collection requests under review by the Office of Management and Budget (OMB) in compliance with the...

75 FR 20601 - Agency Forms Undergoing Paperwork Reduction Act Review

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2010-04-20

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75 FR 18846 - Agency Forms Undergoing Paperwork Reduction Act Review

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2010-04-13

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78 FR 5456 - Agency Forms Undergoing Paperwork Reduction Act Review

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2013-01-25

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75 FR 8723 - Agency Forms Undergoing Paperwork Reduction Act Review

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Scoping review of the literature on shoulder impairments and disability after neck dissection.

PubMed

Goldstein, David P; Ringash, Jolie; Bissada, Eric; Jaquet, Yves; Irish, Jonathan; Chepeha, Douglas; Davis, Aileen M

2014-02-01

The purpose of this article was to provide a review of the literature on shoulder disability after neck dissection. A literature review was performed using Ovid Medline and Embase databases. A total of 306 abstracts and 78 full-text articles were reviewed. Forty-two articles were eligible for inclusion. Patients undergoing nerve-sacrifice neck dissections have greater disability and lower quality of life scores than those undergoing neck dissections with the least manipulation (ie, selective neck dissections). Shoulder impairments can still occur in patients undergoing selective neck dissections. Disability typically improves over time in patients undergoing nerve-sparing neck dissections. There was significant variability in the literature in terms of the prevalence and recovery of shoulder morbidity after neck dissection. This variability may not just be related to surgical technique or rehabilitation, but also to study design, definitions, and the variability in disability questionnaires used. Copyright © 2013 Wiley Periodicals, Inc.

CaMKII in the Cardiovascular System: Sensing Redox States

PubMed Central

Erickson, Jeffrey R.; He, B. Julie; Grumbach, Isabella M.; Anderson, Mark E

2013-01-01

The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca2+/CaM). Under conditions of sustained exposure to elevated Ca2+/CaM CaMKII transitions into a Ca2+/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine 287 in the CaMKII regulatory domain ‘traps’ CaMKII into an open configuration even after Ca2+/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca2+/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease. PMID:21742790

Whether to target single or multiple CDKs for therapy? That is the question.

PubMed

Węsierska-Gądek, Józefa; Maurer, Margarita; Zulehner, Nora; Komina, Oxana

2011-02-01

Complexes consisting of cyclin-dependent kinases (CDKs) and their regulatory subunits (the cyclins) control the progression of normal mammalian cells through the cell cycle. However, during malignant transformation this regulatory apparatus malfunctions, allowing cells to undergo unchecked proliferation. In many cases, the high mitotic potential of malignant cells is due to the constitutive activation of CDK-cyclin complexes, facilitated by the inactivation of cellular CDK inhibitors, such as p16(INK4A) or p27(Kip1), and the loss of functional tumor suppressors, such as the p53 and pRb proteins. It has recently been suggested that pharmacological intervention based on remedying the deficiency or loss of activity of these negative regulators of the cell cycle could be a very effective therapeutic option in the treatment of cancer. Multiple CDK inhibitors have been synthesized over the last two decades, spanning at least five classes of compounds. While these inhibitors can be classified on the basis of their chemical structure, it may be more interesting to categorize them according to their pharmacological nature, as broad-spectrum unspecific, pan-specific, or very selective antagonists. This review offers a critical assessment of the advantages and disadvantages of both pan-specific and highly selective CDK inhibitors in therapy. © 2010 Wiley-Liss, Inc.

Niche markets and evidence assessment in transition: a critical review of proposed drug reforms.

PubMed

Gibson, Shannon G; Lemmens, Trudo

2014-01-01

In response to rising demands and treatment costs, and the need to achieve better value for money in the face of tight fiscal constraints, both the National Health Service and the public drug reimbursement system are undergoing important reforms. Concurrently, the pharmaceutical sector itself is also alleged to be experiencing significant changes, perhaps most notably, a decline of the blockbuster model of drug development and a growing focus on niche market products. As pharmaceutical development strategies evolve and the resulting drug products become more complex, regulatory and policy responses must be able to evolve along with them. We explore how in numerous jurisdictions, including the UK, proposals for 'adaptive licensing' on the regulatory side and 'performance-based risk sharing agreements' on the funding side are shifting the focus of drug regulation and reimbursement towards more incremental access to new therapies and more post-market evidence generation. However, serious questions remain about how such reforms can be successfully implemented and whether they can balance demands for earlier access to promising new therapies with the need for robust evidence on safety, efficacy, and cost-effectiveness. © The Author 2014. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.

Redox regulation of the Calvin–Benson cycle: something old, something new

PubMed Central

Michelet, Laure; Zaffagnini, Mirko; Morisse, Samuel; Sparla, Francesca; Pérez-Pérez, María Esther; Francia, Francesco; Danon, Antoine; Marchand, Christophe H.; Fermani, Simona; Trost, Paolo; Lemaire, Stéphane D.

2013-01-01

Reversible redox post-translational modifications such as oxido-reduction of disulfide bonds, S-nitrosylation, and S-glutathionylation, play a prominent role in the regulation of cell metabolism and signaling in all organisms. These modifications are mainly controlled by members of the thioredoxin and glutaredoxin families. Early studies in photosynthetic organisms have identified the Calvin–Benson cycle, the photosynthetic pathway responsible for carbon assimilation, as a redox regulated process. Indeed, 4 out of 11 enzymes of the cycle were shown to have a low activity in the dark and to be activated in the light through thioredoxin-dependent reduction of regulatory disulfide bonds. The underlying molecular mechanisms were extensively studied at the biochemical and structural level. Unexpectedly, recent biochemical and proteomic studies have suggested that all enzymes of the cycle and several associated regulatory proteins may undergo redox regulation through multiple redox post-translational modifications including glutathionylation and nitrosylation. The aim of this review is to detail the well-established mechanisms of redox regulation of Calvin–Benson cycle enzymes as well as the most recent reports indicating that this pathway is tightly controlled by multiple interconnected redox post-translational modifications. This redox control is likely allowing fine tuning of the Calvin–Benson cycle required for adaptation to varying environmental conditions, especially during responses to biotic and abiotic stresses. PMID:24324475

Protein prenylation: a new mode of host-pathogen interaction.

PubMed

Amaya, Moushimi; Baranova, Ancha; van Hoek, Monique L

2011-12-09

Post translational modifications are required for proteins to be fully functional. The three step process, prenylation, leads to farnesylation or geranylgeranylation, which increase the hydrophobicity of the prenylated protein for efficient anchoring into plasma membranes and/or organellar membranes. Prenylated proteins function in a number of signaling and regulatory pathways that are responsible for basic cell operations. Well characterized prenylated proteins include Ras, Rac and Rho. Recently, pathogenic prokaryotic proteins, such as SifA and AnkB, have been shown to be prenylated by eukaryotic host cell machinery, but their functions remain elusive. The identification of other bacterial proteins undergoing this type of host-directed post-translational modification shows promise in elucidating host-pathogen interactions to develop new therapeutics. This review incorporates new advances in the study of protein prenylation into a broader aspect of biology with a focus on host-pathogen interaction. Copyright © 2011 Elsevier Inc. All rights reserved.

Metabolic pathways for lipid synthesis under nitrogen stress in Chlamydomonas and Nannochloropsis.

PubMed

Banerjee, Avik; Maiti, Subodh K; Guria, Chandan; Banerjee, Chiranjib

2017-01-01

Microalgae are currently being considered as a clean, sustainable and renewable energy source. Enzymes that catalyse the metabolic pathways for biofuel production are specific and require strict regulation and co-ordination. Thorough knowledge of these key enzymes along with their regulatory molecules is essential to enable rational metabolic engineering, to drive the metabolic flux towards the desired metabolites of importance. This paper reviews two key enzymes that play their role in production of bio-oil: DGAT (acyl-CoA:diacylglycerol acyltransferase) and PDAT (phospholipid:diacylglycerol acyltransferase). It also deals with the transcription factors that control the enzymes while cell undergoes a metabolic shift under stress. The paper also discusses the association of other enzymes and pathways that provide substrates and precursors for oil accumulation. Finally a futuristic solution has been proposed about a synthetic algal cell platform that would be committed towards biofuel synthesis.

Acetylation of pregnane X receptor protein determines selective function independent of ligand activation

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

Biswas, Arunima; Pasquel, Danielle; Tyagi, Rakesh Kumar

2011-03-18

Research highlights: {yields} Pregnane X receptor (PXR), a major regulatory protein, is modified by acetylation. {yields} PXR undergoes dynamic deacetylation upon ligand-mediated activation. {yields} SIRT1 partially mediates PXR deacetylation. {yields} PXR deacetylation per se induces lipogenesis mimicking ligand-mediated activation. -- Abstract: Pregnane X receptor (PXR), like other members of its class of nuclear receptors, undergoes post-translational modification [PTM] (e.g., phosphorylation). However, it is unknown if acetylation (a major and common form of protein PTM) is observed on PXR and, if it is, whether it is of functional consequence. PXR has recently emerged as an important regulatory protein with multiple ligand-dependentmore » functions. In the present work we show that PXR is indeed acetylated in vivo. SIRT1 (Sirtuin 1), a NAD-dependent class III histone deacetylase and a member of the sirtuin family of proteins, partially mediates deacetylation of PXR. Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation.« less

Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome.

PubMed

Dong, Xinran; Wang, Xiao; Zhang, Feng; Tian, Weidong

2016-10-01

Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

75 FR 1830 - Final Regulatory Guide: Issuance, Availability

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-13

... review of applications for permits and licenses. RG 5.71, ``Cyber Security Programs for Nuclear... NUCLEAR REGULATORY COMMISSION [NRC-2010-0009] Final Regulatory Guide: Issuance, Availability AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide...

Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations.

PubMed

Rosemann, Achim; Bortz, Gabriela; Vasen, Federico; Sleeboom-Faulkner, Margaret

2016-10-01

In this article, we explore regulatory developments in stem cell medicine in seven jurisdictions: Japan, China, India, Argentina, Brazil, the USA and the EU. We will show that the research methods, ethical standards and approval procedures for the market use of clinical stem cell interventions are undergoing an important process of global diversification. We will discuss the implications of this process for international harmonization and the conduct of multicountry clinical research collaborations. It will become clear that the increasing heterogeneity of research standards and regulations in the stem cell field presents a significant challenge to international clinical trial partnerships, especially with countries that diverge from the regulatory models that have been developed in the USA and the EU.

The economic impact of assisted reproductive technology: a review of selected developed countries.

PubMed

Chambers, Georgina M; Sullivan, Elizabeth A; Ishihara, Osamu; Chapman, Michael G; Adamson, G David

2009-06-01

To compare regulatory and economic aspects of assisted reproductive technologies (ART) in developed countries. Comparative policy and economic analysis. Couples undergoing ART treatment in the United States, Canada, United Kingdom, Scandinavia, Japan, and Australia. Description of regulatory and financing arrangements, cycle costs, cost-effectiveness ratios, total expenditure, utilization, and price elasticity. Regulation and financing of ART share few general characteristics in developed countries. The cost of treatment reflects the costliness of the underlying healthcare system rather than the regulatory or funding environment. The cost (in 2006 United States dollars) of a standard IVF cycle ranged from $12,513 in the United States to $3,956 in Japan. The cost per live birth was highest in the United States and United Kingdom ($41,132 and $40,364, respectively) and lowest in Scandinavia and Japan ($24,485 and $24,329, respectively). The cost of an IVF cycle after government subsidization ranged from 50% of annual disposable income in the United States to 6% in Australia. The cost of ART treatment did not exceed 0.25% of total healthcare expenditure in any country. Australia and Scandinavia were the only country/region to reach levels of utilization approximating demand, with North America meeting only 24% of estimated demand. Demand displayed variable price elasticity. Assisted reproductive technology is expensive from a patient perspective but not from a societal perspective. Only countries with funding arrangements that minimize out-of-pocket expenses met expected demand. Funding mechanisms should maximize efficiency and equity of access while minimizing the potential harm from multiple births.

76 FR 11395 - Reducing Regulatory Burden; Retrospective Review Under E.O. 13563

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-02

... identify specific current regulations that may be outdated, ineffective, or excessively burdensome. The purpose of this regulatory review is to make the Department's regulations more effective and less... review existing significant regulations to determine if they are outmoded, ineffective, insufficient or...

76 FR 18134 - Reducing Regulatory Burden; Review Under E.O. 13563

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-01

... PENSION BENEFIT GUARANTY CORPORATION 29 CFR Chapter XL Reducing Regulatory Burden; Review Under E.O. 13563 AGENCY: Pension Benefit Guaranty Corporation. ACTION: Request for comments. SUMMARY: The Pension Benefit Guaranty Corporation (PBGC) is reviewing its regulations in response to the President's...

75 FR 57460 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-21

... Information Management Services, Office of Management invites comments on the submission for OMB review as... Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and..., Regulatory Information Management Services, Office of Management. Federal Student Aid Type of Review: New...

Mesenchymal Stem Cells Increase T-Regulatory Cells and Improve Healing Following Trauma and Hemorrhagic Shock (MSCs Increase Tregs and Improve Healing After T/HS)

PubMed Central

Gore, Amy V.; Bible, Letitia E.; Song, Kimberly; Livingston, David H.; Mohr, Alicia M.; Sifri, Ziad C.

2015-01-01

Background Rodent lungs undergo full histologic recovery within one week following unilateral lung contusion (LC). However, when LC is followed by hemorrhagic shock (HS), healing is impaired. We hypothesize that the intravenous administration of mesenchymal stem cells (MSC) to animals undergoing combined LC followed by HS (LCHS) will improve wound healing. Methods Male Sprague-Dawley rats (n=5-6/group) were subjected to LCHS with or without the injection of a single iv dose of 5 × 106 MSCs following return of shed blood after HS. Rats were sacrificed seven days following injury. Flow cytometry was used to determine the T regulatory (Treg) cell population in peripheral blood (PB). Lung histology was graded using a well-established lung injury score (LIS). Components of the LIS include average inflammatory cells/high power field (hpf) over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity with total scores ranging from 0-11. Data analyzed by ANOVA followed by Tukey's multiple comparison test, expressed as mean ± SD. p<0.05 considered significant. Results Seven days following isolated LC animals demonstrate lung healing with a LIS unchanged from naive. The addition of HS results in a persistently elevated LIS score, whereas addition of MSC to LCHS decreased the LIS score back to naïve levels. The change in LIS was driven by a significant decrease in edema scores. In rats undergoing LC alone, 10.5 ± 3.3% of CD4+ cells were Tregs. The addition of HS caused no significant change in Treg population (9.3±0.7%), whereas LCHS+MSC significantly increased the population to 18.2±6.8% in PB (p<0.05 vs LCHS). Conclusion Impaired wound healing following trauma and hemorrhagic shock is improved by a single dose of MSCs given immediately after injury. This enhanced healing is associated with an increase in the T regulatory cell population and a significant decrease in lung edema score as compared to animals undergoing LCHS. Further study into the role of Tregs in MSC-mediated wound healing is warranted. PMID:26091313

76 FR 10527 - Regulatory Flexibility Act: Section 610 Review of National Organic Program Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-25

...: This document announces the Agricultural Marketing Service's (AMS) plans to review the National Organic... DEPARTMENT OF AGRICULTURE Agricultural Marketing Service 7 CFR Part 205 [Document Number AMS-NOP-11-0005; NOP-11-01] Regulatory Flexibility Act: Section 610 Review of National Organic Program...

30 CFR 773.11 - Review of compliance history.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Review of compliance history. 773.11 Section... REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.11 Review of compliance history. (a... histories of compliance with the Act or the applicable State regulatory program, and any other applicable...

30 CFR 773.11 - Review of compliance history.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Review of compliance history. 773.11 Section... REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.11 Review of compliance history. (a... histories of compliance with the Act or the applicable State regulatory program, and any other applicable...

30 CFR 773.11 - Review of compliance history.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Review of compliance history. 773.11 Section... REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.11 Review of compliance history. (a... histories of compliance with the Act or the applicable State regulatory program, and any other applicable...

30 CFR 773.11 - Review of compliance history.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Review of compliance history. 773.11 Section... REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.11 Review of compliance history. (a... histories of compliance with the Act or the applicable State regulatory program, and any other applicable...

30 CFR 773.11 - Review of compliance history.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Review of compliance history. 773.11 Section... REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.11 Review of compliance history. (a... histories of compliance with the Act or the applicable State regulatory program, and any other applicable...

76 FR 32133 - FAR Council's Plan for Retrospective Review Under Executive Order 13563-Preliminary Plan

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-03

... (E.O.) 13563, ``Improving Regulation and Regulatory Review.'' The E.O. sets forth principles and... resources and regulatory priorities, under which the agency will periodically review its existing... retrospective analysis. The Council's plan has tentatively identified eight priority initiatives for new or...

76 FR 16700 - Reducing Regulatory Burden; Retrospective Review Under E.O. 13563

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-25

... Regulation and Regulatory Review,'' the Department of Defense invites public comments on how it can change... to determine how its regulations can increase efficiency, transparency, and provide accountability...

9 CFR 124.23 - Final action on regulatory review period determination.

Code of Federal Regulations, 2011 CFR

2011-01-01

... INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND... request under § 124.22 for revision of the regulatory review period determination; (c) A due diligence...

17 CFR 240.19d-3 - Applications for review of final disciplinary sanctions, denials of membership, participation or...

Code of Federal Regulations, 2012 CFR

2012-04-01

... limitations of access to services imposed by self-regulatory organizations. 240.19d-3 Section 240.19d-3... services imposed by self-regulatory organizations. Applications to the Commission for review of any final... prohibition or limitation with respect to access to services offered by a self-regulatory organization or a...

17 CFR 240.19d-3 - Applications for review of final disciplinary sanctions, denials of membership, participation or...

Code of Federal Regulations, 2010 CFR

2010-04-01

... limitations of access to services imposed by self-regulatory organizations. 240.19d-3 Section 240.19d-3... services imposed by self-regulatory organizations. Applications to the Commission for review of any final... prohibition or limitation with respect to access to services offered by a self-regulatory organization or a...

17 CFR 240.19d-3 - Applications for review of final disciplinary sanctions, denials of membership, participation or...

Code of Federal Regulations, 2011 CFR

2011-04-01

... limitations of access to services imposed by self-regulatory organizations. 240.19d-3 Section 240.19d-3... services imposed by self-regulatory organizations. Applications to the Commission for review of any final... prohibition or limitation with respect to access to services offered by a self-regulatory organization or a...

17 CFR 240.19d-3 - Applications for review of final disciplinary sanctions, denials of membership, participation or...

Code of Federal Regulations, 2013 CFR

2013-04-01

... limitations of access to services imposed by self-regulatory organizations. 240.19d-3 Section 240.19d-3... services imposed by self-regulatory organizations. Applications to the Commission for review of any final... prohibition or limitation with respect to access to services offered by a self-regulatory organization or a...

17 CFR 240.19d-3 - Applications for review of final disciplinary sanctions, denials of membership, participation or...

Code of Federal Regulations, 2014 CFR

2014-04-01

... limitations of access to services imposed by self-regulatory organizations. 240.19d-3 Section 240.19d-3... services imposed by self-regulatory organizations. Applications to the Commission for review of any final... prohibition or limitation with respect to access to services offered by a self-regulatory organization or a...

Perspectives on Validation of High-Throughput Assays Supporting 21st Century Toxicity Testing

EPA Science Inventory

In vitro high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. ...

77 FR 4044 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-26

...; cardiovascular disease; diabetes mellitus; adult/older adult immunization, hepatitis B, and/or tuberculosis... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-12-0805] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

75 FR 3737 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-22

... Description Cardiovascular disease (CVD), which includes heart disease, myocardial infarction, and stroke, is... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-10-0612] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

76 FR 40915 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-12

.../2011--Revision--National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Centers for... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-11-0006] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

Information Quality in Regulatory Decision Making: Peer Review versus Good Laboratory Practice.

PubMed

McCarty, Lynn S; Borgert, Christopher J; Mihaich, Ellen M

2012-07-01

There is an ongoing discussion on the provenance of toxicity testing data regarding how best to ensure its validity and credibility. A central argument is whether journal peer-review procedures are superior to Good Laboratory Practice (GLP) standards employed for compliance with regulatory mandates. We sought to evaluate the rationale for regulatory decision making based on peer-review procedures versus GLP standards. We examined pertinent published literature regarding how scientific data quality and validity are evaluated for peer review, GLP compliance, and development of regulations. Some contend that peer review is a coherent, consistent evaluative procedure providing quality control for experimental data generation, analysis, and reporting sufficient to reliably establish relative merit, whereas GLP is seen as merely a tracking process designed to thwart investigator corruption. This view is not supported by published analyses pointing to subjectivity and variability in peer-review processes. Although GLP is not designed to establish relative merit, it is an internationally accepted quality assurance, quality control method for documenting experimental conduct and data. Neither process is completely sufficient for establishing relative scientific soundness. However, changes occurring both in peer-review processes and in regulatory guidance resulting in clearer, more transparent communication of scientific information point to an emerging convergence in ensuring information quality. The solution to determining relative merit lies in developing a well-documented, generally accepted weight-of-evidence scheme to evaluate both peer-reviewed and GLP information used in regulatory decision making where both merit and specific relevance inform the process.

76 FR 32331 - Preliminary Plan for Retrospective Review of Existing Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-06

... review. In addition, DHS launched an IdeaScale Web page; this social media tool provided an additional... agency's regulatory program more effective or less burdensome in achieving its regulatory objectives. DHS...

US regulatory system for genetically modified [genetically modified organism (GMO), rDNA or transgenic] crop cultivars.

PubMed

McHughen, Alan; Smyth, Stuart

2008-01-01

This paper reviews the history of the federal regulatory oversight of plant agricultural biotechnology in the USA, focusing on the scientific and political forces moulding the continually evolving regulatory structure in place today. Unlike most other jurisdictions, the USA decided to adapt pre-existing legislation to encompass products of biotechnology. In so doing, it established an overarching committee (Office of Science and Technology Policy) to study and distribute various regulatory responsibilities amongst relevant agencies: the Food and Drug Administration, Environmental Protection Agency and US Department of Agriculture. This paper reviews the history and procedures of each agency in the execution of its regulatory duties and investigates the advantages and disadvantages of the US regulatory strategy.

[Governance of innovative cardiovascular devices: when evidence is not enough].

PubMed

Addis, Antonio; Davoli, Marina

2016-01-01

Aortic stenosis is the most common valve disease and transcatheter aortic valve implantation (TAVI) is considered as an alternative to surgical valve replacement or to medical treatment in inoperable or high-risk patients. Although physicians have learned how to care for critically ill old patients and enable many to survive, major surgical procedures, operating on patients at very high risk, are often not suitable. Studies showed that selected cohorts of patients undergoing TAVI might have better outcomes in terms of survival and quality of life. However, mortality and safety data associated with the less invasive intervention do not always justify such new technologies for all patients with severe aortic stenosis, taking into account also the high cost associated. A systematic review of the available scientific literature has been performed. In this context, a DECIDE framework has been used providing a systematic and transparent approach for going from evidence to healthcare decisions. Before suggesting final recommendations, historical data of interventions done at regional level and regulatory decisions adopted in other countries following health technology assessment analysis, have been analyzed. All final recommendations based on this document have been discussed and reviewed with a working group done by the health operators directly involved in this technology within the regional health service context. Recommendations for the identification of patients suitable for TAVI are given together with a list of characteristics that should be required to all centers eligible for the performance of TAVI and with a procedure able to allow better quality assurance and prospective monitoring process of all new cases enrolled for such intervention. Impact of these recommendations will be measured using a regional registry collecting data on new patients undergoing TAVI.

Effectiveness of ketamine as an adjuvant to opioid-based therapy in decreasing pain associated with opioid tolerance in adults undergoing orthopedic surgery: a systematic review protocol.

PubMed

Bennett, Marsha; Bonanno, Laura; Kuhn, William

2016-10-01

The objective of this systematic review is to examine the best available evidence on the clinical effectiveness of ketamine as an adjuvant to opioid-based therapy versus opioid-based therapy alone in decreasing perioperative pain associated with opioid tolerance in adult patients, aged 18-70 years, undergoing orthopedic surgical procedures.The following question guides the systematic review: does the administration of ketamine as an adjuvant to opioid-based therapy, compared to opioid-based therapy alone, improve perioperative pain relief in opioid-tolerant adult patients undergoing orthopedic surgical procedures?

77 FR 13155 - Agency Information Collection Activities: Submission for the Office of Management and Budget (OMB...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-05

...: Submission for the Office of Management and Budget (OMB) Review; Comment Request AGENCY: Nuclear Regulatory Commission. ACTION: Notice of the OMB review of information collection and solicitation of public comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) has recently submitted to OMB for review the...

78 FR 70353 - Agency Information Collection Activities: Submission for the Office of Management and Budget (OMB...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-25

...: Submission for the Office of Management and Budget (OMB) Review; Comment Request AGENCY: Nuclear Regulatory Commission. ACTION: Notice of the OMB review of information collection and solicitation of public comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) has recently submitted to OMB for review the...

75 FR 41206 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-15

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-10-0555] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention..., Centers for Disease Control and Prevention (CDC). Background and Brief Description The Office of State...

78 FR 15366 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-11

... biomarkers of early effect (for pulmonary fibrosis, cardiovascular disease, and genetic damage) will be... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-13-12RS] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

76 FR 48164 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-08

... using a prospective experimental design (multiple baselines across groups with randomization). The costs... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-11-11FE] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

76 FR 44336 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-25

... using a prospective experimental design (multiple baselines across groups with randomization). The costs... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-11-11FE] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

77 FR 61406 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-12-12PK] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention... (NCEZID), Centers for Disease Control and Prevention (CDC). Background and Brief Description It is...

77 FR 61409 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-13-12SF] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...--Centers for Disease Control and Prevention (CDC), National Institute for Occupational Safety and Health...

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy.

PubMed

Saraswathula, Anirudh; Reap, Elizabeth A; Choi, Bryan D; Schmittling, Robert J; Norberg, Pamela K; Sayour, Elias J; Herndon, James E; Healy, Patrick; Congdon, Kendra L; Archer, Gerald E; Sanchez-Perez, Luis; Sampson, John H

2016-02-01

Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.

Abscisic-acid-dependent basic leucine zipper (bZIP) transcription factors in plant abiotic stress.

PubMed

Banerjee, Aditya; Roychoudhury, Aryadeep

2017-01-01

One of the major causes of significant crop loss throughout the world is the myriad of environmental stresses including drought, salinity, cold, heavy metal toxicity, and ultraviolet-B (UV-B) rays. Plants as sessile organisms have evolved various effective mechanism which enable them to withstand this plethora of stresses. Most of such regulatory mechanisms usually follow the abscisic-acid (ABA)-dependent pathway. In this review, we have primarily focussed on the basic leucine zipper (bZIP) transcription factors (TFs) activated by the ABA-mediated signalosome. Upon perception of ABA by specialized receptors, the signal is transduced via various groups of Ser/Thr kinases, which phosphorylate the bZIP TFs. Following such post-translational modification of TFs, they are activated so that they bind to specific cis-acting sequences called abscisic-acid-responsive elements (ABREs) or GC-rich coupling elements (CE), thereby influencing the expression of their target downstream genes. Several in silico techniques have been adopted so far to predict the structural features, recognize the regulatory modification sites, undergo phylogenetic analyses, and facilitate genome-wide survey of TF under multiple stresses. Current investigations on the epigenetic regulation that controls greater accessibility of the inducible regions of DNA of the target gene to the bZIP TFs exclusively under stress situations, along with the evolved stress memory responses via genomic imprinting mechanism, have been highlighted. The potentiality of overexpression of bZIP TFs, either in a homologous or in a heterologous background, in generating transgenic plants tolerant to various abiotic stressors have also been addressed by various groups. The present review will provide a coherent documentation on the functional characterization and regulation of bZIP TFs under multiple environmental stresses, with the major goal of generating multiple-stress-tolerant plant cultivars in near future.

Facing regulatory challenges of on-line hemodiafiltration.

PubMed

Kümmerle, Wolfgang

2011-01-01

On-line hemodiafiltration (on-line HDF) is the result of a vision that triggered multifarious changes in very different areas. Driven by the idea to offer better medical treatment for renal patients, technological innovations were developed and established that also constituted new challenges in the field of regulatory affairs. The existing regulations predominantly addressed the quality and safety of those products needed to perform dialysis treatment which were supplied by industrial manufacturers. However, the complexity of treatment system required for the provision of on-line fluids demanded a holistic approach encompassing all components involved. Hence, focus was placed not only on single products, but much more on their interfacing, and the clinical infrastructure, in particular, had to undergo substantial changes. The overall understanding of the interaction between such factors, quite different in their nature, was crucial to overcome the arising regulatory obstacles. This essay describes the evolution of the on-line HDF procedure from the regulatory point of view. A simplified diagram demonstrates the path taken from the former regulatory understanding to the realization of necessary changes. That achievement was only possible through 'management of preview' and consequent promotion of technical and medical innovations as well as regulatory re-evaluations. Copyright © 2011 S. Karger AG, Basel.

OSHA's renewed mandate for regulatory flexibility review: in support of the 1984 ethylene oxide standard.

PubMed

LaMontagne, A D; Kelsey, K T

1998-08-01

The Regulatory Flexibility Act of 1980 requires that all federal agencies consider the impact of regulations on small entities. One of the provisions of the Act requires review of regulations ever 10 years to determine whether such regulations should be continued without changes, rescinded, or amended to make them more effective or less burdensome on businesses. The Small Business Regulatory Enforcement Fairness Act (SBREFA) of 1996 amended and expanded the Regulatory Flexibility Act. Most significantly, SBREFA entitles aggrieved small entities or their representative (e.g., trade associations) to sue OSHA for failure to fulfill Regulatory Flexibility Act requirements. In response to this new political reality, OSHA held the first public meeting of their kind in June of 1997 to gather information on the ethylene oxide and lock-out/tag-out standards for the purposes of Regulatory Flexibility review. This paper presents the development of the Regulatory Flexibility review process and details our analysis of the ethylene oxide standard using OSHA's eight Regulatory Flexibility review criteria. Great progress in ethylene oxide health and safety has been made since the promulgation of the standard in 1984, including a considerable decrease in average workshift exposures. Yet, important concerns remain, such as the lack of safer substitutes for EtO's most common uses, the widespread occurrence of accidental exposures to EtO that are not captured by personal monitoring, and the recent increase in the occurrence of catastrophic EtO explosions. Because of the considerable study that has been devoted to EtO and to the EtO standard, there is a very strong cases for either making the EtO standard more worker protective, or continuing the standard without change while improving outreach and enforcement efforts to address shortcomings. Other valuable standards for which fewer data exist may be inappropriately threatened by the Regulatory Flexibility review process. Importantly, Regulatory Flexibility review could be constructive if accompanied by appropriations to fund sound evaluation studies. Instead, it will likely divert OSHA's limited resources from the numerous urgent health hazard that await initial rule-making. As signified by the designation of "intervention effectiveness research" as one of the 21 priorities on the National Occupational Research Agenda, evaluation studies of OSHA standards and other interventions are urgently needed. The occupational health community's response to this need will play a crucial role in preserving hard-won protections, as well as in developing other urgently needed protections in the future.

76 FR 29246 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-20

... cardiovascular disease have been well documented in the literature, much less is known about work related motor... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-11-11BW] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

76 FR 20353 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-12

... events that they planned. The survey results are necessary to understand how and where HIV/AIDS awareness... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-11-10HC] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

78 FR 75921 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-13

... (42 CFR 71.54) (OMB Control No. 0920-0199, exp. 1/31/2014)--Revision--Office of Public Health... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-14-0199] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention...

78 FR 9697 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-11

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30Day-13-0923] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention... Evaluation of the National Tobacco Prevention and Control Public Education Campaign (OMB No. 0920-0923, exp...

77 FR 508 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-05

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-12-12CO] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention... Evaluation of the National Tobacco Prevention and Control Public Education Campaign--New--National Center for...

75 FR 22138 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-27

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30 Day-10-09AX] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention... Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention (CDC). Background and Brief...

9 CFR 124.23 - Final action on regulatory review period determination.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 180-day period for filing a due diligence petition under § 124.30 unless it receives: (a) New... request under § 124.22 for revision of the regulatory review period determination; (c) A due diligence...

75 FR 75969 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-07

.... ACTION: Comment request. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management Services, Office of Management invites comments on the submission for OMB..., Regulatory Information Management Services, Office of Management. Federal Student Aid Type of Review...

Different contributions of internal reviewers and external experts to labelling decisions on therapeutic indications in new drug reviews in Japan.

PubMed

Yokota, M; Kusama, M; Matsuki, N; Ono, S

2013-12-01

External experts play an important role in shaping regulatory decisions in the new drug review process in the United States, Europe and Japan. No rigorous study has been performed addressing how and to what extent external experts, in contrast to internal reviewers in the agency, influence the regulatory decisions during new drug reviews. We examined their contributions in Japanese regulatory reviews in contrast to the internal reviewers, focusing on the labelling decision on therapeutic indications. With the data set of 219 new molecular entities (NMEs) approved in Japan from 2000 to 2009, we observed how proposed indications in labelling were modified in a stepwise manner during the review process and conducted multinomial logistic analysis to examine the possible mechanism behind. We found that interim assessment of indications by the internal reviewers was modified substantially by the influence of the external experts in about 20% of the 219 NMEs. Our analysis suggested that internal reviewers provided their opinion mainly based on strict review discipline, whereas external experts added flexibility and reality to their reviews. Our analysis revealed different evaluations between internal reviewers and external experts during regulatory discussions in new drug reviews and how the external panel contributes to changing internal decisions. This study provides a new and quantitative approach to better label setting by emphasizing the contributions of each stakeholder in new drug reviews, which would improve the efficiency, quality and transparency of new drug reviews to enhance public health. © 2013 John Wiley & Sons Ltd.

Hydropower Regulatory and Permitting Information Desktop (RAPID) Toolkit

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

Levine, Aaron L

Hydropower Regulatory and Permitting Information Desktop (RAPID) Toolkit presentation from the WPTO FY14-FY16 Peer Review. The toolkit is aimed at regulatory agencies, consultants, project developers, the public, and any other party interested in learning more about the hydropower regulatory process.

75 FR 55295 - List of Rules To Be Reviewed Pursuant to the Regulatory Flexibility Act

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-10

...-3078, IC-29408; File No. S7-20-10] List of Rules To Be Reviewed Pursuant to the Regulatory Flexibility Act AGENCY: Securities and Exchange Commission. ACTION: Publication of list of rules scheduled for review. SUMMARY: The Securities and Exchange Commission is today publishing a list of rules to be...

76 FR 39922 - Office of New Reactors; Proposed Revision 4 to Standard Review Plan Section 8.1 on Electric Power...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-07

... the proposed Revision 4 to Standard Review Plan Section 8.1 on ``Electric Power-- Introduction.'' The... NUCLEAR REGULATORY COMMISSION [NRC-2011-0119] Office of New Reactors; Proposed Revision 4 to Standard Review Plan Section 8.1 on Electric Power--Introduction, Correction AGENCY: Nuclear Regulatory...

75 FR 29588 - Office of New Reactors: Proposed NUREG-0800; Standard Review Plan Section 13.6.6, Draft Revision...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-26

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0184] Office of New Reactors: Proposed NUREG-0800; Standard Review Plan Section 13.6.6, Draft Revision 0 on Cyber Security Plan AGENCY: Nuclear Regulatory... Plants,'' on a proposed Standard Review Plan (SRP) Section 13.6.6 on ``Cyber Security Plan'' (Agencywide...

Benthic macroinvertebrates as indicators of biological condition below hydropower dams on west slope Sierra Nevada streams, California, USA

EPA Science Inventory

Over 50 hydropower dams in California will undergo relicensing by the Federal Energy Regulatory Commission (FERC) in the next 15 years. An interpretive framework for biological data collected by relicensing studies is lacking. This study developed a multi-metric index of biotic...

Using DCOM to support interoperability in forest ecosystem management decision support systems

Treesearch

W.D. Potter; S. Liu; X. Deng; H.M. Rauscher

2000-01-01

Forest ecosystems exhibit complex dynamics over time and space. Management of forest ecosystems involves the need to forecast future states of complex systems that are often undergoing structural changes. This in turn requires integration of quantitative science and engineering components with sociopolitical, regulatory, and economic considerations. The amount of data...

Genomic analysis reveals major determinants of cis-regulatory variation in Capsella grandiflora

PubMed Central

Steige, Kim A.; Laenen, Benjamin; Reimegård, Johan; Slotte, Tanja

2017-01-01

Understanding the causes of cis-regulatory variation is a long-standing aim in evolutionary biology. Although cis-regulatory variation has long been considered important for adaptation, we still have a limited understanding of the selective importance and genomic determinants of standing cis-regulatory variation. To address these questions, we studied the prevalence, genomic determinants, and selective forces shaping cis-regulatory variation in the outcrossing plant Capsella grandiflora. We first identified a set of 1,010 genes with common cis-regulatory variation using analyses of allele-specific expression (ASE). Population genomic analyses of whole-genome sequences from 32 individuals showed that genes with common cis-regulatory variation (i) are under weaker purifying selection and (ii) undergo less frequent positive selection than other genes. We further identified genomic determinants of cis-regulatory variation. Gene body methylation (gbM) was a major factor constraining cis-regulatory variation, whereas presence of nearby transposable elements (TEs) and tissue specificity of expression increased the odds of ASE. Our results suggest that most common cis-regulatory variation in C. grandiflora is under weak purifying selection, and that gene-specific functional constraints are more important for the maintenance of cis-regulatory variation than genome-scale variation in the intensity of selection. Our results agree with previous findings that suggest TE silencing affects nearby gene expression, and provide evidence for a link between gbM and cis-regulatory constraint, possibly reflecting greater dosage sensitivity of body-methylated genes. Given the extensive conservation of gbM in flowering plants, this suggests that gbM could be an important predictor of cis-regulatory variation in a wide range of plant species. PMID:28096395

40 CFR 63.851 - Regulatory authority review procedures.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 11 2014-07-01 2014-07-01 false Regulatory authority review procedures... PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Primary Aluminum Reduction Plants...

40 CFR 63.851 - Regulatory authority review procedures.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 10 2011-07-01 2011-07-01 false Regulatory authority review procedures... PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Primary Aluminum Reduction Plants...

40 CFR 63.851 - Regulatory authority review procedures.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 11 2013-07-01 2013-07-01 false Regulatory authority review procedures... PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Primary Aluminum Reduction Plants...

40 CFR 63.851 - Regulatory authority review procedures.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 11 2012-07-01 2012-07-01 false Regulatory authority review procedures... PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Primary Aluminum Reduction Plants...

75 FR 13105 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-18

... DEPARTMENT OF EDUCATION Submission for OMB Review; Comment Request AGENCY: Department of Education. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 19, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory...

75 FR 12219 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-15

... DEPARTMENT OF EDUCATION Submission for OMB Review; Comment Request AGENCY: Department of Education. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 14, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory...

75 FR 32164 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-07

... DEPARTMENT OF EDUCATION Submission for OMB Review; Comment Request AGENCY: Department of Education. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 7, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory...

75 FR 13733 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-23

... DEPARTMENT OF EDUCATION Submission for OMB Review; Comment Request AGENCY: Department of Education. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 22, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory...

75 FR 22759 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-30

... DEPARTMENT OF EDUCATION Submission for OMB Review; Comment Request AGENCY: Department of Education. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 1, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory...

78 FR 29062 - 2006 Biennial Regulatory Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-17

... Regulatory Review AGENCY: Federal Communications Commission. ACTION: Correcting amendments. SUMMARY: The Federal Communications Commission published a document in the Federal Register on February 6, 2013 (78 FR... INFORMATION: The Federal Communications Commission published a rule on February 6, 2013 which became effective...

Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: Implications for cortical development.

PubMed

Shapiro, Lauren P; Parsons, Ryan G; Koleske, Anthony J; Gourley, Shannon L

2017-05-01

The prevalence of depression, anxiety, schizophrenia, and drug and alcohol use disorders peaks during adolescence. Further, up to 50% of "adult" mental health disorders emerge in adolescence. During adolescence, the prefrontal cortex (PFC) undergoes dramatic structural reorganization, in which dendritic spines and synapses are refined, pruned, and stabilized. Understanding the molecular mechanisms that underlie these processes should help to identify factors that influence the development of psychiatric illness. Here we briefly discuss the anatomical connections of the medial and orbital prefrontal cortex (mPFC and OFC, respectively). We then present original findings suggesting that dendritic spines on deep-layer excitatory neurons in the mouse mPFC and OFC prune at different adolescent ages, with later pruning in the OFC. In parallel, we used Western blotting to define levels of several cytoskeletal regulatory proteins during early, mid-, and late adolescence, focusing on tropomyosin-related kinase receptor B (TrkB) and β1-integrin-containing receptors and select signaling partners. We identified regional differences in the levels of several proteins in early and midadolescence that then converged in early adulthood. We also observed age-related differences in TrkB levels, both full-length and truncated isoforms, Rho-kinase 2, and synaptophysin in both PFC subregions. Finally, we identified changes in protein levels in the dorsal and ventral hippocampus that were distinct from those in the PFC. We conclude with a general review of the manner in which TrkB- and β1-integrin-mediated signaling influences neuronal structure in the postnatal brain. Elucidating the role of cytoskeletal regulatory factors throughout adolescence may identify critical mechanisms of PFC development. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: Implications for cortical development

PubMed Central

Shapiro, Lauren P.; Parsons, Ryan G.; Koleske, Anthony J.; Gourley, Shannon L.

2016-01-01

The prevalence of depression, anxiety, schizophrenia, and drug and alcohol use disorders peaks during adolescence. Further, up to 50% of “adult” mental health disorders emerge in adolescence. During adolescence, the prefrontal cortex undergoes dramatic structural reorganization, in which dendritic spines and synapses are refined, pruned, and stabilized. Understanding the molecular mechanisms that underlie these processes should help to identify factors that influence the development of psychiatric illness. Here we briefly discuss the anatomical connections of the medial and orbital prefrontal cortex (mPFC and OFC, respectively). We then present original findings suggesting that dendritic spines on deep-layer excitatory neurons in the mouse mPFC and OFC prune at different adolescent ages, with later pruning in the OFC. In parallel, we used western blotting to define levels of several cytoskeletal regulatory proteins during early, mid-, and late adolescence, focusing on tropomyosin-related kinase receptor B (TrkB) and β1-integrin-containing receptors and select signaling partners. We identified regional differences in the levels of several proteins in early and mid-adolescence that then converged in early adulthood. We also observed age-related differences in TrkB levels, both full-length and truncated isoforms, Rho-kinase 2 (ROCK2), and synaptophysin in both PFC subregions. Finally, we identified changes in protein levels in the dorsal and ventral hippocampus that were distinct from those in the PFC. We conclude with a general review of the manner in which TrkB- and β1-integrin-mediated signaling influences neuronal structure in the postnatal brain. Elucidating the role of cytoskeletal regulatory factors throughout adolescence may identify critical mechanisms of PFC development. PMID:27735056

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

Student Perceptions of Quality and Satisfaction in Online Education

ERIC Educational Resources Information Center

Simpson, Jill M.; Benson, Angela D.

2013-01-01

The purpose of this study was to examine student perceptions of quality and satisfaction in regionally accredited online courses. Results indicated that undergoing a formal peer review may lead to higher student satisfaction in a course. Results also indicated that being subscribed to a peer review program without undergoing a formal peer review…

77 FR 61415 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention [30-Day-13-12QI] Agency Forms Undergoing Paperwork Reduction Act Review The Centers for Disease Control and Prevention... estimated annual burden is 21,467 hours (see Table). There is no cost to the respondents other than their...

Regulatory and legal review of automated and connected truck platooning technology.

DOT National Transportation Integrated Search

2017-05-01

Commercial truck platooning is a relatively novel concept in Texas and around the country. This white paper : presents the results of a review of state and federal code to identify regulatory and legislative hurdles that : may delay or deter platooni...

75 FR 72818 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-26

... Information Management Services, Office of Management invites comments on the submission for OMB review as... Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and... Division, Regulatory Information Management Services, Office of Management. Federal Student Aid Type of...

Issues in Peer Review of the Scientific Basis for Regulatory Decisions.

ERIC Educational Resources Information Center

American Chemical Society, Washington, DC.

This document is intended to provide a discussion of the issues that need to be addressed in the development of peer review guidelines, the options for addressing the issues, and a range of views about such options. The document focuses on peer review with regard to regulatory decisions and contains major sections which deal with: (1) what should…

Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb.

PubMed

Dias, Sheila; D'Amico, Angela; Cretney, Erika; Liao, Yang; Tellier, Julie; Bruggeman, Christine; Almeida, Francisca F; Leahy, Jamie; Belz, Gabrielle T; Smyth, Gordon K; Shi, Wei; Nutt, Stephen L

2017-01-17

FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear Regulatory Commission activities to prepare for reviewing license applications and issuing licenses

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

Uleck, R.B.; DeFino, C.V.

1991-12-31

The Low-Level Radioactive Waste Policy Amendments Act of 1985 (LLRWPAA) assigned States the responsibility to provide for disposal of commercial low-level radioactive waste (LLRW) by 1993. The LLRWPAA also required the US Nuclear Regulatory Commission (NRC) to establish procedures and develop the technical review capability to process license applications for new LLRW disposal facilities. Under the LLRWPAA, NRC is required, to the extent practicable, to complete its review of an LLRW disposal facility license application within 15 months of its submittal by a State. This provision of the LLRWPAA helps ensure that NRC, in addition to protecting public health andmore » safety and the environment, facilitates States` achievement of LLRWPAA milestones for new facility development. A timely NRC review is needed for States to accomplish their objective of having new disposal facilities in operation on the dates prescribed in the LLRWPAA. To help assure NRC and States` compliance with the provisions of the LLRWPAA, NRC has developed a licensing review strategy that includes: (1) the further development of regulatory guidance, (2) enhancement of licensing review capability, and (3) prelicensing regulatory consultation with potential applicants.« less

Fertility after uterine artery embolization: a review.

PubMed

McLucas, Bruce; Voorhees, William D; Elliott, Stephanie

2016-01-01

Uterine artery embolization (UAE) research has largely been focused on women over 40 years, yet women of reproductive age undergo UAE without any increased morbidity. Some physicians refrain from recommending UAE to women in this age group because of some research findings showing a negative effect on fertility. This review presents a comprehensive discussion of the fertility potential of women undergoing UAE, in terms of pregnancy rates and complications as well as ovarian function and reserve. Findings indicate many benefits for women desiring fertility who undergo UAE over traditional myomectomy.

78 FR 70079 - Appointments to Performance Review Boards for Senior Executive Service

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-22

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0255] Appointments to Performance Review Boards for Senior... for Senior Executive Service. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) has announced the... and awarding authorities on performance appraisal ratings and performance awards for Senior Executives...

76 FR 47089 - Regulatory Review Schedule; Cancellation of Consultation Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-04

... DEPARTMENT OF THE INTERIOR National Indian Gaming Commission 25 CFR Chapter III Regulatory Review Schedule; Cancellation of Consultation Meetings AGENCY: National Indian Gaming Commission. ACTION: Notice. SUMMARY: On November 18, 2010, the National Indian Gaming Commission (NIGC) issued a Notice of Inquiry and...

75 FR 33361 - Notice of Issuance of Regulatory Guide

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-11

... staff needs in its review of applications for permits and licenses. Revision 4 of Regulatory Guide 1.28... (Design and Construction).'' Proposed RG 1.28, Revision 4, extends the scope of the NRC's endorsement to...: Nuclear Regulatory Commission. ACTION: Notice of Issuance and Availability of Regulatory Guide 1.28...

Regulatory Concerns on the In-Containment Water Storage System of the Korean Next Generation Reactor

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

Ahn, Hyung-Joon; Lee, Jae-Hun; Bang, Young-Seok

2002-07-15

The in-containment water storage system (IWSS) is a newly adopted system in the design of the Korean Next Generation Reactor (KNGR). It consists of the in-containment refueling water storage tank, holdup volume tank, and cavity flooding system (CFS). The IWSS has the function of steam condensation and heat sink for the steam release from the pressurizer and provides cooling water to the safety injection system and containment spray system in an accident condition and to the CFS in a severe accident condition. With the progress of the KNGR design, the Korea Institute of Nuclear Safety has been developing Safety andmore » Regulatory Requirements and Guidances for safety review of the KNGR. In this paper, regarding the IWSS of the KNGR, the major contents of the General Safety Criteria, Specific Safety Requirements, Safety Regulatory Guides, and Safety Review Procedures were introduced, and the safety review items that have to be reviewed in-depth from the regulatory viewpoint were also identified.« less

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

75 FR 18168 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management..., Regulatory Information Management Services, Office of Management, publishes that notice containing proposed..., Acting Director, Information Collection Clearance Division, Regulatory Information Management Services...

75 FR 29325 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-25

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management..., Regulatory Information Management Services, Office of Management, publishes that notice containing proposed... Director, Information Collection Clearance Division, Regulatory Information Management Services Office of...

75 FR 39216 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-08

.... SUMMARY: The Director, Information Collection Clearance Division, Regulatory Information Management... Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and Budget, 725.... King, Director, Information Collection Clearance Division, Regulatory Information Management Services...

Anesthetic Considerations in Patients Undergoing Bariatric Surgery: A Review Article

PubMed Central

Soleimanpour, Hassan; Safari, Saeid; Sanaie, Sarvin; Nazari, Mehdi; Alavian, Seyed Moayed

2017-01-01

Context This article discusses the anesthetic considerations in patients undergoing bariatric surgery in the preoperative, intraoperative, and postoperative phases of surgery. Evidence Acquisition This review includes studies involving obese patients undergoing bariatric surgery. Searches have been conducted in PubMed, MEDLINE, EMBASE, Google Scholar, Scopus, and Cochrane Database of Systematic Review using the terms obese, obesity, bariatric, anesthesia, perioperative, preoperative, perioperative, postoperative, and their combinations. Results Obesity is a major worldwide health problem associated with many comorbidities. Bariatric surgery has been proposed as the best alternative treatment for extreme obese patients when all other therapeutic options have failed. Conclusions Anesthetists must completely assess the patients before the surgery to identify anesthesia- related potential risk factors and prepare for management during the surgery. PMID:29430407

Self-Regulation and Approaches to Learning in English Composition Writing

ERIC Educational Resources Information Center

Magno, Carlo

2009-01-01

It is hypothesized in the present study that when learners are tasked to write a composition in a second language (such as English language for Filipinos), they use specific approaches to learning and eventually undergo self-regulatory processes. The present study tested a model showing the shift from process to outcome in writing (Zimmerman &…

Epigenetics as an emerging tool for improvement of fungal strains used in biotechnology.

PubMed

Aghcheh, Razieh Karimi; Kubicek, Christian P

2015-08-01

Filamentous fungi are today a major source of industrial biotechnology for the production of primary and secondary metabolites, as well as enzymes and recombinant proteins. All of them have undergone extensive improvement strain programs, initially by classical mutagenesis and later on by genetic manipulation. Thereby, strategies to overcome rate-limiting or yield-reducing reactions included manipulating the expression of individual genes, their regulatory genes, and also their function. Yet, research of the last decade clearly showed that cells can also undergo heritable changes in gene expression that do not involve changes in the underlying DNA sequences (=epigenetics). This involves three levels of regulation: (i) DNA methylation, (ii) chromatin remodeling by histone modification, and (iii) RNA interference. The demonstration of the occurrence of these processes in fungal model organisms such as Aspergillus nidulans and Neurospora crassa has stimulated its recent investigation as a tool for strain improvement in industrially used fungi. This review describes the progress that has thereby been obtained.

Rho GTPases and their downstream effectors in megakaryocyte biology.

PubMed

Pleines, Irina; Cherpokova, Deya; Bender, Markus

2018-06-18

Megakaryocytes differentiate from hematopoietic stem cells in the bone marrow. The transition of megakaryocytes to platelets is a complex process. Thereby, megakaryocytes extend proplatelets into sinusoidal blood vessels, where the proplatelets undergo fission to release platelets. Defects in platelet production can lead to a low platelet count (thrombocytopenia) with increased bleeding risk. Rho GTPases comprise a family of small signaling G proteins that have been shown to be master regulators of the cytoskeleton controlling many aspects of intracellular processes. The generation of Pf4-Cre transgenic mice was a major breakthrough that enabled studies in megakaryocyte-/platelet-specific knockout mouse lines and provided new insights into the central regulatory role of Rho GTPases in megakaryocyte maturation and platelet production. In this review, we will summarize major findings on the role of Rho GTPases in megakaryocyte biology with a focus on mouse lines in which knockout strategies have been applied to study the function of the best-characterized members Rac1, Cdc42 and RhoA and their downstream effector proteins.

Perspectives on Validation of High-Throughput Assays Supporting 21st Century Toxicity Testing1

PubMed Central

Judson, Richard; Kavlock, Robert; Martin, Matt; Reif, David; Houck, Keith; Knudsen, Thomas; Richard, Ann; Tice, Raymond R.; Whelan, Maurice; Xia, Menghang; Huang, Ruili; Austin, Christopher; Daston, George; Hartung, Thomas; Fowle, John R.; Wooge, William; Tong, Weida; Dix, David

2014-01-01

Summary In vitro, high-throughput screening (HTS) assays are seeing increasing use in toxicity testing. HTS assays can simultaneously test many chemicals, but have seen limited use in the regulatory arena, in part because of the need to undergo rigorous, time-consuming formal validation. Here we discuss streamlining the validation process, specifically for prioritization applications in which HTS assays are used to identify a high-concern subset of a collection of chemicals. The high-concern chemicals could then be tested sooner rather than later in standard guideline bioassays. The streamlined validation process would continue to ensure the reliability and relevance of assays for this application. We discuss the following practical guidelines: (1) follow current validation practice to the extent possible and practical; (2) make increased use of reference compounds to better demonstrate assay reliability and relevance; (3) deemphasize the need for cross-laboratory testing, and; (4) implement a web-based, transparent and expedited peer review process. PMID:23338806

Antibodies to watch in 2014: mid-year update.

PubMed

Reichert, Janice M

2014-01-01

The commercial pipeline of monoclonal antibodies is highly dynamic, with a multitude of transitions occurring during the year as product candidates advance through the clinical phases and onto the market. The data presented here add to that provided in the extensive "Antibodies to watch in 2014" report published in the January/February 2014 issue of mAbs. Recent phase transition data suggest that 2014 may be a banner year for first approvals of antibody therapeutics. As of May 2014, three products, ramucirumab (Cyramza®), siltuximab (Sylvant®) and vedolizumab (Entyvio™), had been granted first approvals in the United States, and four additional antibody therapeutics (secukinumab, dinutuximab, nivolumab, pembrolizumab) are undergoing regulatory review in either the US or the European Union. Other notable events include the start of first Phase 3 studies for seven antibody therapeutics (dupilumab, SA237, etrolizumab, MPDL3280A, bavituximab, clivatuzumab tetraxetan, blinatumomab). Relevant data for these product candidates are summarized, and metrics for antibody therapeutics development are discussed.

A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity.

PubMed

Read, Timothy; Richmond, Phillip A; Dowell, Robin D

2016-01-01

Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant.

A regulatory perspective of clinical trial applications for biological products with particular emphasis on Advanced Therapy Medicinal Products (ATMPs)

PubMed Central

Jones, David R; McBlane, James W; McNaughton, Graham; Rajakumaraswamy, Nishanthan; Wydenbach, Kirsty

2013-01-01

The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non-Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines. PMID:23216470

78 FR 22771 - Statement of Policy on the Development and Review of Regulations and Policies

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-17

... expertise to a regulatory project; such staff may include examiners, economists, lawyers or accountants... Regulatory Enforcement Fairness Act, and Economic Growth and Regulatory Paper Reduction Act of 1996. The FDIC...

75 FR 48319 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-10

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and Budget, 725..., Acting Director, Information Collection Clearance Division, Regulatory Information Management Services...

75 FR 48661 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-11

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and Budget, 725... Carey, Acting Director, Information Collection Clearance Division, Regulatory Information Management...

75 FR 51024 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and Budget, 725... Carey, Acting Director, Information Collection Clearance Division, Regulatory Information Management...

Regulatory T cells in human disease and their potential for therapeutic manipulation

PubMed Central

Taams, Leonie S; Palmer, Donald B; Akbar, Arne N; Robinson, Douglas S; Brown, Zarin; Hawrylowicz, Catherine M

2006-01-01

Regulatory T cells are proposed to play a central role in the maintenance of immunological tolerance in the periphery, and studies in many animal models demonstrate their capacity to inhibit inflammatory pathologies in vivo. At a recent meeting [Clinical Application of Regulatory T Cells, 7–8 April 2005, Horsham, UK, organized by the authors of this review, in collaboration with the British Society for Immunology and Novartis] evidence was discussed that certain human autoimmune, infectious and allergic diseases are associated with impaired regulatory T-cell function. In contrast, evidence from several human cancer studies and some infections indicates that regulatory T cells may impair the development of protective immunity. Importantly, certain therapies, both those that act non-specifically to reduce inflammation and antigen-specific immunotherapies, may induce or enhance regulatory T-cell function. The purpose of this review was to summarize current knowledge on regulatory T-cell function in human disease, and to assess critically how this can be tailored to suit the therapeutic manipulation of immunity. PMID:16630018

75 FR 1088 - Notice of Availability of a Memorandum of Understanding Between the Nuclear Regulatory Commission...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-08

... NUCLEAR REGULATORY COMMISSION [NRC-2009-0578] Notice of Availability of a Memorandum of Understanding Between the Nuclear Regulatory Commission and the Bureau of Land Management AGENCY: Nuclear Regulatory Commission. ACTION: Notice of Availability. FOR FURTHER INFORMATION CONTACT: Mr. Alan Bjornsen, Project Manager, Environmental Review Branch,...

78 FR 63249 - OMB Agency Information Collection Activities: Submission for the Office of Management and Budget...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-23

... NUCLEAR REGULATORY COMMISSION [Docket No. NRC-2013-0116] OMB Agency Information Collection Activities: Submission for the Office of Management and Budget Review; Comment Request AGENCY: Nuclear... comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC) has recently submitted to OMB for review...

77 FR 1524 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Approving...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-10

... initiating and adjudicating various types of actions, including disciplinary, eligibility, expedited, and... also may review the decision. Oral Argument in Review of Proceedings FINRA Rule 9341(a) establishes the procedure for a party requesting an oral argument before the Subcommittee or, if applicable, the Extended...

78 FR 23199 - NASA FAR Supplement Regulatory Review No. 1

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-18

... 2700-AE01 NASA FAR Supplement Regulatory Review No. 1 AGENCY: National Aeronautics and Space Administration. ACTION: Proposed rule. SUMMARY: NASA is updating the NASA FAR Supplement (NFS) with the goal of... existing regulations. The revisions to this rule are part of NASA's retrospective plan under EO 13563...

78 FR 79542 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Order Granting...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-30

... Risk-Based Review Principles Two commenters to the Proposing Release opposed the proposed rules' flexibility permitting members to rely on risk-based or principles- based review standards for specific... Commercial Honor and Principles of Trade), it must include supervision of all of a member's business lines...

21 CFR 60.10 - FDA assistance on eligibility.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) Verifying whether the product was subject to a regulatory review period before its commercial marketing or... whether the permission for commercial marketing or use of the product after the regulatory review period is the first permitted commercial marketing or use of the product either: (i) Under the provision of...

76 FR 31886 - Reducing Regulatory Burden; Retrospective Review Under E.O. 13563

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-02

... OFFICE OF PERSONNEL MANAGEMENT 5 CFR Chapters I and XXXV 45 CFR Chapter VIII 48 CFR Chapters 16, 17, and 21 Reducing Regulatory Burden; Retrospective Review Under E.O. 13563 AGENCY: Office of Personnel Management. ACTION: Request for information. SUMMARY: The Office of Personnel Management has...

76 FR 6094 - FAA Public Forum To Conduct Regulatory Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-03

... DEPARTMENT OF TRANSPORTATION Federal Aviation Administration 14 CFR Parts 27 and 29 FAA Public Forum To Conduct Regulatory Review AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of.... Attendees are not required to register for the Heli-Expo conference to participate in this public forum. FOR...

77 FR 8014 - Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-13

... agenda was developed under the guidelines of Executive Order 12866 ``Regulatory Planning and Review... regulations for review to determine whether they should be modified or eliminated. Proposed rules may be... Unified Agenda will be available online at www.reginfo.gov , in a format that offers users a greatly...

78 FR 44325 - Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-23

... developed under the guidelines of Executive Order 12866 ``Regulatory Planning and Review.'' GSA's purpose in.... GSA also invites interested persons to recommend existing significant regulations for review to... available online at www.reginfo.gov , in a format that offers users a greatly enhanced ability to obtain...

76 FR 54749 - Commission Information Collection Activities (FERC-523); Comment Request; Submitted for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-02

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. IC11-523-001] Commission Information Collection Activities (FERC-523); Comment Request; Submitted for OMB Review AGENCY: Federal Energy Regulatory Commission, Energy. ACTION: Notice. SUMMARY: In compliance with the requirements of section 3507...

A Review of International Telecommunications Industry Issues, Structure, and Regulatory Problems.

ERIC Educational Resources Information Center

Cole, Jack E.; And Others

Industry structure studies prior to 1968 are briefly reviewed, and an overview of industrial and technological developments up to the present is provided through synopses of more recent studies. Areas covered include overseas telephone and record carriers; the creation of the Communications Satellite Corporation; the current regulatory and…

The value and benefits of the International Conference on Harmonisation to drug regulatory authorities: advancing harmonization for better public health.

PubMed

Molzon, J A; Giaquinto, A; Lindstrom, L; Tominaga, T; Ward, M; Doerr, P; Hunt, L; Rago, L

2011-04-01

The International Conference on Harmonisation (ICH) is an unparalleled undertaking, which has brought together drug regulatory authorities and pharmaceutical trade associations from Europe, Japan, and the United States, to discuss the scientific and technical aspects of medical product registration. Launched in 1990, the value and benefits of ICH to regulators are being realized. ICH has harmonized submission requirements and created a harmonized submission format that is relieving both companies and regulatory authorities of the burdens of assembling and reviewing separate submissions for each region. As more countries embrace ICH guidelines, we anticipate additional benefits, including the promotion of good review practices and, ultimately, a common regulatory language that will facilitate further interactions among global drug regulatory authorities.

75 FR 43944 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-27

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and Budget, 725..., Regulatory Information Management Services, Office of Management. Office of Special Education and...

77 FR 28467 - Identifying and Reducing Regulatory Burdens

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-14

... online wherever practicable. Sec. 3. Setting Priorities. In implementing and improving their... regulatory priorities, to promote public participation in retrospective review, to modernize our regulatory..., agencies shall give priority, consistent with law, to those initiatives that will produce significant...

Digital management and regulatory submission of medical images from clinical trials: role and benefits of the core laboratory

NASA Astrophysics Data System (ADS)

Robbins, William L.; Conklin, James J.

1995-10-01

Medical images (angiography, CT, MRI, nuclear medicine, ultrasound, x ray) play an increasingly important role in the clinical development and regulatory review process for pharmaceuticals and medical devices. Since medical images are increasingly acquired and archived digitally, or are readily digitized from film, they can be visualized, processed and analyzed in a variety of ways using digital image processing and display technology. Moreover, with image-based data management and data visualization tools, medical images can be electronically organized and submitted to the U.S. Food and Drug Administration (FDA) for review. The collection, processing, analysis, archival, and submission of medical images in a digital format versus an analog (film-based) format presents both challenges and opportunities for the clinical and regulatory information management specialist. The medical imaging 'core laboratory' is an important resource for clinical trials and regulatory submissions involving medical imaging data. Use of digital imaging technology within a core laboratory can increase efficiency and decrease overall costs in the image data management and regulatory review process.

Flight training efforts would benefit from more flexible aviation regulatory structures.

PubMed

Bent, J

1996-10-01

Training and regulatory issues related to modern flight deck systems are reviewed. Philosophical differences in regulatory bodies in the United States and Europe are highlighted. Methods of changing regulations in Europe and the United States are discussed.

77 FR 66650 - Proposed Revisions to Radiation Protection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-06

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0268] Proposed Revisions to Radiation Protection AGENCY: Nuclear Regulatory Commission. ACTION: Standard review plan-draft section revision; request for comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC or the Commission) is revising the following sections...

A Preliminary Assessment of the Benefits of Reducing Formaldehyde Exposures (1984)

EPA Pesticide Factsheets

The report reviews a variety of regulatory responses that EPA might consider in developing regulatory strategies for controlling human exposures under the Toxic Substance Control Act and previewed issues that may arise in a regulatory impact analysis.

What's the Regulatory Value of a Target Product Profile?

PubMed

Breder, Christopher D; Du, Wenny; Tyndall, Adria

2017-07-01

Target product profiles (TPPs) are used as a regulatory tool for dialog on clinical development or manufacturing plans. Drugs and biologics approved by the FDA that mention TPPs are associated with more efficient regulatory review times, perhaps as a result of increased planning or because the TPP promotes well-organized regulatory dialog. Published by Elsevier Ltd.

The role of T lymphocytes in cancer patients undergoing immunotherapy with autologous dendritic cells.

PubMed

Rodrigues, Cláudia M; Matias, Bruna F; Murta, Eddie F C; Michelin, Márcia A

2011-01-01

Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period.

30 CFR 773.21 - Initial review and finding requirements for improvidently issued permits.

Code of Federal Regulations, 2010 CFR

2010-07-01

... EXPLORATION SYSTEMS UNDER REGULATORY PROGRAMS REQUIREMENTS FOR PERMITS AND PERMIT PROCESSING § 773.21 Initial review and finding requirements for improvidently issued permits. (a) If we, the regulatory authority... paragraph (c) of this section, you may challenge the preliminary finding by providing us with evidence as to...

10 CFR 170.51 - Right to review and appeal of prescribed fees.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 2 2012-01-01 2012-01-01 false Right to review and appeal of prescribed fees. 170.51 Section 170.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FEES FOR FACILITIES, MATERIALS, IMPORT AND EXPORT LICENSES, AND OTHER REGULATORY SERVICES UNDER THE ATOMIC ENERGY ACT OF 1954, AS AMENDED...

10 CFR 170.51 - Right to review and appeal of prescribed fees.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 2 2011-01-01 2011-01-01 false Right to review and appeal of prescribed fees. 170.51 Section 170.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FEES FOR FACILITIES, MATERIALS, IMPORT AND EXPORT LICENSES, AND OTHER REGULATORY SERVICES UNDER THE ATOMIC ENERGY ACT OF 1954, AS AMENDED...

10 CFR 170.51 - Right to review and appeal of prescribed fees.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Right to review and appeal of prescribed fees. 170.51 Section 170.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FEES FOR FACILITIES, MATERIALS, IMPORT AND EXPORT LICENSES, AND OTHER REGULATORY SERVICES UNDER THE ATOMIC ENERGY ACT OF 1954, AS AMENDED...

10 CFR 170.51 - Right to review and appeal of prescribed fees.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Right to review and appeal of prescribed fees. 170.51 Section 170.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FEES FOR FACILITIES, MATERIALS, IMPORT AND EXPORT LICENSES, AND OTHER REGULATORY SERVICES UNDER THE ATOMIC ENERGY ACT OF 1954, AS AMENDED...

10 CFR 170.51 - Right to review and appeal of prescribed fees.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 2 2014-01-01 2014-01-01 false Right to review and appeal of prescribed fees. 170.51 Section 170.51 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) FEES FOR FACILITIES, MATERIALS, IMPORT AND EXPORT LICENSES, AND OTHER REGULATORY SERVICES UNDER THE ATOMIC ENERGY ACT OF 1954, AS AMENDED...

Depressive Symptoms and Parenting Competence: An Analysis of 13 Regulatory Processes

ERIC Educational Resources Information Center

Dix, Theodore; Meunier, Leah N.

2009-01-01

Mechanisms that lead depressive symptoms to undermine parenting are poorly understood. This review examines cognitive, affective, and motivational processes thought to be responsible for the impact of depressive symptoms on parenting. We present a five-step, action-control model and review 152 studies relevant to 13 regulatory processes. Evidence…

The Nature of Procrastination: A Meta-Analytic and Theoretical Review of Quintessential Self-Regulatory Failure

ERIC Educational Resources Information Center

Steel, Piers

2007-01-01

Procrastination is a prevalent and pernicious form of self-regulatory failure that is not entirely understood. Hence, the relevant conceptual, theoretical, and empirical work is reviewed, drawing upon correlational, experimental, and qualitative findings. A meta-analysis of procrastination's possible causes and effects, based on 691 correlations,…

77 FR 26016 - Determination of Regulatory Review Period for Purposes of Patent Extension; Alair Bronchial...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-02

...) has determined the regulatory review period for Alair Bronchial Thermoplasty System and is publishing... submission of an application to the Director of Patents and Trademarks, Department of Commerce, for the... may count toward the actual amount of extension that the Director of Patents and Trademarks may award...

75 FR 77878 - Determination of Regulatory Review Period for Purposes of Patent Extension; FREESTYLE NAVIGATOR

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-14

... determined the regulatory review period for FREESTYLE NAVIGATOR and is publishing this notice of that... the Director of Patents and Trademarks, Department of Commerce, for the extension of a patent which... toward the actual amount of extension that the Director of Patents and Trademarks may award (half the...

76 FR 31349 - Determination of Regulatory Review Period for Purposes of Patent Extension; ACTEMRA

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-31

... Administration (FDA) has determined the regulatory review period for ACTEMRA and is publishing this notice of... applications to the Director of Patents and Trademarks, Department of Commerce, for the extension of patents... actual amount of extension that the Director of Patents and Trademarks may award (for example, half the...

49 CFR 355.23 - Submission of results.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 5 2011-10-01 2011-10-01 false Submission of results. 355.23 Section 355.23... results. Each State shall submit the results of its regulatory review annually with its certification of compliance under § 350.209 of this subchapter. It shall submit the results of the regulatory review with the...

49 CFR 355.23 - Submission of results.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 5 2012-10-01 2012-10-01 false Submission of results. 355.23 Section 355.23... results. Each State shall submit the results of its regulatory review annually with its certification of compliance under § 350.209 of this subchapter. It shall submit the results of the regulatory review with the...

49 CFR 355.23 - Submission of results.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 5 2014-10-01 2014-10-01 false Submission of results. 355.23 Section 355.23... results. Each State shall submit the results of its regulatory review annually with its certification of compliance under § 350.209 of this subchapter. It shall submit the results of the regulatory review with the...

49 CFR 355.23 - Submission of results.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 5 2013-10-01 2013-10-01 false Submission of results. 355.23 Section 355.23... results. Each State shall submit the results of its regulatory review annually with its certification of compliance under § 350.209 of this subchapter. It shall submit the results of the regulatory review with the...

49 CFR 355.23 - Submission of results.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 5 2010-10-01 2010-10-01 false Submission of results. 355.23 Section 355.23... results. Each State shall submit the results of its regulatory review annually with its certification of compliance under § 350.209 of this subchapter. It shall submit the results of the regulatory review with the...

76 FR 11776 - Agency Information Collection Activities; Submission to OMB for Review and Approval; Comment...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-03

... Activities; Submission to OMB for Review and Approval; Comment Request; Regulatory Pilot Projects (Renewal... Management and Budget (OMB), Attention: Desk Officer for EPA, 725 17th Street, NW., Washington, DC 20503. FOR... information about the electronic docket, go to http://www.regulations.gov . Title: Regulatory Pilot Projects...

76 FR 58311 - Draft License Renewal Interim Staff Guidance LR-ISG-2011-05; Ongoing Review of Operating Experience

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-20

... nuclear power plants. In response to a request from the Nuclear Energy Institute (NEI), the NRC is... NUCLEAR REGULATORY COMMISSION [NRC-2011-0191] Draft License Renewal Interim Staff Guidance LR-ISG-2011-05; Ongoing Review of Operating Experience AGENCY: Nuclear Regulatory Commission. ACTION: Draft...

Patients come from populations and populations contain patients. A two-stage scientific and ethics review: The next adaptation for single institutional review boards.

PubMed

Knopman, David; Alford, Eli; Tate, Kaitlin; Long, Mark; Khachaturian, Ara S

2017-08-01

For nearly 50 years, institutional review boards (IRB) and independent ethics committees have featured local oversight as a core function of research ethics reviews. However growing complexity in Alzheimer's clinical research suggests current approaches to research volunteer safety is hampering development of new therapeutics. As a partial response to this challenge, the NIH has mandated that all NIH-funded multi-site studies will use a single Institutional Review Board. The perspective describes a joint program to provide a single IRB of record (sIRB) for phases of multi-site studies. The approach follows two steps. One, an expert Scientific Review Committee (SRC) of senior researchers in the field will conduct the review principally of scientific merit, significance, feasibility, and the likelihood of meaningful results. The second step will be the IRB's regulatory and ethics review. The IRB will apply appropriate regulatory criteria for approval including minimization of risks to subjects and risks reasonable in relation to anticipated benefits, equitable subject selection, informed consent, protections for vulnerable populations, and application of local context considerations, among others. There is a steady demand for scientific, ethical and regulatory review of planned Alzheimer's studies. As of January 15, 2017, there are nearly 400 open studies, Phase II and III, industry and NIH sponsored trials on disease indications affecting memory, movement and mood in the US. The effort will initially accept protocols for studies of Alzheimer's disease, dementia, and related disorders effecting memory, movement and mood. Future aims will be to provide scientific review and, where applicable, regulatory and ethical review in an international context outside North America with sites possibly in Asia, Europe and Australia. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Genomic Organization and Identification of Promoter Regions for the BDNF Gene in the Pond Turtle Trachemys scripta elegans

PubMed Central

Zheng, Zhaoqing; Keifer, Joyce

2014-01-01

Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal development and synaptic function. The BDNF gene undergoes significant activity-dependent regulation during learning. Here, we identified the BDNF promoter regions, transcription start sites, and potential regulatory sequences for BDNF exons I–III that may contribute to activity-dependent gene and protein expression in the pond turtle Trachemys scripta elegans (tBDNF). By using transfection of BDNF promoter/luciferase plasmid constructs into human neuroblastoma SHSY5Y cells and mouse embryonic fibroblast NIH3T3 cells, we identified the basal regulatory activity of promoter sequences located upstream of each tBDNF exon, designated as pBDNFI–III. Further, through chromatin immunoprecipitation (ChIP) assays, we detected CREB binding directly to exon I and exon III promoters, while BHLHB2, but not CREB, binds within the exon II promoter. Elucidation of the promoter regions and regulatory protein binding sites in the tBDNF gene is essential for understanding the regulatory mechanisms that control tBDNF gene expression. PMID:24443176

Genomic organization and identification of promoter regions for the BDNF gene in the pond turtle Trachemys scripta elegans.

PubMed

Ambigapathy, Ganesh; Zheng, Zhaoqing; Keifer, Joyce

2014-08-01

Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal development and synaptic function. The BDNF gene undergoes significant activity-dependent regulation during learning. Here, we identified the BDNF promoter regions, transcription start sites, and potential regulatory sequences for BDNF exons I-III that may contribute to activity-dependent gene and protein expression in the pond turtle Trachemys scripta elegans (tBDNF). By using transfection of BDNF promoter/luciferase plasmid constructs into human neuroblastoma SHSY5Y cells and mouse embryonic fibroblast NIH3T3 cells, we identified the basal regulatory activity of promoter sequences located upstream of each tBDNF exon, designated as pBDNFI-III. Further, through chromatin immunoprecipitation (ChIP) assays, we detected CREB binding directly to exon I and exon III promoters, while BHLHB2, but not CREB, binds within the exon II promoter. Elucidation of the promoter regions and regulatory protein binding sites in the tBDNF gene is essential for understanding the regulatory mechanisms that control tBDNF gene expression.

Spatiotemporal transcriptome provides insights into early fruit development of tomato (Solanum lycopersicum).

PubMed

Zhang, Shuaibin; Xu, Meng; Qiu, Zhengkun; Wang, Ketao; Du, Yongchen; Gu, Lianfeng; Cui, Xia

2016-03-18

Early fruit development is crucial for crop production in tomato. After fertilization, the ovary undergoes cell division and cell expansion before maturation. Although the roles of regulatory signals such as hormone and carbohydrate during early fruit development have been studied, the spatial distribution and the sequential initiation of these regulatory signals still need to be explored. Using the tomato cultivar 'Moneymaker', we analyzed the transcriptome of the ovule and the ovary wall/pericarp dissected from four different stages of the early developing fruits by stereoscope. These datasets give us the whole picture about the spatial and temporal signal distribution in early development of ovule and pericarp. Our results indicate that the hormone signal was initiated in both ovule and pericarp after fertilization. After that, different signals were activated in ovule and pericarp due to their distinct developmental processes. Our study provides spatiotemporal regulatory landscape of gene expression with sequential information which was not studied by previous work and further strengthens the comprehension of the regulatory and metabolic events controlling early fruit development.

HIPAA's Individual Right of Access to Genomic Data: Reconciling Safety and Civil Rights.

PubMed

Evans, Barbara J

2018-01-04

In 2014, the United States granted individuals a right of access to their own laboratory test results, including genomic data. Many observers feel that this right is in tension with regulatory and bioethical standards designed to protect the safety of people who undergo genomic testing. This commentary attributes this tension to growing pains within an expanding federal regulatory program for genetic and genomic testing. The Genetic Information Nondiscrimination Act of 2008 expanded the regulatory agenda to encompass civil rights and consumer safety. The individual access right, as it applies to genomic data, is best understood as a civil-rights regulation. Competing regulatory objectives-safety and civil rights-were not successfully integrated during the initial rollout of genomic civil-rights regulations after 2008. Federal law clarifies how to prioritize safety and civil rights when the two come into conflict, although with careful policy design, the two need not collide. This commentary opens a dialog about possible solutions to advance safety and civil rights together. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

77 FR 7663 - Introduction to the Unified Agenda of Federal Regulatory and Deregulatory Actions

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-13

...The Regulatory Flexibility Act requires that agencies publish semiannual regulatory agendas in the Federal Register describing regulatory actions they are developing that may have a significant economic impact on a substantial number of small entities (5 U.S.C. 602). Executive Order 12866 ``Regulatory Planning and Review,'' signed September 30, 1993 (58 FR 51735), and Office of Management and Budget memoranda implementing section 4 of that Order establish minimum standards for agencies' agendas, including specific types of information for each entry. The Unified Agenda of Federal Regulatory and Deregulatory Actions (Unified Agenda) helps agencies fulfill these requirements. All Federal regulatory agencies have chosen to publish their regulatory agendas as part of the Unified Agenda. Editions of the Unified Agenda prior to fall 2007 were printed in their entirety in the Federal Register. Beginning with the fall 2007 edition, the Internet is the basic means for conveying regulatory agenda information to the maximum extent legally permissible. The complete Unified Agenda for fall 2011, which contains the regulatory agendas for 59 Federal agencies, is available to the public at http:// reginfo.gov. The fall 2011 Unified Agenda publication appearing in the Federal Register consists of agency regulatory flexibility agendas, in accordance with the publication requirements of the Regulatory Flexibility Act. Agency regulatory flexibility agendas contain only those Agenda entries for rules that are likely to have a significant economic impact on a substantial number of small entities and entries that have been selected for periodic review under section 610 of the Regulatory Flexibility Act.

The Saudi Arabia Food and Drug Authority: An Evaluation of the Registration Process and Good Review Practices in Saudi Arabia in Comparison with Australia, Canada and Singapore.

PubMed

Hashan, Hajed; Aljuffali, Ibrahim; Patel, Prisha; Walker, Stuart

This study compares the current regulatory review process and good review practices at the Saudi Food and Drug Authority (SFDA) with those of regulatory agencies in Australia, Canada, and Singapore and identifies opportunities for developing the SFDA as a Regional Centre of Excellence. A questionnaire completed by the SFDA included data regarding the organisation, key milestones, review timelines, and good review practices of the agency. Similar information was obtained within the same timeframe (2014/2015) through the same standard questionnaire regarding the processes and practices for Health Canada, Singapore's Health Sciences Authority, and Australia's Therapeutic Goods Administration. All four regulatory agencies have established target times for scientific assessment and regulatory review, examine dossier sections in parallel, and separate company response time from overall timing. Additionally, all four agencies have instituted good review practices including standard operating procedures, templates, dossier monitoring, and continuous improvement processes, and assign a high priority to transparency in their relationships with the public, healthcare professionals and industry. Of the four agencies, however, only the SFDA requires a Certificate of Pharmaceutical Product (CPP) at the time of the submission and pricing negotiations before final product approval. To assist the SFDA in its efforts to become a Regional Centre of Excellence, it is suggested that the agency explore a risk stratification approach to select dossiers for verification, abridged, or full reviews; use forms of certification other than the CPP; make pricing negotiations independent to the review process; and introduce a feedback process for the quality of the dossier.

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.

78 FR 26090 - Content Specifications and Shielding Evaluations for Type B Transportation Packages

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-03

...The U.S. Nuclear Regulatory Commission (NRC) is issuing Regulatory Issue Summary (RIS) 2013-04, ``Content Specifications and Shielding Evaluations for Type B Transportation Packages.'' This RIS clarifies the NRC's use of staff guidance in NUREG-1609, ``Standard Review Plan for Transport Packages for Radioactive Material,'' for the review of content specifications and shielding evaluations included in the Certificates of Compliance (CoC) and safety analysis reports (SARs) for Type B transportation packages. The RIS does not impose any additional regulatory requirements on NRC licensees.

17 CFR 37.1501 - Chief compliance officer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... facility's self-regulatory program that is requested by the board of directors or the regulatory oversight... compliance office review, look-back, internal or external audit finding, self-reported error, or validated...) Supervising the swap execution facility's self-regulatory program with respect to trade practice surveillance...

Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-related liver fibrosis.

PubMed

Li, Xiaoyan; Su, Yujie; Hua, Xuefeng; Xie, Chan; Liu, Jing; Huang, Yuehua; Zhou, Liang; Zhang, Min; Li, Xu; Gao, Zhiliang

2017-04-11

Liver fibrosis which mainly occurs upon chronic hepatitis virus infection potentially leads to portal hypertension, hepatic failure and hepatocellular carcinoma. However, the immune status of Th17 and Treg cells in liver fibrosis is controversial and the exact mechanisms remain largely elusive. Liver tissues and peripheral blood were obtained simultaneously from 32 hepatitis B virus infected patients undergoing surgery for hepatocellular carcinoma at the medical center of Sun Yat-sen University. Liver tissues at least 3 cm away from the tumor site were used for the analyses. Levels of Th17 cells and regulatory T cells were detected by flow cytometry analysis and immunohistochemistry. In vitro experiment, we adopted magnetic cell sorting to investigate how hepatic stellate cells regulate the levels of Th17 cells and regulatory T cells. We found that hepatic Th17 cells and regulatory T cells were increased in patients with advanced stage HBV-related liver fibrosis. Hepatic stellate cells upregulated the levels of Th17 cells and regulatory T cells via PGE2/EP2 and EP4 pathway. We found that the increased levels of Th17 cells and regulatory T cells were upregulated by hepatic stellate cells. These results may provide insight into the role of hepatic stellate cells and Th17 cells and regulatory T cells in the persistence of fibrosis and into the occurrence of hepatocellular carcinoma following cirrhosis.

76 FR 15323 - Determination of Regulatory Review Period for Purposes of Patent Extension; ATRYN

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-21

... regulatory review period for ATRYN and is publishing this notice of that determination as required by law. FDA has made the determination because of the submission of an application to the Director of Patents... of extension that the Director of Patents and Trademarks may award (for example, half the testing...

77 FR 26017 - Determination of Regulatory Review Period for Purposes of Patent Extension; KALBITOR

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-02

... Administration (FDA) has determined the regulatory review period for KALBITOR and is publishing this notice of... applications to the Director of Patents and Trademarks, Department of Commerce, for the extension of a patent... actual amount of extension that the Director of Patents and Trademarks may award (for example, half the...

75 FR 75678 - Determination of Regulatory Review Period for Purposes of Patent Extension; STELARA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-06

... Administration (FDA) has determined the regulatory review period for STELARA and is publishing this notice of... application to the Director of Patents and Trademarks, Department of Commerce, for the extension of a patent... toward the actual amount of extension that the Director of Patents and Trademarks may award (for example...

75 FR 54887 - Determination of Regulatory Review Period for Purposes of Patent Extension; REPEL-CV

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

... regulatory review period for REPEL-CV and is publishing this notice of that determination as required by law. FDA has made the determination because of the submission of an application to the Director of Patents... extension that the Director of Patents and Trademarks may award (half the testing phase must be subtracted...

75 FR 76739 - Determination of Regulatory Review Period for Purposes of Patent Extension; ILARIS

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-09

... regulatory review period for ILARIS and is publishing this notice of that determination as required by law. FDA has made the determination because of the submission of an application to the Director of Patents... of extension that the Director of Patents and Trademarks may award (for example, half the testing...

75 FR 54152 - Determination of Regulatory Review Period for Purposes of Patent Extension; NEURX DIAPHRAGM...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-03

... determined the regulatory review period for NEURX DIAPHRAGM PACING SYSTEM and is publishing this notice of... application to the Director of Patents and Trademarks, Department of Commerce, for the extension of a patent... toward the actual amount of extension that the Director of Patents and Trademarks may award (half the...

78 FR 12330 - Determination of Regulatory Review Period for Purposes of Patent Extension; SAPIEN TRANSCATHETER...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-22

...) and the Generic Animal Drug and Patent Term Restoration Act (Pub. L. 100-670) generally provide that a..., animal drug product, medical device, food additive, or color additive) was subject to regulatory review... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-E-0196...

77 FR 20830 - Determination of Regulatory Review Period for Purposes of Patent Extension; VIIBRYD

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-06

...) and the Generic Animal Drug and Patent Term Restoration Act (Pub. L. 100-670) generally provide that a..., animal drug product, medical device, food additive, or color additive) was subject to regulatory review... consists of two periods of time: A testing phase and an approval phase. For human drug products, the...

Health Risks and Adverse Reactions to Functional Foods.

PubMed

Ameratunga, Rohan; Crooks, Christine; Simmons, Greg; Woon, See-Tarn

2016-01-01

Functional foods have become increasingly popular with consumers anxious to mitigate the effects of an unhealthy lifestyle or aging. In spite of attractive health claims, these products do not have legal or regulatory status in most countries and are regulated through their health claims. Regulation of functional foods by health claims does not address health risks and adverse effects of these products. In this essay regulatory aspects of functional foods are reviewed along with adverse effects published in the peer-reviewed literature. We detail why the lack of an internationally accepted definition of functional foods places consumers at risk of adverse outcomes. Our review will assist regulatory agencies, manufacturers and consumer groups to assess the benefits and reduce the risks associated with these products.

Regulatory challenges in the review of data from global clinical trials: the PMDA perspective.

PubMed

Asano, K; Tanaka, A; Sato, T; Uyama, Y

2013-08-01

Regulatory agencies face challenges in reviewing data from global clinical trials (GCTs) in the era of globalization of drug development. One major challenge is consideration of ethnic factors in evaluating GCT data so as to extrapolate foreign population data to one's own national population. Here, we present the Pharmaceuticals and Medical Devices Agency (PMDA) perspective in reviewing GCT data in new drug applications (NDAs) and discuss future challenges for new drug approval.

Self-regulatory fatigue in hematologic malignancies: impact on quality of life, coping, and adherence to medical recommendations.

PubMed

Solberg Nes, Lise; Ehlers, Shawna L; Patten, Christi A; Gastineau, Dennis A

2013-03-01

Hematopoietic stem cell transplantation (HSCT) is an intensive cancer therapy entailing numerous physical, emotional, cognitive, and practical challenges. Patients' ability to adjust and cope with such challenges may depend on their ability to exert control over cognitive, emotional, and behavioral processes, that is, ability to self-regulate. Self-regulatory capacity is a limited resource that can be depleted or fatigued (i.e., "self-regulatory fatigue"), particularly in the context of stressful life events such as cancer diagnosis and treatment. This is one of the first studies to examine self-regulatory fatigue in a cancer population. The current study aimed to (1) extract items for a specific scale of self-regulatory capacity and (2) examine the impact of such capacity on adaptation in patients with hematologic malignancies preparing for HSCT. Factor analysis of four existing scales gauging psychological adjustment and well-being in 314 patients preparing for HSCT (63% male and 89% Caucasian) identified 23 items (α = 0.85) related to self-regulatory control or fatigue. This measure was then examined using existing clinical data obtained from 178 patients (57% male and 91% Caucasian) undergoing treatment for hematologic malignancies in relationship to quality of life, coping, and self-reported adherence to physicians' recommendations. Controlling for pain severity, physical fatigue, and depression, self-regulatory fatigue scores were incrementally associated with decreased quality of life, use of avoidance coping strategies, and decreased adherence to physicians' recommendations. These results emphasize the potential role of self-regulatory capacity in coping with and adjusting to hematologic cancers and future research is warranted.

Stem cell regulatory gene expression in human adult dental pulp and periodontal ligament cells undergoing odontogenic/osteogenic differentiation.

PubMed

Liu, Lu; Ling, Junqi; Wei, Xi; Wu, Liping; Xiao, Yin

2009-10-01

During development and regeneration, odontogenesis and osteogenesis are initiated by a cascade of signals driven by several master regulatory genes. In this study, we investigated the differential expression of 84 stem cell-related genes in dental pulp cells (DPCs) and periodontal ligament cells (PDLCs) undergoing odontogenic/osteogenic differentiation. Our results showed that, although there was considerable overlap, certain genes had more differential expression in PDLCs than in DPCs. CCND2, DLL1, and MME were the major upregulated genes in both PDLCs and DPCs, whereas KRT15 was the only gene significantly downregulated in PDLCs and DPCs in both odontogenic and osteogenic differentiation. Interestingly, a large number of regulatory genes in odontogenic and osteogenic differentiation interact or crosstalk via Notch, Wnt, transforming growth factor beta (TGF-beta)/bone morphogenic protein (BMP), and cadherin signaling pathways, such as the regulation of APC, DLL1, CCND2, BMP2, and CDH1. Using a rat dental pulp and periodontal defect model, the expression and distribution of both BMP2 and CDH1 have been verified for their spatial localization in dental pulp and periodontal tissue regeneration. This study has generated an overview of stem cell-related gene expression in DPCs and PDLCs during odontogenic/osteogenic differentiation and revealed that these genes may interact through the Notch, Wnt, TGF-beta/BMP, and cadherin signaling pathways to play a crucial role in determining the fate of dental derived cell and dental tissue regeneration. These findings provided a new insight into the molecular mechanisms of the dental tissue mineralization and regeneration.

Measuring the impact of medicines regulatory interventions – Systematic review and methodological considerations

PubMed Central

Morales, Daniel R.; Pacurariu, Alexandra; Kurz, Xavier

2017-01-01

Aims Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. Methods We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non‐European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. Results From 1246 screened articles, 229 were eligible for full‐text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill‐over effects were rarely evaluated. Two‐thirds used before–after time series and 15.7% before–after cross‐sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). Conclusion Whilst impact evaluation of pharmacovigilance and product‐specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs. PMID:29105853

Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium.

PubMed

Allison, Gretchen; Cain, Yanxi Tan; Cooney, Charles; Garcia, Tom; Bizjak, Tara Gooen; Holte, Oyvind; Jagota, Nirdosh; Komas, Bekki; Korakianiti, Evdokia; Kourti, Dora; Madurawe, Rapti; Morefield, Elaine; Montgomery, Frank; Nasr, Moheb; Randolph, William; Robert, Jean-Louis; Rudd, Dave; Zezza, Diane

2015-03-01

This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Disentangling the many layers of eukaryotic transcriptional regulation.

PubMed

Lelli, Katherine M; Slattery, Matthew; Mann, Richard S

2012-01-01

Regulation of gene expression in eukaryotes is an extremely complex process. In this review, we break down several critical steps, emphasizing new data and techniques that have expanded current gene regulatory models. We begin at the level of DNA sequence where cis-regulatory modules (CRMs) provide important regulatory information in the form of transcription factor (TF) binding sites. In this respect, CRMs function as instructional platforms for the assembly of gene regulatory complexes. We discuss multiple mechanisms controlling complex assembly, including cooperative DNA binding, combinatorial codes, and CRM architecture. The second section of this review places CRM assembly in the context of nucleosomes and condensed chromatin. We discuss how DNA accessibility and histone modifications contribute to TF function. Lastly, new advances in chromosomal mapping techniques have provided increased understanding of intra- and interchromosomal interactions. We discuss how these topological maps influence gene regulatory models.

Regulatory Flexibility: An Individual Differences Perspective on Coping and Emotion Regulation.

PubMed

Bonanno, George A; Burton, Charles L

2013-11-01

People respond to stressful events in different ways, depending on the event and on the regulatory strategies they choose. Coping and emotion regulation theorists have proposed dynamic models in which these two factors, the person and the situation, interact over time to inform adaptation. In practice, however, researchers have tended to assume that particular regulatory strategies are consistently beneficial or maladaptive. We label this assumption the fallacy of uniform efficacy and contrast it with findings from a number of related literatures that have suggested the emergence of a broader but as yet poorly defined construct that we refer to as regulatory flexibility. In this review, we articulate this broader construct and define both its features and limitations. Specifically, we propose a heuristic individual differences framework and review research on three sequential components of flexibility for which propensities and abilities vary: sensitivity to context, availability of a diverse repertoire of regulatory strategies, and responsiveness to feedback. We consider the methodological limitations of research on each component, review questions that future research on flexibility might address, and consider how the components might relate to each other and to broader conceptualizations about stability and change across persons and situations. © The Author(s) 2013.

18 CFR 131.31 - FERC Form No. 561, Annual report of interlocking positions.

Code of Federal Regulations, 2013 CFR

2013-04-01

... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY APPROVED FORMS, FEDERAL POWER ACT AND PUBLIC UTILITY REGULATORY POLICIES ACT OF 1978 FORMS § 131.31 FERC Form No. 561, Annual report of interlocking... the Federal Energy Regulatory Commission's staff for the review and oversight of interlocking...

18 CFR 131.31 - FERC Form No. 561, Annual report of interlocking positions.

Code of Federal Regulations, 2012 CFR

2012-04-01

... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY APPROVED FORMS, FEDERAL POWER ACT AND PUBLIC UTILITY REGULATORY POLICIES ACT OF 1978 FORMS § 131.31 FERC Form No. 561, Annual report of interlocking... the Federal Energy Regulatory Commission's staff for the review and oversight of interlocking...

18 CFR 131.31 - FERC Form No. 561, Annual report of interlocking positions.

Code of Federal Regulations, 2014 CFR

2014-04-01

... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY APPROVED FORMS, FEDERAL POWER ACT AND PUBLIC UTILITY REGULATORY POLICIES ACT OF 1978 FORMS § 131.31 FERC Form No. 561, Annual report of interlocking... the Federal Energy Regulatory Commission's staff for the review and oversight of interlocking...

18 CFR 131.31 - FERC Form No. 561, Annual report of interlocking positions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY APPROVED FORMS, FEDERAL POWER ACT AND PUBLIC UTILITY REGULATORY POLICIES ACT OF 1978 FORMS § 131.31 FERC Form No. 561, Annual report of interlocking... the Federal Energy Regulatory Commission's staff for the review and oversight of interlocking...

17 CFR 201.460 - Record before the Commission.

Code of Federal Regulations, 2010 CFR

2010-04-01

... determination by a self-regulatory organization, the record shall consist of: (i) All items part of the record... for final decision before the Commission reviewing a determination by a self-regulatory organization, the record shall consist of: (i) The record certified pursuant to § 201.420(d) by the self-regulatory...

21 CFR 601.14 - Regulatory submissions in electronic format.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Regulatory submissions in electronic format. 601... SERVICES (CONTINUED) BIOLOGICS LICENSING Biologics Licensing § 601.14 Regulatory submissions in electronic format. (a) General. Electronic format submissions must be in a form that FDA can process, review, and...

21 CFR 601.14 - Regulatory submissions in electronic format.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Regulatory submissions in electronic format. 601... SERVICES (CONTINUED) BIOLOGICS LICENSING Biologics Licensing § 601.14 Regulatory submissions in electronic format. (a) General. Electronic format submissions must be in a form that FDA can process, review, and...

21 CFR 601.14 - Regulatory submissions in electronic format.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Regulatory submissions in electronic format. 601... SERVICES (CONTINUED) BIOLOGICS LICENSING Biologics Licensing § 601.14 Regulatory submissions in electronic format. (a) General. Electronic format submissions must be in a form that FDA can process, review, and...

75 FR 53908 - Method 16C for the Determination of Total Reduced Sulfur Emissions From Stationary Sources

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-02

...: Regulatory Planning and Review B. Paperwork Reduction Act C. Regulatory Flexibility Act D. Unfunded Mandates... disulfide. As described in Method 16A, the sample is collected from the source through a heated probe and..., October 4, 1993) and is therefore not subject to review under the EO. B. Paperwork Reduction Act This...

77 FR 12086 - Final Staff Guidance, Revision 4 to Standard Review Plan; Section 8.1 on Electric Power-Introduction

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-28

... incorporate Revision 4 of SRP Section 8.1 into the next revisions of the Regulatory Guide 1.206, ``Combined..., 2011 (76 FR 31381), the NRC published for public comment the proposed Revision 4 on Section 8.1 on... NUCLEAR REGULATORY COMMISSION [NRC-2011-0119] Final Staff Guidance, Revision 4 to Standard Review...

75 FR 55332 - Determination of Regulatory Review Period for Purposes of Patent Extension; ULORIC

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-10

... extended for a period of up to 5 years so long as the patented item (human drug product, animal drug... periods of time: A testing phase and an approval phase. For human drug products, the testing phase begins... the length of a regulatory review period for a human drug product will include all of the testing...

75 FR 53315 - Determination of Regulatory Review Period for Purposes of Patent Extension; ONGLYZA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-31

... extended for a period of up to 5 years so long as the patented item (human drug product, animal drug... periods of time: A testing phase and an approval phase. For human drug products, the testing phase begins... the length of a regulatory review period for a human drug product will include all of the testing...

75 FR 54344 - Determination of Regulatory Review Period for Purposes of Patent Extension; EFFIENT

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-07

... extended for a period of up to 5 years so long as the patented item (human drug product, animal drug... periods of time: A testing phase and an approval phase. For human drug products, the testing phase begins... the length of a regulatory review period for a human drug product will include all of the testing...

75 FR 55331 - Determination of Regulatory Review Period for Purposes of Patent Extension; SAPHRIS

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-10

... extended for a period of up to 5 years so long as the patented item (human drug product, animal drug... periods of time: A testing phase and an approval phase. For human drug products, the testing phase begins... the length of a regulatory review period for a human drug product will include all of the testing...

75 FR 19407 - Determination of Regulatory Review Period for Purposes of Patent Extension; SAVELLA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-14

... extended for a period of up to 5 years so long as the patented item (human drug product, animal drug... periods of time: A testing phase and an approval phase. For human drug products, the testing phase begins... the length of a regulatory review period for a human drug product will include all of the testing...

The identification of cis-regulatory elements: A review from a machine learning perspective.

PubMed

Li, Yifeng; Chen, Chih-Yu; Kaye, Alice M; Wasserman, Wyeth W

2015-12-01

The majority of the human genome consists of non-coding regions that have been called junk DNA. However, recent studies have unveiled that these regions contain cis-regulatory elements, such as promoters, enhancers, silencers, insulators, etc. These regulatory elements can play crucial roles in controlling gene expressions in specific cell types, conditions, and developmental stages. Disruption to these regions could contribute to phenotype changes. Precisely identifying regulatory elements is key to deciphering the mechanisms underlying transcriptional regulation. Cis-regulatory events are complex processes that involve chromatin accessibility, transcription factor binding, DNA methylation, histone modifications, and the interactions between them. The development of next-generation sequencing techniques has allowed us to capture these genomic features in depth. Applied analysis of genome sequences for clinical genetics has increased the urgency for detecting these regions. However, the complexity of cis-regulatory events and the deluge of sequencing data require accurate and efficient computational approaches, in particular, machine learning techniques. In this review, we describe machine learning approaches for predicting transcription factor binding sites, enhancers, and promoters, primarily driven by next-generation sequencing data. Data sources are provided in order to facilitate testing of novel methods. The purpose of this review is to attract computational experts and data scientists to advance this field. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Xylogenesis in zinnia (Zinnia elegans) cell cultures: unravelling the regulatory steps in a complex developmental programmed cell death event.

PubMed

Iakimova, Elena T; Woltering, Ernst J

2017-04-01

Physiological and molecular studies support the view that xylogenesis can largely be determined as a specific form of vacuolar programmed cell death (PCD). The studies in xylogenic zinnia cell culture have led to many breakthroughs in xylogenesis research and provided a background for investigations in other experimental models in vitro and in planta . This review discusses the most essential earlier and recent findings on the regulation of xylem elements differentiation and PCD in zinnia and other xylogenic systems. Xylogenesis (the formation of water conducting vascular tissue) is a paradigm of plant developmental PCD. The xylem vessels are composed of fused tracheary elements (TEs)-dead, hollow cells with patterned lignified secondary cell walls. They result from the differentiation of the procambium and cambium cells and undergo cell death to become functional post-mortem. The TE differentiation proceeds through a well-coordinated sequence of events in which differentiation and the programmed cellular demise are intimately connected. For years a classical experimental model for studies on xylogenesis was the xylogenic zinnia (Zinnia elegans) cell culture derived from leaf mesophyll cells that, upon induction by cytokinin and auxin, transdifferentiate into TEs. This cell system has been proven very efficient for investigations on the regulatory components of xylem differentiation which has led to many discoveries on the mechanisms of xylogenesis. The knowledge gained from this system has potentiated studies in other xylogenic cultures in vitro and in planta. The present review summarises the previous and latest findings on the hormonal and biochemical signalling, metabolic pathways and molecular and gene determinants underlying the regulation of xylem vessels differentiation in zinnia cell culture. Highlighted are breakthroughs achieved through the use of xylogenic systems from other species and newly introduced tools and analytical approaches to study the processes. The mutual dependence between PCD signalling and the differentiation cascade in the program of TE development is discussed.

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

EARLY EVALUATION OF NEW HEALTH TECHNOLOGIES: THE CASE FOR PREMARKET STUDIES THAT HARMONIZE REGULATORY AND COVERAGE PERSPECTIVES.

PubMed

Levin, Leslie

2015-01-01

With an increasing awareness that active engagement between policy decision makers, HTA agencies, regulators and payers with industry in the premarket space is needed, a disruptive comprehensive approach is described which moves the evidentiary process exclusively into this space. Single harmonized studies pre-market to address regulatory and coverage needs and expectations are more likely to be efficient and less costly and position evidence to drive rather than test innovation. An example of such a process through the MaRS EXCITE program in Ontario, Canada, now undergoing proof of concept, is briefly discussed. Other examples of dialogue between decision makers and industry pre-market are provided though these are less robust than a comprehensive evidentiary approach.

Resolving the problem of compliance with the ever increasing and changing regulations

NASA Astrophysics Data System (ADS)

Leigh, Harley

1992-01-01

The most common problem identified at several U.S. Department of Energy (DOE) sites is regulatory compliance. Simply, the project viability depends on identifying regulatory requirements at the beginning of a specific project to avoid possible delays and cost overruns. The Radioisotope Power Systems Facility (RPSF) is using the Regulatory Compliance System (RCS) to deal with the problem that well over 1000 regulatory documents had to be reviewed for possible compliance requirements applicable to the facility. This overwhelming number of possible documents is not atypical of all DOE facilities thus far reviewed using the RCS system. The RCS was developed to provide control and tracking of all the regulatory and institutional requirements on a given project. WASTREN, Inc., developed the RCS through various DOE contracts and continues to enhance and update the system for existing and new contracts. The RCS provides the information to allow the technical expert to assimilate and manage accurate resource information, compile the necessary checklists, and document that the project or facility fulfills all of the appropriate regulatory requirements. The RCS provides on-line information, including status throughout the project life, thereby allowing more intelligent and proactive decision making. Also, consistency and traceability are provided for regulatory compliance documentation.

[Regulatory science: modern trends in science and education for pharmaceutical products].

PubMed

Beregovykh, V V; Piatigorskaia, N V; Aladysheva, Zh I

2012-01-01

This article reviews modern trends in development of new instruments, standards and approaches to drugs safety, efficacy and quality assessment in USA and EU that can be called by unique term--"regulatory science" which is a new concept for Russian Federation. New education programs (curricula) developed by USA and EU universities within last 3 years are reviewed. These programs were designed in order to build workforce capable to utilize science approach for drug regulation. The principal mechanisms for financing research in regulatory science used by Food and Drug Administration are analyzed. There are no such science and relevant researches in Russian Federation despite the high demand as well as needs for the system for higher education and life-long learning education of specialists for regulatory affairs (or compliance).

Regulatory and Quality Considerations for Continuous Manufacturing May 20-21, 2014 Continuous Manufacturing Symposium.

PubMed

Allison, Gretchen; Cain, Yanxi Tan; Cooney, Charles; Garcia, Tom; Bizjak, Tara Gooen; Holte, Oyvind; Jagota, Nirdosh; Komas, Bekki; Korakianiti, Evdokia; Kourti, Dora; Madurawe, Rapti; Morefield, Elaine; Montgomery, Frank; Nasr, Moheb; Randolph, William; Robert, Jean-Louis; Rudd, Dave; Zezza, Diane

2015-03-01

This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Translating New Science Into the Drug Review Process

PubMed Central

Rouse, Rodney; Kruhlak, Naomi; Weaver, James; Burkhart, Keith; Patel, Vikram; Strauss, David G.

2017-01-01

In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine. PMID:29568713

47 CFR 76.933 - Franchising authority review of basic cable rates and equipment costs.

Code of Federal Regulations, 2012 CFR

2012-10-01

... the imposition of, or increase in, franchise fees or Commission cable television system regulatory..., the increased rate attributable to Commission regulatory fees or franchise fees shall be treated as an... increase in basic tier rates exceeds the increase in regulatory fees or in franchise fees allocable to the...

47 CFR 76.933 - Franchising authority review of basic cable rates and equipment costs.

Code of Federal Regulations, 2011 CFR

2011-10-01

... the imposition of, or increase in, franchise fees or Commission cable television system regulatory..., the increased rate attributable to Commission regulatory fees or franchise fees shall be treated as an... increase in basic tier rates exceeds the increase in regulatory fees or in franchise fees allocable to the...

47 CFR 76.933 - Franchising authority review of basic cable rates and equipment costs.

Code of Federal Regulations, 2013 CFR

2013-10-01

... the imposition of, or increase in, franchise fees or Commission cable television system regulatory..., the increased rate attributable to Commission regulatory fees or franchise fees shall be treated as an... increase in basic tier rates exceeds the increase in regulatory fees or in franchise fees allocable to the...

47 CFR 76.933 - Franchising authority review of basic cable rates and equipment costs.

Code of Federal Regulations, 2014 CFR

2014-10-01

... the imposition of, or increase in, franchise fees or Commission cable television system regulatory..., the increased rate attributable to Commission regulatory fees or franchise fees shall be treated as an... increase in basic tier rates exceeds the increase in regulatory fees or in franchise fees allocable to the...

76 FR 52715 - Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS Subcommittee on Regulatory...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-23

... review Draft Final Regulatory Guide (RG) 1.93, ``Availability of Electric Power Sources,'' Revision 1 and new Draft Final RG 1.218, ``Condition Monitoring Techniques for Electric Cables Used in Nuclear Power... NUCLEAR REGULATORY COMMISSION Advisory Committee on Reactor Safeguards (ACRS); Meeting of the ACRS...

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...

78 FR 19540 - Memorandum of Understanding Between the U.S. Nuclear Regulatory Commission and the Bureau of Land...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-01

... Regulatory Commission and the Bureau of Land Management AGENCY: Nuclear Regulatory Commission. ACTION: Notice... Review Branch, Division of Waste Management and Environmental Protection, Office of Federal and State... the Bureau of Land Management, United States Department of the Interior (BLM) entered into a...

Measuring the impact of medicines regulatory interventions - Systematic review and methodological considerations.

PubMed

Goedecke, Thomas; Morales, Daniel R; Pacurariu, Alexandra; Kurz, Xavier

2018-03-01

Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research. We searched MEDLINE and EMBASE for articles with an empirical analysis evaluating the impact of European Union or non-European Union regulatory actions to safeguard public health published until March 2017. References from systematic reviews and articles from other known sources were added. Regulatory interventions, data sources, outcomes of interest, methodology and key findings were extracted. From 1246 screened articles, 229 were eligible for full-text review and 153 articles in English language were included in the descriptive analysis. Over a third of articles studied analgesics and antidepressants. Interventions most frequently evaluated are regulatory safety communications (28.8%), black box warnings (23.5%) and direct healthcare professional communications (10.5%); 55% of studies measured changes in drug utilization patterns, 27% evaluated health outcomes, and 18% targeted knowledge, behaviour or changes in clinical practice. Unintended consequences like switching therapies or spill-over effects were rarely evaluated. Two-thirds used before-after time series and 15.7% before-after cross-sectional study designs. Various analytical approaches were applied including interrupted time series regression (31.4%), simple descriptive analysis (28.8%) and descriptive analysis with significance tests (23.5%). Whilst impact evaluation of pharmacovigilance and product-specific regulatory interventions is increasing, the marked heterogeneity in study conduct and reporting highlights the need for scientific guidance to ensure robust methodologies are applied and systematic dissemination of results occurs. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

MicroRNA-mediated regulatory circuits: outlook and perspectives

NASA Astrophysics Data System (ADS)

Cora', Davide; Re, Angela; Caselle, Michele; Bussolino, Federico

2017-08-01

MicroRNAs have been found to be necessary for regulating genes implicated in almost all signaling pathways, and consequently their dysfunction influences many diseases, including cancer. Understanding of the complexity of the microRNA-mediated regulatory network has grown in terms of size, connectivity and dynamics with the development of computational and, more recently, experimental high-throughput approaches for microRNA target identification. Newly developed studies on recurrent microRNA-mediated circuits in regulatory networks, also known as network motifs, have substantially contributed to addressing this complexity, and therefore to helping understand the ways by which microRNAs achieve their regulatory role. This review provides a summarizing view of the state-of-the-art, and perspectives of research efforts on microRNA-mediated regulatory motifs. In this review, we discuss the topological properties characterizing different types of circuits, and the regulatory features theoretically enabled by such properties, with a special emphasis on examples of circuits typifying their biological significance in experimentally validated contexts. Finally, we will consider possible future developments, in particular regarding microRNA-mediated circuits involving long non-coding RNAs and epigenetic regulators.

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

Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications.

PubMed

Chang, Lin-Chau; Mahmood, Riaz; Qureshi, Samina; Breder, Christopher D

2017-01-01

Standardised MedDRA Queries (SMQs) have been developed since the early 2000's and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with "narrow terms" to enhance specificity over strategies using "broad terms" to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process. SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions.

Patterns of use and impact of standardised MedDRA query analyses on the safety evaluation and review of new drug and biologics license applications

PubMed Central

Chang, Lin-Chau; Mahmood, Riaz; Qureshi, Samina

2017-01-01

Purpose Standardised MedDRA Queries (SMQs) have been developed since the early 2000’s and used by academia, industry, public health, and government sectors for detecting safety signals in adverse event safety databases. The purpose of the present study is to characterize how SMQs are used and the impact in safety analyses for New Drug Application (NDA) and Biologics License Application (BLA) submissions to the United States Food and Drug Administration (USFDA). Methods We used the PharmaPendium database to capture SMQ use in Summary Basis of Approvals (SBoAs) of drugs and biologics approved by the USFDA. Characteristics of the drugs and the SMQ use were employed to evaluate the role of SMQ safety analyses in regulatory decisions and the veracity of signals they revealed. Results A comprehensive search of the SBoAs yielded 184 regulatory submissions approved from 2006 to 2015. Search strategies more frequently utilized restrictive searches with “narrow terms” to enhance specificity over strategies using “broad terms” to increase sensitivity, while some involved modification of search terms. A majority (59%) of 1290 searches used descriptive statistics, however inferential statistics were utilized in 35% of them. Commentary from reviewers and supervisory staff suggested that a small, yet notable percentage (18%) of 1290 searches supported regulatory decisions. The searches with regulatory impact were found in 73 submissions (40% of the submissions investigated). Most searches (75% of 227 searches) with regulatory implications described how the searches were confirmed, indicating prudence in the decision-making process. Conclusions SMQs have an increasing role in the presentation and review of safety analysis for NDAs/BLAs and their regulatory reviews. This study suggests that SMQs are best used for screening process, with descriptive statistics, description of SMQ modifications, and systematic verification of cases which is crucial for drawing regulatory conclusions. PMID:28570569

Lessons Learned From The Investigational Device Exemption (IDE) Review of Children's Oncology Group Trial AAML1031

PubMed Central

Meshinchi, Soheil; Hunger, Stephen P.; Aplenc, Richard; Adamson, Peter C.; Jessup, J. Milburn

2012-01-01

The FDA is now exerting its regulatory authority over molecular diagnostics and their assays used for medical-decision making in clinical trials by performing pre-Investigational Device Exemption (IDE) reviews in all phases of clinical trials. This review assesses the analytical performance of the assay for the diagnostic and considers how that performance affects the diagnostic and the patient and their risks and benefits from treatment. This manuscript reviews the process of the first review that was performed on a new Children's Oncology Group (COG) Phase III trial in Acute Myelogenous Leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented. PMID:22422407

Sex differences in regulatory cells in experimental stroke.

PubMed

Seifert, Hilary A; Benedek, Gil; Liang, Jian; Nguyen, Ha; Kent, Gail; Vandenbark, Arthur A; Saugstad, Julie A; Offner, Halina

2017-08-01

Stroke is the leading cause of disability in the United States. Sex differences, including smaller infarcts in females and greater involvement of immune-mediated inflammation in males may affect the efficacy of immune-modulating interventions. To address these differences, we sought to identify distinct stroke-modifying mechanisms in female vs. male mice. The current study demonstrated smaller infarcts and increased levels of regulatory CD19 + CD5 + CD1d hi B10 cells as well as anti-inflammatory CD11b + CD206 + microglia/macrophages in the ipsilateral vs. contralateral hemisphere of female but not male mice undergoing 60min middle cerebral artery occlusion followed by 96h of reperfusion. Moreover, female mice with MCAO had increased total spleen cell numbers but lower B10 levels in spleens. These results elucidate differing sex-dependent regulatory mechanisms that account for diminished stroke severity in females and underscore the need to test immune-modulating therapies for stroke in both males and females. Copyright © 2017 Elsevier Inc. All rights reserved.

Priority review drugs approved by the FDA and the EMA: time for international regulatory harmonization of pharmaceuticals?

PubMed

Alqahtani, Saad; Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Eguale, Tewodros

2015-07-01

The US Food and Drug Administration (FDA) priority review process applies to a drug that is considered a significant improvement over the available alternatives. The European Medicines Agency (EMA) accelerated approval applies to a product that is of major public health interest. This study assessed differences in the characteristics of priority review new molecular entities and new therapeutic biologic products approved by the FDA and the EMA. This study includes regulatory information on drug applications, approvals, indications, and orphan designations of all priority review drugs approved by the FDA and the EMA in the period 1999-2011. Descriptive statistics, t-tests, and chi-squared and Wilcoxon tests were performed. Overall, 100 FDA priority review new molecular entities and new therapeutic biologics were approved by both agencies; 87.0% of the products were first approved by the FDA. The average FDA review time (9.2 ± 8.4 months) was significantly lower than the EMA average review time (14.6 ± 4.0 months) (p < 0.0001). The FDA and the EMA granted orphan designation to 43.0% and 33.0%, respectively, of the applications. There were differences in the administration route (1.0% of all products), dosage (8.0%), strength (23%), posology (51.0%), indications (30.0%), restrictions of use (52.0%), limitations of use (19.0%), and outcomes limitations (28.0%) approved by both regulatory agencies. Significant differences exist in the characteristics of the priority review drugs approved by the FDA and the EMA. Harmonization of the US and European regulatory frameworks may facilitate timely approval of pharmaceutical products. Copyright © 2015 John Wiley & Sons, Ltd.

78 FR 75954 - Self-Regulatory Organizations; Financial Industry Regulatory Authority, Inc.; Notice of Filing of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-13

... Form BR, which is used by firms to register their branch offices with FINRA, the New York Stock... location of books and records that are currently only in Section 6 and make them applicable to all members... review of Form BR. As a result of this review, FINRA is proposing to amend Form BR to (1) eliminate...

Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.

PubMed

Sridhara, Rajeshwari; Johnson, John R; Justice, Robert; Keegan, Patricia; Chakravarty, Aloka; Pazdur, Richard

2010-02-24

The Office of Oncology Drug Products (OODP) in the Center for Drug Evaluation and Research at the US Food and Drug Administration began reviewing marketing applications for oncological and hematologic indications in July 2005. We conducted an overview of products that were reviewed by the OODP for marketing approval and the regulatory actions taken during July 2005 to December 2007. We identified all applications that were reviewed by the OODP from July 1, 2005, through December 31, 2007, and reviewed the actions that OODP took. We also sought the basis for the actions taken, including the clinical trial design, endpoints used, patient accrual in the trial(s) supporting approval, and the type of regulatory approval. During the study period, the OODP reviewed marketing applications for 60 new indications and took regulatory action on 58 indications. Regulatory action was based on a risk-benefit evaluation of the data submitted with each application. Products that demonstrated efficacy and had an acceptable risk-benefit ratio were granted either regular or accelerated marketing approval for use in the specific indication that was studied. Regular approval was based on endpoints that demonstrated that the drug provided clinical benefit as evidenced by a longer or better life or a favorable effect on an established surrogate for a longer or better life. Accelerated approval was based on a less well-established surrogate endpoint that was reasonably likely to predict a longer or better life. Of the 53 new indications that were approved during the study period, 39 received regular approval, nine received accelerated approval, and five were converted from accelerated to regular approval. Five applications were not approved, and two applications were withdrawn before any regulatory action was taken. Eighteen of the 53 indications that were approved were for new molecular entities. During the study period, regulatory action was taken on 58 of the 60 marketing applications. Fifty-three applications were approved. A variety of clinical trial endpoints were used in the approval trials.

Development and implementation of clinical trial protocol templates at the National Institute of Allergy and Infectious Diseases.

PubMed

Bridge, Heather; Smolskis, Mary; Bianchine, Peter; Dixon, Dennis O; Kelly, Grace; Herpin, Betsey; Tavel, Jorge

2009-08-01

A clinical research protocol document must reflect both sound scientific rationale as well as local, national and, when applicable, international regulatory and human subject protections requirements. These requirements originate from a variety of sources, undergo frequent revision and are subject to interpretation. Tools to assist clinical investigators in the production of clinical protocols could facilitate navigating these requirements and ultimately increase the efficiency of clinical research. The National Institute of Allergy and Infectious Diseases (NIAID) developed templates for investigators to serve as the foundation for protocol development. These protocol templates are designed as tools to support investigators in developing clinical protocols. NIAID established a series of working groups to determine how to improve its capacity to conduct clinical research more efficiently and effectively. The Protocol Template Working Group was convened to determine what protocol templates currently existed within NIAID and whether standard NIAID protocol templates should be produced. After review and assessment of existing protocol documents and requirements, the group reached consensus about required and optional content, determined the format and identified methods for distribution as well as education of investigators in the use of these templates. The templates were approved by the NIAID Executive Committee in 2006 and posted as part of the NIAID Clinical Research Toolkit [1] website for broad access. These documents require scheduled revisions to stay current with regulatory and policy changes. The structure of any clinical protocol template, whether comprehensive or specific to a particular study phase, setting or design, affects how it is used by investigators. Each structure presents its own set of advantages and disadvantages. While useful, protocol templates are not stand-alone tools for creating an optimal protocol document, but must be complemented by institutional resources and support. Education and guidance of investigators in the appropriate use of templates is necessary to ensure a complete yet concise protocol document. Due to changing regulatory requirements, clinical protocol templates cannot become static, but require frequent revisions.

NRC antitrust licensing actions, 1978--1996

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

Mayer, S.J.; Simpson, J.J.

NUREG-0447, Antitrust Review of Nuclear Power Plants, was published in May 1978 and includes a compilation and discussion of U.S. Nuclear Regulatory Commission (NRC) proceedings and activity involving the NRC`s competitive review program through February 1978, NUREG-0447 is an update of an earlier discussion of the NRC`s antitrust review of nuclear power plants, NR-AIG-001, The US Nuclear Regulatory Commission`s Antitrust Review of Nuclear Power Plants: The Conditioning of Licenses, which reviewed the Commission`s antitrust review function from its inception in December 1970 through April 1976. This report summarizes the support provided to NRC staff in updating the compilation of themore » NRC`s antitrust licensing review activities for commercial nuclear power plants that have occurred since February 1978. 4 refs., 4 tabs.« less

Regulatory RNA Key Player in p53-Mediated Apoptosis in Embryonic Stem Cells | Center for Cancer Research

Cancer.gov

Embryonic stem cells (ESCs) must maintain the integrity of their genomes or risk passing potentially deleterious mutations on to numerous tissues. Thus, ESCs have a unique genome surveillance system and easily undergo apoptosis or differentiation when DNA damage is detected. The protein p53 is known to promote differentiation in mouse ESCs (mESCs), but its role in DNA

77 FR 36907 - Establishment of Restricted Areas R-5402, R-5403A, R-5403B, R-5403C, R-5403D, R-5403E, and R...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

...;Prices of new books are listed in the first FEDERAL REGISTER issue of each #0;week. #0; #0; #0; #0;#0... Analyses Changes to Federal regulations must undergo several economic analyses. First, Executive Order..., the Regulatory Flexibility Act of 1980 (Pub. L. 96-354) requires agencies to analyze the economic...

The Role of T Lymphocytes in Cancer Patients Undergoing Immunotherapy with Autologous Dendritic Cells

PubMed Central

Rodrigues, Cláudia M.; Matias, Bruna F.; Murta, Eddie F.C.; Michelin, Márcia A.

2011-01-01

Introduction: Cancer stems from mutations in specific genes that induce uncontrolled cell proliferation. Dendritic cells (DCs) are important immunologic cells and play a crucial role in the induction of an antitumour response. Patients and methods: We examined the immune response mediated by T lymphocytes, helper T cells, cytotoxic T cells, and regulatory T cells, as well as the cytokines [interleukin (IL)-2, IL-12, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-10], produced by these cell populations, in cancer patients (N = 7) undergoing immunotheraphy with autologous DCs. Results: We observed an initial increase in T helper cells (CD4+) expressing IL-2, IFN-γ, IL-12, TNF-α, and IL-10 after initiation of treatment, with statistically significant for the cytokines IL-2, TNF-α and IL-10. A similar significant effect was observed for IL-2-expressing cytotoxic T cells (CD8+). The percentage of total T cells (CD3+) remained elevated throughout immunotherapy. Regulatory T cells (CD25+/FOXP3+) only showed high percentage of their maximum value when analyzed the pretreatment levels, with statistically significant. Conclusion: Immunotherapy with DCs stimulated the immune response, as evidenced by an increase in percent fluorescence of most cell populations investigated during the specified treatment period. PMID:21603246

Peritonitis due to Curvularia inaequalis in an elderly patient undergoing peritoneal dialysis and a review of six cases of peritonitis associated with other Curvularia spp.

PubMed

Pimentel, Jason D; Mahadevan, Kumar; Woodgyer, Alan; Sigler, Lynne; Gibas, Connie; Harris, Owen C; Lupino, Michael; Athan, Eugene

2005-08-01

Fungal peritonitis due to Curvularia species in patients undergoing peritoneal dialysis is a very rare problem. We report a case of peritonitis caused by Curvularia inaequalis. This is the first report in the English literature of this species causing human infection. We also review the six previously reported cases of continuous ambulatory peritoneal dialysis peritonitis caused by other Curvularia species.

The chemical foundations of nitroalkene fatty acid signaling through addition reactions with thiols.

PubMed

Turell, Lucía; Steglich, Martina; Alvarez, Beatriz

2018-03-22

Nitroalkene fatty acids can be formed in vivo and administered exogenously. They exert pleiotropic signaling actions with cytoprotective and antiinflammatory effects. The presence of the potent electron withdrawing nitro group confers electrophilicity to the adjacent β-carbon. Thiols (precisely, thiolates) are strong nucleophiles and can react with nitroalkene fatty acids through reversible Michael addition reactions. In addition, nitroalkene fatty acids can undergo several other processes including metabolic oxidation, reduction, esterification, nitric oxide release and partition into hydrophobic compartments. The signaling actions of nitroalkenes are mainly mediated by reactions with critical thiols in regulatory proteins. Thus, the thio-Michael addition reaction provides a framework for understanding the molecular basis of the biological effects of nitroalkene fatty acids at the crossroads of thiol signaling and electrophilic lipid signaling. In this review, we describe the reactions of nitroalkene fatty acids in biological contexts. We focus on the Michael addition-elimination reaction with thiols and its mechanism, and extrapolate kinetic and thermodynamic considerations to in vivo settings. Copyright © 2018 Elsevier Inc. All rights reserved.

Outcomes from a postgraduate biomedical technology innovation training program: the first 12 years of Stanford Biodesign.

PubMed

Brinton, Todd J; Kurihara, Christine Q; Camarillo, David B; Pietzsch, Jan B; Gorodsky, Julian; Zenios, Stefanos A; Doshi, Rajiv; Shen, Christopher; Kumar, Uday N; Mairal, Anurag; Watkins, Jay; Popp, Richard L; Wang, Paul J; Makower, Josh; Krummel, Thomas M; Yock, Paul G

2013-09-01

The Stanford Biodesign Program began in 2001 with a mission of helping to train leaders in biomedical technology innovation. A key feature of the program is a full-time postgraduate fellowship where multidisciplinary teams undergo a process of sourcing clinical needs, inventing solutions and planning for implementation of a business strategy. The program places a priority on needs identification, a formal process of selecting, researching and characterizing needs before beginning the process of inventing. Fellows and students from the program have gone on to careers that emphasize technology innovation across industry and academia. Biodesign trainees have started 26 companies within the program that have raised over $200 million and led to the creation of over 500 new jobs. More importantly, although most of these technologies are still at a very early stage, several projects have received regulatory approval and so far more than 150,000 patients have been treated by technologies invented by our trainees. This paper reviews the initial outcomes of the program and discusses lessons learned and future directions in terms of training priorities.

Attacking Cancer’s Achilles Heel: Antagonism of Anti-Apoptotic BCL-2 Family Members

PubMed Central

Opferman, Joseph T.

2015-01-01

Malignant cells routinely violate cellular checkpoints that should initiate cell death in normal cells by triggering pro-apoptotic members of the BCL-2 family of proteins. To escape such death inducing signals, cancer cells often select for up regulation of anti-apoptotic BCL-2 family members including BCL-2, BCL-XL, BFL-1, BCL-W, and MCL-1. These family members prevent death by sequestering pro-apoptotic molecules. To counter this resistance mechanism, small molecule inhibitors of anti-apoptotic BCL-2 family members have been under development. These molecules have shown promise in pre-clinical and clinical testing to overcome apoptotic resistance, prompting cancer cells to undergo apoptosis. Alternatively, other strategies have taken advantage of the normal regulatory machinery controlling anti-apoptotic molecules and have used inhibitors of signaling pathways to down-modulate the expression of anti-apoptotic molecules thus tilting the balance in cancer cells to cell death. This review explores recent developments and strategies aimed at antagonizing anti-apoptotic BCL-2 family member action to promote the induction of cell death in cancer therapy. PMID:26293580

Nma111p, the pro-apoptotic HtrA-like nuclear serine protease in Saccharomyces cerevisiae: a short survey.

PubMed

Fahrenkrog, Birthe

2011-10-01

The baker's yeast, Saccharomyces cerevisiae, is also capable of undergoing programmed cell death or apoptosis, for example in response to viral infection as well as during chronological and replicative aging. Intrinsically, programmed cell death in yeast can be induced by, for example, H2O2, acetic acid or the mating-type pheromone. A number of evolutionarily conserved apoptosis-regulatory proteins have been identified in yeast, one of which is the HtrA (high-temperature requirement A)-like serine protease Nma111p (Nma is nuclear mediator of apoptosis). Nma111p is a nuclear serine protease of the HtrA family, which targets Bir1p, the only known inhibitor-of-apoptosis protein in yeast. Nma111p mediates apoptosis in a serine-protease-dependent manner and exhibits its activity exclusively in the nucleus. How the activity of Nma111p is regulated has remained largely elusive, but some evidence points to a control by phosphorylation. Current knowledge of Nma111p's function in apoptosis will be discussed in the present review.

The function of the Mediator complex in plant immunity.

PubMed

An, Chuanfu; Mou, Zhonglin

2013-03-01

Upon pathogen infection, plants undergo dramatic transcriptome reprogramming to shift from normal growth and development to immune response. During this rapid process, the multiprotein Mediator complex has been recognized as an important player to fine-tune gene-specific and pathway-specific transcriptional reprogramming by acting as an adaptor/coregulator between sequence-specific transcription factor and RNA polymerase II (RNAPII). Here, we review current understanding of the role of five functionally characterized Mediator subunits (MED8, MED15, MED16, MED21 and MED25) in plant immunity. All these Mediator subunits positively regulate resistance against leaf-infecting biotrophic bacteria or necrotrophic fungi. While MED21 appears to regulate defense against fungal pathogens via relaying signals from upstream regulators and chromatin modification to RNAPII, the other four Mediator subunits locate at different positions of the defense network to convey phytohormone signal(s). Fully understanding the role of Mediator in plant immunity needs to characterize more Mediator subunits in both Arabidopsis and other plant species. Identification of interacting proteins of Mediator subunits will further help to reveal their specific regulatory mechanisms in plant immunity.

Mechano-biological Coupling of Cellular Responses to Microgravity

NASA Astrophysics Data System (ADS)

Long, Mian; Wang, Yuren; Zheng, Huiqiong; Shang, Peng; Duan, Enkui; Lü, Dongyuan

2015-11-01

Cellular response to microgravity is a basic issue in space biological sciences as well as space physiology and medicine. It is crucial to elucidate the mechano-biological coupling mechanisms of various biological organisms, since, from the principle of adaptability, all species evolved on the earth must possess the structure and function that adapts their living environment. As a basic element of an organism, a cell usually undergoes mechanical and chemical remodeling to sense, transmit, transduce, and respond to the alteration of gravitational signals. In the past decades, new computational platforms and experimental methods/techniques/devices are developed to mimic the biological effects of microgravity environment from the viewpoint of biomechanical approaches. Mechanobiology of plant gravisensing in the responses of statolith movements along the gravity vector and the relevant signal transduction and molecular regulatory mechanisms are investigated at gene, transcription, and protein levels. Mechanotransduction of bone or immune cell responses and stem cell development and tissue histogenesis are elucidated under microgravity. In this review, several important issues are briefly discussed. Future issues on gravisensing and mechanotransducing mechanisms are also proposed for ground-based studies as well as space missions.

The regulatory mechanism of fungal elicitor-induced secondary metabolite biosynthesis in medical plants.

PubMed

Zhai, Xin; Jia, Min; Chen, Ling; Zheng, Cheng-Jian; Rahman, Khalid; Han, Ting; Qin, Lu-Ping

2017-03-01

A wide range of external stress stimuli trigger plant cells to undergo complex network of reactions that ultimately lead to the synthesis and accumulation of secondary metabolites. Accumulation of such metabolites often occurs in plants subjected to stresses including various elicitors or signal molecules. Throughout evolution, endophytic fungi, an important constituent in the environment of medicinal plants, have known to form long-term stable and mutually beneficial symbiosis with medicinal plants. The endophytic fungal elicitor can rapidly and specifically induce the expression of specific genes in medicinal plants which can result in the activation of a series of specific secondary metabolic pathways resulting in the significant accumulation of active ingredients. Here we summarize the progress made on the mechanisms of fungal elicitor including elicitor signal recognition, signal transduction, gene expression and activation of the key enzymes and its application. This review provides guidance on studies which may be conducted to promote the efficient synthesis and accumulation of active ingredients by the endogenous fungal elicitor in medicinal plant cells, and provides new ideas and methods of studying the regulation of secondary metabolism in medicinal plants.

Heart morphogenesis gene regulatory networks revealed by temporal expression analysis.

PubMed

Hill, Jonathon T; Demarest, Bradley; Gorsi, Bushra; Smith, Megan; Yost, H Joseph

2017-10-01

During embryogenesis the heart forms as a linear tube that then undergoes multiple simultaneous morphogenetic events to obtain its mature shape. To understand the gene regulatory networks (GRNs) driving this phase of heart development, during which many congenital heart disease malformations likely arise, we conducted an RNA-seq timecourse in zebrafish from 30 hpf to 72 hpf and identified 5861 genes with altered expression. We clustered the genes by temporal expression pattern, identified transcription factor binding motifs enriched in each cluster, and generated a model GRN for the major gene batteries in heart morphogenesis. This approach predicted hundreds of regulatory interactions and found batteries enriched in specific cell and tissue types, indicating that the approach can be used to narrow the search for novel genetic markers and regulatory interactions. Subsequent analyses confirmed the GRN using two mutants, Tbx5 and nkx2-5 , and identified sets of duplicated zebrafish genes that do not show temporal subfunctionalization. This dataset provides an essential resource for future studies on the genetic/epigenetic pathways implicated in congenital heart defects and the mechanisms of cardiac transcriptional regulation. © 2017. Published by The Company of Biologists Ltd.

Regulatory Sunset and Review Act of 2013

THOMAS, 113th Congress

Rep. Hultgren, Randy [R-IL-14

2013-01-18

House - 02/28/2013 Referred to the Subcommittee on Regulatory Reform, Commercial And Antitrust Law. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

High rates of venous thromboembolic events in patients undergoing systemic therapy for urothelial carcinoma: A systematic review and meta-analysis.

PubMed

Gopalakrishna, Ajay; Longo, Thomas A; Fantony, Joseph J; Doshi, Uma; Harrison, Michael R; Van Noord, Megan; Inman, Brant A

2016-09-01

Patients undergoing systemic therapy for urothelial carcinoma (UC) are at increased risk for venous thromboembolic (VTE) events. The objective of the current study was to determine the rate of VTE events in patients undergoing systemic therapy for UC and assess factors affecting this rate. This study was registered with the PROSPERO database (CRD42015025774). We searched Pubmed, MEDLINE, EMBASE, The Cochrane Library, CINAHL, and Web of Science libraries through August 2014. As per PRISMA guidelines, 2 reviewers independently reviewed titles and abstracts. Disagreements were arbitrated by a third reviewer. After full text review, data were abstracted and pooled using a random effects model. Authors were contacted for clarification of data. To determine VTE risk factors, subgroup analyses and meta-regression were conducted. We identified 3,635 publications in the initial search, of which 410 met inclusion criteria for full text review. Of these, we were able to obtain data on the outcome of interest for 62 publications. A total of 5,082 patients, of which 77% were male, underwent systemic therapy for UC, with 373 VTE events. The proportion of patients who had had prior surgery, chemotherapy, or radiation was 55%, 25%, and 9%, respectively. Fixed effects and random effects models were used to estimate the VTE rate, yielding event rates of 6.7% and 5.4%, respectively. VTE occurs frequently in patients undergoing systemic therapy for UC. The VTE rate was affected by the country of origin, history of radiation, as well as by the systemic treatment class. The study was limited by the incomplete reporting of all variables of interest. Copyright © 2016 Elsevier Inc. All rights reserved.

Regulatory system reform of occupational health and safety in China.

PubMed

Wu, Fenghong; Chi, Yan

2015-01-01

With the explosive economic growth and social development, China's regulatory system of occupational health and safety now faces more and more challenges. This article reviews the history of regulatory system of occupational health and safety in China, as well as the current reform of this regulatory system in the country. Comprehensive, a range of laws, regulations and standards that promulgated by Chinese government, duties and responsibilities of the regulatory departments are described. Problems of current regulatory system, the ongoing adjustments and changes for modifying and improving regulatory system are discussed. The aim of reform and the incentives to drive forward more health and safety conditions in workplaces are also outlined.

Regulatory system reform of occupational health and safety in China

PubMed Central

WU, Fenghong; CHI, Yan

2015-01-01

With the explosive economic growth and social development, China’s regulatory system of occupational health and safety now faces more and more challenges. This article reviews the history of regulatory system of occupational health and safety in China, as well as the current reform of this regulatory system in the country. Comprehensive, a range of laws, regulations and standards that promulgated by Chinese government, duties and responsibilities of the regulatory departments are described. Problems of current regulatory system, the ongoing adjustments and changes for modifying and improving regulatory system are discussed. The aim of reform and the incentives to drive forward more health and safety conditions in workplaces are also outlined. PMID:25843565

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

A systematic literature review of the effectiveness of occupational health and safety regulatory enforcement.

PubMed

Tompa, Emile; Kalcevich, Christina; Foley, Michael; McLeod, Chris; Hogg-Johnson, Sheilah; Cullen, Kim; MacEachen, Ellen; Mahood, Quenby; Irvin, Emma

2016-11-01

We aimed to determine the strength of evidence on the effectiveness of legislative and regulatory policy levers in creating incentives for organizations to improve occupational health and safety processes and outcomes. A systematic review was undertaken to assess the strength of evidence on the effectiveness of specific policy levers using a "best-evidence" synthesis approach. A structured literature search identified 11,947 citations from 13 peer-reviewed literature databases. Forty-three studies were retained for synthesis. Strong evidence was identified for three out of nine clusters. There is strong evidence that several OHS policy levers are effective in terms of reducing injuries and/or increasing compliance with legislation. This study adds to the evidence on OHS regulatory effectiveness from an earlier review. In addition to new evidence supporting previous study findings, it included new categories of evidence-compliance as an outcome, nature of enforcement, awareness campaigns, and smoke-free workplace legislation. Am. J. Ind. Med. 59:919-933, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

NAFTA Minor Use Joint Reviews

EPA Pesticide Factsheets

EPA and Health Canada Pest Management Regulatory Agency (PMRA) worked together to develop a registration process that will permit a regulatory decision of pesticide uses for the minor use grower communities in both countries simultaneously.

75 FR 21729 - Semiannual Regulatory Agenda, Spring 2010

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

...This agenda provides summary descriptions of significant and not significant regulations being developed in agencies of the U.S. Department of Agriculture (USDA) in conformance with Executive Order 12866 ``Regulatory Planning and Review.''

Challenges in orphan drug development and regulatory policy in China.

PubMed

Cheng, Alice; Xie, Zhi

2017-01-18

While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China.

Actual operation and regulatory activities on steam generator replacement in Japan

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

Saeki, Hitoshi

1997-02-01

This paper summarizes the operating reactors in Japan, and the status of the steam generators in these plants. It reviews plans for replacement of existing steam generators, and then goes into more detail on the planning and regulatory steps which must be addressed in the process of accomplishing this maintenance. The paper also reviews the typical steps involved in the process of removal and replacement of steam generators.

Total Risk Integrated Methodology (TRIM) - Peer Review and Publications

EPA Pesticide Factsheets

Peer review: Consistent with Agency peer review policy, and the 1994 Agency Task Force on Environmental Regulatory Modeling, internal and external peer review has been an integral part of the TRIM development plan.

Effects of preoperative and postoperative resistance exercise interventions on recovery of physical function in patients undergoing abdominal surgery for cancer: a systematic review of randomised controlled trials

PubMed Central

Hashem, Ferhana; Corbett, Kevin; Bates, Amanda; George, Michelle; Hobbs, Ralph Peter; Hopkins, Malcolm; Hutchins, Irena; Lowery, David Peter; Pellatt-Higgins, Tracy; Stavropoulou, Charitini; Swaine, Ian; Tomlinson, Lee; Woodward, Hazel; Ali, Haythem

2018-01-01

Objective To systematically review the effects of preoperative and postoperative resistance exercise training on the recovery of physical function in patients undergoing abdominal surgery for cancer. Data sources A systematic review of English articles using Medline, Physiotherapy Evidence Database, CINAHL and the Cochrane Library electronic databases was undertaken. Eligibility criteria for selecting studies Studies were included if they used a randomised, quasi-randomised or controlled trial study design and compared the effects of a muscle-strengthening exercise intervention (±other therapy) with a comparative non-exercise group; involved adult participants (≥18 years) who had elected to undergo abdominal surgery for cancer; and used muscle strength, physical function, self-reported functional ability, range of motion and/or a performance-based test as an outcome measure. Results Following screening of titles and abstracts of the 588 publications retrieved from the initial search, 24 studies met the inclusion criteria and were accessed for review of the full-text version of the article, and 2 eligible studies met the inclusion criteria and were included in the review. One exercise programme was undertaken preoperatively and the other postoperatively, until discharge from hospital. The exercise interventions of the included studies were performed for five and eight sessions, respectively. There were no differences between groups in either study. Conclusion The only two studies designed to determine whether preoperative or postoperative resistance muscle-strengthening exercise programmes improved or negatively affected physical function outcomes in patients undergoing abdominal surgery for cancer provide inconclusive results. PMID:29719727

77 FR 7980 - Department Regulatory Agenda; Semiannual Summary

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-13

...The Regulatory Agenda is a semiannual summary of all current and projected rulemakings, reviews of existing regulations, and completed actions of the Department. The Agenda provides the public with information about the Department of Transportation's regulatory activity. It is expected that this information will enable the public to be more aware of and allow it to more effectively participate in the Department's regulatory activity. The public is also invited to submit comments on any aspect of this Agenda.

75 FR 79811 - Department Regulatory Agenda; Semiannual Summary

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-20

...The regulatory agenda is a semiannual summary of all current and projected rulemakings, reviews of existing regulations, and completed actions of the Department. The agenda provides the public with information about the Department of Transportation's regulatory activity. It is expected that this information will enable the public to be more aware of and allow it to more effectively participate in the Department's regulatory activity. The public is also invited to submit comments on any aspect of this agenda.

75 FR 21839 - Department Regulatory Agenda; Semiannual Summary

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

...The regulatory agenda is a semiannual summary of all current and projected rulemakings, reviews of existing regulations, and completed actions of the Department. The agenda provides the public with information about the Department of Transportation's regulatory activity. It is expected that this information will enable the public to be more aware of and allow it to more effectively participate in the Department's regulatory activity. The public is also invited to submit comments on any aspect of this agenda.

Why European and United States drug regulators are not speaking with one voice on anti-influenza drugs: regulatory review methodologies and the importance of 'deep' product reviews.

PubMed

Mulinari, Shai; Davis, Courtney

2017-11-09

Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs. We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza's capacity to alleviate symptoms and reduce frequency of complications of influenza. In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer's insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator's reliance on manufacturer-compiled summaries compared to the FDA's examination of original data and documentation from trials. The FDA's more probing and meticulous evaluative methodology allowed its reviewers to develop 'deep' knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs' efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators' assessments are not effectively disseminated and used, resources are used inefficiently.

Universal Design and Multimethod Approaches to Item Review

ERIC Educational Resources Information Center

Johnstone, Christopher J.; Thompson, Sandra J.; Bottsford-Miller, Nicole A.; Thurlow, Martha L.

2008-01-01

Test items undergo multiple iterations of review before states and vendors deem them acceptable to be placed in a live statewide assessment. This article reviews three approaches that can add validity evidence to states' item review processes. The first process is a structured sensitivity review process that focuses on universal design…

International Heart Valve Bank Survey: A Review of Processing Practices and Activity Outcomes

PubMed Central

Albrecht, Helmi; Lim, Yeong Phang; Manning, Linda

2013-01-01

A survey of 24 international heart valve banks was conducted to acquire information on heart valve processing techniques used and outcomes achieved. The objective was to provide an overview of heart valve banking activities for tissue bankers, tissue banking associations, and regulatory bodies worldwide. Despite similarities found for basic manufacturing processes, distinct differences in procedural details were also identified. The similarities included (1) use of sterile culture media for procedures, (2) antibiotic decontamination, (3) use of dimethyl sulfoxide (DMSO) as a cryoprotectant, (4) controlled rate freezing for cryopreservation, and (5) storage at ultralow temperatures of below −135°C. Differences in procedures included (1) type of sterile media used, (2) antibiotics combination, (3) temperature and duration used for bioburden reduction, (4) concentration of DMSO used for cryopreservation, and (5) storage duration for released allografts. For most banks, the primary reasons why allografts failed to meet release criteria were positive microbiological culture and abnormal morphology. On average, 85% of allografts meeting release criteria were implanted, with valve size and type being the main reasons why released allografts were not used clinically. The wide variation in percentage of allografts meeting release requirements, despite undergoing validated manufacturing procedures, justifies the need for regular review of important outcomes as cited in this paper, in order to encourage comparison and improvements in the HVBs' processes. PMID:24163756

Meiosis.

PubMed

Hillers, Kenneth J; Jantsch, Verena; Martinez-Perez, Enrique; Yanowitz, Judith L

2017-05-04

Sexual reproduction requires the production of haploid gametes (sperm and egg) with only one copy of each chromosome; fertilization then restores the diploid chromosome content in the next generation. This reduction in genetic content is accomplished during a specialized cell division called meiosis, in which two rounds of chromosome segregation follow a single round of DNA replication. In preparation for the first meiotic division, homologous chromosomes pair and synapse, creating a context that promotes formation of crossover recombination events. These crossovers, in conjunction with sister chromatid cohesion, serve to connect the two homologs and facilitate their segregation to opposite poles during the first meiotic division. During the second meiotic division, which is similar to mitosis, sister chromatids separate; the resultant products are haploid cells that become gametes. In Caenorhabditis elegans (and most other eukaryotes) homologous pairing and recombination are required for proper chromosome inheritance during meiosis; accordingly, the events of meiosis are tightly coordinated to ensure the proper execution of these events. In this chapter, we review the seminal events of meiosis: pairing of homologous chromosomes, the changes in chromosome structure that chromosomes undergo during meiosis, the events of meiotic recombination, the differentiation of homologous chromosome pairs into structures optimized for proper chromosome segregation at Meiosis I, and the ultimate segregation of chromosomes during the meiotic divisions. We also review the regulatory processes that ensure the coordinated execution of these meiotic events during prophase I.

Resolving the problem of compliance with the ever increasing and changing regulations

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

Leigh, H.

1991-06-01

The most common problem identified at several US Department of Energy (DOE) sites is regulatory compliance. Simply, the project viability depends on identifying regulatory requirements at the beginning of a specific project to avoid possible delays and cost overruns. The Radioisotope Power Systems Facility (RFSP) is using the Regulatory Compliance System (RCS) to deal with the problem that well over 1000 regulatory documents had to be reviewed for possible compliance requirements applicable to the facility. This overwhelming number of possible documents is not atypical of all DOE facilities thus far reviewed using the RCS system. The RCS was developed tomore » provide a control and tracking of all the regulatory and institutional requirements on a given project. WASTREN, Inc., developed the RCS through various DOE contracts and continues to enhance and update the system for existing and new contracts. The RCS provides the information to allow the technical expert to assimilate and manage accurate resource information, compile the checklists, and document that the project or facility fulfills all of the appropriate regulatory requirements. The RCS provides on-line information, including status throughput the project life, thereby allowing more intelligent and proactive decision making. Also, consistency and traceability are provided for regulatory compliance documentation. 1 ref., 1 fig.« less

Do We Need Plant Food Supplements? A Critical Examination of Quality, Safety, Efficacy, and Necessity for a New Regulatory Framework.

PubMed

Abdel-Tawab, Mona

2018-04-01

Given the expanding market of plant food supplements (PFSs) not undergoing any pre-marketing authorization, the overall quality, safety and efficacy of PFSs were subjected to a critical examination. Although many high-quality PFSs exist on the legal market, quality concerns are in general justified. Besides economic adulteration, active ingredients dramatically differing from label claims and among products were reported in several studies. In addition, PFSs sold via the Internet may be intentionally adulterated with undeclared prescription drugs. Compared to PFSs with only one single herb, PFSs containing herbal mixtures were more involved in moderate and severe clinical courses. Although prohibited by regulation, misleading labels on PFSs are common. Above all, only vague evidence for the efficacy of PFSs exists. Notwithstanding the unproven efficacy and insufficient safety assessment, PFSs represent a relevant source for consumers to get access to herbal preparations in the United States and meanwhile also in Europe, as launching of licensed/registered European herbal medicinal products (HMPs) has steadily decreased. However, being non-vitamin, non-mineral products, PFSs are neither food nor drugs. In terms of protecting public health and providing the consumer with high-quality, effective, and safe PFSs, possibilities are shown how to deal with the many challenges of PFSs. Last but not least, suggestions are made for assigning PFSs a separate regulatory category being less regulated compared to HMPs but more strictly regulated compared to food laws including implementation of good manufacturing practices and a scientific pre-marketing review process by an expert commission. Georg Thieme Verlag KG Stuttgart · New York.

AFO Manure Management - Oregon: Plan Review and Public Notice of Substantial Changes

EPA Pesticide Factsheets

Compendium of State Approaches for Manure Management, Part A -- Example of program features for manure management that have a regulatory basis, such as permit provisions and other regulatory program elements.

75 FR 24670 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-05

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information..., Information Collection Clearance Division, Regulatory Information Management Services, Office of Management...

75 FR 18168 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information..., Information Collection Clearance Division, Regulatory Information Management Services, Office of Management...

75 FR 33588 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-14

.... SUMMARY: The Director, Information Collection Clearance Division, Regulatory Information Management... Management Services, Office of Management, publishes that notice containing proposed information collection... Clearance Division, Regulatory Information Management Services, Office of Management. Office of Planning...

75 FR 30006 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-28

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75 FR 8928 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-26

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75 FR 5770 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-04

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management.... The Acting Director, Information Collection Clearance Division, Regulatory Information Management Services, Office of Management, publishes that notice containing proposed information collection requests...

75 FR 22393 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-28

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information..., Information Collection Clearance Division, Regulatory Information Management Services, Office of Management...

75 FR 18169 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information..., Information Collection Clearance Division, Regulatory Information Management Services, Office of Management...

75 FR 982 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-07

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management.... The Acting Director, Information Collection Clearance Division, Regulatory Information Management Services, Office of Management, publishes that notice containing proposed information collection requests...

75 FR 7572 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-22

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information..., Information Collection Clearance Division, Regulatory Information Management Services, Office of Management...

Liver Resection for Colorectal Hepatic Metastases after Systemic Chemotherapy and Selective Internal Radiation Therapy with Yttrium-90 Microspheres: A Systematic Review.

PubMed

Baltatzis, Minas; Siriwardena, Ajith K

2018-06-08

Selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres has been used together with systemic chemotherapy to treat patients with unresectable liver metastases. This study undertook the first systematic pooled assessment of the case profile, treatment and outcome in patients with initially inoperable colorectal hepatic metastases undergoing resection after systemic chemotherapy and SIRT. A systematic review of the literature was performed using Medline and Embase for publications between January 1998 and August 2017. Keywords and MESH headings "SIRT", "Yttrium-99 radio embolization" and "liver metastases" were used. Reports on patients undergoing liver resection after SIRT for colorectal liver metastases were included. Case reports, reviews and papers without original data were excluded. The study protocol was registered with PROSPERO, (registration number: CRD42017072374). The study population comprised of 120 patients undergoing liver resection after chemotherapy and SIRT. The conversion rate to hepatectomy in previously unresectable patients was 13.6% (109 of 802). All studies report a single application of SIRT. The interval from SIRT to surgery ranged from 39 days to 9 months. Overall, there were 4 (3.3%) deaths after hepatectomy in patients treated by chemotherapy and SIRT. This large pooled report of patients undergoing hepatectomy for colorectal liver metastases after chemotherapy and SIRT shows that 13.6% of patients with initially inoperable disease undergo resection with low procedure-related mortality. © 2018 S. Karger AG, Basel.

Regulatory administrative databases in FDA's Center for Biologics Evaluation and Research: convergence toward a unified database.

PubMed

Smith, Jeffrey K

2013-04-01

Regulatory administrative database systems within the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) are essential to supporting its core mission, as a regulatory agency. Such systems are used within FDA to manage information and processes surrounding the processing, review, and tracking of investigational and marketed product submissions. This is an area of increasing interest in the pharmaceutical industry and has been a topic at trade association conferences (Buckley 2012). Such databases in CBER are complex, not for the type or relevance of the data to any particular scientific discipline but because of the variety of regulatory submission types and processes the systems support using the data. Commonalities among different data domains of CBER's regulatory administrative databases are discussed. These commonalities have evolved enough to constitute real database convergence and provide a valuable asset for business process intelligence. Balancing review workload across staff, exploring areas of risk in review capacity, process improvement, and presenting a clear and comprehensive landscape of review obligations are just some of the opportunities of such intelligence. This convergence has been occurring in the presence of usual forces that tend to drive information technology (IT) systems development toward separate stovepipes and data silos. CBER has achieved a significant level of convergence through a gradual process, using a clear goal, agreed upon development practices, and transparency of database objects, rather than through a single, discrete project or IT vendor solution. This approach offers a path forward for FDA systems toward a unified database.

Pediatric Tonsillectomy and Ketorolac.

PubMed

Phillips-Reed, Lesley D; Austin, Paul N; Rodriguez, Ricardo E

2016-12-01

The use of ketorolac in children undergoing tonsillectomy remains limited because of the concern about postoperative bleeding. A search was performed addressing the question: For patients undergoing a surgical tonsillectomy, does a weight-appropriate single dose of intravenous ketorolac affect the incidence of postoperative hemorrhage? Five systematic reviews met the inclusion criteria. A Cochrane Review included 15 studies with 1,101 pediatric subjects and focused on perioperative bleeding requiring intervention. Many of the systematic reviews appraised the same studies. Subgroup analysis often allowed assessment of the effects of ketorolac administration. There was no consensus on the increased risk of bleeding when nonsteriodal anti-inflammatory drugs such as ketorolac are given to pediatric patients undergoing tonsillectomy. The conclusions varied from ketorolac should not be used to it is safe to use with these patients. The perianesthesia team must carefully weigh the risks and benefits before deciding to use ketorolac with this subset of patients. Copyright © 2016 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk

PubMed Central

Shaffer, Fred

2015-01-01

Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self-regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems. PMID:25694852

Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk.

PubMed

McCraty, Rollin; Shaffer, Fred

2015-01-01

Heart rate variability, the change in the time intervals between adjacent heartbeats, is an emergent property of interdependent regulatory systems that operates on different time scales to adapt to environmental and psychological challenges. This article briefly reviews neural regulation of the heart and offers some new perspectives on mechanisms underlying the very low frequency rhythm of heart rate variability. Interpretation of heart rate variability rhythms in the context of health risk and physiological and psychological self-regulatory capacity assessment is discussed. The cardiovascular regulatory centers in the spinal cord and medulla integrate inputs from higher brain centers with afferent cardiovascular system inputs to adjust heart rate and blood pressure via sympathetic and parasympathetic efferent pathways. We also discuss the intrinsic cardiac nervous system and the heart-brain connection pathways, through which afferent information can influence activity in the subcortical, frontocortical, and motor cortex areas. In addition, the use of real-time HRV feedback to increase self-regulatory capacity is reviewed. We conclude that the heart's rhythms are characterized by both complexity and stability over longer time scales that reflect both physiological and psychological functional status of these internal self-regulatory systems.

Warning letters to sponsor-investigators at academic health centres - the regulatory "canaries in a coal mine".

PubMed

O'Reilly, Erin K; Blair Holbein, M E; Berglund, Jelena P; Parrish, Amanda B; Roth, Mary-Tara; Burnett, Bruce K

2013-12-01

This study highlights Warning Letter (WL) findings issued to sponsor-investigators (S-Is) by the Food and Drug Administration (FDA). The online index of WLs issued from October 1, 2007 through September 30, 2012 was reviewed [1]. Through a manual screening process, letters were evaluated if specifically issued to 'clinical investigators', 'sponsors' or 'sponsor-investigators'. A particular focus was given to S-Is at Academic Health Centres (AHCs). Each letter was scored for the presence of violations in 40 general regulatory categories. A review of FDA WLs issued over a five-year period (FDA Fiscal Years 2008-2012) revealed that WLs to S-Is represent half of the WLs issued to all sponsors (16 of 32 letters). A review of these letters indicates that S-Is are not aware of, or simply do not meet, their regulatory responsibilities as either investigators or sponsors. In comparing total sponsor letters to those of S-Is, the most cited violation was the same: a lack of monitoring. A review of publicly available inspection data indicates that these 16 letters merely represent the tip of the iceberg. This review of the WL database reveals the potential for serious regulatory violations among S-Is at AHCs. Recent translational funding initiatives may serve to increase the number of S-Is, especially among Academic Health Centres (AHCs) [2]; thus, AHCs must become aware of this S-I role and work to support investigators who assume both roles in the course of their research.

Clinical Trial of a Comprehensive Treatment for High Functioning Children with ASD

DTIC Science & Technology

2017-07-01

and completion of the regulatory review; (2) implementation of the treatment for sampling wave 2; (3) completion of pretest , posttest , and follow-up...implementation of the treatment for sampling wave 3; (7) completion of pretest , posttest , and follow-up measures for sampling wave 3; (8) enrollment of...of the regulatory review; (2) implementation of the treatment for sampling wave 2; (3) completion of pretest , posttest , and follow-up measures for

Transportation of Large Wind Components: A Permitting and Regulatory Review

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

Levine, Aaron; Cook, Jeff

This report summarizes permitting and regulatory issues associated with transporting wind turbine blades, towers, and nacelles as well as large transformers (wind components). These wind components are commonly categorized as oversized and overweight (OSOW) and require specific permit approvals from state and local jurisdictions. The report was developed based on a Quadrennial Energy Review (QER) recommendation on logistical requirements for the transportation of 'oversized or high-consequence energy materials, equipment, and components.'

Changing innovation into a registered product: From concept to regulatory approval.

PubMed

Rhodes, Linda

2018-05-01

Innovation in animal health pharmaceuticals is important to address unmet and underserved medical needs, and often comes from products initially developed for human medicine. The purpose of the review is to help readers understand how breakthroughs from human biotechnology may be developed for use in veterinary medicine, while understanding the key drivers to success, the difficulties of regulatory approval, and the realistic risks and rewards of developing applications for animals. The types of human drugs which may be useful for veterinary applications are reviewed, including examples. The regulatory path is discussed, with a review of the various oversight agencies, and the categories of data required to be submitted, including safety, efficacy, manufacturing, environmental impact and human food safety. In conclusion, the cost, development time, and barriers to innovation in veterinary medical pharmaceuticals are discussed. Copyright © 2017 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.

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.

T regulatory cells in contact hypersensitivity.

PubMed

Cavani, Andrea

2008-08-01

The review summarizes the recent investigations focused on T regulatory cells in hapten diseases. Multiple mechanisms ensure tolerance to small chemicals penetrating the skin. Among these, specific T regulatory cells play a major role in controlling harmful immune responses to environmental antigens. Most of the T regulatory cells involved in this process belongs to the CD4 subset and suppress hapten-specific immune response through the release of IL-10 and through direct interaction with effector T cells, blocking their function. Methods for in-vitro and in-vivo expansion of specific T regulatory cells may represent an innovative approach for the cure of contact hypersensitivity.

75 FR 8929 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-26

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Management Services, Office of Management, publishes that notice containing proposed information collection... Official, Regulatory Information Management Services, Office of Management. Office of Elementary and...

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Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-27

.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... Information Management Services, Office of Management, publishes that notice containing proposed information... Collection Clearance Division, Regulatory Information Management Services, Office of Management. Institute of...

Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics

PubMed Central

Rykhus, Ryan D.; Shepard, Zachary V.; Young, Alix; Frisby, Hadley; Calder, Kailee A.; Coon, Collin M.; Falk, Justin A.; McAndrews, Sydney R.; Turner, Aspen; Chang, Christina; Michelsohn, Johanna; Petch, Raegan; Dieker, Sarah M.; Markworth, Benjamin H.; Alamo-Perez, Kevin; Hosack, Aaron J.; Berg, Jacob M.; Schmidt, Christian; Storsberg, Joachim; Brown, Mark A.

Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation’s sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics. PMID:29271878

Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials

PubMed Central

Gottlieb, Klaus; Dawson, Jill; Hussain, Fez; Murray, Joseph A.

2015-01-01

Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review. PMID:25725041

Measuring pain in patients undergoing hemodialysis: a review of pain assessment tools

PubMed Central

Upadhyay, Chandani; Cameron, Karen; Murphy, Laura; Battistella, Marisa

2014-01-01

Background Patients undergoing hemodialysis frequently report pain with multifactorial causes, not limited to that experienced directly from hemodialysis treatment. Their pain may be nociceptive, neuropathic, somatic or visceral in nature. Despite this, pain in this population remains under-recognized and under-treated. Although several tools have been used to measure pain in patients undergoing hemodialysis as reported in the literature, none of them have been validated specifically in this population. The objective for this review was to compare and contrast these pain assessment tools and discuss their clinical utility in this patient population. Methods To identify pain assessment tools studied in patients undergoing hemodialysis, a literature search was performed in PubMed and Medline. An expert panel of dialysis and pain clinicians reviewed each tool. Each pain assessment tool was assessed on how it is administered and scored, its psychometric properties such as reliability, validity and responsiveness to change, and its clinical utility in a hemodialysis population. Brief Pain Inventory, McGill Pain Questionnaire, Pain Management Index, Edmonton Symptom Assessment System, Visual Analogue Scale and Faces Pain Scale were evaluated and compared. Results This assessment will help clinicians practicing in nephrology to determine which of these pain assessment tools is best suited for use in their individual clinical practice. PMID:25852910

Generic oncology drugs: are they all safe?

PubMed

Yang, Y Tony; Nagai, Sumimasa; Chen, Brian K; Qureshi, Zaina P; Lebby, Akida A; Kessler, Samuel; Georgantopoulos, Peter; Raisch, Dennis W; Sartor, Oliver; Hermanson, Terhi; Kane, Robert C; Hrushesky, William J; Riente, Joshua J; Norris, LeAnn B; Bobolts, Laura R; Armitage, James O; Bennett, Charles L

2016-11-01

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval. Copyright © 2016 Elsevier Ltd. All rights reserved.

77 FR 73060 - Standard Review Plan for Review of Fuel Cycle Facility License Applications

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-07

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0220] Standard Review Plan for Review of Fuel Cycle... 1, ``Standard Review Plan (SRP) for the Review of a License Application for a Fuel Cycle Facility... for a fuel cycle facility (NUREG-1520) provides NRC staff guidance for reviewing and evaluating the...

Congressional Office of Regulatory Analysis Creation and Sunset and Review Act of 2011

THOMAS, 112th Congress

Rep. Young, Don [R-AK-At Large

2011-01-07

House - 02/08/2011 Referred to the Subcommittee on Regulatory Affairs, Stimulus Oversight and Government Spending . (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

75 FR 347 - Information Collection; Notice of Submission to OMB for Its Review and Approval of the Voluntary...

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2010-01-05

.... The list of program types that appear in the survey (for example, Critical Peak Pricing, Spinning... Management and Budget, Office of Information and Regulatory Affairs, Attention: Federal Energy Regulatory...

76 FR 544 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-05

.... ACTION: Comment request. SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management Services, Office of Management invites comments on the submission for OMB..., Regulatory Information Management Services, Office of Management. Office of Special Education and...

75 FR 63165 - Notice of Submission for OMB Review

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2010-10-14

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75 FR 56521 - Notice of Submission for OMB Review

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Advances in Retinal Prosthetic Research: A Systematic Review of Engineering and Clinical Characteristics of Current Prosthetic Initiatives.

PubMed

Cheng, Derrick L; Greenberg, Paul B; Borton, David A

2017-03-01

To date, reviews of retinal prostheses have focused primarily on devices undergoing human trials in the Western Hemisphere and fail to capture significant advances in materials and engineering research in countries such as Japan and Korea, as well as projects in early stages of development. To address these gaps, this systematic review examines worldwide advances in retinal prosthetic research, evaluates engineering characteristics and clinical progress of contemporary device initiatives, and identifies potential directions for future research in the field of retinal prosthetics. A literature search using PubMed, Google Scholar, and IEEExplore was conducted following the PRISMA Guidelines for Systematic Review. Inclusion criteria were peer-reviewed papers demonstrating progress in human or animal trials and papers discussing the prosthetic engineering design. For each initiative, a description of the device, its engineering considerations, and recent clinical results were provided. Ten prosthetic initiatives met our inclusion criteria and were organized by stimulation location. Of these initiatives, four have recently completed human trials, three are undergoing multi- or single-center human trials, and three are undergoing preclinical animal testing. Only the Argus II (FDA 2013, CE 2011) has obtained FDA approval for use in the United States; the Alpha-IMS (CE 2013) has achieved the highest visual acuity using a Landolt-C test to date and is the only device presently undergoing a multicenter clinical trial. Several distinct approaches to retinal stimulation have been successful in eliciting visual precepts in animals and/or humans. However, many clinical needs are still not met and engineering challenges must be addressed before a retinal prosthesis with the capability to fully and safely restore functional vision can be realized.

Myocardial infarction and subsequent death in a patient undergoing robotic prostatectomy.

PubMed

Thompson, Judy

2009-10-01

A 52-year-old patient, ASA physical status IV, undergoing a radical prostatectomy for cancer with a robotic system had a cardiac arrest 3 hours into the case. All attempts to resuscitate were unsuccessful, and several hours later he was pronounced dead. Underlying patient comorbidity and procedural issues contributed to the patient's death. The patient had a history of coronary artery disease that required the placement of drug-eluting stents 2 years before this surgical procedure. The preoperative cardiac evaluation and pharmacological management of patients with drug-eluting coronary stents are reviewed. There are a number of positional and technical considerations for patients undergoing robotic surgical procedures, especially in relation to the requirement of low-lithotomy and steep Trendelenburg positions. The cardiac and respiratory systems are especially vulnerable to the extreme and lengthy head-down position. The needed positioning, combined with the problems associated with insufflation, presents a unique challenge in anesthetic management. This course reviews the current literature on the surgical implications for patients with drug-eluting stents and the physiologic factors related to position and pneumoperitoneum and their associated stressors. By using a review of the contemporary literature, a best-evidence approach to anesthetic management is reviewed.

Challenges posed to the European pharmaceutical regulatory system by highly personalized medicines.

PubMed

Johnston, John D; Feldschreiber, Peter

2014-03-01

The European pharmaceutical regulatory system has not yet been challenged by issues related to highly personalized medicines such as those to be found with active substances that affect RNA biochemistry. We review the current status of RNA-based pharmacology and present three possible case histories. The implications for the European pharmaceutical regulatory system are discussed. © 2013 The British Pharmacological Society.

Apple miRNAs and tasiRNAs with novel regulatory networks

PubMed Central

2012-01-01

Background MicroRNAs (miRNAs) and their regulatory functions have been extensively characterized in model species but whether apple has evolved similar or unique regulatory features remains unknown. Results We performed deep small RNA-seq and identified 23 conserved, 10 less-conserved and 42 apple-specific miRNAs or families with distinct expression patterns. The identified miRNAs target 118 genes representing a wide range of enzymatic and regulatory activities. Apple also conserves two TAS gene families with similar but unique trans-acting small interfering RNA (tasiRNA) biogenesis profiles and target specificities. Importantly, we found that miR159, miR828 and miR858 can collectively target up to 81 MYB genes potentially involved in diverse aspects of plant growth and development. These miRNA target sites are differentially conserved among MYBs, which is largely influenced by the location and conservation of the encoded amino acid residues in MYB factors. Finally, we found that 10 of the 19 miR828-targeted MYBs undergo small interfering RNA (siRNA) biogenesis at the 3' cleaved, highly divergent transcript regions, generating over 100 sequence-distinct siRNAs that potentially target over 70 diverse genes as confirmed by degradome analysis. Conclusions Our work identified and characterized apple miRNAs, their expression patterns, targets and regulatory functions. We also discovered that three miRNAs and the ensuing siRNAs exploit both conserved and divergent sequence features of MYB genes to initiate distinct regulatory networks targeting a multitude of genes inside and outside the MYB family. PMID:22704043

Meta-Analysis of Postoperative Outcome Parameters Comparing Descemet Membrane Endothelial Keratoplasty Versus Descemet Stripping Automated Endothelial Keratoplasty.

PubMed

Pavlovic, Ivana; Shajari, Mehdi; Herrmann, Eva; Schmack, Ingo; Lencova, Anna; Kohnen, Thomas

2017-12-01

This meta-analysis compares Descemet membrane endothelial keratoplasty (DMEK) with Descemet stripping automated endothelial keratoplasty (DSAEK) to evaluate their strength and weakness profiles. Meta-analysis. We performed a meta-analysis and searched the peer-reviewed literature in PubMed, Cochrane Library, Web of Science, and Embase following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Prospective and retrospective trials performing and comparing DMEK and DSAEK were included. Effects were calculated as odds ratios or standardized mean differences. A total of 11 studies with a total of 723 eyes (350 DMEK and 373 DSAEK) were included. No significant difference was found regarding the total detachment rate, graft failure, and rejection. One of 340 eyes undergoing DMEK showed total detachment and 5 of 363 eyes undergoing DSAEK showed total detachment (P = 0.28). Six of 280 eyes undergoing DMEK showed graft failure; 1 of 313 eyes undergoing DSAEK developed this complication (P = 0.18). No rejection was observed in 158 eyes undergoing DMEK; 4 cases of rejection occurred in 196 eyes undergoing DSAEK (P = 0.37). No significant difference was found regarding endothelial cell loss (P = 0.48). There was a significantly higher partial detachment rate with DMEK: 88 of 340 eyes undergoing DMEK showed partial detachment; 16 of 363 eyes undergoing DSAEK showed this complication (P < 0.00001). DMEK was superior in best-corrected visual acuity after 6 months (P < 0.001), subjective evaluation of visual acuity (P = 0.001), patient satisfaction (P < 0.001), and was the method preferred by patients (P = 0.001). DMEK and DSAEK have a similar complication profile. However, the superiority in the visual outcome and patient satisfaction makes DMEK the preferred option for most patients.

Blood glucose management in the patient undergoing cardiac surgery: A review

PubMed Central

Reddy, Pingle; Duggar, Brian; Butterworth, John

2014-01-01

Both diabetes mellitus and hyperglycemia per se are associated with negative outcomes after cardiac surgery. In this article, we review these associations, the possible mechanisms that lead to adverse outcomes, and the epidemiology of diabetes focusing on those patients requiring cardiac surgery. We also examine outpatient and perioperative management of diabetes with the same focus. Finally, we discuss our own efforts to improve glycemic management of patients undergoing cardiac surgery at our institution, including keys to success, results of implementation, and patient safety concerns. PMID:25429332

Systematic review of qualitative literature on occupational health and safety legislation and regulatory enforcement planning and implementation.

PubMed

MacEachen, Ellen; Kosny, Agnieszka; Ståhl, Christian; O'Hagan, Fergal; Redgrift, Lisa; Sanford, Sarah; Carrasco, Christine; Tompa, Emile; Mahood, Quenby

2016-01-01

The ability of occupational health and safety (OHS) legislation and regulatory enforcement to prevent workplace injuries and illnesses is contingent on political, economic, and organizational conditions. This systematic review of qualitative research articles considers how OHS legislation and regulatory enforcement are planned and implemented. A comprehensive search of peer-reviewed, English-language articles published between 1990 and 2013 yielded 11 947 articles. We identified 34 qualitative articles as relevant, 18 of which passed our quality assessment and proceeded to meta-ethnographic synthesis. The synthesis yielded four main themes: OHS regulation formation, regulation challenges, inspector organization, and worker representation in OHS. It illuminates how OHS legislation can be based on normative suppositions about worker and employer behavior and shaped by economic and political resources of parties. It also shows how implementation of OHS legislation is affected by "general duty" law, agency coordination, resourcing of inspectorates, and ability of workers to participate in the system. The review identifies methodological gaps and identifies promising areas for further research in "grey" zones of legislation implementation.

Extracellular matrix and growth factors in branching morphogenesis

NASA Technical Reports Server (NTRS)

Hardman, P.; Spooner, B. S.

1993-01-01

The unifying hypothesis of the NSCORT in gravitational biology postulates that the ECM and growth factors are key interrelated components of a macromolecular regulatory system. The ECM is known to be important in growth and branching morphogenesis of embryonic organs. Growth factors have been detected in the developing embryo, and often the pattern of localization is associated with areas undergoing epithelial-mesenchymal interactions. Causal relationships between these components may be of fundamental importance in control of branching morphogenesis.

Deregulation of Cell Signaling in Cancer

PubMed Central

Giancotti, Filippo G.

2014-01-01

Summary Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist to proapoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer. PMID:24561200

Gene expression profiling of dendritic cells by microarray.

PubMed

Foti, Maria; Ricciardi-Castagnoli, Paola; Granucci, Francesca

2007-01-01

The immune system of vertebrate animals has evolved to respond to different types of perturbations (invading pathogens, stress signals), limiting self-tissue damage. The decision to activate an immune response is made by antigen-presenting cells (APCs) that are quiescent until they encounter a foreign microorganism or inflammatory stimuli. Early activated APCs trigger innate immune responses that represent the first line of reaction against invading pathogens to limit the infections. At later times, activated APCs acquire the ability to prime antigen-specific immune responses that clear the infections and give rise to memory. During the immune response self-tissue damage is limited and tolerance to self is maintained through life. Among the cells that constitute the immune system, dendritic cells (DC) play a central role. They are extremely versatile APCs involved in the initiation of both innate and adaptive immunity and also in the differentiation of regulatory T cells required for the maintenance of self-tolerance. How DC can mediate these diverse and almost contradictory functions has recently been investigated. The plasticity of these cells allows them to undergo a complete genetic reprogramming in response to external microbial stimuli with the sequential acquisition of different regulatory functions in innate and adaptive immunity. The specific genetic reprogramming DC undergo upon activation can be easily investigated by using microarrays to perform global gene expression analysis in different conditions.

75 FR 9400 - Submission for OMB Review; Comment Request

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.... SUMMARY: The Acting Director, Information Collection Clearance Division, Regulatory Information Management... 1, 2010. ADDRESSES: Written comments should be addressed to the Office of Information and Regulatory... [email protected] with a cc: to [email protected] . SUPPLEMENTARY INFORMATION: Section 3506...

REFINE WETLAND REGULATORY PROGRAM

EPA Science Inventory

The Tribes will work toward refining a regulatory program by taking a draft wetland conservation code with permitting incorporated to TEB for review. Progress will then proceed in developing a permit tracking system that will track both Tribal and fee land sites within reservati...

Low Volume Exemption for New Chemical Review under TSCA

EPA Pesticide Factsheets

Certain categories of new low-volume chemical substances are exempt from full premanufacture notice (PMN) review, i.e., chemicals manufactured at 10,000 kg/year or less. LVE substances undergo a 30-day review and are not subject to a user fee.

76 FR 38654 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... Project Fetal-Infant Mortality Review: Human Immunodeficiency Virus Prevention Methodology (FHPM)--New... Mortality Review: Human Immunodeficiency Virus Prevention Methodology (FHPM) is designed to identify and... investigation and improvement strategy. In order to address perinatal HIV transmission at the community level...

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

Structure of the protein phosphatase 2A holoenzyme.

PubMed

Xu, Yanhui; Xing, Yongna; Chen, Yu; Chao, Yang; Lin, Zheng; Fan, Eugene; Yu, Jong W; Strack, Stefan; Jeffrey, Philip D; Shi, Yigong

2006-12-15

Protein Phosphatase 2A (PP2A) plays an essential role in many aspects of cellular physiology. The PP2A holoenzyme consists of a heterodimeric core enzyme, which comprises a scaffolding subunit and a catalytic subunit, and a variable regulatory subunit. Here we report the crystal structure of the heterotrimeric PP2A holoenzyme involving the regulatory subunit B'/B56/PR61. Surprisingly, the B'/PR61 subunit has a HEAT-like (huntingtin-elongation-A subunit-TOR-like) repeat structure, similar to that of the scaffolding subunit. The regulatory B'/B56/PR61 subunit simultaneously interacts with the catalytic subunit as well as the conserved ridge of the scaffolding subunit. The carboxyterminus of the catalytic subunit recognizes a surface groove at the interface between the B'/B56/PR61 subunit and the scaffolding subunit. Compared to the scaffolding subunit in the PP2A core enzyme, formation of the holoenzyme forces the scaffolding subunit to undergo pronounced conformational rearrangements. This structure reveals significant ramifications for understanding the function and regulation of PP2A.

78 FR 48504 - Proposed Revisions to Maintenance Rule Standard Review Plan

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-08

... Review Plan AGENCY: Nuclear Regulatory Commission. ACTION: Standard review plan-draft section revision... Review Plan for the Review of Safety Analysis Reports for Nuclear Power Plants: LWR Edition,'' Section 17... and Management System (ADAMS): You may access publicly available documents online in the NRC Library...

76 FR 65544 - Standard Format and Content of License Applications for Mixed Oxide Fuel Fabrication Facilities

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-21

...The U.S. Nuclear Regulatory Commission (NRC or Commission) is issuing a revision to regulatory guide (RG) 3.39, ``Standard Format and Content of License Applications for Mixed Oxide Fuel Fabrication Facilities.'' This guide endorses the standard format and content for license applications and integrated safety analysis (ISA) summaries described in the current version of NUREG-1718, ``Standard Review Plan for the Review of an Application for a Mixed Oxide (MOX) Fuel Fabrication Facility,'' as a method that the NRC staff finds acceptable for meeting the regulatory requirements of Title 10 of the Code of Federal Regulations (10 CFR) part 70, ``Domestic Licensing of Special Nuclear Material'' for mixed oxide fuel fabrication facilities.

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

cis-Regulatory Mutations Are a Genetic Cause of Human Limb Malformations

PubMed Central

VanderMeer, Julia E.; Ahituv, Nadav

2011-01-01

The underlying mutations that cause human limb malformations are often difficult to determine, particularly for limb malformations that occur as isolated traits. Evidence from a variety of studies shows that cis-regulatory mutations, specifically in enhancers, can lead to some of these isolated limb malformations. Here, we provide a review of human limb malformations that have been shown to be caused by enhancer mutations and propose that cis-regulatory mutations will continue to be identified as the cause of additional human malformations as our understanding of regulatory sequences improves. PMID:21509892

10 CFR 13.5 - Review by the reviewing official.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Review by the reviewing official. 13.5 Section 13.5 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.5 Review by the reviewing official. (a) If, based on the report of the investigating official under § 13.4(b), the reviewing official determines...

10 CFR 13.5 - Review by the reviewing official.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Review by the reviewing official. 13.5 Section 13.5 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.5 Review by the reviewing official. (a) If, based on the report of the investigating official under § 13.4(b), the reviewing official determines...

Anxiety in women with breast cancer undergoing treatment: a systematic review.

PubMed

Lim, Chi Ching; Devi, M Kamala; Ang, Emily

2011-09-01

Breast cancer is one of the most common cancers worldwide, and anxiety is a psychological morbidity that is inevitable. Many researchers have investigated the prevalence and detrimental effects of anxiety in breast cancer treatment, but little is known about differences in anxiety level among women receiving different breast cancer treatments. A systematic review of all available literature was needed to attain better understanding of anxiety in patients undergoing treatment for breast cancer. This review aimed to determine the best available evidence on the level of anxiety among women with breast cancer who were undergoing cancer treatment(s), and the factor(s) contributing to anxiety in various treatment modalities. The search sought to gather data from published and unpublished studies conducted between 1990 and 2010. An initial search on CINAHL and Medline was done to identify relevant search terms. A search strategy was then developed, using MeSH headings and key words. The following databases were searched: CINAHL, PubMed, ScienceDirect, PsycINFO, Cochrane Database of Systematic Review, Scopus, Wiley InterScience and PsycARTICLES. All papers are quantitative papers (randomised controlled trials and descriptive studies) that examined anxiety level in women with breast cancer of stage 0 to stage IIIA, over and equal to 21 and below 65 years of age, who were undergoing/had undergone treatment restricted to chemotherapy, radiotherapy and/or surgery, and these quantitative papers have made correlations between women's anxiety levels and contributing factors. The Hospital Anxiety and Depression Scale and State-Trait Anxiety Inventory were the two tools most frequently used by these papers to quantify the anxiety level. Two reviewers independently assessed the eligibility of the papers for inclusion. Eighteen papers were selected based on relevance, and assessed for methodological quality using MAStARI. Ten research papers that met our methodological standard were included in the review. Both reviewers agreed on the papers to be included and excluded. Due to the methodological heterogeneity of the included papers, a meta-analysis was not possible. The studies were hence presented in narrative summary. Anxiety seems to be ubiquitous, presenting itself in all treatment types for breast cancer. Anxiety level in women who underwent chemotherapy was highest before the first chemotherapy infusion, mediated by age and trait anxiety. Radiotherapy regimes did not affect anxiety level in radiotherapy-treated patients, and most research concluded that anxiety level was higher among women who underwent mastectomy than those who underwent breast conservation therapy. The prevalence and intensity of anxiety have been shown to be pronounced among breast cancer women who were undergoing/had undergone one or more of the three treatments. Chemotherapy, as compared to other treatments, is shown to be associated with a higher anxiety level. With the prevalence, intensity and correlated factors of anxiety identified through this review, future research may investigate the interventions that could help alleviate anxiety among these patients. Anxiety is prevalent in women with breast cancer undergoing treatment, especially those undergoing chemotherapy. Healthcare professionals should pay greater attention to identify signs of anxiety in patients and design interventions to help alleviate it earlier. © 2011 The Authors. International Journal of Evidence-Based Healthcare © 2011 The Joanna Briggs Institute.

European Ethnopharmaceuticals for Self-Medication in Japan: Review Experience of Vitis vinifera L., Folium Extract and Vitex agnus-castus L., Fructus Extract as OTC Drugs.

PubMed

Hoshino, Tatsuro; Muto, Nanami; Tsukada, Shinsuke; Nakamura, Takatoshi; Maegawa, Hikoichiro

2018-01-06

Since the publication of "Application Guideline for Western Traditional Herbal Medicines as OTC Drugs" in 2007, only two European ethnopharmaceuticals, Vitis vinifera L., folium extract (Antistax) and Vitex agnus-castus L., fructus extract (Prefemin), have been approved as OTC drugs in Japan. In this review, we describe the current regulation of Western ethnopharmaceuticals in Japan, summarize our regulatory experiences and discuss the scientific and regulatory issues involved.

European Ethnopharmaceuticals for Self-Medication in Japan: Review Experience of Vitis vinifera L., Folium Extract and Vitex agnus-castus L., Fructus Extract as OTC Drugs

PubMed Central

Hoshino, Tatsuro; Muto, Nanami; Tsukada, Shinsuke; Nakamura, Takatoshi; Maegawa, Hikoichiro

2018-01-01

Since the publication of “Application Guideline for Western Traditional Herbal Medicines as OTC Drugs” in 2007, only two European ethnopharmaceuticals, Vitis vinifera L., folium extract (Antistax) and Vitex agnus-castus L., fructus extract (Prefemin), have been approved as OTC drugs in Japan. In this review, we describe the current regulation of Western ethnopharmaceuticals in Japan, summarize our regulatory experiences and discuss the scientific and regulatory issues involved. PMID:29316611

77 FR 67678 - Content Specifications and Shielding Evaluations for Type B Transportation Packages

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-13

...The U.S. Nuclear Regulatory Commission (NRC or the Commission) is issuing for public comment Draft Regulatory Issue Summary (RIS) 2012-XX, ``Content Specifications and Shielding Evaluations for Type B Transportation Packages.'' This RIS clarifies the NRC's use of staff guidance in NUREG-1609, ``Standard Review Plan for Transport Packages for Radioactive Material,'' for the review of content specifications and shielding evaluations included in the Certificates of Compliance (CoC) and safety analysis reports (SARs) for Type B transportation packages.

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

Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective.

PubMed

Hussong, David

2010-09-01

For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.

Comparisons of ANS, ASME, AWS, and NFPA standards cited in the NRC standard review plan, NUREG-0800, and related documents

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

Ankrum, A.R.; Bohlander, K.L.; Gilbert, E.R.

This report provides the results of comparisons of the cited and latest versions of ANS, ASME, AWS and NFPA standards cited in the NRC Standard Review Plan for the Review of Safety Analysis Reports for Nuclear Power Plants (NUREG 0800) and related documents. The comparisons were performed by Battelle Pacific Northwest Laboratories in support of the NRC`s Standard Review Plan Update and Development Program. Significant changes to the standards, from the cited version to the latest version, are described and discussed in a tabular format for each standard. Recommendations for updating each citation in the Standard Review Plan are presented.more » Technical considerations and suggested changes are included for related regulatory documents (i.e., Regulatory Guides and the Code of Federal Regulations) citing the standard. The results and recommendations presented in this document have not been subjected to NRC staff review.« less

Proposed Guidance for Preparing and Reviewing Molten Salt Nonpower Reactor Licence Applications (NUREG-1537)

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

Belles, Randy; Flanagan, George F.; Voth, Marcus

Development of non-power molten salt reactor (MSR) test facilities is under consideration to support the analyses needed for development of a full-scale MSR. These non-power MSR test facilities will require review by the US Nuclear Regulatory Commission (NRC) staff. This report proposes chapter adaptations for NUREG-1537 in the form of interim staff guidance to address preparation and review of molten salt non-power reactor license applications. The proposed adaptations are based on a previous regulatory gap analysis of select chapters from NUREG-1537 for their applicability to non-power MSRs operating with a homogeneous fuel salt mixture.

Independence Community College Program Review Process.

ERIC Educational Resources Information Center

Romine, Robert J.

Program review at Independence Community College (ICC) is structured so that every program of study will undergo review within a 5-year period. The purpose of the program review effort is to assess the relationship of inputs to outcomes, so that actual outcomes can be compared to expected outcomes. Each program of study is evaluated according to…

39 CFR 3020.75 - Review.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Review. 3020.75 Section 3020.75 Postal Service POSTAL REGULATORY COMMISSION PERSONNEL PRODUCT LISTS Proposal of the Commission To Modify the Product Lists Described Within the Mail Classification Schedule § 3020.75 Review. The Commission shall review...

75 FR 17438 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-06

... NUCLEAR REGULATORY COMMISSION [Docket No. NRC-2010-0141] Agency Information Collection Activities: Proposed Collection; Comment Request AGENCY: U.S. Nuclear Regulatory Commission (NRC). ACTION: Notice of... new Agreement State applications. Annually for participation by Agreement States in the IMPEP reviews...

Best Practices for Use of Historical Control Data of Proliferative Rodent Lesions.

EPA Science Inventory

The Historical Control Data Working Group under the direction of the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) was tasked with reviewing the current scientific practices, regulatory guidance and relevant literature pertaining ...

78 FR 69139 - Physical Security-Design Certification and Operating Reactors

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-18

... scheduled to close on October 30, 2013. The Nuclear Energy Institute (NEI) submitted a letter on October 9... NUCLEAR REGULATORY COMMISSION [NRC-2013-0225] Physical Security--Design Certification and Operating Reactors AGENCY: Nuclear Regulatory Commission. ACTION: Standard review plan--draft section...

Integrative Therapeutic Approaches for the Management and Control of Nausea in Children Undergoing Cancer Treatment: A Systematic Review of Literature.

PubMed

Momani, Tha'er G; Berry, Donna L

Chemotherapy-induced nausea and vomiting (CINV) continues to be a common symptom experienced by children undergoing cancer treatment despite the use of contemporary antiemetics. Integrative therapeutic approaches in addition to standard pharmacologic antiemetic regimes offer potential to control CINV. The purpose of this review was to identify current evidence on integrative therapeutic approaches for the control of CINV in children with cancer. Online search engines (PubMed, CINAHL, PsychINFO) were queried using MESH terms. Titles, abstracts, and then full-text articles were reviewed for relevance to the review. The search resulted in 53 studies. Twenty-one studies met our review criteria. Integrative therapies identified included acupuncture/acupressure, aromatherapy, herbal supplements, hypnosis, and other cognitive behavioral interventions. Our review identified little information on the effectiveness and safety of most integrative therapeutic approaches for the control and management of CINV in children with cancer. However, evidence from adult cancer studies and some pediatric studies identify promising interventions for further testing.

76 FR 33302 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-08

... this data collection is to provide a systematic and consistent mechanism to review requests that come... significant morbidity and mortality on susceptible populations. In light of current terrorism concerns and the...

Regulatory T cells in the control of host-microorganism interactions (*).

PubMed

Belkaid, Yasmine; Tarbell, Kristin

2009-01-01

Each microenvironment requires a specific set of regulatory elements that are finely and constantly tuned to maintain local homeostasis. Various populations of regulatory T cells contribute to the maintenance of this equilibrium and establishment of controlled immune responses. In particular, regulatory T cells limit the magnitude of effector responses, which may result in failure to adequately control infection. However, regulatory T cells also help limit collateral tissue damage caused by vigorous antimicrobial immune responses against pathogenic microbes as well as commensals. In this review, we describe various situations in which the balance between regulatory T cells and effector immune functions influence the outcome of host-microorganism coexistence and discuss current hypotheses and points of polemic associated with the origin, target, and antigen specificity of both endogenous and induced regulatory T cells during these interactions.

Deciphering the transcriptional cis-regulatory code.

PubMed

Yáñez-Cuna, J Omar; Kvon, Evgeny Z; Stark, Alexander

2013-01-01

Information about developmental gene expression resides in defined regulatory elements, called enhancers, in the non-coding part of the genome. Although cells reliably utilize enhancers to orchestrate gene expression, a cis-regulatory code that would allow their interpretation has remained one of the greatest challenges of modern biology. In this review, we summarize studies from the past three decades that describe progress towards revealing the properties of enhancers and discuss how recent approaches are providing unprecedented insights into regulatory elements in animal genomes. Over the next years, we believe that the functional characterization of regulatory sequences in entire genomes, combined with recent computational methods, will provide a comprehensive view of genomic regulatory elements and their building blocks and will enable researchers to begin to understand the sequence basis of the cis-regulatory code. Copyright © 2012 Elsevier Ltd. All rights reserved.

Management of sickle cell disease in patients undergoing cardiac surgery.

PubMed

Crawford, Todd C; Carter, Michael V; Patel, Rina K; Suarez-Pierre, Alejandro; Lin, Sophie Z; Magruder, Jonathan Trent; Grimm, Joshua C; Cameron, Duke E; Baumgartner, William A; Mandal, Kaushik

2017-02-01

Sickle cell disease is a life-limiting inherited hemoglobinopathy that poses inherent risk for surgical complications following cardiac operations. In this review, we discuss preoperative considerations, intraoperative decision-making, and postoperative strategies to optimize the care of a patient with sickle cell disease undergoing cardiac surgery. © 2017 Wiley Periodicals, Inc.

Factors Affecting Health-Related Quality of Life in Children Undergoing Curative Treatment for Cancer: A Review of the Literature.

PubMed

Momani, Tha'er G; Hathaway, Donna K; Mandrell, Belinda N

2016-01-01

Health-related quality of life (HRQoL) is an important measure to evaluate a child's reported treatment experience. Although there are numerous studies of HRQoL in children undergoing curative cancer treatment, there is limited literature on factors that influence this. To review published studies that describe the HRQoL and associated factors in children undergoing curative cancer treatment. Full-text publications in English from January 2005 to March 2013 were searched in PubMed, PsychINFO, and CINAHL for children ≤18 years of age undergoing curative cancer treatment. HRQoL-associated factors were categorized as cancer diagnosis, treatment, child, family, and community. Twenty-six studies met the inclusion criteria. The most frequently used generic and cancer-specific instruments were PedsQL (Pediatric Quality of Life Inventory) Generic and PedsQL Cancer, respectively. Cancer diagnosis and treatment were the most frequently identified variables; fewer studies measured family and community domains. Gender, treatment intensity, type of cancer treatments, time in treatment, and cancer diagnosis were correlated with HRQoL. Our study highlights the need to develop interventions based on diagnosis and treatment regimen to improve the HRQoL in children undergoing curative cancer treatment. © 2015 by Association of Pediatric Hematology/Oncology Nurses.

Detection of incidental cardiac findings in noncardiac chest computed tomography

PubMed Central

Secchi, Francesco; Di Leo, Giovanni; Zanardo, Moreno; Alì, Marco; Cannaò, Paola Maria; Sardanelli, Francesco

2017-01-01

Abstract The aim of the study was to estimate the rate of incidental cardiac findings (ICF) in patients undergoing noncardiac chest CT. An experienced radiologist retrospectively reviewed 237 consecutive patients (147 males and 90 females with median age of 69 years) undergoing a noncardiac chest CT. ICF at targeted review were compared to those mentioned in original reports (χ2 test). At review, ≥1 ICF was detected in 124/237 patients (52%), for a total of 229 ICF, 158 of them (69%) not originally mentioned. Valvular calcifications were unmentioned in 23/23 (100%) patients, main pulmonary artery dilation in 21/22 (96%), coronary calcifications in 69/86 (80%), right or left atrial dilation in 7/11 (64%), aortic atherosclerosis in 29/62 (47%), and ascending aorta dilatation in 8/18 (44%). All 6 pericardial effusions were originally mentioned. No association with sex (P ≥ .189); positive correlation with age (P < .001). Half of patients undergoing noncardiac chest CT presented ≥1 ICF, independently from sex but increasing with age. Moreover, 69% of detectable ICFs were not originally mentioned. PMID:28723768

Detection of incidental cardiac findings in noncardiac chest computed tomography.

PubMed

Secchi, Francesco; Di Leo, Giovanni; Zanardo, Moreno; Alì, Marco; Cannaò, Paola Maria; Sardanelli, Francesco

2017-07-01

The aim of the study was to estimate the rate of incidental cardiac findings (ICF) in patients undergoing noncardiac chest CT.An experienced radiologist retrospectively reviewed 237 consecutive patients (147 males and 90 females with median age of 69 years) undergoing a noncardiac chest CT. ICF at targeted review were compared to those mentioned in original reports (χ test).At review, ≥1 ICF was detected in 124/237 patients (52%), for a total of 229 ICF, 158 of them (69%) not originally mentioned. Valvular calcifications were unmentioned in 23/23 (100%) patients, main pulmonary artery dilation in 21/22 (96%), coronary calcifications in 69/86 (80%), right or left atrial dilation in 7/11 (64%), aortic atherosclerosis in 29/62 (47%), and ascending aorta dilatation in 8/18 (44%). All 6 pericardial effusions were originally mentioned. No association with sex (P ≥ .189); positive correlation with age (P < .001).Half of patients undergoing noncardiac chest CT presented ≥1 ICF, independently from sex but increasing with age. Moreover, 69% of detectable ICFs were not originally mentioned.

Applications of pharmacogenomics in regulatory science: a product life cycle review.

PubMed

Tan-Koi, W C; Leow, P C; Teo, Y Y

2018-05-22

With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents. Approximately one-third of Food and Drug Administration (FDA)-approved drugs with PGx information in drug labels and half of the European labels posted on PharmGKB website contain recommendations on genetic testing. The drugs affected 19 and 15 World Health Organization Anatomical Therapeutic Chemical drug classes (fourth level) in the United States and Europe, respectively, with protein kinase inhibitors (13 drugs in the United States and 16 drugs in Europe) being most prevalent. Topics of emerging interest were novel technologies, adaptive design in clinical trial and sample collection.

Assessing new developments in the pre-market regulatory process of medical devices in the People's Republic of China.

PubMed

Zhang, Shixuan; Kriza, Christine; Kolominsky-Rabas, Peter L

2014-09-01

The objective of this paper is to provide a systematic overview of the Chinese medical device registration processes, identify challenges and suggest how these can be addressed. In addition, the paper will outline the impact of new policies and regulations since the restructuring of the China FDA. A systematic review was performed for journal articles between the year of 2009 and 2013 in the following databases: PubMed, ScienceDirect and Zhongguozhiwang. The review has identified 184 papers which were potentially relevant. Seventeen articles were included in the review, which highlights the challenges and opportunities related to the medical device registration process. In order to understand the actual impact of the regulation environment and its policies including the lack of regulatory guidance regular assessment updates are crucial. The results of this paper are aimed at informing regulatory bodies, health policy decision makers, national and international Health Technology Assessment networks as well as medical devices manufacturers.

Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale

PubMed Central

Berry, Colin; Brusick, David; Cohen, Samuel M.; Hardisty, Jerry F.; Grotz, V. Lee; Williams, Gary M.

2016-01-01

ABSTRACT Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels. PMID:27652616

Sucralose Non-Carcinogenicity: A Review of the Scientific and Regulatory Rationale.

PubMed

Berry, Colin; Brusick, David; Cohen, Samuel M; Hardisty, Jerry F; Grotz, V Lee; Williams, Gary M

2016-01-01

Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels.

10 CFR 7.16 - Annual comprehensive review.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Annual comprehensive review. 7.16 Section 7.16 Energy NUCLEAR REGULATORY COMMISSION ADVISORY COMMITTEES § 7.16 Annual comprehensive review. (a) The Chairman of the Commission shall conduct an annual comprehensive review of the activities and responsibilities of...

10 CFR 7.16 - Annual comprehensive review.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Annual comprehensive review. 7.16 Section 7.16 Energy NUCLEAR REGULATORY COMMISSION ADVISORY COMMITTEES § 7.16 Annual comprehensive review. (a) The Chairman of the Commission shall conduct an annual comprehensive review of the activities and responsibilities of...

10 CFR 7.16 - Annual comprehensive review.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Annual comprehensive review. 7.16 Section 7.16 Energy NUCLEAR REGULATORY COMMISSION ADVISORY COMMITTEES § 7.16 Annual comprehensive review. (a) The Chairman of the Commission shall conduct an annual comprehensive review of the activities and responsibilities of...

10 CFR 7.16 - Annual comprehensive review.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Annual comprehensive review. 7.16 Section 7.16 Energy NUCLEAR REGULATORY COMMISSION ADVISORY COMMITTEES § 7.16 Annual comprehensive review. (a) The Chairman of the Commission shall conduct an annual comprehensive review of the activities and responsibilities of...

10 CFR 7.16 - Annual comprehensive review.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false Annual comprehensive review. 7.16 Section 7.16 Energy NUCLEAR REGULATORY COMMISSION ADVISORY COMMITTEES § 7.16 Annual comprehensive review. (a) The Chairman of the Commission shall conduct an annual comprehensive review of the activities and responsibilities of...

75 FR 39054 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-07

... NUCLEAR REGULATORY COMMISSION [NRC-2010-0234] Agency Information Collection Activities: Proposed Collection; Comment Request AGENCY: U.S. Nuclear Regulatory Commission (NRC). ACTION: Notice of pending NRC..., or wishing to participate in a license application review for the potential geologic repository. 5...

78 FR 15755 - Proposed Revision to Design of Structures, Components, Equipment and Systems; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-12

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0041] Proposed Revision to Design of Structures, Components, Equipment and Systems; Correction AGENCY: Nuclear Regulatory Commission. ACTION: Standard review... for comments of the proposed revision in Chapter 3, ``Design of Structures, Components, Equipment, and...

78 FR 19541 - Proposed Revision to Design of Structures, Components, Equipment and Systems

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-01

... NUCLEAR REGULATORY COMMISSION [NRC-2013-0041] Proposed Revision to Design of Structures, Components, Equipment and Systems AGENCY: Nuclear Regulatory Commission. ACTION: Standard review plan-draft..., ``Design of Structures, Components, Equipment, and Systems;'' and the request for comment on NUREG-0800...

75 FR 71095 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-22

... addressed to the Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of..., Regulatory Information Management Services, Office of Management. Office of Postsecondary Education Type of... for information should be addressed to U.S. Department of Education, 400 Maryland Avenue, SW., LBJ...

77 FR 3806 - Post Office Closing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-25

... POSTAL REGULATORY COMMISSION [Docket No. A2012-108; Order No. 1147] Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of... for review of the Postal Service's determination to close the South Valley Station post office in...

77 FR 75173 - Comprehensive Assessment of the Process for the Review of Device Submissions; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

... performing the technical analysis, management assessment, and program evaluation tasks required to address... premarket reviews that meet regulatory review standards. 2. Analysis of elements of the review process... process. This includes analysis of root causes for inefficiencies that may affect review performance and...

77 FR 75676 - Standard Review Plan for Review of Fuel Cycle Facility License Applications

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-21

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0220] Standard Review Plan for Review of Fuel Cycle... Review of a License Application for a Fuel Cycle Facility.'' The NRC is extending the public comment... of Fuel Cycle Safety and Safeguards, Office of Nuclear Material Safety and Safeguards. [FR Doc. 2012...

Protective Antigen (PA) and Toxin Neutralization (TNA) Antibody Patterns in Anthrax Vaccinees Undergoing Serial Plasmapheresis

DTIC Science & Technology

2005-03-28

regulatory agencies to ensure the well- being of donors. Studies have shown that weekly plasma FIG. 1. IgG antibody to B . anthracis PA concentrations in...plasmapheresis (P 0.0007) ( B ). 716 PITTMAN ET AL. CLIN. DIAGN. LAB. IMMUNOL. donors may experience declines in total IgG , IgA, and IgM... B ). VOL. 12, 2005 ANTHRAX ANTIBODIES IN IMMUNE PLASMA 717 FIG. 3. Comparative rates of decline between IgG antibody to B . anthracis PA

Potential Implications of Recent and Proposed Changes in the Regulatory Oversight of Solid Organ Transplantation in the United States

PubMed Central

Kasiske, BL; Salkowski, N; Wey, A; Israni, AK; Snyder, JJ

2016-01-01

Every 6 months, the Scientific Registry of Transplant Recipients (SRTR) publishes evaluations of every solid organ transplant program in the US, including evaluations of 1-year patient and graft survival. The Centers for Medicare & Medicaid Services (CMS) and the Organ Procurement and Transplantation Network (OPTN) Membership and Professional Standards Committee (MPSC) use SRTR’s 1-year evaluations for regulatory review of transplant programs. Concern has been growing that the regulatory scrutiny of transplant programs with lower than expected outcomes is harmful, causing programs to undertake fewer high-risk transplants and leading to unnecessary organ discards. As a result, CMS raised its threshold for a “Condition-Level Deficiency” designation of observed relative to expected 1-year graft or patient survival from 1.50 to 1.85. Exceeding this threshold in the current SRTR outcomes report and in one of the four previous reports leads to scrutiny that may result in loss of Medicare funding. For its part, OPTN is reviewing a proposal from the MPSC to also change its performance criteria thresholds for program review, to review programs with “substantive clinical differences.” We review the details and implications of these changes in transplant program oversight. PMID:27401597

Protocol Coordinator | Center for Cancer Research

Cancer.gov

PROGRAM DESCRIPTION Within the Leidos Biomedical Research Inc.’s Clinical Research Directorate, the Clinical Monitoring Research Program (CMRP) provides high-quality comprehensive and strategic operational support to the high-profile domestic and international clinical research initiatives of the National Cancer Institute (NCI), National Institute of Allergy and Infectious Diseases (NIAID), Clinical Center (CC), National Institute of Heart, Lung and Blood Institute (NHLBI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Center for Advancing Translational Sciences (NCATS), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Mental Health (NIMH). Since its inception in 2001, CMRP’s ability to provide rapid responses, high-quality solutions, and to recruit and retain experts with a variety of backgrounds to meet the growing research portfolios of NCI, NIAID, CC, NHLBI, NIAMS, NCATS, NINDS, and NIMH has led to the considerable expansion of the program and its repertoire of support services. CMRP’s support services are strategically aligned with the program’s mission to provide comprehensive, dedicated support to assist National Institutes of Health researchers in providing the highest quality of clinical research in compliance with applicable regulations and guidelines, maintaining data integrity, and protecting human subjects. For the scientific advancement of clinical research, CMRP services include comprehensive clinical trials, regulatory, pharmacovigilance, protocol navigation and development, and programmatic and project management support for facilitating the conduct of 400+ Phase I, II, and III domestic and international trials on a yearly basis. These trials investigate the prevention, diagnosis, treatment of, and therapies for cancer, influenza, HIV, and other infectious diseases and viruses such as hepatitis C, tuberculosis, malaria, and Ebola virus; heart, lung, and blood diseases and conditions; parasitic infections; rheumatic and inflammatory diseases; and rare and neglected diseases. CMRP’s collaborative approach to clinical research and the expertise and dedication of staff to the continuation and success of the program’s mission has contributed to improving the overall standards of public health on a global scale. The Clinical Monitoring Research Program (CMRP) provides comprehensive clinical and administrative support to the National Cancer Institute’s Center for Cancer Research’s (CCR) Protocol Support Office (PSO) for protocol development review, regulatory review, and the implementation process as well as oversees medical writing/editing, regulatory/ compliance, and protocol coordination/navigation and administration. KEY ROLES/RESPONSIBILITIES The Protocol Coordinator III: Provides programmatic and logistical support for the operations of clinical research for Phase I and Phase II clinical trials. Provides deployment of clinical support services for clinical research. Streamlines the protocol development timeline. Provides data and documents collection and compilation for regulatory filing with the U.S. Food and Drug Administration (FDA) and other regulatory authorities.. Provides technical review and report preparation. Provides administrative coordination and general logistical support for regulatory activities. Ensures the provision of training for investigators and associate staff to reinforce and enhance a Good Clinical Practices (GCP) culture. Oversees quality assurance and quality control, performs regulatory review of clinical protocols, informed consent and other clinical documents. Tracks and facilitates a portfolio of protocols through each process step (Institutional Review Board [IRB], Regulatory Affairs Compliance [RAC], Data Safety Monitoring Board [DSMB], Office of Protocol Services). Assists clinical investigators in preparing clinical research protocols, including writing and formatting consent forms. Prepares protocol packages for review and ensures that protocol packages include all of the required material and comply with CCR, NCI and NIH policies. Collaborates with investigators to resolve any protocol/data issues. Coordinates submission of protocols for scientific and ethical review by the Branch scientific review committees, the NCI IRB, and the clinical trial sponsor or the FDA. Monitors the review process and maintains detailed, complete and accurate records for each protocol of the approvals at the various stages of the review process, including new protocol submissions, amendments to protocols, and continuing reviews, as well as other submissions such as adverse events. Attends and prepares minutes for the Branch Protocol Review Committees. Contacts coordinators at other centers for protocols that are performed there to obtain review committee approvals at those centers, maintains records of these approvals and sends protocol amendments and other reports to the participating centers. Maintains a schedule of all review committee submission deadline dates and meeting dates. Assists clinical investigators in understanding and complying with the entire review process. Works closely with the NCI Protocol Review Office in establishing and maintaining a paperless automated document and tracking system for NCI protocols. Converts protocols from Word format to .pdf with bookmarks. Maintains the .pdf version of the most current approved version of each active clinical protocol on a central server. This position is located in Rockville, Maryland.

Intracardiac electrocardiographic assessment of precordial TASER shocks in human subjects: A pilot study.

PubMed

Stopyra, Jason P; Winslow, James E; Fitzgerald, David M; Bozeman, William P

2017-11-01

Case reports of cardiac arrest in temporal proximity to Conducted Electrical Weapon(CEW) exposure raise legitimate concerns about this as a rare possibility. In this pilot study, we respectfully navigate the oversight and regulatory hurdles and demonstrate the intra-shock electrocardiographic effects of an intentional transcardiac CEW discharge using subcutaneous probes placed directly across the precordium of patients with a previously implanted intracardiac EKG sensing lead. Adults scheduled to undergo diagnostic EP studies or replacement of an implanted cardiac device were enrolled. Sterile subcutaneous electrodes were placed at the right sternoclavicular junction and the left lower costal margin at the midclavicular line. A standard police issue TASER Model X26 CEW was attached to the subcutaneous electrodes and a 5 s discharge was delivered. Continuous surface and intracardiac EKG monitoring was performed. A total of 157 subjects were reviewed for possible inclusion and 21 were interviewed. Among these, 4 subjects agreed and completed the study protocol. All subjects tolerated the 5 s CEW discharge without clinical complications. There were no significant changes in mean heart rate or blood pressure. Interrogation of the devices after CEW discharge revealed no ventricular pacing, dysrhythmias, damage or interference with the implanted devices. In this pilot study, we have successfully navigated the regulatory hurdles and demonstrated the feasibility of performing intracardiac EKG recording during intentional precordial CEW discharges in humans. While no CEW-associated dysrhythmias were noted, the size of this preliminary dataset precludes making conclusions about the risk of such events. Larger studies are warranted and should consider exploring variations of the CEW electrode position in relation to the cardiac silhouette. Copyright © 2017. Published by Elsevier Ltd.

Synthetic biology as it relates to CAM photosynthesis: challenges and opportunities.

PubMed

DePaoli, Henrique C; Borland, Anne M; Tuskan, Gerald A; Cushman, John C; Yang, Xiaohan

2014-07-01

To meet future food and energy security needs, which are amplified by increasing population growth and reduced natural resource availability, metabolic engineering efforts have moved from manipulating single genes/proteins to introducing multiple genes and novel pathways to improve photosynthetic efficiency in a more comprehensive manner. Biochemical carbon-concentrating mechanisms such as crassulacean acid metabolism (CAM), which improves photosynthetic, water-use, and possibly nutrient-use efficiency, represent a strategic target for synthetic biology to engineer more productive C3 crops for a warmer and drier world. One key challenge for introducing multigene traits like CAM onto a background of C3 photosynthesis is to gain a better understanding of the dynamic spatial and temporal regulatory events that underpin photosynthetic metabolism. With the aid of systems and computational biology, vast amounts of experimental data encompassing transcriptomics, proteomics, and metabolomics can be related in a network to create dynamic models. Such models can undergo simulations to discover key regulatory elements in metabolism and suggest strategic substitution or augmentation by synthetic components to improve photosynthetic performance and water-use efficiency in C3 crops. Another key challenge in the application of synthetic biology to photosynthesis research is to develop efficient systems for multigene assembly and stacking. Here, we review recent progress in computational modelling as applied to plant photosynthesis, with attention to the requirements for CAM, and recent advances in synthetic biology tool development. Lastly, we discuss possible options for multigene pathway construction in plants with an emphasis on CAM-into-C3 engineering. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Antibodies to watch in 2018.

PubMed

Kaplon, Hélène; Reichert, Janice M

The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the 'Antibodies to watch' article series.

Antibodies to watch in 2018

PubMed Central

Kaplon, Hélène; Reichert, Janice M.

2018-01-01

ABSTRACT The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the ‘Antibodies to watch’ article series. PMID:29300693

Multifarious Roles of Intrinsic Disorder in Proteins Illustrate Its Broad Impact on Plant Biology

PubMed Central

Sun, Xiaolin; Rikkerink, Erik H.A.; Jones, William T.; Uversky, Vladimir N.

2013-01-01

Intrinsically disordered proteins (IDPs) are highly abundant in eukaryotic proteomes. Plant IDPs play critical roles in plant biology and often act as integrators of signals from multiple plant regulatory and environmental inputs. Binding promiscuity and plasticity allow IDPs to interact with multiple partners in protein interaction networks and provide important functional advantages in molecular recognition through transient protein–protein interactions. Short interaction-prone segments within IDPs, termed molecular recognition features, represent potential binding sites that can undergo disorder-to-order transition upon binding to their partners. In this review, we summarize the evidence for the importance of IDPs in plant biology and evaluate the functions associated with intrinsic disorder in five different types of plant protein families experimentally confirmed as IDPs. Functional studies of these proteins illustrate the broad impact of disorder on many areas of plant biology, including abiotic stress, transcriptional regulation, light perception, and development. Based on the roles of disorder in the protein–protein interactions, we propose various modes of action for plant IDPs that may provide insight for future experimental approaches aimed at understanding the molecular basis of protein function within important plant pathways. PMID:23362206

Regulation of thrombosis and vascular function by protein methionine oxidation

PubMed Central

Gu, Sean X.; Stevens, Jeff W.

2015-01-01

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis. PMID:25900980

Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases.

PubMed

Crozet, Pierre; Margalha, Leonor; Confraria, Ana; Rodrigues, Américo; Martinho, Cláudia; Adamo, Mattia; Elias, Carlos A; Baena-González, Elena

2014-01-01

The SNF1 (sucrose non-fermenting 1)-related protein kinases 1 (SnRKs1) are the plant orthologs of the budding yeast SNF1 and mammalian AMPK (AMP-activated protein kinase). These evolutionarily conserved kinases are metabolic sensors that undergo activation in response to declining energy levels. Upon activation, SNF1/AMPK/SnRK1 kinases trigger a vast transcriptional and metabolic reprograming that restores energy homeostasis and promotes tolerance to adverse conditions, partly through an induction of catabolic processes and a general repression of anabolism. These kinases typically function as a heterotrimeric complex composed of two regulatory subunits, β and γ, and an α-catalytic subunit, which requires phosphorylation of a conserved activation loop residue for activity. Additionally, SNF1/AMPK/SnRK1 kinases are controlled by multiple mechanisms that have an impact on kinase activity, stability, and/or subcellular localization. Here we will review current knowledge on the regulation of SNF1/AMPK/SnRK1 by upstream components, post-translational modifications, various metabolites, hormones, and others, in an attempt to highlight both the commonalities of these essential eukaryotic kinases and the divergences that have evolved to cope with the particularities of each one of these systems.

Mechanisms of regulation of SNF1/AMPK/SnRK1 protein kinases

PubMed Central

Crozet, Pierre; Margalha, Leonor; Confraria, Ana; Rodrigues, Américo; Martinho, Cláudia; Adamo, Mattia; Elias, Carlos A.; Baena-González, Elena

2014-01-01

The SNF1 (sucrose non-fermenting 1)-related protein kinases 1 (SnRKs1) are the plant orthologs of the budding yeast SNF1 and mammalian AMPK (AMP-activated protein kinase). These evolutionarily conserved kinases are metabolic sensors that undergo activation in response to declining energy levels. Upon activation, SNF1/AMPK/SnRK1 kinases trigger a vast transcriptional and metabolic reprograming that restores energy homeostasis and promotes tolerance to adverse conditions, partly through an induction of catabolic processes and a general repression of anabolism. These kinases typically function as a heterotrimeric complex composed of two regulatory subunits, β and γ, and an α-catalytic subunit, which requires phosphorylation of a conserved activation loop residue for activity. Additionally, SNF1/AMPK/SnRK1 kinases are controlled by multiple mechanisms that have an impact on kinase activity, stability, and/or subcellular localization. Here we will review current knowledge on the regulation of SNF1/AMPK/SnRK1 by upstream components, post-translational modifications, various metabolites, hormones, and others, in an attempt to highlight both the commonalities of these essential eukaryotic kinases and the divergences that have evolved to cope with the particularities of each one of these systems. PMID:24904600

Signaling molecules involved in the transition of growth to development of Dictyostelium discoideum.

PubMed

Mir, Hina A; Rajawat, Jyotika; Pradhan, Shalmali; Begum, Rasheedunnisa

2007-03-01

The social amoeba Dictyostelium discoideum, a powerful paradigm provides clear insights into the regulation of growth and development. In addition to possessing complex individual cellular functions like a unicellular eukaryote, D. discoideum cells face the challenge of multicellular development. D. discoideum undergoes a relatively simple differentiation process mainly by cAMP mediated pathway. Despite this relative simplicity, the regulatory signaling pathways are as complex as those seen in metazoan development. However, the introduction of restriction-enzyme-mediated integration (REMI) technique to produce developmental gene knockouts has provided novel insights into the discovery of signaling molecules and their role in D. discoideum development. Cell cycle phase is an important aspect for differentiation of D. discoideum, as cells must reach a specific stage to enter into developmental phase and specific cell cycle regulators are involved in arresting growth phase genes and inducing the developmental genes. In this review, we present an overview of the signaling molecules involved in the regulation of growth to differentiation transition (GDT), molecular mechanism of early developmental events leading to generation of cAMP signal and components of cAMP relay system that operate in this paradigm.

Antibody-based therapeutics to watch in 2011

PubMed Central

2011-01-01

This overview of 25 monoclonal antibody (mAb) and five Fc fusion protein therapeutics provides brief descriptions of the candidates, recently published clinical study results and on-going Phase 3 studies. In alphanumeric order, the 2011 therapeutic antibodies to watch list comprises AIN-457, bapineuzumab, brentuximab vedotin, briakinumab, dalotuzumab, epratuzumab, farletuzumab, girentuximab (WX-G250), naptumomab estafenatox, necitumumab, obinutuzumab, otelixizumab, pagibaximab, pertuzumab, ramucirumab, REGN88, reslizumab, solanezumab, T1h, teplizumab, trastuzumab emtansine, tremelimumab, vedolizumab, zalutumumab and zanolimumab. In alphanumeric order, the 2011 Fc fusion protein therapeutics to watch list comprises aflibercept, AMG-386, atacicept, Factor VIII-Fc and Factor IX-Fc. Commercially-sponsored mAb and Fc fusion therapeutics that have progressed only as far as Phase 2/3 or 3 were included. Candidates undergoing regulatory review or products that have been approved may also be in Phase 3 studies, but these were excluded. Due to the large body of primary literature about the candidates, only selected references are given and results from recent publications and articles that were relevant to Phase 3 studies are emphasized. Current as of September 2010, the information presented here will serve as a baseline against which future progress in the development of antibody-based therapeutics can be measured. PMID:21051951

Trans-methylation reactions in plants: focus on the activated methyl cycle.

PubMed

Rahikainen, Moona; Alegre, Sara; Trotta, Andrea; Pascual, Jesús; Kangasjärvi, Saijaliisa

2018-02-01

Trans-methylation reactions are vital in basic metabolism, epigenetic regulation, RNA metabolism, and posttranslational control of protein function and therefore fundamental in determining the physiological processes in all living organisms. The plant kingdom is additionally characterized by the production of secondary metabolites that undergo specific hydroxylation, oxidation and methylation reactions to obtain a wide array of different chemical structures. Increasing research efforts have started to reveal the enzymatic pathways underlying the biosynthesis of complex metabolites in plants. Further engineering of these enzymatic machineries offers significant possibilities in the development of bio-based technologies, but necessitates deep understanding of their potential metabolic and regulatory interactions. Trans-methylation reactions are tightly coupled with the so-called activated methyl cycle (AMC), an essential metabolic circuit that maintains the trans-methylation capacity in all living cells. Tight regulation of the AMC is crucial in ensuring accurate trans-methylation reactions in different subcellular compartments, cell types, developmental stages and environmental conditions. This review addresses the organization and posttranslational regulation of the AMC and elaborates its critical role in determining metabolic regulation through modulation of methyl utilization in stress-exposed plants. © 2017 Scandinavian Plant Physiology Society.

Mipomersen sodium: first global approval.

PubMed

Hair, Philip; Cameron, Fiona; McKeage, Kate

2013-04-01

Mipomersen sodium (Kynamro™) (henceforth mipomersen) is a second-generation antisense oligonucleotide inhibitor of apolipoprotein B-100, which is the main structural component of atherogenic lipid particles. Mipomersen is administered via subcutaneous injection and is indicated as adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH). The drug was developed by Isis Pharmaceuticals, which now collaborates with Genzyme Corporation for on-going development and product marketing. Multinational phase III trials of mipomersen as adjunctive therapy were completed in patients with HoFH, severe FH, heterozygous FH (HeFH) with coronary artery disease (CAD), and in those with hypercholesterolaemia at high risk of CAD. Mipomersen 200 mg once weekly has been approved in the USA as an adjunct to lipid-lowering medications and diet in HoFH patients and is undergoing regulatory review in the EU for the same indication. Genzyme is also conducting a multinational phase III, open-label extension study to evaluate long-term treatment in HoFH and HeFH patients, as well as a multinational trial to evaluate a three-times-per-week mipomersen regimen in patients with severe FH. This article summarises the milestones in the development of once-weekly, subcutaneous mipomersen leading to this first approval.

Enterovirus 71: a whole virion inactivated enterovirus 71 vaccine.

PubMed

Zhou, Yang; Li, Jing-Xin; Jin, Peng-Fei; Wang, Yu-Xiao; Zhu, Feng-Cai

2016-07-01

Enterovirus A71 (EV71) is the predominant causative agent of hand, foot, and mouth disease (HFMD), which is often associated with severe cases and even deaths. EV71-associated epidemics have emerged as a serious threat to public health, particularly in the Asia-Pacific region. We searched PubMed using the terms 'enterovirus 71', 'hand, foot, and mouth disease', and 'vaccine', with no date or language restrictions for all publications before April 27, 2016. Among various vaccine candidates, the alum-adjuvant inactivated EV71 vaccines are most promising. Three alum-adjuvant inactivated EV71 vaccines developed by mainland China showed high efficacy, good immunogenicity persistence and acceptable safety profiles in clinical trials. Recently, two of these EV71 vaccines have been approved for marketing in China and the other one is undergoing the review process of licensure. In this manuscript, we summarized previous study results as well as discussed the regulatory affairs and post-market surveillances issues. Expert commentary: The marketing of EV71 vaccines is a milestone in the controlling of HFMD. International clinical trials are needed to further assess the efficacy and cross-immunogenicity. Establishing a sensitive pathogen monitoring system would be essential to monitor the variation of genotypes and control HFMD epidemics.

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.

40 CFR 26.1604 - EPA review of completed human research.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 1 2014-07-01 2014-07-01 false EPA review of completed human research... OF HUMAN SUBJECTS Review of Proposed and Completed Human Research § 26.1604 EPA review of completed human research. (a) When considering, under any regulatory statute it administers, data from completed...

40 CFR 26.1604 - EPA review of completed human research.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 1 2013-07-01 2013-07-01 false EPA review of completed human research... OF HUMAN SUBJECTS Review of Proposed and Completed Human Research § 26.1604 EPA review of completed human research. (a) When considering, under any regulatory statute it administers, data from completed...

77 FR 77117 - Proposed Revision 0 on Access Authorization-Operational Program

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-31

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10 CFR 12.309 - Judicial review.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 1 2010-01-01 2010-01-01 false Judicial review. 12.309 Section 12.309 Energy NUCLEAR REGULATORY COMMISSION IMPLEMENTATION OF THE EQUAL ACCESS TO JUSTICE ACT IN AGENCY PROCEEDINGS Procedures for Considering Applications § 12.309 Judicial review. Judicial review of final agency decisions on awards may be...

10 CFR 110.40 - Commission review.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 2 2012-01-01 2012-01-01 false Commission review. 110.40 Section 110.40 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXPORT AND IMPORT OF NUCLEAR EQUIPMENT AND MATERIAL Review of License Applications § 110.40 Commission review. (a) Immediately after receipt of a license application for an export...

10 CFR 110.40 - Commission review.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 2 2011-01-01 2011-01-01 false Commission review. 110.40 Section 110.40 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXPORT AND IMPORT OF NUCLEAR EQUIPMENT AND MATERIAL Review of License Applications § 110.40 Commission review. (a) Immediately after receipt of a license application for an export...

10 CFR 110.40 - Commission review.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 2 2013-01-01 2013-01-01 false Commission review. 110.40 Section 110.40 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) EXPORT AND IMPORT OF NUCLEAR EQUIPMENT AND MATERIAL Review of License Applications § 110.40 Commission review. (a) Immediately after receipt of a license application for an export...

76 FR 25674 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

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Reviewing New Chemicals under the Toxic Substances Control Act (TSCA)

EPA Pesticide Factsheets

This microsite will provide information on how EPA’s new chemicals review program works, on the assessment tools and policies EPA uses in this program, and on the regulatory outcomes of EPA’s review of new chemicals notifications.

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Nonlinear Acoustics in Ultrasound Metrology and other Selected Applications.

PubMed

Lewin, Peter A

2010-01-01

A succinct background explaining why, initially, both the scientific community and industry were skeptical about the existence of the nonlinear (NL) wave propagation in tissue will be given and the design of an adequately wideband piezoelectric polymer hydrophone probe that was eventually used to verify that the 1-5 MHz probing wave then used in diagnostic ultrasound imaging was undergoing nonlinear distortion and generated harmonics in tissue will be discussed. The far-reaching implications of the advent of the piezoelectric PVDF polymer material will be reviewed and the advances in ultrasound metrology prompted by the regulatory agencies such as US Food and Drug Administration (FDA) and International Electrotechnical Commission (IEC) will be presented. These advances include the development of absolute calibration techniques for hydrophones along with the methods of accounting for spatial averaging corrections up to 100 MHz and the development of "point-receiver" hydrophone probes utilizing acousto-optic sensors. Next, selected therapeutic applications of nonlinear ultrasonics (NLU), including lithotripters will be briefly discussed. Also, the use of shock waves as pain relief tool and in abating penicillin resistant bacteria that develop rock hard "biofilm" that can be shattered by the finite amplitude wave will also be mentioned. The growing applications of NLU in cosmetic industry where it is used for redistribution and reduction of fatty tissue within the body will be briefly reviewed, and, finally, selected examples of NLU applications in retail and entertainment industry will also be pointed out.

Nonlinear acoustics in ultrasound metrology and other selected applications

NASA Astrophysics Data System (ADS)

Lewin, Peter A.

2010-01-01

A succinct background explaining why, initially, both the scientific community and industry were skeptical about the existence of the nonlinear (NL) wave propagation in tissue will be given and the design of an adequately wideband piezoelectric polymer hydrophone probe that was eventually used to verify that the 1-5 MHz probing wave then used in diagnostic ultrasound imaging was undergoing nonlinear distortion and generated harmonics in tissue will be discussed. The far-reaching implications of the advent of the piezoelectric PVDF polymer material will be reviewed and the advances in ultrasound metrology prompted by the regulatory agencies such as US Food and Drug Administration (FDA) and International Electrotechnical Commission (IEC) will be presented. These advances include the development of absolute calibration techniques for hydrophones along with the methods of accounting for spatial averaging corrections up to 100 MHz and the development of 'point-receiver' hydrophone probes utilizing acousto-optic sensors. Next, selected therapeutic applications of nonlinear ultrasonics (NLU), including lithotripters will be briefly discussed. Also, the use of shock waves as pain relief tool and in abating penicillin resistant bacteria that develop rock hard 'biofilm' that can be shattered by the finite amplitude wave will also be mentioned. The growing applications of NLU in cosmetic industry where it is used for redistribution and reduction of fatty tissue within the body will be briefly reviewed, and, finally, selected examples of NLU applications in retail and entertainment industry will also be pointed out.

76 FR 15859 - Reducing Regulatory Burden; Retrospective Review under E.O. 13563

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-22

... Management, at (202) 501- 1777. SUPPLEMENTARY INFORMATION: A. Background Executive Order 13563 directs each..., ineffective, insufficient, or excessively burdensome.'' The EO calls on every agency to develop ``a... modified, streamlined, expanded or repealed to make the agency's regulatory program more effective and or...

Peer Review Undergoing Revitalization

ERIC Educational Resources Information Center

Sawchuk, Stephen

2009-01-01

Established in the 142,000-student Montgomery County, Maryland, district in 1999, peer assistance and review (PAR)--or "peer review," as it is occasionally called--is actually an old idea. In 1981, the then-president of the Toledo Federation of Teachers, Dal Lawrence, helped create the first PAR program. Almost 30 years later, only a…

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

PubMed Central

Cong, Y; Liu, Z

2015-01-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

Regulatory immune cells in regulation of intestinal inflammatory response to microbiota.

PubMed

Sun, M; He, C; Cong, Y; Liu, Z

2015-09-01

The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3(+) regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders.

Recovery Audit Contractor medical necessity readiness: one health system's journey.

PubMed

Scott, Judith A; Camden, Mindy

2011-01-01

To develop a sustainable approach to Recovery Audit Contractor medical necessity readiness that mitigates the regulatory and financial risks of the organization. Acute care hospitals. Utilizing the model for improvement and plan-do-study-act methodology, this health system designed and implemented a medical necessity case management program. We focused on 3 areas for improvement: medical necessity review accuracy, review timeliness, and physician adviser participation for secondary reviews. Over several months, we improved accuracy and timeliness of our medical necessity reviews while also generating additional inpatient revenue for the health system. We successfully enhanced regulatory compliance and reduced our financial risks associated with Recovery Audit Contractor medical necessity audits. A successful medical necessity case management program can not only enhance regulatory compliance and reduce the amount of payments recouped by Medicare, but also generate additional inpatient revenue for your organization. With health care reform and accountable care organizations on the horizon, hospitals must find ways to protect and enhance revenue in order to carry out their missions. This is one way for case managers to help in that cause, to advocate for the care of their patients, and to bring value to the organization.

Transcription factors involved in drought tolerance and their possible role in developing drought tolerant cultivars with emphasis on wheat (Triticum aestivum L.).

PubMed

Gahlaut, Vijay; Jaiswal, Vandana; Kumar, Anuj; Gupta, Pushpendra Kumar

2016-11-01

TFs involved in drought tolerance in plants may be utilized in future for developing drought tolerant cultivars of wheat and some other crops. Plants have developed a fairly complex stress response system to deal with drought and other abiotic stresses. These response systems often make use of transcription factors (TFs); a gene encoding a specific TF together with -its target genes constitute a regulon, and take part in signal transduction to activate/silence genes involved in response to drought. Since, five specific families of TFs (out of >80 known families of TFs) have gained widespread attention on account of their significant role in drought tolerance in plants, TFs and regulons belonging to these five multi-gene families (AP2/EREBP, bZIP, MYB/MYC, NAC and WRKY) have been described and their role in improving drought tolerance discussed in this brief review. These TFs often undergo reversible phosphorylation to perform their function, and are also involved in complex networks. Therefore, some details about reversible phosphorylation of TFs by different protein kinases/phosphatases and the co-regulatory networks, which involve either only TFs or TFs with miRNAs, have also been discussed. Literature on transgenics involving genes encoding TFs and that on QTLs and markers associated with TF genes involved in drought tolerance has also been reviewed. Throughout the review, there is a major emphasis on wheat as an important crop, although examples from the model cereal rice (sometimes maize also), and the model plant Arabidopsis have also been used. This knowledge base may eventually allow the use of TF genes for development of drought tolerant cultivars, particularly in wheat.

75 FR 21749 - Spring 2010 Semiannual Agenda of Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-26

...In compliance with Executive Order 12866, entitled ``Regulatory Planning and Review,'' and the Regulatory Flexibility Act, as amended, the Department of Commerce (Department), in the spring and fall of each year, publishes in the Federal Register an agenda of regulations under development of review over the next 12 months. Rulemaking actions are grouped according to prerulemaking, proposed rules, final rules, long-term actions, and rulemaking actions completed since the fall 2009 agenda. The purpose of the agenda is to provide information to the public on regulations currently under review, being proposed, or issued by the Department. The agenda is intended to facilitate comments and views by interested members of the public.

N-3 polyunsaturated fatty acid regulation of hepatic gene transcription

PubMed Central

Jump, Donald B.

2009-01-01

Purpose of review The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated fatty acid regulation of hepatic gene transcription. Recent findings Dietary n-3 polyunsaturated fatty acid regulates hepatic gene expression by targeting three major transcriptional regulatory networks: peroxisome proliferator-activated receptor α, sterol regulatory element binding protein-1 and the carbohydrate regulatory element binding protein/Max-like factor X heterodimer. 22 : 6,n-3, the most prominent n-3 polyunsaturated fatty acid in tissues, is a weak activator of peroxisome proliferator-activated receptor α. Hepatic metabolism of 22 : 6,n-3, however, generates 20 : 5,n-3, a strong peroxisome proliferator-activated receptor α activator. In contrast to peroxisome proliferator-activated receptor α, 22 : 6,n-3 is the most potent fatty acid regulator of hepatic sterol regulatory element binding protein-1. 22 : 6,n-3 suppresses sterol regulatory element binding protein-1 gene expression while enhancing degradation of nuclear sterol regulatory element binding protein-1 through 26S proteasome and Erk1/2-dependent mechanisms. Both n-3 and n-6 polyunsaturated fatty acid suppress carbohydrate regulatory element binding protein and Max-like factor X nuclear abundance and interfere with glucose-regulated hepatic metabolism. Summary These studies have revealed unique mechanisms by which specific polyunsaturated fatty acids control peroxisome proliferator activated receptor α, sterol regulatory element binding protein-1 and carbohydrate regulatory element binding protein/Max-like factor X function. As such, specific metabolic and signal transduction pathways contribute significantly to the fatty acid regulation of these transcription factors and their corresponding regulatory networks. PMID:18460914

[Management of Patients on Antithrombotic Agents Undergoing Endoscopy].

PubMed

Kim, Joon Sung; Kim, Byung Wook

2018-05-25

Antithrombotic agents are used increasingly in Asia. The management of patients on antithrombotics undergoing elective or emergency endoscopy has become an increasing clinical challenge for gastroenterologists. Current practice guidelines have been developed by societies from western countries. On the other hand, these guidelines cannot meet the specific needs of the Asian Pacific region, raising the need for separate guidelines in Asia. This review compares the recommendations of previous guidelines with the most recently published Asian guidelines regarding the management of patients on antithrombotic agents undergoing elective and emergency endoscopy.

Review of automated vehicle technology : policy and implementation implications.

DOT National Transportation Integrated Search

2016-03-14

The goals of this project were to undergo a systematic review of automated vehicle technologies with a focus on policy : implications, methods of implementation, regulation by states, and developments occurring on legal fronts, ultimately creating a ...

Protocol Coordinator | Center for Cancer Research

Cancer.gov

PROGRAM DESCRIPTION Within the Leidos Biomedical Research Inc.’s Clinical Research Directorate, the Clinical Monitoring Research Program (CMRP) provides high-quality comprehensive and strategic operational support to the high-profile domestic and international clinical research initiatives of the National Cancer Institute (NCI), National Institute of Allergy and Infectious Diseases (NIAID), Clinical Center (CC), National Institute of Heart, Lung and Blood Institute (NHLBI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Center for Advancing Translational Sciences (NCATS), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Mental Health (NIMH). Since its inception in 2001, CMRP’s ability to provide rapid responses, high-quality solutions, and to recruit and retain experts with a variety of backgrounds to meet the growing research portfolios of NCI, NIAID, CC, NHLBI, NIAMS, NCATS, NINDS, and NIMH has led to the considerable expansion of the program and its repertoire of support services. CMRP’s support services are strategically aligned with the program’s mission to provide comprehensive, dedicated support to assist National Institutes of Health researchers in providing the highest quality of clinical research in compliance with applicable regulations and guidelines, maintaining data integrity, and protecting human subjects. For the scientific advancement of clinical research, CMRP services include comprehensive clinical trials, regulatory, pharmacovigilance, protocol navigation and development, and programmatic and project management support for facilitating the conduct of 400+ Phase I, II, and III domestic and international trials on a yearly basis. These trials investigate the prevention, diagnosis, treatment of, and therapies for cancer, influenza, HIV, and other infectious diseases and viruses such as hepatitis C, tuberculosis, malaria, and Ebola virus; heart, lung, and blood diseases and conditions; parasitic infections; rheumatic and inflammatory diseases; and rare and neglected diseases.  CMRP’s collaborative approach to clinical research and the expertise and dedication of staff to the continuation and success of the program’s mission has contributed to improving the overall standards of public health on a global scale. The Clinical Monitoring Research Program (CMRP) provides comprehensive clinical and administrative support to the National Cancer Institute’s Center for Cancer Research’s (CCR), Office of Regulatory Affairs for protocol development review, regulatory review, and the implementation process as well as oversees medical writing/editing, regulatory/ compliance, and protocol coordination/navigation and administration. KEY ROLES/RESPONSIBILITIES - THIS POSITION IS CONTINGENT UPON FUNDING APPROVAL The Protocol Coordinator II: Provides programmatic and logistical support for the operations of clinical research for Phase I and Phase II clinical trials Provides deployment of clinical support services for clinical research Streamlines protocol development timeline Provides data and document collection and compilation for regulatory filing with the FDA and other regulatory authorities Provides administrative coordination and general logistical support for regulatory activities Ensures the provision of training for investigators and associate staff to reinforce and enhance a GCP culture Provides quality assurance and quality control oversight Performs regulatory review of clinical protocols, informed consent and other clinical documents Tracks and facilitates a portfolio of protocols through each process step (IRB, RAC, DSMB, Office of Protocol Services) Assists clinical investigators in preparing clinical research protocols, including writing and formatting protocol documents and consent forms Prepares protocol packages for review and ensures that protocol packages include all of the required material and comply with CCR, NCI and NIH policies Collaborates with investigators to resolve any protocol/data issues Coordinates submission of protocols for scientific and ethical review by the Branch scientific review committees, the NCI Institutional Review Board (IRB) and the clinical trial sponsor or the FDA Monitors the review process and maintains detailed, complete and accurate records for each protocol of the approvals at the various stages of the review process, including new protocol submissions, amendments to protocols, and continuing reviews, as well as other submissions such as adverse events Attends and prepares minutes for the Branch Protocol Review Committees For protocols that are performed with other research centers: contacts coordinators at other centers to obtain review committee approvals at these centers, maintains records of these approvals at the outside centers in the protocol files, and sends protocol amendments and other reports to the participating centers Maintains a schedule of all review committee submission deadline dates and meeting dates Assists clinical investigators in understanding and complying with the entire review process Works closely with the NCI Protocol Review Office in establishing and maintaining a paperless automated document management and tracking system for NCI protocols Converts protocols from Word format to PDF with bookmarks Maintains the PDF version of the most current approved version of each active clinical protocol on a central server    This position has the option to be located in Frederick or Rockville, Maryland.

The efficacy of palatal augmentation prostheses for speech and swallowing in patients undergoing glossectomy: a review of the literature.

PubMed

Marunick, Mark; Tselios, Nicholas

2004-01-01

This article provides a review of the literature to assist the clinician in determining the efficacy of palatal augmentation prosthesis regarding speech and swallowing for the patient undergoing glossectomy. A MEDLINE search was conducted. Peer-reviewed articles published from 1966 to July 2002 that addressed the question of the efficacy of this prosthesis to improve speech and swallowing after partial or total glossectomy were included. Studies reviewed had to incorporate an objective evaluation of one or both functions. Nine of 130 studies met the selection criteria (4 retrospective, 1 case control, and 4 case reports). A total of 50 subjects were studied, 42 for swallowing and 37 for speech. In 36/42 subjects, treatment was advantageous for swallowing and in 32/37 subjects, it was advantageous for speech. On the basis of the limited evidence available, the functional efficacy of the palatal augmentation prosthesis is supported.

77 FR 4407 - Modernization of Poultry Slaughter Inspection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-27

...The Food Safety and Inspection Service (FSIS) is proposing a new inspection system for young chicken and turkey slaughter establishments that would replace the current Streamlined Inspection System (SIS), the New Line Speed Inspection System (NELS), and the New Turkey Inspection System (NTIS). The Agency is also proposing several changes that would affect all establishments that slaughter poultry other than ratites, regardless of the inspection system under which they operate. This proposed rule is a result of the Agency's 2011 regulatory review efforts conducted under Executive Order 13563 on Improving Regulation and Regulatory Review.

76 FR 40888 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-12

... DEPARTMENT OF EDUCATION Notice of Submission for OMB Review AGENCY: Department of Education... to the Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of... Education Type of Review: Extension. Title of Collection: Impact Aid Program Application for Section 8003...

77 FR 66793 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-07

... DEPARTMENT OF AGRICULTURE Submission for OMB Review; Comment Request November 1, 2012. The Department of Agriculture has submitted the following information collection requirement(s) to OMB for review... should be addressed to: Desk Officer for Agriculture, Office of Information and Regulatory Affairs...

76 FR 36526 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-22

... DEPARTMENT OF EDUCATION Notice of Submission for OMB Review AGENCY: Department of Education... the Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of... Development Type of Review: New. Title of Collection: Evaluation of the Education for Homeless Children and...

76 FR 12717 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-08

... Information Management Services, Office of Management invites comments on the submission for OMB review as... of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and... Information Management Services, Office of Management. Institute of Education Sciences Type of Review...

76 FR 2089 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-12

... Information Management Services, Office of Management invites comments on the submission for OMB review as... Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and... Information Management Services, Office of Management. Office of Postsecondary Education Type of Review...

76 FR 15305 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-21

... Information Management Services, Office of Management invites comments on the submission for OMB review as... Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and... Information Management Services, Office of Management. Office of Postsecondary Education Type of Review...

75 FR 68774 - Notice of Submission for OMB Review

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-09

... Information Management Services, Office of Management invites comments on the submission for OMB review as... Office of Information and Regulatory Affairs, Attention: Education Desk Officer, Office of Management and... Information Management Services, Office of Management. Office of Postsecondary Education Type of Review...

Patella Fractures Prior to Total Knee Arthroplasty: Worse Outcomes but Equivalent Survivorship.

PubMed

Houdek, Matthew T; Shannon, Steven F; Watts, Chad D; Wagner, Eric R; Sems, Stephen A; Sierra, Rafael J

2015-12-01

Distal femur and/or tibial plateau fractures adversely affect outcomes of TKA; however it is unknown if a previous patella fracture affects outcome. We reviewed 113 patients undergoing TKA with a previous patella fracture from 1990 to 2012. Component survival was compared to 19,641 patients undergoing TKA for osteoarthritis during the same period. The 15-year implant survivals following a previous patella fracture was 86%. There was no difference in implant survival compared to patients undergoing TKA for OA (P=0.31). Knee society scores significantly improved following TKA; however patients with a fracture had complications related to knee flexion. Patients undergoing primary TKA following a patella fracture have similar overall revision free survival compared to those undergoing TKA for OA at 15-years. Copyright © 2015 Elsevier Inc. All rights reserved.

76 FR 20970 - Appalachian Power Company; Notice of Availability of Environmental Assessment

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-14

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 739-022-VA] Appalachian... Environmental Policy Act of 1969 and the Federal Energy Regulatory Commission (Commission) regulations, 18 CFR Part 380 (Order No. 486, 52 FR 47879), the Office of Energy Projects has reviewed the application for a...

76 FR 76115 - Revisions to the California State Implementation Plan, Feather River Air Quality Management District

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-06

... the California State Implementation Plan, Feather River Air Quality Management District AGENCY... limited disapproval of revisions to the Feather River Air Quality Management District (FRAQMD) portion of..., Regulatory Planning and Review The Office of Management and Budget (OMB) has exempted this regulatory action...

77 FR 528 - Self-Regulatory Organizations; The National Securities Clearing Corporation; Order Granting...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-05

...-Regulatory Organizations; The National Securities Clearing Corporation; Order Granting Approval of a Proposed Rule Change To Amend Rules Relating To the Creation of a Service To Provide Post-Trade Information... trading activity of their organizations, their correspondent firms, or both through review of post-trade...